| Abstract|| |
Anaplastic carcinoma of pancreas (ACP) are rare pancreatic neoplasms. They are well known to be associated with more aggressive tumor behavior and less favorable prognosis than usual pancreatic ductal adenocarcinoma. Endoscopic-guided fine needle aspiration (EUS-FNA) is now a widely accepted modality in diagnosis of pancreatic lesions. However, only a few reports are available describing cytological features of anaplastic carcinoma. Here, we report two cases of ACP diagnosed on EUS-FNA.
Keywords: Anaplastic carcinoma of pancreas, anaplastic giant cell carcinoma, carcinosarcoma, endoscopic-guided fine needle aspiration (EUS-FNA)
|How to cite this URL:|
Osama MA, Bakshi P, Verma K. Anaplastic (undifferentiated) carcinoma of pancreas, an uncommon variant: Diagnosed on endoscopic-guided fine needle aspiration. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Feb 5]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345881
| Introduction|| |
Undifferentiated (anaplastic) carcinoma of pancreas is recognized as a rare variant of ductal adenocarcinoma in the 2019 WHO classification of pancreatic tumors. It accounts for only 0.8–5.7% of all pancreatic neoplasms. It has a more aggressive behavior and poorer prognosis compared to other pancreatic tumors, and hence, its recognition is important.,, The average age at diagnosis is 62 years., It is classified by WHO as a variant of ductal adenocarcinoma and is defined as a malignant epithelial neoplasm in which a significant component does not show a definitive direction of differentiation. Three histological variants have been described, that is, anaplastic giant cell carcinoma, sarcomatoid carcinoma, and carcinosarcoma.
Endoscopic ultrasound-guided fine needle aspiration (EUS FNA) is now a widely accepted modality in diagnosis of pancreatic lesions., The literature on anaplastic pancreatic carcinoma is very limited, mostly present as a single-case report or occasional case series and the cytological features of anaplastic carcinoma are not well described.,,,,,,,,, We report two cases diagnosed on EUS-FNA.
| Case History|| |
Case 1 was a 62-year-old male who presented with pain abdomen and nausea for 7–10 days. The pain was insidious in onset and gradually worsened. Laboratory examination revealed that the patient was anemic (hemoglobin 10.0 g/dL), and the liver and pancreatic enzymes were in the normal range. Carbohydrate antigen 19-9 levels were mildly elevated (68.3 U/mL). On EUS, the pancreatic head appeared heterogeneous, hypoechoic, bulky, and showed a well-demarcated mass measuring 4 × 3 cm. An enlarged periportal lymph node and multiple SOLs in the left lobe of the liver were also seen. EUS FNA was done from all three sites using 22 G needle, Olympus GF UCT 180 curvilinear scope. Air-dried smears and alcohol fixed smears were prepared and stained with May Grunwald Giemsa and Papanicolaou stain, respectively. Cell block was also prepared.
EUS FNA smears from pancreatic head mass were cellular and showed a tumor [Figure 1]a. Tumor cells were predominantly dispersed singly and were composed of highly pleomorphic large polygonal cells with moderate amount of cytoplasm [Figure 1]b. Interspersed numerous bizarre multinucleate tumor giant cells were identified [Figure 1]c. Mitotic figures were abundant. There was no evidence of glandular or squamous differentiation on smears. Cell block was also prepared and revealed similar tumor [Figure 2]a. On immunohistochemistry (IHC), tumor cells were diffusely positive for pancytokeratin (CK), and CK7 also coexpressed vimentin [Figure 2]b and [Figure 2]c. Tumor cells were negative for synaptophysin, Melan-A, and ALK-1. Smears from liver SOL and periportal lymph node showed metastasis of same. A diagnosis of anaplastic (pleomorphic) giant cell carcinoma was rendered. The patient was given chemotherapy and palliative care, however, died within a few months due to widespread metastasis.
|Figure 1: (a) Highly cellular smears, singly scattered tumor cells (PAP 100x); (b) pleomorphic tumor cells with enlarged hyperchromatic nuclei and atypical mitosis (MGG 200x); and (c) tumor giant cells (PAP 400x)|
Click here to view
|Figure 2: (a) Cell block (HE 100x); (b) Cytokeratin 7 positivity on IHC (200x); and (c) Vimentin positivity on IHC (200x)|
Click here to view
Case 2 was a 68-year-old male who presented with multiple episodes of abdominal pain, vomiting, and diarrhea. Significant weight loss of about 5 kg was noted over 1.5 months. The patient had a past medical history of type 2 diabetes mellitus and hyperlipidemia. A clinical diagnosis of chronic pancreatitis was rendered. Laboratory investigations revealed slightly elevated bilirubin levels with moderately elevated liver enzymes (AST/ALT). EUS showed a 30 × 28 mm hypoechoic mass with necrotic component in pancreatic tail. Interface between mass and splenic vein was lost. EUS-FNA was done from the mass.
