Anatomic pathology selected abstracts

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Correspondence: Dr. G. Stålhammar at gustav.stalhammar@ki.se or Dr. J. Hartman at johan.hartman@ki.se

Evaluation of gastric carcinomas with lymphoid stroma

Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus positivity and mismatch repair deficiency. The authors evaluated molecular alterations in this morphologically homogeneous subtype and compared them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. They identified 31 study cases and subjected them to in situ hybridization for Epstein-Barr virus (EBV)-encoded RNAs and assessed them for mismatch repair (MMR) status. They performed immunostains for PD-L1, β-catenin, and HER2 and sequenced extracted DNA with a comprehensive cancer panel. Most (76 percent) study patients were older adult men with stage I or II disease. Tumors were classified as EBV+/MMR proficient (MMR-P; n = 7), EBV−/MMR deficient (n = 12), and EBV−/MMR-P (n = 12). EBV−/MMR-P tumors were usually located in the proximal stomach (83 percent) and showed heterogeneous growth patterns with glandular differentiation (83 percent). Tumors in all groups showed numerous tumor-infiltrating lymphocytes and PD-L1 expression and infrequent nuclear β-catenin accumulation (10 percent), and they lacked both membranous HER2 staining and HER2 amplification. EBV−/MMR-deficient tumors showed significantly higher tumor mutation burden (P = .001) and KRAS alterations (56 percent) compared with EBV−/MMR-P tumors (nine percent; P = .05). TP53 variants were more common among EBV−/MMR-P tumors (82 percent) than among EBV+/MMR-P (zero; P = .01) and EBV−/MMR-deficient (11 percent; P<.01) tumors. Alterations in KRAS, ARID1A, PIK3CA, and TP53 followed similar patterns of distribution compared with The Cancer Genome Atlas dataset. The authors concluded that gastric carcinomas with lymphoid stroma show a spectrum of molecular changes and frequent PD-L1 expression, raising the possibility that this subgroup of tumors may be susceptible to checkpoint inhibitors or agents that target receptor tyrosine kinase-mediated signaling, or both.

Hissong E, Ramrattan G, Zhang P, et al. Gastric carcinomas with lymphoid stroma: an evaluation of the histopathologic and molecular features. Am J Surg Pathol. 2018;42(4):453–462.

Correspondence: Dr. Erika Hissong at emh9016@nyp.org

TP53 mutations in extrauterine high-grade serous carcinomas with two sites of involvement

A previous multicenter study of 67 cases of stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal sampling identified seven cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. The authors conducted a study to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n = 6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n = 1). Of the seven cases analyzed, one had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, three had tubal high-grade serous carcinomas (±serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, two had bilateral ovarian high-grade serous carcinomas with normal tubes, and one had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All seven cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa show clonal identity between the two sites of involvement, indicating unifocal origin and metastasis rather than multifocal origin. These results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be viewed as constituting a disease site for staging purposes.

Singh N, Faruqi A, Kommoss F, et al. Extrauterine high-grade serous carcinomas with bilateral adnexal involvement as the only two disease sites are clonal based on tp53 sequencing results: implications for biology, classification, and staging. Mod Pathol. 2018;31:652–659.

Correspondence: Dr. Naveena Singh at N.Singh@bartshealth.nhs.uk

Use of NTRK fusions to define a novel uterine sarcoma subtype with features of fibrosarcoma

Tropomyosin receptor kinase inhibitors have shown high response rates in patients with tumors harboring NTRK fusions. The authors identified four NTRK fusion-positive uterine sarcomas that should be distinguished from leiomyosarcoma and undifferentiated uterine sarcoma. NTRK rearrangements were detected by FISH or targeted RNA or DNA sequencing in four undifferentiated uterine sarcomas with spindle cell morphology. Because of histologic overlap with leiomyosarcoma, the authors performed tropomyosin receptor kinase A (TrkA) and pan-Trk immunohistochemistry in 97 uterine leiomyosarcomas. They also performed NTRK1 and NTRK3 FISH on tumors with TrkA or pan-Trk staining, as well as whole transcriptome RNA sequencing of a leiomyosarcoma with TrkA expression and targeted RNA sequencing of two additional undifferentiated uterine sarcomas. Targeted RNA or DNA sequencing or FISH, or both, showed TPM3-NTRK1, LMNA-NTRK1, RBPMS-NTRK3, and TPR-NTRK1 fusions in the study group. All tumors were composed of fascicles of spindle cells. The mitotic index was seven to 30 mitotic figures per 10 high-power fields. Tumor necrosis was seen in two tumors. Desmin, estrogen receptor, and progesterone receptor were negative in all tumors, while pan-Trk was expressed in all tumors, with concurrent TrkA staining in three of the tumors. TrkA or pan-Trk staining, or both, was also seen in six leiomyosarcomas, but these tumors lacked NTRK fusions or alternative isoforms by FISH or whole transcriptome sequencing. No fusions were detected in two undifferentiated uterine sarcomas. NTRK fusion-positive uterine spindle cell sarcomas constitute a novel tumor type with features of fibrosarcoma. Patients with these tumors may benefit from Trk inhibition. TrkA and pan-Trk expression in leiomyosarcomas is rare and does not correlate with NTRK rearrangement.

Chiang S, Cotzia P, Hyman DM, et al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42(6):791–798.

Correspondence: Dr. S. Chiang at chiangs@mskcc.org