November is the Pancreatic Cancer Awareness Month. Recognition of the growing prevalence of pancreatic cancer, with the help of foundations and organizations like the Pancreatobiliary Pathology Society, can help direct resources towards research and clinical care efforts. Thursday, November 17 is World Pancreatic Cancer Day – an even more focused opportunity to recognize this disease and the numerous efforts to improve the care of those affected. Please remember to “wear purple” and spread the word.
We, the Pancreatobiliary Pathology Society, send our support to the survivors, their families and to everyone who has lost a loved one to this deadly disease. This is also an opportunity to thank our membership for their dedication to improve the clinical practice and management of pancreatic cancer and to foster tissue-based research.
PBPS, together with PathCast, organized a free 2-day course which was streamed live on January 29-30, 2022 on FaceBook.com/PathCast as well as YouTube.com/pathCast. Here is link of the recorded course videos:
8:00 – 9:20 AM (EST): Intraductal/cystic lesions of the pancreas (40 minute prerecorded didactic powerpoint – Dr Olca Basturk) followed by a 40 minute slide session on Intraductal/cystic lesions of pancreas – Dr David Klimstra); live Q and A at 9:20 AM (15 minutes) – Dr David Klimstra and Dr Olca Basturk
9:40 – 11:10 AM (EST): Neuroendocrine neoplasms of the pancreas and differential diagnosis: (40 minute prerecorded didactic powerpoint) followed by a 40 minute slide session); live Q and A at 11:10 AM (15 minutes) – Dr Stefano LaRosa and Dr Silvia Uccella
January 30th 2022
8:00 – 8:50 AM (EST): Gallbladder and bile duct: 50 minute didactic lecture followed by a 10 minute live Q and A at 8:50 AM – Dr Volkan Adsay
9:00 – 9:50 AM (EST): Cytology of the Bile Duct: 50 minute didactic lecture followed by a 10 minute live Q and A at 9:50 AM – Dr Michelle Reid
10:05 – 11:20 AM (EST):Pancreatic ductal adenocarcinoma and variants (40 minute pre-recorded didactic powerpoint – Dr Laura Wood); Approach to neoadjuvant treated pancreatic ductal adenocarcinoma (40 minute prerecorded didactic powerpoint – Dr Huamin Wang); Live Q and A at 11:20 AM – Dr Laura Wood and Dr Huamin Wang (15 minutes
A 63-year-old male with past medical history that includes hyperparathyroidism presented with ongoing left hip pain. Evaluation of the etiology of his pain revealed an incidental mid-abdominal mass on lumbar spine MRI. A dedicated CT scan confirmed the presence of a solid, well-demarcated ovoid peripancreatic mass measuring 11 cm. A CT-guided needle biopsy was performed.
Macroscopic Description N/A
Microscopic pictures of the biopsy are shown in Figures 1-3. The histologic examination revealed numerous dilated and thin-walled angulated vascular channels distributed in myxoid matrix. Nested around these vessels are clustered epithelioid to spindle- shaped cells with pale, amphophilic cytoplasm and somewhat atypical, vesicular nuclei. Mitotic figures are scarce and there is no necrosis or significant pleomorphism. Immunohistochemical (IHC) analysis was performed on the biopsy. The neoplastic cells were entirely negative for pan-keratin, CAM 5.2, S100, HMB45, Melan-A, SOX10, MDM2, CDK4, ERG, CD34, CD31, SMA, desmin and MITF.
Please select your diagnosis in the poll, then see the answer and the discussion in the links below.
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Educational Objectives and Discussion:
Identify and describe a rare case of peripancreatic paraganglioma, a rare neoplastic disease that presents considerable diagnostic difficulty.
Review the clinicopathological characteristics of peripancreatic paragangliomas.
Discuss differential diagnosis of peripancreatic paragangliomas.
