Highlights in Pathology - Gynecologic Pathology - December 2018

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December 2018 edition 

LITERATURE HIGHLIGHTS IN GYNECOLOGIC PATHOLOGY IN 2018 - Submitted by Dr. Gulisa Turashvili, Mount Sinai Hospital

International Endocervical Adenocarcinoma Criteria and Classification (IECC): A New Pathogenetic Classification for Invasive Adenocarcinomas of the Endocervix

Stolnicu et al. Am J Surg Pathol. 2018 Feb;42(2):214-226.

https://www.ncbi.nlm.nih.gov/pubmed/29135516

Endocervical adenocarcinomas (ECAs) account for 20-25% of all invasive cervical carcinomas. Although the most common subtype is usual-type ECA which is associated with high risk human papillomavirus (HPV) subtypes, HPV-unassociated ECAs have been increasingly recognized. Accurate diagnosis of these subtypes is essential given the important differences in clinical outcomes of HPV-driven and HPV-unassociated ECAs. The latest World Health Organization (WHO) Classification of Tumours of Female Reproductive Organs classifies ECAs based on descriptive morphologic features, particularly cytoplasmic characteristics, and has important limitations owing to vague and non-reproducible definitions for each histotype. Stolnicu et al. convened an international panel of pathologists to establish a morphologic classification of ECAs linked to etiology based on 409 cases collected from 7 institutions worldwide. The International Endocervical Adenocarcinoma Criteria and Classification (IECC) divides ECAs into two major categories: 1) HPV-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification; 2) Non-HPV-associated adenocarcinoma (NHPVA) with no or limited HPVA features. HPVAs are then subcategorized based on cytoplasmic features, while NHPVAs are subclassified based on established criteria (i.e., gastric-type, clear cell, etc). The study confirms that usual-type ECAs are the most common type worldwide and that mucinous ECAs represent a highly heterogeneous group comprised of both HPVA and NHPVA. Gastric-type ECA is the major NHPVA subtype, while endometrioid and serous ECAs are extraordinarily rare. In addition, NHPVA tumors in this cohort were larger and affected older patients. The authors recommend replacing the current WHO classification with the IECC.

 

Morphologic Features of Gastric-type Cervical Adenocarcinoma in Small Surgical and Cytology Specimens

Turashvili et al. Int J Gynecol Pathol. 2018 May 10.

https://www.ncbi.nlm.nih.gov/pubmed/29750702

Only 5-10% of cervical adenocarcinomas are unrelated to HPV, the most common of which is gastric-type adenocarcinoma (GCA). GCA is defined as a subtype of mucinous adenocarcinoma with gastric differentiation. These are aggressive, chemorefractory tumors with a propensity for peritoneal and abdominal spread and span a morphologic spectrum. The well-differentiated forms (“minimal-deviation adenocarcinoma”) typically exhibit bland morphologic appearances which could lead to misdiagnosis, particularly in limited material. Turashvili et al. sought to characterize the morphologic features of GCA in 59 surgical biopsy and cytology specimens from 23 patients. Histologically, these were carcinomas with obvious glandular differentiation with tumor cells showing pale or foamy cytoplasm, well-defined cytoplasmic borders and mild-to-moderate nuclear pleomorphism with small nucleoli. Cytologically, there were single and crowded clusters of tumor cells with pale, foamy to vacuolated cytoplasm, well-defined cytoplasmic borders and moderately pleomorphic, round to oval nuclei with one or more nucleoli. GCA was suspected by the original pathologist in only 25% of consultation cases. These findings emphasize that awareness of the morphologic features followed by the proper work-up and/or seeking a second opinion is essential for accurate diagnosis of GCA in small surgical and cytology specimens to ensure the institution of appropriate clinical management as early as possible.

 

A Pan-Cancer Landscape Analysis Reveals a Subset of Endometrial Stromal and Pediatric Tumors Defined by Internal Tandem Duplications of BCOR

Juckett LT, Lin DI, Madison R, Ross JS, Schrock AB, Ali S. Oncology. 2018 Oct 31:1-9.

