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Audrey Ziverec, Marie Chanal, Perrine Raymond, Mirela Diana Ilie, Dario De Alcubierre, Arja Pasternack, Olli Ritvos, Gerald Raverot, and Philippe Bertolino

Pituitary tumours are benign neoplasms that derive from hormone-producing cells of the pituitary gland. While medical treatments have emerged for most subtypes, gonadotroph tumours that express follicle-stimulating hormone (FSH) and/or luteinizing hormone still lack therapeutic options apart from surgery and radiotherapy. Activin ligands are physiological regulators of production and secretion of FSH by gonadotroph cells, but their role in gonadotroph tumourigenesis remains little explored. Using the LβT2 mouse gonadotroph cell line which produces FSH under activin stimulation, we first tested whether subcutaneous xenografts of LβT2 cells resulted in tumour formation in Rag2KO mice. Histological analysis confirmed the presence of LβT2 tumours with endothelial cells and macrophages in their microenvironment. FSH expression was found in a subset of clusters of LβT2 cells in the tumours. We subsequently addressed the consequences of targeting activin signalling via injection of a soluble activin decoy receptor (sActRIIB-Fc). sActRIIB-Fc treatment resulted in significantly decreased LβT2 tumour volume. Reduced Smad2 phosphorylation as well as inhibition of tumour-induced FSH production confirmed the efficient targeting of activin-downstream signalling in treated tumours. More interestingly, treated tumours showed significantly fewer endothelial cells associated with reduced Vegfa expression. In vitro treatment of LβT2 cells with sActRIIB-Fc had no effect on cell proliferation or apoptosis, but Vegfa expression was inhibited, pointing to a likely paracrine effect of LβT2 cells on endothelial cells through activin-mediated Vegfa regulation. Further in vitro and in vivo studies are now needed to pinpoint the exact roles of activin signalling in these processes prior to translating these observations to the clinic.

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C Christofer Juhlin, Ozgur Mete, and Zubair W Baloch

The fifth edition of the Classification of Endocrine and Neuroendocrine Tumors has been released by the World Health Organization. This timely publication integrates several changes to the nomenclature of non-neoplastic and neoplastic thyroid diseases, as well as novel concepts that are essential for patient management. The heterogeneous group of non-neoplastic and benign neoplastic lesions are now collectively termed as ‘thyroid follicular nodular disease’ to better reflect the clonal and non-clonal proliferations that clinically present as multinodular goiter. Thyroid neoplasms originating from follicular cells are distinctly divided into benign, low-risk and malignant neoplasms. The new classification scheme stresses that papillary thyroid carcinoma (PTC) should be subtyped based on histomorphologic features irrespective of tumor size to avoid treating all sub-centimeter/small lesions as low-risk disease. Formerly known as the cribriform-morular variant of PTC is redefined as cribriform-morular thyroid carcinoma since this tumor is now considered a distinct malignant thyroid neoplasm of uncertain histogenesis. The ‘differentiated high-grade thyroid carcinoma’ is a new diagnostic category including PTCs, follicular thyroid carcinomas and oncocytic carcinomas with high-grade features associated with poorer prognosis similar to the traditionally defined poorly differentiated thyroid carcinoma as per Turin criteria. In addition, squamous cell carcinoma of the thyroid is now considered a morphologic pattern/subtype of anaplastic thyroid carcinoma. In this review, we will highlight the key changes in the newly devised fifth edition of the WHO classification scheme of thyroid tumors with reflections on its applicability in patient management and future directions in this field.

Open access

Camilo Jimenez, Bennett B Chin, Richard B Noto, Joseph S Dillon, Lilja Solnes, Nancy Stambler, Vincent A DiPippo, and Daniel A Pryma

