Renal Neoplasia in Hyperparathyroidism–Jaw Tumor Syndrome

Abstract

A male patient in his late teens presented with primary hyperparathyroidism and underwent a parathyroidectomy. Germline testing revealed a pathogenic truncating alteration of the CDC73 gene (c.25C>T; p.Arg9Ter). On the basis of these findings, he was diagnosed with hyperparathyroidism–jaw tumor syndrome. In addition, multiple first-degree family members including his father and brother were found to have this syndrome. Approximately 2 decades later, he was found to have a 1.1-cm left renal mass on routine surveillance imaging. This was treated with a partial nephrectomy, and representative images of the renal tumor (hematoxylin and eosin stain, magnification ×100) are shown in Figure 1. This tumor showed a combination of papillary and nested architecture and exhibited inconspicuous nucleoli (World Health Organization grade 1). No recurrences or metastases were identified at 154 months of follow-up. What immunohistochemistry-based marker can be used to screen for tumors arising secondary to hyperparathyroidism–jaw tumor syndrome and what is the expected pattern of expression?a.Calcitonin, loss of stainingb.Parathormone, loss of stainingc.Parafibromin, loss of stainingd.Parafibromin, diffuse overexpression Answer: c Hyperparathyroidism–jaw tumor syndrome is inherited in an autosomal dominant manner secondary to pathogenic mutations of the CDC73 gene.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar Specifically, the pathogenic CDC73 c.25C>T, p.Arg9Ter alteration has been reported in both the somatic and germline setting.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar,2Cetani F. Pardi E. Borsari S. et al.Genetic analyses of the HRPT2 gene in primary hyperparathyroidism: germline and somatic mutations in familial and sporadic parathyroid tumors.J Clin Endocrinol Metab. 2004; 89: 5583-5591Crossref PubMed Scopus (189) Google Scholar These patients typically present with primary hyperparathyroidism secondary to parathyroid tumors, and in a subset of these patients, ossifying fibromas of the maxilla and mandible develop.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar Renal manifestations in this syndrome include cysts, hamartomas, metanephric adenoma, and Wilms tumor.1Carpten J.D. Robbins C.M. Villablanca A. et al.HRPT2, encoding parafibromin, is mutated in hyperparathyroidism–jaw tumor syndrome.Nat Genet. 2002; 32: 676-680Crossref PubMed Scopus (553) Google Scholar,3Carlo M.I. Hakimi A.A. Stewart G.D. et al.Familial kidney cancer: implications of new syndromes and molecular insights.Eur Urol. 2019; 76: 754-764Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google Scholar The spectrum of renal neoplasia in hyperparathyroidism–jaw tumor syndrome is poorly defined because of the rarity of these tumors and limited reports of detailed histopathologic findings.3Carlo M.I. Hakimi A.A. Stewart G.D. et al.Familial kidney cancer: implications of new syndromes and molecular insights.Eur Urol. 2019; 76: 754-764Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google Scholar As the CDC73 gene encodes the parafibromin protein, immunohistochemistry for parafibromin has been proposed as a screening tool for tumors occurring in the context of hyperparathyroidism–jaw tumor syndrome.5Andrici J. Gill A.J. Hornick J.L. Next generation immunohistochemistry: emerging substitutes to genetic testing?.Semin Diagn Pathol. 2018; 35: 161-169Crossref PubMed Scopus (17) Google Scholar Loss of nuclear expression of parafibromin is thought to correlate with pathogenic loss of function alterations of CDC73 and has been proposed as an immunohistochemistry-based screening tool.5Andrici J. Gill A.J. Hornick J.L. Next generation immunohistochemistry: emerging substitutes to genetic testing?.Semin Diagn Pathol. 2018; 35: 161-169Crossref PubMed Scopus (17) Google Scholar This renal tumor exhibited papillary and nested architecture and a cytokeratin 7–positive immunophenotype (Figure 2A-C). Immunohistochemistry for parafibromin showed loss of nuclear expression in tumor cells, in contrast to retained expression in non-neoplastic vascular elements (Figure 2D). In addition to the patient described herein, loss of parafibromin expression has been reported in metachronous renal tumors (metanephric adenomas) for at least 1 other patient with this syndrome.4Gupta S. Vanderbilt C.M. Leibovich B.C. et al.Secondary renal neoplasia following chemotherapy or radiation in pediatric patients.Hum Pathol. 2020; 103: 1-13Crossref PubMed Scopus (5) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT)