Skip to main content
SpringerLink
Log in

Sclerosing Paragangliomas: Correlations of Histological Features with Patients’ Genotype and Vesicular Monoamine Transporter Expression

  • Original Paper
  • Published:
Head and Neck Pathology Aims and scope Submit manuscript

Abstract

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, carrying a germ-line mutation in 40% patients. Sclerosis is a rare histological feature in these tumors. We investigated the possible correlations between histological findings, first sclerosis, immunoreactivity for vesicular catecholamine transporters (VMAT1/VMAT2) and patients’ genotype in a consecutive series of 57 tumors (30 paragangliomas and 27 pheochromocytomas) from 55 patients. The M-GAPP grading system, sclerosis (0–3 scale) and VMAT1/VMAT2 (0–6 scale) immunoreactivity scores were assessed. Germ-line mutations of Succinate Dehydrogenase genes, RET proto-oncogene and Von Hippel Lindau tumor suppressor gene were searched. A germ-line mutation was found in 25/55 (45.5%) patients, mainly with paraganglioma (N = 14/30, 46,66%). Significant (score ≥ 2) tumor sclerosis was found in 9 (16.1%) tumors, i.e., 7 paragangliomas and 2 pheochromocytomas, most of them (8/9) from patients with a germ-line mutation. M-GAPP score was higher in the mutation status (in 76% of patients involving the SDHx genes, in 12% the RET gene and in the remaining 12% the VHL gene) and in tumors with sclerosis (p < 0.05). Spearman’s rank correlation showed a strong correlation of germ-line mutations with M-GAPP (p < 0.0001) and sclerosis (p = 0.0027) scores; a significant correlation was also found between sclerosis and M-GAPP scores (p = 0.029). VMAT1 expression was higher in paragangliomas than in pheochromocytomas (p = 0.0006), the highest scores being more frequent in mutation-bearing patients’ tumors (p < 0.01). VMAT2 was highly expressed in all but two negative tumors. Sclerosis and VMAT1 expression were higher in paragangliomas than in pheochromocytomas; tumor sclerosis, M-GAPP and VMAT1 scores were associated to germ-line mutations. Sclerosis might represent a histological marker of tumor susceptibility, prompting to genetic investigations in paragangliomas.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Data Availability

All data generated or analyzed during this study are included in the manuscript.

Code Availability

Not applicable.

References

  1. Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381(6):552–65.

    Article  CAS  Google Scholar 

  2. Pang Y, Liu Y, Pacak K. Pheochromocytomas and paragangliomas: from genetic diversity to targeted therapies. Cancers (Basel). 2019;11:436.

    Article  CAS  Google Scholar 

  3. Turchini J, Cheung VKY, Tischler AS, De Krijger RR, Gill AJ. Pathology and genetics of phaeochromocytoma and paraganglioma. Histopathology. 2018;72:97–105.

    Article  Google Scholar 

  4. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11:101–11.

    Article  CAS  Google Scholar 

  5. Costa MH, Ortiga-Carvalho TM, Violante AD, Vaisman M. Pheochromocytomas and paragangliomas: clinical and genetic approaches. Front Endocrinol (Lausanne). 2015;17:6:126. https://doi.org/10.3389/fendo.2015.00126.

    Article  Google Scholar 

  6. Sen I, Young WF Jr, Kasperbauer JL, Polonis K, Harmsen WS, Colglazier JJ, DeMartino RR, Oderich GS, Kalra M, Bower TC. Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. J Vasc Surg. 2020;71:1602-12.e2.

    Article  Google Scholar 

  7. Bacca A, Sellari Franceschini S, Carrara D, Bernini M, Zampa V, Taddei S, Miccoli P, Congregati C, Simi P, Ferrari M, Bernini G. Sporadic or familial head neck paragangliomas enrolled in a single center: clinical presentation and genotype/phenotype correlations. Head Neck. 2013;35:23–7.

    Article  Google Scholar 

  8. Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: advances and challenges for the future. J Intern Med. 2009;266:1–4.

    Article  CAS  Google Scholar 

  9. Buffet A, Burnichon N, Favier J, Gimenez-Roqueplo AP. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2020;34:101416. https://doi.org/10.1016/j.beem.2020.101416.

