Multiple Endocrine Neoplasia Type 2A Research Articles

Developing Dynamic Structure-Based Pharmacophore and ML-Trained QSAR Models for the Discovery of Novel Resistance-Free RET Tyrosine Kinase Inhibitors.

Activation of RET tyrosine kinase plays a critical role in the pathogenesis of various cancers, including non-small cell lung cancer, papillary thyroid cancers, multiple endocrine neoplasia type 2A and 2B (MEN2A, MEN2B), and familial medullary thyroid cancer. Gene fusions and point mutations in the RET proto-oncogene result in constitutive activation of RET signaling pathways. Consequently, developing effective inhibitors to target RET is of utmost importance. Small molecules have shown promise as inhibitors by binding to the kinase domain of RET and blocking its enzymatic activity. However, the emergence of resistance due to single amino acid changes poses a significant challenge. In this study, a structure-based dynamic pharmacophore-driven approach using E-pharmacophore modeling from molecular dynamics trajectories is proposed to select low energy favorable hypotheses, and ML-trained QSAR models to predict pIC50 values of compounds. For this aim, extensive small molecule libraries were screened using developed ligand-based models and potent compounds which are capable of inhibiting RET activation were proposed.

Familial DICER1 syndrome with thyroid pathology. A series of clinical cases

Thyroid diseases in childhood occupy the second place after obesity in the structure of the general pathology of the endocrine system, eating disorders and metabolic disorders in children in the Russian Federation. Thyroid cancer in children makes up from 1.5 to 3 % of all malignant tumors, and from 8 to 22 % of malignant solid tumors of the head and neck, and the younger the child’s age, the more aggressive the disease proceeds.Familial forms of thyroid diseases may be associated with geographical features (living in iodine-deficient regions), but may also be part of hereditary syndromes, such as: multiple endocrine neoplasia syndromes (Sipple syndrome, Gorner syndrome, familial medullary thyroid cancer), DICER1 syndrome, Gardner syndrome, Cowden syndrome, McCune–Albright–Braitsev syndrome et al.This article describes several cases of thyroid pathology associated with DICER1 syndrome.

Robotic Left Partial Adrenalectomy in Multiple Endocrine Neoplasia Type 2A and Previous Total Right Adrenalectomy

Robotic Left Partial Adrenalectomy in Multiple Endocrine Neoplasia Type 2A and Previous Total Right Adrenalectomy

Multiple endocrine neoplasia type 2A syndrome presenting with corneal nerve thickening.

Multiple endocrine neoplasia type 2A syndrome presenting with corneal nerve thickening.

SAT521 Predictive Value of Tumor Volumetrics in Patients with Medullary Thyroid Cancer

