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Anatomic pathology selected abstracts

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Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center.

Diagnostic algorithmic proposal based on IHC evaluation of invasive endocervical adenocarcinomas

February 2019—The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas into two main categories based on morphology: human papilloma virus-associated (HPVA) and nonhuman papilloma virus-associated adenocarcinomas. The authors aimed to improve the diagnostic accuracy of the International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical (IHC) evaluation and constructing objective IHC-based algorithms for classifying these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor, progesterone receptor, androgen receptor, vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 virus types. Vimentin, estrogen receptor, and progesterone receptor were expressed in a significant minority of endocervical adenocarcinomas (ECAs), primarily HPVAs, limiting their use in the differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity as it was ubiquitously expressed in gastric-type carcinoma and the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas but not in the vast majority of other subtypes. GATA3 was positive in 10 percent of usual-type adenocarcinomas and single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in six percent of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6 percent of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and nonhuman papilloma virus associates, particularly in gastric-type carcinoma (more than 50 percent of cases). The following diagnostic classification algorithms were developed using these data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, estrogen receptor, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified using HR-HPV ISH and estrogen receptor.

Stolnicu S, Barsan I, Hoang L, et al. Diagnostic algorithmic proposal based on comprehensive immunohistochemical evaluation of 297 invasive endocervical adenocarcinomas. Am J Surg Pathol. 2018;42(8):989–1000.

Correspondence: Dr. R. A. Soslow at soslowr@mskcc.org

PD-L1 IHC staining protocols using antibody clone 28-8 on staining platforms

Several immunohistochemistry assays have been developed to assess tumor programmed death-ligand 1 expression levels in patients who are candidates for programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor therapy. The PD-L1 IHC 28-8 pharmDx kit is FDA-approved as a complementary diagnostic and CE-marked as an in vitro diagnostic device for nivolumab therapy in melanoma and specific lung cancer subtypes, as well as for squamous cell carcinoma of the head and neck and urothelial carcinoma in Europe. Kit availability is limited outside the United States, and its use requires the Dako Autostainer Link 48 platform, which is unavailable in many laboratories. Validated laboratory-developed tests based on 28-8 concentrated antibody outside the kit are needed. The authors conducted a study in which they compared the results from PD-L1 expression level analysis across four immunohistochemistry (IHC) platforms—Dako Autostainer Link 48, Dako Omnis, Leica Bond-III, and Ventana BenchMark Ultra—with the results from the 28-8 pharmDx kit for lung cancer (multiple histologies), melanoma, and head and neck cancer (multiple histologies). Samples were prepared per protocol for each platform and stained using the PD-L1 IHC 28-8 pharmDx kit on the Dako Autostainer Link 48 per protocol for each platform. The control samples (tonsil and placenta tissue; cell lines with prespecified PD-L1 expression levels) were tested to evaluate the specificity and sensitivity of the test assays. An agreement level of 0.90 with the pharmDx kit was set for each platform. The authors assessed inter- and intra-assay reliability. Evaluable samples were lung cancer (29), melanoma (31), and head and neck cancer (30). Mean agreement was calculated for PD-L1 expression levels of one percent or more, five percent or more, 10 percent or more, and 50 percent or more. Mean overall agreement for all indications was 0.87 to 0.99. Inter- and intra-assay of scoring/classification repeatability was 100 percent. The authors concluded that analysis of PD-L1 expression levels using laboratory-developed IHC assays with 28-8 antibody may be permissible if the platform is validated using reference samples with defined expression levels.

Koppel C, Schwellenbach H, Zielinski D, et al. Optimization and validation of PD-L1 immunohistochemistry staining protocols using the antibody clone 28-8 on different staining platforms [published online ahead of print June 26, 2018]. Mod Pathol. doi:10.1038/s41379-018-0071-1.

Correspondence: Dirk Zielinski at dirk.zielinski@targos-gmbh.de

Mesenteric tumor deposits as a prognostic factor in small intestinal neuroendocrine tumors

Mesenteric tumor deposits are an adverse prognostic factor for small intestinal well-differentiated neuroendocrine tumors. According to the eighth edition of the American Joint Committee on Cancer (AJCC) cancer staging manual, any mesenteric tumor deposit larger than 2 cm signifies pN2 disease. Neither this criterion nor multifocality or histologic features of mesenteric tumor deposits have been evaluated critically as prognostic factors for small intestinal neuroendocrine tumors. The authors evaluated 70 small intestinal neuroendocrine tumors with mesenteric tumor deposits for lesional contour, sclerosis, inflammation, calcification, entrapped blood vessels, and perineural invasion. They calculated Ki67 proliferative indices of the largest mesenteric tumor deposit from each case and recorded the number of tumor deposits and size of the largest deposit. The authors assessed associations between these factors—along with patient age, primary tumor Ki67 index, and AJCC stage—and the development of liver metastases and overall survival. The median mesenteric tumor deposit size was 1.5 cm (range, 0.2–7.0 cm), and the median deposit number was one (range, 1–13). Primary and tumor deposit Ki67 indices within a patient were discordant in 40 percent of cases but showed similar hazard ratios for disease-specific survival. The size of tumor deposits did not significantly affect prognosis, whether analyzed on a continuous scale or dichotomized using the recommended 2-cm cutoff. In contrast, an increasing number of deposits were associated with poor prognosis, with multiple deposits conferring an 8.19-fold risk of disease-specific death compared with a single deposit (P = .049). The morphologic features of the deposits had no prognostic impact. The authors concluded that the size of mesenteric tumor deposits does not affect prognosis in small intestinal neuroendocrine tumor patients, but deposit multifocality is associated with shorter disease-specific survival and should be incorporated into future staging criteria.

