Teri A Longacre

All Publications

• Low-grade Serous Carcinoma of the Ovary: Clinicopathologic Analysis of 52 Invasive Cases and Identification of a Possible Noninvasive Intermediate Lesion. American journal of surgical pathology Ahn, G., Folkins, A. K., McKenney, J. K., Longacre, T. A. 2016; 40 (9): 1165-1176

  Abstract

  Low-grade serous carcinoma (LGSC) is an uncommon but distinct histologic subtype of ovarian carcinoma. Although the histologic features and natural history of LGSC have been described in the literature, there is no robust correlative study that has specifically addressed histologic features in correlation with clinical follow-up. To refine the criteria for invasion patterns of LGSC and determine additional clinically pertinent morphologic features of LGSC predisposing to a more aggressive clinical course, the clinicopathologic features of 52 LGSCs were evaluated and compared with those of a large series of serous borderline tumors (SBT), with and without invasive implants. To qualify for LGSC, the tumor needed to demonstrate destructive invasion, nuclear atypia that was mild to moderate at most (grade 1 or 2), and a mitotic index that did not exceed 12 mitoses per 10 high-power fields. On the basis of histologic evaluation, destructive invasion was classified into 7 primary architectural patterns: (1) micropapillary and/or complex papillary; (2) compact cell nests; (3) inverted macropapillae; (4) cribriform; (5) glandular and/or cystic; (6) solid sheets with slit-like spaces; and (7) single cells. Five-year overall survival and disease-free survival for LGSC were 82% (median, 72 mo) and 47% (median, 54 mo), respectively. All the patients with fatal outcome demonstrated tumors showing invasion with predominant patterns of cribriform glands, micropapillae and/or complex papillae, or compact cell nests. Notably, 2 of 9 patients with fatal outcome had only small foci of destructive invasion (2 and 3 mm, respectively) with compact cell nests and cribriform glands as the predominant patterns. There was no statistically significant association between pattern of invasion and disease-free survival. Classic stromal microinvasion, as defined by nondestructive stromal invasion <5 mm was identified in 52% of LGSC and was statistically more frequent in LGSC than in SBT (P<0.001). In 2 LGSCs, there were areas demonstrating an intraluminal solid proliferation of tumor cells with grade 1 or 2 nuclear atypia, which we hypothesize may represent a noninvasive form of LGSC, as similar non-invasive proliferations of morphologically low-grade serous carcinomatous cells were also identified in 8 SBTs, in either solid or compact glandular/papillary formations. One patient with this isolated noninvasive pattern in SBT developed LGSC 40 months after initial operation. LGSC was typically high stage (FIGO stages II to IV, 86%) and bilateral (68%), with multiple foci of invasion (82%). Bilaterality was significantly more common in high-stage disease (P=0.009). LGSC was associated with SBT in 84% of cases, most commonly usual type (27%), followed by cribriform (18%), micropapillary (11%), or mixed cribriform and micropapillary (7%) types; focal micropapillary and/or cribriform features were present in an additional 16%. The presence of intraluminal proliferations of cells resembling LGSC occurring in SBT should prompt additional tumor sampling and assiduous evaluation of implants (if present), as this appears to represent a form of intraepithelial carcinoma, which may be associated with invasion elsewhere.

  View details for DOI 10.1097/PAS.0000000000000693

  View details for PubMedID 27487741

• Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening. Surgical pathology clinics Mills, A. M., Longacre, T. A. 2016; 9 (2): 201-214

  Abstract

  Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed.

  View details for DOI 10.1016/j.path.2016.01.004

  View details for PubMedID 27241104

• Mismatch Repair Protein Expression in Clear Cell Carcinoma of the Ovary: Incidence and Morphologic Associations in 109 Cases. American journal of surgical pathology Bennett, J. A., Morales-Oyarvide, V., Campbell, S., Longacre, T. A., Oliva, E. 2016; 40 (5): 656-663

  Abstract

  Several morphologic features have been reported to be predictive of abnormal expression of mismatch repair (MMR) proteins in endometrial and colon carcinomas. Although it is known that abnormal MMR expression is increased in frequency in ovarian endometrioid and clear cell carcinomas, no such histologic correlation has been identified. We reviewed 109 unselected ovarian clear cell carcinomas for specific tumor characteristics (architecture, nuclear atypia, signet ring cells, stromal hyalinization, background precursor) and inflammatory response (peritumoral lymphocytes found along the leading edge of the tumor, intratumoral stromal inflammation found within the tumor, percentage of plasma cells in the intratumoral stromal inflammation, tumor-infiltrating lymphocytes) and performed immunohistochemistry for all 4 MMR proteins. Abnormal MMR expression was identified in 6% of tumors and included MSH2/MSH6 (3), MLH1/PMS2 (1), MSH6 (1), and PMS2 (1). These patients had a mean age of 40 (range, 31 to 48) years, which contrasted with a mean of 53.2 (range, 28 to 82) years for the overall cohort. One had a concurrent diagnosis of endometrial carcinoma, whereas another had a family history of endometrial carcinoma. None had a personal/family history of colonic carcinoma. Tumors with diffuse intratumoral stromal inflammation and peritumoral lymphocytes were more frequently associated with MMR loss on univariate analysis (P<0.001 and 0.047, respectively) with diffuse intratumoral stromal inflammation remaining a significant independent predictor on multivariate analysis. None of the other morphologic features evaluated reached statistical significance. Although previous series have been unable to identify a relationship between histology and MMR expression, this study identified a correlation with diffuse intratumoral stromal inflammation and peritumoral lymphocytes, 2 features that potentially could be selected for MMR analysis if corroborated by other studies.

  View details for DOI 10.1097/PAS.0000000000000602

  View details for PubMedID 26813747

• Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Krampitz, G. W., George, B. M., Willingham, S. B., Volkmer, J., Weiskopf, K., Jahchan, N., Newman, A. M., Sahoo, D., Zemek, A. J., Yanovsky, R. L., Nguyen, J. K., Schnorr, P. J., Mazur, P. K., Sage, J., Longacre, T. A., Visser, B. C., Poultsides, G. A., Norton, J. A., Weissman, I. L. 2016; 113 (16): 4464-4469

  Abstract

  Pancreatic neuroendocrine tumors (PanNETs) are a type of pancreatic cancer with limited therapeutic options. Consequently, most patients with advanced disease die from tumor progression. Current evidence indicates that a subset of cancer cells is responsible for tumor development, metastasis, and recurrence, and targeting these tumor-initiating cells is necessary to eradicate tumors. However, tumor-initiating cells and the biological processes that promote pathogenesis remain largely uncharacterized in PanNETs. Here we profile primary and metastatic tumors from an index patient and demonstrate that MET proto-oncogene activation is important for tumor growth in PanNET xenograft models. We identify a highly tumorigenic cell population within several independent surgically acquired PanNETs characterized by increased cell-surface protein CD90 expression and aldehyde dehydrogenase A1 (ALDHA1) activity, and provide in vitro and in vivo evidence for their stem-like properties. We performed proteomic profiling of 332 antigens in two cell lines and four primary tumors, and showed that CD47, a cell-surface protein that acts as a "don't eat me" signal co-opted by cancers to evade innate immune surveillance, is ubiquitously expressed. Moreover, CD47 coexpresses with MET and is enriched in CD90(hi)cells. Furthermore, blocking CD47 signaling promotes engulfment of tumor cells by macrophages in vitro and inhibits xenograft tumor growth, prevents metastases, and prolongs survival in vivo.

  View details for DOI 10.1073/pnas.1600007113

  View details for Web of Science ID 000374393800063

  View details for PubMedID 27035983

• Lynch Syndrome Screening in the Gynecologic Tract: Current State of the Art. American journal of surgical pathology Mills, A. M., Longacre, T. A. 2016; 40 (4): e35-44

  Abstract

  Lynch syndrome underlies approximately 5% of endometrial cancers and ?1% of ovarian cancers. Gynecologic malignancies are often the presenting cancer in these patients. Therefore, there is considerable benefit to identifying these patients and enrolling them and affected family members in surveillance programs for secondary malignancies. The molecular basis for Lynch syndrome is a defect in the DNA mismatch repair (MMR) system. Tumors can be screened for these defects using immunohistochemistry to identify loss of MMR proteins or by enlisting polymerase chain reaction to identify the microsatellite instability that attends dysfunctional MMR. However, diagnostic confirmation of Lynch syndrome requires germline mutational testing. The algorithm for screening endometrial carcinomas for Lynch syndrome remains a subject of debate, with some studies supporting universal screening and others proposing a hybrid approach informed by clinicopathologic features. This review discusses the rationales and relative merits of current Lynch syndrome-screening approaches for endometrial and ovarian cancers and provides pathologists with an informed approach to Lynch syndrome testing in gynecologic cancers. It also addresses the clinical difficulties presented by cases with discordant screening and germline results (Lynch-like cancers) and emphasizes the critical role of strong communication with clinician and genetic counseling colleagues to ensure that the significance of a positive screening test is appropriately conveyed to patients. Finally, it discusses the need for more nuanced cost-effective analyses and the potential role for next-generation sequencing panels in future screening efforts.

  View details for DOI 10.1097/PAS.0000000000000608

  View details for PubMedID 26872009

• Intraductal Papillary Mucinous Neoplasms Often Contain Epithelium From Multiple Subtypes and/or Are Unclassifiable AMERICAN JOURNAL OF SURGICAL PATHOLOGY Schaberg, K. B., DiMaio, M. A., Longacre, T. A. 2016; 40 (1): 44-50

  View details for Web of Science ID 000367135400006

• Idelalisib-associated Enterocolitis Clinicopathologic Features and Distinction From Other Enterocolitides AMERICAN JOURNAL OF SURGICAL PATHOLOGY Louie, C. Y., DiMaio, M. A., Matsukuma, K. E., Coutre, S. E., Berry, G. J., Longacre, T. A. 2015; 39 (12): 1653-1660

  View details for DOI 10.1097/PAS.0000000000000525

  View details for Web of Science ID 000365627200006

• Locally Advanced Intrahepatic Cholangiocarcinoma: Complete Pathologic Response to Neoadjuvant Chemotherapy Followed by Left Hepatic Trisectionectomy and Caudate Lobectomy DIGESTIVE DISEASES AND SCIENCES Tran, T. B., Bal, C. K., Schaberg, K., Longacre, T. A., Chatrath, B. S., Poultsides, G. A. 2015; 60 (11): 3226-3229

  View details for DOI 10.1007/s10620-015-3640-x

  View details for Web of Science ID 000363542700012

• KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers. Gastroenterology Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., van de Rijn, M., Quake, S. R., Clarke, M. F., Rothenberg, M. E. 2015; 149 (3): 705-17 e2

  Abstract

  Receptor tyrosine kinase (RTK) inhibitors have advanced colon cancer treatment. We investigated the role of the RTK KIT in development of human colon cancer.An array of 137 patient-derived colon tumors and their associated xenografts were analyzed by immunohistochemistry to measure levels of KIT and its ligand KITLG. KIT and/or KITLG was stably knocked down by expression of small hairpin RNAs from lentiviral vectors in DLD1, HT29, LS174T, and COLO320 DM colon cancer cell lines, and in UM-COLON#8 and POP77 xenografts; cells transduced with only vector were used as controls. Cells were analyzed by real-time quantitative reverse transcription polymerase chain reaction, single-cell gene expression analysis, flow cytometry, and immunohistochemical, immunoblot, and functional assays. Xenograft tumors were grown from control and KIT-knockdown DLD1 and UM-COLON#8 cells in immunocompromised mice and compared. Some mice were given the RTK inhibitor imatinib after injection of cancer cells; tumor growth was measured based on bioluminescence. We assessed tumorigenicity using limiting dilution analysis.KIT and KITLG were expressed heterogeneously by a subset of human colon tumors. Knockdown of KIT decreased proliferation of colon cancer cell lines and growth of xenograft tumors in mice compared with control cells. KIT knockdown cells had increased expression of enterocyte markers, decreased expression of cycling genes, and, unexpectedly, increased expression of LGR5 associated genes. No activating mutations in KIT were detected in DLD1, POP77, or UM-COLON#8 cells. However, KITLG-knockdown DLD1 cells formed smaller xenograft tumors than control cells. Gene expression analysis of single CD44(+) cells indicated that KIT can promote growth via KITLG autocrine and/or paracrine signaling. Imatinib inhibited growth of KIT(+) colon cancer organoids in culture and growth of xenograft tumors in mice. Cancer cells with endogenous KIT expression were more tumorigenic in mice.KIT and KITLG are expressed by a subset of human colon tumors. KIT signaling promotes growth of colon cancer cells and organoids in culture and xenograft tumors in mice via its ligand, KITLG, in an autocrine or paracrine manner. Patients with KIT-expressing colon tumors can benefit from KIT RTK inhibitors.

  View details for DOI 10.1053/j.gastro.2015.05.042

  View details for PubMedID 26026391

• Stereotactic body radiation therapy and central liver toxicity: A case report. Practical radiation oncology Shaffer, J. L., Osmundson, E. C., Visser, B. C., Longacre, T. A., Koong, A. C., Chang, D. T. 2015; 5 (5): 282-285

  View details for DOI 10.1016/j.prro.2015.04.011

  View details for PubMedID 26127008

• KIT Signaling Promotes Growth of Colon Xenograft Tumors in Mice and Is Up-Regulated in a Subset of Human Colon Cancers GASTROENTEROLOGY Chen, E. C., Karl, T. A., Kalisky, T., Gupta, S. K., O'Brien, C. A., Longacre, T. A., De Rijn, M. V., Quake, S. R., Clarke, M. F., Rothenberg, M. E. 2015; 149 (3): 705-?

  View details for DOI 10.1053/j.gastro.2015.05.042

  View details for Web of Science ID 000360269800039

• Better Survival But Changing Causes of Death in Patients With Multiple Endocrine Neoplasia Type 1. Annals of surgery Norton, J. A., Krampitz, G., Zemek, A., Longacre, T., Jensen, R. T. 2015; 261 (6): e147-8

  View details for DOI 10.1097/SLA.0000000000001211

  View details for PubMedID 26291955

• Smad4 inactivation predicts for worse prognosis and response to fluorouracil-based treatment in colorectal cancer JOURNAL OF CLINICAL PATHOLOGY Kozak, M. M., von Eyben, R., Pai, J., Vossler, S. R., Limaye, M., Jayachandran, P., Anderson, E. M., Shaffer, J. L., Longacre, T., Pai, R. K., Koong, A. C., Chang, D. T. 2015; 68 (5): 341-345

  Abstract

  To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31?months compared with 89?months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.

  View details for DOI 10.1136/jclinpath-2014-202660

  View details for Web of Science ID 000353420500004

  View details for PubMedID 25681512

• Lanthanum-Induced Gastrointestinal Histiocytosis. ACG case reports journal Rothenberg, M. E., Araya, H., Longacre, T. A., Pasricha, P. J. 2015; 2 (3): 187-189

  Abstract

  A patient with end-stage renal disease (ESRD) on hemodialysis presented with fever, anorexia, and nausea shortly after starting oral lanthanum carbonate for phosphate control. Gastric and duodenal biopsies demonstrated diffuse histiocytosis with intracellular aggregates of basophilic foreign material. Transmission electron microscopy, an underutilized diagnostic test, revealed the nature of the aggregates as heavy metal particles, consistent with lanthanum. Symptoms and histiocytosis improved after discontinuation of lanthanum. Lanthanum may be an underdiagnosed cause of gastrointestinal histiocytosis.

  View details for DOI 10.14309/crj.2015.50

  View details for PubMedID 26157959

• Metastatic lobular breast carcinoma mimicking primary signet ring adenocarcinoma in a patient with a suspected CDH1 mutation. Journal of clinical oncology Mahmud, N., Ford, J. M., Longacre, T. A., Parent, R., Norton, J. A. 2015; 33 (4): e19-21

  View details for DOI 10.1200/JCO.2013.49.1159

  View details for PubMedID 24590638

• Metastatic Lobular Breast Carcinoma Mimicking Primary Signet Ring Adenocarcinoma in a Patient With a Suspected CDH1 Mutation JOURNAL OF CLINICAL ONCOLOGY Mahmud, N., Ford, J. M., Longacre, T. A., Parent, R., Norton, J. A. 2015; 33 (4): E19-E21

  View details for DOI 10.1200/JCO.2013.49.1159

  View details for Web of Science ID 000352422900002

• Collateral damage: taxane-induced colonic perforation. Digestive diseases and sciences Erdrich, J., Kastenberg, Z. J., DiMaio, M. A., Longacre, T. A., Rhoads, K. F. 2015; 60 (2): 313-315

  View details for DOI 10.1007/s10620-014-3305-1

  View details for PubMedID 25081225

• Gastrointestinal Mucormycosis Initially Manifest as Hematochezia from Arterio-Enteric Fistula DIGESTIVE DISEASES AND SCIENCES Cloyd, J. M., Brown, J., Sinclair, T., Jenks, D., Desai, J., Longacre, T., Chandra, V., Shelton, A. 2014; 59 (12): 2905-2908

  View details for DOI 10.1007/s10620-014-3239-7

  View details for Web of Science ID 000345322100008

• Gastrointestinal mucormycosis initially manifest as hematochezia from arterio-enteric fistula. Digestive diseases and sciences Cloyd, J. M., Brown, J., Sinclair, T., Jenks, D., Desai, J., Longacre, T., Chandra, V., Shelton, A. 2014; 59 (12): 2905-2908

  View details for DOI 10.1007/s10620-014-3239-7

  View details for PubMedID 24906697

• Lynch Syndrome Screening Should Be Considered for All Patients With Newly Diagnosed Endometrial Cancer AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Liou, S., Ford, J. M., Berek, J. S., Pai, R. K., Longacre, T. A. 2014; 38 (11): 1501-1509

  Abstract

  Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.

  View details for Web of Science ID 000343880200006

  View details for PubMedID 25229768

• Risk of Secondary Malignancy (Including Breast) in Patients With Mismatch-repair Protein Deficiency AMERICAN JOURNAL OF SURGICAL PATHOLOGY Clay, M. R., Allison, K. H., Folkins, A. K., Longacre, T. A. 2014; 38 (11): 1494-1500

  View details for Web of Science ID 000343880200005

• Evaluation of intestinal biopsies for pediatric enteropathy: a proposed immunohistochemical panel approach. American journal of surgical pathology Martin, B. A., Kerner, J. A., Hazard, F. K., Longacre, T. A. 2014; 38 (10): 1387-1395

  Abstract

  Congenital enteropathies are rare disorders with significant clinical consequences; however, definitive diagnosis based on morphologic assessment of duodenal biopsies with routine stains alone is often impossible. To determine the role of immunohistochemistry (IHC) in the evaluation for microvillous inclusion disease, congenital tufting enteropathy (intestinal epithelial dysplasia), and enteroendocrine cell dysgenesis, a series of duodenal biopsies from 26 pediatric patients with chronic/intractable diarrhea was retrospectively reviewed. IHC stains for CD10, EpCAM, chromogranin, and villin were performed on all biopsies, and the results were correlated with hematoxylin and eosin and ultrastructural findings using electron microscopy, when available. Biopsies from 2 patients diagnosed with microvillous inclusion disease at the time of original biopsy demonstrated diffuse CD10-positive cytoplasmic inclusions within enterocytes and normal expression of EpCAM and chromogranin. Biopsies from 3 patients, including 2 siblings with confirmed EPCAM mutations, demonstrated complete loss of EpCAM expression and normal expression of CD10 and chromogranin; electron microscopic evaluation revealed characteristic ultrastructural findings of tufting enteropathy. Biopsies from 1 patient with a confirmed NEUROG3 mutation demonstrated an absence of intestinal enteroendocrine cells by chromogranin staining, consistent with enteroendocrine cell dysgenesis. Four patients' biopsies displayed nonspecific staining patterns for CD10 and/or EpCAM with normal expression of chromogranin, and 16 patients' biopsies exhibited normal expression for all 3 markers. Villin stains demonstrated heterogenous brush border labeling with nonspecific cytoplasmic reactivity, a pattern variably present throughout the biopsy series. In conclusion, the routine use of an IHC panel of CD10, EpCAM, and chromogranin is warranted in patients meeting specific age and/or clinical criteria, as the morphologic findings of congenital enteropathies may be subtle, focal, or inapparent on routine stains.

  View details for DOI 10.1097/PAS.0000000000000314

  View details for PubMedID 25188866

• Evaluation of Intestinal Biopsies for Pediatric Enteropathy A Proposed Immunohistochemical Panel Approach AMERICAN JOURNAL OF SURGICAL PATHOLOGY Martin, B. A., Kerner, J. A., Hazard, F. K., Longacre, T. A. 2014; 38 (10): 1387-1395

  View details for Web of Science ID 000342001800010

• Reactive lymphoid hyperplasia of the terminal ileum: a benign (lymphoma-like) condition that may harbor aberrant immunohistochemical patterns or clonal immunoglobulin heavy chain gene rearrangements. Applied immunohistochemistry & molecular morphology Mojtahed, A., Pai, R. K., Anderson, M. W., Arber, D. A., Longacre, T. A. 2014; 22 (8): 585-592

  Abstract

  Small endoscopic biopsies of the terminal ileum may be difficult to assess for early involvement by lymphoma. Immunophenotypic and genotypic analyses are often utilized, but the performance of these studies in this setting is not well defined. Terminal ileal biopsies from 66 patients with prominent lymphoid hyperplasia and abnormal "lymphoma-like" morphology were evaluated by immunohistochemistry (IHC) for CD3, CD5, CD43, CD20, CD21, and CD10 expression and for IGH@ gene rearrangement by polymerase chain reaction using BIOMED-2 primers. Patients ranged in age from 3 to 80 years. Indications for endoscopy included inflammatory bowel disease (29), diarrhea and/or abdominal pain (28), history of lymphoma (13), and others (4). Four biopsies with abnormal morphology had abnormal IHC and a clonal IGH@ peak; all were obtained from patients with a history of lymphoma and determined to be recurrent lymphoma. Three biopsies with abnormal morphology and abnormal IHC but no clonal IGH@ peak were obtained from patients with a history of lymphoma (2) and chronic diarrhea (1); all showed symptom resolution or remission of disease (mean follow-up, 37 mo). Eight biopsies with abnormal morphology but no abnormal IHC expression also had abnormal IGH@ results (4 clonal and 4 borderline). IGH@ evaluation of follow-up biopsies for these cases were nonclonal (7) or clonal, but with a different clone from the prior biopsy (1); follow-up of the 8 patients showed no evidence of lymphoma (mean, 37.8 mo). Abnormal IHC expression pattern or clonal IGH@ rearrangement in endoscopic biopsies of the lymphoid-rich terminal ileum do not necessarily warrant a diagnosis of lymphoma. To prevent misdiagnosis, B-cell clonality studies should only be performed when there is strong clinical suspicion for lymphoma and compelling IHC data; the absence of a reproducible clone in repeat biopsy specimens may be useful in patients that do not have other clinical evidence of lymphoma.

  View details for DOI 10.1097/01.pai.0000446497.93867.98

  View details for PubMedID 24897069

• Reactive Lymphoid Hyperplasia of the Terminal Ileum: A Benign (Lymphoma-like) Condition That May Harbor Aberrant Immunohistochemical Patterns or Clonal Immunoglobulin Heavy Chain Gene Rearrangements APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Mojtahed, A., Pai, R. K., Anderson, M. W., Arber, D. A., Longacre, T. A. 2014; 22 (8): 585-592

  View details for Web of Science ID 000342232700006

• Uterine Rosai-Dorfman Disease (Sinus Histiocytosis With Massive Lymphadenopathy) INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Pan, L. Y., Offman, S. L., Warnke, R. A., Longacre, T. A. 2014; 33 (4): 432-436

  Abstract

  We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases.

  View details for DOI 10.1097/PGP.0b013e3182a03d23

  View details for Web of Science ID 000337737900016

• Molecular assessment of surgical-resection margins of gastric cancer by mass-spectrometric imaging PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Eberlin, L. S., Tibshirani, R. J., Zhang, J., Longacre, T. A., Berry, G. J., Bingham, D. B., Norton, J. A., Zare, R. N., Poultsides, G. A. 2014; 111 (7): 2436-2441

  Abstract

  Surgical resection is the main curative option for gastrointestinal cancers. The extent of cancer resection is commonly assessed during surgery by pathologic evaluation of (frozen sections of) the tissue at the resected specimen margin(s) to verify whether cancer is present. We compare this method to an alternative procedure, desorption electrospray ionization mass spectrometric imaging (DESI-MSI), for 62 banked human cancerous and normal gastric-tissue samples. In DESI-MSI, microdroplets strike the tissue sample, the resulting splash enters a mass spectrometer, and a statistical analysis, here, the Lasso method (which stands for least absolute shrinkage and selection operator and which is a multiclass logistic regression with L1 penalty), is applied to classify tissues based on the molecular information obtained directly from DESI-MSI. The methodology developed with 28 frozen training samples of clear histopathologic diagnosis showed an overall accuracy value of 98% for the 12,480 pixels evaluated in cross-validation (CV), and 97% when a completely independent set of samples was tested. By applying an additional spatial smoothing technique, the accuracy for both CV and the independent set of samples was 99% compared with histological diagnoses. To test our method for clinical use, we applied it to a total of 21 tissue-margin samples prospectively obtained from nine gastric-cancer patients. The results obtained suggest that DESI-MSI/Lasso may be valuable for routine intraoperative assessment of the specimen margins during gastric-cancer surgery.

  View details for DOI 10.1073/pnas.1400274111

  View details for Web of Science ID 000331396500018

  View details for PubMedID 24550265

• Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition BREAST CANCER RESEARCH Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2)

  View details for DOI 10.1186/bcr3640

  View details for Web of Science ID 000338990900021

• Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast cancer research Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2): R36-?

  Abstract

  Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and 5/6 primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.

  View details for DOI 10.1186/bcr3640

  View details for PubMedID 24708766

• Gastrointestinal Stromal Tumor: An Unusual Cause of Gastrointestinal Bleeding DIGESTIVE DISEASES AND SCIENCES Wong, R. J., Longacre, T. A., Poultsides, G., Park, W., Rothenberg, M. E. 2013; 58 (11): 3112-3116

  View details for DOI 10.1007/s10620-013-2678-x

  View details for Web of Science ID 000326188800011

  View details for PubMedID 23633157

• HNF-1 beta in Ovarian Carcinomas With Serous and Clear Cell Change INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY DeLair, D., Han, G., Irving, J. A., Leung, S., Ewanowich, C. A., Longacre, T. A., Gilks, C. B., Soslow, R. A. 2013; 32 (6): 541-546

  Abstract

  Many ovarian tumors, including high-grade serous carcinoma (HGSC), show clear cell change. Accurate diagnosis is important, however, as ovarian clear cell carcinoma (OCCC) is known to be less responsive to traditional types of ovarian cancer chemotherapies. In a previous study, the clinical, morphologic, and immunohistochemical features of 32 ovarian carcinomas, which had been previously diagnosed as pure OCCC (n=11), pure HGSC (n=11), and mixed serous and clear cell (MSC) (n=10), were analyzed. The immunoreactivities of WT1, ER, and p53, as well as the mitotic indices and stages of presentation of the MSC, were similar to those of HGSC. It was consequently concluded that MSC represented HGSC with clear cell change. Hepatocyte nuclear factor-1? (HNF-1?) is a relatively new immunohistochemical marker that has been shown to be rather sensitive and specific for OCCC. We thus sought to evaluate this marker in this specific group of tumors. One block each of pure HGSC and pure OCCC were stained with HNF-1?. In the cases of MSC, 2 blocks were stained when the serous and clear cell components were not present on the same slide. None (0/11) of the pure HGSC showed immunoreactivity for HNF-1?, whereas all (11/11) of the pure OCCC were positive. In the cases of MSC, both the serous and clear cell components were negative for HNF-1?. HNF-1? seems to be a sensitive and specific marker for OCCC and is not expressed in HGSC with clear cell change. The pattern of immunoreactivity of HNF-1? in tumors with both serous and clear cell change supports the conclusion that MSC are HGSC with clear cells.