Abstract Disclosure: N. Behairy: None. S. Gubbi: None. M.G. Pascoal: None. A. Bharadwaj: None. E.C. Wright: None. T. Abijo: None. N. Uttarkar Vikram: None. P. Veeraraghavan: None. C. Cochran: None. J. Glod: None. J. Klubo-Gwiezdzinska: None. Predictive Value of Tumor Volumetrics in Patients with Medullary Thyroid Cancer Background Medullary thyroid cancer (MTC) is a rare endocrine malignancy that can present either as a sporadic disease or as a part of inherited autosomal dominant multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B) syndromes. There is limited data on the prognostic value of the tumor volume (TV) doubling time (TVDT) in patients with sporadic and familial MTC. Therefore, the goal of this study was to examine the association between TVDT and disease-specific survival (DSS) in patients with metastatic MTC. Material and Methods This cohort study included patients with metastatic MTC for whom at least 3 follow-up CT/MRI scans revealed ≥2 measurable lesions and up to the 5 largest lesions in each affected organ were analyzed. The tumor volumes were measured in 2 dimensions (2D) per standard practice reporting and 3 dimensions (3D) using an ellipsoid formula. The average TVDT of all measured lesions in each organ with metastatic deposits was calculated using a previously reported formula. Calcitonin (Ct-DT) and CEA doubling times (CEA-DT) were assessed using the American Thyroid Association Guidelines calculator. The association between DSS and TVDT, Ct-DT, and CEA-DT was tested using Cox regression. Correlations were assessed using a Spearman correlation coefficient. The study was approved by the Institution Review Board. Results The study cohort consisted of 51 patients (27 women, 53%) with age at the initial scan 24 ± 17 years and an average primary tumor size of 3.3±2.0 cm. Seven patients presented with sporadic MTC, 12 with MEN2A and 32 with MEN2B. During a follow-up of 8.0±4.3 years, 28/51 (55%) patients had disease progression and required systemic or local therapies and 9/51 (18%) patients died. A total of 456 scans were analyzed documenting that the organs with the most rapid TVDT were neck masses in 25/51 (49%), liver metastases in 16/51 (31%), lung nodules in 7/51 (14%) and prostate lesions in 3/51 (6%) patients. There was a strong correlation between 2D and 3D TVDT (r = 0.96) as well as between Ct-DT and CEA-DT (r = 0.82). However, the correlation between 2D TVDT and Ct-DT and CEA-DT were low (r = 0.45 for both). The DSS hazard ratios (HR) for DT <1 year compared to ≥3 years were 8.2 (1.5-45.4) for 2D TVDT, 8.7 (1.6-48.2) for 3D TVDT, 15.9 (1.72-146.7) for Ct-DT, and 11.72 (2.0-68.7) for CEA-DT. DSS was not associated with either familial or sporadic etiology of MTC (p = 0.38), gender (p = 0.12), or age at initial scan (p = 0.85). Conclusions Apart from Ct-DT and CEA-DT, TVDT is a valuable prognostic factor in metastatic MTC. Given a strong correlation between 2D and 3D TVDT, standard 2D-based TVDT measurements might be used as an easily obtained and clinically feasible prognostic marker of DSS in MTC patients. Presentation Date: Saturday, June 17, 2023

SAT581 Parathyroid Hormone Related Protein-induced Hypercalcemia In Medullary Thyroid Carcinoma In Pediatric Patient With MEN2A

Abstract Disclosure: S.A. Ackah: None. L.A. DiMeglio: None. J.C. Sanchez: None. G.C. Geddes: None. Background: PTHrp is a well-known cause of hypercalcemia of malignancy. Although PTHrp can often be detected in papillary, follicular and anaplastic thyroid cancers it does not always lead to hypercalcemia. Okotur 2007 described PTHrp in an adult medullary thyroid carcinoma (MTC). No pediatric cases have been described. Case: 8 year old female presented on transfer from hospital in Kenya where she had been admitted for three months with diarrhea and malnourishment (weight Z-score -6.5). She had been initially treated for aspiration pneumonia with negative testing for HIV, tuberculosis, stool cultures and parasites. At our facility, chest, abdomen and pelvis imaging were interpreted as an abscess from perforated appendicitis, bilateral hydroureteronephrosis, bilateral multifocal pneumonia and coronary artery ectasia. She experienced respiratory status decline requiring intubation. Further work up included consults and testing by infectious disease, genetics, immunology, cardiology, gastroenterology, pulmonology, and urology. In Kenya, the patient was initially normocalcemic and the calcium then slowly increased, so that on admission to our facility was found to have calcium 18.3 mg/dL (8.5-10.5), phosphorous 3.3 mg/dL (3.4-5.5), Creatinine 0.3 mg/dL (0.3-0.8), albumin 3.5 g/dL (3.5-4.7), PTH 5 pg/mL(10-65), TSH 1.9 mIU/ml (0.4-4.2), Free T4 0.8 ng/dL(0.6-1.5). IV hydration and pamidronate 0.5 mg/kg x 3 days administration resolved the hypercalemia. Rapid whole genome testing revealed a de novo pathogenic variant in RET (RET NM_020975.6 c.2753T>C; p.M918T) previously reported in individuals with MEN type 2A and 2B phenotypes. Thyroid ultrasound showed 2 nodules. FNA of both showed MTC; MTC was also present on lung biopsy. Screening labs obtained then showed PTHrp 301 pmol/L(adult range 0.0-3.4), Calcitonin 1433 pg/mL(0.0-5.1), VIP <13 pg/mL(0-60), Gastrin 45 pg/mL(0-100), Chromogranin A 4049 ng/mL(0-103), CEA123.7 ng/mL(0.0-2.5), metanephrine 0.91 nmol/L(0.00-0.49), normetanephrine 0.48 nmol/L(0.00-0.89). Bone scan showed diffusely diminished physiological uptake in the growth plates and diffuse bilateral lung uptake. Due to concern about ability to tolerate thyroidectomy, the patient was begun on selpercatinib, an oral chemotherapeutic agent specifically for tumors with disruption of RET gene. On day 11 of treatment, she was extubated to noninvasive respiratory support. Now, 3 months out from pamidronate and her hypercalcemia has not recurred. Conclusions: Hypercalcemia in pediatric patients with low PTH should prompt further workup including PTHrP measurement. In this case, we report a case of a child with MEN 2A and metastasized MTC with hypercalcemia attributable to PTHrp secretion.

