Clinical Focus

  • Anatomic and Clinical Pathology

Administrative Appointments

  • Vice Chair of Pathology for Pediatric Pathology, Stanford University School of Medicine (2015 - Present)
  • Associate Medical Director of Pathology and Clinical Laboratories for Pediatrics, Stanford Children's Health/Stanford Health Care (2014 - Present)
  • Chief of Pathology, Lucile Packard Children’s Hospital, Stanford Children’s Health (2014 - Present)
  • Director of Pediatric Pathology, Stanford University Medical Center (2014 - Present)
  • Vice-Chairman for Anatomical Pathology, Medical College of Wisconsin, Milwaukee, WI (2012 - 2014)
  • Director of Anatomical and Surgical Pathology, Medical College of Wisconsin, Milwaukee, WI (2010 - 2014)
  • Director of Orthopedic Pathology, Yale University School of Medicine, New Haven, CT (2008 - 2009)
  • Director of Pediatric and Developmental Pathology, Yale University School of Medicine, New Haven, CT (2008 - 2009)
  • Assistant Director of Autopsy Services, Yale University School of Medicine, New Haven, CT (2007 - 2009)

Professional Education

  • Residency:Yale-New Haven HospitalCT
  • Board Certification: Pediatric Pathology, American Board of Pathology (2003)
  • Board Certification: Anatomic and Clinical Pathology, American Board of Pathology (2003)
  • Medical Education:Universidad Catolica de Santiago de Guayaquil (1992) Ecuador
  • Fellowship:Children's Hospital BostonMA
  • Board certification, Children's Hospital Boston/Harvard Medical School, Pediatric Pathology (2003)
  • Board certification, Yale-New Haven Hospital/Yale School of Medicine, Anatomical and Clinical Pathology (2002)
  • Professional Certificate, University of New Haven, Health Care Management (2001)
  • MSc, Vrije Universiteit Brussel, Brussels, Belgium, Molecular Biology (1994)
  • MD, Universidad Católica de Santiago de Guayaquil, Ecuador, Medicine and Surgery (1992)

Research & Scholarship

Clinical Trials

  • Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Non-rhabdomyosarcoma Soft Tissue Sarcomas That Can Be Removed by Surgery Not Recruiting

    This randomized phase II/III trial studies how well pazopanib hydrochloride, combination chemotherapy, and radiation therapy work and compares it to radiation therapy alone or in combination with pazopanib hydrochloride or combination chemotherapy in treating patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can be removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as ifosfamide and doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy works better when given with or without combination chemotherapy and/or pazopanib hydrochloride in treating patients with non-rhabdomyosarcoma soft tissue sarcomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Neyssa M. Marina, 650-498-7061.

    View full details


2018-19 Courses


All Publications

  • Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Crossen, S. S., Zambrano, E., Newman, B., Bernstein, J. A., Messner, A. H., Bachrach, L. K., Twist, C. J. 2017; 39 (1): E21-E24


    Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

    View details for DOI 10.1097/MPH.0000000000000686

    View details for Web of Science ID 000391634100006

  • Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions. Journal of pediatric hematology/oncology Crossen, S. S., Zambrano, E., Newman, B., Bernstein, J. A., Messner, A. H., Bachrach, L. K., Twist, C. J. 2016: -?


    Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

    View details for PubMedID 27820122

  • PAX7 Expression in Rhabdomyosarcoma, Related Soft Tissue Tumors, and Small Round Blue Cell Neoplasms. American journal of surgical pathology Charville, G. W., Varma, S., Forgó, E., Dumont, S. N., Zambrano, E., Trent, J. C., Lazar, A. J., van de Rijn, M. 2016; 40 (10): 1305-1315


    Rhabdomyosarcoma, the most common soft tissue malignancy of childhood, is a morphologically variable tumor defined by its phenotype of skeletal muscle differentiation. The diagnosis of rhabdomyosarcoma often relies in part on the identification of myogenic gene expression using immunohistochemical or molecular techniques. However, these techniques show imperfect sensitivity and specificity, particularly in scant tissue biopsies. Here, we expand the toolkit for rhabdomyosarcoma diagnosis by studying the expression of PAX7, a transcriptional regulator of mammalian muscle progenitor cells implicated in the pathogenesis of rhabdomyosarcoma. Immunohistochemical analysis of tissue microarrays using a monoclonal anti-PAX7 antibody was used to characterize PAX7 expression in 25 non-neoplastic tissues, 109 rhabdomyosarcomas, and 697 small round blue cell or other soft tissue tumors. Among non-neoplastic tissues, PAX7 was specifically expressed in adult muscle progenitor cells (satellite cells). In embryonal rhabdomyosarcoma, PAX7 expression was positive in 52 of 63 cases (83%), negative in 9 of 63 cases (14%), and focal in 2 of 63 cases (3%). PAX7-positive embryonal rhabdomyosarcoma cases included several showing focal or negative myogenin expression. PAX7 expression in alveolar rhabdomyosarcoma was positive in 6 of 31 cases (19%), negative in 14 of 31 cases (45%), and focal in 11 of 31 cases (36%). In addition, PAX7 was expressed in 5 of 7 pleomorphic rhabdomyosarcomas (71%) and 6 of 8 spindle cell rhabdomyosarcomas (75%). Among histologic mimics, only Ewing sarcoma showed PAX7 expression (7/7 cases, 100%). In contrast, expression of PAX7 was not seen in the large majority (688/690, 99.7%) of examined cases of other soft tissue tumors, small round blue cell neoplasms, and leukemias/lymphomas. In summary, immunohistochemical analysis of PAX7 expression may be a useful diagnostic tool in the assessment of skeletal muscle differentiation in human tumors.