Peripancreatic paragangliomas can be diagnostically challenging on small biopsies due to morphologic overlap with other primary pancreatic tumors (1, 2). In this case, an initial diagnosis of atypical epithelioid and spindle cell neoplasm was made on the biopsy and decision was made to proceed with surgery. Grossly, the resection specimen showed a 11.8 cm purple-red, ovoid, well-circumscribed peripancreatic mass surrounded by a thin fibrous capsule. Cut surface displayed a tan-pink to dark red, variegated focally nodular cut surface with multiple dilated vessels and focal areas of hemorrhage (Figure 4). Microscopic examination of the resection specimen showed neoplastic cells arranged in nests and trabeculae within a prominent vascular network (Figure 5-7). The cells were predominantly round to oval with some spindling and moderate to abundant eosinophilic granular cytoplasm. Additional IHC on the resection specimen showed that the tumor cells labeled with synaptophysin (strong), chromogranin (patchy) and S100 (patchy) and were negative for cytokeratin (Figures 8-10). In areas the S100 labeled in a sustentacular pattern (Figure 10). Succinate dehydrogenase (SDH) A and B were intact. A final diagnosis of paraganglioma was made. Subsequent blood work showed elevated plasma and urine catecholamines and molecular testing showed no targetable mutations. While the tumor was initially described radiographically as being located in the pancreatic head, subsequent imaging demonstrated a peri-pancreatic localization, much more typical of this entity. It can be critical to consider paraganglioma from both the radiographic and pathologic standpoint as repeated needle biopsies may trigger catecholamine surges and care must be taken during surgical interventions.
The classic microscopic features of paragangliomas are similar irrespective of location and include round-to-polygonal-shaped cells containing amphophilic-to-eosinophilic cytoplasm with stippled, often pleomorphic nuclei containing small inconspicuous nucleoli. In certain cases, cytoplasmic clear cell change, multinucleation, vesicular nuclei, and prominent nucleoli can also be observed (1). The tumor cells usually adopt a nested or organoid (“Zellballen”) pattern separated by highly vascularized fibrous septa. Cases with diffuse growth pattern with only focal areas of nested architecture have been reported (1). In areas of parenchymal invasion, the Zellballen growth pattern can be replaced by irregularly spaced nests of discohesive neoplastic cells. The tumor cells are synaptophysin and chromogranin positive while the surrounding sustentacular cells, label for S100. GATA3 and PHOX2B also show frequent immunoreactivity in extra-adrenal paragangliomas (3-5). Keratin is almost always negative, but rare cases have focal staining. In contrast, paragangliomas in the sacral region are typically keratin positive.
The genetic profile of paraganglioma is similar to that described for pheochromocytomas. Mutations in VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX have been reported (6). Knowledge of these mutations may have significant impact on clinical management and patient outcome. For instance, studies have reported germline mutations in SDHB in up to 30% of patients with metastatic disease arising from sporadic paragangliomas and an association with shorter survival (1, 7, 8). Complete surgical resection of primary and metastatic disease, when possible provides the highest chance for symptom control. Currently, there are no reliable markers to predict malignancy, except the presence of metastases. Increasing tumor size (>5 cm), increasing Ki-67 proliferation rate, SDHB mutation, and MAX mutation have been reported as risk factors for metastatic behavior (9, 10). Various scoring systems (PASS, GAPP), have been developed to predict risk in pheochromocytomas and paragangliomas (11, 12). Patients with paragangliomas ultimately require follow-up as metastatic disease can appear years after diagnosis.
The differential diagnosis of peripancreatic paragangliomas includes pancreatic neuroendocrine tumor (PanNET), acinar cell carcinoma (ACC), spindle cell neoplasms, PEComas, and metastatic renal cell carcinoma (RCC).Peripancreatic paragangliomas and PanNET are both neuroendocrine neoplasms thus sharing many of the same characteristics. PanNETs often show distinctive plasmacytoid morphology, usually display round and uniform nuclei and are generally positive for AE1/AE3 and CAM 5.2 while peripancreatic paragangliomas are distinctly negative. Prominent nucleoli typically seen in ACC can be present in peripancreatic paragangliomas. However, the characteristic stippled chromatin of peripancreatic paraganglioma is absent in ACC. The presence of spindle cell morphology/nuclear pleomorphism in peripancreatic paragangliomas can mimic spindle cell neoplasms. These possibilities can usually be distinguished on the basis of immunohistochemistry. Further, the nuclear pleomorphism in paragangliomas typically has a degenerative appearance. Peripancreatic paragangliomas can show cytoplasmic clear cell change thus mimicking metastatic RCCs. However, metastatic RCCs will express PAX8 and are negative for S100 and neuroendocrine markers.