The objective of this study is to present the complete biomarker response dataset from a pivotal trial evaluating the efficacy and safety of high-specific-activity I-131 meta-iodobenzylguanidine in patients with advanced pheochromocytoma or paraganglioma. Biomarker status was assessed and post-treatment responses were analyzed for catecholamines, metanephrines, and serum chromogranin A. Complete biomarker response (normalization) or partial response, defined as at least 50% reduction from baseline if above the normal range, was evaluated at specified time points over a 12-month period. These results were correlated with two other study objectives: blood pressure control and objective tumor response as per RECIST 1.0. In this open-label, single-arm study, 68 patients received at least one therapeutic dose (~18.5 GBq (~500 mCi)) of high-specific-activity I-131 meta-iodobenzylguanidine. Of the patients, 79% and 72% had tumors associated with elevated total plasma free metanephrines and serum chromogranin A levels, respectively. Best overall biomarker responses (complete or partial response) for total plasma free metanephrines and chromogranin A were observed in 69% (37/54) and 80% (39/49) of patients, respectively. The best response for individual biomarkers was observed 6–12 months following the first administration of high-specific-activity I-131 meta-iodobenzylguanidine. Biochemical tumor marker response was significantly associated with both reduction in antihypertensive medication use (correlation coefficient 0.35; P = 0.006) as well as objective tumor response (correlation coefficient 0.36; P = 0.007). Treatment with high-specific-activity I-131 meta-iodobenzylguanidine resulted in long-lasting biomarker responses in patients with advanced pheochromocytoma or paraganglioma that correlated with blood pressure control and objective response rate. number: NCT00874614.

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Chunyan Hu, Manli Wang, Miao Hu, Shanshan Ma, Bingmo Yang, Wei Xiao, Qian Zhou, Ming Zhou, and Zhong Li

Genistein (GE), the most important phytoestrogen in diet, is known to behave as a partial agonist of estrogen receptor α and shows a proliferative effect on the growth of breast cancer cell lines. Recent research has reported that long-term consumption of low doses of GE results in hormone-independent growth phenotypes of MCF-7 tumors, with increased HER2. Overexpression of HER2 has been associated with endocrine resistance in human breast cancer, but whether long-term low-level GE-induced HER2 expression is the cause of endocrine resistance remains to be determined. Short-term and long-term treatments with GE may have different effects on HER2 expression. We found that low doses of GE had estrogen-like effects and inhibited HER2 expression after short-term exposure in estrogen receptor-positive breast cancers cells. However, in contrast to short-term exposure, long-term exposure induced an increase in HER2 expression, which led to endocrine resistance. During long-term low-level exposure, the continuous activation of ERK1/2-phosphorylated EZH2 at Ser21 resulted in a decrease of lysine 27 trimethylation. As H3K27me3 levels decreased, the expression of interleukin-6 (IL-6) and IL-8 increased, and HER2 levels gradually increased, forming a feedback loop of ERK1/2/EZH2/IL-6 and IL-8/HER2. We identified a novel pathway by which EZH2 phosphorylation contributed to long-term low-level GE-induced HER2 overexpression and provided new insight for long-term low-level GE-induced acquired endocrine resistance. For breast cancer patients, long-term low-level use of soy supplements has potential health risks, and monitoring dietary exposure to GE is advisable when patients are treated with tamoxifen.

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Francesca Branzoli, Betty Salgues, Małgorzata Marjańska, Marie Laloi-Michelin, Philippe Herman, Lauriane Le Collen, Brigitte Delemer, Julien Riancho, Emmanuelle Kuhn, Christel Jublanc, Nelly Burnichon, Laurence Amar, Judith Favier, Anne-Paule Gimenez-Roqueplo, Alexandre Buffet, and Charlotte Lussey-Lepoutre

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the ‘3PAs’ syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

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Andrea Abate, Mariangela Tamburello, Elisa Rossini, Ram Manohar Basnet, Giovanni Ribaudo, Alessandra Gianoncelli, Constanze Hantel, Deborah Cosentini, Marta Laganà, Salvatore Grisanti, Guido Alberto Massimo Tiberio, Maurizio Memo, Alfredo Berruti, and Sandra Sigala

The pharmacological approach to adrenocortical carcinoma (ACC) is based on mitotane with/without etoposide, doxorubicin, and cisplatin, according to the disease stage. Considering the limited efficacy and toxicity of this treatment, new strategies are required. Trabectedin is a marine-derivated antitumoral agent that inhibits oncogenic transcription. We have already demonstrated trabectedin cytotoxic activity at sub-nanomolar concentrations in ACC cells. Here, we expanded the investigation of trabectedin effect on ACC preclinical models, evaluating whether trabectedin could affect ACC cells’ invasiveness and metastasis formation. NCI-H295R, MUC-1, and TVBF-7 cell lines were used. Cell tumor xenografts in Danio rerio embryos were performed. The tumor mass areas and the number of embryos with metastasis were evaluated. The in vitro invasiveness of cells was evaluated. Effects of trabectedin of MMP2, TIMP1, and TIMP2 were evaluated at gene level qRT-PCR. MMP2 secreted in the cell medium was evaluated by Western blot and by zymography. Xenograft experiments demonstrated that trabectedin significantly reduced the tumor area in each ACC cell model and metastasis formation in embryos injected with metastasis-derived cell lines. Trabectedin treatment reduced the invasiveness of ACC cells across the matrix, which was greater at baseline for the metastatic models. In metastatic cell models, protein analysis demonstrated a reduction of MMP2 secretion and activity in the culture medium after treatment. Our results indicate that trabectedin interferes with invasiveness and metastasis processes, both dramatic features of ACC. Furthermore, these results support those previously published in providing the rationale for a clinical evaluation of the efficacy of trabectedin in ACC patients.

