Correspondence

Primary clear cell ductal adenocarcinoma of the pancreas: A case report and clinicopathologic literature review ABSTRACT We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classification, primary clear cell carcinoma of the pancreas is classified as a rare “miscellaneous” carcinoma. The tumor was observed in the distal body and tail of the pancreas of a 74‑year‑old woman. The histopathology of tumor cells showed well‑defined cell membranes, clear cytoplasm, and prominent cell boundaries. Immunohistochemical (IHC) staining showed positive reactions to antibodies against vimentin, cytokeratin 7 (CK‑7), mucicarmine (MUC‑1), periodic acid‑Schiff (PAS), periodic acid‑Schiff with diastase (PASD), carcinoembryonic antigen (CEA), and Carbohydrate Antigen 19‑9 (CA 19‑9). On the other hand, IHC staining was negative for alpha‑fetoprotein (AFP), cytokeratin 20 (CK‑20), HMB45, chromogranin, and synaptophysin. The patient was subsequently diagnosed with a primary solid‑type pancreatic clear cell carcinoma with hepatic metastasis. Herein, we report this rare case and include a review of the current literature of this tumor. KEY WORDS: Clear cell, ductal type, pancreatic neoplasms

INTRODUCTION Clear cell carcinoma of the pancreas was first described by Cubilla and Fitzgerald in 1980 and, since then, unfortunately, there is not much data available in the medical literature on this neoplasm. [1] The incidence and prognosis are not well known. We report this unique case of metastatic primary solid‑type clear cell carcinoma of the pancreas and review the cases that exist in the medical literature. CASE REPORT A 74‑year‑old woman presented to our clinic with episodic epigastric pain, radiating to the back and anorexia for 6 months resulting in weight loss of 10 pounds. She denied any history of smoking, alcohol, or illicit drug use. On clinical examination, her vital signs were stable, and there was no evidence of jaundice. Tenderness was elicited in the epigastrium on superficial and deep palpation. Routine blood tests including amylase and lipase were normal. Her liver enzymes were elevated (alanine aminotransferase 120 U/L, normal 0-37 U/L; aspartate aminotransferase 231 U/L, normal 0-40 U/L). Her serum alkaline phosphatase was 650 U/L (38-126); serum gamma glutamyl transferase, 1,663 U/L (7-50); and total bilirubin,

1.3 mg/dl (0.3-1.2). Tumor marker assay showed CEA > 600 u/ml (0-5) and CA19‑9 > 7,000 u/ml (0-37). Computed tomography (CT) scan showed a 6 × 3.5 cm necrotic pancreatic mass in the distal body and tail of the pancreas, with multiple low attenuation lesions in the liver consistent with metastases. A CT‑guided liver biopsy was undertaken. The histologic examination of the liver biopsy specimens revealed diffuse infiltrating poorly differentiated neoplasm with clear cell features consistent with metastatic clear cell carcinoma. Microscopic examination [Figure 1] exhibited highly atypical glands composed of pleomorphic cells possessing a distinct clear cell component with abundant clear cytoplasm and well‑defined cell borders. These features were present in more than 90% of the tumor cells. Immunohistochemistry (IHC) showed strong and diffuse staining for vimentin, cytokeratin 7 (CK‑7) [Figure 2a], mucicarmine (MUC‑1), periodic acid‑Schiff (PAS), periodic acid‑Schiff with diastase (PA SD), carcinoembr yonic antigen (CEA), and CA19‑9 [Figure 2b]. On the other hand, the IHC staining was negative for alpha‑fetoprotein (AFP), cytokeratin 20 (CK‑20), chromogranin, synaptophysin, HMB‑45, HEPAR 1, and Glypican 3. The clinical presentation, morphological examination, and IHC profile were entirely consistent with metastatic primary pancreatic clear cell carcinoma. The patient was

Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3

Yashpal Modi, Hamid Shaaban1, Dron Gauchan, Michael Maroules, Nalini Parikh1, Gunwant Guron1 Department of Hematology and Oncology, St Joseph’s Regional Medical Center, Paterson, 1 Departments of Pathology, Hematology and Oncology, St Michael’s Medical Center, Newark, NJ, USA For correspondence: Dr. Hamid Shaaban, Department of Hematology and Oncology, St. Michael’s Medical Center, Newark, NJ 07102, USA. E‑mail: [email protected] com

Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.136043 PMID: *** Quick Response Code:

773

Modi, et al.: Clear cell adenocarcinoma of pancreas

a

b

Figure 2: (a) Immunohistochemically, tumor cells showed positivity for cytokeratin 7. (b) Immunohistochemically, tumor cells showed positivity for carbohydrate antigen 19‑9

Figure  1: Infiltrating adenocarcinoma showing a clear cell pattern (H and E, original magnification ×200)

offered palliative chemotherapy, but she declined any further treatment. Instead, she chose to be referred to a different hospital at the request of her family. DISCUSSION We present the clinicopathological, IHC, and molecular findings of metastatic clear cell carcinoma of the pancreas, a very rare malignancy. Clear cell carcinoma is a common variant of carcinoma of kidney, ovary, thyroid, and lung, but this tumor rarely originates from the pancreas. The clear cell variants of pancreatic ductal adenocarcinoma, described in some case reports, demonstrate clear cell changes in both well‑differentiated and moderately differentiated pancreatic adenocarcinomas.[2] In our case, there was an abundance of clear cells in the neoplasm, and they expressed CK7 in the absence of neuroendocrine markers. IHC profile of the clear cells in the tumor displayed a strong positivity for CEA and CA 19‑9, which strongly supported a pancreatic neoplasm of ductal origin. We diagnosed our case as primary clear cell ductal adenocarcinoma of pancreatic cancer based on the morphology, IHC profile, pancreatic and liver masses on radiology, and elevated serum level of CA 19‑9. Table 1 summarizes the findings of the available case reports of clear cell carcinomas of pancreas. The clinical presentation, histomorphology, and IHC profile of these tumors vary in different case reports. Kanai et al. described a case of pancreatic clear cell carcinoma in an autopsy report of a 71‑year‑old man who presented with elevated CEA and CA 19‑9 levels in blood.[3] The bulk of tumor was in the tail of the pancreas with direct extension to the kidney and gastric surface and with metastasis to the lungs in the form of multiple nodules and lymphangiosis carcinomatosa. Taziaux et al. reported an unusual case of pancreatic carcinoma, protruding into the duodenal lumen, with clear 774

cell features in a 70‑year‑old man who presented with anemia and melena.[4] Luttges et al. reported a predominantly intraductal tumor in the head of the pancreas, in which the invasive component consisted exclusively of clear cells in a solid growth pattern with occasional tubular elements.[5] K‑ras oncogene mutation at codon 12 was detected, which is characteristic of conventional ductal adenocarcinoma. Ray et al. described a tumor in the tail of pancreas displaying abundant clear cell morphology.[6]The authors concluded that clear cell carcinoma can be regarded as a rare variant of ductal adenocarcinoma because a K‑ras oncogene mutation was detected. He had a distal pancreatectomy, splenectomy, and partial omentectomy and was healthy at the 2‑month follow‑up visit. Batoroev and Nguyen reported a patient diagnosed with clear cell carcinoma of the pancreas by fine needle aspiration of a 4‑cm pancreatic head mass.[7] Mutation of the K‑ras oncogene is common in neoplasms of ductal origin. However, in the case report of Sasaki et al., a mutation of K‑ras oncogene was not detected in the clear cell tumor that morphologically had a ductal phenotype.[8] Ray et al. were the first to report a case of metastatic pancreatic tumor with marked clear cell changes in a 46‑year‑old white man presenting with a pancreatic pseudocyst.[9] The patient refused palliative chemotherapy and died 3 months after diagnosis. The rhabdoid phenotype represents a common clonal dedifferentiated end point in malignant tumors of varying histogenesis. Lee et al. described a case report of a 66‑year‑old woman who presented with an abdominal mass involving the pancreas tail and liver; histologic evaluation showed a clear cell carcinoma with rhabdoid feature.[10] The cancer progressed and she died a month later. There are no specific diagnostic criteria for the diagnosis of clear cell carcinoma of the pancreas. A biomarker—hepatocyte nuclear factor‑1β (HNF‑1B)—could be utilized to identify clear cell carcinomas; moreover, a higher degree of HNF1B staining without regard to the morphologic subtype correlates with a significantly decreased survival.[10]

Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3

Modi, et al.: Clear cell adenocarcinoma of pancreas

Table 1: The previously reported cases of clear cell carcinoma of the pancreas Author Our case

Year 2013

Age/Sex 74F

Location in Pancreas Body and tail, metastatic to liver

Morphology Highly atypical glands with abundant clear cells with well define borders

Lee et al.

2009

66F

Tail, metastatic to liver

Nests of clear cells with rhabdoid features

Jamali et al.

2007

75M

Uncinate process

Ray et al.

2005

46M

Head, metastatic to omentum

Sasaki et al.

2004

61F

Body

Vacuolated cytoplasm and raisinoid nuclei with rhabdoid components Pleomorphic and hyperchromatic nuclei with abundant clear cytoplasm Clear cell nests with scanty fibrous stroma

Batoroev and Nguyen

2004

60M

Head and body

Ray et al.

2004

75M

Tail

Luttges et al. 1998

53M

Head

Taziaux et al. 1994

70M

Head, extension into duodenum

Kanai et al.

71M

1987

Immunohistochemical Profile Vimentin+, CK‑7+, mucicarmine+, PAS+, PASD+, CEA+, CA19‑9+AFP‑, CK‑20‑, chromogranin‑, synaptophysin‑, HEPAR 1‑, HMB45‑, and Glypican 3‑ Pan‑cytokeratin+, Cytokeratin 7+, CEA+, EMA+Cytokeratin 20 ‑, Chromogranin‑, synaptophysin‑, smooth muscle actin‑, and HMB‑45‑ Cytokeratin markers+Vimentin+ CK7+, CEA+, PSA‑, thyroglobulin‑, HMB45‑, synaptophysin‑, chromogranin A‑ CK* 8+, CK‑19+, CEA‑, CA 19‑9+, NSE‑, chromogranin A‑, synaptophysin‑, insulin‑, glucagon‑, somatostatin‑, gastrin‑, α‑1‑Antitrypsin+, trypsin‑, and HMB45‑ PAS+PASD+Mucicarmine (W) CEA+, Vimentin ‑

Vacuolated cytoplasm and pleomorphic nuclei with conspicuous nucleoli Pleomorphic cells with abundant CK‑7+, CAM 5.2+, clear cytoplasm (>95% clear cells) CK20+, CEA+, NSE+, synaptophysin‑, chromogranin‑, vimentin‑, p53‑, HMB‑45‑CD10‑, PASD§+, α1‑antitrypsin‑ Primarily intraductal with solid CK7+, CK8+, CK18+, invasive clear cell component CK19+, Vimentin‑ PASD+CEA (W) p53+Chromogranin‑ Synaptophysin‑ α‑1‑Antitrypsin+ Cords and nests in highly vascular KL‑1 (epithelial)+ stroma Vimentin+Chromogranin‑ PSA‑ Solid, trabecular, and nested PAS+Alcian blue+Sudan III+

Body and tail, widely metastatic Urbanski and 1982 57M Body, widely metastatic Multiple clear cells interspersed Medline throughout the spindle and giant cells Cubilla and 1980 Unspecified Unspecified Unspecified Fitzgerald

