Context Elucidating the genomic landscape of sporadic parathyroid carcinoma (PC) has been limited by low tumor incidence. Objective Identify driver mutations of sporadic PC and potential actionable pathways. Methods Patients undergoing surgical resection for sporadic PC between 1980 and 2016 at MD Anderson Cancer Center were identified. Patients with sporadic PC according to World Health Organization diagnostic criteria and with available formalin-fixed, paraffin-embedded (FFPE) PC tumor tissue were included and their clinical data analyzed to access extent of disease. Patients with parathyroid tumors of uncertain malignancy or atypical parathyroid neoplasms were excluded. Thirty-one patients meeting diagnostic criteria had available tissue for analysis. FFPE PC tumors were subjected to DNA extraction and next generation whole exome sequencing. All variant calls are single algorithm-only Twenty-nine samples passed quality assurance after DNA extraction. Main Outcome Measures Somatic or private germline mutations present in sporadic PC, identification of pathways involved in tumorigenesis. Results We identified 35 genes with significant mutational load, only 8 genes were previously identified in other PC cohorts. These genes mediate critical processes including chromosome organization, DNA repair, and cell cycle regulations. Gene mutations involved in MAPK signaling and immune response are also heavily implicated. These findings are limited by inherent molecular artifacts in FFPE tissue analysis and the absence of matched germline DNA. Additionally, variant calls are only single algorithm and may include false positive/negative calls. Conclusion We identified 33 new candidate driver genes of sporadic PC, in addition to previously known driver genes CDC73 and MEN1.

Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder characterized by usually benign tumors of the parathyroid glands, pancreatic islet cells, and anterior pituitary. Hyperparathyroidism (HPT) occurs in 90% of MEN1 patients. In rare cases, it is associated with parathyroid carcinoma (PC) or atypical parathyroid neoplasm (APN). We present a cohort of 3 such patients. We performed a retrospective review of our institution's MEN1 database to identify patients who underwent operations for HPT and had a histopathologic diagnosis of PC or APN. Clinical features, genetics, and outcomes were summarized. Of 291 MEN1 patients, 242 had HPT (83.2%). Two of the 242 patients (0.8%) had a histopathologic diagnosis of PC, and 1 (0.4%) had a diagnosis of APN. The patients with PC were male, ages 62 and 56 years at the time of surgery; the patient with APN was female, age 32 years. All patients also had a pancreatic endocrine tumor. The observed genetic mutations in the PC patients were c.703G > A (p.E235K) in exon 4 and c.1378C > T (p.R460X) in exon 10. All 3 patients had recurrence of hypercalcemia, and 2 patients underwent reoperation; pathologic analysis revealed the presence of a hyperplastic gland, not tumor recurrence. No cases had distant metastasis. This is the first report of APN in an MEN1 patient. Although rare, the presence of PC or APN in MEN1 is noteworthy because it affects the management if hypercalcemia recurs, possibly requiring an open approach rather than the minimally invasive techniques used in the reoperative setting for benign disease.

BACKGROUND: Parathyroid carcinoma is a rare endocrine malignancy that lacks an established system for risk categorization. This study evaluated a prognostic scoring system for recurrence-free survival (RFS) of patients with parathyroid carcinoma. STUDY DESIGN: Patients diagnosed and confirmed to have parathyroid carcinoma and who were treated between 1980 and 2016 at The University of Texas MD Anderson Cancer Center were studied retrospectively. Univariate and multivariate Cox proportional hazards regression analyses of RFS were conducted. A prognostic scoring system was created based on multivariate analysis. RESULTS: Sixty-eight patients were evaluated. After a median follow-up of 4.6 years, 26 patients experienced a recurrence. The Kaplan-Meier RFS rates were 85% at 1 year (95% CI 77% to 95%), 67% at 2 years (95% CI 55% to 81%), and 51% at 10 years (95% CI 36% to 72%) after initial operation. Multivariate analysis demonstrated that age older than 65 years, serum calcium level >15 mg/dL, and vascular invasion were negatively correlated with RFS rate. Combining these adverse variables into a prognostic scoring system, we stratified patients into 3 risk groups: low (0 variable; 2-year RFS rate, 93%), moderate (1 variable; 2-year RFS rate, 72%), and high (2 variables; 2-year RFS rate, 27%) (p = 0.001 [log-rank test]; concordance index, 0.70; 95% CI 0.47 to 0.92). CONCLUSIONS: A prognostic scoring system using vascular invasion, age, and serum calcium level at initial parathyroidectomy can be used to predict RFS. This categorization might be helpful for clinical decisions relative to the timing and use of adjuvant therapy. Comprehensive validation using multiple cohorts will be needed to confirm applicability.