Pituitary tumors and the risk of other malignancies- is the relationship coincidental or causal?

Pituitary adenomas are benign neoplasms of the pituitary. The most prevalent are prolactinomas and nonfunctioning pituitary adenomas, followed by growth hormone- and ACTH-secreting adenomas. Most pituitary adenomas seem to be sporadic and their persistent growth is very atypical. No molecular markers predict their behavior. The occurrence of pituitary adenomas and malignancies in the same patient can be either pure coincidence or caused by shared underlying genetic susceptibility involved in tumorigenesis. Detailed family history on cancers/tumors in the first, second and third generation of family members on each side of the family has been reported in a few studies. They found an association of pituitary tumors with positive family history for breast, lung and colorectal cancer. We have reported that in about 50% of patients with pituitary adenomas an association with positive family history for cancer has been found independent of secretory phenotype (acromegaly, prolactinoma, Cushingʼs disease or non-functioning pituitary adenomas). We also found earlier onset of pituitary tumors (younger age at diagnosis of pituitary tumors) in patients with strong family history of cancer. In our recent unpublished series of 1300 patients with pituitary adenomas, 6.8% of patients were diagnosed with malignancy. The latency period between the diagnosis of pituitary adenoma and cancer was variable and in 33% of patients was longer than 5 years. Besides the inherited trophic mechanisms (shared underlying genetic variants), the potential influence of shared complex epigenetic influences (environmental and behavioral factors -obesity, smoking, alcohol intake, insulin resistance) is discussed. Further studies are needed to better understand if patients with pituitary adenomas are at increased risk for cancer.

Investigating the clinical, pathological and molecular profile of oncocytic adrenocortical neoplasms

Background: Malignant oncocytic adrenocortical neoplasms (OANs) are rare tumours with a distinctive biological behavior compared to conventional adrenocortical carcinoma (ACC). The current prognostic systems overestimate the malignant potential of these tumours and guidance for surveillance and treatment strategies are lacking. Aim: To evaluate the utility of clinical, pathological and molecular markers in predicting the biological behavior and outcomes of malignant OANs. Methods: A retrospective clinicopathological review of ten histologically confirmed OANs was carried out. Whole exome sequencing (WES) of germline and paired tumour samples was performed for four of the ten OAN cases and compared to WES data from five cases of conventional ACC and data from The Cancer Genome Atlas (TCGA). We reviewed all cases of malignant OAN reported in the literature and compared to our case series. Results: Eight (80%) tumours were classified as malignant, one borderline and one benign (Lin-Weiss-Bisceglia criteria: LWB). The malignant OAN were larger tumours and had higher MIB index and Helsinki scores. Molecular profiling identified a pathogenic germline variant in MSH6 in an individual in the OAN group. The OAN samples had a lower mutation burden compared to the ACC samples. Somatic driver variants were identified in OAN and ACC samples including a pathogenic missense variant in CTNNB1. Conclusion: In this study, the LWB classification demonstrated sensitivity for the differentiation of benign from malignant OAN. Molecular profiling identified dysregulation in DNA repair and Wnt signaling pathways in both OAN and ACC samples, suggesting a molecular overlap between OAN and conventional ACC.

Hypoxia stimulates angiogenesis and a metabolic switch in human parathyroid adenoma cells

Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are however, unknown. We therefore assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic andydrase 9 (CA9), solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions, and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1) were increased, however Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biasing towards proliferation. Overall, there appeared to be a shift in growth factor signaling pathways from Jak-Stat and Ras signaling, to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.

cfDNA in pancreatic neuroendocrine carcinoma management with Cushing’s syndrome

We report a case of metastatic pancreatic neuroendocrine carcinoma associated with paraneoplastic Cushing’s syndrome, successively treated with five lines of treatment (platin-etoposide, LV5FU2-dacarbazine, Folfirinox, pembrolizumab, and paclitaxel) and anti-secretory treatment. Circulating-free DNA (cfDNA) was analysed at each morphological evaluation starting from the second-line treatment. cfDNA changes were well-correlated with the disease course, and cfDNA may be used as a predictive marker and/or an early marker of response. In addition, absolute count of atypical cells was elevated upon disease progression.

