Pheochromocytoma/paraganglioma (PPGL) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGV). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (fourteen patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remained had samples submitted to complete Next Generation Sequencing (NGS) aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) pathogenic or likely pathogenic variants and VUS and 20 (29.8%) carried only VUS. PGV were found in RET (N=18; 38.3%), VHL (N=10; 21.3%), SDHB and NF1 (N=8; 17% each), and MAX, SDHD, TMEM127, and TP53 (N=1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive (PPV) and negative (NPV) predictive values, respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.
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Jose Viana Lima-Jr, Nilza Maria Scalissi, Kelly Cristina dr Oliveira, Susan C. Lindsey, Caroline Olivati, Elisa Napolitano Ferreira, and Claudio E. Kater
Stéphanie Larose, Dany Rioux, Roula Albadine, and Andre Lacroix
Ectopic ACTH secretion (EAS) is a rare cause of ACTH-dependent Cushing’s syndrome (CS), most often caused by a thoracic neuroendocrine tumor (NET). Large-cell neuroendocrine carcinomas (LCNEC) with EAS are rare and usually present a more severe ACTH secretion and hypercortisolism. We report a 44-yo non-smoker man, who presented clinical and biochemical evidence of ACTH-dependent CS. Desmopressin 10 mcg iv produced a 157% increase in ACTH and a 25% increase in cortisol from baseline; there was no stimulation of ACTH or cortisol during the CRH test and no suppression with high dose dexamethasone. Pituitary MRI identified a 5 mm lesion, but inferior petrosal venous sinus sampling (IPSS) under desmopressin did not identify a central ACTH source. Thorax and abdominal imaging identified a left lung micronodule. Surgery confirmed a lung LCNEC with strongly positive ACTH immunohistochemistry (IHC) in the primary and lymph node metastasis The patient was in CS remission after surgery and adjuvant chemotherapy, but developed a recurrence 9.5 years later, with LCNEC pulmonary left hilar metastases, ectopic CS, and positive ACTH IHC. This is the first report of LCNEC, with morphologic feature of carcinoid tumor of the lung with ectopic ACTH stimulated by desmopressin. Long delay prior to metastatic recurrence indicates relatively indolent NET. This case report indicates that response to desmopressin, which usually occurs in Cushing’s disease or benign neuroendocrine tumors, can occur in malignant LCNEC.
Nele F Lenders, Peter E Earls, Warrick J. Inder, and Ann I McCormack
Objective: Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective.
Results: In 2004, pituitary tumours were classified as ‘typical’ or ‘atypical’, based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms ‘typical’ and ‘atypical’ were omitted, though the importance of proliferative markers Ki67 and mitotic count were acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well differentiated tumours. Whilst ‘high risk’ tumour types have been identified, further work is still required to improve prognostication.
Conclusions: Recent WHO classifications have marked significant progress in diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.
Molly Endicott, Chrissie Thirlwell, and Amy Webster
Diabetes and cancer are two heterogenous diseases which are rapidly increasing in prevalence globally. A link between these two non-communicable diseases was first identified over 100 years ago however, recent epidemiological studies and advances in genomic research have provided greater insight into the association between diabetes and cancer. Epidemiological studies have suggested that individuals with diabetes have an increased risk of several types of cancer (including liver, pancreas, colorectal, breast and endometrial) and an increased risk of cancer mortality. However, this increased risk is not observed in all cancers, for example, there is a reduced risk of prostate cancer in individuals with diabetes. It has also been observed that cancer patients have an increased risk of developing diabetes, highlighting that the relationship between these diseases is not straightforward. Evidence of a shared genetic aetiology along with numerous lifestyle and clinical factors have made it challenging to establish if the relationship between the two diseases is causal or a result of confounding factors. This review takes a pan-cancer approach to highlight the complexities of the interactions between type 2 diabetes (T2D) and cancer development indicating where advances in genomic research have enabled a greater insight into these two diseases.
Katherine A English, Rajesh V Thakker, and Kate E Lines
Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the Multiple Endocrine Neoplasia 1 (MEN1), ATRX Chromatin Remodeler (ATRX), and Death Domain Associated Protein (DAXX) genes, which are found in ~ 40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription via 5’methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG rich areas around gene promoters. However, 5’hydroxymethylcytosine (5hmC), which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have facilitated investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies.
Joel George, John Ramage, Benjamin White, and Rajaventhan Srirajaskanthan
Carcinoid syndrome is the most frequent hormonal complication associated with Neuroendocrine neoplasms. It was first reported in 1954 and the classical symptoms are diarrhoea, flushing and abdominal pain. It is caused by the secretion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patient’s Quality of Life. There are a variety of management options for carcinoid syndrome including medical, surgical and loco-regional interventional radiological procedures. The most widely used are somatostatin analogues with three clinically approved drugs; lanreotide and octreotide (first-generation), and pasireotide (second-generation). Both Everolimus and Interferon used in combination with octreotide have shown significant reduction in urinary 5-HIAA compared to octreotide alone. Telotristat ethyl has been increasingly utilised more for patients with symptoms despite taking somatostatin analogues. It has also been shown to have a significant improvement in bowel movement frequency which was associated with a significant improvement in Quality of Life. Peptide Receptor Radionuclide Therapy has proven symptomatic improvement in patients with uncontrolled symptoms. Chemotherapy is primarily reserved for patients with high proliferation tumours, with limited research on the efficacy in reducing symptoms. Surgical resection remains the optimal treatment due to being the only one that can achieve cure. Liver Directed Therapies are considered in patients where curative resection is not possible. There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.
