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Two Unusual Variants of Pancreatic Neuroendocrine Tumor and Their Potential Pitfalls on Fine-Needle Aspiration Cytology Abby M. Richmond, M.D.,* and Sanjana Mehrotra, M.D.
Endoscopic ultrasound-guided fine-needle aspiration is increasingly utilized for the diagnosis of pancreatic lesions. Although operator dependent, the procedure has good overall performance characteristics and is minimally invasive; however, accuracy and sensitivity are reportedly lower for pancreatic neuroendocrine tumor (PanNET) compared with the more common pancreatic ductal adenocarcinoma (pACA). The underperformance is further exacerbated by the unusual cases of PanNET presenting with variant cytomorphology. We report two separate diagnostically challenging cases: a pigmented PanNET and a clear cell PanNET. We briefly review the literature and emphasize the importance of recognizing these uncommon variants when encountered in aspirate material. Diagn. Cytopathol. C 2017 Wiley Periodicals, Inc. 2017;45:371–378. V Key Words: pancreatic neuroendocrine tumor; pigmented neuroendocrine tumor; clear cell neuroendocrine tumor; lipid-rich neuroendocrine tumor; pancreatic fine needle aspiration
Pancreatic neuroendocrine tumors (PanNET) are rare neoplasms with an incidence of 0.4 per 100,000 people according to 2010 SEER (National Cancer Institute Surveillance, Epidemiology, and End Result) data.1 However,
Department of Pathology, University of Colorado, Aurora, Colorado Conflicts of interest: None Disclosures: None *Correspondence to: Abby M. Richmond, MD, Department of Pathology, University of Colorado School of Medicine, Academic Office 1, 12631 East 17th Avenue, Mailstop B216, Aurora, CO 80045, USA. E-mail: [email protected] Received 16 September 2016; Revised 7 November 2016; Accepted 13 December 2016 DOI: 10.1002/dc.23662 Published online 20 February 2017 in Wiley Online Library (wileyonlinelibrary.com). C 2017 WILEY PERIODICALS, INC. V
due to advances in diagnostic techniques and increased awareness, PanNET now represent up to 10% of pancreatic tumors. PanNET are subdivided into functional and nonfunctional based on the presence of hormone-specific clinical syndromes. Nonfunctional tumors outnumber functional tumors, and although less aggressive than pACA, PanNET are not indolent.2 Nonfunctional tumors present with locally advanced or metastatic disease in over 80% of cases, clinically mimicking pACA. In this scenario, differentiation from pACA is crucial, as surgery may still be considered the primary treatment for even metastatic PanNET.3 Endoscopic ultrasound-guided fineneedle aspiration (EUS-FNA) is safe and incomparably superior for pre-operative investigation of intrapancreatic masses due to the gland’s proximity to the gastrointestinal tract.4 Aspiration of material using a 22 or 25 gauge needle yields a high diagnostic sensitivity and specificity for pancreatic neoplasms overall; however, performance is reportedly lower for PanNET compared with pACA.5–7 In addition, variant cytomorphologic features occasionally characterize the majority or entirety of the PanNET specimen, obscuring the typical neuroendocrine features and suggesting an erroneous diagnosis of either metastasis to the pancreas or a completely different tumor entity. If adequate material is procured, ancillary studies contribute to accurate diagnosis8; however, awareness of rare PanNET variants is requisite to pursuing appropriate ancillary studies. Herein, we report two such cases of potential diagnostic pitfall. The first is a pigmented PanNET mimicking melanoma, and the second is a clear cell PanNET mimicking clear cell carcinomas of pancreatic and extrapancreatic origin. Diagnostic Cytopathology, Vol. 45, No 4
371
Diagnostic Cytopathology DOI 10.1002/dc
RICHMOND AND MEHROTRA
Fig. 1. Coronal image of a CT scan with contrast demonstrating an arterial phase enhancing mass (arrow) within the pancreatic body, representing the pigmented PanNET.
Fig. 2. Coronal image of a CT scan with contrast demonstrating a hyperenhancing mass (arrow) in the pancreatic head and uncinate process, representing the clear cell PanNET.
Case Histories
Materials and Methods
Case One
Aspirate material from each case was evaluated with a rapid Romanowsky stain and Papanicolaou stain. Cell blocks were prepared, and formalin-fixed, paraffin-embedded (FFPE) sections were routinely processed and stained with hematoxylin and eosin (H&E). Immunohistochemical (IHC) studies with appropriate controls for synaptophysin, chromogranin, CD56, and MIB-1/Ki67 were applied to FFPE cell block material of each case. Pancytokeratin (CK), S-100, SOX-10, HMB-45, and MART1 were also evaluated in the first case, while CK7, CK20, CA-IX, Pax-8, RCC, CD10, beta-catenin, and inhibin and special stains for mucin and PAS were also evaluated in the second case (Table I). Representative FFPE sections of the resection specimen (case 1) were routinely processed and stained with H&E. An IHC study for MIB-1/ Ki67 and a special study for Fontana-Masson were applied to representative sections. The anonymity of each patient is maintained, and informed consent and ethics committee approval were not considered necessary for this brief report.
