Pheochromocytomatosis associated with a novel TMEM127 mutation

Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1–1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case

Adipocyte browning and higher mitochondrial function in peri-adrenal but not subcutaneous fat in pheochromocytoma

Context: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein (UCP) 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors. Objective: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME and subcutaneous (SC) fat depots in human adult pheo patients. Design: This was an observational cohort study. Setting: University hospital. Patients: We studied 46 patients who underwent surgery for benign adrenal tumors (21pheos and 25 controls with adrenocortical adenomas). Main outcome measure: We characterized adipocyte browning in pADR, SC, and OME fat depots for histological and immunohistological features, mitochondrial respiration rate, and gene expression. We also determined circulating levels of catecholamines and other browning-related hormones. Results: 11 of 21 pheo pADR adipose samples, but only 1 of 25 pADR samples from control patients, exhibited multilocular adipocytes. The pADR browning phenotype was associated with higher plasma catecholamines and raised UCP1. Mitochondria from multilocular pADR fat of pheo patients exhibited increased rates of coupled and uncoupled respiration. Global gene expression analysis in pADR fat revealed enrichment in β-oxidation genes in pheo patients with multilocular adipocytes. No SC or OME fat depots exhibited aspects of browning. Conclusion: Browning of the pADR depot occurred in half of pheo patients and was associated with increased catecholamines and mitochondrial activity. No browning was detected in other fat depots, suggesting that other factors are required to promote browning in these depots

Adrenal schwannoma can be FDG-Avid on PET/CT: case report and review of historic institutional pathology

Abstract Schwannomas are benign, generally indolent tumors of neural crest origin and comprise the most common histologic tumor of peripheral nerves. Schwannomas are a rare histology for retroperitoneal tumors and very rare histologic findings for tumors of the adrenal gland with fewer than 50 cases in the reported literature. Here we present a case report of a non-hormonally functional but metabolically active adrenal tumor with indeterminate imaging characteristics with final pathology showing a 6.1 cm adrenal schwannoma as well as historical institutional pathology review revealing two additional cases

Pheochromocytomatosis associated with a novel TMEM127 mutation.

Pheochromocytomatosis, a very rare form of pheochromocytoma recurrence, refers to new, multiple, and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma. We here report a case of pheochromocytomatosis in a 70-year-old female. At age 64 years, she was diagnosed with a 6-cm right pheochromocytoma. She underwent laparoscopic right adrenalectomy, during which the tumor capsule was ruptured. At age 67 years, CT of abdomen did not detect recurrence. At age 69 years, she began experiencing episodes of headache and diaphoresis. At age 70 years, biochemical markers of pheochromocytoma became elevated with normal calcitonin level. CT revealed multiple nodules of various sizes in the right adrenal fossa, some of which were positive on metaiodobenzylguanidine (MIBG) scan. She underwent open resection of pheochromocytomatosis. Histological examination confirmed numerous pheochromocytomas ranging 0.1-1.2 cm in size. Next-generation sequencing of a panel of genes found a novel heterozygous germline c.570delC mutation in TMEM127, one of the genes that, if mutated, confers susceptibility to syndromic pheochromocytoma. Molecular analysis showed that the c.570delC mutation is likely pathogenic. Our case highlights the typical presentation of pheochromocytomatosis, a rare complication of adrenalectomy for pheochromocytoma. Previous cases and ours collectively demonstrate that tumor capsule rupture during adrenalectomy is a risk factor for pheochromocytomatosis. We also report a novel TMEM127 mutation in this case. Pheochromocytomatosis is a very rare form of pheochromocytoma recurrence.Pheochromocytomatosis refers to new, multiple and often small pheochromocytomas growing in and around the surgical resection bed of a previous adrenalectomy for a solitary pheochromocytoma.Tumor capsule rupture during adrenalectomy predisposes a patient to develop pheochromocytomatosis.Surgical resection of the multiple tumors of pheochromocytomatosis is recommended.Pheochromocytoma recurrence should prompt genetic testing for syndromic pheochromocytoma

Systemic light-chain amyloidosis incidentally diagnosed after subtotal parathyroidectomy and thyroid lobectomy.

A 74-year-old woman with a history of primary hyperparathyroidism, thyroid nodules, atrial fibrillation and pacemaker placement for sick sinus syndrome presented with fatigue, constipation and persistent lower extremity oedema. She underwent subtotal parathyroidectomy and left thyroid lobectomy. Histopathology revealed amyloidosis affecting the thyroidand parathyroids confirmed by Congo Red Staining with Mayo Clinic subtyping of light chain kappa-type amyloidosis. She was found to have combined systolic and diastolic cardiac dysfunction, carpal tunnel neuropathy and pre-diabetes suggestive of systemic amyloidosis with involvement of the heart, nerves and pancreas. Congo red stain was positive for amyloidosis on bone marrow biopsy suggestive of a diagnosis of systemic amyloidosis. She was treated with daratumumab with good clinical response. This case illustrates the necessity of considering systemic amyloidosis in patients with incidentally discovered diffuse amyloid deposits on biopsy of an endocrine organ, as endocrine effects are a rare but likely underdiagnosed consequence of systemic amyloidosis

Longitudinal Assessment of Quality of Life Following Molecular Testing for Indeterminate Thyroid Nodules.