SAT561 Pathogenic RET V804M Germline Variant Without Clinical Manifestations Of Multiple Endocrine Neoplasia Type 2 In An Elderly Male

Abstract Disclosure: R. Ghosh: None. G. Al-Naqeeb: None. P. Veeraraghavan: None. C. Craig: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. Background: Germline pathogenic variants in the RET protooncogene give rise to multiple endocrine neoplasia (MEN) types 2A and 2B. MEN2A is mainly characterized by MTC (∼100%), pheochromocytoma (PHEO; 4% - 88%), and primary hyperparathyroidism (HPTH; 2% - 30%), while MEN2B predominantly manifests with MTC (100%), PHEO (50%), mucocutaneous neuromas, and marfanoid habitus. Both MEN2A and 2B follow an autosomal dominant mode of inheritance. While certain pathogenic RET variants (M918T, A883F, and C634X) have high penetrance and present with aggressive disease, other variants such as V804M are of low penetrance and manifest with clinically mild disease.Clinical case: A 75-year-old male was referred to our center for further evaluation of the finding of an abnormal RET gene that was identified on a peripheral blood whole-exome gene sequencing research panel performed at an outside center. The patient was noted to have a germline RET c.2410 G>A, p.V804M heterozygous pathogenic variant. The patient denied any history of lump in the neck, symptoms of hyper- or hypothyroidism, tremors, headaches, fatigue, facial flushing, palpitations, constipation, diarrhea, anxiety, depression, or history of fragility fractures. Medical history consisted of hypertension, nephrolithiasis, type 2 diabetes mellitus, obstructive sleep apnea, interstitial pulmonary fibrosis, and colonic diverticula and polyps. Family history was significant for leukemia, colon, and breast cancers, but none of the relatives had a history of MTC, PHEO, or MEN2, and his children, while healthy, had not undergone RET germline testing. Physical examination showed no evidence of hypothyroidism or hyperthyroidism. Neck examination showed no evidence of thyromegaly or cervical lymphadenopathy. Laboratory investigations were unremarkable [serum calcitonin: 7.9 pg/ml (NL: </=14.3), CEA 2.8 mcg/L (NL: 0.8-3.4), thyrotropin (TSH): 1.92 microIU/ml (NL: 0.35-4.94), free thyroxine: 0.9 ng/dl (NL: 0.7-1.5), plasma free normetanephrine: 0.31 nmol/L (NL: <0.9), plasma free metanephrines 0.24 nmol/L (NL: <0.5), parathyroid hormone: 28.2 pg/ml (NL: 15-65), and ionized calcium 1.23 mmol/l (NL: 1.09-1.30)]. Thyroid sonogram was normal. We recommended active annual surveillance with biochemical markers and imaging along with genetic testing of the RET gene in his children. Conclusion: The V804M RET variant has been often associated with MTC or MEN2A phenotypes [1]. However, the variable expression of this variant may lead to a mild clinical phenotype or even absence of MTC/MEN2A manifestations. Hence, active surveillance as opposed to radical surgery like prophylactic thyroidectomy would be more beneficial in patients with no clinical or biochemical evidence of disease. Reference: Pinna et al., 2007, V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype. Thyroid, 17(2), 101-104. Presentation Date: Saturday, June 17, 2023

Diagnostic Utility of Menin Immunohistochemistry in Patients With Multiple Endocrine Neoplasia Type 1 Syndrome.

