Resident Program - Case of the Month

Discussion

Pancreatic cancer is among the most devastating and lethal of all cancers. It comprises just 3 percent of all cancer cases in the United States. More than 53,000 Americans (roughly 50/50 male/female ratio) will be diagnosed this year with pancreatic cancer; more than 43,000 will die from the disease (7 percent of all cancer deaths). The vast majority of pancreatic cancer represent pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year survival rate of less than 8% (for all stages of the disease combined), and is currently the third leading cause of cancer-related deaths in the United States.

Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGCs) is an extremely rare morphologically and clinically distinct variant of PDAC, exhibiting a characteristic preponderance of large, bland, multinucleated osteoclastic giant cells (OGCs). It was first described by Sommers and Meissner in 1954 as “unusual carcinoma of the pancreas.” Later it acquired many different names, like “carcinomas of pancreas simulating giant cell tumor of bone”, “osteoclastic giant cell tumor or carcinoma” and “pleomorphic carcinoma of pancreas, giant cell carcinoma”. In 2010, the World Health Organization classified these tumors as variants of PDAC under the heading “undifferentiated carcinoma with osteoclastic giant cells”. Although genetic studies have demonstrated that UCOGC and conventional PDAC exhibit strikingly similar mutations in KRAS, CDKN2A, TP53 and SMAD4, thus supporting the classification of UCOGC as a PDAC variant, they cannot explain why a recent study showing that tumors with a component of UCOGCs had a better clinical course with significantly longer five-year survival than conventional PDAC.

Tumors of UCOGCs are typically large (several cm) and may exhibit polypoid intraductal or intra-ampullary growth or cystic degeneration or arise in mucinous cystic neoplasm or intraductal papillary mucinous neoplasm. The mean age of patients with UCOGCs is 65 years, predominantly women, many with a PDAC component. UCOGCs have three distinct components: OGCs, large, highly pleomorphic mononuclear malignant tumor giant cells (TGCs) and small, spindled/histiocytoid tumor cells (SHCs), often present in a background of necrosis and neutrophils.

Although the histopathological hallmark of UCOGCs is the characteristic large, bland, multinucleated phagocytic osteoclastic giant cells (OGCs), they are non-neoplastic. Morphologic, immunohistochemical, molecular, and ultrastructural studies have demonstrated that OGCs represent benign histiocytic cells likely recruited chemotactic substances produced by tumor cells, like inflammatory breast cancers and ampullary cancers. The OGCs express CD68, vimentin and leukocyte common antigen, but not keratin, and have wild type p53 staining pattern on IHC.

The true tumor cells of UCOGCs which are often overlooked, are actually the large highly pleomorphic malignant mononuclear tumor giant cells (TGCs) and small spindled/histiocytoid tumor cells (SHCs). On IHC, they are strongly positive for vimentin and variably but typically diffuse keratin, and diffuse positive for p53 (mutant p53 staining pattern). These cells also have an elevated Ki-67 proliferation index. These are often present in a background of necrosis and variable neutrophils, partially due to degenerative cystic change or concomitant neoplastic mucinous cyst (mucinous cystic neoplasm or intraductal papillary mucinous neoplasm).

The three classical components of UCOGCs are identifiable on FNA (fine needle aspiration) in the majority of cases, thus making cytologic diagnosis possible. The OGCs are perhaps easiest to recognize and, once identified, should prompt a search for the other two components (TGCs and SHCs). Tumors may also exhibit extensive fibrosis, hemorrhage, and even osteoid formation, which can lead to nondiagnostic samples, therefore emphasizing the importance of careful cytologic examination and histologic sampling, especially in PDAC with a UCOGCs component. In such mixed cases, the UCOGCs component may be focal, and need more histologic sampling and attentive searching, since tumors with a UCOGCs component have a better clinical course with significantly longer five-year survival than conventional PDAC.

There is also a well-known association between UCOGCs and neoplastic mucinous cysts (IPMN, intra-ampullary tubulopapillary neoplasm, or intraductal papillary neoplasm of bile duct). Knowing this association would be critical in ensuring the resected mucinous cysts thoroughly sampled so that the UCOGCs component may not be over-looked in extensive cystic neoplasms.

