Undifferentiated carcinoma with osteoclast-like giant cells (UC-OGC) is a rare tumor with limited research material. The carcinoma can occur in the pancreas, bile ducts, breast, thyroid, lung, pancreas, and skin, with the pancreas being the commonest site.¹ It is a rare histological subtype of pancreatic ductal adenocarcinoma (PDAC) according to the 5th edition of the World Health Organization classification of digestive system tumors. UC-OGC accounts for less than 1% of pancreatic malignant tumors.^2,3 Rosai described the first case of UC-OGC in the pancreas in 1968.⁴ Since then, only a few cases (approximately 110 cases) have been described. UC-OGC can occur over a wide age range (30–80 years), but the mean age of patients is 60 years.² The male-to-female ratio is 3:2.² UC-OGC can mimic other pancreatic tumors clinically and radiologically. Therefore, histopathology and immunohistochemistry are the diagnostic investigations of choice.² The clinical behavior of this tumor is still unknown, given the limited number of cases.²

This paper discusses an unusual case of UC-OGC in a 62-year-old female who presented with epigastric pain and was diagnosed provisionally with a solid pseudopapillary epithelial neoplasm (SPEN) both clinically and radiologically.

A 62-year-old female presented with epigastric pain refractory to medical treatment for six months. Endoscopic ultrasound (EUS) revealed a large 9×8 cm encapsulated multiloculated cystic mass in the body of the pancreas. The lesion was predominantly hypo-echoic with few hyper-echoic areas. No increased vascularity was observed on Doppler imaging. The lesion was reported as SPEN on EUS. Contrast-enhanced computed tomography (CECT) revealed a large 9.4×7.9 cm heterogeneously enhancing solid cystic mass in the body of the pancreas. No pancreatic duct dilatation or parenchymal calcification was observed. The possibility of a pancreatic neoplasm was kept on CECT. The patient underwent a distal pancreatectomy and was sent for a histopathological examination.

The gross examination revealed a grey–brown mass measuring 16×9.5×8 cm with mucoid material draining out of the cut section. A well-circumscribed tumor, measuring 9×7.5×6.5 cm with solid and cystic components, was observed. A focal area showed a mural nodule with reddish discoloration measuring 2.5×2 cm in cross-section (Fig. 1A). Multiple sections were submitted from the representative areas. A histopathological examination of hematoxylin and eosin (H&E) stained slides under optical microscopy showed a tumor comprised of cysts and glands lined by stratified mucin-producing columnar cells exhibiting high-grade dysplasia at focal areas. Sections from the mural nodule showed a neoplastic mucinous component associated with numerous multinucleated osteoclast-like giant cells with interspersed mononuclear stromal cells, osteoid formation, and a few mononuclear histiocytes. Areas of necrosis, hemorrhage, and hemosiderin-laden macrophages were also observed (Fig. 1B–F). No regional lymph node metastasis was detected in this case. Immunohistochemistry (IHC) analysis was conducted, revealing distinct staining patterns. The giant cells exhibited positivity for CD68 and vimentin, indicating their unique characteristics. By contrast, the mononuclear stromal cells were negative for CD68, highlighting the differential expression within the tumor microenvironment (Fig. 2A, B). Therefore, a diagnosis of UC-OGC associated with mucinous cystic neoplasm was given based on a histopathological examination. No cytogenetic studies were conducted in this case. Adjuvant chemotherapy was not administered post-surgery because of the patient's refusal, considering her fragile health condition. During follow-up, the patient unfortunately succumbed to her condition 10 months after surgery.

Figure 1. (A) Gross image showing a circumscribed tumor with solid and cystic components. A focal area (black solid arrow) shows a yellowish mural nodule. Normal pancreatic parenchyma can be seen at the periphery of the tumor (red solid arrow). (B) Low power view showing different components of UC-OGC: multinucleated giant cells with interspersed mononuclear stromal cells (black solid arrow), osteoid (orange solid arrow) associated with a neoplastic epithelial component with a mucinous lining (green solid arrow) (H&E stain, 40x). (C) Low power view showing multinucleated osteoclast-like giant cells with interspersed mononuclear stromal cells (H&E stain, 100x). (D) High power view showing multinucleated osteoclast-like giant cells (black solid arrow) with interspersed mononuclear stromal cells and tumor giant cells (H&E stain, 100x). (E) Low power view showing neoplastic epithelial component with a mucinous lining (H&E stain, 40x). (F) Low power view showing a neoplastic epithelial component with a mucinous lining exhibiting dysplastic features (H&E stain, 100x).

Figure 2. (A) CD68. (B, C) Vimentin highlighted multinucleated giant cells (IHC, 200x) that were negative for CD45 (IHC, 200x).

