Multiple Relapses of Parathyroid Carcinoma with Severe Systemic Complications - Case Report and Literature Review

Parathyroid carcinoma is an exceptionally uncommon endocrine neoplasm, accounting for less than 1% of parathyroid tumours and also a rare cause of primary hyperparathyroidism. Although this malignant lesion is usually slowly progressive, it is frequently associated with local recurrences and also with metastases involving the local lymph nodes or distant sites. We present a 59-year-old male patient who developed a parathyroid carcinoma metastasis involving the anterior mediastinal lymph nodes and thymus remnants, 3 years after the primary tumour was identified and treated by surgical excision followed by chemo and radiotherapy. The patient presented with severe, symptomatic hyperparathyroidism and a gamma scan revealed increased uptake hyperfixation in the paratracheal lymph nodes. A lymphadenectomy was performed and the gross examination of the specimen showed a pinkish – white, firm, poorly circumscribed mass. The microscopic examination revealed an epithelial proliferation with a predominantly nodular/solid growth pattern, composed of cells exhibiting moderate nuclear pleomorphism, prominent nucleoli and high mitotic activity, involving two lymph nodes and thymus remnants. Upon immunohistochemical analysis, the proliferation showed positive staining for GATA 3, as well as a high Ki 67 index, whereas TTF 1 and thyroglobulin were negative in the tumour cells. Thus, the diagnosis of metastatic parathyroid carcinoma was established. The aim of this paper is to gain further knowledge about the histopathological and immunohistochemical features, as well as about the clinical behaviour of parathyroid malignant lesions, especially considering their rarity.

Filamin A and Parafibromin Expression in Parathyroid Carcinoma

Objective: Parathyroid carcinoma (PC), atypical parathyroid tumors (APT) and parathyroid adenoma (PA) present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. Design: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. Methods: Tissue microarray slides were immunohistochemically stained with FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. Results: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (p = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (p = 0.014, p = 0.017 and p = 0.049, respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (p < 0.001). Conclusion: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

Remote access endoscopic parathyroidectomy: a study of 17 cases from Central India

<p><strong>Background: </strong>It has been debated that "remote access endoscopic parathyroidectomy" requires extensive dissection, thereby, increasing the risk of complications. Hence, the aim of this study is to assess the feasibility and safety of remote access endoscopic parathyroidectomy via the unilateral axilla-breast approach (ABA) and transoral vestibular approach (TOEPVA). </p><p><strong>Method: </strong>The study includes 17 patients with primary hyperparathyroidism undergoing endoscopic parathyroidectomy from January 2016 to December 2020. Of these, 11 patients underwent parathyroidectomy via unilateral ABA and 6 had TOEPVA. Preoperatively, ultrasonography of neck, sestamibi scan and CT scan neck were done to localise the diseased gland. Post operatively, Serum calcium and parathyroid hormone levels were monitored.</p><p><strong>Results</strong>: The mean age of patients was 35.6±10.5 years. Except one, all the patients were females. The mean operative time of the unilateral ABA and TOEPVA group was 93.67±28.64 minutes and 138.6±31 minutes respectively. Except for three patients, in all the patients, the parathormone levels normalised. One patient had hungry bone syndrome postoperatively. The mean hospital stay of the unilateral ABA and TOEPVA group was 3±1.5 days and 4±3.09 days respectively. One patient had post-operative transient recurrent laryngeal nerve paresis. Seroma and surgical emphysema were seen in two patients each. </p><p><strong>Conclusions</strong>: Remote Access Endoscopic parathyroidectomy may be considered safe in treatment of parathyroid tumours. Precise preoperative localisation is mandatory. In addition to a magnified view and a better illumination, the potential advantages of endoscopic techniques are better cosmetic results, decreased hospital stay and better patient comfort.</p>

Parathyroid disorders and diseases altering calcium metabolism

The control of body calcium involves a balance—chiefly under the control of parathyroid hormone (PTH)—between the amounts that are absorbed from the gut, deposited into bone and into cells, and excreted from the kidney. Abnormalities of the parathyroid glands themselves will cause derangements of calcium homeostasis and several clinical disorders. PTH oversecretion due to parathyroid tumours, which affect 3 in 1000 of the population, is a major cause of hypercalcaemia which may be associated with kidney stones, osteoporosis, and peptic ulcers. PTH deficiency, which results in hypocalcaemia and occurs in 1 in 4000 live births, may be associated with epilepsy, tetany, cataracts, skeletal malformations, and abnormal dentition. This chapter will review the physiological and biochemical mechanisms underlying extracellular calcium homeostasis, the clinical features of hypercalcaemia and hypocalcaemia, the clinical disorders associated with abnormal calcium homeostasis and their management, and the genetic basis for disorders of calcium metabolism.

Profiling analysis of long non-coding RNA and mRNA in parathyroid carcinoma

Parathyroid carcinoma (PCa) is a rare endocrine neoplasia that typically has unfavourable outcomes. The contribution of long non-coding RNAs (lncRNAs) to the development of malignant and benign parathyroid tumours remains largely unknown. In this study, we explored transcriptomic profiling of lncRNA and mRNA expression in 6 PCa, 6 parathyroid adenoma (PAd) and 4 normal parathyroid (PaN) tissues. In total, 2641 lncRNA transcripts and 2165 mRNA transcripts were differentially expressed between PCa and PAd. Enrichment analysis demonstrated that dysregulated transcripts were involved mainly in the extracellular matrix (ECM)–receptor interaction and energy metabolism pathways. Bioinformatics analysis suggested that ATF3, ID1, FOXM1, EZH2 and MITF may be crucial to parathyroid carcinogenesis. Series test of cluster analysis segregated differentially expressed lncRNAs and mRNAs into several expression profile models, among which the ‘plateau’ profile representing components specific to parathyroid carcinogenesis was selected to build a co-expression network. Seven lncRNAs and three mRNAs were selected for quantitative RT-PCR validation in 16 PCa, 41 PAd and 4 PaN samples. Receiver-operator characteristic curves analysis showed that lncRNA PVT1 and GLIS2-AS1 yielded the area under the curve values of 0.871 and 0.860, respectively. Higher hybridization signals were observed in PCa for PVT1 and PAd for GLIS2-AS1. In conclusion, the current evidence indicates that PAd and PCa partially share common signalling molecules and pathways, but have independent transcriptional events. Differentially expressed lncRNAs and mRNAs have intricate interactions and are involved in parathyroid tumourigenesis. The lncRNA PVT1 and GLIS2-AS1 may be new potential markers for the diagnosis of PCa.

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

A MEN1 pancreatic neuroendocrine tumour mouse model under temporal control

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1L/L), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic β-cell-specific NET model under temporal control (Men1L/L/RIP2-CreER). Men1L/L/RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2–2.5, 2.9–3.5 and 4.5–5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1L/L/RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining β-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1L/L/RIP2-CreER) to study early events in the development of pancreatic β-cell NETs.