A clinical diagnosis of multiple endocrine neoplasia type 1 (MEN1) syndrome is usually confirmed with genetic testing in the germline. It is expected that menin protein expression is lost in MEN1-related tumors. Therefore, we investigated the potential of menin immunohistochemistry in parathyroid adenomas as an additional tool in the recognition and genetic diagnosis of MEN1 syndrome. Local pathology archives were searched for parathyroid tumors from patients with MEN1 syndrome and without MEN1, including sporadic, patients with multiple endocrine neoplasia type 2A and hyperparathyroidism-jaw parathyroid tumors. Menin immunohistochemistry was performed and its use to identify MEN1-related tumors was assessed. Twenty-nine parathyroid tumors from 16 patients with MEN1 and 61 patients with parathyroid tumors from 32 non-MEN1 were evaluated. Immunohistochemical nuclear menin loss in one or more tumors was found in 100% of patients with MEN1 and 9% of patients with non-MEN1. In patients with multiple tumors, menin loss in at least one tumor was seen in 100% of 8 patients with MEN1 and 21% of patients with 14 non-MEN1. Using a cutoff of at least 2 tumors showing menin loss per patient, the positive and negative predictive values for the diagnosis MEN1 were both 100%. The practical and additional value of menin immunohistochemistry in clinical genetic MEN1 diagnosis is further illustrated by menin immunohistochemistry in 2 cases with a germline variant of unknown significance in the MEN1 gene. Menin immunohistochemistry is useful in the recognition of MEN1 syndrome as well as in the clinical genetic analysis of patients with inconclusive MEN1 germline testing.

Elderly Male with Multiple Endocrine Neoplasia Type 2A: A Diagnostic Journey

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1399269: Never Too Old for Genetics: An Unusually Late Presentation of Medullary Thyroid Cancer in MEN2A

Virtually all germline RET pathogenic variant carriers develop medullary thyroid carcinoma (MTC). If possible, thyroidectomy should be performed prophylactically, before developing MTC. We describe a patient with pheochromocytoma found to have a germline RET p.Cys634Ser pathogenic variant at age sixty years who would be categorized as high risk based on genotype classification described by the American Thyroid Association and would have warranted prophylactic thyroidectomy at a young age. A 60-year-old man with history of hypothyroidism and osteopenia was found to have an adrenal mass during evaluation for kidney stones. It measured 4.1 x 3.2 x 3.8 cm on CT scan of abdomen and pelvis. MRI with and without gadolinium revealed a 4 cm left adrenal mass with T2 enhancement. Diagnosis of pheochromocytoma was confirmed with elevated levels of plasma free metanephrine and normetanephrine. The adrenal nodule showed avid uptake on PET CT Gallium-68 DOTATATE scan. No uptake was noted on the contralateral adrenal gland or in the neck. Patient underwent left adrenalectomy. Surgical pathology confirmed pheochromocytoma. Patient also had evidence of primary hyperparathyroidism (pHPT). Germline genetic analysis revealed a RET c.1900T >A(p.Cys634Ser) pathogenic variant confirming the diagnosis of multiple endocrine neoplasia type 2A (MEN2A). Calcitonin level was noted to be mildly elevated at 27.8 pg/ml. Subsequently, patient underwent total thyroidectomy, subtotal parathyroidectomy and bilateral central neck dissection. Surgical pathology revealed multifocal MTC, diffuse C-cell hyperplasia, and a foci of papillary thyroid microcarcinoma. Immunohistochemistry for calcitonin revealed diffuse C-cell hyperplasia. Patient was doing well on postoperative follow up and calcitonin level downtrended to < 2 pg/ml. Nearly all patients with MEN2A have either C-cell hyperplasia (CCH) or MTC, approximately 50% have a pheochromocytoma and 20-30% have pHPT. Age-related penetrance of CCH and hMTC is mutation dependent. Peak incidence in index patients is in the third decade of life in MEN2A. Our patient presented in the sixth decade of life. We decided to pursue genetic testing. The DOTATE scan did not show uptake in the neck and the calcitonin was only mildly elevated. However, as there is known complete penetrance of MTC in patients with MEN2A syndrome, patient underwent total thyroidectomy with central neck dissection with results of surgical pathology confirming presence of MTC. This case highlights the importance of considering genetic syndromes even in patients who present at older ages and challenges the classic genotype-phenotype correlation of the RET p.Cys634Ser pathogenic variant and MTC.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930–2021: A Nationwide Population-Based Retrospective Study