    Article  CAS  Google Scholar 

  10. Tischler AS, de Krijger RR, Gill A, Kawashima A, Kimura N, Komminoth P. Tumours of the adrenal medulla and extra-adrenal paraganglia. In: Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of tumours of endocrine organs, vol. 4. Lyon: IARC Press; 2017. p. 179–207.

    Google Scholar 

  11. Javidiparsijani S, Brickman A, Lin DM, Rohra P, Ghai R, Bitterman P, Reddi V, Al-Khudari S, Gattuso. Is regional lymph node metastasis of head and neck paraganglioma a sign of aggressive clinical behavior: a clinical/pathologic review. Ear Nose Throat J. 2021;100:447–53.

    Article  Google Scholar 

  12. Plaza JA, Wakely PE Jr, Moran C, Fletcher CD, Suster S. Sclerosing paraganglioma: report of 19 cases of an unusual variant of neuroendocrine tumor that may be mistaken for an aggressive malignant neoplasm. Am J Surg Pathol. 2006;30:7–12.

    Article  Google Scholar 

  13. Santi R, Franchi A, Saladino V, Trovati M, Cenacchi G, Squadrelli-Saraceno M, Nesi G. Sclerosing paraganglioma of the carotid body: a potential pitfall of malignancy. Head Neck Pathol. 2015;9:300–4.

    Article  Google Scholar 

  14. Ng E, Duncan G, Choong AM, Francis L, Foster W, Kruger A. Sclerosing paragangliomas of the carotid body: a series of a rare variant and review of the literature. Ann Vasc Surg. 2015;29(7):1454.e5. https://doi.org/10.1016/j.avsg.2015.04.083.

    Article  Google Scholar 

  15. Wang Y, Li M, Deng H, Pang Y, Liu L, Guan X. The systems of metastatic potential prediction in pheochromocytoma and paraganglioma. Am J Cancer Res. 2020;10:769–80.

    CAS  Google Scholar 

  16. Henry JP, Botton D, Sagne C, Isambert MF, Desnos C, Blanchard V, Raisman-Vozari R, Krejci E, Massoulie J, Gasnier B. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules. J Exp Biol. 1994;196:251–62.

    Article  CAS  Google Scholar 

  17. Bacca A, Pucci A, Lorenzini D, Chiacchio S, Volterrani D, Ferrari M, Sellari Franceschini S, Materazzi G, Basolo F, Bernini G. Vesicular monoamine transporters expression in pheochromocytomas and paragangliomas according to scintigraphy and positron emission tomography behavior. Q J Nucl Med Mol Imaging. 2021;65:396–401.

    Google Scholar 

  18. Bombardieri E, Maccauro M, De Deckere E, Savelli G, Chiti A. Nuclear medicine imaging of neuroendocrine tumours. Ann Oncol. 2001;12(Suppl 2):51–61.

    Article  Google Scholar 

  19. Koh JM, Ahn SH, Kim H, Kim BJ, Sung TY, Kim YH, Hong SJ, Song DE, Lee SH. Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma. PLoS One. 2017;12:e0187398.

    Article  Google Scholar 

  20. 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;21:405–14.

    Article  Google Scholar 

  21. Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SK, Murad MH, Naruse M, Pacak K, Young WF Jr, Endocrine Society. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915–42.

    Article  CAS  Google Scholar 

  22. van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Rivière J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruïne AP, Maher ER, Tissier F, Méatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, François J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–71. https://doi.org/10.1016/S1470-2045(09)70164-0.

    Article  CAS  Google Scholar 

  23. Papathomas TG, Oudijk L, Persu A, Gill AJ, van Nederveen F, Tischler AS, Tissier F, Volante M, Matias-Guiu X, Smid M, Favier J, Rapizzi E, Libe R, Currás-Freixes M, Aydin S, Huynh T, Lichtenauer U, van Berkel A, Canu L, Domingues R, Clifton-Bligh RJ, Bialas M, Vikkula M, Baretton G, Papotti M, Nesi G, Badoual C, Pacak K, Eisenhofer G, Timmers HJ, Beuschlein F, Bertherat J, Mannelli M, Robledo M, Gimenez-Roqueplo AP, Dinjens WN, Korpershoek E, de Krijger RR. SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T). Mod Pathol. 2015;28:807–21. https://doi.org/10.1038/modpathol.2015.41.

