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Center for Diabetes and Endocrine Research, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA
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Summary
Large-cell neuroendocrine carcinoma (LCNEC) is a rare neuroendocrine prostatic malignancy. It usually arises after androgen deprivation therapy (ADT), while de novo cases are even more infrequent, with only six cases described. The patient was a 78-year-old man with no history of ADT who presented with cervical lymphadenopathy. Diagnostic approaches included PET/CT, MRI, CT scans, ultrasonography, biopsies, and cytological and immunohistochemical evaluations. Results showed a poorly differentiated carcinoma in the thyroid gland accompanied by cervical lymph node enlargement. Thyroid surgery revealed LCNEC metastasis to the thyroid gland. Additional metastases were identified in both the adrenal glands. Despite appropriate treatment, the patient died of the disease. De novo LCNEC of the prostate is a rare, highly aggressive tumor with a poor prognosis. It is resistant to most therapeutic agents, has a high metastatic potential, and is usually diagnosed at an advanced stage. Further studies are required to characterize this tumor.
Learning points
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De novo LCNECs of the prostate gland can metastasize almost anywhere in the body, including the thyroid and adrenal glands.
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LCNECs of the prostate are usually associated with androgen-depriving therapy, but de novo cases are also notable and should be accounted for.
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Further studies are required to fully understand and treat LCNECs more effectively.
Search for other papers by Iris Dirven in
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Summary
The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up.
Learning points
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Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy.
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A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination.
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For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.
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University of Melbourne, Parkville, Victoria, Australia
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Summary
Acanthosis nigricans (AN) is a common dermatosis associated with hyperinsulinemia and insulin resistance. However, AN has been rarely reported in patients with insulinoma, a state of persistent hyperinsulinemia. We present a case of metastatic insulinoma, in whom AN manifested after the first cycle of peptide receptor radionuclide therapy (PRRT). A 40-year-old man was diagnosed with metastatic insulinoma after 5 months of symptomatic hypoglycemia. Within 1 month post PRRT, the patient became euglycemic but developed a pigmented, pruritic rash which was confirmed on biopsy as AN. We discuss the rare manifestation of AN in subjects with insulinoma, the role of insulin in the pathogenesis of AN, malignant AN in non-insulin-secreting malignancies and association with other insulin-resistant endocrinopathies such as acromegaly.
Learning points
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Acanthosis nigricans (AN) is a common dermatosis which is typically asymptomatic and associated with the hyperinsulinemic state.
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Malignant AN can rapidly spread, cause pruritus and affect mucosa and the oral cavity.
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AN is extremely rare in patients with insulinoma despite marked hyperinsulinemia.
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Peptide receptor radionuclide therapy might have triggered TGF-α secretion in this subject which led to malignant AN.
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Rapid spread or unusual distribution of pruritic AN warrants further investigation to exclude underlying malignancy.
Search for other papers by Adrian Po Zhu Li in
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Division of Cancer Studies, King’s College London, London, UK
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Faculty of Life Sciences and Medicine, School of Life Course Sciences, King’s College London, London, UK
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Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, UK
Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
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Search for other papers by Simon J B Aylwin in
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Obesity, Type 2 Diabetes and Immunometabolism Research Group, Department of Diabetes, Faculty of Life Sciences, School of Life Course Sciences, King’s College London, London, UK
Division of Reproductive Health, Warwick Medical School, University of Warwick, Coventry, UK
Search for other papers by Georgios K Dimitriadis in
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Summary
A 49-year-old teacher presented to his general physician with lethargy and lower limb weakness. He had noticed polydipsia, polyuria, and had experienced weight loss, albeit with an increase in central adiposity. He had no concomitant illnesses and took no regular medications. He had hypercalcaemia (adjusted calcium: 3.34 mmol/L) with hyperparathyroidism (parathyroid hormone: 356 ng/L) and hypokalaemia (K: 2.7 mmol/L) and was admitted for i.v. potassium replacement. A contrast-enhanced CT chest/abdomen/pelvis scan revealed a well-encapsulated anterior mediastinal mass measuring 17 × 11 cm with central necrosis, compressing rather than invading adjacent structures. A neck ultrasound revealed a 2 cm right inferior parathyroid lesion. On review of CT imaging, the adrenals appeared normal, but a pancreatic lesion was noted adjacent to the uncinate process. His serum cortisol was 2612 nmol/L, and adrenocorticotrophic hormone was elevated at 67 ng/L, followed by inadequate cortisol suppression to 575 nmol/L from an overnight dexamethasone suppression test. His pituitary MRI was normal, with unremarkable remaining anterior pituitary biochemistry. His admission was further complicated by increased urine output to 10 L/24 h and despite three precipitating factors for the development of diabetes insipidus including hypercalcaemia, hypokalaemia, and hypercortisolaemia, due to academic interest, a water deprivation test was conducted. An 18flurodeoxyglucose-PET (FDG-PET) scan demonstrated high avidity of the mediastinal mass with additionally active bilateral superior mediastinal nodes. The pancreatic lesion was not FDG avid. On 68Ga DOTATE-PET scan, the mediastinal mass was moderately avid, and the 32 mm pancreatic uncinate process mass showed significant uptake. Genetic testing confirmed multiple endocrine neoplasia type 1.
