Answer: Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Microscopic description:
The tumor had a predominantly solid architecture and was primarily composed of loosely cohesive sheets of large ovoid-to-polygonal tumor cells. Focal glandular architecture was also seen. The tumor cells had large atypical vesicular nuclei, prominent nucleoli, and
eosinophilic to amphophilic cytoplasm with abundant intracytoplasmic eosinophilic globules, which displaced the tumor nuclei peripherally, creating a rhabdoid appearance. Multifocal lymphovascular and perineural invasion, abnormal mitoses, and areas of necrosis were also present.

Immunohistochemistry and special stains:
The tumor cells were positive for pancytokeratin (AE1/AE3), vimentin, and EMA. Ki-67 immunostain was positive in 60% of tumor cells. Intracytoplasmic eosinophilic globules were positive for PAS and were resistant to diastase digestion. Tumor cells showed diffuse loss of INI1 immunostain not only in solid areas, but also in areas of glandular differentiation. The tumor cells were negative for CK7, CD10, synaptophysin, chromogranin, and CD34.

Molecular analysis:
SMARCB1 gene mutation was detected.

Final diagnosis:  

Undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Educational Objectives and Discussion:

Educational Objectives
1. Review undifferentiated carcinoma of pancreas and its subtypes

2. Discuss the clinicopathologic features of a recently described entity, pancreatic undifferentiated rhabdoid carcinoma

3. Understand pertinent differential diagnosis for undifferentiated carcinoma, sarcomatoid type with rhabdoid features

Discussion

Undifferentiated carcinoma is one of the histologic subtypes of pancreatic ductal adenocarcinoma. Tumors are usually hypercellular and composed of poorly cohesive tumor cells which often coexpress cytokeratin and vimentin. Osteoclast-like giant cells are typically lacking. Perineural and vascular invasion are also frequent findings. The current (5^th) edition of WHO Classification of Tumors (Digestive System Tumors) recognizes three subtypes of undifferentiated carcinoma based on the tumor’s morphological patterns. These include anaplastic, sarcomatoid, and carcinosarcoma (1).

Sarcomatoid type undifferentiated carcinoma is composed of poorly cohesive atypical spindle-shaped tumor cells resembling a sarcoma. Tumors may contain admixed heterologous elements including bone and cartilage. At least 80% of the tumor typically shows spindle cells, with or without heterologous differentiation (1). A more specific morphologic type of sarcomatoid undifferentiated carcinomas with rhabdoid features has also been described, as with the case illustrated here (2). These are composed of sheets of dishesive rhabdoid cells with myxoid stroma. Pleomorphic giant cells, spindling and tubular components may also be seen and loss of nuclear positivity for SMARCB1 (INI1) is characteristic. SMARCB1/INI1 is known to encode for a tumor suppressor gene located on chromosomal band 22q11.2 (3, 4), and is a core subunit of a group of chromatin-modeling complexes, the SWI/SNF family. Biallelic inactivation of this gene is associated with highly malignant tumors with prominent rhabdoid morphology, including malignant rhabdoid tumor (both renal and “pure” extrarenal), atypical teratoid/rhabdoid tumor, epithelioid sarcoma and renal medullary carcinoma, among others. (3, 5, 6, 7).

Agaimy et al. recently described a group of pancreatic undifferentiated carcinomas with prominent rhabdoid morphology, which they named pancreatic undifferentiated rhabdoid carcinoma (PURC) (8). The authors described 14 such cases from their home institution as well as an additional 46 cases discovered on review of the literature. There were 44 males and 16 females (male-to-female ratio=2.8:1) of mean age 65 years (range 30 -96 years). Patients had an extremely poor prognosis with 45 of 49 (92%) with available follow-up information reportedly dying of disease within 1-19 months.

Agaimy et al also described two distinct subtypes of pancreatic undifferentiated rhabdoid carcinoma based both on the histomorphologic features and molecular profiles. One subtype is the pleomorphic giant cell subtype which shows highly pleomorphic neoplastic cells with abundant eosinophilic cytoplasm frequently containing rhabdoid inclusions. Molecular studies have shown this particular subtype to have a strong association with KRAS alteration and intact SMARCB1 gene. The second subtype, which is similar to the current case, is the monomorphic anaplastic subtype. This subtype shows uniformly atypical rhabdoid cytological features without significant pleomorphism. The tumor cells in the monomorphic anaplastic subtype have medium to large vesicular nuclei, prominent nucleoli, and eosinophilic cytoplasm which frequently contains rhabdoid cytoplasmic inclusions. This subtype shows diffuse loss of SMARCB1 nuclear immunostain as well as SMARCB1 gene mutation. However, no KRAS alterations are detected in these tumors (8).