A 66-year-old Caucasian man with a past medical history significant for diabetes mellitus type 2 and Hepatitis C induced cirrhosis was found to have a 13 mm enhancing mass in the body of the pancreas during routine computed tomography (CT) for hepatic surveillance (Fig. 1). The patient was asymptomatic, apart from a recent worsening of diabetes requiring initiation of insulin therapy. Tumor markers, including alpha-fetoprotein, cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), chromogranin-A, and glucagon, were within normal limits. The patient underwent EUS-FNA of the lesion followed by distal pancreatectomy and splenectomy.
Case Two A 51-year-old woman without significant past medical history presented to her primary care physician for hematuria secondary to nephrolithiasis. CT intravenous pyelogram revealed a 7.4 cm heterogeneously enhancing, partially necrotic mass in the head of the pancreas, image characteristics concerning for malignancy. Mass lesions of the genitourinary tract were not seen. A staging CT (Fig. 2) revealed the mass to efface the portal vein and near-circumferentially encase the superior mesenteric artery. Metastases were not identified on imaging. Serum chromogranin-A was elevated to 160 ng/mL (reference range 0–95 ng/mL). Serum CA19-9 and CEA were within normal limits. She subsequently underwent EUS-FNA of the lesion to obtain a diagnosis. 372
Diagnostic Cytopathology, Vol. 45, No 4
Results Case One Light microscopic evaluation of the aspirate material demonstrated a highly cellular lesion present as dispersed individual cells and loose aggregates of cells. The cells contained uniform eccentric nuclei with finely stippled chromatin and moderate amounts of cytoplasm. Brownblack granular pigment was present both within lesional
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF PANCREATIC NEUROENDOCRINE TUMOR VARIANTS Table I. Immunohistochemical Results, Reagents, and Titration Results Antibody
Case 1
Synaptophysin Chromogranin-A CD56 MIB-1/Ki67
1 1 (focal) 1
Two Unusual Variants of Pancreatic Neuroendocrine Tumor and Their Potential Pitfalls on Fine-Needle Aspiration Cytology Abby M. Richmond, M.D.,* and Sanjana Mehrotra, M.D.
Endoscopic ultrasound-guided fine-needle aspiration is increasingly utilized for the diagnosis of pancreatic lesions. Although operator dependent, the procedure has good overall performance characteristics and is minimally invasive; however, accuracy and sensitivity are reportedly lower for pancreatic neuroendocrine tumor (PanNET) compared with the more common pancreatic ductal adenocarcinoma (pACA). The underperformance is further exacerbated by the unusual cases of PanNET presenting with variant cytomorphology. We report two separate diagnostically challenging cases: a pigmented PanNET and a clear cell PanNET. We briefly review the literature and emphasize the importance of recognizing these uncommon variants when encountered in aspirate material. Diagn. Cytopathol. C 2017 Wiley Periodicals, Inc. 2017;45:371–378. V Key Words: pancreatic neuroendocrine tumor; pigmented neuroendocrine tumor; clear cell neuroendocrine tumor; lipid-rich neuroendocrine tumor; pancreatic fine needle aspiration
Pancreatic neuroendocrine tumors (PanNET) are rare neoplasms with an incidence of 0.4 per 100,000 people according to 2010 SEER (National Cancer Institute Surveillance, Epidemiology, and End Result) data.1 However,
Department of Pathology, University of Colorado, Aurora, Colorado Conflicts of interest: None Disclosures: None *Correspondence to: Abby M. Richmond, MD, Department of Pathology, University of Colorado School of Medicine, Academic Office 1, 12631 East 17th Avenue, Mailstop B216, Aurora, CO 80045, USA. E-mail: [email protected] Received 16 September 2016; Revised 7 November 2016; Accepted 13 December 2016 DOI: 10.1002/dc.23662 Published online 20 February 2017 in Wiley Online Library (wileyonlinelibrary.com). C 2017 WILEY PERIODICALS, INC. V
