November is Pancreatic Cancer Awareness Month, a time dedicated to raising awareness about this deadly disease and advocating for early detection, research, and improved treatment options. During this awareness month, organizations like the Pancreatobiliary Pathology Society, healthcare professionals, and communities come together to educate the public about the risk factors, symptoms, and importance of early diagnosis. By spreading awareness, we can encourage individuals to pay attention to their bodies, recognize potential warning signs, and seek medical advice promptly. Additionally, Pancreatic Cancer Awareness Month serves as a reminder of the urgent need for research funding to develop better diagnostic tools and innovative treatments, ultimately improving the chances of survival for those diagnosed with this devastating disease.
Supporting Pancreatic Cancer Awareness Month also means extending a hand to patients and their families, offering them the emotional and practical support they need. It’s an opportunity for communities to come together to honor the memories of those who have fought or are currently fighting pancreatic cancer. By fostering a sense of unity and understanding, we can work towards a future where pancreatic cancer is diagnosed at an earlier stage, treatments are more effective, and, ultimately, find a cure for this challenging illness.
Also, Thursday, November 16 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.
Olca Basturk, President Pancreatobiliary Pathology Society
The Case of the Quarter (CoQ) Committee for the Pancreatobiliary Pathology Society is seeking six new committee members to join our team for a term of 2 years starting from March 1, 2024.
The CoQ will publish six times each year (January 15th, March 15th, May 15th, July 15th, September 15th and November 15th) on the PBPS website. Every CoQ committee member is responsible for submitting or soliciting at least one case during each year of their term on the CoQ committee. The CoQ members are responsible for the selection, writing, editing, and final submission of an interesting CoQ for publication on PBPS website (https://pbpath.org/). The CoQ is a valued educational tool among our community and a great way to network with others in the field.
Interested PBPath members should send their CV to firstname.lastname@example.org by Friday September 15, 2023. Applicants must be members of the Pancreatobiliary Pathology Society.
We are gearing up for another annual USCAP meeting! Our Companion Society session will be held on Sunday, March 12th from 10:30 AM to 12:30 PM in Great Hall A of the New Orleans Convention Center. The PBPS Annual Business Meeting will immediately follow.
This year’s companion meeting will have two components: Part I will be dedicated to presentations on Interpretation of Small Biopsies and Frozen Sections of the Pancreatobiliary Tract. The chosen topics represent expert evaluations of the full spectrum of small biopsies one may see in practice, from the cytopathologist’s perspective (Dr. Martha Pitman – WHO International Classification System for the Reporting of Pancreatobiliary Cytology Specimens) to their histomorphologic characteristics (Dr. Alyssa Krasinskas – Bile Duct and Ampulla; Dr. Claudio Luchini – Pancreas), and frozen section evaluation (Dr. Wendy Frankel). Part II will be dedicated to an interactive discussion moderated by Drs. Vikram Deshpande and Grace Kim. For this part, we will utilize the PBPath Society Twitter account to post questions in advance (Please keep an eye on our Twitter account https://twitter.com/pbpath for more information on that).
Thanks to the members of the Executive and Education Committees who are dedicated to the growth of our Society and have worked hard to increase our outreach and be impactful, there is more good news:
The PBPath Society, in collaboration with the Chinese American Pathologist Association (CAPA), will participate in the 13th annual Asia Pacific International Academy of Pathology meeting in Malaysia in June, 2023. Ampullary carcinoma (Dr. Volkan Adsay) cholangiocarcinoma (Dr. Seung Mo Hong) and intraductal papillary neoplasms of the bile duct (Dr. Yoh Zen) will be discussed. Additionally, Drs. Alyssa Krasinskas and Barbara Centeno will present our society’s official short course titled “The ABCs to XYZs of Pancreatic Surgical and Cytopathology” at the next annual CAP meeting in October, 2023.
Lastly, if you have not already done so, we would also like to take this opportunity to remind you to renew your membership. We look forward to seeing you all in New Orleans, LA!
Olca Basturk, President Pancreatobiliary Pathology Society
The PBPS is now accepting applications for this year’s PBPS Abstract Award. This award will go to a pathology trainee with an abstract (poster/platform) in pancreatobiliary pathology to be presented at the 2023 USCAP Annual Meeting. Submitted abstracts will be evaluated by the members of Education Committee for originality, scientific merit, and presentation. The selected winner will be notified by email from the Chair of Education Committee and the winner will receive a $500 prize. The qualifications for this award are listed below:
Only abstracts that were accepted for presentation at this year’s annual USCAP meeting are qualified for the PBPS Best Abstract Award.