    View details for DOI 10.1097/PAS.0000000000000717

    View details for PubMedID 27526298

  • First case of infectious endocarditis caused by Parvimonas micra. Anaerobe Gomez, C. A., Gerber, D. A., Zambrano, E., Banaei, N., Deresinski, S., Blackburn, B. G. 2015; 36: 53-55


    P. micra is an anaerobic Gram-positive cocci, and a known commensal organism of the human oral cavity and gastrointestinal tract. Although it has been classically described in association with endodontic disease and peritonsillar infection, recent reports have highlighted the role of P. micra as the primary pathogen in the setting of invasive infections. In its most recent taxonomic classification, P. micra has never been reported causing infectious endocarditis in humans. Here, we describe a 71 year-old man who developed severe native valve endocarditis complicated by aortic valvular destruction and perivalvular abscess, requiring emergent surgical intervention. Molecular sequencing enabled identification of P. micra.

    View details for DOI 10.1016/j.anaerobe.2015.10.007

    View details for PubMedID 26485192

  • Sarcoma Resection With and Without Vascular Reconstruction: A Matched Case-control Study ANNALS OF SURGERY Poultsides, G. A., Tran, T. B., Zambrano, E., Janson, L., Mohler, D. G., Mell, M. W., Avedian, R. S., Visser, B. C., Lee, J. T., Ganjoo, K., Harris, E. J., Norton, J. A. 2015; 262 (4): 632-640


    To examine the impact of major vascular resection on sarcoma resection outcomes.En bloc resection and reconstruction of involved vessels is being increasingly performed during sarcoma surgery; however, the perioperative and oncologic outcomes of this strategy are not well described.Patients undergoing sarcoma resection with (VASC) and without (NO-VASC) vascular reconstruction were 1:2 matched on anatomic site, histology, grade, size, synchronous metastasis, and primary (vs. repeat) resection. R2 resections were excluded. Endpoints included perioperative morbidity, mortality, local recurrence, and survival.From 2000 to 2014, 50 sarcoma patients underwent VASC resection. These were matched with 100 NO-VASC patients having similar clinicopathologic characteristics. The rates of any complication (74% vs. 44%, P = 0.002), grade 3 or higher complication (38% vs. 18%, P = 0.024), and transfusion (66% vs. 33%, P < 0.001) were all more common in the VASC group. Thirty-day (2% vs. 0%, P = 0.30) or 90-day mortality (6% vs. 2%, P = 0.24) were not significantly higher. Local recurrence (5-year, 51% vs. 54%, P = 0.11) and overall survival after resection (5-year, 59% vs. 53%, P = 0.67) were similar between the 2 groups. Within the VASC group, overall survival was not affected by the type of vessel involved (artery vs. vein) or the presence of histology-proven vessel wall invasion.Vascular resection and reconstruction during sarcoma resection significantly increases perioperative morbidity and requires meticulous preoperative multidisciplinary planning. However, the oncologic outcome appears equivalent to cases without major vascular involvement. The anticipated need for vascular resection and reconstruction should not be a contraindication to sarcoma resection.

    View details for DOI 10.1097/SLA.0000000000001455

    View details for Web of Science ID 000367999800009

  • Unusual pulmonary findings in mucolipidosis II PEDIATRIC PULMONOLOGY Ishak, M., Zambrano, E. V., Bazzy-Asaad, A., Esquibies, A. E. 2012; 47 (7): 719-721


    We report undescribed pulmonary findings in a child with mucolipidosis II (ML-II). Children with ML-II bear significant pulmonary morbidity that may include extensive pulmonary fibrosis, persistent hemosiderosis as well as pulmonary airway excrescences as they reach preschool age.

    View details for DOI 10.1002/ppul.21599

    View details for Web of Science ID 000305070100016

    View details for PubMedID 22162509

  • Focal Increases of Fetal Macrophages in Placentas from Pregnancies with Histological Chorioamnionitis: Potential Role of Fibroblast Monocyte Chemotactic Protein-1 AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY Toti, P., Arcuri, F., Tang, Z., Schatz, F., Zambrano, E., Mor, G., Niven-Fairchild, T., Abrahams, V. M., Krikun, G., Lockwood, C. J., Guller, S. 2011; 65 (5): 470-479


     Histopathological chorioamnionitis (HCA) is caused by microbial-driven infiltration of leukocytes to the maternal-fetal interface resulting in adverse neonatal outcomes in a subset of pregnancies. The role of placental villus macrophages (i.e. Hofbauer cells, HBCs) in the pathophysiology of HCA is unelucidated. The number of HBCs in human term placental villi in HCA and control groups was compared using immunohistochemistry. Levels of monocyte chemotactic protein (MCP-1) expression were measured in primary cultures of syncytioytrophoblasts (SCTs) and fibroblasts (FIBs) treated with bacterial compounds [lipopolysaccharide (LPS) and peptidoglycan] and pro-inflammatory cytokines (TNF-α and IL-1β) using ELISA and quantitative real-time PCR. Immunohistochemistry revealed a focal increase in HBCs in HCA. Treatment of FIBs with LPS, IL-1β, and TNF-α significantly increased MCP-1 mRNA and protein expression. Conversely, MCP-1 mRNA and protein levels were virtually undetectable in treated and untreated SCTs. These results demonstrate cell-type-specific regulation of MCP-1 expression in human placenta. A model is presented in which bacterial products and inflammatory cytokines initiate a fibroblast-driven cytokine cascade resulting in recruitment of fetal monocytes to placenta which focally increases levels of HBCs in pregnancies complicated by HCA.

    View details for DOI 10.1111/j.1600-0897.2010.00927.x

    View details for Web of Science ID 000289172000003

    View details for PubMedID 21087336

    View details for PubMedCentralID PMC3071455

  • A unique case of rhabdoid tumor presenting as hemoperitoneum in an infant JOURNAL OF PEDIATRIC SURGERY Malhotra, Y., Fitzgerald, T. N., Jubinsky, P. T., Harper, H., Silva, C. T., Zambrano, E., Diefenbach, K. A., Moss, R. L., Bhandari, V. 2011; 46 (1): 247-251


    We report the first pediatric case of an extrarenal, noncentral nervous system, diffusely metastatic, gastrointestinal rhabdoid tumor in a 106-day-old, previous 25-week preterm infant. The unusual clinical presentation, the diagnosis, and biology of this tumor as well as the etiology of hemoperitoneum in neonates and infants are discussed.

