Highlights in Pathology

Highlights in Gynecological Pathology

January 2019

LITERATURE HIGHLIGHTS IN GI PATHOLOGY IN 2018 - Submitted by Corwyn Rowsell, MD, FRCPC, FCAP, St. Michael's Hospital

Happy New Year!  As a new CPD initiative, I have been asked to summarize some GI literature of general interest from the past year.  I have selected the five articles below as they represent a variety of disease processes and GI sites, and address practical issues encountered by surgical pathologists.  It is by no means a ranking of which papers are best or most important  - I would be delighted to hear from others which papers they would have chosen!

Carr N,  et al.  The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinoma, and pseudomyxoma peritionei. (2017) Histopathology 71, 847-858.

Admittedly, I’m cheating a bit on this one as it is technically a December 2017 paper, but  I figure it is close enough to 2018 and definitely worth a read!  This review article is an excellent summary of the new classification of appendiceal neoplasia based on the consensus terminology adopted by the Peritoneal Surface Oncology Group International (PSOGI).   If you are rushed for time, scanning the tables of terminology and histological features is still worthwhile.  Here are a few of the highlights: 1) Defining histological features of low grade appendiceal mucinous neoplasms (LAMN).  2) Introduction of the high grade appendiceal mucinous neoplasm (HAMN), which essentially has features of a LAMN but with high grade atypia.  3) Rejection of ‘adenoma’ terminology for appendiceal lesions, with the exception of colorectal-type adenomas.  4) Recommending the term ‘serrated polyp’ for serrated lesions of the appendix as opposed to colonic terminology such as ‘sessile serrated adenoma’.  5) The importance of signet ring cells as a defining feature of poorly differentiated mucinous adenocarcinoma.  There is also a summary of the new staging system, in which LAMNs are staged as pTis if they do not extend beyond muscularis propria, but are staged as pT3 if either mucin or neoplastic epithelium involves the subserosa or mesoappendix, and pT4 if mucin or neoplastic epithelium involves serosa/adjacent structures.

Hissong E, Jessurun J, Yantiss R.  Findings in exudates can help distinguish benign gastric ulcers from ulcerated adenocarcinomas.  (2018) Histopathology 73, 215-219.

This paper might prompt us all to pay a little more attention to the debris we often see in biopsies of gastric ulcers.  The authors examined 50 cases of ulcerated adenocarcinoma and 50 site-matched control cases of benign ulcer samples with respect to the contents of the debris.  Amounts of inflammation or cellular debris were similar in both groups.  They found, however, that ulcerated adenocarcinomas were significantly more likely to be associated with non-Helicobacter bacterial colonies (76% of  ulcerated cancers vs 22% of benign ulcers).  Furthermore, the finding of filamentous bacteria or fungi  in the exudate was highly specific for carcinoma (98%).  Not surprisingly, intestinal metaplasia was more closely associated with carcinoma than benign ulcers, and the authors propose that it is the hypochlorhydria associated with atrophy and intestinal metaplasia that create a more permissive environment for diverse micro-organisms to grow.   The bottom line – the finding of bacterial colonies in gastric ulcer debris should prompt a diligent search for evidence of malignancy on the slide, and perhaps a comment in cases where malignancy is not found, particularly in superficial or scant biopsy specimens.

Tse J, et al. Syphilis of the Aerodigestive Tract.  (2018) Am J Surg Pathol  42, 472-478.

Syphilis rates are on the rise in North America, and it is a disease that we can easily overlook if we are not alert to the histopathological patterns it may produce in extragenital sites.  Classically, we tend to think of plasma cells as a key histologic finding, but this paper describes three histologic patterns found in their evaluation of 12 cases of syphilis of the aerodigestive tract: 1) plasma-cell rich 2) lymphohistiocytic (+/- granulomata)  3) lymphoma-like with an activated immune response and large, atypical lymphoid cells.  The authors highlight some key differential diagnoses for each pattern (IgG4-related disease for pattern 1, fungal and mycobacterial infection for pattern 2, lymphoma for pattern 3).  The authors also warn of the possibility of false negative silver stains (e.g. Steiner) for syphilis and recommend using immunohistochemistry.  A word of caution (both from the paper and from my personal/institutional experience) – the Treponema antibody is not entirely specific and does cross-react with other spirochetes including Brachyspira, so serologic confirmation is still necessary even when the IHC is positive!

Chiu K, Riddell RH, Schaeffer DF.  DALM, rest in peace: a pathologist’s perspective on dysplasia in the post-DALM era.  (2018) Mod Pathol 31, 1180-1190.

Are gastroenterologists and surgeons still asking you to distinguish between a DALM (dysplasia-associated lesion or mass) vs sporadic adenoma in inflammatory bowel disease patients?  Add this useful review paper to your armamentarium!  Challenges in histologically distinguishing sporadic adenomas from IBD-associated polypoid dysplasia as well as studies showing that polypoid IBD-associated dysplasia may be safely treated by complete endoscopic removal render the DALM concept less helpful in determining patient management.  Also, advances in endoscopy such as high definition endoscopy and chromoendoscopy have likely rendered many previously ‘invisible’ flat dysplasia into endoscopically visible lesions.  The authors discuss the 2015 SCENIC consensus statement where DALM-related terminology was rejected in favour of descriptors based on the Paris classification.  In a nutshell, dysplasia is divided into invisible (not seen on endoscopy; found on random mucosal biopsies) vs. visible (biopsy or endoscopic resection of a lesion seen on endoscopy).  Visible dysplasia is further categorized as polypoid or non-polypoid, with polypoid lesions described as pedunculated or sessile, and non-polypoid lesions subdivided into superficial elevated, flat, or depressed categories.   The paper also includes a helpful diagram showing treatment recommendations based on the type of lesion and degree of dysplasia.

Knijn N, van Exsel U, de Noo M, Nagtegaal I.  The value of intramural venous invasion in colorectal cancer – a systematic review and meta-analysis.  (2018) Histopathology 72, 721-728. 

We are accustomed to diligently searching for evidence of extramural venous invasion in our colorectal cancer resection specimens, but intramural venous invasion has garnered relatively little attention until recently.  The authors of this paper have endeavoured to address the issue of the importance of IMVI via a systematic review and meta-analysis.  They conclude that  IMVI is underreported (the rate of IMVI was 17.6% in studies where slides were reviewed specifically for IMVI, vs studies that just relied on pathology reports), and that use of elastic stains results in increased detection over H&E alone.  IMVI was significantly associated with decreased cancer-specific survival, with a borderline significant effect on overall survival and local recurrence rates.  Interestingly,  the authors also concluded that there was no significant prognostic difference between EMVI and IMVI, suggesting that simply identifying venous invasion is more important than its location. 

December 2018

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.


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.


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.


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.


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.


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.



December 2018 - Gynecologic Pathology