    Article  CAS  Google Scholar 

  24. Fottner C, Helisch A, Anlauf M, Rossmann H, Musholt TJ, Kreft A, Schadmand-Fischer S, Bartenstein P, Lackner KJ, Klöppel G, Schreckenberger M, Weber MM. 6-18F-fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to 123I-metaiodobenzyl-guanidine scintigraphy in the detection of extraadrenal and hereditary pheochromocytomas and paragangliomas: correlation with vesicular monoamine transporter expression. J Clin Endocrinol Metab. 2010;95:2800–10.

    Article  CAS  Google Scholar 

  25. Lee H, Jeong S, Yu Y, Kang J, Sun H, Rhee JK, Kim YH. Risk of metastatic pheochromocytoma and paraganglioma in SDHx mutation carriers: a systematic review and updated meta-analysis. J Med Genet. 2020;57:217–25.

    Article  CAS  Google Scholar 

  26. Crona J, Lamarca A, Ghosal S, Welin S, Skogseid B, Pacak K. Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocr Relat Cancer. 2019;26:539–50.

    Article  CAS  Google Scholar 

  27. Saveanu A, Muresan M, De Micco C, Taieb D, Germanetti AL, Sebag F, Henry JF, Brunaud L, Enjalbert A, Weryha G, Barlier A. Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18:287–300.

    Article  Google Scholar 

  28. Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA. 1996;93:5166–71.

    Article  CAS  Google Scholar 

  29. van Berkel A, Rao JU, Lenders JW, Pellegata NS, Kusters B, Piscaer I, Hermus AR, Plantinga TS, Langenhuijsen JF, Vriens D, Janssen MJ, Gotthardt M, Timmers HJ. Semiquantitative 123I-metaiodobenzylguanidine scintigraphy to distinguish pheochromocytoma and paraganglioma from physiologic adrenal uptake and its correlation with genotype-dependent expression of catecholamine transporters. J Nucl Med. 2015;56:839–46.

    Article  Google Scholar 

  30. Cho YY, Kwak MK, Lee SE, Ahn SH, Kim H, Suh S, Kim BJ, Song KH, Koh JM, Kim JH, Lee SH. A clinical prediction model to estimate the metastatic potential of pheochromocytoma/paraganglioma: ASES score. Surgery. 2018;164:511–7.

    Article  Google Scholar 

  31. Eisenhofer G, Tischler AS. Neuroendocrine cancer. Closing the GAPP on predicting metastases. Nat Rev Endocrinol. 2014;10:315–6.

    Article  CAS  Google Scholar 

  32. Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57:411–20.

    Article  CAS  Google Scholar 

  33. Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK, Timmers HJ, Bornstein SR, Lenders JW. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer. 2010;18:97–111.

    Article  Google Scholar 

  34. Chiarugi P, Cirri P. Metabolic exchanges within tumor microenvironment. Cancer Lett. 2016;380:272–80.

    Article  CAS  Google Scholar 

  35. Kuroda N, Tamura M, Ohara M, Hirouchi T, Mizuno K, Miyazaki E, Hayashi Y, Lee GH. Possible identification of third stromal component in extraadrenal paraganglioma: myofibroblast in fibrous band and capsule. Med Mol Morphol. 2008;41:59–61.

    Article  Google Scholar 

  36. D’Antongiovanni V, Martinelli S, Richter S, Canu L, Guasti D, Mello T, Romagnoli P, Pacak K, Eisenhofer G, Mannelli M, Rapizzi E. The microenvironment induces collective migration in SDHB-silenced mouse pheochromocytoma spheroids. Endocr Relat Cancer. 2017;24:555–64.

    Article  Google Scholar 

  37. Richter S, D’Antongiovanni V, Martinelli S, Bechmann N, Riverso M, Poitz DM, Pacak K, Eisenhofer G, Mannelli M, Rapizzi E. Primary fibroblast co-culture stimulates growth and metabolism in Sdhb-impaired mouse pheochromocytoma MTT cells. Cell Tissue Res. 2018;374:473–85.

