Evaluation of malignant parathyroid tumours in two European cohorts of patients with sporadic primary hyperparathyroidism

Abstract

Purpose Parathyroid carcinoma (PC) is remarkable for its rare occurrence and challenging diagnostics. PC accounts for 0.1-5 % cases of primary hyperparathyroidism (PHPT). The differentiation from benign tumours is difficult even by morphological criteria. To address these issues, we assessed the PC frequency in two separate European PHPT cohorts and evaluated the demographic, clinical, morphological and molecular background. Methods A retrospective study was carried out, using continuously maintained database (2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014) of PHPT patients from two tertiary referral university hospitals in Europe. The demographic, clinical data and frequency of PC among surgically treated PHPT was detected. Immunohistochemistry (IHC) was performed to detect parafibromin, representing protein product of HRPT2 gene and proliferation marker Ki-67. Results Both PHPT cohorts were characterised by close mean age values (58.6 and 58.0 years) and female predominance. The frequency of PC differed significantly between the cohorts: 2.1 vs. 0.3 %; p=0.004. PC was characterised by invariable complete loss of parafibromin contrasting with parathyroid adenomas. The proliferation fraction was similar in both PC cohorts (10.6 and 11.0 %). PC showed significantly higher proliferation fraction than typical parathyroid adenomas (1.6 %), atypical adenomas (1.6 %) or adenomas featuring focal loss of parafibromin (2.2 %). Conclusions PC frequency can range significantly between the two European cohorts. The differences can be attributable to selection bias of patients referred for surgery and are not caused by discordant definition of malignant parathyroid histology. Diffuse loss of parafibromin and increased proliferation fraction by Ki-67 are valuable adjuncts in PC diagnostics due to significant differences with various clinical and morphological subtypes of adenoma.

Atypical parathyroid adenomas: challenging lesions in the differential diagnosis of endocrine tumors

“…In most consecutive series of patients undergoing surgery for PHPT, the incidence of atypical parathyroid adenoma ranged from 0.5 to 4.4% (de Meneses Montenegro et al 2006, Ippolito et al 2007, Juhlin et al 2010, O'Neal et al 2011, Ricci et al 2012, Chandramohan et al 2014, Haglund et al 2015, McCoy et al 2015, Quinn et al 2015, Schneider et al 2015, Ozolins et al 2016, Mamedova et al 2017. An incidence as high as 14% has been reported in the Asian countries (Cakir et al 2016, Hu et al 2018.…”

“…Some authors, according to the criteria of Seethala and coworkers (Seethala et al 2009), defined the diagnosis of atypical adenomas when at least two of the following features were present, namely intraoperative adherence, bands of fibrosis, pronounced trabecular growth, strong mitotic activity, necrosis, diffuse sheet-like monotonous small cells with high nuclear/cytoplasmic ratio, cellular atypia and nucleolomegaly, in the absence of unequivocal signs of malignancy (Mishra & Newman 2014, McCoy et al 2015, Cakir et al 2016, Ozolins et al 2016. Conversely, Kumari and coworkers, according to the histological criteria of Chan, established the diagnosis of atypical adenoma when one to three of the above features were present (Chan 2007.…”

“…Eighty-five percent of specimen diagnosed as atypical adenomas has a Ki-67 proliferative index <5% (100/117). Studies on atypical adenomas have shown a variable rate of Ki-67 overexpression ranging from 0 to 67% (Stojadinovic et al 2003, Ozolins et al 2016, Hosny Mohammed et al 2017 (Table 3). Ozolins and coworkers found that a high Ki-67 expression was of diagnostic value for parathyroid carcinoma, being detected in 87% of cases compared with 0% in both benign and atypical adenomas (Ozolins et al 2016).…”

“…Studies on atypical adenomas have shown a variable rate of Ki-67 overexpression ranging from 0 to 67% (Stojadinovic et al 2003, Ozolins et al 2016, Hosny Mohammed et al 2017 (Table 3). Ozolins and coworkers found that a high Ki-67 expression was of diagnostic value for parathyroid carcinoma, being detected in 87% of cases compared with 0% in both benign and atypical adenomas (Ozolins et al 2016). Similarly, two other studies found an almost exclusive staining in carcinomas (60 and 27%), being absent in atypical adenomas and only present in 6 and 2% of benign adenomas (Stojadinovic et al 2003, Fernandez-Ranvier et al 2009.…”

“…Nuclear parafibromin loss (diffuse and/or focal) has been shown in up to 100% of parathyroid carcinomas in the majority of the studies, and rarely in benign adenomas (up to 13%) (Juhlin et al 2006, Cetani et al 2007, Guarnieri et al 2012, Sulaiman et al 2012a, Kruijff et al 2014, Quinn et al 2015, Ozolins et al 2016, Ryhänen et al 2017 and seems to predict the negative clinical outcome (Cetani et al 2007, Witteveen et al 2011 (Table 3). Hu and coworkers conducted a meta-analysis which included ten studies with a total of 202 patients with parathyroid carcinomas.…”