Serum osteopontin can improve papillary thyroid cancer risk assessment of Bethesda III thyroid nodules: a preliminary study

Objective: Thyroid cancer can be detected in 5–10% of patients with thyroid nodules. Management may be a challenge if fine-needle aspiration biopsy yields Bethesda III findings. Most of these cases undergo surgery and are ultimately found benign. Our aim was to evaluate whether serum osteopontin can accurately estimate thyroid cancer risk in cases with cytologically Bethesda III thyroid nodules and, thereby, decrease the number of unnecessary surgical interventions. Design and Methods: We obtained blood samples of cases with repeated cytologically Bethesda III thyroid nodules before surgery, and followed up the pathology results after thyroidectomy. We evaluated serum osteopontin from 36 patients with papillary thyroid cancer and compared them with 40 benign cases. Results: Serum osteopontin levels in patients with papillary thyroid cancer are significantly higher than in benign cases (mean serum osteopontin: 10.48 ± 3.51 ng/mL vs 6.14 ± 2.29 ng/mL, p<0.001). The area under the receiver operating characteristics curve was 0.851, suggesting that serum osteopontin could have considerable discriminative performance. Conclusions: In our preliminary study, high serum osteopontin levels can predict the risk of papillary thyroid cancer in thyroid nodules with Bethesda III cytology. Further studies are necessary to confirm these findings.

FOXE1 polymorphism rs965513 predisposes to thyroid cancer in a European cohort

Objective: FOXE1 is an intronless gene on chromosome 9 which plays a significant role in thyroid morphogenesis. Mutations in FOXE1 are associated with thyroid phenotypes including congenital hypothyroidism, thyroid dysgenesis and thyroid cancer. This study aims to investigate the frequency and impact of a single nucleotide polymorphism(rs965513, G>A) at 9q22.23 in a Western European cohort of patients with differentiated thyroid cancer(DTC), compared to controls. Design: This is a candidate gene case control study. Methods: 277 patients with histologically confirmed DTC were recruited from tertiary referral centres in Ireland and France. 309 cancer-free controls were recruited from the community. DNA was extracted from buccal swabs or whole blood of control subjects and patients with DTC. Allelic and genotypic frequencies among patients were compared with controls, to assess the risk for disease conferred by homozygous and heterozygous carriers compared to wild-type genotypes. Genotyping was performed using Taqman-based PCR. Results: 277 patients with confirmed DTC and 309 non-cancer controls were genotyped. The frequency of the minor allele among cases was 0.45 compared to 0.34 among controls. The genotypic odds ratio for heterozygotes was 1.66(CI 1.16-2.39, p=0.00555), increasing to 2.93(CI 1.70-5.05, p=0.00007) for rare homozygotes. All subjects were in Hardy-Weinberg equilibrium(X2, p=0.09, p=0.07 respectively). Conclusions: This FOXE1 polymorphism is a low penetrance variant associated with DTC susceptibility in this cohort. The minor allele was identified among patients with thyroid cancer significantly more frequently than controls. An allele dosage effect was observed, with rare homozygous genotypes conferring greater risk than heterozygotes.

Epidemiology of craniopharyngiomas: a population based study in Malta

Background: Despite being benign tumours, craniopharyngiomas are challenging to manage and can cause significant morbidity and mortality in both the paediatric and adult population. The aim of the study was to analyse epidemiology of craniopharyngioma, patient and tumour characteristics through a population-based study in Malta, enabling a better quantification of the disease burden. Method: A thorough research was carried out to identify the number of patients who were diagnosed with craniopharyngiomas. Epidemiological data, including both Standardised incidence rates (SIR) and prevalence rates were established in a well-defined population. For incidence estimates, patients who were diagnosed between 2008 and 2019 were included. The background population formed 4.8 million patient-years at risk. Result: 29 subjects were identified and included in our study. The overall SIR was 0.3/100,000/year, with a higher SIR for males compared to females (0.4/100,000/year and 0.2/100,000/year, respectively). The highest SIR was recorded in the 10-19 year age group. The estimated prevalence rate amounted to 5.27/100,000 people, with a lower prevalence rate for childhood onset when compared to the adult-onset category (2.03/100,000 vs 3.24/100,000 people). The median longest tumour diameter was 31.0mm (IQR 21-41), with statistically significant difference between childhood- and adult-onset disease; 43.0mm (IQR 42.5-47.25) vs 27.0mm (IQR 20.55-31.55) (P=0.011). Conclusion: Through this population-based study, accurate and up-to-date prevalence and incidence rates for craniopharyngiomas are reported. These provide a clearer reflection of the true health burden of the disease.