due to advances in diagnostic techniques and increased awareness, PanNET now represent up to 10% of pancreatic tumors. PanNET are subdivided into functional and nonfunctional based on the presence of hormone-specific clinical syndromes. Nonfunctional tumors outnumber functional tumors, and although less aggressive than pACA, PanNET are not indolent.2 Nonfunctional tumors present with locally advanced or metastatic disease in over 80% of cases, clinically mimicking pACA. In this scenario, differentiation from pACA is crucial, as surgery may still be considered the primary treatment for even metastatic PanNET.3 Endoscopic ultrasound-guided fineneedle aspiration (EUS-FNA) is safe and incomparably superior for pre-operative investigation of intrapancreatic masses due to the gland’s proximity to the gastrointestinal tract.4 Aspiration of material using a 22 or 25 gauge needle yields a high diagnostic sensitivity and specificity for pancreatic neoplasms overall; however, performance is reportedly lower for PanNET compared with pACA.5–7 In addition, variant cytomorphologic features occasionally characterize the majority or entirety of the PanNET specimen, obscuring the typical neuroendocrine features and suggesting an erroneous diagnosis of either metastasis to the pancreas or a completely different tumor entity. If adequate material is procured, ancillary studies contribute to accurate diagnosis8; however, awareness of rare PanNET variants is requisite to pursuing appropriate ancillary studies. Herein, we report two such cases of potential diagnostic pitfall. The first is a pigmented PanNET mimicking melanoma, and the second is a clear cell PanNET mimicking clear cell carcinomas of pancreatic and extrapancreatic origin. Diagnostic Cytopathology, Vol. 45, No 4
371
Diagnostic Cytopathology DOI 10.1002/dc
RICHMOND AND MEHROTRA
Fig. 1. Coronal image of a CT scan with contrast demonstrating an arterial phase enhancing mass (arrow) within the pancreatic body, representing the pigmented PanNET.
Fig. 2. Coronal image of a CT scan with contrast demonstrating a hyperenhancing mass (arrow) in the pancreatic head and uncinate process, representing the clear cell PanNET.
Case Histories
Materials and Methods
Case One
Aspirate material from each case was evaluated with a rapid Romanowsky stain and Papanicolaou stain. Cell blocks were prepared, and formalin-fixed, paraffin-embedded (FFPE) sections were routinely processed and stained with hematoxylin and eosin (H&E). Immunohistochemical (IHC) studies with appropriate controls for synaptophysin, chromogranin, CD56, and MIB-1/Ki67 were applied to FFPE cell block material of each case. Pancytokeratin (CK), S-100, SOX-10, HMB-45, and MART1 were also evaluated in the first case, while CK7, CK20, CA-IX, Pax-8, RCC, CD10, beta-catenin, and inhibin and special stains for mucin and PAS were also evaluated in the second case (Table I). Representative FFPE sections of the resection specimen (case 1) were routinely processed and stained with H&E. An IHC study for MIB-1/ Ki67 and a special study for Fontana-Masson were applied to representative sections. The anonymity of each patient is maintained, and informed consent and ethics committee approval were not considered necessary for this brief report.
A 66-year-old Caucasian man with a past medical history significant for diabetes mellitus type 2 and Hepatitis C induced cirrhosis was found to have a 13 mm enhancing mass in the body of the pancreas during routine computed tomography (CT) for hepatic surveillance (Fig. 1). The patient was asymptomatic, apart from a recent worsening of diabetes requiring initiation of insulin therapy. Tumor markers, including alpha-fetoprotein, cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), chromogranin-A, and glucagon, were within normal limits. The patient underwent EUS-FNA of the lesion followed by distal pancreatectomy and splenectomy.
Case Two A 51-year-old woman without significant past medical history presented to her primary care physician for hematuria secondary to nephrolithiasis. CT intravenous pyelogram revealed a 7.4 cm heterogeneously enhancing, partially necrotic mass in the head of the pancreas, image characteristics concerning for malignancy. Mass lesions of the genitourinary tract were not seen. A staging CT (Fig. 2) revealed the mass to efface the portal vein and near-circumferentially encase the superior mesenteric artery. Metastases were not identified on imaging. Serum chromogranin-A was elevated to 160 ng/mL (reference range 0–95 ng/mL). Serum CA19-9 and CEA were within normal limits. She subsequently underwent EUS-FNA of the lesion to obtain a diagnosis. 372
Diagnostic Cytopathology, Vol. 45, No 4
Results Case One Light microscopic evaluation of the aspirate material demonstrated a highly cellular lesion present as dispersed individual cells and loose aggregates of cells. The cells contained uniform eccentric nuclei with finely stippled chromatin and moderate amounts of cytoplasm. Brownblack granular pigment was present both within lesional
Diagnostic Cytopathology DOI 10.1002/dc
CYTOLOGY OF PANCREATIC NEUROENDOCRINE TUMOR VARIANTS Table I. Immunohistochemical Results, Reagents, and Titration Results Antibody
Case 1
Synaptophysin Chromogranin-A CD56 MIB-1/Ki67
1 1 (focal) 1
