Ann Folkins

All Publications

• Endometriosis Malignant Transformation Review: Rhabdomyosarcoma Arising From an Endometrioma. JSLS : Journal of the Society of Laparoendoscopic Surgeons Nezhat, C., Vu, M., Vang, N., Ganjoo, K., Karam, A., Folkins, A., Nezhat, A., Nezhat, F. ; 23 (4)

  Abstract

  Endometriosis is a widely known benign disease, but 0.5%-1% of cases are associated with malignancy. It has been linked with ovarian neoplasms, particularly endometrioid and clear cell adenocarcinoma histology. Rhabdomyosarcomas are rarely associated with endometriosis.A 35-year-old patient underwent surgical management of endometriomas to optimize infertility treatment. She later developed abdominal pain with rapid recurrence of ovarian masses. This prompted additional surgery with biopsies diagnosing ovarian rhabdomyosarcoma. Retroactive review of pathologic specimens from her prior surgery demonstrated the neoplasm originated from her prior endometrioma. Focal areas suggested possible underlying ovarian adenosarcoma with stromal overgrowth.The incidence of rhabdomyosarcoma arising from endometriosis is exceedingly rare. The accuracy of diagnosing endometriosis and ruling out neoplasm requires coordinated efforts of a multidisciplinary team, involving radiologists, pathologists, oncologists, and gynecologic surgeons.

  View details for DOI 10.4293/JSLS.2019.00038

  View details for PubMedID 31624455

  View details for PubMedCentralID PMC6791399

• Fumarate Hydratase-Deficiency Should be Considered in the Differential Diagnosis of Uterine and Extra-Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP) Weiel, J. J., Devereaux, K., Folkins, A., Longacre, T. NATURE PUBLISHING GROUP. 2020: 1155?56

  View details for Web of Science ID 000518328902353

• Molecular Classification of Metastatic and Recurrent Endometrial Endometrioid Carcinoma Devereaux, K., Chow, S., Steiner, D., Peters-Schulze, G., Ho, C., Suarez, C., Folkins, A., Howitt, B. NATURE PUBLISHING GROUP. 2020: 1041?42

  View details for Web of Science ID 000518328902228

• Molecular Classification of Metastatic and Recurrent Endometrial Endometrioid Carcinoma Devereaux, K., Chow, S., Steiner, D., Peters-Schulze, G., Ho, C., Suarez, C., Folkins, A., Howitt, B. NATURE PUBLISHING GROUP. 2020: 1041?42

  View details for Web of Science ID 000518328802228

• Fumarate Hydratase-Deficiency Should be Considered in the Differential Diagnosis of Uterine and Extra-Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP) Weiel, J. J., Devereaux, K., Folkins, A., Longacre, T. NATURE PUBLISHING GROUP. 2020: 1155?56

  View details for Web of Science ID 000518328802353

• Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Tavallaee, M., Steiner, D. F., Zehnder, J. L., Folkins, A. K., Karam, A. K. 2019; 38 (4): 386?92

  View details for DOI 10.1097/PGP.0000000000000507

  View details for Web of Science ID 000471670300012

• Case 2: Infant with Early Direct Hyperbilirubinemia. NeoReviews Kumbhat, N., Folkins, A., Hawksley, C., Cohen, R. 2019; 20 (6): e350?e352

  View details for DOI 10.1542/neo.20-6-e350

  View details for PubMedID 31261099

• Low-grade Serous Neoplasia of the Female Genital Tract. Surgical pathology clinics Folkins, A. K., Longacre, T. A. 2019; 12 (2): 481?513

  Abstract

  Low-grade serous neoplasia of the gynecologic tract includes benign (serous cystadenomas), borderline, and malignant lesions (low-grade serous carcinoma). Classification of these lesions relies on rigorous attention to several pathologic features that determine the prognosis and the need for adjuvant therapy. Risk stratification of serous borderline tumor behavior based on histologic findings and criteria for low-grade serous carcinoma are the primary focus of this article, including the redesignation of invasive implants of serous borderline tumor as low-grade serous carcinoma based on the similar survival rates. The molecular underpinnings of these tumors are also discussed, including their potential for prognostication.

  View details for DOI 10.1016/j.path.2019.02.006

  View details for PubMedID 31097112

• Molecular and Cellular Characterization of Placenta Previa and Accreta. Zhang, E. T., Rivera, K., Hannibal, R. L., McGowan, K., Zhu, X., Meinhardt, G., Knoefler, M., Pollheimer, J., Folkins, A., Lyell, D. J., Baker, J. C. SAGE PUBLICATIONS INC. 2019: 262A?263A

  View details for Web of Science ID 000459610400590

• Immediate intraoperative sentinel lymph node analysis by frozen section is predictive of lymph node metastasis in endometrial cancer. Journal of robotic surgery Renz, M., Marjon, N., Devereaux, K., Raghavan, S., Folkins, A. K., Karam, A. 2019

  Abstract

  Sentinel lymph nodes sampling (SLN) in endometrial cancer is being evaluated as a means to gather prognostic information about lymphatic metastasis while avoiding the morbidity associated with complete lymphadenectomy. SLN ultrastaging has been advocated to identify low-volume metastases, but its value remains uncertain. This study aims to evaluate a pathological protocol for the immediate intraoperative SLN work-up using H&E staining alone. In this retrospective single-center study, patients received standardized cervical injection of indocyanine green, SLN mapping followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy. SLNs were entirely frozen, multiple H&E stained sections prepared and evaluated intraoperatively. No immunohistochemistry was performed. SLN results were compared with the complete lymphadenectomy specimen. Over 3.5 years, 90 patients were identified who underwent SLN mapping and subsequent complete pelvic lymphadenectomy. At least one SLN was detected in 79 (88%) patients. The median number of SLNs removed was 2.0. Para-aortic SLNs were detected in 7%. Final pathology showed 67% Type I tumors, 76% locally confined. The mean number of lymph nodes removed during complete lymphadenectomy was 21. In this series, only 6 patients had lymph node metastases. 5/6 were identified by the described SLN approach resulting in 83.3% sensitivity and a negative predictive value of 98.7%. Our approach permits immediate intraoperative results and helps guide the primary surgery. The immediate SLN work-up using frozen sections showed both high accuracy and negative predictive value. The comparably lower sensitivity may be related to the low number of patients with positive lymph nodes (7.6%).

  View details for PubMedID 30687881

• Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Nwachukwu, C. R., Harris, J. P., Chin, A., Von Eyben, R., Giaretta, S., Shaffer, J. L., Hiniker, S. M., Kapp, D. S., Folkins, A. K., Kidd, E. A. 2019; 38 (6): 588?96

  Abstract

  To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66?mo [95% confidence interval (CI), 31-96], 34?mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31?mo, P=0.02 and 35 vs 16?mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.

  View details for DOI 10.1097/PGP.0000000000000568

  View details for PubMedID 31593028

• Prognostic Significance of P16 Expression and P53 Expression in Primary Vaginal Cancer. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Nwachukwu, C. R., Harris, J. P., Chin, A., Von Eyben, R., Giaretta, S., Shaffer, J. L., Hiniker, S. M., Kapp, D. S., Folkins, A. K., Kidd, E. A. 2018

  Abstract

  To evaluate the correlation between p16 expression and clinical outcomes in patients with primary vaginal cancer treated with definitive radiotherapy. P16 immunohistochemical was performed on 25 patient samples and recorded from pathology reports in 7 patients. P53 immunohistochemical was performed on 3 p16-negative samples. Baseline characteristics were compared using the Fisher exact test. Outcomes were compared using log-rank tests, and cox proportional hazards models. Survival and recurrence analysis was performed with the Kaplan-Meier method and cumulative incidence estimates. P16 expression was positive in 29 patients and negative in 3 patients. Two of the p16-negative tumors showed positive expression of p53. The median overall survival, progression-free survival and 2-yr cumulative incidence of recurrence were 66mo [95% confidence interval (CI), 31-96], 34mo (95% CI, 21-86), and 19% (95% CI, 7%-34%), respectively. P16-positive tumors had higher median overall survival and progression-free survival compared with p16-negative tumors (82 vs. 31mo, P=0.02 and 35 vs 16mo, P=0.04, respectively). The 2-yr cumulative incidence of recurrence was 14% for p16-positive tumors compared with 67% for p16-negative tumors (P=0.07). On univariable analysis, p16-negative status, age older than 65, and advanced stage were associated with inferior overall survival. P16 negativity is an independent predictor of inferior overall survival. P16-positive vaginal cancers have a better prognosis and decreased incidence of recurrence compared with p16-negative tumors. These prognostic findings associated with p16-negative vaginal cancers will need to be confirmed in larger patient cohorts.

  View details for PubMedID 30516621

• Omentum immune microenvironment: Metastatic niche for ovarian cancer Krishnan, V., Raju, P. A., Vierkoetter, K., Patel, S., Youngyunpipatkul, J., Tallapragada, S., Schaar, B., Folkins, A. K., Herzenberg, L. A., Dorigo, O. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-5074

  View details for Web of Science ID 000468819504076

• Case of Metastatic Extramammary Paget Disease of the Vulva Treated Successfully With Trastuzumab Emtansine JCO PRECISION ONCOLOGY Hsieh, G. L., English, D. P., Tu, P., Folkins, A. K., Karam, A. K. 2018; 2

  View details for DOI 10.1200/PO.17.00204

  View details for Web of Science ID 000462083700001

• Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Ozen, M., Zhao, H., Kalish, F., Yang, Y., Folkins, A., Burd, I., Wong, R. J., Stevenson, D. K. 2018; 79 (5): e12829

  Abstract

  Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring.Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry.CD3+ CD4+ CD25+ (Tregs) and CD3+ CD8+ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3+ CD8+ T cells, and an increase in CD4+ /CD8+ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI.Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

  View details for PubMedID 29484761

• Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists Tavallaee, M., Steiner, D. F., Zehnder, J. L., Folkins, A. K., Karam, A. K. 2018

  Abstract

  Low-grade serous carcinomas only rarely coexist with or progress to high-grade tumors. We present a case of low-grade serous carcinoma with transformation to carcinosarcoma on recurrence in the lymph node. Identical BRAF V600E and telomerase reverse transcriptase promoter mutations were identified in both the original and recurrent tumor. Given that telomerase reverse transcriptase promotor mutations are thought to play a role in progression of other tumor types, the function of telomerase reverse transcriptase mutations in BRAF mutated low-grade serous carcinoma deserves investigation.

  View details for PubMedID 29620581

• CONGENITAL SYPHILLIS PRESENTING AS DIRECT HYPERBILIRUBINEMIA DIAGNOSED BY PLACENTAL PATHOLOGY Kumbhat, N. P., Folkins, A., Cohen, R. BMJ PUBLISHING GROUP. 2018: 263?64

  View details for DOI 10.1136/jim-2017-000663.478

  View details for Web of Science ID 000432007400486

• Utility of p16 Immunohistochemistry in Evaluating Negative Cervical Biopsies Following High-risk Pap Test Results AMERICAN JOURNAL OF SURGICAL PATHOLOGY Shain, A. F., Kwok, S., Folkins, A. K., Kong, C. S. 2018; 42 (1): 69?75

  Abstract

  The Lower Anogenital Squamous Terminology (LAST) Standardization Project for human papilloma virus (HPV)-associated lesions specifically recommends the use of p16 immunohistochemistry (IHC) as an adjunct to morphologic assessment of cervical biopsies interpreted as negative or low-grade squamous intraepithelial lesion (LSIL) from patients with prior high-risk Pap test results (high-grade squamous intraepithelial lesion [HSIL], atypical squamous cells cannot exclude HSIL, atypical glandular cells [AGC], or HPV16 atypical squamous cells of undetermined significance [ASC-US]). The impetus for this recommendation is to increase detection of missed high-grade disease. However, the quality of evidence supporting this recommendation was lower than that for the other LAST recommendations addressing improved consistency in the diagnosis of HSIL with the use of p16. A database search spanning 10 years identified 341 cases (encompassing 736 discrete biopsy specimens) interpreted as negative for dysplasia from 330 patients with a prior high-risk Pap result (atypical squamous cells cannot exclude HSIL, HSIL, atypical glandular cells, not otherwise specified [AGC-NOS], atypical endocervical cells--NOS [AEC-NOS], and AEC-favor neoplastic). p16 IHC was performed and detected missed abnormalities in 11/341 (3.2%) cases. The abnormalities corresponded to missed foci of HSIL (cervical intraepithelial neoplasia [CIN] 2) (n=1), SIL-indeterminate grade (n=7), atypical squamous metaplasia (n=2), and LSIL [CIN1]) (n=1). Subsequent histologic follow-up identified HSIL or greater in 6/8 (75%) p16 cases versus 20/79 (25.3%) p16 cases (P=0.0079). p16 IHC performed on biopsies interpreted as negative from patients with prior high-risk Pap test results increased the detection rate of missed SIL. A p16 result also significantly increased the likelihood of HSIL on subsequent biopsy. Although further studies are required to determine what percentage of missed HSIL justifies the additional cost, improved detection of HSIL in high-risk patients may lead to fewer diagnostic procedures and fewer patients lost to follow-up.