    Article  CAS  Google Scholar 

  38. Blažević A, Hofland J, Hofland LJ, Feelders RA, de Herder WW. Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum. Endocr Relat Cancer. 2018;25:R115-30.

    Article  Google Scholar 

  39. das Neves Pereira JC, da Silva AG, Soares F, Ab’Saber AM, Schmidt A, Rodrigues OR, Garippo A, Capelozzi M, de Campos JR, Takagaki T, Jatene FB, Martins S, Capelozzi VL. Nuclear and environment morphometric profile in tumor size and nodal metastasis of resected typical pulmonary carcinoid. Pathol Res Pract. 2004;200:459–67.

    Article  Google Scholar 

  40. García-Suárez O, García B, Fernández-Vega I, Astudillo A, Quirós LM. Neuroendocrine tumors show altered expression of chondroitin sulfate, glypican 1, glypican 5, and syndecan 2 depending on their differentiation grade. Front Oncol. 2014;4:15. https://doi.org/10.3389/fonc.2014.00015.

    Article  Google Scholar 

  41. Laskaratos FM, Rombouts K, Caplin M, Toumpanakis C, Thirlwell C, Mandair D. Neuroendocrine tumors and fibrosis: an unsolved mystery? Cancer. 2017;123:4770–90.

    Article  Google Scholar 

Download references

Acknowledgements

The Authors wish to thank Mrs. Alice Cocco, B.Sc., for excellent technical assistance.

Funding

From Italian Ministry of Research and Health to G. Bernini.

Author information

Author notes

  1. Daniele Lorenzini

    Present address: INT (National Institute of Tumors), Milan, Italy

Authors and Affiliations

  1. Department of Histopathology, Pisa University Hospital and Pisa University (FB), Via Roma, 57, 56126, Pisa, Italy

    Angela Pucci, Iosè Di Stefano, Beatrice Belgio, Daniele Lorenzini, Liborio Torregrossa & Fulvio Basolo

  2. Department of Clinical and Experimental Medicine, Pisa University Hospital and Pisa University (FB), Pisa, Italy

    Alessandra Bacca & Giampaolo Bernini

  3. Institute of Life Sciences, Scuola Superiore Sant’Anna, Pisa, Italy

    Ivana Barravecchia & Debora Angeloni

  4. Department of Diagnostic, Interventional and Vascular Radiology and of Nuclear Medicine, Pisa University Hospital and Pisa University, Pisa, Italy

    Serena Chiacchio

  5. Department of Translational Research and New Medical Technology, Pisa University Hospital and Pisa University, Pisa, Italy

    Caterina Congregati

  6. Department of Surgical, Molecular and Clinical Pathology and Critical Care, Pisa University Hospital and Pisa University, Pisa, Italy

    Gabriele Materazzi

  7. Department of Cardiovascular Surgery, Pisa University Hospital and Pisa University, Pisa, Italy

    Mauro Ferrari

Authors
  1. Angela Pucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandra Bacca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivana Barravecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iosè Di Stefano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Beatrice Belgio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniele Lorenzini
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liborio Torregrossa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Serena Chiacchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Caterina Congregati
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gabriele Materazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mauro Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Debora Angeloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Giampaolo Bernini
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Fulvio Basolo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by AP and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Conceptualization: AP, AB, GB, FB; Methodology: AP, AB, GB; Formal analysis and investigation: AP, AB, IB, IDS, BB, DL, LT, SC, CC; Writing—original draft preparation: AP; Writing—review and editing: AP, AB, DA; Funding acquisition: GB; Resources: GB; Supervision: FB, GB; GM, MF.

Corresponding author

Correspondence to Angela Pucci.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study was approved by the Institutional Ethics Committee and conformed to the Declaration of Helsinki.

Consent to Participate

The informed consent was obtained from each patient.

Consent for Publication

All co-authors have approved this paper and have given the consent for publication.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pucci, A., Bacca, A., Barravecchia, I. et al. Sclerosing Paragangliomas: Correlations of Histological Features with Patients’ Genotype and Vesicular Monoamine Transporter Expression. Head and Neck Pathol 16, 998–1011 (2022). https://doi.org/10.1007/s12105-022-01455-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12105-022-01455-4

Keywords

Search

Navigation