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Tuberous sclerosis complex mutations in patients with pancreatic neuroendocrine tumors. Observations on phenotypic and treatment-related associations

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Abstract

Pancreatic neuroendocrine tumors (PanNETs) in familial tuberous sclerosis (TSC1 and TSC2 mutations) have been known and studied. However, little is known about PanNET patients harboring the very rare (less than 2%) sporadic TSC mutations. Some renal tumors have been shown to harbor sporadic TSC mutations, with a distinctive morphological correlate. We hereby describe this rather unusual molecular alteration in well-differentiated pancreatic neuroendocrine tumors (WD PanNETs) with a focus on their morphology and treatment outcomes. Six cases of WD PanNETs harboring sporadic TSC mutations were identified retrospectively. H&E slides and corresponding immunostains were reviewed for all cases. Clinical, molecular, and radiological information was obtained using the electronic medical records. Cohort consisted of 4 males and 2 females. Median age at diagnosis was 50 years (range 33–74 years). Origin of neoplasm was the pancreas and, in all but one, patient had liver metastasis by the time of presentation. Six out of six cases demonstrated a unique tumor morphology, with ample eosinophilic cytoplasm. Tumors were arranged in sheets and nests; prominent cystic change was noted in one case. Two cases were additionally biopsied post-treatment with capecitabine and temozolomide, and showed even more abundant oncocytic cytoplasm, eccentric nuclei, and a prominent cherry red nucleolus, and were arranged in a cluster of 3–4 cells, separated by stromal cells. Every patient had a different TSC2 variant with no cases of TSC1 mutations. Other common variants included MEN1 (4/6), DAXX (2/6), and TP53 (2/6). Per the WH0 2019 classification, tumors were graded as NET-G3 (n = 3) and NET-G2 (n = 3). Ki-67 s ranged from 7.2 to 60. All cases had retained MMR protein expression. The majority of patients (4/6) have expired. Although they received multiple treatments, a consistent pattern observed in patients was marked radiologic response to chemotherapy with capecitabine and temozolomide (offered in 5/6 patients) with duration of responses reaching 11 months in the majority of cases, with one patient showing near complete pathologic response of localized disease. TSC2 mutations may confer distinctive appearance in WD PanNETs, reminiscent of their effects in renal tumors. Although not entirely specific, this distinct morphological pattern with abundant eosinophilic cytoplasm in WD PanNETs could be reflective of an associated TSC mutation, with suggestions of significant therapeutic response to a specific cytotoxic chemotherapy.

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References

  1. Dasari A, Shen C, Halperin D et al (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 3(10):1335–1342. https://doi.org/10.1001/jamaoncol.2017.0589

    Article  PubMed  PubMed Central  Google Scholar 

  2. Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE (2021) Pancreatic neuroendocrine tumors: molecular mechanisms and therapeutic targets. Cancers (Basel) 13(20). https://doi.org/10.3390/cancers13205117

  3. Jensen RT, Berna MJ, Bingham DB, Norton JA (2008) Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 113(7 Suppl):1807–1843. https://doi.org/10.1002/cncr.23648

    Article  PubMed  Google Scholar 

  4. Sreenarasimhaiah J, Armstrong LA, Tang SJ, Barnett C (2009) Pancreatic somatostatinoma and tuberous sclerosis: case report of an exceedingly rare association. Gastrointest Endosc 69(2):379–381. https://doi.org/10.1016/j.gie.2008.04.057

    Article  PubMed  Google Scholar 

  5. Merritt JL 2nd, Davis DM, Pittelkow MR, Babovic-Vuksanovic D (2006) Extensive acrochordons and pancreatic islet-cell tumors in tuberous sclerosis associated with TSC2 mutations. Am J Med Genet A 140(15):1669–1672. https://doi.org/10.1002/ajmg.a.31351

    Article  PubMed  Google Scholar 

  6. Francalanci P, Diomedi-Camassei F, Purificato C et al (2003) Malignant pancreatic endocrine tumor in a child with tuberous sclerosis. Am J Surg Pathol 27(10):1386–1389. https://doi.org/10.1097/00000478-200310000-00012

    Article  PubMed  Google Scholar 

  7. Eledrisi MS, Stuart CA, Alshanti M (2002) Insulinoma in a patient with tuberous sclerosis: is there an association? Endocr Pract Mar-Apr 8(2):109–112. https://doi.org/10.4158/EP.8.2.109

    Article  Google Scholar 

  8. Verhoef S, van Diemen-Steenvoorde R, Akkersdijk WL et al (1999) Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur J Pediatr 158(4):284–287. https://doi.org/10.1007/s004310051073

    Article  CAS  PubMed  Google Scholar 

  9. Boubaddi NE, Imbert Y, Tissot B, et al 1997 [Secreting insulinoma and Bourneville’s tuberous sclerosis]. Gastroenterol Clin Biol 21(4):343. Insulinome secretant et sclerose tubereuse de Bourneville