  View details for DOI 10.1097/PGP.0b013e318273fd07

  View details for Web of Science ID 000325853900003

  View details for PubMedID 24071869

• Integrative Bioinformatics Links HNF1B with Clear Cell Carcinoma and Tumor-Associated Thrombosis PLOS ONE Cuff, J., Salari, K., Clarke, N., Esheba, G. E., Forster, A. D., Huang, S., West, R. B., Higgins, J. P., Longacre, T. A., Pollack, J. R. 2013; 8 (9)

  View details for DOI 10.1371/journal.pone.0074562

  View details for Web of Science ID 000326405300182

• Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

  Abstract

  Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (?50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

  View details for DOI 10.1016/S1470-2045(13)70253-5

  View details for PubMedID 23845225

• Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

  Abstract

  Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (?50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

  View details for DOI 10.1016/S1470-2045(13)70253-5

  View details for PubMedID 23845225

• p16 Is Superior to ProEx C in Identifying High-grade Squamous Intraepithelial Lesions (HSIL) of the Anal Canal AMERICAN JOURNAL OF SURGICAL PATHOLOGY Bala, R., Pinsky, B. A., Beck, A. H., Kong, C. S., Welton, M. L., Longacre, T. A. 2013; 37 (5): 659-668

  Abstract

  Although the incidence of human papillomavirus (HPV)-associated anal neoplasia is increasing, interobserver and intraobserver reproducibility in the grading of biopsy specimens from this area remains unacceptably low. Attempts to produce a more reproducible grading scheme have led to the use of biomarkers for the detection of high-risk HPV (HR-HPV). We evaluated the performance of standard morphology and biomarkers p16, ProEx C, and Ki-67 in a set of 75 lesions [17 nondysplastic lesions, 23 low-grade squamous intraepithelial lesions (LSIL)/condyloma, 20 high-grade squamous intraepithelial lesions (HSIL), 15 invasive squamous cell carcinomas] from the anal and perianal region in 65 patients and correlated these findings with HPV subtype on the basis of a type-specific multiplex real-time polymerase chain reaction assay designed to detect HR-HPV. A subset of cases with amplifiable HPV DNA was also sequenced. HSIL was typically flat (15/20), and only a minority (4/20) had koilocytes. In contrast, only 1 LSIL was flat (1/23), and the remainder were exophytic. The majority of LSIL had areas of koilocytic change (20/23). HR-HPV DNA was detected in the majority (89%) of invasive carcinomas and HSIL biopsies, 86% and 97% of which were accurately labeled by strong and diffuse block-positive p16 and ProEx C, respectively. LSIL cases, however, only infrequently harbored HR-HPV (13%); most harbored low-risk HPV (LR-HPV) types 6 and 11. Within the LSIL group, p16 outperformed ProEx C, resulting in fewer false-positive cases (5% vs. 75%). Ki-67 was also increased in HR-HPV-positive lesions, although biopsies with increased inflammation and reactive changes also showed higher Ki-67 indices. These data suggest that strong and diffuse block-positive nuclear and cytoplasmic labeling with p16 is a highly specific biomarker for the presence of HR-HPV in anal biopsies and that this finding correlates with high-grade lesions.

  View details for DOI 10.1097/PAS.0b013e31828706c0

  View details for Web of Science ID 000317663100005

  View details for PubMedID 23552383

• Interobserver Variability in the Interpretation of Tumor Cell Necrosis in Uterine Leiomyosarcoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Lim, D., Alvarez, T., Nucci, M. R., Gilks, B., Longacre, T., Soslow, R. A., Oliva, E. 2013; 37 (5): 650-658

  Abstract

  On the basis of the most recent World Health Organization classification, distinction of leiomyosarcoma (LMS) from leiomyoma is based on the presence of the following morphologic criteria: (1) nuclear atypia; (2) mitotic index; and (3) tumor cell necrosis (TCN). Unlike ischemic-type necrosis, which may be seen in benign and malignant smooth muscle tumors (SMTs), TCN is thought to be found only in LMS. The distinction between these 2 types of necrosis can be challenging, especially during the early stages, when necrotic foci are small, or when overlapping features are identified. The aim of this study is to assess the interobserver variability in the interpretation of TCN in uterine LMS. Thirty-four LMS cases were retrieved, and a representative hematoxylin and eosin slide showing 1 area of necrosis was selected from each case. Pathologists from 6 different institutions subspecializing in gynecologic pathology performed a blinded, independent review of the slides. Using the current World Health Organization criteria for assessment of TCN, they had to classify the necrotic foci into: (1) TCN; (2) no TCN; or (3) indeterminate for TCN. Agreement among panelists was categorized as: full-all pathologists in agreement; partial-4 or 5 pathologists in agreement; no agreement-?3 pathologists placing the case into the same category. Full agreement regarding the presence or absence of TCN was reached in 12 cases (35%) (7 thought to show TCN); partial agreement in 16 (47%); and no general consensus was obtained in 6 (18%). Overall, the level of agreement was moderate (?=0.436). In 8 of 34 instances (23.5%), ?1 pathologist made a diagnosis of "TCN" and ?1 pathologist made the diagnosis of "no TCN" for the same slide. The number of cases diagnosed as "indeterminate for TCN" by each pathologist ranged from 0 to 10 with a mean of 5.8. In 20 cases, at least 1 pathologist diagnosed "indeterminate for TCN" (59%), at least 2 and 3 were undecided in 10 (29%) and 4 (12%) cases, respectively, and 4 pathologists diagnosed "indeterminate for TCN" in 1 instance. When excluding foci of necrosis diagnosed as "indeterminate" by any pathologist, disagreement occurred in 2/14 (14%) cases. From these results we conclude that the level of interobserver agreement among expert gynecologic pathologists in the assessment of TCN in uterine SMTs is only moderate. These results further reiterate the importance of assessing for both nuclear atypia and mitotic activity when differentiating between benign and malignant SMTs and not relying solely on the presence of TCN.

  View details for DOI 10.1097/PAS.0b013e3182851162

  View details for Web of Science ID 000317663100004

  View details for PubMedID 23552382

• Cell Cycle Regulatory Markers in Uterine Atypical Leiomyoma and Leiomyosarcoma Immunohistochemical Study of 68 Cases With Clinical Follow-up AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Ly, A., Balzer, B. L., Hendrickson, M. R., Kempson, R. L., McKenney, J. K., Longacre, T. A. 2013; 37 (5): 634-642

  Abstract

  Cell cycle regulatory protein expression by immunohistochemical assay may have diagnostic utility in the distinction of uterine leiomyosarcoma from leiomyoma variants. p16, p21, p27, and p53 protein expression was evaluated by immunohistochemistry on 44 atypical leiomyomas (mean follow-up, 50.8 mo), 16 leiomyosarcomas (mean follow-up, 29.7 mo), and 8 cellular leiomyomas (mean follow-up, 22.6 mo). Nuclear staining was semiquantitatively scored on 1 representative section per case as negative (0%), focal (>0% to 33%), patchy (>33% to 66%), or diffuse (>66%). In addition, staining intensity was noted as weak, moderate, or strong. Proliferative index was gauged by Ki-67 and PHH3 immunohistochemical staining. One of 35 atypical leiomyoma patients with follow-up data developed an extrauterine recurrence 25.7 months after hysterectomy, whereas a second had intrauterine recurrence 24.9 months after myomectomy. Seven of 8 patients with leiomyosarcoma with follow-up had recurrence within the follow-up period, whereas there were no recurrences in patients with cellular leiomyoma. The Ki-67 proliferation index ranged from 0% to 25% in atypical leiomyoma (mean, 2%) and 6% to 50% in leiomyosarcoma (mean, 25%) with 0% to 10% in cellular leiomyoma (mean, 3%), whereas the PHH3 proliferation index ranged from 0% to 3% in atypical leiomyoma (mean, <1%) and 0% to 10% in leiomyosarcoma (mean, 2%) with 0% to 2% in cellular leiomyoma (mean, <1%). The atypical leiomyoma with extrauterine recurrence was diffusely positive for p21, but showed only weak focal (<33%) staining for all other cell cycle markers. Uterine atypical leiomyomas, cellular leiomyomas, and leiomyosarcomas demonstrate a heterogenous pattern of cell cycle regulatory protein expression. Caution should be exercised in distinguishing leiomyosarcoma from atypical leiomyoma variants on the basis of cell cycle protein expression alone. In our study, cell cycle markers were not useful for predicting recurrence in atypical leiomyoma.

  View details for DOI 10.1097/PAS.0b013e318287779c

  View details for Web of Science ID 000317663100002

• Atypical Leiomyomas of the Uterus A Clinicopathologic Study of 51 Cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Ly, A., Mills, A. M., McKenney, J. K., Balzer, B. L., Kempson, R. L., Hendrickson, M. R., Longacre, T. A. 2013; 37 (5): 643-649

  Abstract

  Atypical leiomyoma is a well-described smooth muscle neoplasm of the uterus. Only 1 study has addressed long-term clinical follow-up in a large series, and little is known about the adequacy of treatment by myomectomy. The surgical pathology archives were searched for consecutive cases of uterine atypical leiomyoma from 1992 to 2003. Glass slides were reviewed to confirm the diagnoses, and patient age, treatment modality, and clinical follow-up data were recorded. Fifty-one atypical leiomyomas with available glass slides and clinical follow-up data were identified. Thirty tumors exhibited diffuse, moderately to severely atypical cells, whereas 21 showed atypical cells in a more focal or patchy distribution. Twelve had ischemic-type necrosis. By the highest count method, 37 cases were found to have ?1 MF/10 HPF, 13 showed 1 to 3 MF/10 HPF, and 1 was nearly entirely necrotic precluding mitotic assessment. Among cases in which adjacent non-neoplastic tissue was well visualized, all were found to have pushing margins (46 cases). The average tumor size was 6.8 cm (median 6.5 cm; range, 0.7 to 14 cm). The average patient age was 42.5 years (median 42 y; range, 21 to 72 y). In all cases, the initial diagnostic procedure was hysterectomy (34) or myomectomy (17). Average follow-up was 42 months (range, 0.3 to 121.8 mo). Of those treated with hysterectomy, 1 had recurrent atypical leiomyoma in the retroperitoneum at 87.5 months, 1 died of other causes, and the remaining 32 (94%) were free of disease. Of the myomectomy group, 82% had no evidence of recurrent disease on follow-up: 2 had residual atypical leiomyoma in the subsequent hysterectomy specimen; and 1 underwent second myomectomy for atypical leiomyoma with 2 subsequent successful pregnancies. Atypical leiomyoma has a low rate of extrauterine, intra-abdominal recurrence (<2%) with a negligible risk for distant metastasis. Patients may be treated by myomectomy alone with successful pregnancy, but should be monitored for local intrauterine residual/recurrent disease.

  View details for DOI 10.1097/PAS.0b013e3182893f36

  View details for Web of Science ID 000317663100003

• Ovarian Surface Epithelial Neoplasms in the Pediatric Population Incidence, Histologic Subtype, and Natural History AMERICAN JOURNAL OF SURGICAL PATHOLOGY Hazard, F. K., Longacre, T. A. 2013; 37 (4): 548-553

  Abstract

  Surface epithelial neoplasms account for a small but significant proportion of pediatric ovarian tumors. The overall incidence, prevalence of histologic subtypes, and natural history of these neoplasms has not been thoroughly evaluated. A retrospective review of the pathology archives of Stanford University School of Medicine yielded 69 surface epithelial ovarian tumors in 64 pediatric patients 18 years of age or younger from 1974 to 2010. Tumors comprised benign (57.8%), borderline/low malignant potential (LMP) (37.5%), and malignant (4.7%) subgroups and exhibited serous, mucinous, and mixed histology; there were no clear cell, pure endometrioid, or transitional (Brenner) tumors. In addition, no high-grade carcinomas were identified. Clinical follow-up data were available in a subset of patients (maximum follow-up, 22 y). Similar numbers of recurrences were found in each of the 3 subgroups. However, overall survival was 100% for benign and borderline/LMP tumors and 50% for carcinomas. The type of surgical management and the use of chemotherapy varied; 2 patients with borderline/LMP tumors were treated by sterilizing procedures and/or chemotherapy. These data suggest that surface epithelial neoplasms comprise a small but significant proportion of ovarian tumors in the pediatric population, and they exhibit a marked preponderance for benign, borderline, and low-grade malignant subgroups. In contrast to their adult counterpart, high-grade serous carcinoma in children is extraordinarily rare and not seen in this series. Given this difference, uniform treatment modalities with consideration for ovarian conservation and fertility preservation should be rigorously adopted in any pediatric patient with a suspected ovarian surface epithelial neoplasm.

  View details for DOI 10.1097/PAS.0b013e318273a9ff

  View details for Web of Science ID 000316184000009

  View details for PubMedID 23388124

• Laboratory-Developed L1 Sequencing and Type-Specific, Real-Time Polymerase Chain Reaction for the Detection and Typing of Human Papillomaviruses in Formalin-Fixed, Paraffin-Embedded Tissues ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Mills, A., Balasubramaniam, R., Longacre, T. A., Kong, C. S., Pinsky, B. A. 2013; 137 (1): 50-54

  Abstract

  The detection and typing of high-risk and low-risk human papillomavirus (HPV) in archival formalin-fixed, paraffin-embedded tissues by nucleic acid amplification testing is an important adjunct to immunohistochemical staining in evaluation of squamous cell proliferations of the oropharynx, larynx, and anal canal.To evaluate semiautomated, xylene-free extraction from formalin-fixed, paraffin-embedded tissues combined with laboratory-developed HPV L1 sequencing and type-specific HPV 6, 11, 16, and 18 real-time polymerase chain reaction for identification and typing of HPV in the clinical laboratory.We evaluated the adequacy of extraction using ?-globin amplification and compared L1 sequencing and real-time polymerase chain reaction methods for typing accuracy using 68 formalin-fixed, paraffin-embedded tissues, including 56 anorectal biopsy or surgical resection specimens and 12 laryngeal papilloma specimens from patients with recurrent respiratory papillomatosis.Adequate DNA was obtained from 68 of 68 specimens analyzed and all were HPV positive. In 47 cases where L1 sequencing demonstrated that the predominant HPV type was 6, 11, 16, or 18, type-specific, real-time polymerase chain reaction provided concordant results. Sequencing revealed additional low-risk (HPV 40) and high-risk HPV types (HPV 31, 33, 56, and 58) in anorectal specimens, whereas HPV 6 or 11 were the types found in laryngeal papillomas.Both L1 sequencing and type-specific, real-time polymerase chain reaction are suitable methods for routine HPV testing of formalin-fixed, paraffin-embedded tissues in a clinical laboratory setting.

  View details for DOI 10.5858/arpa.2011-0392-OA

  View details for Web of Science ID 000313625100009

  View details for PubMedID 23276174

• Hereditary gynaecological malignancies: advances in screening and treatment HISTOPATHOLOGY Folkins, A. K., Longacre, T. A. 2013; 62 (1): 2-30

  Abstract

  In the last two decades there have been significant advances in our understanding of female genital tract tumours. The discovery of BRCA1 and BRCA2 genes in ovarian cancer and the mismatch repair genes in endometrial carcinoma has revolutionized our approach to the diagnosis and screening of women for ovarian and uterine cancers. This review discusses the pathogenesis of these two hereditary syndromes in depth and explains how the molecular genetics is tailoring the manner in which these diseases are diagnosed and potentially treated. Other, less common hereditary conditions associated with gynaecological tract manifestations, such as Cowden syndrome, Peutz-Jeghers syndrome, Gorlin syndrome and hereditary leiomyomatosis and renal cell carcinoma, are also summarized briefly.

  View details for DOI 10.1111/his.12028

  View details for Web of Science ID 000312533600002

  View details for PubMedID 23240667

• Clear Cell Carcinoma of the Female Genital Tract (Not Everything Is as Clear as it Seems) ADVANCES IN ANATOMIC PATHOLOGY Offman, S. L., Longacre, T. A. 2012; 19 (5): 296-312

  Abstract

  Clear cell carcinoma has a storied history in the female genital tract. From the initial designation of ovarian clear cell adenocarcinoma as "mesonephroma" to the linkage between vaginal clear cell carcinoma and diethylstilbestrol exposure in utero, gynecologic tract clear cell tumors have puzzled investigators, posed therapeutic dilemmas for oncologists, and otherwise presented major differential diagnostic challenges for pathologists. One of the most common errors in gynecologic pathology is misdiagnosis of clear cell carcinoma, on both frozen section and permanent section. Given the poor response to platinum-based chemotherapy for advanced-stage disease and increased risk of thromboembolism, accurate diagnosis of clear cell carcinoma is important in the female genital tract. This review (1) presents the clinical and pathologic features of female genital tract clear cell carcinomas; (2) highlights recent molecular developments; (3) identifies areas of potential diagnostic confusion; and (4) presents solutions for these diagnostic problems where they exist.

  View details for DOI 10.1097/PAP.0b013e31826663b1

  View details for Web of Science ID 000307875800002

  View details for PubMedID 22885379

• Are Women With Endocervical Adenocarcinoma at Risk for Lynch Syndrome? Evaluation of 101 Cases Including Unusual Subtypes and Lower Uterine Segment Tumors INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Mills, A. M., Liou, S., Kong, C. S., Longacre, T. A. 2012; 31 (5): 463-469

  Abstract

  It is well documented that endometrial and ovarian carcinoma are associated with Lynch syndrome (LS), but the association, if any, between endocervical carcinoma and LS has not been fully evaluated. The relationship between endocervical carcinoma and LS is particularly relevant, given the apparent affinity of LS-associated endometrial carcinomas for the lower uterine segment and the attendant difficulties in determining tumor origin at this site. In this study, we examined mismatch repair (MMR) protein expression (MLH1, MSH2, MSH6, and PMS2) in 60 endocervical adenocarcinomas, including variants (minimal deviation adenocarcinoma, mesonephric adenocarcinoma, adenosquamous carcinoma, clear cell carcinoma) and a series of well-characterized lower-uterine segment carcinomas of known endocervical or endometrial origin (n=41). Two of the lower uterine segment tumors occurred in risk-reducing hysterectomy specimens from known LS patients. All endocervical adenocarcinomas including variants and lower uterine segment endocervical tumors (1 from a known LS patient) were proficient in all 4 MMR proteins. In contrast, 2/20 (10%) lower uterine segment endometrial cancers were deficient in at least 1 MMR (1 from a known LS patient). These data provide evidence that, unlike endometrial and ovarian adenocarcinoma, there is no association between LS and endocervical carcinoma. MMR testing is prudent in lower uterine segment tumors in women with possible LS, especially those for which definitive site of origin cannot be determined.

  View details for DOI 10.1097/PGP.0b013e31824a1dad

  View details for Web of Science ID 000307647800011

  View details for PubMedID 22833088

• Prediction of BRCA1 Germline Mutation Status in Women With Ovarian Cancer Using Morphology-based Criteria Identification of a BRCA1 Ovarian Cancer Phenotype AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fujiwara, M., McGuire, V. A., Felberg, A., Sieh, W., Whittemore, A. S., Longacre, T. A. 2012; 36 (8): 1170-1177

  Abstract

  Specific morphologic features that may predict BRCA1 germline mutation in ovarian cancer have neither been well described nor independently tested. We identified 5 morphologic features associated with BRCA1 mutation status in a series of 20 ovarian cancers from BRCA1 mutation carriers: (1) modified Nottingham grade 3; (2) serous/undifferentiated histology; (3) prominent intraepithelial lymphocytes; (4) marked nuclear atypia with giant/bizarre forms; and (5) abundant mitotic figures. These morphologic features were then tested on 325 ovarian tumors drawn from a population-based Greater Bay Area Cancer Registry and classified into 3 categories independent of the BRCA1 status: "Compatible with BRCA1," "Possibly compatible with BRCA1," and "Not compatible with BRCA1." All "Compatible with BRCA1" tumors were additionally investigated for presence of dominant adnexal mass, fallopian tube mucosal involvement, and uterine cornu involvement. The positive and negative predictive values for "Compatible with BRCA1" were 11/42 (26.2%) and 267/283 (94.3%), respectively, whereas combining the "Compatible with BRCA1" and "Possibly compatible with BRCA1" had positive and negative predictive values of 18/85 (21.2%) and 231/240 (96.3%), respectively. Although dominant adnexal mass and uterine cornu involvement did not add further predictive value, the likelihood of BRCA1 positivity increased to 42.9% when a tumor with "Compatible with BRCA1" histology was also associated with fallopian tube mucosal involvement. The combination of modified Nottingham grade 3 serous or undifferentiated histology, prominent intraepithelial lymphocytes, marked nuclear atypia with giant/bizarre nuclei, and high mitotic index should help to identify women for BRCA1 mutational analysis in the appropriate clinical setting. Ovarian tumors lacking this specific phenotype are unlikely to be associated with BRCA1 and should not undergo mutational analysis in the absence of other indications.

  View details for DOI 10.1097/PAS.0b013e31825d9b8d

  View details for Web of Science ID 000306656500008

  View details for PubMedID 22790858

• Risk factors for uncommon histologic subtypes of breast cancer using centralized pathology review in the Breast Cancer Family Registry BREAST CANCER RESEARCH AND TREATMENT Work, M. E., Andrulis, I. L., John, E. M., Hopper, J. L., Liao, Y., Zhang, F. F., Knight, J. A., West, D. W., Milne, R. L., Giles, G. G., Longacre, T. A., O'Malley, F., Mulligan, A. M., Southey, M. C., Hibshoosh, H., Terry, M. B. 2012; 134 (3): 1209-1220

  Abstract

  Epidemiologic studies of histologic types of breast cancer including mucinous, medullary, and tubular carcinomas have primarily relied on International Classification of Diseases-Oncology (ICD-O) codes assigned by local pathologists to define histology. Using data from the Breast Cancer Family Registry (BCFR), we compared histologic agreement between centralized BCFR pathology review and ICD-O codes available from local tumor registries among 3,260 breast cancer cases. Agreement was low to moderate for less common histologies; for example, only 55 and 26 % of cases classified as mucinous and medullary, respectively, by centralized review were similarly classified using ICD-O coding. We then evaluated risk factors for each histologic subtype by comparing each histologic case group defined by centralized review with a common set of 2,997 population-based controls using polytomous logistic regression. Parity [odds ratio (OR) = 0.4, 95 % confidence interval (95 % CI): 0.2-0.9, for parous vs. nulliparous], age at menarche (OR = 0.5, 95 % CI: 0.3-0.9, for age ?13 vs. ?11), and use of oral contraceptives (OCs) (OR = 0.5, 95 % CI: 0.2-0.8, OC use >5 years vs. never) were associated with mucinous carcinoma (N = 92 cases). Body mass index (BMI) (OR = 1.05, 95 % CI: 1.0-1.1, per unit of BMI) and high parity (OR = 2.6, 95 % CI: 1.1-6.0 for ?3 live births vs. nulliparous) were associated with medullary carcinoma (N = 90 cases). We did not find any associations between breast cancer risk factors and tubular carcinoma (N = 86 cases). Relative risk estimates from analyses using ICD-O classifications of histology, rather than centralized review, resulted in attenuated, and/or more imprecise, associations. These findings suggest risk factor heterogeneity across breast cancer tumor histologies, and demonstrate the value of centralized pathology review for classifying rarer tumor types.

  View details for DOI 10.1007/s10549-012-2056-y

  View details for Web of Science ID 000307273300029

  View details for PubMedID 22527103

• Endometriosis Does Not Confer Improved Prognosis in Ovarian Carcinoma of Uniform Cell Type AMERICAN JOURNAL OF SURGICAL PATHOLOGY Cuff, J., Longacre, T. A. 2012; 36 (5): 688-695

  Abstract

  The role of endometriosis in ovarian cancer, disease progression, and survival is a subject of active investigation. A series of 144 ovarian cancers with clear cell or endometrioid histology or associated endometriosis, all classified on the basis of strict histologic criteria, was evaluated to further explore the relationship between endometriosis-associated ovarian cancer and age at presentation, FIGO stage, histology, presence of synchronous primary disease elsewhere in the mullerian tract, and survival. Patients with endometrioid carcinomas were significantly younger (mean, 52 y) in comparison with patients with either clear cell carcinoma (mean, 55 y) or mixed tumors (mean, 59 y; P=0.002). Clear cell carcinoma presented as low-stage disease (FIGO I) in 33% of cases compared with endometrioid carcinomas in 97% of cases and mixed carcinomas in 27% of cases. Endometriosis was associated with 53% of clear cell carcinomas, 33% of endometrioid carcinomas, and 45% of mixed tumors (P<0.001). Synchronous primary tumors, observed in 31% of endometrioid tumors, 5% of mixed tumors, and in 2% of clear cell tumors (P<0.001), were unlikely to be associated with endometriosis (P=0.04). Univariate analysis of the aggregate cohort demonstrated that the single best overall predictor of disease-free survival was FIGO stage at presentation (P<0.001), followed by histologic subtype (P=0.003). Endometriosis did not have a significant relationship with disease-free survival (P=0.7). We conclude that the link between endometriosis and ovarian cancer is much stronger for clear cell carcinoma than for other histologic subtypes (P<0.001). Furthermore, when uniform histologic criteria are applied, true mixed endometrioid and clear cell carcinomas are uncommon; most endometriosis-associated mixed tumors are heterogenous mixtures of endometrioid, mucinous, and serous histology with areas of clear cell cytoplasm. Endometriosis per se does not appear to predict prognosis in clear cell and endometrioid tumors, with the possible exception of tumors with mixed histology. Until more data are collected, pathologists should classify ovarian tumors with mixed histology as a separate and potentially unique biological and prognostic group.

  View details for DOI 10.1097/PAS.0b013e31824b6eed

  View details for Web of Science ID 000302814000005

  View details for PubMedID 22498820

• The impact of chemotherapy and fertility-sparing surgery on recurrence of serous borderline ovarian tumors: A multi-institutional study of 491 patients Brooks, R., Ghezelayagh, T., Kiet, T., Fuh, K., Ueda, S., Longacre, T., Teng, N., Chen, L., Chan, J. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2012: S5-S5

  View details for DOI 10.1016/j.ygyno.2011.12.007

  View details for Web of Science ID 000303227600008

• Myometrial Xanthomatosis: Possible Relationship to Prior Pregnancy Procedure INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY DiMaio, M. A., Longacre, T. A. 2012; 31 (2): 174-179

  View details for DOI 10.1097/PGP.0b013e3182243581

  View details for Web of Science ID 000300457300012

• Myometrial xanthomatosis: possible relationship to prior pregnancy procedure. International journal of gynecological pathology DiMaio, M. A., Longacre, T. A. 2012; 31 (2): 166-171

  Abstract

  We report 3 unique cases of extensive myometrial infiltration by foamy histiocytes in uteri removed for benign conditions. The histologic findings were similar and consisted of diffuse infiltration of myometrium by clusters, cords, and sheets of CD163-positive histiocytes with no other significant inflammatory cell component. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm, but in 1 case eosinophilic granular cytoplasm was also present. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. All cases involved young, parous women who had remote prior surgical interventions involving the uterus; 2 patients had a prior cesarean section and 1 had a prior therapeutic abortion. There was no associated neoplastic or infectious condition in any of the cases, and no patient had a prior history of pelvic inflammatory disease. Although we were unable to obtain more detailed obstetric history, an exuberant and persistent reaction to the surgical procedure and/or to a carrier substance for uterotonic intramyometrial injection may be the basis for this unusual reaction, which we designate as myometrial xanthomatosis.

