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Amyloid-Rich Pancreatic Neuroendocrine Tumors: a Potential Diagnostic Pitfall in Endoscopic Ultrasound–Guided Fine Needle Aspiration Cytology (EUS-FNAC)

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Abstract

Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms that include even rarer variants that may pose different diagnostic problems, especially in fine needle aspiration cytology (FNAC). We describe the diagnostic clues of the amyloid-rich variant of PanNETs in endoscopic ultrasound (EUS)–guided fine needle aspiration cytology (EUS-FNAC). Three cases of PanNETs with an amyloid-rich stromal component were retrieved and retrospectively reviewed. For every case, the pancreatic lesion was investigated by a EUS-FNAC procedure. The final diagnosis was supported by immunocytochemistry and Congo red staining. All cases had similar EUS-FNAC features: neoplastic cells were entrapped in an eosinophilic, homogeneous dense and amorphous matrix. The neuroendocrine nature was confirmed by immunoexpression of synaptophysin and chromogranin A, while the amorphous stroma was characterized as amyloid based on positive Congo red staining. Regarding the hormonal profile, no insulin or proinsulin reactivity was observed, but all cases were diffusely positive for amylin. The diagnosis of uncommon variants of PanNETs, such as the amyloid-rich, is challenging especially in EUS-FNAC procedures because of a unique and misleading morphology, potentially mimicking fibrotic conditions and amyloid deposition within systemic amyloidosis. In cytology specimens, the presence of amorphous material requires amyloid deposition to be considered in the differential diagnosis of pancreatic neoplasms with neuroendocrine phenotype.

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Data Availability

The datasets generated and/or analyzed during the current study are not publicly available due to privacy reasons but are available from the corresponding author on reasonable request.

References

  1. Paquin SC, Sahai AV (2014) Techniques for EUS-guided FNA cytology. Gastrointest Endosc Clin N Am 24 (1):71-81. doi:https://doi.org/10.1016/j.giec.2013.08.007

    Article  PubMed  Google Scholar 

  2. Saxena P, El Zein M, Stevens T, Abdelgelil A, Besharati S, Messallam A, Kumbhari V, Azola A, Brainard J, Shin EJ, Lennon AM, Canto MI, Singh VK, Khashab MA (2018) Stylet slow-pull versus standard suction for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic lesions: a multicenter randomized trial. Endoscopy 50 (5):497-504. doi:https://doi.org/10.1055/s-0043-122381

    Article  PubMed  Google Scholar 

  3. Wang Y, Chen Q, Wang J, Wu X, Duan Y, Yin P, Guo Q, Hou W, Cheng B (2018) Comparison of modified wet suction technique and dry suction technique in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for solid lesions: study protocol for a randomized controlled trial. Trials 19 (1):45. doi:https://doi.org/10.1186/s13063-017-2380-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Turner BG, Cizginer S, Agarwal D, Yang J, Pitman MB, Brugge WR (2010) Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy. Gastrointest Endosc 71 (1):91-98. doi:https://doi.org/10.1016/j.gie.2009.06.017

    Article  PubMed  Google Scholar 

  5. Pitman MB, Centeno BA, Ali SZ, Genevay M, Stelow E, Mino-Kenudson M, Castillo CF, Schmidt CM, Brugge WR, Layfield LJ (2014) Standardized terminology and nomenclature for pancreatobiliary cytology: The Papanicolaou Society of Cytopathology Guidelines. Cytojournal 11 (Suppl 1):3. doi:https://doi.org/10.4103/1742-6413.133343

    Article  PubMed  PubMed Central  Google Scholar 

  6. Chen S, Lin J, Wang X, Wu HH, Cramer H (2014) EUS-guided FNA cytology of pancreatic neuroendocrine tumour (PanNET): a retrospective study of 132 cases over an 18-year period in a single institution. Cytopathology 25 (6):396-403. doi:https://doi.org/10.1111/cyt.12137

    Article  CAS  PubMed  Google Scholar 

  7. Jarboe EA, Layfield LJ (2011) Cytologic features of pancreatic intraepithelial neoplasia and pancreatitis: potential pitfalls in the diagnosis of pancreatic ductal carcinoma. Diagn Cytopathol 39 (8):575-581. doi:https://doi.org/10.1002/dc.21430