  10. Larson AM, Hedgire SS, Deshpande V et al (2012) Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex. Clin Genet 82(6):558–563. https://doi.org/10.1111/j.1399-0004.2011.01805.x

    Article  CAS  PubMed  Google Scholar 

  11. Park R. Chatterjee D AM, Trikalinos N (2020) Exceptional response to neoadjuvant capecitabine and temozolomide in TSC2-mutant pancreatic neuroendocrine tumor. Current Problems in Cancer: Case Reports 2(15). https://doi.org/10.1016/j.cpccr.2020.100037

  12. Tate JG, Bamford S, Jubb HC et al (2019) COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res 47(D1):D941–D947. https://doi.org/10.1093/nar/gky1015

    Article  CAS  PubMed  Google Scholar 

  13. Reyna-Fabian ME, Hernandez-Martinez NL, Alcantara-Ortigoza MA et al (2020) First comprehensive TSC1/TSC2 mutational analysis in Mexican patients with tuberous sclerosis complex reveals numerous novel pathogenic variants. Sci Rep 10(1):6589. https://doi.org/10.1038/s41598-020-62759-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xue Y, Reid MD, Pehlivanoglu B et al (2020) Morphologic variants of pancreatic neuroendocrine tumors: clinicopathologic analysis and prognostic stratification. Endocr Pathol 31(3):239–253. https://doi.org/10.1007/s12022-020-09628-z

    Article  CAS  PubMed  Google Scholar 

  15. Arva NC, Pappas JG, Bhatla T et al (2012) Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis–case report and review of the literature. Am J Surg Pathol 36(1):149–153. https://doi.org/10.1097/PAS.0b013e31823d0560

    Article  PubMed  Google Scholar 

  16. Mehta S, Rusyn L, Ginsburg H, Hajdu C, Kohn B (2019) Pancreatic neuroendocrine tumor in a young child with tuberous sclerosis complex 1. J Endocr Soc 3(6):1201–1206. https://doi.org/10.1210/js.2019-00051

    Article  PubMed  PubMed Central  Google Scholar 

  17. Klimstra DS, Beltran H, Lilenbaum R, Bergsland E (2015) The spectrum of neuroendocrine tumors: histologic classification, unique features and areas of overlap. Am Soc Clin Oncol Educ Book 92–103. https://doi.org/10.14694/EdBook_AM.2015.35.92

  18. Jiao Y, Shi C, Edil BH et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331(6021):1199–1203. https://doi.org/10.1126/science.1200609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hackeng WM, Brosens LAA, Kim JY et al (2022) Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size. Gut 71(5):961–973. https://doi.org/10.1136/gutjnl-2020-322595

    Article  CAS  PubMed  Google Scholar 

  20. Marinoni I, Kurrer AS, Vassella E et al (2014) Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 146(2):453–60 e5. https://doi.org/10.1053/j.gastro.2013.10.020

    Article  CAS  PubMed  Google Scholar 

  21. Zhang MY, He D, Zhang S, Liu JY (2022) Genetic alterations of both MEN1/ATRX and TP53/RB1 in pancreatic neuroendocrine neoplasms. Pancreas 51(6):e91–e93. https://doi.org/10.1097/MPA.0000000000002091

    Article  CAS  PubMed  Google Scholar 

  22. Tjota M, Chen H, Parilla M, Wanjari P, Segal J, Antic T (2020) Eosinophilic renal cell tumors with a TSC and MTOR gene mutations are morphologically and immunohistochemically heterogenous: clinicopathologic and molecular study. Am J Surg Pathol 44(7):943–954. https://doi.org/10.1097/PAS.0000000000001457

    Article  PubMed  Google Scholar 

  23. Chen YB, Mirsadraei L, Jayakumaran G et al (2019) Somatic mutations of TSC2 or MTOR characterize a morphologically distinct subset of sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm. Am J Surg Pathol 43(1):121–131. https://doi.org/10.1097/PAS.0000000000001170

    Article  PubMed  PubMed Central  Google Scholar 

  24. Palsgrove DN, Li Y, Pratilas CA et al (2018) Eosinophilic solid and cystic (ESC) renal cell carcinomas harbor TSC mutations: molecular analysis supports an expanding clinicopathologic spectrum. Am J Surg Pathol 42(9):1166–1181. https://doi.org/10.1097/PAS.0000000000001111

    Article  PubMed  PubMed Central  Google Scholar 

  25. Parilla M, Kadri S, Patil SA et al (2018) Are sporadic eosinophilic solid and cystic renal cell carcinomas characterized by somatic tuberous sclerosis gene mutations? Am J Surg Pathol 42(7):911–917. https://doi.org/10.1097/PAS.0000000000001067