  View details for DOI 10.1097/PGP.0b013e3182243581

  View details for PubMedID 22317875

• A Clinicopathological and Immunohistochemical Study of 54 Cases of Dysgerminoma and Gonadoblastoma Karnezis, A. N., Jalas, J. R., Li, Y., Lou, Y. C., Chen, L., Longacre, T. A., Zaloudek, C. J. NATURE PUBLISHING GROUP. 2012: 280A-280A

  View details for Web of Science ID 000299986901451

• Breast Cancer Prognosis in BRCA1 and BRCA2 Mutation Carriers: An International Prospective Breast Cancer Family Registry Population-Based Cohort Study JOURNAL OF CLINICAL ONCOLOGY Goodwin, P. J., Phillips, K., West, D. W., Ennis, M., Hopper, J. L., John, E. M., O'Malley, F. P., Milne, R. L., Andrulis, I. L., Friedlander, M. L., Southey, M. C., Apicella, C., Giles, G. G., Longacre, T. A. 2012; 30 (1): 19-26

  Abstract

  To compare breast cancer prognosis in BRCA1 and BRCA2 mutation carriers with that in patients with sporadic disease.An international population-based cohort study was conducted in Canada, the United States, and Australia of 3,220 women with incident breast cancer diagnosed between 1995 and 2000 and observed prospectively. Ninety-three had BRCA1 mutations; 71, BRCA2 mutations; one, both mutations; 1,550, sporadic breast cancer; and 1,505, familial breast cancer (without known BRCA1 or BRCA2 mutation). Distant recurrence and death were analyzed.Mean age at diagnosis was 45.3 years; mean follow-up was 7.9 years. Risks of distant recurrence and death did not differ significantly between BRCA1 mutation carriers and those with sporadic disease in univariable and multivariable analyses. Risk of distant recurrence was higher for BRCA2 mutation carriers compared with those with sporadic disease in univariable analysis (hazard ratio [HR], 1.63; 95% CI, 1.02 to 2.60; P = .04). Risk of death was also higher in BRCA2 carriers in univariable analysis (HR, 1.81; 95% CI, 1.15 to 2.86; P = .01). After adjustment for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, no differences were observed for distant recurrence (HR, 1.00; 95% CI, 0.62 to 1.61; P = 1.00) or death (HR, 1.12; 95% CI, 0.70 to 1.79; P = .64).Outcomes of BRCA1 mutation carriers were similar to those of patients with sporadic breast cancer. Worse outcomes in BRCA2 mutation carriers in univariable analysis seem to reflect the presence of more adverse tumor characteristics in these carriers. Similar outcomes were identified in BRCA2 carriers and those with sporadic disease in multivariable analyses.

  View details for DOI 10.1200/JCO.2010.33.0068

  View details for Web of Science ID 000302617900009

  View details for PubMedID 22147742

• Copy Number Aberrations in Benign Serous Ovarian Tumors: A Case for Reclassification? CLINICAL CANCER RESEARCH Hunter, S. M., Anglesio, M. S., Sharma, R., Gilks, C. B., Melnyk, N., Chiew, Y., deFazio, A., Longacre, T. A., Huntsman, D. G., Gorringe, K. L., Campbell, I. G. 2011; 17 (23): 7273-7282

  Abstract

  Serous ovarian carcinomas are the predominant epithelial ovarian cancer subtype and it has been widely believed that some or all of these may arise from precursors derived from the ovarian surface epithelium or fimbriae, although direct molecular evidence for this is limited. This study aimed to conduct copy number (CN) analysis using a series of benign and borderline serous ovarian tumors to identify underlying genomic changes that may be indicative of early events in tumorigenesis.High resolution CN analysis was conducted on DNA from the epithelial and fibroblast components of a cohort of benign (N = 39) and borderline (N = 24) serous tumors using the Affymetrix OncoScan assay and SNP6.0 arrays.CN aberrations were detected in the epithelium of only 2.9% (1 of 35) of serous cystadenomas and cystadenofibromas. In contrast, CN aberrations were detected in the epithelium of 67% (16 of 24) of the serous borderline tumors (SBT). Unexpectedly, CN aberrations were detected in the fibroblasts of 33% (13 of 39) of the benign serous tumors and in 15% (3 of 20) of the SBTs. Of the 16 cases with CN aberrations in the fibroblasts, 12 of these carried a gain of chromosome 12.Chromosome 12 trisomy has been previously identified in pure fibromas, supporting the concept that a significant proportion of benign serous tumors are in fact primary fibromas with an associated cystic mass. This is the first high resolution genomic analysis of benign serous ovarian tumors and has shown not only that the majority of benign serous tumors have no genetic evidence of epithelial neoplasia but that a significant proportion may be more accurately classified as primary fibromas.

  View details for DOI 10.1158/1078-0432.CCR-11-2080

  View details for Web of Science ID 000298133600010

  View details for PubMedID 21976534

• A Prospective Study of Total Gastrectomy for CDH1-Positive Hereditary Diffuse Gastric Cancer ANNALS OF SURGICAL ONCOLOGY Chen, Y., Kingham, K., Ford, J. M., Rosing, J., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Chun, N., Kurian, A., Norton, J. A. 2011; 18 (9): 2594-2598

  Abstract

  Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome. Up to 30% of families with HDGC have mutations in the E-cadherin gene, CDH1. The role of prophylactic versus therapeutic gastrectomy for HDGC was studied prospectively.Eighteen consecutive patients with CDH1 mutations and positive family history were studied prospectively, including 13 without and 5 with symptoms. Proportions were compared by Fisher's exact test, and survival by the Breslow modification of the Wilcoxon rank-sum test.Each patient underwent total gastrectomy (TG), and 17 (94%) were found to have signet ring cell adenocarcinoma. Twelve of 13 asymptomatic patients had T1, N0 cancer, and only 2/12 (16%) had it diagnosed preoperatively despite state-of-the-art screening methods. Each asymptomatic patient did well postoperatively, and no patient has recurred. For five symptomatic patients, each (100%) was found to have signet ring cell adenocarcinoma (P = 0.002 versus asymptomatic) by preoperative endoscopy; three (60%) had lymph node involvement and two (40%) had distant metastases at time of operation. Two-year survival was 100% for asymptomatic and 40% for symptomatic patients (P < 0.01).The data show that asymptomatic patients with family history of HDGC and CDH1 mutation have high probability of having signet ring cell adenocarcinoma of the stomach that is not able to be diagnosed on endoscopy; when symptoms arise, the diagnosis can be made by endoscopy, but they have metastases and decreased survival. Surveillance endoscopy is of limited value, and prophylactic gastrectomy (PG) is recommended for patients with family history of HDGC and CDH1 mutations.

  View details for DOI 10.1245/s10434-011-1648-9

  View details for Web of Science ID 000294346700027

  View details for PubMedID 21424370

• A two-antibody mismatch repair protein immunohistochemistry screening approach for colorectal carcinomas, skin sebaceous tumors, and gynecologic tract carcinomas MODERN PATHOLOGY Mojtahed, A., Schrijver, I., Ford, J. M., Longacre, T. A., Pai, R. K. 2011; 24 (7): 1004-1014

  Abstract

  Mismatch repair protein immunohistochemistry is a widely used method for detecting patients at risk for Lynch syndrome. Recent data suggest that a two-antibody panel approach using PMS2 and MSH6 is an effective screening protocol for colorectal carcinoma, but there are limited data concerning this approach for extraintestinal tumors. The purpose of this study was to review the utility of a two-antibody panel approach in colorectal carcinoma and extraintestinal tumors. We evaluated mismatch repair protein expression in two cohorts: (1) a retrospective analysis of intestinal and extraintestinal tumors (n=334) tested for mismatch repair protein immunohistochemistry and (2) a prospectively accrued series of intestinal, gynecologic tract, and skin sebaceous neoplasms (n=98). A total of 432 cases were analyzed, including 323 colorectal, 50 gynecologic tract, 49 skin sebaceous, and 10 other neoplasms. Overall, 102/432 tumors (24%) demonstrated loss of at least one mismatch repair protein. Concurrent loss of MLH1 and PMS2 was the most common pattern of abnormal expression (50/432, 12%) followed by concurrent loss of MSH2 and MSH6 (33/432, 8%). Of 55 cases with abnormal PMS2 expression, 5 (9%) demonstrated isolated loss of PMS2 expression. Of 47 cases with abnormal MSH6 expression, 14 (30%) demonstrated isolated loss of MSH6 expression. Isolated loss of MLH1 or MSH2 was not observed. Colorectal carcinomas more frequently demonstrated abnormal expression of PMS2 (39/59, 66%). Skin sebaceous neoplasms more frequently demonstrated abnormal expression of MSH6 (18/24, 75%, respectively). A total of 65 tumors with abnormal mismatch repair protein expression were tested for microsatellite instability (MSI): 47 (72%) MSI high, 9 (14%) MSI low, and 9 (14%) microsatellite stable (MSS). Abnormal MSH6 expression accounted for 14/18 (78%) cases that were MSS or MSI low. Our findings confirm the utility of a two-antibody approach using PMS2 and MSH6 in colorectal carcinoma and indicate that this approach is effective in extraintestinal neoplasms associated with Lynch syndrome.

  View details for DOI 10.1038/modpathol.2011.55

  View details for Web of Science ID 000292319700014

  View details for PubMedID 21499234

• Low-grade Mucinous Adenocarcinoma of the Uterine Corpus: A Rare and Deceptively Bland Form of Endometrial Carcinoma AMERICAN JOURNAL OF SURGICAL PATHOLOGY Fujiwara, M., Longacre, T. A. 2011; 35 (4): 537-544

  Abstract

  Uterine corpus mucinous epithelial proliferations present diagnostic challenges due to histologic similarities to cervical lesions. We present a rare but distinctive endocervical-like mucinous carcinoma of the uterine corpus resembling adenoma malignum of the cervix that can be mistaken for a benign endometrial process. The clinical-pathologic features of 16 endometrial carcinomas exhibiting a pure endocervical-like mucinous proliferation were evaluated. Hysterectomy and available prehysterectomy specimens were assessed for architectural complexity, nuclear pleomorphism, macronucleoli, nuclear pseudostratification, mitotic index, necrosis, prominent neutrophils, and voluminous extracellular mucin (mucin encompassing >50% of a ×40 field). Cases involving the cervix or lower uterine segment were confirmed as endometrial in origin based on immunohistochemical stains (estrogen receptor, progesterone receptor, p16, and vimentin). Patient age ranged from 45 to 70 years; 6 of 16 (38%) were premenopausal, 11 of 16 (69%) had abnormal bleeding, and 7 of 16 (44%) had a history of hormonal therapy. Prehysterectomy diagnoses were benign in 2 of 16 (13%) cases, borderline in 9 of 16 (56%) cases, and carcinoma in 5 of 16 (31%) cases, whereas 8 of 16 (50%) hysterectomy specimens showed myoinvasive adenocarcinoma. With the exception of 2 cases, architectural complexity was low-to-moderate and no specimens showed marked nuclear pleomorphism. Macronucleoli and abundant mitotic activity were absent. Nuclear pseudostratification was present in 7 of 16 (44%) cases, necrosis in 1 of 16 (6%) cases, prominent neutrophils in 7 of 16 (44%) cases, and voluminous extracellular mucin in 9 of 16 (56%) cases. Cytologically bland mucinous epithelial proliferations should be diagnosed with caution in endometrial samplings. The presence of an endocervical-like mucinous epithelial process in association with voluminous extracellular mucin should prompt consideration for a low-grade mucinous adenocarcinoma of the uterine corpus.

  View details for DOI 10.1097/PAS.0b013e31820f1cc2

  View details for Web of Science ID 000288491600009

  View details for PubMedID 21378544

• Endocervical Fibroblastic Malignant Peripheral Nerve Sheath Tumor (Neurofibrosarcoma): Report of a Novel Entity Possibly Related to Endocervical CD34 Fibrocytes AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Karamchandani, J. R., Vogel, H., Longacre, T. A. 2011; 35 (3): 404-412

  Abstract

  Primary cervical stromal sarcomas are rare neoplasms that have been poorly characterized. We report the clinical, histologic, and immunohistologic features of 3 primary endocervical S100 protein (S100p)-positive and CD34-positive sarcomas, herein designated as fibroblastic malignant peripheral nerve sheath sarcoma (endocervical neurofibrosarcoma), 2 of which occurred in women younger than 35 years of age. All tumors presented as a cervical polyp or mass lesion; 1 extended into the pelvic side wall and vaginal soft tissue. The tumors measured 2.0 to 8.0 cm, and were composed of compact fascicles of spindled cells arranged in herringbone, loose fascicular, or ill-defined storiform patterns. A focal whorled architecture was identified in all 3 tumors, but distinct Antoni A areas and Verocay bodies were absent. Ultrastructural examination in 1 case confirmed the presence of fibrocyte-like differentiation. Strong, diffuse, and in 1 case, patchy S100p expression was seen in all cases; strong and diffuse CD34 expression was also present in all tumors. Adjacent uninvolved endocervical stroma also showed CD34 positivity but expression was much less dramatic than in tumor cells. All other markers of neural, melanocytic, smooth muscle, endometrial stromal, and epithelial differentiation were negative. One of the tumors behaved extremely aggressively with extensive pelvic involvement, resulting in patient death within 16 months of diagnosis; another tumor was associated with pelvic recurrence 13 months after diagnosis; and the third tumor had an indolent course with no evidence of recurrence at 33 months after complete excision and local radiotherapy, although follow-up was limited. Review of large numbers of mesenchymal tumors in the uterus did not show similar tumors. Endocervical neurofibrosarcoma should be distinguished from solitary fibrous tumor, endometrial stromal sarcoma, leiomyosarcoma, melanoma, and other spindle cell neoplasms. The prominent fibroblastic endoneurial-like differentiation seen in this peripheral nerve sheath tumor may be related to the presence of a rich mucosal stromal fibrocyte network in the endocervix.

  View details for DOI 10.1097/PAS.0b013e318208f72e

  View details for Web of Science ID 000287441200011

  View details for PubMedID 21317712

• Atypical Endometrial Hyperplasia and Well Differentiated Endometrioid Adenocarcinoma of the Uterine Corpus. Surgical pathology clinics Mills, A. M., Longacre, T. A. 2011; 4 (1): 149-198

  Abstract

  The distinction between atypical endometrial hyperplasia and well differentiated adenocarcinoma of the endometrium is one of the more difficult differential diagnoses in gynecologic pathology. Different pathologists apply different histologic criteria, often with different individual thresholds for atypical endometrial hyperplasia and grade 1 adenocarcinoma. While some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), almost all current diagnostic criteria use a series of histologic features - usually a combination of architecture and cytology - for diagnosing atypical hyperplasia and adenocarcinoma. This article presents evidence-based histologic criteria for atypical endometrial hyperplasia and low grade endometrial carcinoma (both FIGO grade 1 and 2) with emphasis on common and not so common histologic mimics. Grade 3 endometrioid carcinoma is discussed in the Oliva and Soslow article in this publication.

  View details for DOI 10.1016/j.path.2010.12.007

  View details for PubMedID 26837292

• Hepatic Epithelioid Hemangioendothelioma DIGESTIVE DISEASES AND SCIENCES Liu, Y. I., Brown, S. S., Elihu, A., Bonham, C. A., Concepcion, W., Longacre, T. A., Kamaya, A. 2011; 56 (2): 303-306

  View details for DOI 10.1007/s10620-010-1470-4

  View details for Web of Science ID 000286664900006

  View details for PubMedID 21053076

• PAX8 and WT1 Are Superior to PAX2 and BRST2 in Distinguishing Mullerian Tract Tumors from Breast Carcinomas DiMaio, M. A., Beck, A. H., Montgomery, K. D., West, R. B., Longacre, T. A., Kong, C. S. NATURE PUBLISHING GROUP. 2011: 243A-243A

  View details for Web of Science ID 000287282301183

• PAX8 and WT1 Are Superior to PAX2 and BRST2 in Distinguishing Mullerian Tract Tumors from Breast Carcinomas. DiMaio, M. A., Beck, A. H., Montgomery, K. D., West, R. B., Longacre, T. A., Kong, C. S. NATURE PUBLISHING GROUP. 2011: 243A-243A

  View details for Web of Science ID 000291285000468

• Capsule Endoscopy in the Diagnosis of Suspected Small Bowel Involvement with Crohn's Disease DIGESTIVE DISEASES AND SCIENCES Sharaf, R. N., Levesque, B. G., Shah, S., Longacre, T., Pasricha, P. J. 2011; 56 (1): 46-48

  View details for DOI 10.1007/s10620-010-1355-6

  View details for Web of Science ID 000286005900007

  View details for PubMedID 20668937

• Endometrial hyperplasia SEMINARS IN DIAGNOSTIC PATHOLOGY Mills, A. M., Longacre, T. A. 2010; 27 (4): 199-214

  Abstract

  Endometrial hyperplasia is a heterogeneous set of pathologic lesions that range from mild, reversible glandular proliferations to direct cancer precursors. These lesions comprise a continuum of morphologic appearances, with the earliest proliferation represented by crowded glands with simple tubular architecture lined by cells resembling proliferative endometrium, whereas advanced proliferations in this continuum are characterized by crowded glands with complex architecture, often containing cells with nuclear atypia resembling low-grade endometrioid adenocarcinoma. The former "early" proliferations may be isolated to an endometrial polyp, but advanced proliferations are generally more diffusely present throughout the endometrium. There are at least three major classification systems for endometrial carcinoma precursor lesions, each of which trend toward overlap at the complex end of the spectrum. Although some classifications are based on a series of molecular genetic alterations (which may or may not translate into biologically or clinically relevant risk lesions), each classification scheme ultimately uses a series of histologic features, usually a combination of architecture and cytology, to establish a diagnosis of hyperplasia. Because different pathologists may apply different histologic criteria for endometrial hyperplasia depending on the classification system used, this article will provide an overview of the classifications used in current daily practice, present the histologic criteria and relative merits of each classification system, and discuss common and not so common causes of misclassification.

  View details for DOI 10.1053/j.semdp.2010.09.002

  View details for Web of Science ID 000285798000002

  View details for PubMedID 21309256

• AXL Is an Essential Factor and Therapeutic Target for Metastatic Ovarian Cancer CANCER RESEARCH Rankin, E. B., Fuh, K. C., Taylor, T. E., Krieg, A. J., Musser, M., Yuan, J., Wei, K., Kuo, C. J., Longacre, T. A., Giaccia, A. J. 2010; 70 (19): 7570-7579

  Abstract

  The receptor tyrosine kinase AXL is thought to play a role in metastasis; however, the therapeutic efficacy of an AXL-targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced-stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and matrix metalloproteinase activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines the soluble AXL receptor as a therapeutic candidate agent for treatment of metastatic ovarian cancer, for which current therapies are ineffective.

  View details for DOI 10.1158/0008-5472.CAN-10-1267

  View details for Web of Science ID 000282647700021

  View details for PubMedID 20858715

• A Panel of 3 Markers Including p16, ProExC, or HPV ISH is Optimal for Distinguishing Between Primary Endometrial and Endocervical Adenocarcinomas AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kong, C. S., Beck, A. H., Longacre, T. A. 2010; 34 (7): 915-926

  Abstract

  Endometrial and endocervical adenocarcinomas may seem histologically identical and it can be difficult to determine primary site of origin based on morphology alone. As the distinction is significant and cannot always be made on the basis of clinical findings, various immunohistochemical panels have been proposed to aid in determining site of origin. Stains for vimentin, estrogen receptor (ER), progesterone receptor (PR), monoclonal carcinoembryonic antigen, p16 and ProExC, and HPV in situ hybridization (ISH), were performed on 283 tissue microarray (TMA) cores and 38 whole sections. The TMA consisted of 214 endometrial carcinomas, 33 endocervical adenocarcinomas, and 36 problematic cases. The endometrial and endocervical carcinomas represented usual endometrioid and mucinous types, and special variants (uterine serous carcinoma, uterine clear cell carcinoma, minimal deviation endocervical adenocarcinoma, cervical small cell carcinoma, adenoid basal cell carcinoma, mesonephric carcinoma). Univariate analysis showed that 6 markers (vimentin, ER, PR, p16, ProExC, and HPV ISH) performed well in distinguishing between endocervical and endometrial origin for the usual endometrioid and mucinous types. Multivariate analysis showed that vimentin, p16, and HPV ISH are the strongest predictors of site. Using a script written in R, the diagnostic accuracy of all possible combinations of markers was evaluated and it was shown that a 3 marker panel including vimentin, ER, or PR, and an HPV marker (p16, ProExC, or HPV ISH) is optimal for determining site of origin for usual endometrial and endocervical adenocarcinomas. However, these panels do not perform well with special variant carcinomas.

  View details for DOI 10.1097/PAS.0b013e3181e3291e

  View details for Web of Science ID 000279167400001

  View details for PubMedID 20534993

• Cell Cycle Regulatory Markers in Uterine Atypical Leiomyoma, Cellular Leiomyoma, STUMP and Leiomyosarcoma: Immunohistochemical Study of 74 Cases with Clinical Follow-Up Mills, A. M., Ly, A., Balzer, B. L., Hendrickson, M. R., Kempson, R. L., McKenney, J. K., Longacre, T. A. NATURE PUBLISHING GROUP. 2010: 255A-256A

  View details for Web of Science ID 000274337301158

• Ovarian Carcinosarcomas Associated With Prolonged Use of Tamoxifen Case Reports INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Lavie, O., Longacre, T., Segev, Y., Husain, A. 2009; 19 (9): 1521-1523

  Abstract

  Recent studies have indicated that the risk associated with tamoxifen may be substantially higher for uterine malignant mixed müllerian tumors and uterine sarcomas.We present 2 cases of ovarian carcinosarcomas in patients with a personal history of breast carcinoma who were treated for a prolonged period with tamoxifen.To our knowledge, these 2 cases are the first to describe the possible association between ovarian carcinosarcomas and previous personal and familial history of breast carcinoma and\or prolonged use of tamoxifen. These cases may suggest that like in the uterus, tamoxifen has a possible delayed effect, which might be responsible for the formation of aggressive tumors of unclear pathogenesis in the ovaries.

  View details for DOI 10.1111/IGC.0b013e3181a83fbf

  View details for Web of Science ID 000272898400010

  View details for PubMedID 19955929

• Smooth Muscle Tumors of the Female Genital Tract. Surgical pathology clinics Mills, A. M., Longacre, T. A. 2009; 2 (4): 625-677

  Abstract

  Smooth muscle tumors are the most common among mesenchymal tumors in the female genital tract. The vast majority of these neoplasms are clinically benign and easy to diagnose. In contrast, leiomyosarcomas are highly aggressive tumors that may pose considerable diagnostic problems when they display unusual (myxoid or epithelioid) morphology, ambiguous histologic features for malignancy, or an unusual anatomic distribution. Diagnostic criteria for these problematic tumors vary depending on the site and type of histologic differentiation, and are based on a combination of 3 major criteria: (1) moderate to severe cytologic atypia; (2) increased mitotic index; and (3) tumor cell necrosis. Certain benign smooth muscle proliferations may show worrisome histologic features or unusual growth patterns, causing concern for leiomyosarcoma. Furthermore, other tumors, including perivascular epithelioid tumors, may mimic leiomyosarcoma. Careful attention to the clinical and anatomic setting, cytologic and architectural features, and immunohistochemical characteristics are helpful in distinguishing these entities. This article discusses conventional smooth muscle tumors as well as unusual subtypes, with emphasis on the diagnostic criteria and problems in differential diagnosis that arise at each site within the female genital tract.

  View details for DOI 10.1016/j.path.2009.08.019

  View details for PubMedID 26838774

• Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility HUMAN MOLECULAR GENETICS Nicholas, C. R., Haston, K. M., Grewall, A. K., Longacre, T. A., Pera, R. A. 2009; 18 (22): 4376-4389

  Abstract

  Ten to 15% of couples are infertile, with the most common causes being linked to the production of few or no oocytes or sperm. Yet, our understanding of human germ cell development is poor, at least in part due to the inaccessibility of early stages to genetic and developmental studies. Embryonic stem cells (ESCs) provide an in vitro system to study oocyte development and potentially treat female infertility. However, most studies of ESC differentiation to oocytes have not documented fundamental properties of endogenous development, making it difficult to determine the physiologic relevance of differentiated germ cells. Here, we sought to establish fundamental parameters of oocyte development during ESC differentiation to explore suitability for basic developmental genetic applications using the mouse as a model prior to translating to the human system. We demonstrate a timeline of definitive germ cell differentiation from ESCs in vitro that initially parallels endogenous oocyte development in vivo by single-cell expression profiling and analysis of functional milestones including responsiveness to defined maturation media, shared genetic requirement of Dazl, and entry into meiosis. However, ESC-derived oocyte maturation ultimately fails in vitro. To overcome this obstacle, we transplant ESC-derived oocytes into an ovarian niche to direct their functional maturation and, thereby, present rigorous evidence of oocyte physiologic relevance and a potential therapeutic strategy for infertility.

  View details for DOI 10.1093/hmg/ddp393

  View details for Web of Science ID 000271107300014

  View details for PubMedID 19696121

• Diversion Colitis in a 19-Year-Old Female with Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome DIGESTIVE DISEASES AND SCIENCES Talisetti, A., Longacre, T., Pai, R. K., Kerner, J. 2009; 54 (11): 2338-2340

  View details for DOI 10.1007/s10620-009-0882-5

  View details for Web of Science ID 000270836900007

  View details for PubMedID 19582576

• Appendiceal Mucinous Neoplasms Clinicopathologic Study of 116 Cases With Analysis of Factors Predicting Recurrence AMERICAN JOURNAL OF SURGICAL PATHOLOGY Pai, R. K., Beck, A. H., Norton, J. A., Longacre, T. A. 2009; 33 (10): 1425-1439

  Abstract

  The classification and nomenclature of appendiceal mucinous neoplasms are controversial. To determine the outcome for patients with appendiceal mucinous neoplasms and further evaluate whether they can be stratified into groups that provide prognostic information, the clinicopathologic features of 116 patients (66 with clinical follow-up) with appendiceal mucinous neoplasms were studied. From a wide variety of histopathologic features assessed, the important predictors that emerged on univariate statistical analysis were presence of extra-appendiceal neoplastic epithelium (P=0.01), high-grade cytology (P<0.0001), architectural complexity (P<0.001), and invasion (P<0.001). Stratification using a combination of these predictors resulted in a 4-tiered classification scheme. All 16 patients with mucinous neoplasms confined to the appendix and lacking high-grade cytology, architectural complexity, and invasion were alive with no recurrences at median 59 months follow-up (=mucinous adenoma). One of 14 patients with low-grade cytology and acellular peritoneal mucin deposits developed recurrent tumor within the peritoneum at 45 months with no patient deaths to date (median, 48-mo follow-up) (=low-grade mucinous neoplasm with low risk of recurrence). None of the 2 patients with acellular peritoneal mucinous deposits outside of the right lower quadrant developed recurrence at 163 and 206 months. Twenty-seven patients with low-grade mucinous neoplasms with extra-appendiceal neoplastic epithelium had 1-year, 3-year, 5-year, and 10-year overall survival rates of 96%, 91%, 79%, and 46%, respectively, at median 53 months follow-up (=low-grade mucinous neoplasm with high risk of recurrence). Three of the 4 patients with extra-appendiceal epithelium limited to the right lower quadrant developed full-blown peritoneal disease at 6, 41, and 99 months follow-up and 1 patient eventually died of disease. Nine patients with appendiceal neoplasms with invasion or high-grade cytology and follow-up showed 1-year, 3-year, and 5-year overall survival rates of 86%, 57%, and 28% (=mucinous adenocarcinoma). At 10 years, all patients with mucinous adenocarcinoma were either dead or lost to follow-up. Appendiceal mucinous neoplasms can be stratified into 4 distinct risk groups on the basis of a careful histopathologic assessment of cytoarchitectural features and extent of disease at presentation.

