Undifferentiated carcinoma with osteoclastic giant cells of pancreas (UOC) is a rare pancreatic cancer that is commonly associated with conventional pancreatic ductal adenocarcinoma (PDAC). It is an epithelial-derived tumor with mesenchymal differentiation. The tumors occur in the head, body and tail of the pancreas without preference.

Grossly, tumors are larger than classical PDAC and are often well-circumscribed. The majority of UOCs have some cystic component which may represent tumor cell degeneration, or rarely, adjacent neoplastic mucinous cysts (IPMN or MCN). The latter may result in under sampling of the UOC component and misdiagnosis. In a minority of cases focally hemorrhagic polypoid lesions within ducts may be seen. Histologically, the tumors are defined by the presence of benign osteoclastic giant cells (OGCs) with densely eosinophilic cytoplasm and multiple (>20) bland, oval nuclei that cluster centrally within the cell. Nucleoli may or may not be prominent. These cells are distributed amidst sarcomatoid cells which may occasionally produce osteoid. OGCs are histiocytic cells thought to be recruited by the sarcomatoid component of the tumor.

A recent paper by Reid, et al, characterized the largest cytologic series of UOC to date and highlighted useful diagnostic cytologic features of this tumor. The paper also identified clinicopathologic associations that distinguish the variant from PDAC. On Diff-Quik, Papanicolaou smears, or Thin-Prep slides three well-defined cell types are appreciated: multinucleated OGCs, large tumor giant cells (TGCs), and smaller bland spindled/histiocytoid tumor cells (SHCs). The smears show variable cellularity with clustered and singly dispersed TGCs and SHCs. Background necrotic debris is observed in the majority of specimens. Adenocarcinoma cells are also frequently noted on smears and are present in sheets, clusters, and single cells that may or may not have intracytoplasmic mucin vacuoles. On the cell block, OGCs are readily identifiable as well as single-cell and confluent necrosis.

Immunohistochemical stains complement the cytomorphologic diagnosis, which can be challenging. CD68 is a histiocytic marker that can be used to differentiate between OGCs and SHCs as it is diffusely and strongly positive in OGCs but typically negative in SHCs. Pancytokeratin (AE1/AE3) is positive in neoplastic epithelial cells as well as TGCs and SHCs. Epithelial membrane antigen (EMA) is variably positive in the neoplastic cells (TGCs and SHCs). Expression of SMARCB1 (INI-1) is retained in UOC, although it is lost in undifferentiated rhabdoid carcinoma of the pancreas. S100 is a pertinent negative stain because these tumors may mimic melanoma. Ki-67 proliferation index is variable and ranges from low to high.

Multinucleated giant cells may be observed in diverse pancreatic masses including chronic pancreatitis, pancreatic neuroendocrine tumor (PanNET), and solid pseudopapillary neoplasm (SPN). These lesions have multinucleated cells that may be reactive or neoplastic. However, distinction from UOC is facilitated by other cytologic characteristics of the above named entities. Neoplastic cells of SPN have open chromatin and longitudinal nuclear grooves, while PanNETs exhibit clustered or singly dispersed plasmacytoid cells with salt-and pepper chromatin. Chronic pancreatitis may exhibit exuberant granulation tissue formation with atypical histiocytic cells, mimicking UOC. A high Ki-67 proliferation index, CD68 positivity in OGCs and epithelial marker positivity in SHCs and TGCs can facilitate accurate diagnosis of UOC.

Atypical cells with bizarre nuclear features and hyperchromasia mimicking the TGCs of UOC are frequently seen in other primary pancreatic neoplasms such as undifferentiated PDAC or undifferentiated rhabdoid carcinoma. These TGC-like cells may also be seen in metastatic lesions such as malignant melanoma, leiomyosarcoma, and rhabdomyosarcoma. OGCs are not present in undifferentiated PDAC nor are they observed in undifferentiated rhabdoid carcinoma. Additionally, undifferentiated rhabdoid carcinoma exhibits loss of INI-1 or KRAS mutations. Malignant melanoma may have spindled or multinucleated tumor giant cells, is distinguished from UOCs by expression of melanoma markers (s100, HMB-45, and Melan-A), markers that are negative in UOC.

UOCs have been recently shown to have better outcome than conventional PDAC (5 year survival 59% vs 16%, respectively). However, fine needle aspiration (FNA) may influence survival in patients with UOC. A cohort of 14 patients with UOC who received FNA were compared to patients with UOC that were not aspirated and there was a statistically significant difference in survival between the groups (8 vs 92.4 months, p=0.0135, respectively). While the findings raise concern about the safety of FNA in UOC, the cohort is too small to make any definite conclusions. Nevertheless, identification of UOC on FNA appears to have substantial prognostic implications. This underscores the importance of correct identification of UOC on cytology specimens, particularly when the 3 classical cell types (OGCs, TGCs, and SHCs) are present.