Immunohistochemical Markers of the Hypoxic Response Can Identify Malignancy in Phaeochromocytomas and Paragangliomas and Optimize the Detection of Tumours with VHL Germline Mutations

Overview

Journal Br J Cancer

Specialty Oncology

Date 2012 Dec 22

PMID 23257898

Citations 23

Authors

D J Pinato

R Ramachandran

S T K Toussi

M Vergine

N Ngo

R Sharma

T Lloyd

K Meeran

F Palazzo

N Martin

B Khoo

R Dina

T M Tan

Affiliations

Soon will be listed here.

Abstract

Background: There are no reliable markers of malignancy in phaeochromocytomas (PCC) and paragangliomas (PGL). We investigated the relevance of the mammalian target of rapamycin (mTOR)/AKT and hypoxic pathways as novel immunohistochemical markers of malignancy.

Methods: Tissue microarray blocks were constructed with a total of 100 tumours (10 metastatic) and 20 normal adrenomedullary samples. Sections were immunostained for hypoxia-inducible factor 1α (Hif-1α), vascular endothelial growth factor A (VEGF-A), mTOR, carbonic anhydrase IX (CaIX) and AKT. The predictive performance of these markers was studied using univariate, multivariate and receiver operating characteristic analyses.

Results: In all, 100 consecutive patients, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Univariate analyses showed Hif-1α overexpression, tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1α, necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1α was the most discriminatory biomarker for the presence of metastatic diffusion. Strong membranous CaIX expression was seen in von Hippel-Lindau (VHL) PCC as opposed to other subtypes.

Conclusion: Lack of vascular invasion, tumour necrosis and low Hif-1α expression identify tumours with lower risk of malignancy. We propose membranous CaIX expression as a potential marker for VHL disease in patients presenting with PCC.

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References

Gimenez-Roqueplo A, Lehnert H, Mannelli M, Neumann H, Opocher G, Maher E . Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf). 2006; 65(6):699-705. DOI: 10.1111/j.1365-2265.2006.02714.x. View

Gottlieb E, Tomlinson I . Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer. 2005; 5(11):857-66. DOI: 10.1038/nrc1737. View

Thompson L . 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; 26(5):551-66. DOI: 10.1097/00000478-200205000-00002. View

Takekoshi K, Isobe K, Yashiro T, Hara H, Ishii K, Kawakami Y . Expression of vascular endothelial growth factor (VEGF) and its cognate receptors in human pheochromocytomas. Life Sci. 2003; 74(7):863-71. DOI: 10.1016/j.lfs.2003.07.036. View

Favier J, Plouin P, Corvol P, Gasc J . Angiogenesis and vascular architecture in pheochromocytomas: distinctive traits in malignant tumors. Am J Pathol. 2002; 161(4):1235-46. PMC: 1867278. DOI: 10.1016/S0002-9440(10)64400-8. View

Manger W, Eisenhofer G . Pheochromocytoma: diagnosis and management update. Curr Hypertens Rep. 2004; 6(6):477-84. DOI: 10.1007/s11906-004-0044-2. View

Dahia P, Ross K, Wright M, Hayashida C, Santagata S, Barontini M . A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005; 1(1):72-80. PMC: 1183527. DOI: 10.1371/journal.pgen.0010008. View

Eisenhofer G, Tischler A, de Krijger R . Diagnostic tests and biomarkers for pheochromocytoma and extra-adrenal paraganglioma: from routine laboratory methods to disease stratification. Endocr Pathol. 2011; 23(1):4-14. DOI: 10.1007/s12022-011-9188-1. View

Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y . Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol. 2005; 16(1):23-32. DOI: 10.1385/ep:16:1:023. View

10.

Giatromanolaki A, Harris A . Tumour hypoxia, hypoxia signaling pathways and hypoxia inducible factor expression in human cancer. Anticancer Res. 2002; 21(6B):4317-24. View

11.

Covello K, Kehler J, Yu H, Gordan J, Arsham A, Hu C . HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006; 20(5):557-70. PMC: 1410808. DOI: 10.1101/gad.1399906. View

12.

Strong V, Kennedy T, Al-Ahmadie H, Tang L, Coleman J, Fong Y . Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery. 2008; 143(6):759-68. DOI: 10.1016/j.surg.2008.02.007. View

13.

Bowman A, Gabra H, Langdon S, Lessells A, Stewart M, Young A . CA125 response is associated with estrogen receptor expression in a phase II trial of letrozole in ovarian cancer: identification of an endocrine-sensitive subgroup. Clin Cancer Res. 2002; 8(7):2233-9. View

14.

Gill A, Benn D, Chou A, Clarkson A, Muljono A, Meyer-Rochow G . Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010; 41(6):805-14. DOI: 10.1016/j.humpath.2009.12.005. View

15.

Reisch N, Peczkowska M, Januszewicz A, Neumann H . Pheochromocytoma: presentation, diagnosis and treatment. J Hypertens. 2006; 24(12):2331-9. DOI: 10.1097/01.hjh.0000251887.01885.54. View

16.

Loboda A, Jozkowicz A, Dulak J . HIF-1 and HIF-2 transcription factors--similar but not identical. Mol Cells. 2010; 29(5):435-42. DOI: 10.1007/s10059-010-0067-2. View

17.

Gimm O, DeMicco C, Perren A, Giammarile F, Walz M, Brunaud L . Malignant pheochromocytomas and paragangliomas: a diagnostic challenge. Langenbecks Arch Surg. 2011; 397(2):155-77. DOI: 10.1007/s00423-011-0880-x. View

18.

Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L . SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011; 96(9):E1472-6. DOI: 10.1210/jc.2011-1043. View

19.

Salmenkivi K, Haglund C, Ristimaki A, Arola J, Heikkila P . Increased expression of cyclooxygenase-2 in malignant pheochromocytomas. J Clin Endocrinol Metab. 2001; 86(11):5615-9. DOI: 10.1210/jcem.86.11.8052. View

20.

Salmenkivi K, Heikkila P, Liu J, Haglund C, Arola J . VEGF in 105 pheochromocytomas: enhanced expression correlates with malignant outcome. APMIS. 2003; 111(4):458-64. DOI: 10.1034/j.1600-0463.2003.1110402.x. View