  View details for Web of Science ID 000270399700001

  View details for PubMedID 19641451

• Primary squamous cell carcinoma of the stomach with paraneoplastic leukocytosis: a case report and review of literature HUMAN PATHOLOGY Callacondo-Riva, D., Ganoza-Salas, A., Anicama-Lima, W., Quispe-Mauricio, A., Longacre, T. A. 2009; 40 (10): 1494-1498

  Abstract

  Apparently pure, primary squamous cell carcinoma of the stomach is exceedingly rare. To date, less than 100 cases have been reported. Here, we describe a case of primary squamous cell carcinoma arising in the gastric antrum of an 83-year-old man with persistent leukocytosis, which resolved on resection of the tumor. No foci of squamous metaplasia or gland-forming elements were identified in the resection specimen, although there was marked chronic gastritis with intestinal metaplasia. There was no evidence of Helicobacter, fungal, or parasitic infection. Immunohistochemical and in situ hybridization studies for human papillomavirus and Epstein-Barr virus were negative. This case suggests that gastric squamous cell carcinoma likely arises in the setting of long-standing, chronic inflammation, and like squamous cell carcinoma in other organ systems, may be associated with paraneoplastic leukocytosis.

  View details for DOI 10.1016/j.humpath.2009.02.014

  View details for Web of Science ID 000270166200018

  View details for PubMedID 19467693

• Adenomatoid tumors of the female and male genital tracts: a clinicopathological and immunohistochemical study of 44 cases MODERN PATHOLOGY Sangoi, A. R., McKenney, J. K., Schwartz, E. J., Rouse, R. V., Longacre, T. A. 2009; 22 (9): 1228-1235

  Abstract

  Adenomatoid tumors of the female and male genital tracts are well characterized as mesothelial in origin, but a detailed histological and immunohistochemical analysis comparing both traditional and newer mesothelial markers across gender and site has not been formally conducted. A variety of morphologic features previously described as characteristic of adenomatoid tumors were evaluated in 44 adenomatoid tumors from the male and female genital tracts. Immunohistochemical analysis with pankeratin (AE1/CAM5.2), WT-1, calretinin, CK5/6, D2-40, and caldesmon was also performed. The extent and intensity of staining were scored semiquantitatively on one representative section per case and mean value for each parameter was calculated. All (n=44) the adenomatoid tumors from both the female and male genital tracts demonstrated a distinctive thread-like bridging strand pattern. Lymphoid aggregates were seen in all 12 adenomatoid tumors of male patients, but in only 4 of 32 (13%) tumors in female patients (P<0.0001). The remaining morphologic features were variably present with no clear sex predilection. Pankeratin, calretinin, and D2-40 reactivity were identified in all female (n=32) and male (n=12) genital tract adenomatoid tumors. Adenomatoid tumors expressed WT-1 in 11/12 (92%) male patients and in 31/32 (97%) female patients. In male patients, reactivity for CK5/6 and caldesmon was found in 1/12 (8%) and 0/12 (0%) adenomatoid tumors (respectively), whereas reactivity in female patients was found in 5/32 (16%) and 1/32 (3%); respectively. Female tumors differ from their male counterparts by the frequent absence of lymphoid aggregates and the presence of a circumscribed margin when occurring in the fallopian tube. Of the putative mesothelial markers evaluated, calretinin, D2-40, and WT-1 show a similar immunoprofile and have a higher sensitivity than CK5/6 and caldesmon in genital tract adenomatoid tumors. However, the presence of additional, often strong expression of WT-1 in normal tissues of the female genital tract limits the utility of WT-1 in this setting.

  View details for DOI 10.1038/modpathol.2009.90

  View details for Web of Science ID 000269448700012

  View details for PubMedID 19543245

• Massive Extra-adrenal Retroperitoneal Paraganglioma: Pre-operative Embolization and Resection DIGESTIVE DISEASES AND SCIENCES Rosing, J. H., Jeffrey, R. B., Longacre, T. A., Greco, R. S. 2009; 54 (8): 1621-1624

  View details for DOI 10.1007/s10620-009-0804-6

  View details for Web of Science ID 000267485400002

  View details for PubMedID 19408117

• Utility of Microtubule Associated Protein-2 (MAP-2) Immunohistochemistry for Identification of Ganglion Cells in Paraffin-Embedded Rectal Suction Biopsies AMERICAN JOURNAL OF SURGICAL PATHOLOGY Burtelow, M. A., Longacre, T. A. 2009; 33 (7): 1025-1030

  Abstract

  Identification of rare ganglion cells in rectal suction biopsies can be difficult for surgical pathologists who only occasionally encounter rectal suction biopsies for the diagnosis of Hirschsprung disease. We evaluated the utility of a monoclonal antibody directed against microtubule associated protein-2 (MAP-2), a marker of neuronal differentiation, to detect ganglion cells in formalin-fixed, paraffin-embedded tissue sections. The presence of ganglion cells was evaluated retrospectively by immunohistochemical staining for MAP-2 in 78 biopsies from 56 patients with ganglion cells present on hematoxylin and eosin (H&E) stain and 91 biopsies from 46 patients with no ganglion cells present on H&E stain. A total of 78 biopsies from 49 patients diagnosed as equivocal or suboptimal for ganglion cells on H&E stain were also examined. MAP-2 antibody clearly highlighted ganglion cell bodies in all 78 biopsies with ganglion cells present on H&E stain, including immature forms, and was negative in 88 biopsies with no ganglion cells present on H&E stain. In 3 biopsies from 2 patients with no ganglion cells present on H&E stain, MAP-2 antibody highlighted rare ganglion cells and in each case, the patient was confirmed not to have Hirschsprung disease on follow-up biopsy. MAP-2 immunoreactive cells were also identified in 14 biopsies from 12 patients diagnosed as equivocal for identification of ganglion cells on H&E stain. Three of these patients were found not to have Hirschsprung disease on repeat rectal suction biopsy and 6 additional patients in this group showed no evidence of Hirschsprung disease by clinical follow-up. This study indicates that MAP-2 antibody is a sensitive and specific immunohistochemical marker that can confirm ganglion cells in paraffin-embedded rectal suction biopsies and may eliminate the need for repeat biopsy in select cases.

  View details for Web of Science ID 000268043400007

  View details for PubMedID 19363440

• Abdominal Pain, Gastrointestinal Bleeding, and Weight Loss in a 17-Year-Old Male DIGESTIVE DISEASES AND SCIENCES Fuentebella, J., Bass, D., Longacre, T., Ro, K. 2009; 54 (4): 722-724

  View details for DOI 10.1007/s10620-008-0644-9

  View details for Web of Science ID 000263832600004

  View details for PubMedID 19082713

• Expression of the Urothelial Differentiation Markers GATA3 and Placental S100 (S100P) in Female Genital Tract Transitional Cell Proliferations AMERICAN JOURNAL OF SURGICAL PATHOLOGY Esheha, G. E., Longacre, T. A., Atkins, K. A., Higgins, J. P. 2009; 33 (3): 347-353

  Abstract

  The degree of urothelial differentiation in putative transitional (urothelial) proliferations in the female genital tract is still controversial. To further investigate the similarities (or dissimilarities) between female genital tract transitional proliferations and bladder urothelium, we evaluated the expression of S100P and GATA3, 2 proteins that we previously found to be strongly expressed in bladder urothelial tumors, in 25 benign ovarian Brenner tumors, 19 Walthard cell nests (17 tubal and 2 ovarian hilus), 1 mature teratoma with a benign urothelial proliferation, 2 proliferating (borderline) ovarian Brenner tumors, 1 malignant Brenner tumor, and 12 ovarian transitional cell carcinomas (TCC). Each lesion was also evaluated for p63 expression by immunohistochemistry. Immunostaining was performed on formalin-fixed, paraffin-embedded tissue sections using the avidin-biotin-peroxidase complex method. Eighty-eight percent of Brenner tumors were positive for S100P, whereas 96% and 100% were positive for GATA3 and p63, respectively. One of 2 proliferating Brenner tumors was positive for S100P, whereas both cases were positive for GATA3 and p63; the malignant Brenner tumor was positive for S100P and p63, but negative for GATA3. Only 17% of TCC were positive for S100p, whereas 33% and 50% of TCC were positive for GATA3 and p63, respectively. Tubal Walthard cell nests were either completely negative or showed only scattered positive staining for S100P; in contrast, 89.5% and 100% of Walthard nests, including the 2 ovarian cases were positive for GATA3 and p63. The teratoma-associated benign urothelial proliferation was also negative for S100P, but positive for GATA3 and p63. Although proliferating and malignant Brenner tumors may exhibit a more intermediate immunoprofile, expression of S100P, GATA3, and p63 by a majority of ovarian Brenner tumors underscores the similarity between these neoplasms and urothelial proliferations of bladder origin. The indeterminate phenotype seen in Walthard nests and ovarian TCC suggests that these proliferations may represent an incomplete or alternate form of differentiation.

  View details for Web of Science ID 000263765800003

  View details for PubMedID 19092634

• Prognosis in BRCA1, BRCA2 associated breast cancer (BC): a prospective Breast Cancer Family Registry (BCFR) international population-based cohort study Goodwin, P., Phillips, K., West, D., Ennis, M., Hopper, J., John, E., O'Malley, F., Milne, R., Andrulis, I., Friedlander, M., Longacre, T. AMER ASSOC CANCER RESEARCH. 2009: 178S-178S

  View details for Web of Science ID 000262583200363

• Atypical Leiomyomas of the Uterus: A Clinicopathologic Study of 46 Cases Ly, A., McKenney, J. K., Longacre, T. A., Kempson, R. L., Hendrickson, M. R. NATURE PUBLISHING GROUP. 2009: 225A-225A

  View details for Web of Science ID 000262371501029

• Adenomatoid Tumors of the Female and Male Genital Tracts: A Morphological and Immunohistochemical Study of 34 Cases Sangoi, A. R., Schwartz, E. J., McKenney, J. K., Rouse, R. V., Longacre, T. A. NATURE PUBLISHING GROUP. 2009: 235A-236A

  View details for Web of Science ID 000262371501075

• Diagnostic problems in anal pathology ADVANCES IN ANATOMIC PATHOLOGY Longacre, T. A., Kong, C. S., Welton, M. L. 2008; 15 (5): 263-278

  Abstract

  Anal squamous cell carcinoma and its precursor lesions are increasing in incidence in the United States and Europe. This trend predates human immunodeficiency virus/acquired immune deficiency syndrome and has been associated with persistent high-risk human papilloma virus (HPV) genotype infection, previous lower genital tract dysplasia/carcinoma, high frequency anoreceptive intercourse, heavy cigarette smoking, immunosuppression in solid organ transplant and immune disorders, and human immunodeficiency virus seropositivity. Screening protocols for at-risk patients are under active investigation and pathologists are often asked to assess anal canal and perianal biopsies for the presence of dysplasia and/or invasive carcinoma. Because underdiagnosis and overdiagnosis of anal cancer and precancer may lead to inappropriate treatment, it is important for the pathologist to be aware of current screening strategies, specific risk lesions, and the role of pathology in initial diagnosis and evaluation of anal biopsy and/or resection specimens. Standardized histologic criteria and uniform terminology should be used for reporting all anal canal and perianal squamous intraepithelial lesions. HPV subtyping, anal cytology, and recently identified biomarkers, such as p16 and Becton Dickinson ProEx C may provide additional information in problematic cases, but it is important to be aware of the limitations of these assays. HPV has been linked to all the major histologic subtypes of anal carcinoma (eg, basaloid, cloacogenic, transitional, etc.) and this association is strongest for anal canal lesions. With the possible exception of the microcystic pattern, histologic subtype does not seem to predict prognosis; and anal squamous cell carcinomas should be classified as either keratinizing or nonkeratinizing. Poorly differentiated squamous cell carcinomas have a worse prognosis and should be distinguished from poorly differentiated adenocarcinoma, melanoma, and neuroendocrine tumors. Very well differentiated squamous cell carcinoma with pushing margins (so-called giant condyloma of Buschke and Lowenstein) should be classified as verrucous carcinoma; this tumor shows aggressive local infiltration but does not metastasize. As all anal condylomata may harbor foci of high-grade dysplasia or invasive carcinoma, careful sectioning and complete histologic examination is required.

  View details for Web of Science ID 000259172900002

  View details for PubMedID 18724100

• PROGNOSIS IN HEREDITARY (BRCA1, BRCA2 ASSOCIATED) AND NON-FAMILIAL (NF) BREAST CANCER (BC): RESULTS OF A PROSPECTIVE BREAST CANCER FAMILY REGISTRY (BCFR) INTERNATIONAL POPULATION-BASED COHORT STUDY Goodwin, P., Phillips, K., West, D., Ennis, M., Hopper, J., John, E., O'Malley, F., Milne, R., Andrulis, I., Longacre, T. OXFORD UNIV PRESS. 2008: 78-78

  View details for Web of Science ID 000259973300184

• Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger AMERICAN JOURNAL OF SURGICAL PATHOLOGY Jensen, K. C., Mariappan, M. R., Putcha, G. V., Husain, A., Chun, N., Ford, J. M., Schrijver, I., Longacre, T. A. 2008; 32 (7): 1029-1037

  Abstract

  Ovarian malignancies occurring in the setting of hereditary nonpolyposis colorectal carcinoma syndrome typically present in young women, often as the first or "sentinel" cancer, but the frequency of microsatellite instability (MSI) and mismatch repair (MMR) defects in ovarian surface epithelial malignancies in women

  View details for Web of Science ID 000257298000010

  View details for PubMedID 18469706

• Mixed ovarian epithelial carcinomas with clear cell and serous components are variants of high-grade serous carcinoma - An interobserver correlative and immunohistochemical study of 32 cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Han, G., Gilks, C. B., Leung, S., Eivanowich, C. A., Irving, J. A., Longacre, T. A., Soslow, R. A. 2008; 32 (7): 955-964

  Abstract

  There are conflicting data about chemoresistance and prognosis in ovarian clear cell carcinoma (CCC). This could be due to significant interobserver variation in the diagnosis of CCC and other ovarian surface epithelial tumors containing clear cells. Thirty-two cases previously diagnosed as CCC, high-grade ovarian serous carcinoma (SC), and mixed surface epithelial carcinoma (SEC) with clear cell and serous components were reviewed by 4 gynecologic pathologists blinded to the original diagnoses. Interobserver reproducibility was evaluated. Each case was also assessed using immunohistochemical markers Wilm tumor 1, estrogen receptor, and p53. The interobserver reproducibility was greatest for pure CCC (kappa of 0.82), and lowest for the mixed SEC (kappa of 0.32). Moderate agreement was seen in the pure SC category (kappa of 0.59). All pure SC and most mixed SEC presented as stage III or IV diseases. Most pure CCC presented as stage I or II diseases. Immunoreactivities of the mixed SECs were similar to those of pure SC, but significantly different from those of pure CCC for Wilm tumor 1 (P=0.0011 for both components), estrogen receptor (P=0.0003 for clear cell component, P=0.0001 for serous component), and p53 (P=0.0062 for both components). The serous and clear cell components of mixed SEC showed higher mitotic rates than pure CCC (P=0.004 and P=0.023, respectively), but the mitotic rate of pure SC was similar to the mixed SEC. We conclude that (1) pure CCC is reproducibly diagnosed. (2) The diagnosis of mixed ovarian SEC with clear cell component is not reproducible. (3) Mixed SEC with clear cell and serous components show similar stage, mitotic activities, and immunoreactivities to those of pure SC, and likely represent SC with clear cell changes.

  View details for Web of Science ID 000257298000001

  View details for PubMedID 18460981

• Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. American journal of surgical pathology Rogers, W. M., Dobo, E., Norton, J. A., Van Dam, J., Jeffrey, R. B., Huntsman, D. G., Kingham, K., Chun, N., Ford, J. M., Longacre, T. A. 2008; 32 (6): 799-809

  Abstract

  Hereditary diffuse gastric cancer is a rare autosomal dominant cancer susceptibility syndrome caused by germline E-cadherin (CDH1) mutations in 40% of cases with a high degree of penetrance. Screening endoscopy has not been useful in identifying early cancer, in part owing to conflicting data concerning site(s) of involvement in the stomach and the lack of endoscopically detectable pathology. Risk-reducing total gastrectomy specimens from 8 asymptomatic adults with germline mutations in the CDH1 gene (3 different pedigrees) were studied using a sequential serial sectioning protocol with submission of the entire stomach for histologic analysis. The presence, size, and distribution of signet ring cell clusters were determined for each section and geographic maps of the invasive foci were constructed and compared with gastrectomy specimens from patients with germline E-cadherin mutation and symptomatic gastric cancer. All but 1 of the asymptomatic patients with germline mutations in the CDH1 gene had negative endoscopic screening. All risk-reducing gastrectomy specimens were macroscopically normal. All contained multiple foci (mean, 10.9) of microscopic intramucosal signet ring cell carcinoma confined to the superficial gastric mucosa; no invasion of submucosa was identified. In situ carcinoma was present in 6/8 cases. The majority of signet ring foci were located in the proximal one third of the stomach, most within oxyntic-type mucosa. The number and size of foci were not related to age, but there was a trend toward more severe disease burden in women. Stomachs from the symptomatic group of patients with germline CDH1 mutations exhibited infiltrative foci with higher Ki-67 labeling that extended well beyond the superficial mucosa. In addition, while superficial signet ring cancer exhibited decreased or absent E-cadherin and beta-catenin protein expression in all cases studied, deeply invasive signet ring cancer showed reversion to E-cadherin and beta-catenin protein expression in a subset of mutation carriers. Our study indicates that superficial intramucosal signet ring carcinoma, although widespread, is predominantly located in the proximal one third of the stomach in patients with E-cadherin gene mutations. The observed site predilection suggests a possible role for geographically targeted endoscopic surveillance biopsy in patients who elect to delay surgical intervention.

  View details for DOI 10.1097/PAS.0b013e31815e7f1a

  View details for PubMedID 18391748

• Development of a minimal residual disease ovarian cancer model in immunocompetent mice Shin, J. Y., Baker, J., Beilhack, A., Longacre, T. A., Nishimura, R., Negrin, R. S., Chan, J. K. AMER SOC CLINICAL ONCOLOGY. 2008

  View details for Web of Science ID 000208457402080

• Ovarian mature teratomas with mucinous epithelial neoplasms: Morphologic heterogeneity and association with pseudomyxoma peritonei AMERICAN JOURNAL OF SURGICAL PATHOLOGY McKenne, J. K., Soslow, R. A., Longaere, T. A. 2008; 32 (5): 645-655

  Abstract

  Mucinous epithelial neoplasms arising in association with mature teratomas are a heterogeneous group of tumors, but with the exception of a single recent study, their full histologic spectrum, detailed immunophenotype, and association with classic pseudomyxoma peritonei (PMP) have not been fully studied. The morphologic, immunohistochemical, and clinical features of 42 patients with mucinous epithelial tumors arising in association with mature ovarian teratomas were evaluated. The patients' ages ranged from 17 to 66 years (mean, 39 y). Tumor size ranged from 5.5 to greater than 200 cm. Most teratoma-associated mucinous tumors were unilateral, although 1 patient harbored bilateral mucinous tumors in association with bilateral teratomas. In all cases, the teratomatous component consisted of mature elements. Using the 2003 World Health Organization criteria for ovarian intestinal type mucinous neoplasms, 17 (40%) were classified as mucinous cystadenoma, 16 (38%) as intestinal-type mucinous epithelial neoplasm of low malignant potential (IM-LMP), 4 (10%) as intraepithelial carcinoma (IEC), and 5 (12%) as invasive mucinous carcinoma. Mucinous cystadenomas had a varied epithelial lining consisting of lower gastroenteric, gastric foveolar, or müllerian appearance. In contrast, the IM-LMP, IEC, and invasive carcinoma cases had a more uniform lower gastroenteric histology. For mucinous cystadenomas, a cytokeratin (CK) 7+/CK20- phenotype (5/13; 38%) was equally as common as a CK7-/CK20+ phenotype (5/13; 38%), with the remaining cases coexpressing both keratins (CK7+/CK20+: 3/13; 23%). In contrast, IM-LMP, IEC, and invasive adenocarcinomas more frequently had a CK7-/CK20+ phenotype (56%, 50%, and 100%, respectively). A CK7+/CK20-phenotype was rare in these later 3 morphologic groups (6%). Of the 42 total cases, 55% had pseudomyxoma ovarii and 24% had classic PMP (1 cystadenoma, 6 IM-LMP, and 3 invasive carcinomas), whereas 5% had more localized accumulations of peritoneal mucin (both IM-LMP). Pathologic evaluation of the peritoneum in these 12 cases revealed 6 with acellular mucin alone, 3 with low-grade mucinous epithelium (all 3 with ovarian IM-LMP), and 3 with high-grade mucinous carcinomatosis (all 3 with ovarian mucinous adenocarcinoma). No appendiceal lesions were identified. Follow-up was available in 48% of patients (mean, 61 mo). The only adverse outcomes occurred in the 3 patients with ovarian carcinoma and associated peritoneal carcinomatosis. We report that a significant proportion of mucinous tumors associated with mature ovarian teratomas present with clinical PMP, which in most cases is associated with IM-LMP. PMP in this setting may harbor microscopic intra-abdominal low-grade mucinous epithelium that is histologically and immunophenotypically similar to that typically seen in appendiceal-related PMP. Pseudomyxoma ovarii is common in this setting, particularly in tumors with IM-LMP histology, but pseudomyxoma ovarii is not predictive of PMP. Ovarian teratoma-associated benign and IM-LMP mucinous neoplasms with microscopic peritoneal low-grade mucinous epithelium do not seem to be at significant risk for intra-abdominal recurrence, but numbers are few and follow-up is limited. In contrast, teratomas with an invasive carcinomatous component and microscopic peritoneal carcinomatosis follow an aggressive clinical course.

  View details for Web of Science ID 000255559800001

  View details for PubMedID 18344868

• Emi1 protein accumulation implicates misregulation of the anaphase promoting complex/cyclosome pathway in ovarian clear cell carcinoma MODERN PATHOLOGY Guetgemann, I., Lehman, N. L., Jackson, P. K., Longacre, T. A. 2008; 21 (4): 445-454

  Abstract

  Clear cell carcinoma is a clinically and pathologically distinct entity among surface epithelial ovarian neoplasms, recognized for its resistance to standard platinum-based chemotherapy at advanced stage disease and poor prognosis. Despite advances in our understanding of the biology of other surface epithelial ovarian neoplasms, very little is known about the molecular genetic mechanisms that are involved in clear cell tumorigenesis. Early mitotic inhibitor-1 (Emi1) protein is a key cell cycle regulator, that promotes S-phase and mitotic entry by inhibiting the anaphase promoting complex. In cell culture systems, overexpression of Emi1 leads to tetraploidy and genomic instability, especially in the absence of normal p53 function. We investigated Emi1 protein expression in ovarian neoplasms using a tissue microarray constructed from 339 primary ovarian surface epithelial (serous, endometrioid, clear cell, and mucinous) and peritoneal (serous) neoplasms, stromal and mesenchymal tumors, germ cell tumors, and normal ovarian tissue. Significant overexpression of Emi1 protein was present in 82% (27/33) clear cell carcinoma, including one borderline tumor in a diffuse, granular cytoplasmic and perinuclear staining pattern, independent of patient age, presence of ovarian and/or pelvic endometriosis, and FIGO stage. In contrast, only 10% (17/177) primary ovarian and primary peritoneal serous carcinomas, 0% (0/10) mucinous carcinomas, and 19% (6/32) endometrioid carcinomas exhibited significant Emi1 protein overexpression. Accumulation of Emi1 protein was not linked to Ki-67 labeling index, but was directly correlated with cyclin E and inversely correlated with ER in clear cell carcinoma (P<0.001). Emi1 protein expression was present in mixed endometrioid/clear cell tumors but absent in tumors with mixed serous/clear cell histology. These findings represent a potentially important insight into the molecular pathway underlying ovarian carcinogenesis and provide a possible cell cycle model for the development and progression of ovarian clear cell carcinoma.

  View details for DOI 10.1038/modpathol.3801022

  View details for Web of Science ID 000254288500011

  View details for PubMedID 18204430

• Low-grade mucinous epithelial neoplasm (intestinal type) arising in a mature sacrococcygeal teratoma with late recurrence as pseudomyxoma peritonei HUMAN PATHOLOGY McKenney, J. K., Longacre, T. A. 2008; 39 (4): 629-632

  Abstract

  Mucinous epithelial neoplasms associated with mature teratomas are well described in the gonads, and some examples have presented with clinical pseudomyxoma peritonei. The association between pseudomyxoma peritonei and an extragonadal teratoma is limited to a single case report. We describe a mature teratoma in the sacrococcygeal region associated with an intestinal-type mucinous epithelial neoplasm that recurred with a disseminated intraperitoneal low-grade mucinous epithelial neoplasm and mucinous ascites. To our knowledge, this is the first reported case of a mature teratoma-associated mucinous epithelial neoplasm from any anatomical site with documented late recurrence as pseudomyxoma peritonei.

  View details for DOI 10.1016/j.humpath.2007.08.021

  View details for Web of Science ID 000254273900022

  View details for PubMedID 18289636

• Oncofetal protein glypican-3 distinguishes yolk sac tumor from clear cell carcinoma of the ovary AMERICAN JOURNAL OF SURGICAL PATHOLOGY Esheba, G. E., Pate, L. L., Longacre, T. A. 2008; 32 (4): 600-607

  Abstract

  Clear cell carcinoma (CCC) of the ovary is the surface epithelial neoplasm most often confused with primitive germ cell tumors, particularly yolk sac tumor (YST) and dysgerminoma. OCT3/4 has proven to be a sensitive and relatively specific marker for the latter entity, but existing markers for YST are limited. Recent studies suggest that glypican-3 (GPC3), an oncofetal protein expressed in fetal liver and malignant tumors of hepatocytic lineage, is also expressed in germ cell tumors, particularly YST. To investigate whether GPC3 is useful in distinguishing YST from ovarian CCC, we studied the expression of GPC3 in a large series of ovarian neoplasms and compared it to the expression profiles of CK7 and alpha-fetoprotein. Tissue microarrays containing over 400 benign and malignant ovarian neoplasms, including 34 CCCs were stained with monoclonal GPC3 (clone 1G12, Biomosaics, Burlington, VT). These arrays contained a wide assortment of ovarian surface epithelial neoplasms and sex cord stromal neoplasms, as well as germ cell tumors. Full paraffin tissue sections from 32 YSTs and 10 CCCs were also assessed. All but one YST (97%), including those associated with mixed germ cell tumor were positive for GPC3, whereas all teratomas and embryonal carcinomas were negative. Both cytoplasmic and membrane staining were present in the positive cases, with no background staining. The syncytiotrophoblastic cells in the germ cell tumors and placental villi included in the arrays were also positive for GPC3. Most CCCs (83%) were completely negative for GPC3, as were 99% serous, 94% endometrioid, and 100% mucinous tumors. Five CCCs exhibited focal, moderate to strong GPC3 expression and in 2 the expression was focal and weak. All other tissues, including normal ovary were negative for GPC3. GPC3 seems to be a promising diagnostic marker for differentiating YST from ovarian CCC (P < 0.0001). Because GPC3 may be associated with alpha-fetoprotein expression, further studies are required to determine the utility of GPC3 in differentiating YST from CCC with hepatoid differentiation.