  View details for PubMedID 29112019

• Extent of lymphovascular space invasion may predict lymph node metastasis in uterine serous carcinoma GYNECOLOGIC ONCOLOGY Qian, Y., Pollom, E. L., Nwachukwu, C., Seiger, K., von Eyben, R., Folkins, A. K., Kidd, E. A. 2017; 147 (1): 24?29

  Abstract

  Emerging evidence suggests that extent of lymphovascular space invasion (LVSI) predicts for risk of lymph node metastasis in endometrioid uterine cancers. However, this correlation remains unknown in the setting of uterine serous carcinoma (USC). We sought to examine the association between extent of LVSI and other histopathologic characteristics with risk of nodal metastasis for women with USC.Pathological data from all cases of uterine serous carcinoma between July 1998 to July 2015 at our institution were reviewed. Descriptive, univariate, and multivariate logistic regression analysis of selected pathologic features were performed.88 patients with USC underwent total abdominal or laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and selective lymphadenectomy. Surgical staging revealed the following FIGO stage distributions: I (41%), II (8%), III (32%), IV (19%). LVSI was present in 44 (50%) patients. 36 patients (41%) had LN metastases with median number of total nodes removed of 17 (range, 1-49). On univariate analysis, depth of myometrial invasion, LVSI, tumor size, and cervical stromal involvement were significantly associated with nodal involvement. In a multivariate model, LVSI (OR 6.25, 95% CI 2.2-18.0, p<0.01) and cervical stromal involvement (OR 3.33, 95% CI 1.10-10.0, p=0.03) were the only factors that remained significant. Among patients with LVSI-positive disease, extensive LVSI was associated with increased risk of nodal involvement compared to focal LVSI (90% vs 29%, p=0.04).Presence and extent of LVSI, and cervical stromal invasion are important predictors for lymph node metastasis in uterine serous carcinoma.

  View details for PubMedID 28709703

  View details for PubMedCentralID PMC5605436

• Interobserver Reproducibility Among Gynecologic Pathologists in Diagnosing Heterologous Osteosarcomatous Component in Gynecologic Tract Carcinosarcomas. International journal of gynecological pathology Sangoi, A. R., Kshirsagar, M., Roma, A. A., Horvai, A. E., Chivukula, M., Ellenson, L. H., Fadare, O., Folkins, A. K., Garg, K., Hanley, K., Longacre, T. A., Haas, J., McCluggage, W. G., McKenney, J. K., Nucci, M. R., Oliva, E., Park, K. J., Parkash, V., Quick, C. M., Rabban, J. T., Rutgers, J. K., Soslow, R., Vang, R., Yemelyanova, A., Zaloudek, C., Beck, A. H. 2017

  Abstract

  Distinguishing hyalinized stroma from osteoid production by a heterologous osteosarcomatous component can be challenging in gynecologic tract carcinosarcomas. As heterologous components in a carcinosarcoma may have prognostic and therapeutic implications, it is important that these are recognized. This study examines interobserver reproducibility among gynecologic pathologists in the diagnosis of osteosarcomatous components, and its correlation with expression of the novel antibody SATB2 (marker of osteoblastic differentiation) in these osteosarcomatous foci. Digital H&E images from 20 gynecologic tract carcinosarcomas were reviewed by 22 gynecologic pathologists with a request to determine the presence or absence of an osteosarcomatous component. The 20 preselected cases included areas of classic heterologous osteosarcoma (malignant cells producing osteoid; n=10) and osteosarcoma mimics (malignant cells with admixed nonosteoid matrix; n=10). Interobserver agreement was evaluated and SATB2 scored on all 20 cases and compared with the original diagnoses. Moderate agreement (Fleiss' ?=0.483) was identified for the 22 raters scoring the 20 cases with a median sensitivity of 7/10 and a median specificity of 9/10 for the diagnosis of osteosarcoma. SATB2 showed 100% sensitivity (10/10) and 60% (6/10) specificity in discriminating classic osteosarcoma from osteosarcoma mimics. Utilizing negative SATB2 as a surrogate marker to exclude osteosarcoma, 73% (16/22) of the reviewers would have downgraded at least 1 case to not contain an osteosarcomatous component (range, 1-6 cases, median 1 case). Gynecologic pathologists demonstrate only a moderate level of agreement in the diagnosis of heterologous osteosarcoma based on morphologic grounds. In such instances, a negative SATB2 staining may assist in increasing accuracy in the diagnosis of an osteosarcomatous component.

  View details for DOI 10.1097/PGP.0000000000000329

  View details for PubMedID 28221217

• 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

• Nomogram to Predict Risk of Lymph Node Metastases in Patients With Endometrioid Endometrial Cancer. International journal of gynecological pathology Pollom, E. L., Conklin, C. M., von Eyben, R., Folkins, A. K., Kidd, E. A. 2016; 35 (5): 395-401

  Abstract

  Pelvic lymphadenectomy in early-stage endometrial cancer is controversial, but the findings influence prognosis and treatment decisions. Noninvasive tools to identify women at high risk of lymph node metastasis can assist in determining the need for lymph node dissection and adjuvant treatment for patients who do not have a lymph node dissection performed initially. A retrospective review of surgical pathology was conducted for endometrioid endometrial adenocarcinoma at our institution. Univariate and multivariate logistic regression analysis of selected pathologic features were performed. A nomogram to predict for lymph node metastasis was constructed. From August 1996 to October 2013, 296 patients underwent total abdominal or laparoscopic hysterectomy, bilateral salpingo-oophorectomy, and selective lymphadenectomy for endometrioid endometrial adenocarcinoma. Median age at surgery was 62.7 yr (range, 24.9-93.6 yr). Median number of lymph nodes removed was 13 (range, 1-72). Of all patients, 38 (12.8%) had lymph node metastases. On univariate analysis, tumor size ?4 cm, grade, lymphovascular space involvement, cervical stromal involvement, adnexal or serosal or parametrial involvement, positive pelvic washings, and deep (more than one half) myometrial invasion were all significantly associated with lymph node involvement. In a multivariate model, lymphovascular space involvement, deep myometrial invasion, and cervical stromal involvement remained significant predictors of nodal involvement, whereas tumor size of ?4 cm was borderline significant. A lymph node predictive nomogram was constructed using these factors. Our nomogram can help estimate risk of nodal disease and aid in directing the need for additional surgery or adjuvant therapy in patients without lymph node surgery. Lymphovascular space involvement is the most important predictor for lymph node metastases, regardless of grade, and should be consistently assessed.

  View details for DOI 10.1097/PGP.0000000000000246

  View details for PubMedID 26598977

• Hemophagocytic lymphohistiocytosis as a paraneoplastic syndrome associated with ovarian dysgerminoma. Gynecologic oncology reports Nosratian-Baskovic, M., Tan, B., Folkins, A., Chisholm, K. M., Dorigo, O. 2016; 17: 38-41

  Abstract

  ?Ovarian dysgerminoma associated with paraneoplastic fever, cytopenia and splenomegaly?Complete symptom resolution resulted from tumor resection and medical management?Non-hematolymphoid neoplasms are part of differential diagnosis in secondary HLH.