Differential Diagnosis

1. Chronic pancreatitis - Chronic pancreatitis at advanced stage usually has extensive fibrosis affecting most of the parenchyma with remaining elements (atrophic acinar cells, islets, thick-walled blood vessels, and prominent nerves). Although there is only perilobular fibrosis in some areas, other areas show diffuse intralobular fibrosis and perilobular fibrosis which can cause duct distortions and dilatations with occasional formation of a retention cyst, thus mimicking neoplastic mucinous cysts. However, the lumens of these interlobular ducts are often filled with calculi and protein plugs. The duct epithelium is either atrophic or completely replaced by polymorphocellular inflammatory tissue including reactive multinucleated giant cells. On IHC, the remaining acinar cells are strongly positive for pancreatic enzymes and pancreatic stone protein, and the duct epithelium are usually positive for HLA-DR and cytokines such as fibroblast growth factor (FGF) and transforming growth factors beta 1 (TGFβ1). The myofibroblasts are positive for smooth muscle actin and desmin. The lymphocytic infiltrate consists largely of T lymphocytes.
2. Undifferentiated rhabdoid pancreatic carcinomas - The undifferentiated rhabdoid pancreatic carcinomas, usually as advanced tumors in old patients with a mean age of 65 years, has prominent eosinophilic rhabdoid cells with pleomorphic nuclei and prominent nucleoli, which may mimic the TGCs of UCOGCs. However, the osteoclast-like giant cells (OGCs) are not a component of the undifferentiated rhabdoid pancreatic carcinomas. Histologically tumors qualified as pleomorphic giant cell and monomorphic anaplastic carcinomas. A glandular component may also be observed. On IHC, the rhabdoid tumor cells in the majority of cases are positive for cytokeratin and vimentin, and negative for membranous β-catenin and E-cadherin. The undifferentiated rhabdoid pancreatic carcinomas often have heterogeneous genetic backgrounds, loss of nuclear SMARCB1 (INI1) or KRAS mutations.
3. Clear Cell Sarcoma-like Tumor of the GI Tract with Osteoclast-like Giant Cells - Clear Cell Sarcoma-like Tumor of the GI Tract (CCSLGT) with Osteoclast-like Giant Cells is an extremely rare neoplasm that has exclusively described within the abdominal cavity and predominantly in younger adults, with a median age of 35 years but wide age distribution (10- 81 years) and equal sex distribution. It is mostly in the wall of the small bowel (including ileum and jejunum), with other sites including the stomach, colon, and peritoneum documented. It is an aggressive neoplasm that frequently presents with metastatic disease and has a high mortality rate. Histologically, it is usually composed of medium-sized primitive ovoid or epithelioid cells with pale or clear cytoplasm that are arranged in sheets or in papillary or alveolar architectures. A characteristic feature of CCSLGT is the presence of CD68-positive, multinucleated osteoclast-like giant cells (although the number of osteoclast-like giant cells varies markedly, and not all CCSLGT has such osteoclast-like giant cells), which be confused with the OGCs of UCOGCs. However, On IHC, CCSLGT is positive for S100 protein and neuroendocrine markers, but invariably negative for melanocyte specific markers (HMB-45 or Melan-A), markers associated with gastrointestinal stromal tumor (CD117, DOG1, CD34), and desmin, smooth muscle actin, pancytokeratin AE1/AE3 and CD99. The etiology of CCSLGT is unknown, but many studies have shown associations with EWSR1-CREB1 gene fusions and, less frequently, with EWSR1-ATF1 fusions.
4. Malignant melanoma metastasized to the pancreas - Malignant melanoma is a notorious mimicker of almost every tumor, and frequently metastasizes to the pancreas. Melanoma tumor cells may be spindled or epithelioid and single, with prominent nucleoli that mimic TGCs of UCOGCs. In addition, there are also multinucleated tumor giant cells may be confused with the OGCs of UCOGCs, thus malignant melanoma metastasized to the pancreas may be confused with UCOGCs. On IHC, melanoma cells are positive for melanoma markers (S100, melan-A, and HMB-45), but negative for histiocytic and epithelial markers.
5. Undifferentiated pancreatic ductal adenocarcinoma, not otherwise specified - The undifferentiated PDACs, not otherwise specified, have highly pleomorphic malignant tumor cells that show brisk mitotic activity, enlarged, hyperchromatic, markedly pleomorphic nuclei with high N:C ratio, irregular nuclear membrane, coarse chromatin and a fair amount of vacuolated cytoplasm on cytology, clustered or singly dispersed, in a background of necrosis. However, the lack OGCs in these tumors distinguishes them from UCOGCs. On IHC, the tumor cells in undifferentiated PDAC are positive for keratin, but negative for histiocytic markers like CD68.
6. Metastatic hepatocellular carcinoma - Hepatocellular carcinoma (HCC) is a highly malignant neoplasm, often presenting at late stage. Extrahepatic metastasis of HCC to the pancreas is rare, and can mimic primary pancreatic neoplasms. The tumor cells have enlarged, hyperchromatic, markedly pleomorphic nuclei with irregular distribution of nuclear chromatin, prominent eosinophilic nucleoli, focal nuclear vacuolization and abundant granular eosinophilic cytoplasm with cholestasis. It is crucial to be aware of this differential diagnosis in the evaluation of FNA cytology of pancreatic neoplasms. On IHC, HCC tumor cells are positive for hepar-1 and glypican-3.

References

Agaimy A, Haller F, Frohnauer J, Schaefer IM, Ströbel P, Hartmann A, Stoehr R, Klöppel G. Pancreatic undifferentiated rhabdoid carcinoma: KRAS alterations and SMARCB1 expression status define 2 subtypes. Mod Pathol. 2015; 28:248-260.

Bergmann F, Esposito I, Michalski CW, Herpel E, Friess H, Schimacher P. Early undifferentiated pancreatic carcinoma with osteoclast-like giant cells: direct evidence for ductal evolution. Am J Surg Pathol. 2007; 31:1919–25.

