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Purpose: Pheochromocytomas (PCCs) exhibit malignant potential, but current histological modalities for the proper detection of aggressive behavior are debated. The two most widespread algorithms are the “Pheochromocytoma of the Adrenal Gland Scaled Score” (PASS) and the “Grading System for Adrenal Pheochromocytoma and Paraganglioma” (GAPP), both which mostly rely on histological parameters to identify PCC patients at risk of disseminated disease. Since the algorithms are derived from studies using predominantly sporadic PCCs, little is known whether the PASS or GAPP scores can predict malignant potential in hereditary cases.Methods: PASS and GAPP were applied on 41 PCCs; 13 PCCs were diagnosed in ten multiple endocrine neoplasia type 2A (MEN 2A) patients carrying established germline RET proto-oncogene mutations, as well as 28 assumed sporadic PCCs.Results: Six out of thirteen MEN 2A tumors (46%) exhibited PASS scores ≥ 4, indicative of a potential for aggressive behavior. In addition, 7/13 tumors (54%) exhibited GAPP scores ≥ 3, indicative of a “moderately differentiated type” with risk of future recurrence. All MEN 2A PCCs with an elevated PASS score also displayed an elevated GAPP score. In contrast, 4/28 (14%) sporadic PCCs demonstrated PASS scores ≥ 4, and 9/28 (32%) displayed GAPP scores ≥ 3. Follow-up found all cases in the study are free of metastatic or recurrent disease.Conclusions: We conclude that the PASS and GAPP scoring systems might be suboptimal for determining true malignant potential in PCCs with constitutional RET mutations and advocate restrictive use of these scores in MEN 2A cases until the results are reproduced in larger numbers. [ABSTRACT FROM AUTHOR]

Simple Summary: In a cohort study involving 393 patients with differentiated thyroid cancer, TERT promoter mutations were found to act as an independent poor prognostic factor based on the American Joint Committee on Cancer (AJCC) tumor-node-metastasis 8th edition (TNM-8) in differentiated thyroid carcinoma (DTC) patients, regardless of the histological types or stage at diagnosis. Since the current AJCC TNM-8 is insufficient to distinguish the risk of mortality in patients with differentiated thyroid cancer, a proposal for a new survival prediction model that includes the TERT promoter mutational state is required. Our research group has previously shown that the presence of TERT promoter mutations is an independent prognostic factor, by applying the TERT mutation status to the variables of the AJCC 7th edition. This study aimed to determine if TERT mutations could be independent predictors of thyroid cancer-specific mortality based on the AJCC TNM 8th edition, with long-term follow-up. This was a retrospective study of 393 patients with pathologically confirmed differentiated thyroid carcinoma (DTC) after thyroidectomy at a tertiary Korean hospital from 1994 to 2004. The thyroid cancer-specific mortality rate was 6.9% (5.2% for papillary and 15.2% for follicular cancers). TERT promoter mutations were identified in 10.9% (43/393) of DTC cases (9.8% of papillary and 16.7% of follicular cancer) and were associated with older age (p < 0.001), the presence of extrathyroidal invasion (p < 0.001), distant metastasis (p = 0.001), and advanced stage at diagnosis (p < 0.001). The 10-year survival rate in mutant TERT was 67.4% for DTC patients (vs. 98% for wild-type; adjusted hazard ratio (HR) of 9.93, (95% CI: 3.67–26.90)) and 75% for patients with papillary cancer (vs. 99%; 18.55 (4.83–71.18)). In addition, TERT promoter mutations were related to poor prognosis regardless of histologic type (p < 0.001 for both papillary and follicular cancer) or initial stage (p < 0.001, p = 0.004, and p = 0.086 for stages I, II, and III and IV, respectively). TERT promoter mutations comprise an independent poor prognostic factor after adjusting for the clinicopathological risk factors of the AJCC TNM 8th edition, histologic type, and each stage at diagnosis, which could increase prognostic predictability for patients with DTC. [ABSTRACT FROM AUTHOR]

Mutations of the Telomerase reverse transcriptase (TERT) gene promoter are recurrently found in follicular thyroid carcinoma (FTC) and follicular tumors of uncertain malignant potential (FT-UMP), but nearly never in follicular thyroid adenoma (FTA). We, therefore, believe these mutations could signify malignant potential. At our department, postoperative TERT promoter mutational testing of FT-UMPs was implemented in 2014, with a positive mutation screening leading to vigilant follow-up and sometimes adjuvant treatment. To date, we screened 51 FT-UMPs and compared outcomes to 40 minimally invasive FTCs (miFTCs) with known TERT genotypes. Eight FT-UMPs (16%) displayed TERT promoter mutations, of which four cases underwent a completion lobectomy at the discretion of the patient, and a single patient also opted in for radioiodine (RAI) treatment. Three mutation-positive patients developed distant metastases, registered in one patient receiving a completion lobectomy and in two patients with no additional treatment. Three out of four patients who received additional surgery, including the RAI-treated patient, are still without metastatic disease. We conclude that FT-UMPs with TERT promoter mutations harbor malignant potential and exhibit at least similar recurrence rates to TERT-promoter-mutated miFTCs. Mutational screening should constitute a cornerstone analysis in the histopathological work-up of FT-UMPs. [ABSTRACT FROM AUTHOR]