Only trainees (medical students, residents, or fellows) are qualified for this award. The submitting trainee must be a member of the PBPS. Please note that associate membership in the PBPS is free for trainees. Trainees are strongly encouraged to apply.
The submitting trainee must be first author (except in rare instances in which the trainee may be listed as the senior author).
Trainees will not receive an award if they have won in the prior year. If you are the winner of the PBPS award for last year, then you do not qualify for consideration for the current year.
The deadline for submission of Award applications is 12:00 pm (US Central time) on February 6, 2023.
A 41 y/o male initially presented with nausea, vomiting, epigastric pain and severe diarrhea. Imaging (CT scan and MRI) revealed a 3.9 cm hypervascular mass centered on the pancreatic uncinate process with no evidence of metastatic disease. The imaging findings were concerning for lymphoma or a neuroendocrine tumor. Laboratory studies including amylase, lipase, and CA 19-9 were within normal limits. Endoscopy with fine needle biopsy of the lesion was performed.
The biopsy showed infiltrating neoplastic cells characterized by cytologically bland nuclei and abundant finely vacuolated, clear cytoplasm embedded in a collagenized/fibrotic stroma [Figure 1A/B]. No necrosis or mitotic figures were identified. The remainder of the biopsy material showed unremarkable pancreatic parenchyma and reactive lymphoid tissue.
Please select your diagnosis in the poll, then see the answer and the discussion in the links below.
Identify and describe the histologic features of lipid rich variant of PanNET
Review the clinical implications of a diagnosis of lipid rich variant of PanNET
Discuss the differential diagnosis for lipid rich variant of PanNET
Discussion Immunohistochemical stains were performed on the biopsy material. The neoplastic cells were positive for pan-CK (strong and diffuse), synaptophysin (strong and diffuse) [Figure 2], chromogranin (strong but focal) and inhibin (strong and diffuse) while negative for CK7, RCC, PAX-8, S-100, Melan-A (MART-1), and beta catenin. A MIB-1 (Ki-67) stain showed a low proliferation index (<3%). A diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 1, lipid rich variant was rendered.
The patient subsequently underwent surgical resection (pancreaticoduodenectomy). Sectioning of the pancreas revealed a tan-white to tan-yellow, stellate, firm, fibrous mass measuring 4.0 cm in greatest dimension. The microscopic and immunophenotypic features of the tumor in the resection specimen mirrored those of the biopsy material. Sections showed neoplastic cells arranged in nests/clusters and cords, surrounded by marked collagenized/fibrotic stroma [Figure 3]. The tumor cells demonstrated clear/foamy vacuolated cytoplasm and small uniform nuclei with finely dispersed chromatin [Figure 4]. Mitotic figures were virtually absent. The MIB-1 (Ki-67) stain was repeated on the resection specimen and showed a proliferation index of 5-7% in hot spots. A final diagnosis of well-differentiated pancreatic neuroendocrine tumor, Grade 2, lipid rich variant was rendered
PanNET with vacuolated, lipid rich cytoplasm was first described in 1997 by Ordonez and Silva . Singh et al and Xue et al’s series on PaNET variant cases both offered additional valuable contributions to the literature [2,3]. The lipid rich variant affects both men and women and can occur in the head or tail of the pancreas, ranging in size from 2-11 cm. Microscopically, this variant represents a diagnostic challenge (see differential diagnosis section). The prototypical neuroendocrine growth pattern may be absent. The cytologic features are deceptively bland; tumor cells are characterized by round to pyknotic nuclei with fine chromatin and inconspicuous nucleoli. The classic stippled “salt and pepper” chromatin may not be evident. Nuclear “endocrine” atypia is also not identified. The cytoplasm is not only clear but also finely vacuolated; lipid droplets and neuroendocrine secretory granules can be identified ultrastructurally with electron microscopy. Mitotic activity is absent to low and MIB-1 (Ki-67) staining usually does not exceed 5% based on published data [2,3]. Given how unusual these histologic features are compared to a typical low grade neuroendocrine tumor, immunohistochemical stains are an essential adjunct aid. The neoplastic cells routinely express pan-cytokeratin and neuroendocrine markers chromogranin and synaptophysin (focal to diffuse staining). Inhibin and HIF-1α staining can be seen in a subset of tumors, while Melan-A (MART-1) and MUC6 expression is absent . Xue et al. include the lipid rich variant in the “aggressive variant group” alongside hepatoid, oncocytic, plasmacytoid, and discohesive variants due to propensity for greater tumor size, T-stage, metastases, and progression rates . Furthermore, patients with lipid rich PanNET fall into one of two categories: younger patients with familial/functional/syndromic tumors (rare) and older patients with non-functioning/sporadic tumors (common). While inhibin, HIF-1α, and Melan-A (MART-1) expression by immunohistochemistry in clear cell PanNET has a strong association with von Hippel Lindau (VHL) disease, this correlation is less robust in lipid rich PaNET [2,4]. Regardless, it may still be prudent for clinicians to exclude VHL disease or MEN1 (multiple endocrine neoplasia type 1) syndrome as lipid rich PaNETs have rarely been reported in these patients .