    View details for DOI 10.1016/j.jpedsurg.2010.08.051

    View details for Web of Science ID 000286194200056

    View details for PubMedID 21238679

  • Amniotic Fluid Angiopoietin-1, Angiopoietin-2, and Soluble Receptor Tunica Interna Endothelial Cell Kinase-2 Levels and Regulation in Normal Pregnancy and Intraamniotic Inflammation-Induced Preterm Birth JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Buhimschi, C. S., Bhandari, V., Dulay, A. T., Thung, S., Abdel-Razeq, S. S., Rosenberg, V., Han, C. S., Ali, U. A., Zambrano, E., Zhao, G., Funai, E. F., Buhimschi, I. A. 2010; 95 (7): 3428-3436


    Angiopoietin-1 (Ang-1) and Ang-2 act selectively on endothelial cells by engaging the Tunica interna endothelial cell kinase-2 (Tie2) receptor. A soluble form of Tie2 (sTie2) blocks angiopoietin bioactivity.The aim of the study was to characterize changes and expression patterns of Ang-1, Ang-2, and sTie2 in amniotic fluid (AF) and placenta during human pregnancy and intraamniotic inflammation (IAI)-induced preterm birth.We conducted a cross-sectional study at a tertiary university hospital.AF levels of Ang-1, Ang-2, and sTie2 were evaluated in 176 women during second trimester (n = 40), third trimester (n = 37), and preterm labor (positive IAI, n = 50; negative IAI, n = 49). Placenta and cord blood of select women were analyzed.Ang-1, Ang-2, sTie2, and IL-6 were evaluated by ELISA. Real-time PCR measured Ang-1, Ang-2, and Tie2 placental mRNA levels. Placenta was immunostained for Ang-1 and Ang-2. Placental explant cultures were stimulated with lipopolysaccharide, Pam3Cys, and modulators of protein synthesis/secretion (cycloheximide, monensin, and brefeldin A).In normal pregnancy, the levels and ratios of AF Ang-1, Ang-2, and sTie2 varied with gestational age (GA) (P < 0.001). PCR revealed corresponding changes in placental Ang-1 and Ang-2, but not Tie2, mRNA. IAI raised AF Ang-1, Ang-2, and sTie2 above the expected level for GA without affecting their placental mRNA. Ang-2 immunoreactivity appeared enhanced in areas of villous edema. AF Ang-2/Ang-1 ratio was an important determinant of cord blood IL-6 (P < 0.001). Ex-vivo, sTie2 release was increased by Golgi disrupting but not bacterial mimic agents.Ang-1, Ang-2, and sTie2 are physiological constituents of AF that are GA and IAI regulated. Ang-2/Ang-1 ratio may play a role in modulating the fetal inflammatory response to IAI. Placental sTie2 shedding likely involves a Golgi-mediated mechanism.

    View details for DOI 10.1210/jc.2009-2829

    View details for Web of Science ID 000279589600048

    View details for PubMedID 20410222

    View details for PubMedCentralID PMC2928907

  • NUT gene rearrangement in a poorly-differentiated carcinoma of the submandibular gland. Head and neck pathology Ziai, J., French, C. A., Zambrano, E. 2010; 4 (2): 163-168


    NUT midline carcinomas (NMC) are a rare, recently described class of poorly-differentiated tumors that exhibit rapid onset and highly aggressive clinicopathologic behavior. These tumors are defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14, most commonly in a balanced translocation with the BRD4 gene on chromosome 19p13.1, resulting in the characteristic BRD4-NUT fusion gene and protein which blocks epithelial differentiation through chromatin binding. NMC frequently involve midline structures of adolescents and young adults and affect the head and neck region in 50% of cases. To our knowledge, only one case has been previously reported involving a salivary gland. Here, we present a case of a NMC of the salivary gland in an adolescent male presenting with an intermittently painful left submandibular mass of 3 months duration.

    View details for DOI 10.1007/s12105-010-0174-6

    View details for PubMedID 20352379

    View details for PubMedCentralID PMC2878624

  • Pulmonary Squamous Cell Carcinoma Associated With Repaired Congenital Tracheoesophageal Fistula and Esophageal Atresia PEDIATRIC PULMONOLOGY Esquibies, A. E., Zambrano, E., Ziai, J., Kesebir, D., Touloukian, R. J., Egan, M. E., Reyes-Mugica, M., Bazzy-Asaad, A. 2010; 45 (2): 202-204


    We report a 19-year-old man with pulmonary squamous cell carcinoma (SCC) who had a history of vertebral, anal, cardiac, tracheal, esophageal, renal, and radial limb defects (VACTERL) association and tracheoesophageal fistula (TEF) + esophageal atresia (EA) repair as an infant. Children that undergo TEF + EA repair may have an increased risk for developing cancer as they reach adulthood.

    View details for DOI 10.1002/ppul.21148

    View details for Web of Science ID 000274374700014

    View details for PubMedID 20054858

  • Intracranial benign fibrous histiocytomas: a case report and review JOURNAL OF NEURO-ONCOLOGY Moliterno, J. A., Sood, S., Zambrano, E., Kim, J. H., Piepmeier, J. M., Baehring, J. M. 2009; 92 (2): 203-209


    Fibrous histiocytomas are rare lesions, more commonly encountered in soft tissues and bones. They are uncommon as an intracranial lesion. Although there have been several reports about malignant fibrous histiocytomas, less is known about the benign variant of these intracranial tumors as they are often misclassified as other types of tumors. We describe a child who presented with seizure and was subsequently found to have a large temporal lesion. Pathology revealed benign fibrous histiocytoma. We also review other cases reported in the literature in an effort to provide further insight into the diagnosis and management of this rare tumor.