  View details for DOI 10.1016/j.gore.2016.05.013

  View details for PubMedID 27354999

  View details for PubMedCentralID PMC4909829

• Placental and Clinical Characteristics of Term Small-for-Gestational-Age Neonates: A Case-Control Study PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Chisholm, K. M., Folkins, A. K. 2016; 19 (1): 37-46

  View details for DOI 10.2350/15-04-1621-OA.1

  View details for Web of Science ID 000373286000005

• Prenatal hydrops foetalis associated with infantile free sialic acid storage disease. Journal of obstetrics and gynaecology Chock, V. Y., MILAN, K. E., Folkins, A. K., Hazard, F. K., Bernstein, J. A., Hintz, S. R. 2015; 35 (8): 850-852

  View details for DOI 10.3109/01443615.2015.1017558

  View details for PubMedID 26076308

• Variable color Doppler sonographic appearances of retained products of conception: radiologic-pathologic correlation. Abdominal imaging Kamaya, A., Krishnarao, P. M., Folkins, A. K., Jeffrey, R. B., Desser, T. S., Maturen, K. E. 2015; 40 (7): 2683-2689

  Abstract

  Retained products of conception (RPOC) displays variable vascularity, ranging from avascular to markedly vascular on color Doppler sonography. We hypothesize that variability in sonographic vascularity may be due to histopathologic variation in the placental tissue.After institutional review board approval, sonographic images and pathologic specimens were retrospectively reviewed in 26 patients with pathologically proven RPOC. Ultrasound (US) images were scored 0-3 for the degree of vascularity by two radiologists blinded to the diagnosis. Corresponding pathologic specimens were evaluated for vascularization of chorionic villi, degree of inflammation, morphology of maternal arteries, chorionic villous preservation, and percentage of clot, membranes, chorionic villi, and decidua/myometrium. Statistical analysis, including multiple linear regression, was performed.RPOC with histologically avascular chorionic villi or those with markedly reduced vascularization had significantly lower US vascularity scores (p = 0.030) than those with chorionic villi showing normal or decreased vascularization. Sonographically avascular RPOC had a significantly lower percentage villi (p = 0.028) and higher percentage of decidua (p = 0.004) than specimens where US showed any Doppler vascularity. Histologic vascularity of villi (p = 0.049) and non-observation of maternal arteries (p = 0.001) were significant predictors of US vascularity scores in multivariate linear regression analysis, while inflammation of villi (p = 0.053) was a marginally significant predictor.Histologic vascularity of villi appears to contribute to the observed variation in sonographic vascularity. This finding may underlie known differences in clinical outcomes between sonographic vascularity groups.

  View details for DOI 10.1007/s00261-015-0424-x

  View details for PubMedID 25862548

• Cost and turn-around time display decreases inpatient ordering of reference laboratory tests: a time series. BMJ quality & safety Fang, D. Z., Sran, G., Gessner, D., Loftus, P. D., Folkins, A., Christopher, J. Y., Shieh, L. 2014; 23 (12): 994-1000

  Abstract

  Reference tests, also known as send-out tests, are commonly ordered laboratory tests with variable costs and turn-around times. We aim to examine the effects of displaying reference laboratory costs and turn-around times during computerised physician order entry (CPOE) on inpatient physician ordering behaviour.We conducted a prospective observational study at a tertiary care hospital involving inpatient attending physicians and residents. Physician ordering behaviour was prospectively observed between September 2010 and December 2012. An intervention was implemented to display cost and turn-around time for reference tests within our CPOE. We examined changes in the mean number of monthly physician orders per inpatient day at risk, the mean cost per order, and the average turn-around time per order.After our intervention, the mean number of monthly physician orders per inpatient day at risk decreased by 26% (51 vs 38, p<0.0001) with a decrease in mean cost per order (US$146.50 vs US$134.20, p=0.0004). There were no significant differences in mean turn-around time per order (5.6 vs 5.7?days, p=0.057). A stratified analysis of both cost and turn-around time showed significant decreases in physician ordering. The intervention projected a mean annual savings of US$330?439. Reference test cost and turn-around time variables were poorly correlated (r=0.2). These findings occurred in the setting of non-significant change to physician ordering in a control cohort of non-reference laboratory tests.Display of reference laboratory cost and turn-around time data during real-time ordering may result in significant decreases in ordering of reference laboratory tests with subsequent cost savings.

  View details for DOI 10.1136/bmjqs-2014-003053

  View details for PubMedID 25165402

• 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

  Abstract

  Lynch syndrome (LS) is an autosomal dominant inherited disease that is associated with an increased risk for colorectal and endometrial cancer due to germline mutations in mismatch-repair (MMR) genes. Whereas primary tumors in this syndrome are widely recognized, the relative risk(s) of secondary malignancies, particularly breast cancer, in LS patients are still poorly characterized. To provide an improved assessment of these risks, MMR status was evaluated in secondary tumors from a series of patients with index tumors of known MMR status (both proficient and deficient). A total of 1252 tumors (index tumors) and all secondary malignancies were tested for MMR by immunohistochemistry (MSH2, MSH6, MLH1, PMS2) between 1992 and 2013. Tumors with MLH1/PMS2 deficiency were tested for hypermethylation or BRAF mutation, when appropriate. Of the 1252 index tumors, 162 were MMR deficient (dMMR), and, of that subset, 32 secondary tumors were identified (19.7%). In contrast, 80 secondary tumors were identified in the proficient (intact) group (7.3%). Although secondary malignancies were more common in the dMMR group (P=0.0001), there was no trend in tumor type. Specifically, breast cancer was not overly represented in the dMMR group. When secondary tumors had dMMR, they were more likely to have deficiency in MSH2/MSH6 than in MLH1/PMS2 (P=0.01). Of the patients with tumors exhibiting dMMR, women were more likely to have a dMMR secondary tumor in this series (P=0.0001); however, breast cancer was not overly represented, and our study provides no evidence that it is more frequent in LS. MSH2/MSH6 deficiency is more commonly associated with a secondary tumor compared with MLH1/PMS2 deficiency, when methylation/BRAF status is taken into account.

  View details for Web of Science ID 000343880200005

• Evaluation of serial urine viral cultures for the diagnosis of cytomegalovirus infection in neonates and infants. Pediatric and developmental pathology Chisholm, K. M., Aziz, N., McDowell, M., Guo, F. P., Srinivas, N., Benitz, W. E., Norton, M. E., Gutierrez, K., Folkins, A. K., Pinsky, B. A. 2014; 17 (3): 176-180

  Abstract

  Cytomegalovirus (CMV) is the most common cause of congenital infection worldwide. Urine viral culture is the standard for CMV diagnosis in neonates and infants. The objectives of this study were to compare the performance of serial paired rapid shell vial cultures (SVC) and routine viral cultures (RVC), and to determine the optimal number of cultures needed to detect positive cases. From 2001 to 2011, all paired CMV SVC and RVC performed on neonates and infants less than 100 days of age were recorded. Testing episodes were defined as sets of cultures performed within 7 days of one another. A total of 1264 neonates and infants underwent 1478 testing episodes; 68 (5.4%) had at least one episode with a positive CMV culture. In episodes where CMV was detected before day 21 of life, the first specimen was positive in 100% (16/16) of cases. When testing occurred after 21 days of life, the first specimen was positive in 82.7% (43/52) of cases, requiring three cultures to reach 100% detection. The SVC was more prone to assay failure than RVC. Overall, when RVC was compared to SVC, there was 86.0% positive agreement and 99.9% negative agreement. In conclusion, three serial urine samples are necessary for detection of CMV in specimens collected between day of life 22 and 99, while one sample may be sufficient on or before day of life 21. Though SVC was more sensitive than RVC, the risk of SVC failure supports the use of multimodality testing to optimize detection.