    Article  PubMed  Google Scholar 

  26. Tanaka Y, Kato K, Notohara K et al (2001) Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res 61(23):8401–8404

    CAS  PubMed  Google Scholar 

  27. Tejpar S, Michils G, Denys H et al (2005) Analysis of Wnt/beta catenin signalling in desmoid tumors. Acta Gastroenterol Belg 68(1):5–9

    CAS  PubMed  Google Scholar 

  28. Koike H, Nishida Y, Kohno K et al (2019) Is immunohistochemical staining for beta-catenin the definitive pathological diagnostic tool for desmoid-type fibromatosis? A multi-institutional study? Hum Pathol 84:155–163. https://doi.org/10.1016/j.humpath.2018.09.018

    Article  CAS  PubMed  Google Scholar 

  29. Lam AK, Saremi N (2017) Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer. Endocr Relat Cancer 24(4):R109–R121. https://doi.org/10.1530/ERC-17-0014

    Article  CAS  PubMed  Google Scholar 

  30. Hoang MP, Amirkhan RH (2003) Inhibin alpha distinguishes hemangioblastoma from clear cell renal cell carcinoma. Am J Surg Pathol 27(8):1152–1156. https://doi.org/10.1097/00000478-200308000-00014

    Article  PubMed  Google Scholar 

  31. de Alava E (2017) Ewing sarcoma, an update on molecular pathology with therapeutic implications. Surg Pathol Clin 10(3):575–585. https://doi.org/10.1016/j.path.2017.04.001

    Article  PubMed  Google Scholar 

  32. Cooper GW, Hong AL (2022) SMARCB1-deficient cancers: novel molecular insights and therapeutic vulnerabilities. Cancers (Basel) 14(15). https://doi.org/10.3390/cancers14153645

  33. Shia J, Guillem JG, Moore HG et al (2004) Patterns of morphologic alteration in residual rectal carcinoma following preoperative chemoradiation and their association with long-term outcome. Am J Surg Pathol 28(2):215–223. https://doi.org/10.1097/00000478-200402000-00009

    Article  PubMed  Google Scholar 

  34. Shia J, McManus M, Guillem JG et al (2011) Significance of acellular mucin pools in rectal carcinoma after neoadjuvant chemoradiotherapy. Am J Surg Pathol 35(1):127–134. https://doi.org/10.1097/PAS.0b013e318200cf78

    Article  PubMed  Google Scholar 

  35. Pai RK, Pai RK (2018) Pathologic assessment of gastrointestinal tract and pancreatic carcinoma after neoadjuvant therapy. Mod Pathol 31(1):4–23. https://doi.org/10.1038/modpathol.2017.87

    Article  CAS  PubMed  Google Scholar 

  36. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026

    Article  CAS  PubMed  Google Scholar 

  37. de Mestier L, Dromain C, d’Assignies G et al (2014) Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art. Endocr Relat Cancer 21(3):R105–R120. https://doi.org/10.1530/ERC-13-0365

    Article  CAS  PubMed  Google Scholar 

  38. Kunz PL, Graham NT, Catalano PJ et al (2022) A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors (ECOG-ACRIN E2211). J Clin Oncol 101200JCO2201013. https://doi.org/10.1200/JCO.22.01013

  39. Sundin A, Rockall A (2012) Therapeutic monitoring of gastroenteropancreatic neuroendocrine tumors: the challenges ahead. Neuroendocrinology 96(4):261–271. https://doi.org/10.1159/000342270

    Article  CAS  PubMed  Google Scholar 

  40. Vullierme MP, Ruszniewski P, de Mestier L (2021) Are recist criteria adequate in assessing the response to therapy in metastatic NEN? Rev Endocr Metab Disord 22(3):637–645. https://doi.org/10.1007/s11154-021-09645-1

    Article  CAS  PubMed  Google Scholar 

  41. Franz DN, Capal JK (2017) mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disorders. Orphanet J Rare Dis 12(1):51. https://doi.org/10.1186/s13023-017-0596-2

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Immunology, Washington University School of Medicine, 425 S Euclid Ave., St. Louis, MO, 63110, USA

    Pooja Navale

  2. Department of Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Deyali Chatterjee

  3. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Malak Itani

  4. Department of Medicine, Division of Oncology, Washington University Medical School, St. Louis, MO, USA

    Nikolaos A. Trikalinos

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  1. Pooja Navale
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  4. Nikolaos A. Trikalinos
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Contributions

PN and NT contributed to the study conception/design and data collection. PN and DC performed the review of the pathology slides. MI contributed to data collection. The first draft of the manuscript was written by PN. All authors have read and approved the final manuscript.

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Correspondence to Pooja Navale.

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Navale, P., Chatterjee, D., Itani, M. et al. Tuberous sclerosis complex mutations in patients with pancreatic neuroendocrine tumors. Observations on phenotypic and treatment-related associations. Virchows Arch 483, 167–175 (2023). https://doi.org/10.1007/s00428-023-03570-1

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