BackgroundMolecular testing can refine the risk of malignancy in cytologically indeterminate thyroid nodules and can reduce the need for diagnostic thyroidectomy. However, quality of life (QOL) in patients mananged with molecular testing is not well studied.ObjectiveWe aimed to assess the QOL of patients undergoing surveillance after a benign molecular test result, or thyroidectomy after a suspicious molecular test result.MethodsThis prospective longitudinal follow-up of the Effectiveness of Molecular Testing Techniques for Diagnosis of Indeterminate Thyroid Nodules randomized trial utilized the Thyroid-Related Patient-Reported Outcome, 39-item version (ThyPro-39) to assess the QOL of patients with indeterminate cytology on thyroid fine needle aspiration (FNA) biopsy. All patients underwent molecular testing at the time of initial FNA. A mixed-effect model was used to determine changes in QOL over time.ResultsOf 252 eligible patients, 174 completed the assessment (69% response rate). Molecular test results included 72% (n = 124) benign and 28% (n = 50) suspicious. ThyPro-39 scores of benign molecular test patients were unchanged from baseline (following initial FNA and molecular test results) to 18 months of ultrasound surveillance. Baseline symptoms of goiter, anxiety, and depression were more severe for patients with suspicious compared with benign molecular test results. At a median of 8 months after thyroidectomy, suspicious molecular test patients reported improved symptoms of goiter, anxiety, and depression.ConclusionA benign molecular test provides sustained QOL throughout ultrasound surveillance, without worsening anxiety or depression relating to the risk of malignancy. Definitive surgery results in improvement of QOL in patients with suspicious molecular tests

Patient Preference in Physician Decision-Making for Patients With Low- to Intermediate-Risk Differentiated Thyroid Cancer

This survey study describes the association between patient preference and physician decision-making in thyroid cancer

Diagnostic Value of Molecular Testing in Sonographically Suspicious Thyroid Nodules.

ObjectiveMolecular testing can refine the diagnosis for the 20% of thyroid fine-needle aspiration biopsies that have indeterminate cytology. We assessed the diagnostic accuracy of molecular testing based on ultrasound risk classification.MethodsThis retrospective cohort study analyzed all thyroid nodules with indeterminate cytology at an academic US medical center (2012-2016). All indeterminate nodules underwent reflexive molecular testing with the Afirma Gene Expression Classifier (GEC). Radiologists performed blinded reviews to categorize each nodule according to the American Thyroid Association (ATA) ultrasound classification and the American College of Radiology Thyroid Imaging, Reporting and Data System. GEC results and diagnostic performance were compared across ultrasound risk categories.ResultsOf 297 nodules, histopathology confirmed malignancy in 65 (22%). Nodules by ATA classification were 8% high suspicion, 44% intermediate, and 48% low/very low suspicion. A suspicious GEC result was more likely in ATA high-suspicion nodules (81%) than in nodules of all other ATA categories (57%; P = .04). The positive predictive value (PPV) of GEC remained consistent across ultrasound categories (ATA high suspicion, 64% vs all other ATA categories, 48%; P = .39). The ATA high-suspicion category had higher specificity than a suspicious GEC result (93% vs 51%; P < .01). A suspicious GEC result did not increase specificity for the ATA high-suspicion category.ConclusionThe PPV of molecular testing remained consistent across ultrasound risk categories. However, a suspicious GEC result was very likely in ATA high-suspicion nodules and did not improve specificity in this sonographic category

Recruitment and remodeling of peridroplet mitochondria in human adipose tissue.

Beige adipocyte mitochondria contribute to thermogenesis by uncoupling and by ATP-consuming futile cycles. Since uncoupling may inhibit ATP synthesis, it is expected that expenditure through ATP synthesis is segregated to a disparate population of mitochondria. Recent studies in mouse brown adipocytes identified peridroplet mitochondria (PDM) as having greater ATP synthesis and pyruvate oxidation capacities, while cytoplasmic mitochondria have increased fatty acid oxidation and uncoupling capacities. However, the occurrence of PDM in humans and the processes that result in their expansion have not been elucidated. Here, we describe a novel high-throughput assay to quantify PDM that is successfully applied to white adipose tissue from mice and humans. Using this approach, we found that PDM content varies between white and brown fat in both species. We used adipose tissue from pheochromocytoma (Pheo) patients as a model of white adipose tissue browning, which is characterized by an increase in the capacity for energy expenditure. In contrast with control subjects, PDM content was robustly increased in the periadrenal fat of Pheo patients. Remarkably, bioenergetic changes associated with browning were primarily localized to PDM compared to cytoplasmic mitochondria (CM). PDM isolated from periadrenal fat of Pheo patients had increased ATP-linked respiration, Complex IV content and activity, and maximal respiratory capacity. We found similar changes in a mouse model of re-browning where PDM content in whitened brown adipose tissue was increased upon re-browning induced by decreased housing temperature. Taken together, this study demonstrates the existence of PDM as a separate functional entity in humans and that browning in both mice and humans is associated with a robust expansion of peri-droplet mitochondria characterized by increased ATP synthesis linked respiration