Deckard-Janatpour K, Kragel S, Teplitz RL, Min BH, Gumerlock PH, Frey CF, Ruebner BH. Tumors of the pancreas with osteoclast-like and pleomorphic giant cells: an immunohistochemical and ploidy study. Arch Pathol Lab Med. 1998; 122:266-272.

Dhall D, Klimstra DS. The cellular composition of osteoclastlike giant cell-containing tumors of the pancreatobiliary tree. Am J Surg Pathol. 2008; 32:335-337.

Fitzhugh VA, Kim SA, Borcich A, Zhu H, Wu M, Szporn AH, Chen H. Metastatic hepatocellular carcinoma presenting as a pancreatic mass by computed tomography scan and mimicking a primary neuroendocrine tumor: a potential pitfall in aspiration cytology. Diagn Cytopathol. 2009; 37(12):915-9.

Gao L, Li ZS, Jin ZD, Man XH, Zhang MH, Zhu MH. Undiffer- entiated carcinoma with osteoclast-like giant cells of the pancreas diagnosed by endoscopic ultrasonography-guided fine-needle aspira- tion. Chin Med J (Engl). 2009; 122:1598-1600.

Georgiou GΚ, Balasi E, Siozopoulou V, Tsili A, Fatouros M, Glantzounis G. Undifferentiated carcinoma of the head of pancreas with osteoclast-like giant cells presenting as a symptomatic cystic mass, following acute pancreatitis: Case report and review of the literature. Int J Surg Case Rep. 2016; 19:106-8.

Gocke CD, Dabbs DJ, Benko FA, Silverman JF. KRAS oncogene mutations suggest a common histogenetic origin for pleomorphic giant cell tumor of the pancreas, osteoclastoma of the pancreas, and pancreatic duct adenocarcinoma. Hum Pathol. 1997; 28:80–3.

Hoorens A, Prenzel K, Lemoine NR, Kloppel G. Undifferentiated carcinoma of the pancreas: analysis of intermediate filament profile and Ki-ras mutations provides evidence of a ductal origin. J Pathol. 1998; 185:53-60.

Lewandrowski KB, Weston L, Dickersin GR, Rattner DW, Compton CC. Giant cell tumor of the pancreas of mixed osteoclastic and pleomorphic cell type: evidence for a histogenetic relationship and mesenchymal differentiation. Hum Pathol. 1990; 21:1184–7.

Lowe CJ Jr, Riepe SP, Wood WC. Hepatocellular carcinoma presenting as a pancreatic head mass: report of an unusual case. Am J Clin Oncol. 1997; 20(5):509-10.

Molberg KH, Heffess C, Delgado R, Albores-Saavedra J. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and periampullary region. Cancer. 1998; 82:1279–1287.

Mullick SS, Mody DR. “Osteoclastic” giant cell carcinoma of the pancreas. Report of a case with aspiration cytology. Acta Cytol. 1996; 40:975-979.


Muraki T, Reid MD, Basturk O, Jang KT, Bedolla G, Bagci P, Mittal P, Memis B, Katabi N, Bandyopadhyay S, Sarmiento JM, Krasinskas A, Klimstra DS, Adsay V. Undifferentiated carcinoma with osteoclastic giant cells of the pancreas: clinicopathologic analysis of 38 cases highlights a more protracted clinical course than currently appreciated. Am J Surg Pathol. 2016; 40:1203-1216. 


Paal E, Thompson LD, Frommelt RA, Przygodzki RM, Heffess CS. A clinicopathologic and immunohistochemical study of 35 anaplastic carcinomas of the pancreas with a review of the literature. Ann Diagn Pathol. 2001; 5:129–140.

Reid MD, Muraki T, HooKim K, Memis B, Graham RP, Allende D, Shi J, Schaeffer DF, Singh R, Basturk O, Adsay V. Cytologic features and clinical implications of undifferentiated carcinoma with osteoclastic giant cells of the pancreas: An analysis of 15 cases. Cancer Cytopathol. 2017; 125(7):563-575.

Rosai J. Carcinoma of pancreas simulating giant cell tumor of bone. Electron-microscopic evidence of its acinar cell origin. Cancer. 1968; 22:333-344. 


Sah SK, Li Y, Li Y. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a rare case report and review of the literature. Int J Clin Exp Pathol. 2015; 8(9): 11785–11791.

Terada T, Maruo H. Unusual extrahepatic metastatic sites from hepatocellular carcinoma. Int J Clin Exp Pathol. 2013; 6(5): 816–820.

Texler ML, Pierides J, Maddern GJ. Case report: A hepatocellular carcinoma metastasis in the distal pancreas. J Gastroenterol Hepatol. 1998;13(5):467-70.

Wang J, Thway K. Clear cell sarcoma-like tumor of the gastrointestinal tract: an evolving entity. Arch Pathol Lab Med. 2015 Mar;139(3):407-12. doi: 10.5858/arpa.2013-0547-RS.