  View details for DOI 10.2350/14-01-1432-OA.1

  View details for PubMedID 24617645

• Diagnosis of Congenital CMV Using PCR Performed on Formalin-fixed, Paraffin-embedded Placental Tissue. American journal of surgical pathology Folkins, A. K., Chisholm, K. M., Guo, F. P., McDowell, M., Aziz, N., Pinsky, B. A. 2013; 37 (9): 1413-1420

  Abstract

  Congenital cytomegalovirus (CMV) infection may be asymptomatic until hearing loss manifests in childhood. Because diagnosis of congenital CMV requires viral detection within an infant's first 21 days of life, CMV polymerase chain reaction (PCR) on formalin-fixed, paraffin-embedded (FFPE) placental tissue provides a unique opportunity to identify congenital exposure in cases in which CMV is not initially suspected. To assess the utility of this approach, a database of all CMV cultures performed from July 2001 to March 2012 was used to identify infants in whom urine CMV cultures were obtained within 100 days of life. Corresponding placentas were then identified through the pathology database. The database was also queried to identify placentas in which CMV immunohistochemical analysis had been performed. CMV PCR was positive in FFPE placental tissue from 100% (5/5) of cases in which the first urine culture collected before the first 21 days of life was positive. Placentas from 20 infants with negative CMV urine cultures were CMV PCR negative. Interestingly, CMV was detected in 12.5% (1/8) of placentas in which the first CMV-positive urine culture was collected after the first 21 days of life. Furthermore, 4% (1/26) of placentas with chronic villitis by histology (no urine cultures available) were CMV PCR positive. In the 10 CMV PCR-positive placentas, including 3 cases of fetal demise, CMV immunohistochemistry was positive in just 6 cases. These results suggest that the confirmation of CMV exposure in utero by PCR of FFPE placental tissue provides a useful adjunct to histologic evaluation and may identify infants requiring close clinical follow-up.

  View details for DOI 10.1097/PAS.0b013e318290f171

  View details for PubMedID 23797721

• 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

• The impact of tissue block sampling on the detection of p53 signatures in fallopian tubes from women with BRCA 1 or 2 mutations (BRCA+) and controls MODERN PATHOLOGY Mehra, K. K., Chang, M. C., Folkins, A. K., Raho, C. J., Lima, J. F., Yuan, L., Mehrad, M., Tworoger, S. S., Crum, C. P., Saleemuddin, A. 2011; 24 (1): 152-156

  Abstract

  The tubal p53 signature is a putative precursor to pelvic serous carcinoma, but its frequencies in women with inherited mutations in the BRCA1 or BRCA2 genes (BRCA+) and controls has been controversial. An initial section and two levels (100-200??m) from every block in BRCA+ (24) and control tubes (40) were stained for p53. The frequency of p53 signatures was computed between the populations and across the three levels from each block, and analyzed by Fisher exact test. A total of 17 (71%) BRCA+ and 20 (50%) control tubes were p53 signature positive (P=0.12); 21 and 16% of all tissue blocks sectioned harbored signatures (P=0.29), and 76 and 67% were found in the fimbria. In 49 and 32% of p53 signature positive cases in the two groups, the p53 signatures were not discovered until the second or third round of sectioning. In all, 38 and 40% of BRCA+ and control subjects harbored p53 signatures in more than one focus in a single block. In one case (BRCA+), a highly atypical proliferation was identified in one serial section. The p53 signatures are more common than previously reported and the frequency of detection increases as a function of sectioning through the tissue block, both in absolute frequency and in numbers of p53 signatures detected in a given block. There is a trend for a higher absolute frequency of p53 signatures (71 vs 50%; P=0.12) in BRCA+ subjects, but this is not reflected in a greater average number of p53 signatures or positive blocks per case. This study underscores the importance of systematic immunohistochemical examination of fallopian tubes when conducting epidemiological studies that compare the frequency of p53 signatures in different populations. Attention to this detail is critical when exploring risk factors germane to early serous carcinogenesis.

  View details for DOI 10.1038/modpathol.2010.171

  View details for Web of Science ID 000285868900017

  View details for PubMedID 20871594

• Evaluation of vascular space involvement in endometrial adenocarcinomas: laparoscopic vs abdominal hysterectomies 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Folkins, A. K., Nevadunsky, N. S., Saleemuddin, A., Jarboe, E. A., Muto, M. G., Feltmate, C. M., Crum, C. P., Hirsch, M. S. NATURE PUBLISHING GROUP. 2010: 1073?79

  Abstract

  Recent reports have described 'vascular pseudoinvasion' in total laparoscopic hysterectomies with endometrial carcinoma. To better understand this phenomenon, we compared pathologic findings in these laparoscopic and total abdominal hysterectomies performed for uterine endometrioid adenocarcinoma. Reports from 58 robotically assisted laparoscopic and 39 abdominal hysterectomies with grade 1 or 2 endometrioid endometrial adenocarcinomas were reviewed for stage, depth of invasion, vascular space involvement, uterine weight, and lymph node metastases. In addition, attention was given to possible procedural artifacts, including vertical endomyometrial clefts, and inflammatory debris, benign endometrial glands, and disaggregated tumor cells in vascular spaces. All foci with vascular involvement were reviewed by three gynecologic pathologists. Nine of the 58 (16%) laparoscopic and 3 of the 39 (7%) abdominal hysterectomies contained vascular space involvement based on the original pathology reports (P-value=0.0833). No one histologic feature consistently distinguished laparoscopic from abdominal cases on blind review of the available cases. Disaggregated intravascular tumor cells were significantly associated with reported vascular involvement in both procedures (P-values<0.001 and 0.016), most of which were corroborated on review. Laparoscopic procedures tend to have a higher index of vascular involvement, which is associated with lower stage, fewer lymph node metastases, and less myometrial invasion; however, pathologists cannot consistently determine the procedure on histologic findings alone. Moreover, there is significant inter-observer variability in distinguishing true from artifactual vascular space involvement, even among pathologists at the same institution. The clinical significance of apparent true vascular space involvement seen adjacent to artifacts is unclear, as is the impact of laparoscopic hysterectomy on recurrence risk.