EUS FNA smears from pancreatic tail mass showed a tumor with biphasic appearance [Figure 3]a and [Figure 3]b. The epithelial fragments showed moderately pleomorphic nuclei, irregular nuclear membrane, coarse chromatin, nucleoli, mitosis, and focal glandular arrangement compatible with adenocarcinoma [Figure 3]c. The other component consisted of fragments of high-grade spindle cell sarcomatous elements [Figure 3]d. The tumor cells were spindled in appearance in a loose fascicular arrangement and showed marked pleomorphism, hyperchromasia, and prominent nucleoli. Mitotic figures were not appreciated on morphology in the spindle areas. Necrosis was seen focally. On IHC, the epithelial component was diffusely positive for cytokeratin. The spindle cell component was negative for cytokeratin and positive for vimentin representing sarcomatous areas of the tumor [Figure 4]a, [Figure 4]b, [Figure 4]c. A final diagnosis of carcinosarcoma was made. The patient was lost to follow-up.
|Figure 3: (a, b) Biphasic appearance showing epithelial and sarcomatous areas (PAP 100x); (c) fragments of tumor cells showing glandular elements (MGG 400x); and (d) sarcomatous area showing markedly pleomorphic nuclei (PAP 200x)|
Click here to view
|Figure 4: IHC: (a) Epithelial elements – cytokeratin positive (200x); (b) sarcomatous area – vimentin positive (200x); and (c) sarcomatous area – cytokeratin negative (200x)|
Click here to view
| Discussion|| |
Anaplastic carcinoma of pancreas (ACP) is a rare histologic subtype of pancreatic ductal adenocarcinoma (PDAC). The incidence of ACP varies from 0.8 to 5.7% of all pancreatic neoplasms. It has an aggressive behavior with a poorer prognosis than the usual ductal adenocarcinoma.,, Lack of specific imaging features makes distinction of anaplastic carcinoma difficult from usual ductal adenocarcinoma preoperatively. These tumors are usually diagnosed at an advanced stage with metastasis to the liver and/or invasion of adjacent organs or the peritoneal cavity. In our case, the tumor showed necrosis and metastasis to the liver and the surrounding lymphnodes. Endoscopic ultrasound provides a high-resolution imaging of pancreas and the adjacent structures including lymphnodes and vessels. In contrast to the uniform hypoechogenic appearance of typical adenocarcinoma, undifferentiated pancreatic carcinoma shows both hyper and hypoechoic areas, thus appearing heterogenous. EUS also offers an added advantage of tissue sampling, which is a gold standard of diagnosis. Chen G et al. in their meta-analysis of 31 articles showed a high sensitivity and specificity of endoscopic ultrasound and fine needle aspiration in diagnosing undifferentiated pancreatic carcinoma.
According to WHO, anaplastic carcinoma is a malignant epithelial neoplasm in which a significant component does not show a definitive direction of differentiation. Three histological variants have been described, that is, anaplastic giant cell carcinoma, sarcomatoid carcinoma, and carcinosarcoma.
The anaplastic (pleomorphic) giant cell carcinoma is a highly anaplastic tumor with bizarre pleomorphic mononucleate and multinucleated tumor giant cells. On the other hand, undifferentiated carcinoma with osteoclast-like giant cells is recognized as a distinct variant of ductal adenocarcinoma of pancreas. It is characterized histologically by the presence of highly pleomorphic neoplastic mononuclear epithelial cells accompanied by nonneoplastic osteoclast-like histiocytic giant cells. The giant cells in this tumor are nonneoplastic and are reactive to vimentin and CD 68 and are negative for epithelial markers. It needs to be differentiated from anaplastic (pleomorphic) giant cell carcinoma as it has a different clinical course, carries a better prognosis, and is amenable to resection.,,,,
WHO classification of Tumors of the Exocrine Pancreas lists sarcomatoid carcinoma, carcinosarcoma, anaplastic giant cell carcinoma, as well as undifferentiated carcinoma with osteoclast-like giant cells under the section of undifferentiated (anaplastic) carcinoma, a variant of ductal adenocarcinoma. Carcinosarcomas are rare tumors with a biphasic histological pattern of carcinomatous and sarcomatous components. They are composed of mixed malignant epithelial (most commonly moderately differentiated ductal adenocarcinoma) and high-grade sarcomatous areas. On IHC, carcinomatous areas are positive for epithelial markers, while sarcomatous areas are negative. They express mesenchymal markers instead. Ruess et al., reported a case of a pancreatic carcinosarcoma showing a positive expression of pancytokeratin in the carcinomatous part (vimentin negative) and a strong positive expression of vimentin in the sarcomatous part (very focally positive for pancytokeratin). Similar IHC findings were observed in our case.
Sarcomatoid carcinomas show a predominance of spindle cell morphology, but evidence of epithelial derivation, that is, positivity for epithelial markers (cytokeratins) on IHC in spindle cells.