    View details for DOI 10.1007/s11060-008-9743-x

    View details for Web of Science ID 000263647500010

    View details for PubMedID 19030779

  • Multinodular Goiter and Primary Hyperparathyroidism: A Circuitous Route to Diagnosing Metastatic Uveal Melanoma ENDOCRINE PATHOLOGY Theoharis, C. G., Carling, T., Buza, N., Zambrano, E., Sosa, J. A. 2008; 19 (4): 294-298


    Uveal melanoma spreads exclusively via a hematogenous route and is notable for its latency. Liver metastases are common; however, metastatic spread to unusual sites has been encountered. We report the case of metastatic uveal melanoma in a woman with multinodular goiter and primary hyperparathyroidism. The patient presented with hypercalcemia and an elevated intact parathyroid hormone level, in conjunction with a follicular neoplasm in the setting of goiter. She underwent an uneventful total thyroidectomy and parathyroidectomy. Postoperatively, she became normocalcemic. Histopathologic analyses revealed metastatic uveal melanoma cells within both the multinodular goiter and parathyroid adenoma. At present, she is enrolled in a phase II trial for disseminated uveal melanoma. This is a report of uveal melanoma metastatic to both a parathyroid adenoma and a nodular hyperplastic thyroid. Additionally, this case serves to display the unusual metastatic potential of uveal melanoma.

    View details for DOI 10.1007/s12022-008-9041-3

    View details for Web of Science ID 000261967400011

    View details for PubMedID 18758693

  • Placental expression of ceruloplasmin in pregnancies complicated by severe preeclampsia LABORATORY INVESTIGATION Guller, S., Buhimschi, C. S., Ma, Y. Y., Huang, S. T., Yang, L., Kuczynski, E., Zambrano, E., Lockwood, C. J., Buhimschi, I. A. 2008; 88 (10): 1057-1067


    There is consensus that ischemia/reperfusion injury associated with preeclampsia (PE) promotes both placental damage and the release of factors leading to maternal endothelium dysfunction, a hallmark of this potentially life-threatening syndrome. These factors include plasminogen activator inhibitor-1 (PAI-1) and soluble fms-like tyrosine kinase-1 (sFlt-1). The goal of this study was to further characterize placental factors involved in the pathophysiology of PE. Thus, DNA microarray gene profiling was utilized to identify mRNA differentially regulated in placentas from women with severe PE compared to both preterm (PC) and term control (TC) groups. Microarray studies detected an upregulation of mRNA for ceruloplasmin, a copper-containing iron transport protein with antioxidant ferroxidase properties, in PE compared to PC and TC placentas, respectively. Quantitative real-time PCR confirmed these results by demonstrating significant increases in ceruloplasmin mRNA in PE vs PC and TC placentas. Supporting previous reports, the expression of sFlt-1 and PAI-1 were also upregulated in PE placentas. Immunohistochemistry localized ceruloplasmin to the intervillous space in PE and PC placentas, whereas stronger syncytial staining was noted in PE. Western blotting confirmed a significant increase in ceruloplasmin levels in placental tissue in PE compared to PC groups. PCR identified the presence of mRNA for ceruloplasmin in primary cultures of syncytiotrophoblasts, but not villous-derived fibroblasts, suggesting that syncytium is the site of ceruloplasmin synthesis in placenta. Hypoxic treatment (1% O(2)) of syncytiotrophoblasts enhanced levels of ceruloplasmin mRNA approximately 25-fold, a significantly greater upregulation than that noted for PAI-1 and sFlt-1, suggesting that enhanced ceruloplasmin expression is a sensitive marker of syncytial hypoxia. We suggest that syncytial ceruloplasmin and its associated ferroxidase activity, induced by the hypoxia accompanying severe PE, is important in an endogenous cellular program to mitigate the damaging effects of subsequent reperfusion injury at this site.

    View details for DOI 10.1038/labinvest.2008.74

    View details for Web of Science ID 000259445300004

    View details for PubMedID 18679377

    View details for PubMedCentralID PMC2682720

  • Fetal heart rate monitoring patterns in women with amniotic fluid proteomic profiles indicative of inflammation AMERICAN JOURNAL OF PERINATOLOGY Buhimschi, C. S., Abdel-Razeq, S., Cackovic, M., Pettker, C. M., Dulay, A. T., Bahtiyar, M. O., Zambrano, E., Martin, R., Norwitz, E. R., Bhandari, V., Buhimschi, I. A. 2008; 25 (6): 359-372


    We hypothesized that abnormal fetal heart rate monitoring patterns (FHR-MPs) occur more often in pregnancies complicated by intra-amniotic inflammation. Therefore, our objective was to examine the relationships among FHR-MP abnormalities, intra-amniotic inflammation and/or infection, acute histological chorioamnionitis, and early-onset neonatal sepsis (EONS) in pregnancies complicated by preterm birth. Additionally, the ability of various FHR-MPs to predict EONS was investigated. FHR-MPs from 87 singleton premature neonates delivered within 48 hours from amniocentesis (gestational age, mean +/- SD: 28.9 +/- 3.3 weeks) were analyzed blindly using strict National Institute of Child Health and Human Development criteria. Strips were evaluated at three time points: at admission, at amniocentesis, and prior to delivery. Intra-amniotic inflammation was established based on a previously validated proteomic fingerprint (mass-restricted score). Diagnoses of histological chorioamnionitis and EONS were based on well-recognized pathological, clinical, and laboratory criteria. We determined that fetuses of women with severe intra-amniotic inflammation had a higher FHR baseline throughout the entire monitoring period and an increased frequency of a nonreactive FHR-MP at admission. Of all FHR-MPs, a nonreassuring test at admission had 32% sensitivity, 95% specificity, 73% positive predictive value, 77% negative predictive value, and 76% accuracy in predicting EONS. Although a nonreassuring FHR-MP at admission was significantly associated with EONS after correcting for gestational age (odds ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P = 0.030), the majority of the neonates that developed EONS had an overall reassuring FHR-MP. Nonreassuring FHR-MPs at either amniocentesis or delivery had no association with EONS. We conclude that in cases complicated by preterm birth, a nonreassuring FHR-MP at the initial evaluation is a specific but not a sensitive predictor of EONS. An abnormal FHR-MP can thus raise the level of awareness that a fetus with EONS may be born, but it is not a useful clinical indicator of the need for antibiotic treatment of the neonate.