  View details for Web of Science ID 000254562800013

  View details for PubMedID 18277882

• Ovarian clear cell carcinoma with papillary features: A potential mimic of serous tumor of low malignant potential AMERICAN JOURNAL OF SURGICAL PATHOLOGY Sangoi, A. R., Soslow, R. A., Teng, N. N., Longacre, T. A. 2008; 32 (2): 269-274

  Abstract

  The differential diagnostic problems usually associated with clear cell carcinoma (CCC) of the ovary have been well characterized and include primitive germ cell tumor, sex cord stromal tumor, and metastasis. Distinction from other types of surface epithelial carcinoma may also pose a diagnostic challenge, but the potential for misdiagnosis of serous tumor of low malignant potential (S-LMP) is not well recognized. We report 13 cases of ovarian CCC with prominent papillary architecture that were initially misdiagnosed as S-LMP or low-grade serous carcinoma either on frozen section or at final diagnosis. The ages of the patients ranged from 39 to 65 years (mean, 52.2 y). All patients presented with a pelvic mass; 1 was undergoing evaluation for infertility. Macroscopically, most were described as unilateral, multilocular cysts with internal papillary structures. On microscopic examination, each tumor had a papillary architecture that accounted for 30% to 95% of the tumor; in 6 cases, the cores of the papillae were hyalinized. The neoplastic cells covering the papillae had clear to granular and eosinophilic cytoplasm. Hobnail cells were focal and often subtle. Most had a low mitotic index (9/13) and/or deceptively bland cytology (8/13); only careful attention to the cytologic features and/or mitotic index allowed correct identification of the tumor type in 5 cases. Six were associated with pelvic/ovarian endometriosis. Ten were Federation of Gynecology and Obstetrics stage I (8 IA, 2 IC), 2 were stage II (1 IIB, 1 IIC), and 1 stage IIIC. CCC with prominent papillary architecture is uncommon, but may pose a challenging differential diagnosis with S-LMP, resulting in inadequate staging and delayed treatment. Features most helpful in distinguishing papillary CCC are unilaterality, nonhierarchical branching, monomorphous cell population, and the presence of more typical CCC patterns elsewhere in the tumor. The presence of endometriosis, although not specific, should also prompt consideration for papillary CCC. Increased numbers of mitotic figures may not be present and high-grade cytologic atypia may be focal, requiring careful examination of multiple tumor sections for detection. As CCC and S-LMP exhibit significantly different immunoreactivity for Wilms' Tumor 1 and estrogen receptor, these markers may also be useful adjunctive tests in problematic cases.

  View details for Web of Science ID 000252759900012

  View details for PubMedID 18223330

• Estrogen receptor-negative invasive breast cancer: Imaging features of tumors with and without human epidermal growth factor receptor type 2 overexpression RADIOLOGY Wang, Y., Ikeda, D. M., Narasimhan, B., Longacre, T. A., Bleicher, R. J., Pal, S., Jackman, R. J., Jeffrey, S. S. 2008; 246 (2): 367-375

  Abstract

  To prospectively determine if estrogen receptor (ER)-negative human epidermal growth factor receptor type 2 (HER2)-positive and ER-negative HER2-negative breast cancers have distinguishing clinical and imaging features with use of retrospectively identified patients and tissue samples.This HIPAA-compliant study was institutional review board approved. Informed consent was obtained from living patients and waived for deceased patients. Mean patient age at diagnosis was 53 years (range, 31-84 years). Clinical history; histopathologic, mammographic, and breast sonographic findings; and HER2 status as determined with immunohistochemistry or fluorescent in situ hybridization were evaluated in 56 women with ER-negative breast cancer. Imaging appearances and clinicopathologic characteristics were correlated with tumor HER2 status. P < .05 indicated a significant difference.Lesion margins on mammograms (P = .028) and sonograms (P = .023), calcifications on mammograms (P = .003), and clinical cancer stage at diagnosis (P = .029) were significantly associated with HER2 status. In contrast to ER-negative HER2-negative tumors, ER-negative HER2-positive tumors were more likely to have spiculated margins (56% vs 15%), be associated with calcifications (65% vs 21%), and be detected at a higher cancer stage (74% vs 57%).Biologic diversity of cancers may manifest in imaging characteristics, and, conversely, studying the range of imaging features of cancers may help refine current molecular phenotypes.

  View details for DOI 10.1148/radio1.2462070169

  View details for Web of Science ID 000252796300005

  View details for PubMedID 18180338

• Lymphatic vascular invasion in ovarian serous tumors of low malignant potential with stromal microinvasion - A case control study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Sangoi, A. R., McKenney, J. K., Dadras, S. S., Longacre, T. A. 2008; 32 (2): 261-268

  Abstract

  Stromal microinvasion in ovarian serous tumors of low malignant potential (S-LMP) stratifies patients at long-term risk for disease progression independent of stage and primary ovarian histology. Despite the histologic impression and often-quoted incidence of lymphatic vascular invasion (LVI) in S-LMP with stromal microinvasion, there has been no formal evaluation in a case control series of S-LMP. The presence and extent of (LVI) was assessed in 20 S-LMP with stromal microinvasion and 20 S-LMP case controls without stromal microinvasion and compared with a series of low-grade and high-grade serous carcinomas using D2-40 monoclonal antibody recognizing podoplanin, a novel lymphatic endothelial marker. S-LMP case controls were matched for primary ovarian histology (usual vs. micropapillary), International Federation of Gynecology and Obstetrics (FIGO) stage, and age (best possible match). The patterns of stromal microinvasion included individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, and inverted macropapillae. Immunohistologic staining with D2-40 monoclonal antibody clearly identified intratumoral LVI in 12/20 (60%) S-LMP with stromal microinvasion and 0/20 S-LMP without stromal microinvasion. Although only 4/13 (31%) low-grade serous carcinomas and 7/20 (35%) high-grade serous carcinomas had intratumoral LVI, hilar LVI was more common in the carcinomas (15% low-grade; 69% high-grade). Intratumoral LVI in S-LMP ranged from focal (6 cases) to multifocal (6 cases, maximum of 5 discrete foci) in any 1 section and included isolated single cells, simple papillae, and in 1 case, cribriform glands. Multifocal LVI was identified in 1 study patient who was pregnant. One of the 12 S-LMP patients with LVI had an intra-abdominal recurrence with high-grade disease at 16 months; whereas all other patients with follow-up were free of disease. LVI in ovarian S-LMP was significantly associated with the presence of stromal microinvasion (P<0.0001) and is independent of age, stage, primary ovarian histology, and pattern or extent of microinvasion. The presence of LVI in microinvasive S-LMP corroborates the view that microinvasion represents an early, but very low risk, invasive process that morphologically links S-LMP and low-grade serous carcinoma.

  View details for Web of Science ID 000252759900011

  View details for PubMedID 18223329

• HOXA7 in epithelial ovarian cancer: Interrelationships between differentiation and clinical features REPRODUCTIVE SCIENCES Ota, T., Gilks, C. B., Longacre, T., Leung, P. C., Auersperg, N. 2007; 14 (6): 605-614

  Abstract

  Interrelationships between HOXA7 expression and ovarian cancer progression are investigated by cDNA array and by immunohistochemistry of normal ovaries and 538 epithelial ovarian tumor microarrays. Outcomes of patients and HOXA7 expression were compared by Kaplan-Meier survival curves. HOXA7 mRNA expression was higher in carcinomas than in benign tumors. HOXA7 protein was absent in normal surface epithelium but appeared in metaplastic regions. All carcinomas stained for HOXA7 protein, with staining intensities unrelated to histotype, grade, or patient outcome. There were significant associations of strong HOXA7 staining of stroma and tumor nuclei with the clear cell histotype (stroma: P = .0022, nuclei: P = .0003) and of weak/absent staining with serous carcinomas. Tumor E-cadherin expression correlated significantly with HOX7 staining in stroma (P = .0002) but not within tumors. HOXA7 staining of tumor cell nuclei is correlated significantly with improved disease-specific survival (P = .0104), which is suggestive of the biological and potentially clinical importance of subcellular HOXA7 localization.

  View details for DOI 10.1177/1933719107307781

  View details for Web of Science ID 000250634600012

  View details for PubMedID 17959889

• Recommendations for the reporting of fallopian tube neoplasms HUMAN PATHOLOGY Longacre, T. A., Oliva, E., Soslow, R. A. 2007; 38 (8): 1160-1163

  Abstract

  Primary malignancies of the fallopian tube are extremely uncommon, in part due to (admittedly arbitrary) definitional criteria. By convention, epithelial tumors that involve the ovary or peritoneal surfaces are considered to have arisen either in the ovary or endometrium or, in absence of significant ovarian or endometrial involvement, in the peritoneum, irrespective of whether or not the fallopian tube mucosa is also involved. Evidence from the World Health Organization and more recently, from case-control studies of BRCA mutation carriers suggests the fallopian tube may have a more direct role in the development of at least some of these carcinomas. An alternative hypothesis for the origin of ovarian and peritoneal carcinoma has even been proposed, based on the concept of transport and implantation of malignant cells from the tube to the ovary and peritoneum. Malignancies in the fallopian tube can therefore be classified as (1) arising primarily in the fallopian tube, either from preexisting endometriosis (or more rarely, a mature teratoma) or directly from tubal mucosa with metastasis to adjacent tissues; (2) arising in the ovary, endometrium, or peritoneum with metastasis to the tubal serosa or mucosa; or (3) arising primarily in the fallopian tube as well as in the ovary, endometrium, or peritoneum (simultaneous primary tumors). Since there are currently no evidence based criteria for distinguishing primary tubal carcinoma from primary ovarian or primary endometrial carcinoma in patients with high stage disease, the Association of Directors of Anatomic and Surgical Pathology recommended strategies for assignment of site of origin are based on current standard practices.

  View details for DOI 10.1016/j.humpath.2006.11.010

  View details for Web of Science ID 000248339300006

  View details for PubMedID 17270244

• Endoscopic mucosal resection of a solitary gastric plasmacytoma DIGESTIVE ENDOSCOPY Roost, J., Mai, H., Banerjee, S., Longacre, T., Van Dam, J. 2007; 19 (3): 139-141

  View details for DOI 10.1111/j.1443-1661.2007.00686.x

  View details for Web of Science ID 000254344800006

• CDH1 truncating mutations in the E-cadherin gene - An indication for total gastrectomy to treat hereditary diffuse gastric cancer ANNALS OF SURGERY Norton, J. A., Ham, C. M., Van Dam, J., Jeffrey, R. B., Longacre, T. A., Huntsman, D. G., Chun, N., Kurian, A. W., Ford, J. M. 2007; 245 (6): 873-879

  Abstract

  Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer.Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with D-2 node dissection and Roux-en-Y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically.Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51-57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality.CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.

  View details for DOI 10.1097/01.sla.0000254370.29893.e4

  View details for Web of Science ID 000246873000007

  View details for PubMedID 17522512

• Role of human papillomavirus in squamous cell metaplasia-dysplasia-carcinoma of the rectum AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kong, C. S., Welton, M. L., Longacre, T. A. 2007; 31 (6): 919-925

  Abstract

  Primary colorectal squamous cell carcinoma (SCC) and squamous dysplasia are uncommon and little is known about their pathogenesis. Most have been reported in association with ulcerative colitis and other chronic disease states. Although cervical and anal SCC have been strongly linked to human papillomavirus (HPV) infection, the role of HPV in rectal squamous carcinoma has not been well-examined. We evaluated 3 cases of primary rectal SCC for the presence of high-risk HPV by immunohistochemistry for p16(INK4A), in situ hybridization, and polymerase chain reaction. HPV type 16 was detected by polymerase chain reaction in all cases. In addition, all cases exhibited diffuse strong reactivity for p16(INK4A) and punctate nuclear staining by Ventana HPVIII in situ hybridization. The presence of HPV 16 in all three cases suggests that high-risk HPV infection is a risk factor for rectal SCC, particularly in patients with underlying chronic inflammatory disease processes or altered immune status. Further studies are warranted to determine if SCC occurring more proximal in the colon are also HPV-dependent or occur via another, HPV-independent pathway.

  View details for Web of Science ID 000246872500014

  View details for PubMedID 17527081

• Interobserver variation in the diagnosis of ovarian clear cell carcinoma and mixed ovarian epithelial carcinomas with a clear cell component Han, G., Gilks, C. B., Leung, S., Ewanowich, C. A., Irving, J. A., Longacre, T. A., Soslow, R. A. NATURE PUBLISHING GROUP. 2007: 200A-200A

  View details for Web of Science ID 000244935301333

• Recommendations for the reporting of fallopian tube neoplasms VIRCHOWS ARCHIV Longacre, T. A., Oliva, E., Soslow, R. A. 2007; 450 (1): 25-29

  View details for DOI 10.1007/s00428-006-0303-5

  View details for Web of Science ID 000244213600003

  View details for PubMedID 17334802

• BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays AMERICAN JOURNAL OF SURGICAL PATHOLOGY Bane, A. L., Beck, J. C., Bleiweiss, I., Buys, S. S., Catalano, E., Daly, M. B., Giles, G., Godwin, A. K., Hibshoosh, H., Hopper, J. L., John, E. M., Layfield, L., Longacre, T., Miron, A., Senie, R., Southey, M. C., West, D. W., Whittemore, A. S., Wu, H., Andrulis, I. L., O'Malley, F. P. 2007; 31 (1): 121-128

  Abstract

  A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.

  View details for Web of Science ID 000243236000015

  View details for PubMedID 17197928

• Pseudomyxoma peritonei syndrome: classification of appendiceal mucinous tumours. Cancer treatment and research Pai, R. K., Longacre, T. A. 2007; 134: 71-107

  View details for PubMedID 17633048

• p16(INK4A) immunohistochemistry is superior to HPV in situ hybridization for the detection of high-risk HPV in atypical squamous metaplasia AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kong, C. S., Balzer, B. L., Troxell, M. L., Patterson, B. K., Longacre, T. A. 2007; 31 (1): 33-43

  Abstract

  In situ hybridization (ISH) assays for high-risk human papillomavirus (HR-HPV) and immunohistochemical (IHC) assays for surrogate markers such as p16 can be useful in detecting HR-HPV in cervical dysplasia, but the use of these markers in problematic cervical biopsies has not been well-established. We evaluated 3 chromogenic ISH assays (Ventana INFORM HPVII and HPVIII and DakoCytomation GenPoint) in conjunction with p16 IHC and HPV polymerase chain reaction in a study set consisting of 12 low-grade squamous intraepithelial lesions, 16 high-grade squamous intraepithelial lesions, and 30 benign cervix samples. A test set of 28 cases of atypical squamous metaplasia were also evaluated withVentana HPVIII ISH and p16 IHC. In the study set, the sensitivity of the DakoCytomation ISH assay (which detects HPV subtypes 16, 18, 31, 33, 35, 39, 45, 52, 56, 58, 59, and 68) was similar to the Ventana HPVII assay but less than that of the Ventana HPVIII ISH assay (both of which detect HPV subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 66) and less than p16 IHC (55.6% vs. 53.6 vs. 69.2% vs. 82.1%). All HPV ISH assays exhibited 100% specificity. p16 reactivity consisted of 2 patterns: focal strong and diffuse strong. Because focal strong p16 reactivity was identified in benign squamous epithelium (6.7% cases) and dysplastic epithelium, it was considered an equivocal result and only diffuse strong reactivity was considered to be specific for the presence of HR-HPV. In the squamous intraepithelial lesions study set, the difference in sensitivity between Ventana HPVIII ISH and p16 was not statistically significant. However, in the atypical squamous metaplasia test set cases, p16 reactivity (focal strong and diffuse strong) was significantly more sensitive than Ventana HPVIII ISH in correlating with the presence of human papillomavirus as detected by polymerase chain reaction (83.3% vs. 33.3% P=0.004). Because focal strong p16 reactivity is less specific, cases with this staining pattern are considered atypical and require further evaluation by other means. Overall, p16 IHC is considered the best candidate for the initial assessment of cervical biopsies that are histologically indeterminate for dysplasia given its wide availability, comparative ease of interpretation, and high sensitivity and specificity.

  View details for Web of Science ID 000243236000004

  View details for PubMedID 17197917

• Patterns of stromal invasion in ovarian serous tumors of low malignant potential (borderline tumors): A reevaluation of the concept of stromal microinvasion AMERICAN JOURNAL OF SURGICAL PATHOLOGY McKenney, J. K., Balzer, B. L., Longacre, T. A. 2006; 30 (10): 1209-1221

  Abstract

  Stromal-epithelial patterns of invasion in serous tumors of the ovary have been subclassified as destructive and nondestructive. By definition, well-differentiated serous tumors featuring destructive stromal invasion are classified as low-grade serous carcinomas whereas those with either no stromal invasion or stromal microinvasion are classified as serous tumors of low malignant potential (S-LMP). The histologic features of stromal microinvasion in ovarian S-LMP have been addressed in a variety of studies, but controversy persists regarding diagnostic criteria and prognostic significance, particularly in patients with high-stage disease. In addition, a subset of otherwise typical S-LMP has patterns of invasion that are not classic destructive invasion and do not meet the current diagnostic criteria for stromal microinvasion because of either qualitative features or size restrictions. To further evaluate the full histologic spectrum of stromal-epithelial patterns of invasion in otherwise typical S-LMP, we examined a series of 60 ovarian S-LMP (34 FIGO stage I; 26 FIGO stages II, III, and IV) with stromal-epithelial alterations not meeting criteria for classic destructive invasion. This group of cases included those meeting the definition of microinvasion and a subset that would be excluded based on size measurements or unusual qualitative features, but did not exhibit significant stromal reaction. Five patterns of invasion were identified: individual eosinophilic cells and cell clusters, cribriform, simple and noncomplex branching papillae, inverted macropapillae, and micropapillae. Individual, discrete aggregates of invasive epithelium ranged from 1 to 12 mm (mean, 1.4 mm) in greatest linear dimension as measured by conventional methods. The number of discrete foci ranged from 1 to greater than 10; in 7 tumors (12%), the invasive foci were diffusely scattered throughout the stroma without discrete aggregates. These stromal-epithelial alterations were associated with disease progression and/or death due to disease in 9 of 50 (18%) patients with follow-up (mean, 92.5 mo) and were covariant with other adverse prognostic features (invasive implants, nodular lymph node aggregates, high stage, and unresectable disease). Disease progression was most strongly linked to the presence of micropapillae, but the majority of patients with adverse outcome had the more common, classic stromal-epithelial patterns associated with microinvasion (ie, individual cells, cell clusters, and simple papillae). Neither size of the largest contiguous aggregate nor extent of stromal involvement correlated with outcome. Classic microinvasion disproportionately occurred in patients presenting during pregnancy (P<0.0001), and was not associated with adverse outcome in that setting, but follow-up was limited. Based on the cumulative outcome data, the presence of stromal-epithelial patterns of invasion distinct from classic destructive invasion in otherwise typical S-LMP stratifies patients at long-term risk for disease progression, but does not warrant a diagnosis of carcinoma or a change in current management schemes. Maintaining classification as a serous tumor of low malignant potential (serous borderline tumor) with stromal invasion seems appropriate even in the presence of diffuse stromal involvement or discrete aggregates measuring greater than 3 (or 5) mm. As the stromal-epithelial alteration featuring micropapillae may represent a comparatively higher-risk lesion with a clinical course analogous to that of low-grade serous carcinoma, pathologists should identify this specific stromal-epithelial pattern in the diagnostic report until sufficient data is acquired to form more definitive conclusions regarding its prognosis.

  View details for Web of Science ID 000240892800001

  View details for PubMedID 17001150

• Outcomes of women with metachronous breast and ovarian carcinomas GYNECOLOGIC ONCOLOGY Liou, W., Hamilton, C. A., Cheung, M. K., Osann, K., Longacre, T. A., Teng, N. N., Husain, A., Dirbas, F. M., Chan, J. K. 2006; 103 (1): 190-194

  Abstract

  Women with a history of breast cancer have a significantly increased risk of developing a second primary ovarian cancer and vice versa. We proposed to determine the characteristics and outcomes of women diagnosed with metachronous breast and ovarian cancer.Patients were identified from the Surveillance, Epidemiology, and End Results program database between 1988 and 2001. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes.Of 704 women, 526 developed breast cancer then ovarian cancer (B-O) and 178 developed ovarian cancer then breast cancer (O-B). The mean age at diagnosis of the first cancer in the B-O versus O-B group was 60.3 versus 58.9 years, respectively (P = 0.23). Twenty-five percent of women in the B-O group had stage I-II ovarian cancer versus 63% in the O-B group (P < 0.001). The percentage of those with stage I-II breast cancer was 94% and 91% in the B-O versus O-B group, respectively (P = 0.13). Women in the B-O group had more high grade of ovarian cancer compared to those in the O-B group (P < 0.001). The mean time interval between diagnoses of breast then ovarian versus ovarian then breast cancer was 58 versus 56 months, respectively (P = 0.42).In the largest series to date, we found that women diagnosed with ovarian cancer first had significantly more early stage and lower grade ovarian cancers with better survival compared to those with breast cancer followed by ovarian cancer. Since half of the women had their second cancer beyond 5 years, continued surveillance of these high risk patients is recommended.

  View details for DOI 10.1016/j.ygyno.2006.02.022

  View details for Web of Science ID 000240887100036

  View details for PubMedID 16569424

• Lymph node involvement in ovarian serous tumors of low malignant potential (borderline tumors) - Pathology, prognosis, and proposed classification AMERICAN JOURNAL OF SURGICAL PATHOLOGY McKenney, J. K., Balzer, B. L., Longacre, T. A. 2006; 30 (5): 614-624

  Abstract

  The occurrence of regional lymph node involvement (LNI) in patients with primary ovarian serous tumors of low malignant potential (S-LMP), although well described in the literature, continues to be problematic. Most studies indicate that LNI is not associated with an adverse prognosis, but there has not been a comprehensive study addressing the histologic patterns of LNI, the importance, if any, of classifying the type of LNI (ie, as either noninvasive or invasive in analogy to peritoneal implant classification), or the presence and significance of associated endosalpingiosis. To further evaluate LNI in S-LMP, 74 patients with ovarian S-LMP and a lymph node biopsy or sampling were studied. Thirty-one of 74 patients had LNI in pelvic (18; 58%), mesenteric/omental (9; 29%), paraaortic (8; 26%), or supradiaphragmatic (2; 6%) lymph nodes. The number of involved nodes ranged from 1 to 20 (mean, 11.1). Four patterns of LNI were identified: individual cells, clusters of cells, and simple, nonbranching papillae (28 of 31; 90%); intraglandular (21 of 31; 68%); cells with prominent cytoplasmic eosinophilia ("eosinophilic cell" pattern) (16 of 31; 52%); and micropapillary pattern (5 of 31; 16%). LNI was diffuse in at least one lymph node in 13 patients (42%) and formed nodular aggregates greater than 1 mm in 6 patients (19%). Nodal endosalpingiosis was present in 58% of cases with LNI compared with 35% without LNI (P=0.06). There was no significant difference in survival for patients with LNI compared with patients without LNI. However, the presence of discrete nodular aggregates of epithelium greater than 1 mm in linear dimension without intervening lymphoid tissue was associated with a statistically significant decreased disease-free survival when compared with other patterns of LNI (P=0.02). Nodular aggregates were strongly associated with desmoplastic fibrous stromal reaction (P=0.001) and micropapillary architecture (0.02). There was also a trend for decreased survival among patients with LNI without associated endosalpingiosis (56%) compared with patients with LNI associated with endosalpingiosis (85%) and those with endosalpingiosis only (93%). This study suggests that patients with ovarian S-LMP may be further substratified into risk categories by the presence of nodular aggregates of S-LMP in lymph nodes, a feature that is more common in cases with micropapillary architecture and associated stromal reaction in the intranodal tumor. This high risk pattern of LNI may have a predictive value similar to invasive peritoneal implants and deserves independent evaluation in future studies of S-LMP.

  View details for Web of Science ID 000237261500008

  View details for PubMedID 16699316

• Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers BRITISH JOURNAL OF CANCER Hamilton, C. A., Cheung, M. K., Osann, K., Chen, L., Teng, N. N., Longacre, T. A., Powell, M. A., Hendrickson, M. R., Kapp, D. S., Chan, J. K. 2006; 94 (5): 642-646

  Abstract

  To compare the survival of women with uterine papillary serous carcinoma (UPSC) and clear cell carcinoma (CC) to those with grade 3 endometrioid uterine carcinoma (G3EC). Demographic, pathologic, treatment, and survival information were obtained from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Data were analysed using Kaplan-Meier and Cox proportional hazards regression methods. Of 4180 women, 1473 had UPSC, 391 had CC, and 2316 had G3EC cancers. Uterine papillary serous carcinoma and CC patients were older (median age: 70 years and 68 vs 66 years, respectively; P<0.0001) and more likely to be black compared to G3EC (15 and 12% vs 7%; P<0.0001). A higher proportion of UPSC and CC patients had stage III-IV disease compared to G3EC patients (52 and 36% vs 29%; P<0.0001). Uterine papillary serous carcinoma, CC and G3EC patients represent 10, 3, and 15% of endometrial cancers but account for 39, 8, and 27% of cancer deaths, respectively. The 5-year disease-specific survivals for women with UPSC, CC and G3EC were 55, 68, and 77%, respectively (P<0.0001). The survival differences between UPSC, CC and G3EC persist after controlling for stage I-II (74, 82, and 86%; P<0.0001) and stage III-IV disease (33, 40, and 54; P<0.0001). On multivariate analysis, more favourable histology (G3EC), younger age, and earlier stage were independent predictors of improved survival. Women with UPSC and CC of the uterus have a significantly poorer prognosis compared to those with G3EC. These findings should be considered in the counselling, treating and designing of future trials for these high-risk patients.

  View details for DOI 10.1038/sj.bjc.6603012

  View details for Web of Science ID 000235868700007

  View details for PubMedID 16495918

• Ductal carcinoma in situ of the breast with osteoclast-like giant cells HUMAN PATHOLOGY Krishnan, C., Longacre, T. A. 2006; 37 (3): 369-372

  Abstract

  Mammary carcinoma with multinucleated osteoclast-like giant cells (OGCs) is a rare, distinctive variant of breast carcinoma. To date, all of these instances have been described as part of an invasive carcinoma. Here, we report a case of ductal carcinoma in situ of the breast with numerous admixed OGCs present within gland lumens without an associated invasive component. Similar to invasive carcinomas with OGCs, both the in situ carcinoma and the OGCs exhibited overexpression for vascular endothelial growth factor. This case expands the spectrum of tumors associated with OGCs and provides further evidence for the possible role of vascular endothelial growth factor in the stromal-epithelial interactions of in situ mammary carcinoma.

  View details for DOI 10.1016/j.humpath.2005.11.012

  View details for Web of Science ID 000236161500016

  View details for PubMedID 16613333

• Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study MODERN PATHOLOGY Longacre, T. A., Ennis, M., Quenneville, L. A., Bane, A. L., Bleiweiss, I. J., Carter, B. A., Catelano, E., Hendrickson, M. R., Hibshoosh, H., Layfield, L. J., Memeo, L., Wu, H., O'Malley, F. P. 2006; 19 (2): 195-207

  Abstract

  The United States National Cancer Institute Breast/Ovarian Cancer Family Registry is the largest international Registry of this type; over 37 724 individuals have been enrolled to date. One activity of this Registry is the semicentralized pathologic review of tumors from all probands. Given the semicentralized nature of the review, this study was undertaken to determine the reproducibility, source(s) of classification discrepancies and stratagems to circumvent discrepancies for histologic subtyping and grading of invasive breast cancer among the reviewing pathologists. A total of 13 pathologists reviewed 35 invasive breast cancers and classified them by primary and secondary histologic type, Nottingham grade and score. Lymph-vascular space invasion, circumscribed margins, syncytial growth and lymphocytic infiltrate were also evaluated. A training session using a separate set of slides was conducted prior to the study. General agreement, in terms of category-specific kappa's and percent agreement, and accuracy of classification relative to a reference standard were determined. Classification of histologic subtype was most consistent (and accurate) for mucinous carcinoma (kappa=1.0), followed by tubular (kappa=0.8) and lobular subtypes (kappa=0.8). Classification of medullary subtype was moderate (kappa=0.4), but additional evaluation of degree of lymphocytic infiltrate, syncytial growth and circumscribed margins identified most cases. Category-specific kappa's were moderate to good for Nottingham grade (kappa=0.5-0.7), with the greatest agreement obtained in categorizing grade I (kappa=0.7), and grade III tumors (kappa=0.7). A flexible classification strategy that employs individual and combined criteria provides good interobserver agreement for invasive breast cancers with uniform, unambiguous histology and compensates for classification discrepancies in the more histologically ambiguous or heterogeneous cancers.