Pancreatic malignancies are the second most common gastrointestinal tumors, with PDAC being the most common subtype.⁵ UC-OGC is classified as a subtype of PDAC. These neoplasms are contemplated as epithelial-derived tumors with differentiation toward mesenchymal elements.³ On the other hand, the origin of this tumor is not completely understood because of the limited number of cases.⁵ The common clinical presentations of UC-OGC are epigastric pain, lower back pain, loss of appetite, weight loss, jaundice, nausea, and anemia.^3,5 It mostly affects the head or body of the pancreas, but the bile ducts or other organs can also be affected.² The size of these tumors ranges from 2–25 cm, with a mean size of approximately 9 cm.² In this case report, the tumor size was 9×7.5×6.5 cm. UC-OGC can occur as a pure tumor, or it may be associated with other pancreatic tumors like PDAC, intraductal papillary mucinous neoplasm, or mucinous cystic neoplasms.^1,5 In the present case, it was associated with high-grade mucinous cystic neoplasm. The differential diagnosis of UC-OGC includes undifferentiated ductal adenocarcinoma, SPEN, and cystic neoplasms.² A radiological investigation of choice for this tumor is a CT scan that shows a large solid-cystic mass with areas of hemorrhage and necrosis, which occasionally can mimic other pancreatic tumors, as in the present case.⁶ Tumor markers, e.g., CEA and CA 19-9, are normal in most patients. Hence, they are of little help in a diagnosis.^2,3 The histopathology of UC-OGC shows three components: osteoclast-like giant cells, mononuclear histiocytes, and mononuclear stromal cells.² Osteoclast-like giant cells are considered the non-neoplastic component of this tumor.¹ One hypothesis suggests that osteoclast-like giant cells appear due to the chemotactic mechanism by tumor cells in their microenvironment. The association between the presence of osteoclast-like giant cells and the prognosis of UC-OGC is not completely understood because of the scarcity of case reports and case series on this topic.¹ In contrast, the histological features of SPEN show solid areas composed of sheets or cords of uniform cells interspersed with numerous blood vessels, along with numerous areas of cystic degeneration, which may show areas of infarction, hemorrhage, and foci of calcification. The presence of pseudopapillary patterns and pseudorosettes is pathognomonic for SPEN.⁷ IHC of UC-OGC revealed osteoclast-like giant cells positive for histiocytic markers, such as CD 68 (cluster of differentiation 68), vimentin, and leucocyte common antigen, but they are negative for epithelial markers.^2,5 By contrast, mononuclear stromal cells are positive for epithelial markers, such as cytokeratin and epithelial membrane antigen, and negative for histiocytic markers.² The molecular landscape of PDAC is well-defined in the literature, with somatic alterations involving four key driver genes: the oncogene KRAS and the tumor suppressor genes TP53, CDKN2A, and SMAD4.⁸ According to Luchini et al., somatic mutations in these four PDAC driver genes are observed in cases of UC-OGC. According to their study, all eight cases had mutations in KRAS in codon 12, and seven out of eight cases harbored TP53 mutations. Only one case showed a non-synonymous missense mutation in SMAD4, while two carcinomas had mutations in CDKN2A. Beyond these well-documented PDAC driver genes, additional mutations found included a missense mutation in PTEN and a frameshift deletion in BAP1.⁸ The treatment guidelines are limited. The options range from distal pancreatectomy, middle segment pancreatectomy, or Whipple’s procedure, depending upon the location of the tumor in the pancreas with or without additional chemotherapy or radiation therapy.^3,9 No standardized treatment exists, and the effectiveness of chemotherapy and radiation therapy remains poorly documented because of the rarity of UC-OGC.⁹ Some authors also suggested the use of monoclonal antibodies PD-1 or PDL-1 for treatment.⁹ The prognosis of UC-OGC varies widely from four months to 10 years.¹⁰ The impression of older studies is that these tumors are highly aggressive and frequently surgically unresectable. Moreover, early recurrence occurs even after complete surgical removal.^1,10 Yong Gao et al. reported that the rate of recurrence and metastasis is high, with a median survival of only 13 months.³ They also reported that postoperative adjuvant chemotherapy may help improve patient survival.³ Nevertheless, recent studies have shown that pure UC-OGC of the pancreas has more indolent behavior and a significantly better prognosis than conventional PDAC.^1,10 Muraki et al.¹¹ examined 38 cases of UC-OGC and showed that these tumors have a more sustained clinical course than previously believed. Kobayashi et al.¹² reported some good prognostic components like a younger age of presentation, female phenotype, smaller size lesions, and uninvolved lymph nodes, but more data is needed to standardize the treatment and prognosis of UC-OGC.

UC-OGC is an extremely uncommon pancreatic cancer with unique characteristics and histopathological features. Becoming familiar with its clinical, radiological, and histopathological features is important for an early and accurate diagnosis because this tumor has a better prognosis than conventional PDAC. Surgery is still believed to be the first-line treatment, but the role of radiotherapy and chemotherapy is still not well understood because of the limited studies on this tumor. Ultimately, when treating UC-OGC and other rare cancers, healthcare providers must employ flexible thinking and innovative application of their knowledge of the cancer pathophysiology to ensure appropriate treatment.

Dr. Gargi Kapatia was involved in final evaluation of the case, manuscript drafting, editing and revision. Dr. Akriti Jindal took part in evaluation of the case and manuscript drafting. Dr. Gourav Kaushal was involved in the management of the patient. Dr. Ankita Soni and Dr. Manjit Kaur Rana was involved in the final evaluation of the case.

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