    View details for DOI 10.1055/s-2008-1078761

    View details for Web of Science ID 000257328800008

    View details for PubMedID 18512201

    View details for PubMedCentralID PMC2724874

  • Microvillus inclusion disease associated with coarctation of the aorta and bicuspid aortic valve JOURNAL OF CLINICAL GASTROENTEROLOGY Gathungu, G. N., Pashankar, D. S., Sarita-Reyes, C. D., Zambrano, E., Reyes-Mugica, M., Brueckner, M., Mistry, P. K., Husain, S. Z. 2008; 42 (4): 400-403


    Microvillus inclusion disease is a life-threatening diarrheal disorder of infancy characterized by the presence of microvillus inclusions within the intestinal epithelium. We report a case of a neonate with microvillus inclusion disease that was associated with coarctation of the aorta and bicuspid aortic valve, cardiac malformations within the spectrum of left ventricular outlet tract obstruction. Possible links between the intestinal and cardiac phenotypes are discussed.

    View details for Web of Science ID 000254629300014

    View details for PubMedID 18277898

  • Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis OBSTETRICS AND GYNECOLOGY Buhimschi, I. A., Zambrano, E., Pettker, C. M., Bahtiyar, M. O., Paidas, M., Rosenberg, V. A., Thung, S., Salafia, C. M., Buhimschi, C. S. 2008; 111 (2): 403-412


    To estimate the relationship between histologic chorioamnionitis and four amniotic fluid proteomic biomarkers characteristic of inflammation (defensins 2 and 1, calgranulins C and A).One hundred fifty-eight women with singleton pregnancies had a clinically indicated amniocentesis to rule out inflammation and infection in the context of preterm labor or preterm premature rupture of membranes. A proteomic fingerprint (Mass Restricted score) was generated from amniotic fluid using surface-enhanced laser desorption ionization time-of-flight mass spectrometry. The Mass Restricted score ranges from 0 to 4 (none to all four biomarkers present) in direct relationship with severity of intra-amniotic inflammation. Presence or absence of biomarkers was analyzed in relationship to placental pathology. Criteria for severity of histologic chorioamnionitis were 3 stages and 4 grades of inflammation of the amnion, choriodecidua and chorionic plate.The prevalence of histologic chorioamnionitis was 64% (stage I 12%, stage II 16%, and stage III 37%). The Mass Restricted score significantly correlated with stages of histologic chorioamnionitis (r=0.539, P<.001), grades of choriodeciduitis (r=0.465, P<.001), and amnionitis (r=0.536, P<.001). African-American women were overrepresented in the group with severe inflammation (Mass Restricted score 3-4, P=.022). Of the four biomarkers of the Mass Restricted score, calgranulin C had the strongest relationship with presence of stage III chorioamnionitis, independent of race, amniocentesis-to-delivery interval, and gestational age.Proteomic analysis of amniotic fluid provides an opportunity for early recognition of histologic chorioamnionitis. This methodology may in the future identify candidates for antenatal therapeutic interventions.II.

    View details for Web of Science ID 000252762300020

    View details for PubMedID 18238979

  • Histological characteristics of singleton placentas delivered before the 28th week of gestation PATHOLOGY Hecht, J. L., Allred, E. N., Kliman, H. J., Zambrano, E., Doss, B. J., Husain, A., Pflueger, S. M., Chang, C., Livasy, C. A., Roberts, D., Bhan, I., Ross, D. W., Senagore, P. K., Leviton, A. 2008; 40 (4): 372-376


    The placenta is a record of the fetal environment and its examination may provide information about the baby's subsequent growth and development. We describe the histological characteristics of 947 singleton placentas from infants born between 23 and 27 weeks gestation.Consent was obtained from mothers who delivered before 28 weeks (clinical estimate). We evaluated the gross and histopathological features of the placenta and assessed pair-wise correlations between variables.Lesions of uteroplacental circulation (abruption, extensive infarction or thrombosis, marked basal or perivillous fibrin deposition, increased syncytial knots) were inversely related to those associated with inflammation of the membranes and cord. Earlier age favoured inflammatory variables, while older age favoured characteristics attributed to impaired blood flow. We observed inflammation of the chorionic plate in 43%, the cord in 19%, and of chorionic plate vessels in 30%. Of the placentas with umbilical cord inflammation, 8% had no inflammation of the chorionic plate.This study population is unique in its size and recruitment by gestational age rather than birth weight. Inflammation occurred frequently, but not in placentas that had characteristics of vasculopathy. The prevalence of inflammation decreased with increasing gestational age, while vasculopathy increased. Funisitis need not be accompanied by chorionic inflammation.