    Article  PubMed  Google Scholar 

  8. Fujii LL, Levy MJ (2014) Pitfalls in EUS FNA. Gastrointest Endosc Clin N Am 24 (1):125-142. doi:https://doi.org/10.1016/j.giec.2013.08.003

    Article  PubMed  Google Scholar 

  9. Samad A, Attam R, Jessurun J, Pambuccian SE (2014) Psammoma bodies and abundant stromal amyloid in an endoscopic ultrasound guided fine needle aspirate (EUS-FNA) of a pancreatic neuroendocrine tumor: a potential pitfall. Diagn Cytopathol 42 (9):766-771. doi:https://doi.org/10.1002/dc.22975

    Article  PubMed  Google Scholar 

  10. Richmond AM, Mehrotra S (2017) Two unusual variants of pancreatic neuroendocrine tumor and their potential pitfalls on fine-needle aspiration cytology. Diagn Cytopathol 45 (4):371-378. doi:https://doi.org/10.1002/dc.23662

    Article  PubMed  Google Scholar 

  11. Jahan A, Yusuf MA, Loya A (2015) Fine-Needle Aspiration Cytology in the Diagnosis of Pancreatic Neuroendocrine Tumors: A Single-Center Experience of 25 Cases. Acta Cytol 59 (2):163-168. doi:https://doi.org/10.1159/000381173

    Article  CAS  PubMed  Google Scholar 

  12. Klöppel G, Couvelard A, Hruban RH, Klimstra DS, Komminoth P, Osamura RY, Perren A, Rindi G (2017) Neoplasms of the neuroendocrine pancreas. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) WHO classification of tumours of endocrine organs, 4th edn. IARC press, Lyon, pp 209-234

    Google Scholar 

  13. Diaz Del Arco C, Diaz Perez JA, Ortega Medina L, Sastre Valera J, Fernandez Acenero MJ (2016) Reliability of Ki-67 Determination in FNA Samples for Grading Pancreatic Neuroendocrine Tumors. Endocr Pathol 27 (4):276-283. doi:https://doi.org/10.1007/s12022-016-9455-2

    Article  CAS  PubMed  Google Scholar 

  14. Blank A, Schmitt A, Perren A (2015) Pathology: Classification and Immunoprofile. Front Horm Res 44:104-114. doi:https://doi.org/10.1159/000382135

    Article  PubMed  Google Scholar 

  15. Grillo F, Valle L, Ferone D, Albertelli M, Brisigotti MP, Cittadini G, Vanoli A, Fiocca R, Mastracci L (2017) KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment? Endocrine 57 (3):494-502. doi:https://doi.org/10.1007/s12020-017-1364-8

    Article  CAS  PubMed  Google Scholar 

  16. Uccella S, La Rosa S, Volante M, Papotti M (2018) Immunohistochemical Biomarkers of Gastrointestinal, Pancreatic, Pulmonary, and Thymic Neuroendocrine Neoplasms. Endocr Pathol 29 (2):150-168. doi:https://doi.org/10.1007/s12022-018-9522-y

    Article  PubMed  Google Scholar 

  17. Pacchioni D, Papotti M, Macri L, Forte G, Bussolati G (1996) Pancreatic oncocytic endocrine tumors. Cytologic features of two cases. Acta Cytol 40 (4):742-746. doi:https://doi.org/10.1159/000333950

    Article  CAS  PubMed  Google Scholar 

  18. Naringrekar H, Vogel A, Prestipino A, Shahid H (2017) Imitators of chronic pancreatitis: diffuse neuroendocrine tumour of the pancreas. BJR Case Rep 3 (4):20170015. doi:https://doi.org/10.1259/bjrcr.20170015

    Article  PubMed  PubMed Central  Google Scholar 

  19. Komminoth P, Heitz PU, Roth J (1999) Human Insulinomas: Clinical, Cellular, and Molecular Aspects. Endocr Pathol 10 (4):269-281. doi:https://doi.org/10.1007/bf02739769