Learning points
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In young patients presenting with primary hyperparathyroidism, clinicians should be alerted to the possibility of other underlying endocrinopathies.
In patients with multiple endocrine neoplasia type 1 (MEN-1) and ectopic adrenocorticotrophic hormone syndrome (EAS), clinicians should be alerted to the possibility of this originating from a neoplasm above or below the diaphragm.
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Although relatively rare compared with sporadic cases, thymic carcinoids secondary to MEN-1 may also be associated with EAS.
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Electrolyte derangement, in particular hypokalaemia and hypercalcaemia, can precipitate mild nephrogenic diabetes insipidus.
Search for other papers by Vinaya Srirangam Nadhamuni in
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Summary
A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.
Learning points
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It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (1): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation (1).
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Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis.
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Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (1). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.
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Search for other papers by Miguel Debono in
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Summary
In this case report, we describe the management of a patient who was admitted with an ectopic ACTH syndrome during the COVID pandemic with new-onset type 2 diabetes, neutrophilia and unexplained hypokalaemia. These three findings when combined should alert physicians to the potential presence of Cushing’s syndrome (CS). On admission, a quick diagnosis of CS was made based on clinical and biochemical features and the patient was treated urgently using high dose oral metyrapone thus allowing delays in surgery and rapidly improving the patient’s clinical condition. This resulted in the treatment of hyperglycaemia, hypokalaemia and hypertension reducing cardiovascular risk and likely risk for infection. Observing COVID-19 pandemic international guidelines to treat patients with CS has shown to be effective and offers endocrinologists an option to manage these patients adequately in difficult times.
Learning points
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This case report highlights the importance of having a low threshold for suspicion and investigation for Cushing’s syndrome in a patient with neutrophilia and hypokalaemia, recently diagnosed with type 2 diabetes especially in someone with catabolic features of the disease irrespective of losing weight.
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It also supports the use of alternative methods of approaching the diagnosis and treatment of Cushing’s syndrome during a pandemic as indicated by international protocols designed specifically for managing this condition during Covid-19.
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Search for other papers by Maria M Byrne in
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Summary
A 41-year-old male presented to the Emergency Department with a 6-month history of back and hip pain. Skeletal survey revealed bilateral pubic rami fractures and MRI of the spine demonstrated multiple thoracic and lumbar fractures. Secondary work up for osteoporosis was undertaken. There was no evidence of hyperparathyroidism and the patient was vitamin D replete. Testosterone (T) was low at 1.7 nmol/L (8.6–29.0) and gonadotrophins were undetectable. The patient failed a 1 mg dexamethasone suppression test (DST) with a morning cortisol of 570 nmol/L (<50) and subsequently a low dose DST with a cortisol post 48 h of dexamethasone of 773 nmol/L (<50) and an elevated ACTH 98 ng/L. A corticotropin-releasing factor (CRF) test suggested ectopic ACTH secretion. The patient was commenced on teriparatide for osteoporosis and metyrapone to control the hypercortisolaemia. A positron emission tomography (PET) scan to look for the source of ACTH secretion demonstrated right neck adenopathy. Biopsy and subsequent lymph node dissection were performed and histology revealed a metastatic neuroendocrine tumour. Immunostaining was positive for calcitonin and thyroid transcription factor 1 (TTF1). Serum calcitonin was also significantly elevated at 45 264 ng/L (<10). The patient proceeded to a total thyroidectomy and left neck dissection. Histology confirmed a 7 mm medullary thyroid carcinoma (MTC). Post-operatively, the patient commenced vandetanib therapy and achieved a clinical and biochemical response. After approximately 18 months of vandetanib therapy, the patient developed recurrent disease in his neck. He is currently on LOXO-292 and is doing well 36 months post-diagnosis.