Alcian green+PAS+PASD+Oil Red‑O‑ Mucin+

*CK=Cytokeratin, CEA=Carcinoembryonic antigen, NSE=Neuron‑specific enolase, PASD=Periodic acid‑Schiff with diastase, PAS=Periodic acid‑Schiff, ‑ Indicates negative; +, indicates positive; W=Weak, PSA=Prostate‑specific antigen, AFP=Alpha‑fetoprotein, CA 19‑9=Carbohydrate antigen 19‑9

In conclusion, we report a rare case of clear cell ductal adenocarcinoma of the pancreas with a review of the related literature. Currently, there are no specific diagnostic criteria for this tumor. The literature review suggests that in addition to the characteristic morphology and IHC stains, special investigations such as gene analysis for detecting K‑ras mutations and biomarker studies like HNF‑1B would aid in the identification of this rare neoplasm. Further studies and more case reports are needed to clarify the prognostic significance of the clear cell differentiation of these tumors. REFERENCES 1. Cubilla AL, Fitzgerald PJ. Cancer (non‑endocrine) of the pancreas: A suggested classification. In: Disease of the Pancreas. International Academy of Pathology Monographs. Baltimore, Md: Williams and

Wilkins Co.; 1980. p. 82‑110. 2. Urbanski SJ, Medline A. Giant cell carcinoma of pancreas with clear cell pattern in metastases. Hum Pathol 1982;13:1047‑9. 3. Kanai N, Nagaki S, Tanaka T. Clear cell carcinoma of the pancreas. Acta Pathol Jpn 1987;37:1521‑6. 4. Taziaux P, Dallemagne B, Delforge M, Corhay‑Abraham F, Jardon‑Jeghers C, Cobut M, et al.An exceptional observation of clear cell pancreatic cancer.. J Chir (Paris) 1994;131:86‑9. 5. Luttges J, Vogel I, Menke M, Henne‑Bruns D, Kremer B, Kloppel G. Clear cell carcinoma of the pancreas: An adenocarcinoma with ductal phenotype. Histopathology 1998;32:444‑8. 6. Ray S, Lu Z, Rajendiran S. Clear cell ductal adenocarcinoma of pancreas: A case report and review of literature. Arch Pathol Lab Med 2004;128:693‑6. 7. Batoroev YK, Nguyen GK. Clear cell carcinoma of the pancreas in fine‑needle aspirate. Diagn Cytopathol 2005;32:249‑51. 8. Sasaki A, Ishio T, Bandoh T, Shibata K, Matsumoto T, Aramaki M, et al. Clear cell carcinoma of the pancreas: An adenocarcinoma with

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Modi, et al.: Clear cell adenocarcinoma of pancreas

unusual phenotype of duct cell origin. J Hepatobiliary Pancreat Surg 2004;11:140‑4. 9. Ray B, New NE, Wedgwood KR. Clear cell carcinoma of exocrine pancreas: A rare tumor with an unusual presentation. Pancreas 2005;30:184‑5. 10. Lee HY, Lee DG, Chun K, Lee S, Song SY. Clear cell carcinoma of the pancreas: A case report and review of the literature. Cancer Res Treat 2009;41:175‑81.

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Cite this article as: Modi Y, Shaaban H, Gauchan D, Maroules M, Parikh N, Guron G. Primary clear cell ductal adenocarcinoma of the pancreas: A case report and clinicopathologic literature review. J Can Res Ther 2014;10:773-6. Source of Support: Nil, Conflict of Interest: No.

Journal of Cancer Research and Therapeutics - July-September 2014 - Volume 10 - Issue 3

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Primary clear cell ductal adenocarcinoma of the pancreas: a case report and clinicopathologic literature review.

We present a very rare, interesting case of a carcinoma of the pancreas with predominantly abundant clear cell morphology. According to the WHO classi...
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