Singhi AD, Hruban RH, Fabre M, Imura J, Schulick R, Wolfgang C, Ali SZ. Peripancreatic paraganglioma: a potential diagnostic challenge in cytopathology and surgical pathology. Am J Surg Pathol. 2011 Oct;35(10):1498-504. doi: 10.1097/PAS.0b013e3182281767. https://pubmed.ncbi.nlm.nih.gov/21921779/
Zeng J, Simsir A, Oweity T, Hajdu C, Cohen S, Shi Y. Peripancreatic paraganglioma mimics pancreatic/gastrointestinal neuroendocrine tumor on fine needle aspiration: Report of two cases and review of the literature. Diagn Cytopathol. 2017 Oct;45(10):947-952. doi: 10.1002/dc.23761. https://pubmed.ncbi.nlm.nih.gov/28560856/
Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, Langfort R, Waloszczyk P, Biernat W, Lasota J, Wang Z. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am Surg Pathol. 2014 Jan;38(1):13-22. doi: 10.1097/PAS.0b013e3182a0218f. https://pubmed.ncbi.nlm.nih.gov/24145643/
Lee JP, Hung YP, O’Dorisio TM, Howe JR, Hornick JL, Bellizzi AM. Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas. Histopathology. 2017 Oct;71(4):503-510. doi: 10.1111/his.13243. https://pubmed.ncbi.nlm.nih.gov/28464318/
So JS, Epstein JI. GATA3 expression in paragangliomas: a pitfall potentially leading to misdiagnosis of urothelial carcinoma. Mod Pathol. 2013 Oct;26(10):1365-70. doi: 10.1038/modpathol.2013.76. https://pubmed.ncbi.nlm.nih.gov/23599157/
Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012 May;44(5):328-33. doi: 10.1055/s-0031-1301302. https://pubmed.ncbi.nlm.nih.gov/22328163/
Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. doi: 10.1210/jc.2006-0423. https://pubmed.ncbi.nlm.nih.gov/16912137/
Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007 Oct;92(10):3822-8. doi: 10.1210/jc.2007-0709. https://pubmed.ncbi.nlm.nih.gov/17652212/
Kimura N, Takayanagi R, Takizawa N, Itagaki E, Katabami T, Kakoi N, Rakugi H, Ikeda Y, Tanabe A, Nigawara T, Ito S, Kimura I, Naruse M; Phaeochromocytoma Study Group in Japan. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014 May 6;21(3):405-14. doi: 10.1530/ERC-13-0494. https://pubmed.ncbi.nlm.nih.gov/24521857/
Assadipour Y, Sadowski SM, Alimchandani M, Quezado M, Steinberg SM, Nilubol N, Patel D, Prodanov T, Pacak K, Kebebew E. SDHB mutation status and tumor size but not tumor grade are important predictors of clinical outcome in pheochromocytoma and abdominal paraganglioma. Surgery. 2017 Jan;161(1):230-239. doi: 10.1016/j.surg.2016.05.050. https://pubmed.ncbi.nlm.nih.gov/27839933/
Kimura N, Takekoshi K, Naruse M. Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine. J Clin Med. 2018. Sep; 7(9): 242. https://pubmed.ncbi.nlm.nih.gov/30150569/
Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002 May;26(5):551-66. doi: 10.1097/00000478-200205000-00002. https://pubmed.ncbi.nlm.nih.gov/11979086/
The PBPath Website/Membership committee is seeking new committee members to join our team, for a term of 3 years. The website/membership team member(s) will help the Pancreatobiliary Pathology Society maintain and expand our membership, post updates to our website, and send newsletters to our members. Experience with WordPress and/or HTML is a plus, but not required.
The ideal candidates possess a willingness to learn and a team-player mentality.
Interested PBPath members should send CV to firstname.lastname@example.org. Successful committee members must be active members of the Pancreatobiliary Pathology Society.
The Pancreatobiliary Pathology Society Executive Committee