Learning points
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Unexplained osteoporosis requires thorough investigation and the workup for secondary causes is not complete without excluding glucocorticoid excess.
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MTC should be considered when searching for sources of ectopic ACTH secretion.
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Resistance to tyrosine kinase inhibitors is well described with MTC and clinicians should have a low threshold for screening for recurrent disease.
Search for other papers by Celina Caetano in
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Search for other papers by Faripour Forouhar in
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Division of Pediatric Hematology/Oncology, Connecticut Children’s Medical Center, Hartford, Connecticut, USA
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Search for other papers by Carl Malchoff in
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Summary
Familial paraganglioma syndrome type 1 (PGL-1) is maternally imprinted, caused by SDHD mutations on the paternally inherited allele, and presents with paragangliomas and pheochromocytomas that are usually benign. We describe a kindred with a germline c.57delG SDHD mutation that demonstrates an aggressive and possibly expanded phenotype. Eight individuals across four generations were heterozygous for the c.57delG SDHD mutation. The three with known paternal inheritance were clinically affected. The aggressive phenotype was manifested by a neck paraganglioma with distant metastases, and to a lesser degree a neck paraganglioma infiltrating into local connective tissue and a pheochromocytoma presenting at age 8 y. A pulmonary capillary hemangioma may expand the SDHD phenotype. We conclude that the c.57delG SDHD mutation may confer a more aggressive and possibly expanded phenotype than other SDHD mutations.
Learning points:
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The c.57delG SDHD mutation may confer a more aggressive phenotype than other mutations associated with familial paraganglioma syndrome type 1.
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A capillary hemangioma, a component of other pseudohypoxia states, was observed in the lung of a single member of the c.57delG SDHD kindred.
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This report supports the hypothesis of others that mutations found near the beginning of the SDHD open reading frame are more likely to demonstrate an aggressive phenotype.
Search for other papers by Michele Fosci in
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Summary
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
Learning points:
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A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists.
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In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical.
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The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis.
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This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
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School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
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Pituitary adenomas are the commonest sellar tumours. Pituitary metastases are very rare, with the most common primaries being breast and lung cancers. We report the case of an 83-year-old man with a history of breast carcinoma who presented with recent-onset headaches and progressive deterioration of visual acuity. MRI brain showed a large sellar and suprasellar mass compressing the optic chiasm and involving the pituitary stalk. Transsphenoidal debulking resulted in symptomatic relief and visual recovery. Specimen examination revealed a combination of a gonadotroph pituitary adenoma that was infiltrated by metastatic breast carcinoma. He had no symptoms of diabetes insipidus. He was subsequently treated with pituitary radiotherapy. This is a very rare presentation of a pituitary mass with mixed pathology. To our knowledge, this is the third description of a breast carcinoma metastasis into a gonadotroph cell pituitary adenoma.
Learning points:
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Infiltrating metastases into pituitary adenomas are very rare but do occur.
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To our knowledge this is the third case of breast adenocarcinoma metastasising to a gonadotroph pituitary adenoma.
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Pituitary metastases should always be considered in rapidly evolving pituitary symptoms in a cancer patient.
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Not all complex pituitary lesions are associated with panhypopituitarism.
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Early invasive local management (TSS and post TSS radiotherapy) can provide rapid satisfactory outcomes.