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Wenwen Li, Teng Wang, Guobin Fu, Yuan Xu, Nasha Zhang, Linyu Han, and Ming Yang

Papillary thyroid cancer (PTC) is one of the histological subtypes of thyroid cancer which is the most common endocrine malignancy in the world. The disrupted balance of the adenosine-to-inosine (A-to-I) RNA editing due to dysregulation of the editing genes exists in thyroid cancer. However, it is still largely unknown how functional single-nucleotide polymorphisms (SNPs) in the A-to-I RNA editing genes contribute to PTC genetic susceptibility. In this study, we systematically annotated and investigated the role of 28 potential functional SNPs of ADAR, ADARB1, ADARB2 and AIMP2 in PTC. We identified ADARB2 rs904957 and rs1007147 genetic variants which are associated with significantly elevated PTC risk in two case–control sets consisting of 2020 PTC cases and 2021 controls. Further investigations disclosed that ADARB2 could inhibit cell viability and invasion capabilities of PTC cells as a novel tumor suppressor. The ADARB2 rs904957 thymine-to-cytosine (T-to-C) polymorphism in gene 3'-untranslated region enhances miR-1180-3p-binding affinity and represses ADARB2 expression through an allele-specific manner. In line with this, carriers with the rs904957 C allele correlated with decreased tumor suppressor ADARB2 expression in tissue specimens showed notably increased risk of developing PTC compared to the T allele carriers. Our findings highlight that the A-to-I RNA editing gene ADARB2 SNPs confer PTC risk. Importantly, these insights would improve our understanding for the general roles of RNA editing and editing genes during cancer development.

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Xiang Zhang, Ya Hu, Ming Cui, Mengyi Wang, Xiaobin Li, Yalu Zhang, Sen Yang, Surong Hua, Meiping Shen, and Quan Liao

Tumour microenvironment has been recognized as a crucial factor influencing disease progression. However, relevant features and function are insufficiently understood in parathyroid neoplasia. Single-cell RNA sequencing was performed to profile the transcriptome of 27,251 cells from four parathyroid adenoma (PA) tissue samples. External transcriptomic datasets and immunofluorescence staining of a tissue microarray was set for expression validation. Eight major cell types and various subpopulations were finely identified in PA. We found that a subcluster of tumour endocrine cells with low copy number variation probably presented as a resting state. Diverse infiltrating immune cell subtypes were identified, constructing an immunosuppressive microenvironment. Tumour-associated macrophages, which indicated an anti-inflammatory phenotype, significantly increased in PA. Inflammatory tumour-associated fibroblasts (iTAFs) was newly verified and highlighted on the role of stromal-immune crosstalk. Positive correlation between iTAFs and increased CD163+ macrophages was uncovered. Moreover, CXCL12 and receptors signalling was important for tumour angiogenesis and immune infiltration. Our findings provide a comprehensive landscape interpreting tumour cell heterogeneity, cell diversity, and immune regulation in parathyroid neoplasia. The valuable resources may promote the understanding of parathyroid tumour microenvironment.

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Pia Roser, Bianca M Leca, Claudia Coelho, Klaus-Martin Schulte, Jackie Gilbert, Eftychia E Drakou, Christos Kosmas, Ling Ling Chuah, Husam Wassati, Alexander D. Miras, James Crane, Simon J B Aylwin, Ashley B. Grossman, and Georgios K. Dimitriadis

Parathyroid carcinoma is one of the least common endocrine malignancies, and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT,, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle-Ottawa Scale for observational studies.

Seventy-five studies were included from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The five-year overall survival ranged from 60% to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrants multidisciplinary management in a ‘centre of excellence’ with a track record in PC management.