Differentiation of ACP from a poorly differentiated PDAC is based on morphology as ACP are poorly cohesive, cellular, highly pleomorphic, stroma poor, and show no differentiation. PDAC shows some evidence of glandular differentiation. IHC plays an important role in differentiating ACP from other pleomorphic malignant tumors like malignant melanoma, sarcomas like malignant fibrous histiocytoma, anaplastic large cell lymphoma, and choriocarcinoma. Demonstration of positivity for epithelial markers (CK, CK7, CK19, EMA) supports an epithelial origin and differentiates it from other pleomorphic malignant tumors. ACP often shows coexpression of vimentin and CK in epithelial component as was seen in our case as well., Other metastatic carcinomas are ruled out by clinical and radiological correlation.
ACP shows aggressive tumor behavior and prognosis is extremely poor with average survival of 5 months.,,, Lymph node metastasis substantially worsens the prognosis and is found in around 40% cases., They are frequently diagnosed at an advanced stage with adjacent organ involvement and distant metastasis.
| Conclusion|| |
ACP is a rare malignancy with poor prognosis and aggressive behavior. Preoperative clinical and radiological diagnosis is difficult as there are no specific features to distinguish it from PDAC. Recognition of its distinct cytomorphological features on EUS-FNA in conjunction with IHC can lead to diagnosis of this rare entity preoperatively helping in planning an effective treatment strategy.
Ethical approval is generally not required for publishing case reports from our institution.
Declaration of patient consent
The authors certify that they have obtained the appropriate consent from the patient. The patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands that the name and initials will not be published, and due efforts have been made to conceal the same.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Clark CJ, Graham RP, Arun JS, Harmsen WS, Reid-Lombardo KM. Clinical outcomes for anaplastic pancreatic cancer: A population-based study. J Am Coll Surg 2012;215:627-34.
Hoshimoto S, Matsui J, Miyata R, Takigawa Y, Miyauchi J. Anaplastic carcinoma of the pancreas: Case report and literature review of reported cases in Japan. World J Gastroenterol 2016;22:8631-7.
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;5:129-40.
Chen G, Liu S, Zhao Y, Dai M, Zhang T. Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration for pancreatic cancer: A meta-analysis. Pancreatology 2013;13:298-304.
Hewitt MJ, McPhail MJ, Possamai L, Dhar A, Vlavianos P, Monahan KJ. EUS-guided FNA for diagnosis of solid pancreatic neoplasms: A meta-analysis. Gastrointest Endosc 2012;75:319-31.
Aldaoud N, Joudeh A, Al-Momen S, Alnahawi M, Al-Abbadi MA. Anaplastic carcinoma arising in a mucinous cystic neoplasm masquerading as pancreatic pseudocyst. Diagn Cytopathol 2016;44:538-42.
Chopra S, Wu ML, Imagawa DK, Lee J, Gu M. Endoscopic ultrasound-guided fine-needle aspiration of undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: A report of 2 cases with literature review. Diagn Cytopathol 2007;35:601-6.
Ergün M, Aydoğ G, Kayaçetın E, Şaşmaz N. A case of anaplastic carcinoma of pancreas diagnosed with endoscopic ultrasound-guided fine needle aspiration cytology. Turk J Gastroenterol 2012;23:828-9.
Khashab MA, Emerson RE, DeWitt JM. Endoscopic ultrasound-guided fine-needle aspiration for the diagnosis of anaplastic pancreatic carcinoma: A single-center experience. Pancreas 2010;39:88-91.
Layfield LJ, Bentz J. Giant-cell containing neoplasms of the pancreas: An aspiration cytology study. Diagn Cytopathol 2008;36:238-44.
Mannan R, Khanna M, Bhasin TS, Misra V, Singh PA. Undifferentiated carcinoma with osteoclast-like giant cell tumor of the pancreas: A discussion of rare entity in comparison with pleomorphic giant cell tumor of the pancreas. Indian J Pathol Microbiol 2010;53:867-8.
] [Full text]
Maksymov V, Khalifa MA, Bussey A, Carter B, Hogan M. Undifferentiated (anaplastic) carcinoma of the pancreas with osteoclast-like giant cells showing various degree of pancreas duct involvement. A case report and literature review. JOP 2011;12:170-6.
Loya AC, Ratnakar KS, Shastry RA. Combined osteoclastic giant cell and pleomorphic giant cell tumor of the pancreas: A rarity. An immunohistochemical analysis and review of the literature. JOP 2004;5:220-4.
Ezenekwe AM, Collins BT, Ponder TB. Mixed osteoclastic/pleomorphic giant cell tumor of the pancreas: A case report. Acta Cytol 2005;49:549-53.
Bosman F, Carneiro F, Hruban R, Theise ND. Ductal adenocarcinoma variants and mixed neoplasms of the pancreas. In: World Health Organization Classification of Tumours of the Digestive System. 4th
ed. Lyon, France: IARC Press; 2010. p. 292-5.
Ruess DA, Kayser C, Neubauer J, Fichtner-Feigl S, Hopt UT, Wittel UA. Carcinosarcoma of the pancreas: Case report with comprehensive literature review. Pancreas 2017;46:1225-33.
Department of Cytopathology, Sir Gangaram Hospital, Old Rajinder Nagar, New Delhi
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]