  View details for DOI 10.1038/modpathol.3800496

  View details for Web of Science ID 000234843300005

  View details for PubMedID 16341153

• Amplification of EMSY, a novel oncogene on 11q13, in high grade ovarian surface epithelial carcinomas GYNECOLOGIC ONCOLOGY Brown, L. A., Irving, J., Parker, R., Kim, H., Press, J. Z., Longacre, T. A., Chia, S., Magliocco, A., Makretsov, N., Gilks, B., Pollack, J., Huntsman, D. 2006; 100 (2): 264-270

  Abstract

  Amplification of the 11q13 locus is commonly observed in a number of human cancers including both breast and ovarian cancer. Cyclin D1 and EMS1 have been implicated as candidate oncogenes involved in the emergence of amplification at this locus. Detailed analysis of the 11q13 amplicon in breast cancer led to the discovery of four regions of amplification suggesting the involvement of other genes. Here, we investigate the role of EMSY, a recently described BRCA2 interacting protein, as a key element of the 11q13 amplicon in ovarian cancer. EMSY maps to 11q13.5 and is amplified in 13% of breast and 17% of ovarian carcinomas.EMSY amplification was assessed by fluorescent in-situ hybridization (FISH) in 674 ovarian cancers in a tissue microarray and correlated with histopathological subtype and tumor grade. A detailed map of the 11q13 amplicon in 51 cases of ovarian cancer was obtained using cDNA-array-based comparative genomic hybridization (aCGH). To further characterize the role of EMSY within this amplicon, we evaluated both the amplification profiles and RNA expression levels of EMSY and two other genes from the 11q13 amplicon in an additional series of 22 ovarian carcinomas.EMSY amplification was seen in 52/285 (18%) high grade papillary serous carcinomas, 4/27 (15%) high grade endometrioid carcinomas, 3/38 (8%) clear cell carcinomas, and 3/10 (30%) undifferentiated carcinomas. aCGH mapping of 11q13 in ovarian cancer showed that EMSY localized to the region with the highest frequency of copy number gain. Cyclin D1 and EMS1 showed a lower frequency of copy number gain. A highly significant correlation between EMSY gene amplification and RNA expression was also observed (P = 0.0001). This was a stronger correlation than for other genes at 11q13 including Cyclin D1 and PAK1.These findings support the role of EMSY as a key oncogene within the 11q13 amplicon in ovarian cancer.

  View details for DOI 10.1016/j.ygyno.2005.08.026

  View details for Web of Science ID 000235022800009

  View details for PubMedID 16236351

• Utility of syndecan-1 (CD138) expression in the diagnosis of undifferentiated malignant neoplasms - A tissue microarray study of 1,754 cases APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Kambham, N., Kong, C., Longacre, T. A., Natkunam, Y. 2005; 13 (4): 304-310

  Abstract

  Syndecan-1, a heparan sulfate-rich membrane glycoprotein, is expressed in plasma cells and is considered a reliable marker of plasmacytic differentiation. However, it has not been widely tested in non-hematolymphoid tissues, and thus its utility in the setting of an undifferentiated malignant neoplasm has not been evaluated. The authors conducted an extensive study of CD138 staining in over 1,700 normal, benign, and malignant non-hematolymphoid tissues, using five tissue microarrays. Immunohistochemical staining was performed with two commercially available CD138 monoclonal antibodies directed against syndecan-1 (Serotec, Oxford, UK, and DAKO, Carpenteria, CA). In addition to the specific membrane staining, many normal tissues and epithelial tumors showed strong cytoplasmic immunoreactivity. A small subset of mesenchymal neoplasms also showed membrane and cytoplasmic immunoreactivity. In squamous cell carcinoma of the head and neck, renal cell carcinoma, and prostate adenocarcinoma, the intensity of CD138 staining inversely correlated with the histologic grade of the carcinoma. However, statistically significant staining differences and their correlation with histologic grades differed depending on whether the Serotec or the DAKO antibody was used. These results indicate that CD138 immunoreactivity is widespread in normal and neoplastic epithelial tissues, as well as a variety of undifferentiated epithelial and mesenchymal processes. The authors conclude that the expression of syndecan-1, although relatively specific to plasma cells within the hematolymphoid system, should be interpreted with extreme caution in the setting of an undifferentiated neoplasm. Furthermore, the two commercially available monoclonal CD138 antibodies tested in this study showed significant differences in their immunoreactivity in different tumor types.

  View details for Web of Science ID 000233572700002

  View details for PubMedID 16280658

• Appendiceal mucinous tumors and pseudomyxoma peritonei - Histologic features, diagnostic problems, and proposed classification ADVANCES IN ANATOMIC PATHOLOGY Pai, R. K., Longacre, T. A. 2005; 12 (6): 291-311

  Abstract

  Pseudomyxoma peritonei is an overused and underspecified condition that has garnered much attention in the historic literature. In recent years, this condition has been convincingly linked to appendiceal mucinous neoplasms, yet there has been insufficient attention to the histologic characteristics, classification, and differential diagnostic considerations of these neoplasms when encountered by the surgical pathologist. This review provides a coherent approach to the diagnosis and classification of appendiceal mucinous tumors and the peritoneal implants associated with the pseudomyxoma peritonei syndrome with emphasis on differential diagnostic considerations and recommendations for the final pathology report.

  View details for Web of Science ID 000233951400001

  View details for PubMedID 16330927

• Serous tumours of low malignant potential (serous borderline tumours): moving toward detente HISTOPATHOLOGY Longacre, T. A., Kempson, R. L., Hendrickson, M. R. 2005; 47 (3): 315-318

  View details for Web of Science ID 000231394800010

  View details for PubMedID 16115233

• Characterization of a recurrent germ line mutation of the E-cadherin gene: Implications for genetic testing and clinical management CLINICAL CANCER RESEARCH Suriano, G., Yew, S., Ferreira, P., Senz, J., Kaurah, P., Ford, J. M., Longacre, T. A., NORTON, J. A., Chun, N., Young, S., Oliveira, M. J., MacGillivray, B., Rao, A., Sears, D., Jackson, C. E., Boyd, J., Yee, C., Deters, C., Pai, G. S., Hammond, L. S., McGivern, B. J., Medgyesy, D., Sartz, D., Arun, B., Oelschlager, B. K., Upton, M. P., Neufeld-Kaiser, W., Silva, O. E., Donenberg, T. R., Kooby, D. A., Sharma, S., Jonsson, B. A., Gronberg, H., Gallinger, S., Seruca, R., Lynch, H., Huntsman, D. G. 2005; 11 (15): 5401-5409

  Abstract

  To identify germ line CDH1 mutations in hereditary diffuse gastric cancer (HDGC) families and develop guidelines for management of at risk individuals.We ascertained 31 HDGC previously unreported families, including 10 isolated early-onset diffuse gastric cancer (DGC) cases. Screening for CDH1 germ line mutations was done by denaturing high-performance liquid chromatography and automated DNA sequencing.We identified eight inactivating and one missense CDH1 germ line mutation. The missense mutation conferred in vitro loss of protein function. Two families had the previously described 1003C>T nonsense mutation. Haplotype analysis revealed this to be a recurrent and not a founder mutation. Thirty-six percent (5 of 14) of the families with a documented DGC diagnosed before the age of 50 and other cases of gastric cancer carried CDH1 germ line mutations. Two of 10 isolated cases of DGC in individuals ages <35 years harbored CDH1 germ line mutations. One mutation positive family was ascertained through a family history of lobular breast cancer (LBC) and another through an individual with both DGC and LBC. Occult DGC was identified in five of six prophylactic gastrectomies done on asymptomatic, endoscopically negative 1003C>T mutation carriers.In addition to families with a strong history of early-onset DGC, CDH1 mutation screening should be offered to isolated cases of DGC in individuals ages <35 years and for families with multiple cases of LBC, with any history of DGC or unspecified GI malignancies. Prophylactic gastrectomy is potentially a lifesaving procedure and clinical breast screening is recommended for asymptomatic mutation carriers.

  View details for Web of Science ID 000230878900012

  View details for PubMedID 16061854

• Multinucleated epithelial giant cells in colorectal polyps - A potential mimic of viropathic and/or dysplastic changes AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kambham, N., Troxell, M., Longacre, T. A. 2005; 29 (7): 912-919

  Abstract

  Multinucleated epithelial giant cells (MEG) simulating viral cytopathic effect and/or dysplasia have been reported in the esophagus in association with inflammation, but the occurrence of similar cells in the colon has not been documented. Twenty-three colon specimens (22 biopsies and 1 partial colectomy) featuring MEG from 21 patients were evaluated for a variety of histologic features and correlated with clinical, endoscopic, and follow-up data. Patients included 9 males and 12 females (mean age, 64.9 years; range, 45-86 years). Eleven cases were obtained from 10 asymptomatic patients undergoing surveillance biopsies. Presenting symptoms in the remaining patients were dyspepsia, anemia, abdominal pain, and hematochezia. Over half (13 of 23) of the specimens were from descending and rectosigmoid colon, and almost all were visualized as polyps on endoscopy. Microscopically, all but 1 of the cases featured multiple MEG (range, 6 to >50 cells per biopsy) in the base and mid crypt zones of inflamed polyps with serrated architecture. Immunohistochemical stains for CMV, HSV, adenovirus, EBV, and polyoma virus were negative and no viral particles were identified on ultrastructural examination. Nuclear staining for hMLH1 and hMSH2, markers of microsatellite instability, was similar in distribution to adjacent serrated crypts, but reduced staining intensity was noted in occasional multinucleated cells. Expression of Ki-67 and cleaved caspase 3 was consistent with a quiescent or low proliferative state. Clinical follow-up was available for 9 patients (mean duration, 22.7 months). One patient died of heart failure; all others were well at last follow-up. Bizarre MEG may occasionally be seen within the crypts of inflamed polyps with serrated architecture, raising concern for dysplasia or viral infection. Immunohistochemical and ultrastructural studies fail to establish a viral etiology, and follow-up does not indicate clinically aggressive disease. These changes appear to represent a nonspecific, possibly degenerative response to inflammation and injury, and should be distinguished from dysplasia.

  View details for Web of Science ID 000230102600009

  View details for PubMedID 15958856

• Ovarian serous tumors of low malignant potential (Borderline tumors) - Outcome-based study of 276 patients with long-term (>= 5-year) follow-up AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., McKenney, J. K., Tazelaar, H. D., Kempson, R. L., Hendrickson, M. R. 2005; 29 (6): 707-723

  Abstract

  The natural history, classification, and nomenclature of ovarian serous tumors of low malignant potential (S-LMP) (serous tumors of borderline malignancy, atypical proliferating tumors) are controversial. To determine long-term outcome for patients with S-LMP and further evaluate whether S-LMP can be stratified into clinically benign and malignant groups, the clinicopathologic features of 276 patients with S-LMP and > or =5 year follow-up were studied. The histology of the ovarian primary, extraovarian implants, and recurrent tumor(s) were characterized using World Health Organization criteria and correlated with FIGO stage and clinical follow-up. After censoring nontumor deaths, overall survival and disease-free survival for the 276 patients was 95% (98% FIGO stage I; 91% FIGO II-IV) and 78% (87% FIGO stage I; 65% FIGO stage II-IV), respectively. Unresectable disease (P < 0.001) and invasive implants (P < 0.001) were associated with decreased survival. When compared with typical S-LMP, S-LMP with micropapillary features were more strongly associated with invasive implants (P < 0.008) and decreased overall survival (P = 0.004), but patient outcome with micropapillary S-LMP was not independent of implant type. Stromal microinvasion in the primary tumor was also correlated with adverse outcome, independent of stage of disease, micropapillary architecture, and implant type (P = 0.03). There was no association between outcome and lymph node status. Transformation to low-grade serous carcinoma occurred in 6.8% of patients at intervals of 7 to 288 months (58% > or = 60 months) and was strongly associated with increased tempo of disease and decreased survival (P < 0.001). S-LMP forms a heterogeneous group, morphologically and clinically distinct from benign serous tumors and serous carcinoma. The majority of S-LMP are clinically benign, but recurrences are not uncommon, and persistent disease as well as deaths occur. Progression to low-grade serous carcinoma is highly predictive of more aggressive disease. Other features associated with recurrent and/or progressive disease include FIGO stage, invasive implants, microinvasion in the primary tumor, and micropapillary architecture. These predictors tend to co-occur, and no single clinical or pathologic feature or combination of features identify all adverse outcomes. The small, but significant risk of progression over time to low-grade serous carcinoma emphasizes the need for prolonged follow-up in patients with S-LMP.

  View details for Web of Science ID 000229348500001

  View details for PubMedID 15897738

• Progress in ovarian cancer survival during the past 15 years - An aggregate interval analysis Cheung, M. K., Manuel, M., Osann, K., Husain, A., Longacre, T., Chan, J. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: 118S-118S

  View details for Web of Science ID 000228065900267

• Distinction between serous tumors of low malignant potential and serous carcinomas based on global mRNA expression profiling GYNECOLOGIC ONCOLOGY Gilks, C. B., Vanderhyden, B. C., Zhu, S., van de Rijn, M., Longacre, T. A. 2005; 96 (3): 684-694

  Abstract

  The molecular pathogenesis of ovarian serous tumors of low malignant potential (S-LMP) is not well understood, although the collective data suggest that they arise through molecular mechanisms distinct from those leading to conventional serous carcinomas (S-Ca). To further examine the molecular differences between these two diseases, we studied the gene expression pattern of ovarian S-LMP and S-Ca using high-density spotted cDNA and tissue microarrays.Total RNA from 23 ovarian S-LMP and S-Ca was analyzed on 43,200 spot cDNA microarrays and the differential expression of proteins encoded by differentially expressed genes was validated using tissue microarrays.Unsupervised hierarchical clustering analysis of filtered data showed a complete separation between S-LMP and S-Ca, based predominantly on a small set of genes expressed at higher levels in S-LMP than in S-Ca. Many genes previously identified as up-regulated in ovarian carcinoma relative to normal ovarian tissue were expressed at even higher levels in S-LMP. These genes included mucin-1, mesothelin, HE4, PAX 8, and apolipoprotein J/clusterin. Immunohistochemical staining of tissue microarrays confirmed higher expression of selected proteins encoded by these genes in the S-LMP. Few genes were expressed at a higher level in S-Ca; these included E2F1, topoisomerase IIalpha, and cyclin E, with higher levels of cyclin E protein confirmed by immunohistochemistry.S-LMP and S-Ca are distinguished at the molecular level by a relatively small gene set, suggesting the pathogenesis of S-LMP as well as S-Ca may involve molecular pathways that escape detection by global gene expression profiling. In order to obtain biologically and clinically relevant information about the mechanisms involved in ovarian carcinogenesis, future studies based on molecular profiles of ovarian cancer should include analyses of low malignant potential tumors. Inclusion of such tumors is also critical to the evaluation of the efficacy of potential new diagnostic and/or therapeutic biomarkers.

  View details for DOI 10.1016/j.ygyno.2004.11.039

  View details for Web of Science ID 000227615600017

  View details for PubMedID 15721412

• Acute colitis secondary to self-administered alcohol enemas: A mimic of ischemic colitis JOURNAL OF CLINICAL GASTROENTEROLOGY Randolph, M., Longacre, T. A., Gerson, L. B. 2005; 39 (1): 78-79

  View details for Web of Science ID 000225904500020

  View details for PubMedID 15599218

• Endometrial adenocarcinoma associated with subtle lymph-vascular space invasion and lymph node metastasis: A histologic pattern mimicking intravascular and sinusoidal histiocytes INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY McKenney, J. K., Kong, C. S., Longacre, T. A. 2005; 24 (1): 73-78

  Abstract

  Lymph-vascular space invasion has been established as an independent prognostic factor in endometrial adenocarcinoma. Despite the importance of its recognition, the histologic patterns of lymph-vascular space involvement have not been well addressed in the surgical pathology literature. We report three cases of endometrioid adenocarcinoma of the uterine corpus associated with a subtle pattern of lymph-vascular space invasion closely mimicking intravascular histiocytes. Two cases had regional lymph node metastases composed of morphologically similar cells.

  View details for DOI 10.1097/01.pgp.0000148340.62017.e3

  View details for Web of Science ID 000226146300008

  View details for PubMedID 15626920

• Serous borderline (low malignant potential, atypical proliferative) ovarian tumors: Workshop perspectives HUMAN PATHOLOGY Bell, D. A., Longacre, T. A., Prat, J., Kohn, E. C., Soslow, R. A., Ellenson, L. H., Malpica, A., Stoler, M. H., Kurman, R. J. 2004; 35 (8): 934-948

  Abstract

  Although the category of serous borderline ovarian tumor (S-BOT) was established more than 30 years ago, the nomenclature and prognostic significance of various histological features of these neoplasms continues to engender controversy. The Borderline Ovarian Tumor Workshop was held in Bethesda, MD, in August 2003 in an attempt to examine the existing data, establish areas of agreement, and identify areas needing further investigation. This report addresses 6 areas of controversy regarding S-BOT: (1) tumors with and without a micropapillary architecture (typical vs micropapillary type), (2) peritoneal implants, (3) stromal microinvasion, (4) ovarian surface involvement, (5) lymph node involvement, and (6) recurrent tumors. Each of these issues is addressed by summarizing the data in the literature on which the discussions were based, areas of agreement that emerged, divergent opinions and the reasoning behind them, and the conclusions of the participants with recommended nomenclature.

  View details for DOI 10.1016/j.humpath.2004.03.005

  View details for Web of Science ID 000223440100004

  View details for PubMedID 15297961

• Oviductal glycoprotein, a new differentiation-based indicator present in early ovarian epithelial neoplasia and cortical inclusion cysts GYNECOLOGIC ONCOLOGY Woo, M. M., Gilks, C. B., Verhage, H. G., Longacre, T. A., Leung, P. C., Auersperg, N. 2004; 93 (2): 315-319

  Abstract

  With neoplastic progression, the precursor of epithelial ovarian cancers, the ovarian surface epithelium (OSE), undergoes Mullerian differentiation, usually of the oviductal type. The aim of this study was to examine the expression of oviduct-specific glycoprotein (OGP), a marker of normal oviductal epithelium, for use as a diagnostic or prognostic marker for ovarian cancer.Immunohistochemical analysis for OGP was performed on 389 ovarian tumors and 19 normal ovaries, as well as 433 cases representing 45 normal tissues and 51 benign and malignant tumor types from 37 different tissues.OGP was absent in OSE but present in 28 of 31 epithelial inclusion cysts, 13 of 14 (93%) serous cystadenomas, and 46 of 65 (71%) serous borderline tumors. Of 183 serous adenocarcinomas, 26 (14%) were positive for OGP, including 5 of 8 (63%) grade I, 7 of 41 (17%) grade II, and 14 of 134 (10%) grade III carcinomas. OGP was found in 7 of 14 (50%) borderline and 9 of 15 (60%) malignant mucinous ovarian tumors and in 10 of 39 (26%) endometrioid adenocarcinomas. The localization of OGP in the lumen of glandular structures suggested that it was secreted. OGP was absent in 41 of 45 normal tissues and positive in oviduct and, weakly, in salivary gland, duodenum, and ileum. Forty-six types of nongynecologic tumors were negative, as were gynecologic neoplasms except for 2 of 47 cervical and 3 of 56 endometrial carcinomas.OGP is a new tubal differentiation marker which characterizes benign and borderline serous neoplasms and may indicate early events in ovarian carcinogenesis.

  View details for DOI 10.1016/j.ygyno.2004.01.047

  View details for Web of Science ID 000221120500007

  View details for PubMedID 15099939

• Adenomatoid tumors of the female and male genital tracts express WT1 INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Schwartz, E. J., Longacre, T. A. 2004; 23 (2): 123-128

  Abstract

  Adenomatoid tumors are benign proliferations most often encountered in the female and male genital tracts. The mesothelial phenotype of these unusual tumors has been established by a variety of ultrastructural and immunohistochemical studies, although their etiology is by no means certain. The expression of the Wilms' tumor suppressor gene, WT1, in normal, hyperplastic, and malignant mesothelial cells prompted us to analyze the expression pattern of WT1 in a series of 24 adenomatoid tumors occurring in the uterus, fallopian tube, ovary, epididymis, scrotum, and testis. Twenty-three of the tumors expressed WT1 protein and the same number expressed calretinin, another marker of mesothelial differentiation. The one tumor that failed to stain with calretinin was positive for WT1. These results provide further support for mesothelial differentiation of adenomatoid tumors and suggest that the presence of WT1 expression may be useful in the differential diagnosis of these uncommon neoplasms, especially when they present in unusual settings or expression of other mesothelial markers is absent.

  View details for DOI 10.1097/01.pgp.0000116625.23685.20

  View details for Web of Science ID 000220452800006

  View details for PubMedID 15084840

• Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis GYNECOLOGIC ONCOLOGY Juretzka, M. M., Jensen, K. C., Longacre, T. A., Teng, N. N., Husain, A. 2004; 93 (1): 107-111

  Abstract

  The objectives of this study were to (1) determine the incidence of lymph node micrometastasis in cervical cancer by immunohistochemical analysis and (2) determine if the presence of micrometastasis is a poor prognostic feature in early cervical cancer.We retrospectively reviewed the medical records of 62 patients who underwent radical hysterectomy and lymphadenectomy for FIGO stage IA2-IB2 cervical cancer at Stanford University Hospital from 1990 to 2000. Forty-nine patients with negative lymph nodes were identified. A total of 976 formalin-fixed paraffin-embedded pelvic lymphadenectomy specimens were serially sectioned and stained with anti-cytokeratin antibodies AE1 and AE1/CAM5.2.Six patients had stage IA2 disease, 37 had stage IB1, and 6 had IB2. The mean age of the patients was 44 years (range, 24-76). Seventy-one percent had squamous cell carcinomas, 22% had adenocarcinomas, and 6% had other types. Lymph node micrometastases were immunohistochemically detected in 4 of the 49 (8.1%) patients, comprising 4 of 976 (0.41%) pelvic lymph nodes examined. Twelve of 45 (15.6%) patients with negative nodes had lymph-vascular space invasion (LVSI) whereas 3 of 4 (75%) patients with micrometastases had LVSI. At a mean follow-up time of 39.4 months, 2 of 4 (50%) patients with micrometastasis had recurrent disease, while 3 of 45 (6.7%) patients without micrometastasis developed recurrent disease.These preliminary data suggest that immunohistochemical detection of pelvic lymph nodes is more frequent in patients with LVSI and may identify patients needing adjuvant chemoradiation.

  View details for DOI 10.1016/j.ygyno.2003.11.033

  View details for Web of Science ID 000220850800016

  View details for PubMedID 15047221

• Cytomegalovirus infection in steroid-refractory ulcerative colitis - A case-control study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Kambham, N., Vij, R., Cartwright, C. A., Longacre, T. 2004; 28 (3): 365-373

  Abstract

  Cytomegalovirus (CMV) infection is reported to be a cause of steroid-refractory ulcerative colitis (UC), but the strength of this association has not been tested in a case control study. Controlled studies have also not been performed to determine the sensitivity of available immunohistochemical techniques to detect CMV in this setting. The pathology database at Stanford Hospital was searched for UC patients with a diagnosis of "severe colitis" between the years 1992 and 2002 and medical records were reviewed. Forty patients were identified with refractory UC, defined as poor response to highdose systemic steroids for >2 weeks. Another group of 40 patients with severe, but nonrefractory, UC was case-matched for age and year of biopsy. A series of 40 patients who underwent colectomy for reasons other than inflammatory bowel disease with representative sections of "normal" colon were selected as noncolitis controls. CMV inclusions were detected on hematoxylin and eosin (H&E) in 2 of 40 patients with refractory UC, but not in other patients. Immunohistochemistry (IHC) detected CMV in 10 of 40 (25%) patients with refractory UC and 1 of 40 (2.5%) patients with nonrefractory UC (P = 0.007). The CMV-positive cases initially identified on IHC but not on H&E were re-reviewed for viral inclusions on H&E: 3 had rare, but typical, inclusions; 3 had atypical inclusions; and 3 had no inclusions. CMV was not detected by H&E or IHC in 40 noncolitis controls. Of 10 steroid-refractory UC patients with CMV detected, 7 were refractory to cyclosporin or 6-mercaptopurine/azathioprine (70%) and 6 had undergone proctocolectomy (60%) prior to detection of the CMV. Two patients with recognized CMV infection were treated with gancyclovir, improved, and were able to taper off steroids and avoid proctocolectomy. This study provides evidence that unrecognized and therefore untreated CMV infection is significantly associated with steroid-refractory UC. Moreover, IHC is more sensitive than H&E for detection of CMV and should be considered as part of the routine evaluation of steroid-refractory UC patients, before proceeding with other medical or surgical therapy that may be unnecessary once the CMV is treated.

  View details for Web of Science ID 000189316500009

  View details for PubMedID 15104299

• Gene expression patterns in ovarian carcinomas MOLECULAR BIOLOGY OF THE CELL Schaner, M. E., Ross, D. T., Ciaravino, G., Sorlie, T., Troyanskaya, O., Diehn, M., Wang, Y. C., Duran, G. E., Sikic, T. L., Caldeira, S., Skomedal, H., Tu, I. P., Hernandez-Boussard, T., Johnson, S. W., O'Dwyer, P. J., Fero, M. J., Kristensen, G. B., Borresen-Dale, A. L., Hastie, T., Tibshirani, R., van de Rijn, M., Teng, N. N., Longacre, T. A., Botstein, D., Brown, P. O., Sikic, B. I. 2003; 14 (11): 4376-4386

  Abstract

  We used DNA microarrays to characterize the global gene expression patterns in surface epithelial cancers of the ovary. We identified groups of genes that distinguished the clear cell subtype from other ovarian carcinomas, grade I and II from grade III serous papillary carcinomas, and ovarian from breast carcinomas. Six clear cell carcinomas were distinguished from 36 other ovarian carcinomas (predominantly serous papillary) based on their gene expression patterns. The differences may yield insights into the worse prognosis and therapeutic resistance associated with clear cell carcinomas. A comparison of the gene expression patterns in the ovarian cancers to published data of gene expression in breast cancers revealed a large number of differentially expressed genes. We identified a group of 62 genes that correctly classified all 125 breast and ovarian cancer specimens. Among the best discriminators more highly expressed in the ovarian carcinomas were PAX8 (paired box gene 8), mesothelin, and ephrin-B1 (EFNB1). Although estrogen receptor was expressed in both the ovarian and breast cancers, genes that are coregulated with the estrogen receptor in breast cancers, including GATA-3, LIV-1, and X-box binding protein 1, did not show a similar pattern of coexpression in the ovarian cancers.