    View details for DOI 10.1080/00313020802035865

    View details for Web of Science ID 000255435800006

    View details for PubMedID 18446627

    View details for PubMedCentralID PMC2990223

  • Characterization of chorioamnionitis in 2nd-trimester C-section placentas and correlation with microorganism recovery from subamniotic tissues PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Hecht, J. L., Onderdonk, A., Delaney, M., Allred, E. N., Kliman, H. J., Zambrano, E., Pflueger, S. M., Livasy, C. A., Bhan, I., Leviton, A. 2008; 11 (1): 15-22


    Prolonged exposure to infection appears to influence fetal/neonatal development. We characterize the relationship between histologic patterns of inflammation and microorganism recovery from the placentas of live born infants delivered before the 28th postmenstrual week. The subamniotic parenchyma of 835 placentas delivered by cesarean section were cultured and evaluated for specific histologic patterns of inflammation in a blinded fashion. Cases with prolonged membrane rupture were excluded. Microorganisms were recovered from 41% of placentas. Microorganisms found more frequently in placentas with high-grade chorionic plate inflammation include Actinomyces, Prevotella bivia, Corynebacterium sp., Escherichia coli, Peptostreptococcus magnus, multiple species of Streptococci, and Mycoplasma sp., including Ureaplasma urealyticum. These microorganisms were also associated with fetal vasculitis (neutrophilic infiltration of chorionic plate stem vessels or umbilical cord). Recovery of microorganisms from placental parenchyma is associated with histologic inflammation. The same microorganisms responsible for inciting high-grade chorionic plate inflammation are also most likely to promote fetal inflammation.

    View details for DOI 10.2350/07-06-0285.1

    View details for Web of Science ID 000252835600003

    View details for PubMedID 18237241

  • Chromosomal rearrangements in lipofibromatosis CANCER GENETICS AND CYTOGENETICS Kenney, B., Richkind, K. E., Friedlaender, G., Zambrano, E. 2007; 179 (2): 136-139


    Lipofibromatosis is a relatively rare pediatric neoplasm, which usually manifests as an ill-defined soft tissue mass involving the upper and lower distal extremities, the trunk, and, less frequently, the head. To date, no cytogenetic abnormalities have been reported in this uncommon neoplasm. We present a case of lipofibromatosis featuring a three-way t(4;9;6) translocation in a 5-year-old boy.

    View details for DOI 10.1016/j.cancergencyto.2007.08.011

    View details for Web of Science ID 000251478000008

    View details for PubMedID 18036401

  • Congenital panfollicular nevus associated with polydactyly JOURNAL OF CUTANEOUS PATHOLOGY Kim, J., Zambrano, E. V., McNiff, J. M. 2007; 34: 14-17


    A 2-year-old girl presented with ulnar-sided duplication of the left thumb distal to the interphalangeal joint and syndactyly of the first web space. She also had several asymptomatic pink-tan cutaneous papules, involving the first and second ray of the left hand and wrist, clinically resembling a linear epidermal nevus. Microscopically, the papules were composed of well-circumscribed aggregates of basaloid epithelium within the dermis. No normal hair follicles were identified. Follicular germ and papillae were identified, representing abortive attempts at hair follicle formation. The features were remarkably similar to a novel entity described by Finn and Argenyi as congenital panfollicular nevus. In our case, the congenital panfollicular nevus was associated with distal thumb polysyndactyly, which may suggest an important link between limb patterning and hair follicle development.

    View details for DOI 10.1111/j.1600-0560.2006.00714.x

    View details for Web of Science ID 000250842500003

    View details for PubMedID 17997731

  • Solid variant of aneurysmal bone cyst with a novel (X;9) translocation CANCER GENETICS AND CYTOGENETICS Kenney, B., Richkind, K. E., Zambrano, E. 2007; 178 (2): 155-159


    Aneurysmal bone cysts (ABC) are locally destructive bone lesions occurring predominantly in young adults. There has been debate as to the neoplastic nature of these lesions. In recent years, however, compelling evidence of clonal chromosomal abnormalities has indicated a likely neoplastic origin. Although relatively few ABC have been assessed cytogenetically, many of those which have been studied have shown abnormalities of chromosome 17, particularly t(16;17)(q22;p13). We present a case of ABC in a 4-year-old female, which demonstrated the novel translocation t(X;9)(q26;q32).

    View details for DOI 10.1016/j.cancergencyto.2007.07.016

    View details for Web of Science ID 000250688800011

    View details for PubMedID 17954273

  • Reference weights for placentas delivered before the 28th week of gestation PLACENTA Hecht, J. L., Kliman, H. J., Allred, E. N., Pflueger, S. M., Chang, C., Doss, B. J., Roberts, D., Livasy, C. A., Bhan, I., Zambrano, E., Ross, D. W., Senagore, P., Husain, A. N., Leviton, A. 2007; 28 (10): 987-990


    Very few studies have measured the weight of large numbers of placentas delivered before the 28th post-menstrual week.We measured the weight of 930 singleton placentas delivered before the 28th post-menstrual week, and examined the distributions of weights in selected groups (week of gestation, reason for preterm birth, birth weight Z-score categories, placenta histology). We excluded 90 singleton placentas based on growth restriction as indicated by birth weight Z-score, resulting in a normative sample of 840 placentas. Weights for unfused twin placentas are also presented.Standard weights derived from our data set differ from those previously published, partly due to a larger sample size. Placenta weight varied with birth weight. Placentas from pregnancies ending due to preeclampsia, fetal indications or those showing evidence of poor perfusion on histology were among the smallest and their weights correlated with the smallest birth weights for gestational age.Placenta weights appear to be influenced by multiple maternal and fetal processes. We present a standard weight table for singleton placentas among live infants born between 23 and 27 completed weeks.