The pathologist should keep a broad differential diagnosis in mind when approaching a low-grade pancreatic lesion with clear/vacuolated cytoplasm: Clear cell PanNET: PanNET with clear cell change are not uncommon and have a strong association with VHL disease, particularly when HIF-1α, inhibin, and/or Melan-A (MART-1) expression by immunohistochemistry is seen in addition to traditional neuroendocrine markers. VHL-associated clear cell PanNETs usually occur in younger women and are non-functioning tumors [4-7]. While the cytoplasm is clear, it lacks the vacuolated/microvesicular appearance of lipid rich PanNET. Solid pseudopapillary neoplasm (SPN): SPNs are uniquely characterized by pseudopapilla, nuclear grooves, and hyaline globules. SPNs can exhibit clear cytoplasm and frequently contain foamy macrophages, and therefore could appear similar to lipid rich PanNET in small biopsy specimens. While SPNs can express synaptophysin, chromogranin is usually negative. More importantly, nuclear staining of the neoplastic cells with beta catenin is a key diagnostic clue for the diagnosis of SPN, reflecting underlying mutations in CTNNB1 . Additionally, these tumors most commonly occur in adolescent girls/young women under the age of 35 and arise most frequently in the body or tail of the pancreas. Perivascular epithelioid cell tumor (PEComa or so called “sugar tumor”): PEComas are rare mesenchymal neoplasms with myomelanocytic differentiation. The tumors grow in sheets or nests and are characterized by epithelioid cells with clear to eosinophilic, granular cytoplasm, which has a moth-eaten appearance (“spider cells”) with a spindle cell component present in a minority of cases. Co-expression of smooth muscle markers (SMA, desmin, h-caldesmon) and melanoma markers (e.g. Melan-A/MART-1, HMB45) is characteristic. Neuroendocrine labeling and strong and diffuse keratin expression is notably absent . Morphologic patterns of pancreatic ductal adenocarcinoma: While pancreatic ductal carcinoma typically shows significant cytologic atypia and has a uniquely infiltrating gland-forming growth pattern accompanied by a desmoplastic stromal response, certain morphologic patterns can appear deceptively bland and lack gland formation. The foamy gland and clear cell patterns of invasive ductal adenocarcinoma of the pancreas both are included in this category. Helpful distinguishing characteristics from lipid rich PanNET include gland formation, possible presence of mucin and the lack of neuroendocrine marker expression. Additionally, PanNETs most often present as well-circumscribed lesion on imaging/EUS/gross examination, as opposed to the poorly-defined, infiltrative growth pattern seen with ductal adenocarcinomas . Adrenal cortical tissue/neoplasm: Adrenal cortical tissue/neoplasms share many overlapping histopathologic features with lipid rich PanNET and immunohistochemistry can be a helpful aid. Adrenal cortical lesions mark with antibodies to SF-1, calretinin, inhibin, Melan-A (MART-1), and CD68 . Adrenal cortical lesions however lack keratin and neuroendocrine marker positivity. Please note, that inhibin expression (as in our case) can be seen in a subset of lipid rich PanNET; therefore, a broad panel of stains is essential. Clear cell renal cell carcinoma (ccRCC): ccRCC should always be considered when encountering pancreatic lesions with “clear” cytoplasm. Renal cell carcinoma is in fact the most common reason for a metastasis to the pancreas. While PAX-8 is a helpful ancillary screening marker used for renal cell carcinoma, it is important to note that PanNET can also express PAX-8 . Therefore, additional antibodies such as RCC and CD10 (for renal cell carcinoma) and synaptophysin and chromogranin (for PaNET) should be included as part of the larger panel of stains.