https://www.ncbi.nlm.nih.gov/pubmed/30380541

The X-linked BCOR gene (BCL-6 Corepressor), a member of the Polycomb Repressive Complex 1 (PRC1), potentiates transcriptional repression through BCL6 binding of PRC1 and influences gene expression through histone deacetylase interaction. Alterations of BCOR have been linked to mesenchymal tumors, often as a result of gene fusions. More recently, BCOR internal tandem duplications (ITDs) have been identified in small series of pediatric sarcomas and rare adult tumors, including endometrial stromal sarcomas (ESS). Juckett et al. set out to determine the frequency and genomic spectrum of BCOR ITDs in 140,411 unique advanced cancer types. All cases were sequenced by hybrid-capture-NGS-based comprehensive genomic profiling of 186-315 genes plus introns from 14 to 28 cancer-associated genes and RNA for 265 genes for some cases. BCOR ITDs were identified in 0.024% of cases (33/140,411), the majority of which were sarcomas (63.6%; 21/33), including uterine (52.4%; 11/21) and non-uterine/pediatric (42.8%; 9/21) sarcomas. The ITDs occurred in exon 15, near C-terminus in most cases (69.7%; 23/33). All uterine sarcomas lacked gene fusions typically associated with ESS and exhibited similar morphologic features consistent with high-grade ESS. In addition, 90% of cases contained a round cell component. These findings confirm that BCOR ITDs define a subset of unique high-grade ESS, and this paper characterizes the largest series to date. The significance of identification of uterine ESS harboring BCOR ITD cannot be overstated given that these tumors may respond to anthracycline-based chemotherapy regimens.

 

Novel PLAG1 Gene Rearrangement Distinguishes a Subset of Uterine Myxoid Leiomyosarcoma From Other  Uterine Myxoid Mesenchymal Tumors

Arias-Stella JA 3rd, Benayed R, Oliva E, Young RH, Hoang LN, Lee CH, Jungbluth AA, Frosina D, Soslow RA, Antonescu CR, Ladanyi M, Chiang S. Am J Surg Pathol. 2018 Nov 27.

https://www.ncbi.nlm.nih.gov/pubmed/30489320

Myxoid leiomyosarcoma is a rare morphologic variant of uterine leiomyosarcoma, often exhibiting a deceptively bland appearance leading to misdiagnosis. Furthermore, myxoid leiomyosarcomas show extensive morphologic and immunophenotypic overlap with many benign and malignant uterine mesenchymal tumors, including myxoid inflammatory myofibroblastic tumor and endometrial stromal sarcoma with myxoid features, particularly those with BCOR aberrations. Based on limited clinical data, myxoid leiomyosarcomas are more aggressive than conventional leiomyosarcomas. Until recently, little was known about molecular alterations involved in the pathogenesis of these tumors. Arias-Stella et al. performed targeted RNA sequencing, fluorescence in situ hybridization (FISH) for PLAG1, BCOR, BCORL1, HMGA2 and ALK and immunohistochemistry for BCOR, PLAG1 and ALK on 19 uterine tumors previously diagnosed as myxoid leiomyosarcomas. Besides clinicopathological characterization of 15 cases in which the diagnosis of myxoid leiomyosarcoma was confirmed, there were novel TRPS1-PLAG1 or RAD51B-PLAG1 fusions detected in 4 tumors. FISH confirmed the presence of fusions in 3 of 4 cases. Diffuse immunohistochemical expression of PLAG1 was identified in 7 tumors, including 4 with PLAG1 rearrangement. No morphologic differences were found among PLAG1 fusion-positive and fusion-negative tumors. These findings suggest that PLAG1 rearrangements underpin approximately 25% of myxoid leiomyosarcomas and targeted PLAG1 sequencing may serve as a useful biomarker in diagnostically challenging cases.

 

Endometrial Carcinoma Diagnosis: Use of FIGO Grading and Genomic Subcategories in Clinical Practice: Recommendations of the International Society of Gynecological Pathologists

Soslow RA, Tornos C, Park KJ, Malpica A, Matias-Guiu X, Oliva E, Parkash V, Carlson J, McCluggage WG, Gilks CB. Int J Gynecol Pathol. 2019 Jan;38 Suppl 1:S64-S74.

https://www.ncbi.nlm.nih.gov/pubmed/30550484

A review by Soslow et al. sought to address 2 important issues in the diagnosis of endometrial carcinoma and developed recommendations from the International Society of Gynecological Pathologists Endometrial Carcinoma project: 1) Grading of endometrioid adenocarcinomas – a 3-tiered grading system is based on the degree of glandular differentiation and it is considered standard by International Federation of Gynecology and Obstetrics (FIGO), the American College of Obstetricians and Gynecologists, and the College of American Pathologists. However, this system suffers from poor reproducibility and its use is not supported by the current evidence base. The authors recommend moving toward a binary grading scheme by considering FIGO grade 1 and 2 tumors "low grade" and FIGO grade 3 tumors "high grade"; 2) Incorporation of the 4 genomic subtypes (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient) of endometrial carcinoma defined by The Cancer Genome Atlas (TCGA) into clinical practice – although the recent evidence suggests that these subtypes can be reproducibly diagnosed on biopsy/curettage and hysterectomy specimens and the classification is powerfully prognostically relevant, the authors believe that it is too premature to recommend its routine use. Laboratories undertaking this genomic classification should report it in conjunction with histotype and grade. Important related and unresolved issues are also discussed.

 

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