  View details for DOI 10.1038/modpathol.2010.91

  View details for Web of Science ID 000280563900005

  View details for PubMedID 20473276

• Utility of Chromosomal Chromogenic in Situ Hybridization as an Alternative to Flow Cytometry and Cytogenetics in the Diagnosis of Early Partial Hydatidiform Moles A Validation Study 15th World Congress on Gestational Trophoblastic Diseases Folkins, A., Cruz, L., Goldstein, D. P., Berkowitz, R. S., Crum, C., Kindelberger, D. SCI PRINTERS & PUBL INC. 2010: 275?78

  Abstract

  The introduction of p57 immunohistochemistry has aided the distinction between early complete moles (CMs) and hydropic abortus (HA), but no single technique has emerged for the distinction between early partial moles (PMs) and HA. Flow cytometry and cytogenetics have been used, but these require specialized equipment/expertise. The goal of this study is validation of chromosome in situ hybridization (CrISH), focusing on comparing the results to those obtained by cytogenetic methods.Archival paraffin blocks from molar and nonmolar gestations were retrieved. Sections were labeled with a chromosome 10 probe. Hybridization and visualization were performed using standard protocols. One hundred nuclei per sample were scored for the number ofsignals.Of 50 hydatidiform moles, 22 were PMs and 28 were CMs. The CMs showed 2 signals in 25 cases and 4 signals in 3 cases. The PMs showed 3 signals in 21 cases and 2 signals in 1 case. For the HAs there were 2 signals in 24 cases, and 1 case had 3 signals. Concordance between CrISH and flow cytometry studies for molar gestations was 95%.CrlSH is a highly effective adjunct in differentiating between PM and CM and between PM and HA. CrlSH is a simple, cost effective adjunct in evaluating molar gestations.

  View details for Web of Science ID 000280968800002

  View details for PubMedID 20795338

• Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective HISTOPATHOLOGY Jarboe, E. A., Folkins, A. K., Drapkin, R., Ince, T. A., Agoston, E. S., Crum, C. P. 2009; 55 (5): 619-619

  View details for DOI 10.1111/j.1365-2559.2009.03408.x

  View details for Web of Science ID 000271466800014

  View details for PubMedID 19912369

• Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer GYNECOLOGIC ONCOLOGY Folkins, A. K., Saleemuddin, A., Garrett, L. A., Garber, J. E., Muto, M. G., Tworoger, S. S., Crum, C. P. 2009; 115 (1): 108-111

  Abstract

  Many ovarian carcinomas are presumed to arise within ovarian cortical inclusion cysts (CICs). This study examined the frequency of ovarian CICs in relation to epidemiologic risk factors in women with BRCA1 and BRCA2 (BRCA+) mutations.BRCA+ women who underwent risk-reducing bilateral salpingo-oophorectomy were studied (n=74). Fifteen demographic variables (e.g., age at time of surgery, age at first birth, age at menopause, body mass index (BMI), gravidity) from a review of the medical records and three pathologic variables (cystic and atretic follicles, corpora lutea) were recorded. Statistical associations were made using T-test or Chi Square analysis and logistic regression analysis for p-trend.Women whose ovaries contained 7 for more CICs were older at first birth (p=0.034), surgery (p=0.059), menopause (p=0.046) and had a higher BMI (p=0.034) than those with <7 CICs. Regression analysis revealed a significant association between CICs and increasing BMI (p=0.01).CICs correlate with greater body mass index, similar to low-grade serous and endometrioid tumors and in contrast to high-grade serous carcinoma and its putative precursor in the fallopian tube. A model is presented for ovarian and tubal pathways to pelvic cancer that are linked to different microscopic precursors with distinct epidemiologic correlates.

  View details for DOI 10.1016/j.ygyno.2009.06.032

  View details for Web of Science ID 000269965700021

  View details for PubMedID 19615727

• Intercepting early pelvic serous carcinoma by routine pathological examination of the fimbria MODERN PATHOLOGY Semmel, D. R., Folkins, A. K., Hirsch, M. S., Nucci, M. R., Crum, C. P. 2009; 22 (8): 985-988

  Abstract

  Recent evidence indicates that the distal fallopian tube is the principal site of early serous cancer in women with a hereditary risk for ovarian cancer. Moreover, the fimbria is involved by early cancer in a significant minority of pelvic serous carcinomas, irrespective of whether the patient has a hereditary BRCA1 or BRCA2 mutation. In addition, the distal tube has been identified occasionally as a site of concurrent endometrioid tumors in women with endometrial carcinoma. Although the risk of sporadic fimbrial tumors in otherwise healthy women without genetic risk is unknown, routine histological examination of the fimbria provides the opportunity to determine the risk of such an event. To illustrate this point, a case of a woman who underwent surgery for an ovarian fibroma is presented. The distal tube was submitted, and found to harbor a focus of serous tubal intraepithelial carcinoma (STIC) with a 2-mm invasive tumor. Incidentally discovered carcinomas underscore the potential risk, albeit low, of concurrent unsuspected malignancy in the distal fallopian tube and emphasize the importance of routine pathological examination of the fimbria in all salpingectomies. The rationale for this strategy, and its potential effect on early detection and in uncovering persons or families potentially at risk for ovarian cancer, is discussed.

  View details for DOI 10.1038/modpathol.2009.64

  View details for Web of Science ID 000268540400001

  View details for PubMedID 19407856

• Precursors to pelvic serous carcinoma and their clinical implications GYNECOLOGIC ONCOLOGY Folkins, A. K., Jarboe, E. A., Roh, M. H., Crum, C. P. 2009; 113 (3): 391-396

  Abstract

  Pelvic serous carcinoma has traditionally been viewed as a rapidly evolving malignancy, due principally to its late stage at diagnosis and tendency for poor outcome, both in the endometrium and the upper genital tract. Recently, studies of women with BRCA1 or BRCA2 mutations (BRCA+) undergoing risk reducing salpingo-oophorectomy have highlighted the distal fallopian tube as a common (80%) site of tumor origin and additional studies of unselected women with pelvic serous carcinoma have demonstrated that serous tubal intraepithelial carcinoma may precede a significant percentage of these tumors. This review examines the serous carcinogenic spectrum in the fallopian tube, highlighting recent evidence that these tumors may follow a defined precursor that has been present for a prolonged interval. The data supporting a candidate precursor, the implications of these findings for early detection and prevention of pelvic serous carcinoma and the caveats, are discussed.

