A Nomogram for Relapse/Death and Contemplating Adjuvant Therapy for Parathyroid Carcinoma.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with an increased incidence in the last decade. There is no reliable prognostic staging system for PC. Several hosts, tumors, and tumor microenvironment factors have been negatively correlated with survival in the last decade. Surgical resection with negative margins is still the standard of treatment in PC. Chemo and radiotherapy have no proven beneficial effect. A new promising approach with molecular profiling could lead to adjuvant therapies.

Using a Novel Diagnostic Nomogram to Differentiate Malignant from Benign Parathyroid Neoplasms.

We sought to develop an immunohistochemical (IHC) tool to support the diagnosis of parathyroid carcinoma (PC) and help differentiate it from atypical parathyroid neoplasms (atypical) and benign adenomas. Distinguishing PC from benign parathyroid neoplasms can be challenging. Many cases of PC are histopathologically borderline for definitive malignancy. Recently, individual IHC biomarkers have been evaluated to aid in discrimination between parathyroid neoplasms. PC, atypical parathyroid neoplasms, and parathyroid adenomas treated at our institution from 1997 to 2014 were studied retrospectively. IHC analysis was performed to evaluate parafibromin, retinoblastoma (RB), protein gene product 9.5 (PGP9.5), Ki67, galectin-3, and E-cadherin expression. Receiver operating characteristic (ROC) analysis and multivariable logistic regression model for combinations of biomarkers were evaluated to classify patients as PC or atypical/adenoma. A diagnostic nomogram using 5 biomarkers was created for PC. Sixty-three patients were evaluated. The percent staining of parafibromin (p < 0.0001), RB (p = 0.04), Ki67 (p = 0.02), PGP9.5 (p = 0.04), and Galectin-3 (p = 0.01) differed significantly in the three diagnostic groups. ROC analysis demonstrated that parafibromin had the best performance in discriminating PC from atypical/adenoma; area under the curve (AUC) was 81% (cutoff, 92.5%; sensitivity rate, 64%; specificity rate, 87%). We created a diagnostic nomogram using a combination of biomarkers; AUC was 84.9% (95% confidence interval, 73.4-96.4%). The optimism-adjusted AUC for this model was 80.5% (mean absolute error, 0.043). A diagnostic nomogram utilizing an immunoexpression, a combination of immunohistochemical biomarkers, can be used to help differentiate PC from other parathyroid neoplasms, thus potentially improving diagnostic classification.

Epigenetic processes in sporadic parathyroid neoplasms.

Parathyroid tumors (PTs) are highly variable in their genetic background. Increasing evidence demonstrates that endocrine diseases can be caused by epigenetic alterations. The present review is focused on epigenetic aberrations related to PTs. DNA methylation, posttranslational histone modification, and noncoding RNAs are epigenetic mechanisms involved in parathyroid tumorigenesis. The information in this review has the potential to define epigenetic signatures associated with PTs for future use as diagnostic markers and lead to the development of new epigenetic drugs with therapeutic applications for these tumors. However, several epigenetic aspects regarding the biomarkers involved and their interactions in tumorigenesis on PTs are still unknown. Key to future epigenetic research would be a focus on global epigenetic identification of biomarkers in the different types of PTs, especially in parathyroid carcinoma. Better understanding may be useful for diagnostic and therapeutic uncertainty.

Prognostic Scoring System to Risk Stratify Parathyroid Carcinoma.

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.

Clinical Features, Treatments, and Outcomes of Patients with Thymic Carcinoids and Multiple Endocrine Neoplasia Type 1 Syndrome at MD Anderson Cancer Center.

Thymic carcinoids are rare neuroendocrine tumors that occur in 1-5 % of patients with multiple endocrine neoplasia type 1 (MEN1) and are a major cause of morbidity and mortality. The few published reports associate these tumors with male sex and smoking. Our objective was to describe cases of these tumors treated at our institution. We performed a retrospective chart review of all patients diagnosed with MEN1 at our tertiary referral center from 1980 to 2014. Patients with a histopathologic, fine-needle aspiration, or clinical diagnosis of a thymic carcinoid were included. Two hundred ninety-one patients fulfilled the criteria for a diagnosis of MEN1. Clinicopathologic characteristics, MEN1 genetic testing results, treatments, and survival rates were analyzed. Nine patients had a thymic carcinoid, six men (67 %) and three women (33 %). Six patients were non-smokers (67 %). Two patients had synchronous (22 %) and eight patients (89 %) had metachronous distant metastasis. The 10-year overall survival rate was 45 % (lower 95 % upper 95 % CI 20-100 %). The 10-year disease-free survival rate was 42 % (lower 95 % upper 95 % CI 15-100 %). Five patients had MEN1 genetic testing, and the genotypes of affected individuals were p.W341X, c.275_286delGCTTCACCGCCC, p.R98X, c.1350+(1_11)del11, and partial duplication of exons 9 and 10. A higher percentage of MEN1-related thymic carcinoids can occur in women and in non-smokers than previously reported. Both novel and known mutations were present in our cohort. Eighty nine percent of patients developed a metachronous metastasis from the thymic carcinoid. Patients with MEN1 and thymic carcinoids should be followed closely.

Parathyroid carcinoma and atypical parathyroid neoplasms in MEN1 patients; A clinico-pathologic challenge. The MD Anderson case series and review of the literature.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.