Studies of primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia type 2A (MEN 2A) shows divergence in frequency, disease definition, reporting of clinical characteristics and traces of selection bias. This is a nationwide population-based retrospective study of PHPT in MEN 2A, suggesting a representative frequency, with complete reporting and a strict PHPT definition. The Danish MEN 2A cohort 1930-2021 was used. Of 204 MEN 2A cases, 16 had PHPT, resulting in a frequency of 8% (CI, 5-12). Age-related penetrance at 50 years was 8% (CI, 4-15). PHPT was seen in the American Thyroid Association moderate (ATA-MOD) and high (ATA-H) risk groups in 62% and 38% of carriers, respectively. Median age at PHPT diagnosis was 45 years (range, 21-79). A total of 75% were asymptomatic and 25% were symptomatic. Thirteen underwent parathyroid surgery, resulting in a cure of 69%, persistence in 8% and recurrence in 23%. In this first study with a clear PHPT definition and no selection bias, we found a lower frequency of PHPT and age-related penetrance, but a higher age at PHPT diagnosis than often cited. This might be affected by the Danish RET p.Cys611Tyr founder effect. Our study corroborates that PHPT in MEN 2A is often mild, asymptomatic and is associated with both ATA-MOD and ATA-H variants. Likelihood of cure is high, but recurrence is not infrequent and can occur decades after surgery.

A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family

This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling.

[Hereditary medullary thyroid cancer].

ParafollicularC cells progress via C cell hyperplasia to medullary thyroid cancer (MTC), which can be present even in the first years of life in multiple endocrine neoplasia (MEN) type2A and 2B patients. Basal calcitonin and carcinoembryonic antigen (CEA) are useful tumor markers for the diagnosis and monitoring. The prognosis depends on the stage when the disease is diagnosed and there is a good genotype-phenotype correlation with the RET proto-oncogene, which can be used for estimation of the risk. The risk-stratified prophylactic thyroidectomy plays a decisive role in the prognosis of known gene mutation carriers.

Pediatric Thyroidectomy: Experience From a Portuguese Hospital.

Background and objective Pediatric thyroid disease requiring surgery is rare. Thyroid nodules are a frequent indication for surgery and are mostly benign. However, up to 25% of cases can be malignant. In this study, we aimed to describe our center's experience with regard to pediatric thyroid surgery. Methods This was a retrospective transverse study involving pediatric patients who underwent thyroid surgery at a tertiary hospital between January 2010 and December 2021. Results A total of 14 patients underwent 15 surgeries. The main reason for referral to pediatric endocrinology was thyroid nodules (n=10). Thirteen fine needle aspirations (FNAs) were performed, with follicular tumor (n=6) being the most common finding. The median age of patients at surgery was 15.9 years [interquartile range(IQR): 14.0-16.8]. The most common surgical indications were the presence of a follicular tumor on FNA (n=5) and thyroid nodule size causing symptoms (n=5). There was one case of prophylactic thyroidectomy due to the identification of a multiple endocrine neoplasia type 2A (MEN2A) mutation. The most frequently described histopathology results were follicular adenoma (n=6) and colloid nodular goiter (n=6). Three postoperative complications were observed in three different patients: bilateral lesion of the recurrent laryngeal nerve, cervical hematoma, and transient hypoparathyroidism with hypocalcemia. Conclusion In our study, the most frequent surgical indication was a follicular tumor. A good correlation was found between FNA cytology and final histopathology results, which is in accordance with previous studies. This reinforces the importance of FNA in diagnosis and surgical planning. The rate of complications in our study is comparable to that in larger single-center series in the literature.

Case Presentation MEN2A

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant disorder that can be distinguished as three different syndromes: multiple endocrine neoplasia type 2A (MEN2A). MEN2B and familial medullary thyroid carcinoma (FMTC). This disorder is usually caused by the mutations of the rearranged during transfection protooncogene gene (RET) or the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1).