  View details for DOI 10.1016/j.ygyno.2009.01.013

  View details for Web of Science ID 000266320300019

  View details for PubMedID 19237187

• Risk factors for a serous cancer precursor ("p53 signature") in women with inherited BRCA mutations GYNECOLOGIC ONCOLOGY Saleemuddin, A., Folkins, A. K., Garrett, L., Garber, J., Muto, M. G., Crum, C. P., Tworoger, S. 2008; 111 (2): 226-232

  Abstract

  Pelvic (ovarian) serous carcinomas frequently contain p53 mutations. Recently, a candidate serous cancer precursor (the p53 signature) with p53 mutations and other features in common with serous cancer has been discovered in distal fallopian tube mucosa. This study examined the relationship of putative ovarian cancer risk factors with the presence of p53 signatures in women with BRCA mutations (BRCA+).Fallopian tubes from 75 BRCA+ women were immunostained for p53 signatures and correlated with age at first childbirth, parity, oral contraceptive use, body mass index (BMI), and BRCA subtype (1 or 2). Statistical analysis was performed with the T-test or Chi-square analysis and logistic regression adjusting for age and parity.Thirty-eight percent of the tubes contained p53 signatures, which were significantly associated with older age at first childbirth (mean 30.8 vs. 28.4 years; p=0.04) and lower parity (mean 1.4 vs. 2.2; p=0.01) in univariate analyses. The unadjusted odds ratios were 3.8 (p-trend=0.04) for first childbirth>/=30 years versus <30 and 0.2 (p-trend=0.01) for parity >/= 3 versus nulliparous women. After adjusting for age and parity, the trend for age at first childbirth became non-significant (adjusted odds ratio 3.5; p-trend=0.15), while that for parity remained significant (adjusted odds ratio 0.2; p-trend 0.02).The p53 signature is significantly associated with lower parity and possibly higher age at first childbirth, further linking this entity to serous cancer via risk factors associated with ovulation. The p53 signature merits consideration as a surrogate marker for serous cancer risk.

  View details for DOI 10.1016/j.ygyno.2008.07.018

  View details for Web of Science ID 000260987700012

  View details for PubMedID 18718648

• Tubal and ovarian pathways to pelvic epithelial cancer: a pathological perspective HISTOPATHOLOGY Jarboe, E. A., Folkins, A. K., Drapkin, R., Ince, T. A., Agoston, E. S., Crum, C. P. 2008; 53 (2): 127-138

  Abstract

  Prolongation of ovarian epithelial cancer survival depends on early detection or improved responses to chemotherapy. Gains in either have been modest at best. Understanding the diverse pathogenesis of this disease is critical to early intervention or prevention. This review addresses six important variables, including (i) cell of origin, (ii) site of origin, (iii) initial genotoxic events, (iv) risks imposed by hereditary and other promoting conditions, (v) subsequent factors that promote different patterns of metastatic spread, and (vi) prospects for intervention. This review proposes two distinct pathways to pelvic epithelial cancer. The first initiates in ovarian surface epithelium (OSE), Mullerian inclusions or endometriosis in the ovary. The second arises from the endosalpinx and encompasses a subset of serous carcinomas. The serous carcinogenic sequence in the distal fallopian tube is described and contrasted with lower grade serous tumors based on tumour location, earliest genetic change and ability (or lack of) to undergo terminal (ciliated) differentiation. Ultimately, a clear understanding of tumour origin and the mechanism(s) leading to the earliest phases of the serous and endometrioid carcinogenic sequences may hold the greatest promise for designing prevention strategies and/or developing new therapies.

  View details for DOI 10.1111/j.1365-2559.2007.02938.x

  View details for Web of Science ID 000258504400001

  View details for PubMedID 18298580

• Adenofibroma of the fimbria: A common entity that is indistinguishable from ovarian adenofibroma INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Bossuyt, V., Medeiros, F., Drapkin, R., Folkins, A. K., Crum, C. P., Nucci, M. R. 2008; 27 (3): 390-397

  Abstract

  Fallopian tube adenofibromas (FTAs) are considered rare, but their frequency has never been determined by systematic sampling of this organ. To determine the morphological spectrum and prevalence of FTAs, we analyzed a consecutive series of fallopian tubes removed during surgery for a wide range of disorders. Fallopian tubes were completely evaluated with attention to the fimbriated end (sectioning and extensively examining the fimbria [SEE-FIM] protocol). Discrete localized subepithelial stromal proliferations with alterations in plical architecture and a glandular component were classified as FTAs. Fallopian tube adenofibromas less than 3 mm were classified as incipient adenofibromas (iFTAs). The association of FTAs with ovarian adenofibromas (OAs) was also evaluated. Twenty-six of 28 (30% overall frequency) consecutively examined bilateral fallopian tube specimens contained adenofibromas (FTAs and iFTAs); all confined to the fimbria. Twelve FTAs were identified (11 cases; 14% frequency), 3 of which exceeded 1 cm. Twenty-nine iFTAs were identified (18 cases; 20% frequency); iFTAs were multiple in 10, bilateral in 4, and associated with an FTA in 3 cases. Three (25%) of 12 OAs with completely examined fallopian tubes were associated with FTAs. Stroma in both iFTAs and FTAs was CD10 and inhibin positive, and the epithelial phenotype of both iFTAs and OAs was identical, composed of secretory and ciliated cells. The fimbrial endosalpinx and the ovarian cortex share the potential for similar specialized stromal expansions with the formation of biphasic tumors with endosalpingeal epithelial differentiation. Similar to reports of serous and endometrioid tumors in both the distal fallopian tube and ovary, FTAs highlight a shared epithelial-mesenchymal differentiation pathway in the fimbrial-ovarian region. Whether the shared tumor phenotype in these 2 organs is coincidental or interdependent bears further investigation.

  View details for DOI 10.1097/PGP.0b013e3181639a82

  View details for Web of Science ID 000257277900010

  View details for PubMedID 18580316

• A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations GYNECOLOGIC ONCOLOGY Folkins, A. K., Jarboe, E. A., Saleemuddin, A., Lee, Y., Callahan, M. J., Drapkin, R., Garber, J. E., Muto, M. G., Tworoger, S., Crum, C. P. 2008; 109 (2): 168-173

  Abstract

  Early serous carcinomas predominate in the fimbria of women with BRCA mutations (BRCA+). An entity in non-neoplastic mucosa sharing several properties of early serous carcinomas--the "p53 signature"--has been described in the distal fallopian tube and proposed as a precursor to serous carcinomas. This study compared the prevalence of p53 signatures in ovarian cortical inclusion cysts (CICs) and fallopian tubes from BRCA+ women and explored their relationship.All tissues from 75 completely excised ovaries and tubes obtained during prophylactic surgery were studied by conventional microscopy, immunostaining for p53, and in selected cases, gamma-H2AX (DNA damage). P53 signatures were defined as 12 or more consecutive p53-positive secretory cell nuclei. Their prevalence in fallopian tubes and CICs was recorded, compared to an existing database of consecutive women without a suspicion of BRCA+ or ovarian cancer, and correlated with the number of CICs.Tubal p53 signatures were detected in 29 of 75 cases (38%); 20 of 30 (66%) signatures examined were gamma-H2AX-positive. One ovary contained a small gamma-H2AX negative p53 signature on the ovarian surface; no p53 signatures were identified in CICs. The prevalence of BRCA+ p53 tubal signatures was similar to that of women with unknown BRCA status (38 v 33%). Presence of p53 signatures did not correlate with number of CICs.p53 signatures were common in the fallopian tubes of BRCA+ women, were not identified in CICs, and did not correlate with the latter. The tubal p53 signature merits serious consideration as an important early event in serous carcinogenesis in BRCA+ women.

