ACTH-secreting medullary thyroid cancer: a case series

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing’s syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing’s syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing’s syndrome in metastatic MTC

Personalised Medicine for Thyroid Cancer

Background: Thyroid cancer incidence is increasing worldwide, including both indolent and advanced thyroid cancer. Radioactive iodine (RAI) is frequently used after total thyroidectomy to treat remnant thyroid tissue as well as microscopic and residual disease. Risk stratification is vital in thyroid cancer management to guide treatment decisions and to avoid over or under treatment. Method: Assess the changes in RAI administration at a quaternary centre over the past decade. Identify those factors associated with risk of thyroid cancer recurrence and develop a predictive model to personalise risk stratification. Establish the role of functional imaging techniques in radio-iodine refractory disease. Determine the utility of liquid biopsies in thyroid cancer. Results: Chapter Two describes a reduction in RAI activity prescription in a quaternary centre over the past decade, without evidence of a negative impact on cancer recurrence. Chapter Three identifies that factors additional to those described in current international guidelines are associated with thyroid cancer recurrence. A predictive risk model was built incorporating these risk factors into the algorithm. Chapter Four describes the development of an online clinical support tool to translate the predictive risk model into clinical practice. The tool was shown to have high clinical utility in a pilot study and was non inferior to expert clinical opinion. Chapter Five demonstrates the development of the I-PET score, which combines whole body iodine scans and FDG PET scans to aid prognostication and potentially identify candidates for redifferentiation therapy. Finally, Chapter Six demonstrates the utility of ctDNA to detect cancer driver mutations, monitor treatment response and potentially identify treatment resistance using a simple non-invasive blood test. Conclusion: This thesis provides a comprehensive body of research focused on providing personalised management for patients with thyroid cancer

Translational Utility of Liquid Biopsies in Thyroid Cancer Management

Liquid biopsies are a novel technique to assess for either circulating tumor cells (CTC) or circulating tumor DNA (ctDNA and microRNA (miRNA)) in peripheral blood samples of cancer patients. The diagnostic role of liquid biopsy in oncology has expanded in recent years, particularly in lung, colorectal and breast cancer. In thyroid cancer, the role of liquid biopsy in either diagnosis or prognosis is beginning to translate from the lab to the clinic. In this review, we describe the evolution of liquid biopsies in detecting CTC, ctDNA and miRNA in thyroid cancer patients, together with its limitations and future directions in clinical practice

MEN4, the MEN1 mimicker : a case series of three phenotypically heterogenous patients with unique CDKN1B mutations

Context: Germline CDKN1B pathogenic variants result in multiple endocrine neoplasia type 4 (MEN4), an autosomal dominant hereditary tumor syndrome variably associated with primary hyperparathyroidism, pituitary adenoma, and duodenopancreatic neuroendocrine tumors. Objective: To report the phenotype of 3 unrelated cases each with a unique germline CDKN1B variant (of which 2 are novel) and compare these cases with those described in the current literature. Design/Methods: Three case studies, including clinical presentation, germline, and tumor genetic analysis and family history. Setting: Two tertiary University Hospitals in Sydney, New South Wales, and 1 tertiary University Hospital in Canberra, Australian Capital Territory, Australia. Outcome: Phenotype of the 3 cases and their kindred; molecular analysis and tumor p27kip1 immunohistochemistry. Results: Family A: The proband developed multiglandular primary hyperparathyroidism, a microprolactinoma and a multifocal nonfunctioning duodenopancreatic neuroendocrine tumor. Family B: The proband was diagnosed with primary hyperparathyroidism from a single parathyroid adenoma. Family C: The proband was diagnosed with a nonfunctioning pituitary microadenoma and ectopic Cushing's syndrome from an atypical thymic carcinoid tumor. Germline sequencing in each patient identified a unique variant in CDKN1B, 2 of which are novel (c.179G >A, p.Trp60*; c.475G >A, p.Asp159Asn) and 1 previously reported (c.374_375delCT, p.Ser125*). Conclusions: Germline CDKN1B pathogenic variants cause the syndrome MEN4. The phenotype resulting from the 3 pathogenic variants described in this series highlights the heterogenous nature of this syndrome, ranging from isolated primary hyperparathyroidism to the full spectrum of endocrine manifestations. We report the first described cases of a prolactinoma and an atypical thymic carcinoid tumor in MEN4