    View details for DOI 10.1016/j.placenta.2007.04.009

    View details for Web of Science ID 000249650500002

    View details for PubMedID 17573110

  • Mesenchymal hamartoma of the liver associated with features of Beckwith-Wiedemann Syndrome and high serum alpha-fetoprotein levels PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Cajaiba, M. M., Sarita-Reyes, C., Zambrano, E., Reyes-Mugica, M. 2007; 10 (3): 233-238


    A 5-month-old girl with clinical features of Beckwith-Wiedemann syndrome (BWS), including a repaired omphalocele, an earlobe crease, enlarged adrenal glands, renal size discrepancy, and hyperinsulinemic hyperglycemia, presented with a 1.9-cm liver nodule. Markedly increased serum alpha-fetoprotein (AFP) levels (1,060,000 mg/L), highly suspicious for hepatoblastoma, were detected, and resection of the liver mass was performed. Histologic sections showed features characteristic of a mesenchymal hamartoma of the liver (MHL). No features of embryonal or fetal hepatocellular proliferation or heterologous stromal components were noted. By immunohistochemistry, the hepatocytes expressed AFP, but no nuclear accumulation of beta-catenin was present. Electron microscopy revealed normal, mature hepatocytes. Here we address the diagnostic challenge of the uncommon association of MHL and BWS in the setting of markedly elevated serum AFP levels. In addition, we analyze the unusual pancreatic lesion (focal endocrine adenomatosis) leading to severe hyperinsulinemic hypoglycemia in a patient with possible BWS. We emphasize that MHLs may present with markedly increased serum AFP levels, mimicking hepatoblastomas, and may also be part of the expanding spectrum of findings of BWS.

    View details for DOI 10.2350/06-07-0128.1

    View details for Web of Science ID 000247950200009

    View details for PubMedID 17535089

  • Pediatric sclerosing rhabdomyosarcoma INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Zambrano, E., Perez-Atayde, A. R., Ahrens, W., Reyes-Mugica, M. 2006; 14 (3): 193-199


    Sclerosing rhabdomyosarcoma, a particular phenotypic variant of rhabdomyosarcoma initially described in the adult population, has emerged as a potential pitfall in the evaluation of pediatric sarcomas. Because of its densely hyalinized collagenous matrix and its occasional expression of a pseudovascular pattern of growth, sclerosing rhabdomyosarcoma has been at times misdiagnosed as chondrosarcoma, osteosarcoma, or angiosarcoma. We describe 3 pediatric patients with sclerosing rhabdomyosarcoma and provide a detailed description of its distinguishing pathologic features. Awareness about this rhabdomyosarcoma variant and careful immunophenotypical evaluation are necessary to establish the correct diagnosis. Although no specific genetic aberrations have been recognized, yet the cytogenetic findings in 2 tumors of this series suggest a link with embryonal rhabdomyosarcoma. It is likely that further genotyping will result in better nosologic delineation of sclerosing rhabdomyosarcoma and that it will uncover pathogenetically and prognostically relevant genes.

    View details for DOI 10.1177/1066896906290558

    View details for Web of Science ID 000239776300002

    View details for PubMedID 16959698

  • Extranodal marginal zone B-cell lymphoma/maltoma of the lip in a child INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Zambrano, E., Mejia-Mejia, O., Bifulco, C., Shin, J., Reyes-Mugica, M. 2006; 14 (2): 163-169


    All forms of cutaneous lymphomas are rare in children. Extranodal marginal zone B-cell lymphomas (EMZBL)/mucosa-associated lymphoid tissue (MALT) lymphomas are unusual neoplasms in children and young adults. We report a case of an EMZBL/MALT lymphoma of the lip in a previously healthy 14-year-old boy without immunodeficiency, confirmed by immunohistochemistry and documentation of clonal rearrangement of the immunoglobulin heavy-chain gene. Additionally, we present a review of the differential diagnosis of skin and mucosal lymphoid proliferations in childhood.

    View details for Web of Science ID 000237702800013

    View details for PubMedID 16703182

  • Total parenteral nutrition induced liver pathology: An autopsy series of 24 newborn cases PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Zambrano, E., El-Hennawy, M., Ehrenkranz, R. A., Zelterman, D., Reyes-Mugica, M. 2004; 7 (5): 425-432


    Total parenteral nutrition (TPN)-induced liver injury is a common complication in neonates managed with newborn intensive care. In several of these cases, irreversible and even fatal liver damage may develop, with patients dying of liver failure. In spite of multiple studies over several years, the pathogenesis of TPN-induced liver damage remains poorly understood. Clinical data from 24 neonates with clinical history of receiving TPN who died at Yale-New Haven Children's Hospital and had autopsies performed, were collected by medical record review without knowledge of liver pathology findings. Liver histological sections from these patients were evaluated for multiple parameters without knowledge of the clinical course. Continuous data were analyzed by Wilcoxon signed-rank test and Mann-Whitney test, and dichotomous data by Fisher's exact test; P < 0.05 was considered significant. Different histopathological abnormalities with varying degrees of severity were observed. A progression in the severity of histopathological changes in relation to duration of TPN administration (DTPN) was found. While patients with DTPN of < 2 wk had no fibrosis or only mild degrees of fibrosis, patients with more than 6 wk of DTPN developed moderate-to-severe fibrosis. Similar results were observed for cholestasis and bile duct proliferation. We did not find significant differences for birth weight, gestational age, occurrence of necrotizing enterocolitis, sepsis, or enteral feedings between the group with normal-to-mild liver changes ( n = 16), and the group with moderate-to-severe liver changes ( n = 8). On the other hand, DTPN was significantly different between these two groups ( P = 0.008). Also, patients small for gestational age ( P = 0.003) and patients with bronchopulmonary dysplasia ( P = 0.001) were more commonly seen in the group with moderate-to-severe histopathological findings. Intracellular copper was detected in 12.5% of patients with moderate-to-severe liver changes, and was found in 50% of patients with normal-to-mild liver findings ( P = 0.04). Detection of copper from tissue sections also decreased with DTPN, being observed in 57% of patients with < 2 wk DTPN and in none of the patients with > 12 wk DTPN. Our findings confirm the known significant relationship between the duration of TPN and liver injury. While previously described associations with birth weight, gestational age, enteral feedings, necrotizing enterocolitis, and sepsis were not noted, our study suggests that poor intrauterine growth may be a significant clinical risk factor for TPN-induced liver injury. In addition, our findings suggest that copper may have a protective effect against the development of TPN-induced liver damage.