  View details for Web of Science ID 000186738300005

  View details for PubMedID 12960427

• Serous tumors of low malignant potential: Stanford update Longacre, T., Tazelaar, H., Kempson, R., Hendrickson, M. NATURE PUBLISHING GROUP. 2003: 199A-199A

  View details for Web of Science ID 000180720100918

• Emi-1 is upregulated in clear cell carcinomas of the ovary: A preliminary comparative analysis of protein expression using ovarian tissue arrays Gutgemann, I., Hsiu, I., Lehman, N., Montgomery, K., Masek, M., Jackson, P., Longacre, T. NATURE PUBLISHING GROUP. 2003: 191A-191A

  View details for Web of Science ID 000180720100879

• Protein expression study of ovarian surface epithelial neoplasms using tissue microarray analysis: Emergence of a clear cell signature profile Balzer, B., Schaner, M., Ross, D., Montgomery, K., Teng, N., Sikic, B., Longacre, T. NATURE PUBLISHING GROUP. 2003: 181A-181A

  View details for Web of Science ID 000180732500839

• Protein expression study of ovarian surface epithelial neoplasms using tissue microarray analysis: Emergence of a clear cell signature profile Balzer, B., Schaner, M., Ross, D., Montgomery, K., Teng, N., Sikic, B., Longacre, T. NATURE PUBLISHING GROUP. 2003: 181A-181A

  View details for Web of Science ID 000180720100836

• CagA status of Helicobacter pylori infection and p53 gene mutations in gastric adenocarcinoma CARCINOGENESIS Shibata, A., Parsonnet, J., Longacre, T. A., Garcia, M. I., Puligandla, B., Davis, R. E., Vogelman, J. H., Orentreich, N., Habel, L. A. 2002; 23 (3): 419-424

  Abstract

  Infection with Helicobacter pylori (H. pylori) increases stomach cancer risk. Helicobacter pylori strains with the cag pathogenicity island (PAI) induce more severe inflammation in the gastric epithelium and are more strongly associated with stomach cancer risk than strains lacking the PAI. We examined whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains. DNA from 105 microdissected tumor specimens was analyzed for mutation in exons 5-8 of the p53 gene by polymerase chain reaction-based single-strand conformation polymorphism followed by direct DNA sequencing. Enzyme-linked immunosorbent assays for IgG antibodies against H. pylori and CagA were performed on sera collected 2-31 years prior to cancer diagnosis. Tumors from CagA(+) subjects were significantly more likely to have p53 mutations than tumors from CagA(-) subjects (including H. pylori- and H. pylori(+)/CagA(-)): odds ratio = 3.72; 95% confidence interval, 1.06-13.07 after adjustment for histologic type and anatomic subsite of tumor and age at diagnosis and sex of subjects. Mutations were predominantly insertions and deletions (43%) as well as transition mutations at CpG dinucleotides (33%). The data suggest that CagA(+) H. pylori infection, when compared with CagA(-) infection or the absence of H. pylori infection, is associated with a higher prevalence of p53 mutation in gastric adenocarcinoma.

  View details for Web of Science ID 000174710400006

  View details for PubMedID 11895856

• Distinction between low grade endometrial stromal sarcoma and smooth muscle tumors by cDNA gene array analysis West, R. B., Linn, S. C., Nielsen, T., Zhu, S., Longacre, T., Husain, A., Alter, O., Patel, R., Brown, P. O., Botstein, D., Rubin, B. P., Goldblum, J. R., van de Rijn, M. NATURE PUBLISHING GROUP. 2002: 213A-214A

  View details for Web of Science ID 000173379700909

• Histological classification of gastric adenocarcinoma for epidemiological research: Concordance between pathologists CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Shibata, A., Longacre, T. A., Puligandla, B., Parsonnet, J., Habel, L. A. 2001; 10 (1): 75-78

  Abstract

  Epidemiology of gastric adenocarcinoma suggests that intestinal-type and diffuse-type cancers develop through distinct causal pathways. To examine the differences in risk factors and molecular changes between the histological types, reliable data on histological typing are essential. We evaluated the concordance between two pathologists in assessment of 95 gastric adenocarcinomas for Laurén classification and tumor grade. Two pathologists, each blinded to the other's assessment, reviewed H&E-stained slides of gastric tumor. The responses of the two pathologists for histological type were considered as concordant if they fell on one of the three categories (intestinal type, diffuse type, or other). Tumor grade was classified into three categories (well, moderately, or poorly differentiated). The pathologists agreed on the classification of histological type for 71 of 92 (77%) tumors. Kappa coefficient was 0.59 (95% confidence interval, 0.44-0.73). Concordance for tumor grade was 87%, with a kappa coefficient of 0.72 (95% confidence interval, 0.57-0.87). Both observed concordance and kappa coefficient for histological type and tumor grade were similar across three calendar periods of study. Interobserver agreement was virtually identical between tumors with biopsy specimens only and those with surgical specimens. Although the level of disagreement for histological type observed in this study is comparable with that in other studies, the resulting misclassification would lead to the reduction in observed differences in prevalence and odds ratio estimates between two histological types.

  View details for Web of Science ID 000166651600012

  View details for PubMedID 11205493

• Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Ramos, P. C., Kapp, D. S., Longacre, T. A., Teng, N. N. 2000; 10 (5): 429-434

  View details for Web of Science ID 000165402900013

• p53 overexpression and cell proliferation index in gastric cancer by anatomic subsite. Shibata, A., Garcia, M. I., Longacre, T. A., Puligandla, B., Parsonnet, J., Vogelman, J., Orentreich, N., Habel, L. A. OXFORD UNIV PRESS INC. 2000: S77-S77

  View details for Web of Science ID 000087460400307

• Malignant granular cell tumor of the vulva in a 17-year-old: Case report and literature review. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Ramos, P. C., Kapp, D. S., Longacre, T. A., Teng, N. N. 2000; 10 (5): 429-434

  Abstract

  Granular cell tumors are uncommon soft tissue tumors. Although the majority of these tumors are benign, a rare malignant variant exists which is aggressive, with local recurrence rates up to 70% and 3-year survival rates of less than 50%. We present a case of malignant granular cell tumor of the vulva in a 17-year-old, the sixth such case to be reported at this site. She was treated with a left hemivulvectomy and ipsilateral groin node dissection followed by postoperative radiation therapy. She remains free of disease at 16 months. Patients with malignant granular cell tumor or granular cell tumor of malignant potential are best managed with wide local excision and regional lymph node dissection.

  View details for PubMedID 11240710

• Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex-cord-like elements HUMAN PATHOLOGY Baker, R. J., Hildebrandt, R. H., Rouse, R. V., Hendrickson, M. R., Longacre, T. A. 1999; 30 (6): 671-679

  Abstract

  Uterine mesenchymal neoplasms with sex-cord-like elements are designated as endometrial stromal tumor with sex-cord-like elements (ESTSCLE) or uterine tumor resembling ovarian sex-cord tumor (UTROSCT), depending on the extent of sex-cord-like differentiation. Occasionally, sex-cord elements similar to those in ESTSCLE and UTROSCT occur in uterine adenosarcomas. To determine whether the sex-cord-like elements in these tumors show immunohistological evidence of sex-cord differentiation, we studied a series of uterine neoplasms for expression of inhibin, a peptide hormone expressed by normal ovarian granulosa cells and ovarian sex-cord neoplasms, and CD99, a protein also expressed by granulosa cells, Sertoli cells, and some ovarian sex-cord tumors. Thirty uterine mesenchymal neoplasms (five epithelioid or plexiform smooth muscle tumors, three endometrial stromal tumors, two mixed endometrial stromal and smooth muscle tumors, 10 ESTSCLE, five UTROSCT, and five miscellaneous stromal processes) and five epithelial neoplasms were evaluated for expression of CD99 (clone 12E7) and inhibin (clone R1) in formalin-fixed, paraffin-embedded tissue. Three of 10 (30%) ESTSCLE and five of five (100%) UTROSCT were inhibin and CD99 immunoreactive. Inhibin staining was confined to the areas with sex-cord-like differentiation, and staining was generally much stronger and more extensive in areas featuring prominent foam cells. There were no differences in the degree or intensity of staining for inhibin in premenopausal and postmenopausal women. CD99 expression tended to correlate with inhibin and was typically confined to similar cell types in the individual neoplasms. Weak CD99 immunoreactivity was seen in one additional epithelioid smooth muscle tumor, whereas all other mesenchymal and epithelial neoplasms studied for inhibin and CD99 were negative. These results provide further immunohistological support for true sex-cord differentiation within uterine mesenchymal proliferations and suggest that the degree of sex-cord differentiation may correlate with the expression of these markers.

  View details for Web of Science ID 000080836900014

  View details for PubMedID 10374776

• Diffusely infiltrative endometrial adenocarcinoma - An adenoma malignum pattern of myoinvasion AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., Hendrickson, M. R. 1999; 23 (1): 69-78

  Abstract

  The prognostic significance of a diffusely infiltrative intramyometrial growth pattern was evaluated in 110 cases of low-stage (stages I and II) endometrial adenocarcinoma. Fifty cases were associated with diffuse infiltration (DI group), and 50 cases had more conventional granulation tissue type intramyometrial infiltration (GTT group). Ten cases with carcinomatous involvement of deeply situated adenomyosis (ADMY group) were also studied. The diffusely infiltrative "adenoma malignum" growth pattern featured typically round, regular individual glands, clearly within myometrium but with minimal or absent stromal or inflammatory cell response. Myoinvasion of the conventional sort was characterized by irregular, sharply angulated abnormal glands within myometrium without interposed normal glands or endometrial stroma. The abnormal glands were surrounded, at least focally, by edematous stroma with granulation tissue type reaction and/or an inflammatory cell infiltrate. Mean follow-up was 77.8 months (range 3-219 months) for the patients with diffusely infiltrative myoinvasion and deep adenomyosis and 86.9 months (range 1-206 months) for the patients with conventional myoinvasion. Recurrence-free survival for patients with stage I disease and conventional myoinvasion (94%) was similar to that of patients with diffuse adenoma malignum infiltration (98%; p = 0.13). Survival rates for both groups were also similar. Two (4%) of the 50 patients with diffusely infiltrative adenoma malignum pattern of myoinvasion died of endometrial carcinoma 36 and 72 months after hysterectomy, and 2 (4%) of the 50 patients with conventional myoinvasion died 34 and 67 months after hysterectomy (p = 0.41). Survival in these patients correlated with depth of myometrial invasion and stage. There were no recurrences in the patients with deep adenomyosis. These results suggest that although endometrial carcinomas with diffuse myometrial infiltration are fully capable of aggressive clinical behavior, they do not appear to behave any more aggressively than those with conventional myometrial invasion. Prognostic indicators of clinically aggressive disease are similar to those that have been previously identified for endometrial carcinomas with the more conventional pattern of myometrial infiltration. They include cervical involvement, deep myometrial invasion, higher histologic grade, and lymph-vascular space invasion. Endometrial carcinomas with extensive involvement of adenomyosis and adjacent foci of minimal myometrial infiltration appear to have very low malignant potential, but the number of cases with this finding and adequate clinical follow-up is limited. This finding needs to be confirmed in a much larger series of cases.

  View details for Web of Science ID 000077886000007

  View details for PubMedID 9888705

• Initial experience with a physiologic morcellating resectoscope JOURNAL OF THE AMERICAN ASSOCIATION OF GYNECOLOGIC LAPAROSCOPISTS Kresch, A. J., Longacre, T., Feste, J. R., Lotze, E. C., Westland, A., Miller, G., Savage, G. 1998; 5 (4): 419-421

  Abstract

  A new physiologic morcellating resectoscope allows operative hysteroscopy to be performed with a physiologic distention medium, thus reducing the risk of dilutional hyponatremia and cerebral edema secondary to excessive absorption of nonphysiologic fluid. To study this new technology, we gathered in vitro data with the SL resectoscope with dual-function electrode (FemRx, Sunnyvale, CA). Coupled to a standard monopolar electrosurgery unit and operating in normal saline or Ringer's lactate solution, extirpated uteri showed equivalent depth of tissue necrosis with this new physiologic morcellating resectoscope as with a conventional monopolar resectoscope used in an electrically nonconductive fluid.

  View details for Web of Science ID 000082612600015

  View details for PubMedID 9782148

• Chemo-radiotherapy for localized pancreatic cancer: Increased dose intensity and reduced acute toxicity with concomitant radiotherapy and protracted venous infusion 5-fluorouracil INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Poen, J. C., Collins, H. L., Niederhuber, J. E., Oberhelman, H. A., Vierra, M. A., Bastidas, A. J., Young, H. S., Slosberg, E. A., Jeffrey, B. R., Longacre, T. A., Fisher, G. A., Goffinet, D. R. 1998; 40 (1): 93-99

  Abstract

  Although concomitant radiation therapy (RT) and bolus 5-Fluorouracil (5-FU) have been shown to improve survival in locally confined pancreatic cancer, most patients will eventually succumb to their disease. Since 1994, we have attempted to improve efficacy by administering 5-FU as a protracted venous infusion (PVI). This study compares treatment intensity and acute toxicity of consecutive protocols of concurrent RT and 5-FU by bolus injection or PVI.Since 1986, 74 patients with resected or locally advanced pancreatic cancer were treated with continuous course RT and concurrent 5-FU by bolus injection (n = 44) or PVI throughout the course of RT (n = 30). Dose intensity was assessed for both 5-FU and radiotherapy. Toxicity endpoints which could be reliably and objectively quantified (e.g., neutropenia, weight loss, treatment interruption) were evaluated.Cumulative 5-FU dose (mean = 7.2 vs. 2.5 gm/m2, p < 0.001) and weekly 5-FU dose (mean = 1.3 vs. 0.5 gm/m2/wk, p < 0.001) were significantly higher for patients receiving PVI 5-FU. Following pancreaticoduodenectomy, 95% of PVI patients maintained a RT dose intensity of > or = 900 cGy/wk, compared with 63% of those receiving bolus 5-FU (p = 0.02). No difference was seen for patients with locally advanced disease (72% vs. 76%, p = n.s.). Grade II-III neutropenia was less common for patients treated with PVI (13% vs. 34%, p = 0.05). Grade II-III thrombocytopenia was uncommon (< or = 3%) in both treatment groups. Mean percent weight loss (3.8% vs. 4.1%, p = n.s.) and weight loss > or = 5% of pre-treatment weight (21% vs. 31%, p = n.s.) were similar for PVI and bolus treatment groups, respectively. Treatment interruptions for hematologic, gastrointestinal or other acute toxicities were less common for patients receiving PVI 5-FU (10% vs. 25%, p = 0.11).Concurrent RT and 5-FU by PVI was well tolerated and permitted greater chemotherapy and radiotherapy dose intensity with reduced hematologic toxicity and fewer treatment interruptions compared with RT and bolus 5-FU. Longer follow-up will be needed to assess late effects and the impact on overall survival.

  View details for Web of Science ID 000071164200015

  View details for PubMedID 9422563

• Diffusely infiltrative endometrial adenocarcinoma: An adenoma malignum pattern of myoinvasion Longacre, T. A., Hendrickson, M. R. NATURE PUBLISHING GROUP. 1998: 108A-108A

  View details for Web of Science ID 000071793400645

• Value of inhibin in the identification of granulosa cell tumors of the ovary HUMAN PATHOLOGY Hildebrandt, R. H., Rouse, R. V., Longacre, T. A. 1997; 28 (12): 1387-1395

  Abstract

  Inhibins are peptide hormones that participate in the regulation of the pituitary-gonadal feedback system and are selectively expressed by cells of sex cord-stromal derivation. To determine the efficacy of this marker for distinguishing granulosa cell tumors, 134 primary and metastatic lesions of the ovary were evaluated for expression of the alpha-subunit of inhibin in routinely processed formalin-fixed, paraffin-embedded tissue. A variety of sex cord-stromal tumors (SCST), including 35 adult and juvenile granulosa cell tumors, 14 fibroma-thecomas, and 18 other sex cord-stromal proliferations, were studied. In addition, 33 surface epithelial neoplasms, 12 germ cell tumors, 11 metastases, and 11 miscellaneous ovarian neoplastic proliferations were evaluated. Among the non-granulosa cell neoplasms, special emphasis was placed on primary neoplasms and metastases that histologically simulated granulosa cell tumors. Thirty-three of 35 (94%) granulosa cell tumors were immunoreactive compared with 2 of 12 (17%) primary ovarian endometrioid tumors, one of nine (11%) primary ovarian transitional cell (Brenner) proliferations, and 3 of 17 (18%) other primary and metastatic poorly differentiated (undifferentiated) carcinomas. In 31 of the 35 granulosa cell tumors, inhibin staining was of moderate to strong intensity or was present in at least half of the constituent cells, whereas only 2 of 33 primary surface epithelial neoplasms fulfilled the same criteria, showing weak staining of 70% to 80% of the cells. In contrast, 10 of 14 (71%) ovarian fibroma-thecomas and 17 of 18 (94%) other sex cord-stromal proliferations were positive for inhibin. Nonneoplastic luteinized stromal cells stained for inhibin in 29 of 85 cases in which they could be evaluated. The results of this study show that although it is not completely specific and cannot reliably distinguish granulosa cell tumors from fibroma-thecomas or other ovarian sex cord-stromal proliferations, inhibin can be used to help distinguish sex cord-stromal neoplasms from most primary and metastatic non-SCST. Caution should be exercised in the interpretation of inhibin-positive cells, because a wide variety of primary and metastatic ovarian tumors may contain significant numbers of positively staining luteinized cells.

  View details for Web of Science ID 000071093200010

  View details for PubMedID 9416696

• Bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis following controlled ovarian hyperstimulation and in vitro fertilization JOURNAL OF ASSISTED REPRODUCTION AND GENETICS Ditkoff, E. C., Tucker, T., LEVINE, R. U., Lindheim, S. R., Sauer, M. V., Longacre, T. 1997; 14 (4): 230-233

  Abstract

  We report a case of bilateral serous cystadenofibromas clinically simulating hyperreactio luteinalis during a normal pregnancy resulting from controlled ovarian stimulation and in vitro fertilization. Incomplete regression at 2-year follow-up prompted surgical intervention. This case demonstrates that the clinical and sonographic features that have been associated with hyperreactio luteinalis are not specific for this condition and emphasizes the need for close clinical follow-up in all presumptive cases for which a histologic diagnosis has not been established.

  View details for Web of Science ID A1997WV35600012

  View details for PubMedID 9130073

• Multiple mesenteric lymphatic cysts: An unusual feature of mesenteric panniculitis (Sclerosing mesenteritis) JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY Johnson, L. A., Longacre, T. A., Wharton, K. A., Jeffrey, R. B. 1997; 21 (1): 103-105

  View details for Web of Science ID A1997WF02100019

  View details for PubMedID 9022778

• Desmoplastic and spindle-cell malignant melanoma - An immunohistochemical study AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., Egbert, B. M., Rouse, R. V. 1996; 20 (12): 1489-1500

  Abstract

  The clinical, histologic, and immunohistologic features of 22 desmoplastic melanomas (DMM), 10 mixed desmoplastic and spindle-cell melanomas (DMM/SMM), and two cellular spindle-cell melanomas (SMM) were studied. Patients ranged in age from 35 to 91 years (mean, 67) and included 23 men and 11 women. Seventeen cases occurred in sun-damaged skin of the head and neck. 11 were on the extremities, and six on the trunk. Except for two cases, all were Clark's level IV or V. Twenty-two (65%) cases were associated with a recognizable overlying pigmented lesion. Thirty of 32 (94%) DMM and DMM/SMM were clearly positive for S100. S100 staining was limited to < 5% of the spindle cells in two DMM/SMM. All DMM were negative when stained with HMB45. Three DMM/ SMM were immunoreactive with HMB45, as were both SMM. CD68 staining was limited to < 5% of the spindle cells in two of 32 DMM and DMM/SMM and 20% of the cells in one of two SMM. Nine (32%) DMM and DMM/SMM contained significant numbers of spindle cells immunoreactive for SMA but not desmin. In five cases, the number of actin-positive spindle cells. Two color stains for SMA and S100 demonstrated that these smooth-muscle actin positive cells constituted a separate spindle-cell population, consistent with reactive myofibroblasts. This study indicates that the immunohistologic features of desmoplastic melanoma differ from those of conventional melanoma. If a problematic spindle-cell skin lesion is a suspected melanocytic process, HMB45 is unlikely to provide confirmatory (or exclusionary) evidence for the diagnosis of DMM. Similarly, because of the variability in S100 expression in this neoplasm, the absence of S100 staining should not be relied on too heavily to exclude DMM if the clinical and histologic features favor that diagnosis. Caution should be exercised in the interpretation of numerous actin-positive spindle cells in isolation of additional confirmatory or exclusionary data as desmoplastic melanomas may contain significant numbers of these cells.

  View details for Web of Science ID A1996VV54400008

  View details for PubMedID 8944042

• Lymphangioleiomyomatosis of the uterus simulating high-stage endometrial stromal sarcoma GYNECOLOGIC ONCOLOGY Longacre, T. A., Hendrickson, M. R., Kapp, D. S., Teng, N. N. 1996; 63 (3): 404-410

  Abstract

  Symptomatic uterine lymphangioleiomyomatosis (LAM) simulating high-stage uterine sarcoma in a patient with tuberous sclerosis complex is reported. A 49-year-old female presented with abdominal pain and anemia. Preoperative workup revealed a uterine mass and a large amount of peritoneal free fluid and possible metastatic implant along the lateral edge of the liver. The patient also had a large right pleural effusion. A fungating anterior uterine fundal mass with apparent perforation and intraabdominal hemorrhage was found on laparotomy. A portion of the mass was excised and initially interpreted as an endometrial stromal sarcoma. Microscopic examination revealed multiple vascular epithelioid smooth muscle proliferations in the uterus and serosal surface of the fallopian tube and periaortic lymph node lymphangioleiomyomas. The uterine, fallopian tube, and nodal lesions were positive for smooth muscle actin, desmin, and HMB-45, findings characteristic of LAM. Additional examination of the patient revealed stigmata of tuberous sclerosis complex. Although uterine LAM is uncommon, it may be associated with pelvic and/or abdominal symptoms and may simulate a primary uterine mesenchymal neoplasm.

  View details for Web of Science ID A1996VY31800021

  View details for PubMedID 8946880

• Adenoid cystic carcinoma of the submandibular gland with symptomatic ovarian metastases INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Longacre, T. A., OHANLAN, K., Hendrickson, M. R. 1996; 15 (4): 349-355

  Abstract

  We report the clinical and pathologic features of an adenoid cystic carcinoma of the submandibular gland that metastasized to the ovaries 10 years after initial presentation. A 30-year-old woman underwent excision of a right submandibular adenoid cystic carcinoma followed by regional external beam radiation therapy. Three years later, she underwent extended hepatic resection and localized radiotherapy to the hepatic region for metastatic disease. The patient was without evidence of disease for 7 years when she developed pelvic pain and a pelvic mass was found. A solid and cystic 10-cm left ovarian mass and a single metastatic tumor nodule involving the right ovary were excised via the laparoscope. Histologically, the tumor was identical to the patient's initial salivary gland neoplasm. The neoplastic cells were CAM 5.2 positive, S100 positive, muscle-specific actin positive, and smooth muscle actin positive. Ultrastructurally, characteristic pseudocysts (pseudolumina) with abundant basal lamina and true glandular lumina lined by short microvilli were present. Other than a single anecdotal account of a parotid gland adenoid cystic carcinoma, this case represents the first documented report of an adenoid cystic carcinoma of salivary gland origin that was associated with symptomatic ovarian metastases. This case demonstrates that the ovary is a potential site for metastatic disease many years following the diagnosis and treatment for a primary neoplasm however uncommon or remote the site of origin. Since metastatic adenoid cystic carcinoma can rarely present as an ovarian mass, a clinical history of this neoplasm should be heavily weighed in the differential diagnosis of any unusual ovarian tumor with a predominant cribriform, trabecular, or tubular pattern.

  View details for Web of Science ID A1996VJ06600008

  View details for PubMedID 8886883

• Transitional cell neoplasms of the ovary and urinary bladder: A comparative immunohistochemical analysis INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Soslow, R. A., Rouse, R. V., Hendrickson, M. R., Silva, E. G., Longacre, T. A. 1996; 15 (3): 257-265

  Abstract

  Walthard cell nests, the Brenner tumor (benign, proliferating, low malignant potential, and malignant), and primary ovarian transitional cell carcinoma are considered to be primary female genital tract proliferations of transitional-type (urothelial) epithelium on conventional light microscopic grounds. In order to further investigate the similarities (or dissimilarities) of proliferations of female genital tract transitional epithelium and urothelium, we compared transitional cell proliferations (TCPs) of the female genital tract (n = 25) and urinary bladder (n = 15) using antibodies to carcinoembryonic antigen (CEA; clone 0062), carbohydrate determinant 19-9 (CA19-9; clone 1116-NS-19-9), cytokeratin 7 (CK-7; clone OV-TL 12/30), and cytokeratin 20 (CK-20; clone Ks 20.8), four monoclonal antibodies that have been shown to stain transitional cell urothelial proliferations. Both groups of tumors exhibited significant staining for CEA, CA19-9, and CK-7, and the difference in numbers of cases staining was not significant. CA19-9 was present in 15 of 25 female genital tract TCPs as compared with 12 of 15 bladder TCPs; CEA was present in 17 of 25 female genital tract TCPs and nine of 15 comparable bladder TCPs. CK-7 was present in all cases studied with the exception of one Walthard cell nest and a malignant Brenner tumor that was not immunoreactive with the other antibodies tested. In contrast, 13 of 15 bladder TCPs were CK-20 positive, whereas only one of 25 female genital tract TCPs was positive (< 5% of cells). Walthard cell nests and benign Brenner tumors were more likely to be CA19-9 positive than were Brenner tumors of low malignant potential, malignant Brenner tumors, and primary transitional cell carcinoma of the ovary. We conclude that despite their apparent morphologic and immunologic similarity to TCPs of the urinary bladder (particularly at the histologically low-grade end of the transitional cells spectrum), Walthard cell nests and ovarian Brenner tumors constitute an immunophenotypically distinct form of TCP.

  View details for Web of Science ID A1996UU92400011

  View details for PubMedID 8811388

• Atypical polypoid adenomyofibroma (APA) versus well-differentiated endometrial carcinoma with prominent stromal matrix: An immunohistochemical study INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Soslow, R. A., Chung, M. H., Rouse, R. V., Hendrickson, M. R., Longacre, T. A. 1996; 15 (3): 209-216

  Abstract

  It can be extremely difficult in some cases to distinguish atypical polypoid adenomyomas (APAs) from invasive adenocarcinoma in an endometrial curettage or biopsy specimen. In order to determine if immunophenotypic features can be exploited to differentiate between these two entities in problematic cases, a series of APAs and myoinvasive well-differentiated endometrial carcinomas (WDCAs) were studied with a panel of standard immunohistochemical markers. All 23 APAs had stromal smooth muscle actin (SMA) reactivity, 12 of 23 had variable degrees of stromal desmin reactivity, and nine of 22 had CD34-positive stromal cells. All epithelial components of the APAs were cytokeratin (AE1 and CAM5.2) positive, whereas 22 of 23 were positive for estrogen receptor (ER) and progesterone receptor (PR). Among the 10 myoinvasive WDCAs, all contained at least some SMA-positive stromal cells, seven of 10 desmin-positive stromal cells, and four of eight CD34-positive stromal cells. All carcinomas studied demonstrated CAM5.2 and PR-positive epithelia; nine of 10 were ER positive. We conclude that the immunophenotype of APAs does not differ significantly from well-differentiated endometrial adenocarcinoma and that immunophenotyping is of little value in distinguishing APA from carcinoma. Because the stroma in APAs histologically and immunophenotypically more closely resembles a hybrid myofibromatous stroma, we prefer to refer to these lesions with the modified designation "atypical polypoid adenomyofibroma," although "APA" may be retained for clinical use.