  View details for DOI 10.1016/j.ygyno.2008.01.012

  View details for Web of Science ID 000256205600004

  View details for PubMedID 18342932

• Serous carcinogenesis in the fallopian tube: A descriptive classification INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY Jarboe, E., Folkins, A., Nucci, M. R., Kindelberger, D., Drapkin, R., Miron, A., Lee, Y., Crum, C. P. 2008; 27 (1): 1-9

  Abstract

  The fimbria is the most common site of early serous cancer (tubal intraepithelial carcinoma or STIC) in women with BRCA mutations (BRCA+). A candidate serous cancer precursor--the p53 signature--has been found in nonneoplastic secretory cells of the fimbria, suggesting serous carcinogenesis in the tube (SCAT). This study surveyed fallopian tubes from 3 populations to characterize the morphological and immunohistochemical correlates of SCAT. The SCAT sequence was defined by strong nuclear p53 staining and DNA damage (gamma-H2AX+) in secretory cells and subdivided morphologically by (1) degree of nuclear stratification, (2) proliferative index, and (3) degree of disorganized growth. Fallopian tubes from women without a current ovarian cancer, women with BRCA mutations, and women with a coexisting pelvic serous cancer were completely examined. p53 signatures exhibited cuboidal to pseudostratified, polarized p53+ epithelial segments with variable nuclear enlargement and a MiB1 index of 0% to 30%. Tubal intraepithelial carcinomas contained from single (uncommon) to multilayered, poorly polarized, uninterrupted neoplastic cell populations that completely displaced the normal mucosa; MiB1 index exceeded 45% and was usually more than 70%. An uncommon third category, p53-positive foci with features intermediate between p53 signatures and STICs, exhibited preserved epithelial polarity, pseudostratification, incomplete replacement of the adjacent normal ciliated cells, and a MiB1 index between 40% and 75%. Transitions from 1 category to another were documented. Combined with recent reports associating STICs with pelvic serous cancer, this continuum of epithelial change validates the SCAT sequence and the fimbrial secretory cell as the site of origin for many serous carcinomas.

  View details for DOI 10.1097/pgp.0b013e31814b191f

  View details for Web of Science ID 000252124400001

  View details for PubMedID 18156967

• Improving the Deaf community's access to prostate and testicular cancer information: a survey study BMC PUBLIC HEALTH Folkins, A., Sadler, G. R., Ko, C., Branz, P., Marsh, S., Bovee, M. 2005; 5

  Abstract

  Members of the Deaf community face communication barriers to accessing health information. To resolve these inequalities, educational programs must be designed in the appropriate format and language to meet their needs.Deaf men (102) were surveyed before, immediately following, and two months after viewing a 52-minute prostate and testicular cancer video in American Sign Language (ASL) with open text captioning and voice overlay. To provide the Deaf community with information equivalent to that available to the hearing community, the video addressed two cancer topics in depth. While the inclusion of two cancer topics lengthened the video, it was anticipated to reduce redundancy and encourage men of diverse ages to learn in a supportive, culturally aligned environment while also covering more topics within the partnership's limited budget. Survey data were analyzed to evaluate the video's impact on viewers' pre- and post-intervention understanding of prostate and testicular cancers, as well as respondents' satisfaction with the video, exposure to and use of early detection services, and sources of cancer information.From baseline to immediately post-intervention, participants' overall knowledge increased significantly, and this gain was maintained at the two-month follow-up. Men of diverse ages were successfully recruited, and this worked effectively as a support group. However, combining two complex cancer topics, in depth, in one video appeared to make it more difficult for participants to retain as many relevant details specific to each cancer. Participants related that there was so much information that they would need to watch the video more than once to understand each topic fully. When surveyed about their best sources of health information, participants ranked doctors first and showed a preference for active rather than passive methods of learning.After viewing this ASL video, participants showed significant increases in cancer understanding, and the effects remained significant at the two-month follow-up. However, to achieve maximum learning in a single training session, only one topic should be covered in future educational videos.

  View details for DOI 10.1186/1471-2458-5-63

  View details for Web of Science ID 000230793200001

  View details for PubMedID 15938751

• Does HER2/neu expression provide prognostic information in patients with advanced urothelial carcinoma? CANCER Gandour-Edwards, R., Lara, P. N., Folkins, A. K., LaSalle, J. M., Beckett, L., Li, Y. J., Meyers, F. J., DeVere-White, R. 2002; 95 (5): 1009-1015

  Abstract

  Muscle-invasive urothelial carcinoma of the bladder is a highly lethal malignancy, particularly in the setting of locally advanced or metastatic disease. Prior reports of HER2/neu (c-erbB-2 or HER2) expression in bladder carcinoma have been mixed; therefore, its value in predicting metastasis or response to therapy has not been established in this tumor type. Thus, the authors evaluated a possible correlation between HER2 expression in patients with high-grade, muscle-invasive urothelial carcinoma of the bladder and outcome in patients who received paclitaxel-based chemotherapy.Archival tumor tissues from patients with advanced urothelial carcinoma who were enrolled on two clinical trials of paclitaxel-based chemotherapy regimens were analyzed for HER2/neu expression by immunohistochemistry (IHC). The authors correlated HER2 expression by IHC with clinical outcomes, such as response rate, progression free survival, and overall survival, using univariate analysis.Thirty-nine tumor specimens were assessed for HER2 expression, most of which (70%) were collected from patients with metastatic disease. All were high-grade urothelial carcinomas (transitional cell carcinomas, Grade 3). Strong HER2 expression (2+/3+) was seen in 28 patients (71%). Patients with responding disease had an HER2 expression rate of 78%, similar to the rate seen in patients with stable disease (75%). In contrast, patients with progressive disease had an HER2 expression rate of 50%, although this difference did not reach statistical significance. However, univariate analysis showed that increased HER2 expression predicted an improvement in progression free and overall survival. When HER2 status was used as a dichotomous variable, tumors with positive HER2 expression did not have any association with response or with progression free survival; however, positive HER2 status was associated significantly with a decreased risk of death (P = 0.03).This study of HER2 expression in bladder carcinoma focused on patients who were treated prospectively in a standardized fashion, unlike prior studies that have evaluated banked, archival specimens. The authors confirmed the findings of others that high-grade, muscle-invasive urothelial carcinoma of the bladder has a significant rate of HER2 expression (71%). However, contrary to other reports, the current study found that HER2 expression in the context of paclitaxel-based chemotherapy decreased the risk of death significantly. Further research is warranted on the possible association of HER2 expression with chemosensitivitiy in urothelial carcinoma as well as the efficacy of HER2-targeted therapies (such as trastuzumab) for patients with high-grade, muscle-invasive urothelial carcinoma of the bladder.

  View details for DOI 10.1002/cncr.10808

  View details for Web of Science ID 000177606000009

  View details for PubMedID 12209684