    View details for DOI 10.1007/s10024-001-0154-7

    View details for Web of Science ID 000225134400005

    View details for PubMedID 15547767

  • Chronic granulomatous disease 91st Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Zambrano, E., Esper, F., Rosenberg, R., Kim, J., Reyes-Mugica, M. ALLIANCE COMMUNICATIONS GROUP DIVISION ALLEN PRESS. 2003: 577–81

    View details for DOI 10.1007/s10024-003-0706-0

    View details for Web of Science ID 000187526500017

    View details for PubMedID 15018460

  • An osteoclast-rich tumor of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: Reports of 6 cases of a GIST simulator INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY Zambrano, E., Reyes-Mugica, M., Franchi, A., Rosai, J. 2003; 11 (2): 75-81


    Six cases are reported of an osteoclast-rich tumor of the gastrointestinal tract that should be segregated from GIST. Five of the cases were located in the small bowel and one in the stomach. The age of the patients ranged from 13 to 37 years. The tumors behaved aggressively, with metastases to regional lymph nodes, liver, and other intra-abdominal sites. Microscopically, the tumor cells were medium-sized, predominantly oval, relatively monomorphic, diffusely immunoreactive for S-100-protein, and negative for CD117, CD34, HMB-45, and Mart-1. They were admixed with scattered osteoclast-like, multinucleated giant cells which were S-100-protein negative and KP1-positive. One case studied cytogenetically had the karyotype 46XX t(12;22)(q13;q12). The cases here reported are interpreted as examples of a distinctive type of gastrointestinal neoplasm which shares some features with clear cell sarcoma of soft parts (melanoma of soft parts), including in one case the chromosomal translocation that is characteristically associated with that entity.

    View details for Web of Science ID 000182841400002

    View details for PubMedID 12754623

  • Renal cell carcinoma with t(X;17): Singular pediatric neoplasm with specific phenotype/genotype features PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Zambrano, E., Reyes-Mugica, M. 2003; 6 (1): 84-87


    Renal cell carcinomas in children are extremely rare and are usually associated with specific chromosomal rearrangements, different from those seen in adult patients. We present the case of a 9-year-old girl with a renal cell carcinoma with t(X;17) diagnosed at our institution. We also review the pertinent literature, with an emphasis on the genetic and molecular aspects associated with this rare neoplasm.

    View details for DOI 10.1007/s10024-002-1010-0

    View details for Web of Science ID 000180838800013

    View details for PubMedID 12469236

  • Hormonal activity may predict aggressive behavior in neuroblastoma PEDIATRIC AND DEVELOPMENTAL PATHOLOGY Zambrano, E., Reyes-Mugica, M. 2002; 5 (2): 190-199


    Overproduction of catecholamines (dopamine [DA], norepinephrine [NE]) and their metabolites (homovanillic [HVA] and vanillylmandelic [VMA] acids) characterizes neuroblastoma (NB). In previous studies, increased urinary DA/NE, and DA/VMA ratios have been associated with poor prognosis, whereas low DA/NE ratios have been associated with longer disease-free survival. Higher urinary VMA, HVA, and NE levels have been found in association with low MYCN amplification, in contrast to cases with high MYCN amplification in which normal levels have been found. It is then believed that an "immature" catecholamine pattern indicates poor prognosis. We correlated urinary DA, NE, VMA, and HVA levels with age, clinical tumor stage, histological features (favorable [FH]/unfavorable [UH]) and MYCN status of 33 patients with NB. DA/VMA and DA/HVA ratios were also calculated. Wilcoxon rank sum and chi-squared tests were performed to determine statistical significance. Eighty-eight percent (15/17) of stage 3-4 cases had DA levels >2 times the upper limit of normal, but only 8% (1/12) of stage 1-2 cases had DA levels twice the upper limit of normal. In 61% (11/18) of stage 3-4 cases, the VMA level was >10 times the upper limit of normal, in contrast to stage 1-2 cases, in which only one patient (1/15) had a VMA level >10 times the upper limit of normal. Similar findings were obtained with urinary HVA and NE. Patients older than 12 months of age at diagnosis also had higher urinary levels of DA, VMA, HVA, and NE than those of patients younger than 12 months of age at diagnosis. Eighty-two percent (14/17) of stage 3-4 cases had DA/VMA ratios <0.78, with the other 18% (3/17) showing ratios between 1.4 and 8.82 (all stage 4 and >12 months of age). In contrast, all stage 1-2 cases ((12)) had ratios <1.4. All (12/12) non- MYCN-amplified cases had DA/VMA ratios <1.4 (0.06-0.84), while one MYCN-amplified case (1/3) had a ratio of 8.82; the other two MYCN-amplified cases had DA/VMA ratios of 0.09-0.11. Twenty-nine percent (2/7) of cases with UH had a DA/VMA ratio >1.4, but in all FH cases (14/14) the DA/VMA ratio was <1.4 (0.08-0.084). Similar to previous studies, we found that aggressive NB is associated with higher urinary levels of DA, VMA, HVA, and NE. We also confirmed the previous observation that there appears to be a subset of NB in which a possible blockade in DA metabolism is associated with poor prognostic features (>12 months, stage 4, UH, and MYCN amplification). A seemingly novel observation in our study is that all high DA/HVA and DA/VMA ratios were obtained in stage 4 tumors, suggesting an association between the inability to metabolize DA and the acquisition of metastatic potential. On the basis of our results, we would like to emphasize the importance of determining not only DA, HVA, and VMA urinary levels, to support the diagnosis of NB, but also DA/HVA and DA/VMA ratios as a rapid initial assessment of prognosis in these patients.

    View details for DOI 10.1007/s10024-001-0145-8

    View details for Web of Science ID 000174456600011

    View details for PubMedID 11910515

  • Isolated noncompaction of the ventricular myocardium: Clinical and molecular aspects of a rare cardiomyopathy LABORATORY INVESTIGATION Zambrano, E., Marshalko, S. J., Jaffe, C. C., Hui, P. 2002; 82 (2): 117-122

    View details for Web of Science ID 000174045900001

    View details for PubMedID 11850525