  View details for Web of Science ID A1996UU92400004

  View details for PubMedID 8811381

• Atypical polypoid adenomyofibromas (atypical polypoid adenomyomas) of the uterus - A clinicopathologic study of 55 cases AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., Chung, M. H., Rouse, R. V., Hendrickson, M. R. 1996; 20 (1): 1-20

  Abstract

  We present the clinicopathological and immunohistochemical features of 55 atypical polypoid adenomyofibromas, a definitional expansion of an entity previously reported as "atypical polypoid adenomyoma" (APA) of the uterus. Patients ranged in age from 25 to 73 (mean, 39.9) years. All but two of the patients were premenopausal, and 14 were undergoing evaluation for infertility. Histologically, the lesions featured a biphasic proliferation of architecturally complex and cytologically atypical endometrial glands within a myofibromatous stroma. The histologic pattern ranged from widely separated and loosely clustered irregular but branched glands embedded in broad zones of cellular myofibromatous stroma to those possessing crowded, markedly complex, branching glands separated by sparse intersecting fascicles of fibromuscular tissue. The stroma in all cases was actin or desmin positive or both. Morular/squamous metaplasia was present in all but two cases and florid in most. All cases exhibited architecturally complex glands, and in 25 cases the architectural complexity was indistinguishable from that of well-differentiated endometrial adenocarcinoma, as we have defined it; that is, they had a high architectural index. Twenty-nine patients were initially treated with polypectomy or curettage followed by hormonal therapy; persistent or recurrent APA developed in 45% of the patients in this group (33% with low architectural index vs. 60% with high architectural index). Five patients had successful pregnancies despite persistent disease. Superficial myoinvasion was identified in the hysterectomy specimen in two of 12 APAs with a high architectural index but not in 21 APAs with a low architectural index. All patients are alive and well 1 to 112 months after diagnosis (mean, 25.2 months). On the basis of this study, we propose that APAs with markedly complex glands (high architectural index) be designated "atypical polypoid adenomyofibromas of low malignant potential" (APA-LMP) to emphasize the potential risk for myometrial invasion. A treatment program featuring local excision accompanied by close follow-up is warranted for APA despite the presence of recurrent or persistent disease. Patients with APA-LMP may also, in selected cases, be managed with less than hysterectomy, although (as with the usual well-differentiated carcinoma) there is a small but definite risk associated with this approach.

  View details for Web of Science ID A1996TQ55700001

  View details for PubMedID 8540600

• The female genital tract. Pathology (Philadelphia, Pa.) Longacre, T. A., Teng, N. N., Hendrickson, M. R. 1996; 3 (2): 427-492

  View details for PubMedID 8795830

• Estrogen and progesterone receptors and anti-gross cystic disease fluid protein 15 (BRST-2) fail to distinguish metastatic breast carcinoma from eccrine neoplasms MODERN PATHOLOGY Wallace, M. L., Longacre, T. A., SMOLLER, B. R. 1995; 8 (9): 897-901

  Abstract

  Cutaneous metastases of breast carcinoma can be histologically similar to primary skin tumors with eccrine differentiation. We compared the immunohistochemical staining characteristics of 15 metastatic breast carcinoma skin lesions in 12 patients to those of a series of primary eccrine tumors using estrogen receptor, progesterone receptor, and anti-gross cystic disease fluid protein-15 markers. Anti-gross cystic disease fluid protein-15 positivity was noted in 7 of 15 breast carcinoma skin metastases, 0 of 5 benign eccrine tumors, 1 of 6 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinoma. Estrogen receptor positivity was found in 1 of 15 metastatic breast carcinoma skin lesions, 0 of 5 benign eccrine tumors, 2 of 8 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinoma. Progesterone receptor positivity was identified in 15 of 15 metastatic breast carcinoma skin lesions, 2 of 5 benign eccrine tumors, 5 of 8 microcystic adnexal carcinomas, and 1 of 1 metastatic sweat gland adenocarcinomas. These results indicate that standard immunohistochemical staining for estrogen receptors, progesterone receptors, and gross cystic fluid protein-15 markers will not reliably distinguish primary (or metastatic) eccrine tumors from cutaneous metastases of breast carcinoma.

  View details for Web of Science ID A1995TK95100002

  View details for PubMedID 8751328

• OVARIAN-CARCINOMA METASTASES TO GASTROINTESTINAL-TRACT APPEAR TO SPREAD LIKE COLON-CARCINOMA - IMPLICATIONS FOR SURGICAL RESECTION OHANLAN, K. A., Kargas, S., Schreiber, M., Burrs, D., Mallipeddi, P., Longacre, T., Hendrickson, M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 1995: 200-206

  Abstract

  To profile the incidence of mesenteric lymph node metastases in patients with ovarian carcinoma and metastases to the gastrointestinal tract in order to determine the optimal technique for surgical debulking.The slides and charts of all patients with ovarian carcinoma who had undergone bowel resection were retrospectively reviewed and follow-up information was obtained.Of 100 separate bowel resections 44% had penetration of metastases to the muscularis, 18% had invasion through the submucosa, 4% had mucosal perforation, and two patients had clinical perforation. Fifty-five percent of all resections demonstrated lymph-vascular space invasion (LVSI). In the 33 specimens which included pathologic analysis of mesenteric lymph nodes, 79% had positive LVSI, which correlated with the presence of mesenteric lymph node metastases (P = 0.05) but not histologic grade (P = 0.20). When surgery was performed for secondary debulking, the frequency of mesenteric node metastasis was higher (P = 0.15). There was a trend for patients with positive mesenteric nodes to fail sooner (median survival, 20 months vs 32 months).Because ovarian carcinoma metastases to the gastrointestinal tract are frequently associated with metastases to mesenteric lymph nodes, gynecologic oncology surgeons may wish to consider resection of the mesentery in a wedge fashion similar to current standards of resection for primary bowel carcinoma in cases in which a bowel resection is being performed with the intent to debulk to zero visible residual disease.

  View details for Web of Science ID A1995TD64900008

  View details for PubMedID 7590473

• ESOPHAGEAL SUBMUCOSAL GLAND DUCT ADENOMA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Rouse, R. V., Soetikno, R. M., Baker, R. J., BARNARD, I. C., Triadafilopoulos, G., Longacre, T. A. 1995; 19 (10): 1191-1196

  Abstract

  An 81-year-old man with a 3-year history of dysphagia underwent endoscopic resection of a 1-cm-diameter distal esophageal mass. Examination revealed a submucosal neoplasm with a circumscribed growth pattern composed of tubules, cysts, and papillae in association with a marked interstitial lymphoid infiltrate. The cyst lumens and papillae were lined by two to six layers of cytologically bland cuboidal to columnar cells with rare mitotic figures. The basal layer of cells was uniformly positive for smooth-muscle actin. Mucin-positive intracytoplasmic lumens were focally present, but cytoplasmic mucin was not seen. There was no evidence of Barrett's metaplastic epithelium. These features are similar to those in two, possibly three, previously reported cases of esophageal adenomas and bear a resemblance to sialadenoma papilliferum, a rare neoplasm of the minor salivary glands. Their clinicopathologic and immunohistologic features suggest that these neoplasms derive from the submucosal gland ducts. Comparison with the previously reported cases indicates that although the proportions of the various components (tubules, cysts, and papillae) may vary, all cases appear to pursue a slowly growing, clinically indolent course with no evidence of recurrence after complete resection.

  View details for Web of Science ID A1995RX22600009

  View details for PubMedID 7573677

• PROPOSED CRITERIA FOR THE DIAGNOSIS OF WELL-DIFFERENTIATED ENDOMETRIAL CARCINOMA - A DIAGNOSTIC-TEST FOR MYOINVASION AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., Chung, M. H., Jensen, D. N., Hendrickson, M. R. 1995; 19 (4): 371-406

  Abstract

  Existing criteria for separating clinically benign but architecturally complex or cytologically atypical endometrial proliferations (hyperplasia or metaplasia) from well-differentiated endometrial carcinoma are underspecified and poorly reproducible, in part due to the absence of a uniformly agreed on methodologically independent outcome against which to judge the efficacy of competing sets of criteria. Because myoinvasion is the first unambiguous indicator of clinically aggressive behavior for proliferations in this spectrum, we have employed the presence or absence of myoinvasion as a tool to develop clinically meaningful diagnostic criteria for the separation of complex atypical hyperplasia/metaplasia from well-differentiated carcinoma (CAHM/WDCA). We obtained the paired endometrial samplings and hysterectomy specimens of 520 patients; these were split into a training set of 306 cases and a test set of 214. The presence or absence of myoinvasion was assessed from an examination of the hysterectomy specimen. For the purposes of this study, myoinvasion was defined as the presence of irregular intramyometrial glands surrounded by a granulation tissue-like response. To determine the morphologic features that were most predictive of myoinvasion, a series of endometrial architectural, cytological, and stromal features was initially evaluated on the training set (149 myoinvasive and 157 nonmyoinvasive). Using a variety of exploratory data techniques including the classification algorithm CART, we developed a diagnostic rule for predicting myoinvasion that employed one architectural feature (glandular complexity captured by a pictorial architectural index) and two cytological features (nuclear pleomorphism and prominence of nucleoli). Extensive squamous differentiation, fibroblastic stroma, necrosis, stromal foam cells, and other cytologic features did not provide additional predictive value when cross-validated. The true misclassification rate of the CART-generated prediction rule was further assessed by applying the rule to the test set drawn largely from community hospitals. The sensitivity and specificity of this rule for detecting myoinvasion was 99.5 and 57%. The likelihood ratio was 2:1, (i.e., using prior odds of myoinvasion in the CAHM/WDCA spectrum of 1:10, the posterior odds on myoinvasion using the CART-generated rule would be 1:5). Comparison of the CART-generated myoinvasion prediction rule with the Kurman and Norris endometrial stromal invasion criteria for well differentiated endometrial carcinoma (25), using receiver operator characteristic curve (ROC) techniques, demonstrated a significant improvement in the ability to separate myoinvasive from non-myoinvasive endometrial proliferations with the CART-generated rule; the average area under the curve for the CART-generated rule was 0.78 (SE = 0.02) versus 0.67 (SE = 0.03) for the endometrial stromal invasion criteria.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for Web of Science ID A1995QQ47400001

  View details for PubMedID 7694941

• UTERINE PAPILLARY SEROUS CARCINOMA REVISITED GYNECOLOGIC ONCOLOGY Hendrickson, M. R., Longacre, T. A., Kempson, R. L. 1994; 54 (3): 261-263

  View details for Web of Science ID A1994PK89200001

  View details for PubMedID 8088601

• HEMATOGONES IN THE BONE-MARROW OF ADULTS - IMMUNOPHENOTYPIC FEATURES, CLINICAL SETTINGS, AND DIFFERENTIAL-DIAGNOSIS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Davis, R. E., Longacre, T. A., Cornbleet, P. J. 1994; 102 (2): 202-211

  Abstract

  Hematogones (HGs) comprise a B-lineage lymphoid precursor cell population in the bone marrow (BM) that may simulate acute lymphoblastic leukemia or lymphoma. Increased numbers of HGs have been noted in children, but few reports describe their occurrence in adults. We identified 13 adult patients with significant numbers of BM lymphoid cells with the morphologic and immunophenotypic features of HGs. Common features in these patients included (1) presence of small numbers of lymphoid cells in the BM aspirate with morphologic features of HGs; (2) absence of cytologic atypia or abnormal localization of lymphoid cells in the BM biopsy; (3) absence of abnormal morphology or CD10 (common acute lymphoblastic leukemia antigen) expression in circulating lymphocytes; (4) normal BM karyotype; (5) persistence of cytopenia(s) without apparent cause, often for a prolonged period of time; and (6) no evidence of neoplastic marrow involvement, confirmed by clinical follow-up. Flow cytometry demonstrated surface expression of CD10, CD19, a lower percentage of CD20, minimal expression of CD22, and limited but polyclonal immunoglobulin light chain. Nine patients had received previous immunosuppressive therapy or BM transplantation or both, seven for hematolymphoid neoplasia. However, four patients with cytopenias of unknown etiology had no antecedent history of malignancy or marrow suppressive therapy. These findings demonstrate the clinical, morphologic, and immunophenotypic features of HGs in adults, and emphasize the difficulty in distinguishing these cells from residual marrow blasts after chemotherapy.

  View details for Web of Science ID A1994PA50000014

  View details for PubMedID 8042590

• ATYPICAL FIBROXANTHOMA - MULTIPLE IMMUNOHISTOLOGIC PROFILES AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., SMOLLER, B. R., Rouse, R. V. 1993; 17 (12): 1199-1209

  Abstract

  The clinical, histologic, and immunohistochemical features of 37 cases of atypical fibroxanthoma (AFX) are presented. Patients ranged in age from 13 to 95 years (mean, 69). Thirty AFXs occurred on the head and neck, and seven lesions developed on the trunk or extremities. The morphologic spectrum varied from a predominant spindle cell pattern with focal cellular pleomorphism to numerous bizarre epithelioid cells with multinucleated giant cells. The spindle cell component in these lesions ranged from 10 to 90% of the constituent cells. Most (31 of 37) AFXs also contained pleomorphic giant cells. Small numbers of S-100-positive dendritic cells were present in 11 cases. Five cases showed variable reactivity with anti-factor-XIIIa. Fifteen (41%) of the AFXs stained for muscle-specific actin or smooth muscle actin and 21 (57%) expressed CD68 (detected with monoclonal KP1), a monocyte-macrophage marker. Reactivity for these antigens was seen in all lesional cell types (spindled, epithelioid, and bizarre). Four immunologic profiles were observed: CD68 only (13 cases), actin only (7 cases), double positives (8 cases), and double negatives (9 cases). No significant differences in staining characteristics were observed in the head and neck versus the trunk and extremity lesions. These results expand the immunohistochemical spectrum of AFX, suggest the concept of heterogenous bimodal "fibrohistiocytic" and "myofibroblastic" phenotypes, and provide further evidence that an integrative, nonalgorithmic approach is necessary in the analysis of these and other spindle cell cutaneous lesions.

  View details for Web of Science ID A1993MJ16100001

  View details for PubMedID 8238729

• LEUKEMIA-CUTIS - ANALYSIS OF 50 BIOPSY-PROVEN CASES WITH AN EMPHASIS ON OCCURRENCE IN MYELODYSPLASTIC SYNDROMES AMERICAN JOURNAL OF CLINICAL PATHOLOGY Longacre, T. A., SMOLLER, B. R. 1993; 100 (3): 276-284

  Abstract

  The hematologic, cytomorphologic, and cytogenetic features of 50 cases of leukemia cutis (LC), occurring in 40 patients, are presented. The patients' ages ranged from 19 to 75 years (mean, 42 years). The primary hematologic diagnoses in these patients included acute non-lymphoblastic leukemia (ANLL), 13 patients; myelodysplastic syndrome (MDS), 19 patients; chronic lymphocytic leukemia, 3 patients; chronic granulocytic leukemia, 3 patients; and polycythemia vera, 1 patient. Leukemia cutis developed in one patient without any known prior or subsequent hematologic disorder. The 13 cases of ANLL included French-American-British types M1 (1 case), M2 (5 cases), M3 (1 case), M4 (5 cases), and M5 (1 case). Leukemia cutis preceded blood and/or bone marrow manifestations of leukemia in nine patients with MDS and one with ANLL. The interval from skin biopsy to systemic leukemia ranged from 3 weeks to 20 months (mean, 6 months). In seven patients with MDS and three patients with ANLL, LC occurred concomitantly with leukemic transformation. Only two patients with MDS and LC did not have progression to acute leukemia during the 20 and 24 months they have been observed. Diagnoses other than LC initially were considered in five of the patients. LC was characterized most often by a dense mixed cellular dermal infiltrate that circumscribed vascular and adnexal structures. Nine patients with MDS (47%) and one with ANLL (8%) had complex chromosomal abnormalities in their bone marrow samples at the time of LC. This article reports the occurrence of LC in patients with MDS and suggests that LC is an early manifestation of leukemic transformation in these patients. These results may be important in identifying high-risk patients for early interventional therapy.

  View details for Web of Science ID A1993LX16000014

  View details for PubMedID 8379536

• Well-differentiated serous neoplasms of the ovary. Pathology (Philadelphia, Pa.) Longacre, T. A., Kempson, R. L., Hendrickson, M. R. 1993; 1 (2): 255-306

  Abstract

  Serous neoplasms of the ovary, which constitute the largest subgroup of the surface epithelial tumors, cluster into three distinctly clinicopathologic groups: benign neoplasms, which are architecturally noncomplex, confined to the ovary, and composed of cytologically bland cells; carcinomatous neoplasms, which have spread beyond the ovary and are cytologically malignant; and an intermediate group, which raises serious problems in taxonomy, differential diagnosis, and prognosis. This chapter focuses on differential diagnosis, emphasizing the authors' experience as well as reports from other investigators.

  View details for PubMedID 9420921

• MORPHOLOGIC CRITERIA FOR WELL DIFFERENTIATED ENDOMETRIAL CARCINOMA - A PROPOSED DIAGNOSTIC-TEST FOR MYOINVASION Longacre, T. A., Chung, M. H., Jensen, D., Hendrickson, M. R. NATURE PUBLISHING GROUP. 1993: A76-A76

  View details for Web of Science ID A1993KJ10200444

• Classification of surface epithelial neoplasms of the ovary. Pathology (Philadelphia, Pa.) Hendrickson, M. R., Longacre, T. A. 1993; 1 (2): 189-254

  Abstract

  Surface epithelial neoplasms of the ovary, which represent about two-thirds of all primary ovarian neoplasms and almost 90% of all malignant ovarian tumors, are a variegated and heterogeneous collection of proliferations. The standard classification of ovarian neoplasms is the system developed by the World Health Organization in 1973; various studies, however, have found that observer variability for problematic cases is substantial. Prognosis and quality assurance make this variability a major concern. The authors examine the reasons behind this variability, the theories behind classification systems in general, problems of taxonomy, and the significance of confidence intervals. Appendices develop more fully the authors' approach to problems of classification and interobserver agreement, with notes on specific differentiated types of ovarian neoplasms.

  View details for PubMedID 9420920

• Clinicopathology of malignant surface epithelial neoplasms of the ovary. Pathology (Philadelphia, Pa.) Hendrickson, M. R., Longacre, T. A., Kempson, R. L. 1993; 1 (2): 367-410

  Abstract

  Because clinical outcome in patients with malignant surface epithelial neoplasms (M-SENs) of the ovary is highly varied, stratification of patients into favorable and unfavorable prognostic groups is an important clinicopathologic function. This chapter analyzes the various prognostic factors, with an emphasis on M-SENs of grades II and III.

  View details for PubMedID 9420924

• KI-1 (CD30) EXPRESSION IN DIFFERENTIATION OF LYMPHOMATOID PAPULOSIS FROM ARTHROPOD BITE REACTIONS MODERN PATHOLOGY SMOLLER, B. R., Longacre, T. A., Warnke, R. A. 1992; 5 (5): 492-496

  Abstract

  Lymphomatoid papulosis (LP) is an uncommon cutaneous T-cell lymphoproliferative disorder that can mimic arthropod bite reactions clinically and histologically. Erythematous, crusted papules and nodules occur mainly on extremities of young adults and, when biopsied, display a superficial and deep perivascular infiltrate characterized by atypical lymphocytes and scattered eosinophils. Arthropod bite reactions may show an identical histologic pattern. It has been suggested that up to 10% of patients with LP will eventually develop lymphoma. We examined biopsies from 10 cases of LP and six cases of arthropod bite reactions diagnosed by clinical history and prolonged follow-up, with BerH2, an antibody directed against the Ki-1 antigen (CD30) and found it to be useful in helping distinguish between the two entities. All cases of LP examined showed scattered Ki-1-positive large, atypical lymphocytes in the dermis. In the arthropod bite reactions, there was virtually no staining with BerH2 antibody. This suggests that the abnormal activated T-cells, which comprise the cellular infiltrate in LP, are not present in arthropod bite reactions.

  View details for Web of Science ID A1992JP04900004

  View details for PubMedID 1344811

• MIXED HYPERPLASTIC ADENOMATOUS POLYPS SERRATED ADENOMAS - A DISTINCT FORM OF COLORECTAL NEOPLASIA AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., FENOGLIOPREISER, C. M. 1990; 14 (6): 524-537

  Abstract

  We present the clinicopathologic characteristics of 110 colorectal mixed hyperplastic adenomatous polyps (MHAP) that exhibited the architectural but not the cytologic features of a hyperplastic polyp. They are compared with 60 traditional adenomas, 40 hyperplastic polyps, and five colonic polyps that contained admixed but well-defined hyperplastic and adenomatous glands (HP/AD). The patients with MHAP ranged in age from 15 to 88 years (mean, 63 years). Five patients had two or more (up to seven) lesions. MHAP measured 0.2-7.5 cm in diameter. They were distributed throughout the colorectum, but a slight preponderance of large lesions (more than 1.0 cm) occurred in the cecum and appendix. All MHAP were characterized by a serrated glandular pattern simulating that seen in hyperplasia (27% of MHAP were initially diagnosed as hyperplastic polyps). However, MHAP were distinguished by the presence of goblet cell immaturity, upper zone mitoses, prominence of nucleoli, and the absence of a thickened collagen table. Although surface mitotic activity, nuclear pseudostratification, and nuclear cytoplasmic ratio were greater in MHAP than in hyperplastic polyps, they were slightly less than in traditional adenomas. Thirty-seven percent of MHAP contained foci of significant dysplasia; 11% contained areas of intramucosal carcinoma. We conclude that these lesions reflect a morphologically unique variant of adenoma and suggest that they be termed "serrated adenoma" in order to emphasize their neoplastic nature. We further offer the hypothesis that MHAP may arise from the neoplastic transformation of a more differentiated cell in the crypt than the traditional adenoma.

  View details for Web of Science ID A1990DF47800003

  View details for PubMedID 2186644

• AGGRESSIVE JEJUNAL LYMPHOMA OF LARGE GRANULAR LYMPHOCYTES - IMMUNOHISTOCHEMICAL, ULTRASTRUCTURAL, MOLECULAR, AND DNA CONTENT-ANALYSIS AMERICAN JOURNAL OF CLINICAL PATHOLOGY Longacre, T. A., LISTROM, M. B., SPIGEL, J. H., Willman, C. L., Dressler, L., Clark, D. 1990; 93 (1): 124-132

  Abstract

  An unusual large cell lymphoma of the proximal jejunum with large granular lymphocyte (LGL) morphologic characteristics and T-helper/inducer cell phenotype is described. Although the cells strongly expressed Leu-7 (HNK-1), studies with antibodies directed against the more specific natural killer (NK) antigens, CD16 (Leu-11) and Leu-19, were negative. Ultrastructural analysis of the neoplastic cells demonstrated substantial numbers of electron-dense granules and rare parallel tubular arrays. Clonal rearrangement of the T-cell receptor beta chain gene and germline configuration of the immunoglobulin heavy chain gene confirmed the T-cell origin of the neoplastic cells. This lymphoma pursued an aggressive clinical course, with rapid dissemination to the lungs and central nervous system. DNA content analysis indicated that a similar DNA aneuploid population was present in the jejunal primary and lung tissue at recurrence. There was no evidence of nodal, peripheral blood, splenic, or bone marrow involvement. Morphologic and functional similarities between the lymphoid tissues of the gastrointestinal tract and lung have previously prompted a classification of the immune system into distinct peripheral somatic and mucosal components. Based on the distribution and migratory properties of the tumor cells in this case, the authors propose that this lymphoma arose from a minor mucosa-associated LGL subset that may be unrelated to circulating LGLs. In addition, these observations emphasize that prominent granulated cytomorphologic features may be seen in neoplastic disorders with the T-helper/inducer phenotype, as well as in the more widely recognized lymphoproliferative disorders of NK and cytotoxic/suppressor cell types.

  View details for Web of Science ID A1990CH03500021

  View details for PubMedID 2153002

• ATYPICAL CUTANEOUS LYMPHOPROLIFERATIVE DISORDER RESEMBLING MYCOSIS-FUNGOIDES IN AIDS - REPORT OF A CASE WITH CONCURRENT KAPOSIS SARCOMA AMERICAN JOURNAL OF DERMATOPATHOLOGY Longacre, T. A., FOUCAR, K., Koster, F., Burgdorf, W. 1989; 11 (5): 451-456

  Abstract

  A variety of neoplastic disorders have been described in patients with AIDS. Kaposi's sarcoma is the most common neoplasm and is recognized as one of the diagnostic criteria for AIDS. Unusual mucocutaneous carcinomas have also been reported in these patients, as have a variety of lymphoid neoplasms, including Hodgkin's and non-Hodgkin's lymphomas (NHLs). The NHLs that occur in AIDS patients are usually of B-cell or non-B, non-T-cell phenotype. In contrast, T-cell lymphomas have only rarely been reported in this patient population. We present the clinical, morphologic, and immunologic features of an atypical, cutaneous lymphoproliferative disorder resembling mycosis fungoides that developed in a 28-year-old homosexual man with AIDS and disseminated mucocutaneous Kaposi's sarcoma.

  View details for Web of Science ID A1989AT34000007

  View details for PubMedID 2802106

• HEMATOGONES - A MULTIPARAMETER ANALYSIS OF BONE-MARROW PRECURSOR CELLS BLOOD Longacre, T. A., FOUCAR, K., Crago, S., Chen, I. M., Griffith, B., Dressler, L., McConnell, T. S., Duncan, M., Gribble, J. 1989; 73 (2): 543-552

  Abstract

  Morphologically distinct lymphoid cells with homogeneous, condensed chromatin and scant cytoplasm can be observed in large numbers in the bone marrow of children with a variety of hematologic and nonhematologic disorders. In some patients, these cells may account for greater than 50% of the bone marrow cells, creating a picture that can be confused with acute lymphoblastic leukemia (ALL) or metastatic tumor. Although originally called hematogones (HGs), a variety of other names have been proposed for these unique cells. The clinical significance of expanded HGs has not been resolved, and the biologic features of these cells are incompletely described. In this study, we correlate the clinical, morphologic, cytochemical, flow cytometric, molecular, and cytogenetic properties of bone marrow samples from 12 children with substantial numbers of HGs (range 8% to 55% of bone marrow cells). Diagnoses in these patients included anemia, four; neutropenia, one; anemia and neutropenia, one; idiopathic thrombocytopenic purpura, two; retinoblastoma, two; Ewing's sarcoma, one; and germ cell tumor, one. Flow cytometric analyses of bone marrow cells demonstrated a spectrum extending from early B-cell precursors (CD10+, CD19+, TdT+, HLA-Dr+) to mature surface immunoglobulin-bearing B cells in these patients, corroborating our morphologic impression of HGs, intermediate forms, and mature lymphocytes. DNA content was normal, and no clonal abnormality was identified by either cytogenetic or immunoglobulin and T-cell receptor (TCR) gene rearrangement studies. Follow-up ranged from 3 months to 3 years. None of the patients has developed acute leukemia or bone marrow involvement by solid tumor. The possible role of HGs in immune recovery and hematopoiesis is presented.

  View details for Web of Science ID A1989T128400030

  View details for PubMedID 2917189

• A CORRELATIVE MORPHOLOGICAL-STUDY OF HUMAN-BREAST AND ENDOMETRIUM IN THE MENSTRUAL-CYCLE AMERICAN JOURNAL OF SURGICAL PATHOLOGY Longacre, T. A., Bartow, S. A. 1986; 10 (6): 382-393

  Abstract

  Seventy-five premenopausal women autopsied under medical examiner auspices were selected for a correlative study of breast and endometrial morphology proceeding through the menstrual cycle. Criteria for selection included adequate preservation of the endometrial and breast tissue, relatively even distribution of women by age (range 15-56), menstrual cycle date, and parity status. Hormonal therapy and disease states that might influence pituitary-ovarian cycling were reasons for exclusion from the study. Proliferative phase breast was characterized by small lobules with few terminal duct structures. Terminal duct epithelial mitoses were uncommon. Intralobular stroma was condensed and continuous with interlobular stroma. Secretory phase breasts were characterized by increasing size of lobules and number of terminal duct structures and duct epithelial basal vacuolization and mitoses. Intralobular stroma became increasingly loose and edematous. Stromal lymphocytic population increased toward the end of secretory phase. Perimenstrual breasts underwent lobular contraction with necrosis and sloughing of duct epithelium. There was a concomitant marked increase in lobular stromal lymphocytic infiltrate and metachromasia. These features heralded a return to the proliferative phase appearance. These marked cyclical changes have implications for routine pathologic diagnosis as well as for the newer noninvasive diagnostic techniques.

  View details for Web of Science ID A1986C526500003

  View details for PubMedID 3717495