Answer: Medullary carcinoma

 

Microscopic appearance:

Histopathological examination revealed a cellular neoplasm composed of relatively monomorphic cells with high N:C ratio and vesicular nuclei. The neoplasm had a syncytial growth pattern without obvious gland formation (Figure 1), scant stroma and overall pushing border (Figure 2) with focal microscopic infiltrative interface with the adjacent tissues (Figure 3). There was also a diffuse lymphocytic infiltration within the tumor (tumor-infiltrating lymphocytes, TILs). No confluent necrosis was identified. Lymphovascular invasion (involving both lymphatic spaces and large vessels) and lymph node metastases (in two lymph nodes, with extranodal extension) were present. No in-situ lesions, such as pancreatic intraepithelial neoplasia (PanIN) or adenomatous change in the duodenal or ampullary mucosa were identified.  

 

Immunohistochemistry:

Performed immunohistochemical stains reveal that the tumor cells are positive for CK7 (Figure 4), MUC1/ EMA (Figure 5), and CK8/18, while negative for CK20, CDX2, MUC2, MUC5AC, Chromogranin, and Synaptophysin. CD3 highlighted intra- and peri-tumoral T lymphocytes, CD20 highlighted some peri-tumoral B lymphocytes, no intratumoral B lymphocytes were identified. Althoug expression of MLH1 and PMS2 proteins was retained, expression of MSH2 (Figure 6) and MSH6 proteins was absent in the cells. EBV-encoded RNA (EBER) in-situ hybridization was also negative in the tumor cells.

 

Molecular analysis:

Multiplex PCR for MSI, using HNPCC KIT 1-FL with 5 MSI markers (BAT-25, BAT-26, NR-21, NR-22, NR-24) reveled alterations in all 5 molecular markers, indicating microsatellite instable phenotype (MSI-H).

 

Final histological diagnosis: Medullary carcinoma of the pancreas.

 

Discussion:

Medullary carcinoma of the pancreas is a rare subtype of pancreatic neoplasms, pathogenetically and behaviorally distinct from pancreatic ductal adenocarcinoma (PDAC)¹. Recognition of this subtype is important, not only for prognostic, but also for therapeutic purposes. Syncytial growth pattern composed of pleomorphic cells with no gland formation, pushing borders and the presence of intra- and peri-tumoral lymphocytes are helpful histological findings.

 

Medullary carcinoma of the pancreas has been recognized as a distinct but rare entity for only about two decades (first reported in 1998 by Goggins M et al²). Unlike conventional PDAC, the incidence of KRAS mutations is very low in this tumor type. Medullary carcinoma of the pancreas has a better prognosis than conventional PDAC³. Like other medullary carcinomas involving the tubular gastrointestinal tract, a significant proportion of medullary carcinomas of the pancreas reveal high microsatellite instability (MSI)⁴. A subset of these patients has been shown to carry germline mutations of mismatch repair genes (Lynch syndrome). Isolated cases with synchronous/metachronous colonic adenocarcinoma linked to Lynch syndrome have been reported⁵. In cases that are not linked to Lynch syndrome, there is an increased association with family history of other cancers. A case of medullary carcinoma of the pancreas was reported to be associated with EBV⁵.

 

With the current advances in oncology, promising treatment modalities have emerged, such as using immune checkpoint inhibitors in solid tumors with MSI-high phenotype, including pancreatic cancers⁶. Although MSI-high phenotype is very rare in conventional PDACs, overall accounting for <1% of all cases⁷; given its important therapeutic implications, MSI should at least be routinely investigated in the pancreatic cancer types in which an increased frequency of MSI-high phenotypes are encountered, such as medullary carcinoma or colloid carcinoma, and results should be integrated into the final pathology report.

 

Medullary carcinomas should be distinguished from

– Poorly differentiated pancreatic ductal adenocarcinomas, which almost always have some degree of gland formation, usually reveal an abundant desmoplastic stroma, an infiltrative growth pattern, and at least a focal intracytoplasmic mucin production.

 

– Poorly differentiated neuroendocrine carcinomas, which are composed of tumor cells arranged in nests and sheets, usually show an infiltrative growth pattern and abundant intratumoral necrosis. Granular chromatin and nuclear molding would also suggest neuroendocrine differentiation, and staining for neuroendocrine markers (chromogranin and synaptophysin) would confirm the diagnosis. There are also usually no intratumoral lymphocytes, unlike medullary carcinomas.

 

– High-grade lymphoma, such as diffuse large B-cell lymphoma, would also usually have a syncytial growth pattern, but intratumoral infiltration with mature lymphocytes are not a feature. Specific immunohistochemical stains to ascertain the cell lineage is necessary for the correct diagnosis.

 

– Metastatic melanoma is a consideration on H&E evaluation. Relevant history and immunohistochemical markers are necessary to exclude this diagnosis.

 

References:

1. WHO Classification of Tumours Editorial Board. Digestive system tumours. Lyon (France): International Agency for Research on Cancer; 2019.
2. Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol. 1998 Jun;152(6):1501-7. Am J Pathol. 1998 Jun;152(6):1501-7.
3. Mostafa ME, Erbarut-Seven I, Pehlivanoglu B, Adsay V. Pathologic classification of “pancreatic cancers”: current concepts and challenges. Chin Clin Oncol. 2017 Dec;6(6):59.
4. Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res 2001;61:3139-44.
5. Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol. 2000 May;156(5):1641-51.
6. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413.
7. Luchini C, Bibeau F, Ligtenberg MJL, Singh N, Nottegar A, Bosse T, Miller R, Riaz N, Douillard JY, Andre F, Scarpa A. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol. 2019 May 6 [Epub ahead of print].

 

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Case contributed by:

Claudio Luchini, MD, PhD

Associate Professor of Pathology

Department of Diagnostics and Public Health

Section of Pathology

University and Hospital Trust of Verona

37134 Verona, Italy

Email: claudio.luchini@univr.it

 

 

Deyali Chatterjee, MD

Assistant Professor

Department of Pathology and Immunology

Washington University School of Medicine

425 S Euclid Ave

St. Louis, MO 63110

Email: deyali@wustl.edu