    Article  CAS  PubMed  Google Scholar 

  20. Hackeng WM, Schelhaas W, Morsink FHM, Heidsma CM, van Eeden S, Valk GD, Vriens MR, Heaphy CM, Nieveen van Dijkum EJM, Offerhaus GJA, Dreijerink KMA, Brosens LAA (2020) Alternative Lengthening of Telomeres and Differential Expression of Endocrine Transcription Factors Distinguish Metastatic and Non-metastatic Insulinomas. Endocr Pathol. doi:https://doi.org/10.1007/s12022-020-09611-8

  21. Krishna SG, Bhutani MS, Mosher CH, Staerkel GA, Weston BR (2013) A first report of endoscopic ultrasound for the diagnosis of pancreatic amyloid deposition in immunoglobulin light chain (AL) amyloidosis (primary amyloidosis). JOP 14 (3):283-285. doi:https://doi.org/10.6092/1590-8577/1505

    Article  PubMed  PubMed Central  Google Scholar 

  22. Joachim CL, Mori H, Selkoe DJ (1989) Amyloid beta-protein deposition in tissues other than brain in Alzheimer’s disease. Nature 341 (6239):226-230. doi:https://doi.org/10.1038/341226a0

    Article  CAS  PubMed  Google Scholar 

  23. Sipe JD, Cohen AS (2000) Review: history of the amyloid fibril. J Struct Biol 130 (2-3):88-98. doi:https://doi.org/10.1006/jsbi.2000.4221

    Article  CAS  PubMed  Google Scholar 

  24. Tharp WG, Sarkar IN (2013) Origins of amyloid-beta. BMC Genomics 14:290. doi:https://doi.org/10.1186/1471-2164-14-290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Greenwald J, Riek R (2010) Biology of amyloid: structure, function, and regulation. Structure 18 (10):1244-1260. doi:https://doi.org/10.1016/j.str.2010.08.009

    Article  CAS  PubMed  Google Scholar 

  26. Bardin RL, Barnes CE, Stanton CA, Geisinger KR (2004) Soft tissue amyloidoma of the extremities: a case report and review of the literature. Arch Pathol Lab Med 128 (11):1270-1273. doi:https://doi.org/10.1043/1543-2165(2004)128<1270:STAOTE>2.0.CO;2

    Article  PubMed  Google Scholar 

  27. Elkins CT, Scharschmidt TJ, Wakely PE, Jr. (2012) Amyloidomas of soft parts: diagnosis by fine-needle aspiration. Diagn Cytopathol 40 Suppl 2:E126-130. doi:https://doi.org/10.1002/dc.22844

    Article  PubMed  Google Scholar 

  28. Falconi M, Bartsch DK, Eriksson B, Kloppel G, Lopes JM, O'Connor JM, Salazar R, Taal BG, Vullierme MP, O’Toole D, Barcelona Consensus Conference p (2012) ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 95 (2):120-134. doi:https://doi.org/10.1159/000335587

  29. Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, Kos-Kudla B, Kwekkeboom D, Rindi G, Kloppel G, Reed N, Kianmanesh R, Jensen RT, Vienna Consensus Conference p (2016) ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 103 (2):153-171. doi:https://doi.org/10.1159/000443171

  30. Holzer K (2018) Surgical strategies for small sporadic neuroendocrine pancreatic tumors. Chirurg 89 (6):422-427. doi:https://doi.org/10.1007/s00104-018-0632-3

    Article  CAS  PubMed  Google Scholar 

  31. Akirov A, Larouche V, Alshehri S, Asa SL, Ezzat S (2019) Treatment Options for Pancreatic Neuroendocrine Tumors. Cancers (Basel) 11 (6). doi:https://doi.org/10.3390/cancers11060828

  32. Farchoukh L, Pantanowitz L, Xing J, Monaco SE (2019) Azzopardi Phenomenon Associated with Small Cell Carcinoma. Diagn Cytopathol 47 (8):837-838. doi:https://doi.org/10.1002/dc.24188