PSAT013 Elevated Plasma Free Metanephrines with No Evidence of Pheochromocytoma in a Patient with Multiple Endocrine Neoplasia Type 2A

Abstract Background Adrenal medullary hyperplasia (AMH) is arbitrarily defined by adrenal medullary proliferation measuring less than 1 cm while larger lesions are considered pheochromocytoma. Some patients with MEN2 present with adrenal medullary hyperplasia (AMH), which is a precursor of pheochromocytomas. Clinical Case A 22-year-old female with a past medical history of MEN2A. She is positive for germline mutation in RET proto-oncogene at 10q11.2 exon 11, position 634 from cysteine to arginine. She was evaluated for a 1cm left thyroid nodule, which required total thyroidectomy for Medullary Thyroid Cancer. Pathology revealed a 0.5cm deposit on the largest dimension, clear margins, and no angiovascular, or lymphovascular invasion, surgery was complicated by hypoparathyroidism. She complained of intermittent anxiety and fatigue but was otherwise asymptomatic. Physical examination is unremarkable except for thyroidectomy scar and multiple exostoses. On 8/5/2011 plasma-free metanephrines were elevated at 83 pg/ml (&amp;lt;57pg/ml) and Free normetanephrine was 45 pg/ml (&amp;lt;145pg/ml). Over the next years, her plasma-free metanephrine levels have been checked approximately every 6 months ranging between 63-106pg/ml with free plasma normetanephrine in normal ranges (30-81pg/ml). However, on 2/2021, her plasma normetanephrine level increased to 304pg/ml. More recently, on 11/30/2021 her free normetanephrine levels reached 671pg/ml and free Metanephrine 131pg/ml. She had two MRIs of the abdomen and pelvis over the years and both showed unremarkable adrenal glands. NM I-123 MIBG scintigraphy reported physiologic symmetric activity in the adrenal glands. Finally, she had GA-68 DOTATATE PET/CT with no suspicious radiotracer avid lesion in the abdominopelvic organs. Given the persistent elevation on plasma metanephrines, we decided to start the patient on Doxazosin prophylactically while we continue biochemical and imaging surveillance. Conclusion Our patient has a persistent elevation in plasma-free metanephrines with no evidence of pheochromocytoma in abdominal imaging. The earliest abnormality in the adrenal medulla in patients with MEN 2 is diffuse hyperplasia with a reduction in the cortical/medullary ratio (1). This hyperplasia is considered to be a precursor of pheochromocytoma in patients with MEN 2 and in our case the most likely explanation for the progressive elevation in plasma-free metanephrines (1). There is a strong molecular relationship between AMH and Pheochromocytoma (2), close monitoring for progression to pheochromocytoma is necessary for all patients with AMH. The presence of markedly elevated plasma metanephrines in an asymptomatic patient with no evidence of pheochromocytoma poses a therapeutic dilemma for preemptive use of alpha blockade and the potential need for a medical alert bracelet. References (1) Cho, K et al "Adrenal Medullary disease in Multiple Endocrine Neoplasia II". AJR 134: 23-29. (2) Korpershoek, E et al "Adrenal Medullary Hyperplasia Is a Precursor Lesion for Pheochromocytoma in MEN2 Syndrome". Neoplasia. 2014 Oct; 16(10): 868–873 Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Pheochromocytoma recurrence in hereditary disease: does a cortical-sparing technique increase recurrence rate?