Gonzalez RS, Cates JMM, Shi C. Number, not size, of mesenteric tumor deposits affects prognosis of small intestinal well-differentiated neuroendocrine tumors. Mod Pathol. 2018;31(10):1560–1566.

Correspondence: Dr. R. S. Gonzalez at raul_gonzalez@urmc.rochester.edu

Surgical excision for flat epithelial atypia in directional vacuum-assisted biopsy of breast microcalcifications

The authors conducted a study to analyze the clinicopathological features of patients with flat epithelial atypia, diagnosed during directional vacuum-assisted biopsy targeting microcalcifications, to identify the upgrade rate to in situ ductal or invasive breast carcinoma and determine factors predicting carcinoma in the subsequent excision. They retrospectively evaluated the histological, clinical, and mammographic features of 69 cases from 65 women with directional vacuum-assisted biopsy-diagnosed flat epithelial atypia with or without atypical ductal hyperplasia or atypical lobular hyperplasia, which underwent subsequent surgical excision. Mammography was used to evaluate the extent and percentage of microcalcifications sampled by directional vacuum-assisted biopsy. All biopsy and surgical excision slides were reviewed. The women ranged in age from 40 to 85 years (mean, 57 years). All but one patient presented with only mammographically detected microcalcifications. The latter had associated architectural distortion. The extent of calcifications was less than 1 cm (n = 47), 1 to 3 cm (n = 15), more than 3 cm (n = 6), and no measurement (n = 1). A mean of 11 cores (range, 6–25) was obtained from each lesion. Post-biopsy mammogram revealed that more than 90 percent of calcifications were removed in 81 percent of cases. Pure flat epithelial atypia represented nearly two-thirds of directional vacuum-assisted biopsy specimens (n = 43; 62 percent), while flat epithelial atypia coexisted with atypical ductal hyperplasia (18 cases; 26 percent) or atypical lobular hyperplasia (eight cases; 12 percent). Upon excision, none of the cases were upgraded to in situ ductal or invasive breast cancer. In one case, however, an incidental, tubular carcinoma (4 mm) was found away from the biopsy site. Excluding this case, the upgrade rate was zero. This study adds to growing evidence that the diagnosis of flat epithelial atypia on directional vacuum-assisted biopsy for microcalcifications as the only imaging finding is not associated with a significant upgrade to carcinoma on excision. Therefore, excision may not be necessary. Furthermore, excision may not be necessary for flat epithelial atypia with atypical ductal hyperplasia limited to two terminal duct-lobular units or less if at least 90 percent of calcifications have been removed on biopsy.

McCroskey Z, Sneige N, Herman CR, et al. Flat epithelial atypia in directional vacuum-assisted biopsy of breast microcalcifications: surgical excision may not be necessary. Mod Pathol. 2018;31:1097–1106.

Correspondence: Dr. Nour Sneige at nsneige@houstonmethodist.org

Analysis of fibroepithelial lesions of the breast

Mammary fibroepithelial lesions encompass a wide spectrum of tumors ranging from an indolent fibroadenoma to a potentially fatal malignant phyllodes tumor. Application of the criteria used to classify them based on morphological assessment is often challenging, and there is no consensus as to what constitutes an adequate resection margin. The authors studied a retrospective cohort of 213 fibroepithelial lesions in 178 patients—80 fibroadenomas with unusual features and 133 phyllodes tumors (63 benign, 41 borderline, and 29 malignant)—to describe the spectrum of changes within each group, with special emphasis on evaluating margins. Outcome data were available for 153 fibroepithelial lesions in 139 patients (median, 56 months; range, 3–249 months). Positive final margin (tumor transected), age younger than 50 years, and a predominantly myxoid stroma were statistically significant predictors of local recurrence, while age older than 50 years, stromal overgrowth, diffuse marked atypia, necrosis, and mitotic index of 10 or more per 10 high-power fields were predictive of distant metastases. Tumors with satellite/bulging nodules were at a significantly higher risk of having a final positive resection margin. These findings highlight two important aspects of the interpretation and reporting of fibroepithelial lesions. First, the amount of myxoid stroma and the presence of satellite nodules are clinically relevant and should be routinely assessed and reported. Second, infiltrative border might not be a prerequisite for the diagnosis of malignant phyllodes tumor, while the presence of tumor necrosis, massive stromal overgrowth, or mitotic index of 25 or more per 10 high-power fields is diagnostic of malignant phyllodes tumor. On the other hand, increased mitotic index outside the range of the World Health Organization guidelines and in the absence of other worrisome features should be treated with caution since it can be found in benign tumors.

Slodkowska E, Nofech-Mozes S, Xu B, et al. Fibroepithelial lesions of the breast: a comprehensive morphological and outcome analysis of a large series. Mod Pathol. 2018;31:1073–1084.

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