    Article  PubMed  Google Scholar 

  33. Halliday BE, Silverman JF, Finley JL (1998) Fine-needle aspiration cytology of amyloid associated with nonneoplastic and malignant lesions. Diagn Cytopathol 18 (4):270-275. doi:https://doi.org/10.1002/(sici)1097-0339(199804)18:4<270::aid-dc4>3.0.co;2-g

    Article  CAS  PubMed  Google Scholar 

  34. Michael CW, Naylor B (1999) Amyloid in cytologic specimens. Differential diagnosis and diagnostic pitfalls. Acta Cytol 43 (5):746-755. doi:https://doi.org/10.1159/000331286

    Article  CAS  PubMed  Google Scholar 

  35. Bartow SA, Mukai K, Rosai J (1981) Pseudoneoplastic proliferation of endocrine cells in pancreatic fibrosis. Cancer 47 (11):2627-2633. doi:https://doi.org/10.1002/1097-0142(19810601)47:11<2627::aid-cncr2820471118>3.0.co;2-c

    Article  CAS  PubMed  Google Scholar 

  36. Stelow EB, Bardales RH, Lai R, Mallery S, Linzie BM, Crary GS, Stanley MW (2005) The cytological spectrum of chronic pancreatitis. Diagn Cytopathol 32 (2):65-69. doi:https://doi.org/10.1002/dc.20160

    Article  PubMed  Google Scholar 

  37. Detlefsen S, Kloppel G (2018) IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis. Virchows Arch 472 (4):545-556. doi:https://doi.org/10.1007/s00428-017-2275-z

    Article  CAS  PubMed  Google Scholar 

  38. Chatzipantelis P, Salla C, Konstantinou P, Karoumpalis I, Sakellariou S, Doumani I (2008) Endoscopic ultrasound-guided fine-needle aspiration cytology of pancreatic neuroendocrine tumors: a study of 48 cases. Cancer 114 (4):255-262. doi:https://doi.org/10.1002/cncr.23637

    Article  PubMed  Google Scholar 

  39. Ling W, Huang YM, Qiao YC, Zhang XX, Zhao HL (2019) Human Amylin: From Pathology to Physiology and Pharmacology. Curr Protein Pept Sci 20 (9):944-957. doi:https://doi.org/10.2174/1389203720666190328111833

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. A. Gambella and E. C. Falco contributed equally to this work.

Authors and Affiliations

  1. Division of Pathology, Città della Salute e della Scienza Hospital, Turin, Italy

    Alessandro Gambella, Enrico Costantino Falco, Francesca Maletta & Donatella Pacchioni

  2. Department of Oncology, University of Turin, Turin, Italy

    Jasna Metovic & Mauro Papotti

  3. Division of Gastroenterology, Città della Salute e della Scienza Hospital, Turin, Italy

    Claudio De Angelis

  4. Department of Medicine and Surgery, University of Insubria, Varese, Italy

    Roberta Maragliano & Silvia Uccella

  5. Anatomia Patologica, Università di Torino, Via Santena 7, I-10126, Torino, Italy

    Mauro Papotti

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  1. Alessandro Gambella
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Contributions

Conceptualization: Papotti Mauro, Pacchioni Donatella

Data collection and curation: Gambella Alessandro, Falco Enrico Costantino, Metovic Jasna, Maletta Francesca, De Angelis Claudio, Maragliano Roberta, Uccella Silvia, Pacchioni Donatella, Papotti Mauro

Writing—original draft: Gambella Alessandro, Falco Enrico Costantino

Supervision: Papotti Mauro

All authors edited, reviewed, and approved the manuscript.

Corresponding author

Correspondence to Mauro Papotti.

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The authors declare that they have no conflict of interest.

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The study was conducted in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) and of the University of Turin.

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Gambella, A., Falco, E.C., Metovic, J. et al. Amyloid-Rich Pancreatic Neuroendocrine Tumors: a Potential Diagnostic Pitfall in Endoscopic Ultrasound–Guided Fine Needle Aspiration Cytology (EUS-FNAC). Endocr Pathol 32, 318–325 (2021). https://doi.org/10.1007/s12022-020-09625-2

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