Figure-6.-INI1-immunohistochemical-stain-20X

Differential diagnosis:

The morphologic features of undifferentiated carcinoma, sarcomatoid type with rhabdoid features raises several differential diagnoses one of which is poorly differentiated neuroendocrine carcinoma, particularly the large cell variant. The large cell variant of neuroendocrine carcinoma is often composed of round to polygonal cells which can have vesicular nuclei and prominent nucleoli. Glandular differentiation can rarely be present. However, unlike pancreatic undifferentiated carcinomas with rhabdoid morphology neuroendocrine carcinoma almost always expresses at least one neuroendocrine marker (synaptophysin and chromogranin) and shows intact INI1 (9).

Solid pseudopapillary neoplasm (SPN) is another differential to consider. The presence of a pancreatic neoplasm in a female in her 20’s should always raise the possibility of SPN as a
differential diagnosis. The presence of PAS-positive and diastase resistant intracytoplasmic globules is also characteristic of SPN. However, SPN often has a “pseudo-papillary” morphology, with nuclear beta-catenin labeling and is negative or focally positive for cytokeratin (1,10).

Melanomas can also display rhabdoid morphology, and can lose HMB45 and Melan-A expression. However, melanoma with rhabdoid morphology is often is positive for S100, shows intact INI1 staining and is cytokeratin negative (11).

Proximal-type epithelioid sarcoma is another neoplasm that can have predominant rhabdoid features with negative INI1 staining/INI1 loss. Differentiating undifferentiated carcinoma with rhabdoid features and SMARCB1 (INI1) loss from proximal-type epithelioid sarcoma can be very difficult. However, the presence of glandular architecture in this case makes this entity less likely. CD34 immunostain is positive in approximately 50% of epithelioid sarcoma (8,12).

References:

1.WHO Classification of Tumours Editorial Board, World Health Organization., International Agency for Research on Cancer. Digestive system tumours. 5th ed. Lyon: IARC Press; 2019.
2. Alguacil-Garcia A, Weiland LH. The histologic spectrum, prognosis, and histogenesis of the sarcomatoid carcinoma of the pancreas. Cancer 1977;39:1181-1189.
3. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017;108(4):547-552.
4. Cho YM, Choi J, Lee OJ, et al. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features. Pathol Int 2006;56:702-706.
5.Fuller CE. All things rhabdoid and SMARC: An enigmatic exploration with Dr. Louis P. Dehner. Semin Diagn Pathol. 2016;33(6):427‐440.
6. Donner LR, Wainwright LM, Zhang F, et al. mutation of the INI1 gene in composite rhabdoid tumor of the endometrium. Hum Pathol 2007;38:935–939.
7. Fuller CE, Pfeifer J, Humphrey P, et al. Chromosome 22q dosage in composite extrarenal rhabdoid tumors:clonal evolution or a phenotypic mimic? HumPathol 2001;32:1102–8.
8. Agaimy A, Haller F, Frohnauer J, et al. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define two subtypes. Mod Pathol. 2015;28(2):248‐260.
9. Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol. 2014;38(4):437‐447.
10. Odze RD, Goldblum JR. Odze and Goldblum surgical pathology of the GI tract, liver, biliary tract, and pancreas. Third edition. ed. Philadelphia, PA: Saunders/Elsevier; 2015:xix, 1612 pages.
11. Abbott JJ, Amirkhan RH, Hoang MP. Malignant Melanoma With a Rhabdoid Phenotype: Histologic, Immunohistochemical, and Ultrastructural Study of a Case and Review of the Literature. Arch Pathol Lab Med. 2004;128(6):686-8
12. Sullivan LM, Folpe AL, Pawel BR, et al. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol 2013;26:385-392.

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Case contributed by:

Aaron Sohn, M.D.
Anatomic and Clinical Pathology Resident, PGY-4
Baylor University Medical Center, Dallas, TX

Atin Agarwal, M.D.
Staff Pathologist
Baylor University Medical Center, Dallas, TX

Conflict of Interest: NO