 Ordonez NG, Silva EG. “Islet cell tumor with vacuolated, lipid rich cytoplasm: a new histologic variant of islet cell tumor.” Histopathology 1997; 31:157-160.  Singh R, Reid MD et al. “Lipid-rich variant of pancreatic endocrine neoplasms.” Am J Surg Pathol 2006; 30:194-200.  Xue Y. et al “Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognodtic stratification.” Endocr Pathol 2020 31:3, 239-253.  Hoang MP, Hruban RH et al. “Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel Lindau disease.” Am J Surg Pathol 2001; 25:602-609.  Guarda LA, Silva EG et al. “Clear cell islet cell tumor.” Am J Surg Pathol 1983; 79:512-517.  Mount SL, Weaver DL et al. “Von Hippel Lindau disease presenting as a pancreatic neuroendocrine tumor.” Virchows Arch 1995; 426:523-528  Musso C, Paraf F. et al. “Pancreatic neuroendocrine tumors and von Hippel Lindau disease” Ann Pathol. 2000; 20:130-133.  Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, Washington KM, Carneiro F, Cree IA; WHO Classification of Tumours Editorial Board. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020 Jan; 76(2):182-188. doi: 10.1111/his.13975. Epub 2019 Nov 13. PMID: 31433515; PMCID: PMC7003895.  Sangoi A., Fujiwara M et al. “Immunohistochemical Distinction of Primary Adrenal Cortical Lesions from Metastatic Clear Cell Renal Cell Carcinoma: A Study of 248 Cases.” Am J Surg Pathol 2011; 35(5): 678-686.  Bellizi AM “Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: wat can brown do for you?” Hum Pathol 2020; 96:8-33.
Case contributed by:
Susanne K. Jeffus, MD – University of Arkansas for Medical Sciences Camila Simoes, MD – University of Arkansas for Medical Sciences Felicia D. Allard, MD – University of Arkansas for Medical Sciences
Special thanks to David Klimstra, MD, of Memorial Sloan Kettering Cancer Center for his consultative expertise.
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
November is Pancreas Cancer Awareness Month, and today (Thursday, November 18) is World Pancreatic Cancer Day, when “loved ones, communities and organizations around the world unite to shine a light on pancreatic cancer” (World Pancreatic Cancer Day) specifically to raise awareness of the disease and its presenting symptoms, in hopes for earlier detection and a greater possibility of survival. Please take this opportunity to reflect on our PBPS’s efforts to enhance collaboration, stimulate research, and disseminate knowledge about pancreatic and biliary diseases – wear purple! And tell your colleagues, friends, and associates about what we are doing to help combat pancreatic cancer. PBPS members have an understanding of these diseases (plural intended) that provides a vital context for clinical and basic researchers, so engagement of pathologists in the study of pancreatic neoplasia is a key to success. I know I am preaching to the choir here, but we need to actively (aggressively) engage with other researchers to ensure our impact is contributed!
There are many updates from the leadership of our Society. We have enhanced our website with additional content, including the ongoing “Case of the Quarter” feature, led by Dr. Elizabeth Thompson and our new “Challenging Case” content, which will allow the posting of whole slide images of truly challenging or controversial cases to enable members to contribute their comments about the findings. This feature is led by Dr. Rondell Graham and will establish an interesting dialog about these diagnostic conundrums.
In other news, the Grossing Working Group, led by Dr. Grace Kim and Dr. Daniela Allende, published a paper in Am J Surg Pathol recently detailing their recommendations for grossing pancreatic specimens, entitled Towards a More Standardized Approach to Pathologic Reporting of Pancreatoduodenectomy Specimens for Pancreatic Ductal Adenocarcinoma: Cross-continental and Cross-specialty Survey from the Pancreatobiliary Pathology Society Grossing Working Group (PMID 33899890; https://pubmed.ncbi.nlm.nih.gov/33899790/). This paper will hopefully help standardize our approach to these challenging specimens, and I congratulate the members of this working group.
Members of the PBPS are also participating in a number of courses. Drs. Olca Basturk and Michelle Reid presented a session at the CAP annual meeting on September 28 entitled EUS-Guided and “SpyBite” Biopsies of Pancreatic and Biliary Tract Lesions (FNA versus Biospy), which explored the relative utility of different diagnostic approaches to pancreatic lesions. Soon there will also be a PathCast course organized with the PBPS, which will be a FREE 2 day online course, aired on January 29-30, 2022. Details on the content and how to attend will be sent soon!
Finally, we are eagerly anticipating the next USCAP meeting, which is scheduled to be an in-person event, happily. In addition to the PBPS Companion Meeting, there promises to be multiple presentations and courses on pancreatobiliary pathology, and details will be provided in another missive early in the new year. For now, please remind your trainees about the PBPS abstract prize for USCAP submissions on pancreatobiliary topics. The prize is for trainees only and comes with a $500 cash award and the opportunity to be honored at the Companion Society meeting and photographed with me (booster stool will be provided). The deadline to submit abstracts for consideration is February 1, 2022, and they should be emailed to Dr. Michell Reid, Chair of the Education Committee (email@example.com).
I will write again with more updates soon. Thank you for your participation in the PBPS; with your help we are succeeding in bringing these important topics to center stage in the pathology community, and the response and impact has already been tremendous!
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.
Click Here To See The Answer
Click Here To See The Discussion
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/