BackgroundPosterior retroperitoneoscopic adrenalectomy is an appealing approach for patients with hereditary pheochromocytoma and lends well to cortex preservation. We sought to examine pheochromocytoma recurrence in patients with hereditary pheochromocytoma in the era of posterior retroperitoneoscopic adrenalectomy and evaluate the predictors of recurrence. MethodsPatients with hereditary pheochromocytoma who underwent adrenalectomy for pheochromocytoma between 1995 and 2020 with biochemical cure and follow-up >1 year were identified. Recurrence was defined as plasma metanephrines above the upper limit of normal with radiographic evidence of disease in the ipsilateral adrenal bed. ResultsSeventy-eight hereditary pheochromocytoma patients (median age = 32.4 years; 60.3% women) underwent 114 adrenalectomies for pheochromocytoma. Of these patients, 40 had multiple endocrine neoplasia type 2A (51.3%), 10 had multiple endocrine neoplasia type B (12.8%), 17 had von Hippel-Lindau disease (21.8%), and 11 had neurofibromatosis type 1 (14.1%). Thirty-eight adrenalectomies (33.3%) were performed before the introduction of posterior retroperitoneoscopic adrenalectomy and 76 (66.7%) after. Cortical-sparing technique was performed in 62 (54.4%) adrenalectomies, with no difference in its use before and after posterior retroperitoneoscopic adrenalectomy introduction (P > .05). During a median follow-up of 80.7 months (interquartile range 43.4–151.2), 12 ipsilateral recurrences (10.5%) were identified. There was no difference in recurrence before and after the introduction of posterior retroperitoneoscopic adrenalectomy or by surgical technique or approach of the entire cohort (P > .05). Recurrence was more common in those with RET M918T mutation (23.5% vs 8.2%; P = .05). Patients with RET M918T mutations had a shorter recurrence-free survival (P = .013). On multivariate analysis, only RET M918T mutation was independently associated with an increased recurrence risk (hazard ratio = 4.30; 95% confidence interval, 1.26–14.66; P = .019). ConclusionThe introduction of posterior retroperitoneoscopic adrenalectomy did not influence the recurrence rate after adrenalectomy for hereditary pheochromocytoma patients. Patients with a RET M918T germline mutation are at increased risk for pheochromocytoma recurrence and may benefit from initial total adrenalectomy.

[Clinical and genetic analysis of seven Chinese pedigrees affected with multiple endocrine neoplasia type 2A with cutaneous lichen amyloidosis].

To explore the pathological characteristics and significance of RET proto-oncogene screening in multiple endocrine neoplasia type 2A (MEN2A) with cutaneous lichen amyloidosis (CLA). Clinical data of 51 members from 7 unrelated pedigrees of MEN2A-CLA were collected. Systemic clinical investigations including biochemical testing, imaging examination, germline RET variant screening and histopathological examination were carried out. RET gene variants were detected in 28 patients with MEN2A (C634G/F/R/S/W and C611Y) including 12 males and 16 females, with the mean age of diagnosis being (41.1 ± 18.3) years old, which were consistent with their clinical manifestations. The incidence of medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), hyperparathyroidism (HPTH) and CLA among 28 MEN2A patients were 89.3%, 28.6%, 7.1% and 28.6%, respectively. Comparison of the incidence of MTC/PHEO/HPTH and CLA between C611Y and C634G/F/R/S/W, only PHEO and CLA in C611Y were lower than those in C634G/F/R/S/W (P < 0.05; P < 0.05). Among 8 patients with CLA, the male to female ratio was 2 : 6. The clinical features included pruritus in the interscapular region and presence of dry, thickened, scaly, brown pigment, clustered or desquamate-like plaques. The mean onset age of CLA [(18.4 ± 4.6) years] versus the mean age at diagnosis of CLA or MEN2A were significantly different (P < 0.001; P < 0.001). MEN2A-CLA may be the early clinical manifestation of MEN2A and most frequently occurred along with RET-C634 variant. To facilitate the recognition of MEN2A-CLA, to combine family investigation and screening of RET variant are helpful for early diagnosis and standardized treatment, which can improve the long-term outcome of MEN2A-specific tumors.

Incidentally-Diagnosed Multiple Endocrine Neoplasia IIA (Sipple Syndrome) with Bilateral Pheochromocytoma and Medullary Thyroid Carcinoma

Incidentally-Diagnosed Multiple Endocrine Neoplasia IIA (Sipple Syndrome) with Bilateral Pheochromocytoma and Medullary Thyroid Carcinoma

Incidentally-diagnosed type IIa multiple endocrine neoplasia (Sipple syndrome) with bilateral pheochromocytoma and medullary thyroid carcinoma. Report of one case

Incidentally-diagnosed type IIa multiple endocrine neoplasia (Sipple syndrome) with bilateral pheochromocytoma and medullary thyroid carcinoma. Report of one case