Annabelle G Hayes, Masoumeh G Shirazi, Anand Thiyagarajah, David J Torpy, and Sunita M C De Sousa
Cabergoline-associated valvulopathy (CAV) is defined by the echocardiographic triad of moderate or severe regurgitation, valvular thickening and restricted valvular motion. While it is a well-described complication of dopamine agonist therapy in Parkinson’s disease, only three convincing cases of CAV have previously been described in the treatment of prolactinoma, with none involving the tricuspid valve. We describe a case of CAV affecting the tricuspid valve, ultimately resulting in the patient’s death. The novel finding of CAV affecting the tricuspid valve suggests a possible link between confirmed cases of CAV and the echocardiographic surveillance studies of cabergoline-treated prolactinoma patients which have mostly demonstrated subclinical tricuspid valve changes. The risk of CAV, although small, prompts a mindful prescription of dopamine agonist therapy for prolactinomas and consideration of measures to minimise cabergoline exposure. The cumulative cabergoline doses and duration of therapy associated with CAV in published cases exceed what has been evaluated in case series and surveillance studies, underscoring the importance of case reports in understanding CAV.
Sofia Maria Lider Burciulescu, Caren Randon, Frederic Duprez, Wouter Huvenne, David Creytens, Kathleen B M Claes, Robin de Putter, Guy T’Sjoen, Corin Badiu, and Bruno Lapauw
Pheochromocytomas (PHEO) and paragangliomas (PGL) can occur sporadic or within genetic predisposition syndromes. Despite shared embryology, there are important differences between PHEO and PGL. The aim of this study was to describe the clinical presentation and disease characteristics of PHEO/PGL. A retrospective analysis of consecutively registered patients diagnosed with or treated for PHEO/PGL in a tertiary care centre was performed. Patients were compared according to anatomic location (PHEO vs PGL) and genetic status (sporadic vs hereditary). In total, we identified 38 women and 29 men, aged 50 ± 19 years. Of these, 42 (63%) had PHEO, and 25 (37%) had PGL. Patients with PHEO presented more frequently with sporadic than hereditary disease (45 years vs 27 (77%) vs 8 (23%)) than patients with PGL (9 (36%) vs 16 (64%), respectively) and were older at diagnosis (55 ± 17 vs 40 ± 18 years, P = 0.001), respectively). About half of the cases in both PHEO and PGL were diagnosed due to disease-related symptoms. In patients with PHEO, tumour diameter was larger (P = 0.001), metanephrine levels higher (P = 0.02), and there was more frequently a history of cardiovascular events than in patients with PGL. In conclusion, we found that patients with PGL more frequently have a hereditary predisposition than those with PHEO, contributing to the fact that diagnosis is generally made earlier in PGL. Although diagnosis in both PHEO and PGL was mostly due to related symptoms, patients with PHEO more often presented with cardiovascular comorbidities than those with PGL which might relate to a higher number of functionally active tumours in the former.
Trinidad Raices, María Luisa Varela, Adriana María Belén Abiuso, Elba N Pereyra, Carolina Mondillo, Omar P Pignataro, and María Fernanda Riera
Curcumin has been ascribed with countless therapeutic effects, but its impact on testicular function has been scarcely researched. Leydig cells comprise the androgen-secreting population of the testis and may give rise to Leydig cell tumours (LCTs). Due to their steroid-secreting nature, LCTs entail endocrine, reproductive, and psychological disorders. Approximately 10% are malignant and do not respond to chemotherapy and radiotherapy. The aim of this study was to assess curcumin’s impact on Leydig cells’ functions and its potential effect on LCT growth. In vitro assays on MA-10 Leydig cells showed that curcumin (20–80 µmol/L) stimulates acute steroidogenesis, both in the presence and absence of db-cAMP. This effect is accompanied by an increase in StAR expression. Regarding curcumin’s in vitro cytostatic capacity, we show that 40–80 µmol/L curcumin reduces MA-10 Leydig cells’ proliferative capacity, which could be explained by the arrest in G2/M and the reduced viability due to the activation of the apoptotic pathway. Finally, CB6F1 mice were inoculated with MA-10 cells to generate ectopic LCT in both flanks. They received i.p. injections of 20 mg/kg curcumin or vehicle every other day for 15 days. We unveiled curcumin’s capacity to inhibit LCT growth as evidenced by reduced tumour volume, weight, and area under the growth curves. No detrimental effects on general health parameters or testicular integrity were observed. These results provide novel evidence of curcumin’s effects on the endocrine cell population of the testis and propose this natural compound as a therapeutic agent for LCT.