Multiple Endocrine Neoplasia 2A Research Articles

Diagnostic and Surgical Challenges Associated With Sporadic Multiple Endocrine Neoplasia 2A Presenting as Non-syndromic Primary Hyperparathyroidism.

Diagnostic and Surgical Challenges Associated With Sporadic Multiple Endocrine Neoplasia 2A Presenting as Non-syndromic Primary Hyperparathyroidism.

A rare case of medullary carcinoma

Medullary thyroid cancer (MTC) accounts for 5–10 % of all thyroid cancers. Most cases (75 %) are sporadic, but the proportion of patients with MTC and a familial predisposition syndrome is the highest among those with any hereditary cancer syndrome (about 25 %), and this possibility should be considered when examining a patient with MTC. Familial syndromes include multiple endocrine neoplasia (MEN) 2A, MEN 2B, and non-MEN familial MTC (familial MTC). Familial MTC syndromes occur in approximately one case per 30,000 of the population. Reduced penetrance and clinical variability are well-established features of many monogenic disorders, particularly phenotypes associated with the RET proto-oncogene. They require an individual assessment of the pathogenic effects and clinical significance of any identified new sequence of the RET va­riant as prerequisites for individual genetic counseling and planning of medical monitoring and treatment. Diagnostic criteria for the disease have been outlined, molecular and genetic aspects have been discussed, and the determination of treatment and further observation has been addressed. The article describes a clinical case of a rare variant of MTC. Treatment of this pathology with radical extrafascial thyroidectomy is under consideration. Given the ineffectiveness of radioiodine and chemotherapy, the main task in the treatment of MTC is early diagnosis, radical surgical intervention, and active monitoring aimed at early detection of disease recurrence. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutations and the timing of prophylactic thyroidectomy proposed by the American Thyroid Association. The introduction of molecular genetic research into clinical practice for the purpose of diagnosing MTC allows for the objective assessment of the genetic lineage of the disease within a biological family. A timely diagnosis of MTC makes it possible to prescribe an adequate treatment at the stage of preclinical manifestations of the disease, which can significantly increase the quality and duration of life.

FRI213 Multiple Endocrine Neoplasia Syndromes: A Rare Case With Variable Presentation

Abstract Disclosure: D.J. Gomez D' Aza: None. M. Kasap: None. T. Zahedi: None. F. Zhang: None. Introduction: Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant inherited groups of disorders characterized by the presence of two or more primary endocrine glands tumors. MEN type 1 is usually associated with neoplastic lesions of the pituitary gland, the parathyroid gland, and the pancreas. MEN type 2 typically presents with overgrowth of parathyroid, adrenal glands (pheochromocytoma), and parathyroid hyperplasia (MEN 2A), Marfanoid body habitus, or mucosal neuromas (MEN 2B). It can also manifest with non-endocrine tumors including carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas, and germline mutations (MEN type 4). It is extremely rare for MEN type 1 syndrome to have concomitant pheochromocytoma. Case Report: We present a case of a 69 yo female with multiple comorbidities who was hospitalized for heart failure exacerbation. CT scan showed incidental findings of a 4.1 cm right adrenal nodule, a 2.1 cm left anterior mediastinum nodule, and a 1.1 cm oval pituitary mass. She had multiple episodes of hypertension urgency during the last two years. After patient recovered to her base line, workup labs revealed elevated serum Catecholamine with Metanephrine 431.1 pg/mL, Normetanephrine 466.5 pg/mL, Norepinephrine 137 pg/mL, and high PTH 258 pg/mL. Further study was normal for pituitary function tests, aldosterone, renin, cortisol, thyroid, and renal function. PET scan showed mild hypermetabolic activity in bilateral adrenal glands without any abnormal hypermetabolic activity in the chest. Thyroid Ultrasound identified a 1 cm thyroid nodule. Phenoxybenzamine was started due to concern for pheochromocytoma. Patient was monitored closely since she declined surgical intervention. Discussion: MEN syndromes have variable clinical presentation with multiple hormone excess. This patient has imaging and laboratory findings highly suggestive of MEN syndrome with pituitary adenoma, pheochromocytoma, and hyperparathyroidism. Further work up and genetic testing would be helpful to identify the mutation of MEN type 1 or type 2. Clinicians should be aware of the variable presentation of MEN syndrome, and prompt treatment is warranted to prevent life-threatening conditions. Presentation: Friday, June 16, 2023

Clinical presentation of MEN 2A in index vs. non-index patients.

Differences in syndromic manifestations of multiple endocrine neoplasia 2 A (MEN2A) between index and non-index patients are ill-defined. Cross-sectional analysis of 602 REarranged during Transfection (RET) carriers (156 index and 446 non-index patients) who underwent thyroidectomy, adrenalectomy, and/or parathyroidectomy between 1985 and 2022, stratified by mutational risk. Index patients were 5.8-13.9 years older at thyroidectomy than non-index patients, at which point they had developed 10.6-14.4 mm larger medullary thyroid cancers. Correlations between index status and primary tumor size (ρ = 0.489-0.544) were stronger than correlations between index status and age at thyroidectomy (ρ = 0.359-0.438). For pheochromocytoma and primary hyperparathyroidism, no significant differences were noted. When stratified by time of surgery before vs. in the new millennium, age at thyroidectomy fell significantly only for non-index patients in the new millennium: from 28.6 to 21.2 years (moderate-high risk mutations; P = 0.049) and from 23.1 to 12.3 years (high-risk mutations; P < 0.001). All other inter-millennium comparisons did not reach statistical significance. These findings imply that differences between index and non-index patients impact the first syndromic manifestation without extending to subsequent syndromic manifestations. Because they exhibited similar age and tumor characteristics for the secondary and tertiary manifestations of MEN2A, screening for these syndromic components remains an integral element of MEN2A management in index and non-index patients alike. Wider use of population genomic screening may work to diminish the observed disparities between index and non-index patients going forward.

The Changing Face of Multiple Endocrine Neoplasia 2A: From Symptom-Based to Preventative Medicine.

Early genetic association studies yielded too high risk estimates for multiple endocrine neoplasia (MEN2A), suggesting a need for extended surgery. The objective was to delineate temporal changes in MEN2A presentation by birth cohort analyses. Birth cohort analyses (10-year increments; ≤1950 to 2011-2020) of carriers of rearranged during transfection (RET) mutations who underwent surgery for MEN2A. Included in this study were 604 carriers (155 index, 445 nonindex, 4 additional patients), with 237 carriers harboring high-risk mutations, 165 carriers moderate-high risk mutations, and 202 carriers low-moderate risk mutations. With increasing recency of birth cohorts, there was a continual decline in index patients from 41-74% to 0% (P < .001) and of medullary thyroid cancer (MTC) from 96-100% to 0-33% (P < .001). Node metastases diminished from 62-70% to 0% (P ≤ .001; high and low-moderate risk mutations), whereas biochemical cure after thyroidectomy surged from 17-33% to 100% (P ≤ .019; high and low-moderate mutations). Surgical interventions for MEN2A-related tumors were performed increasingly earlier, causing median carrier age to fall: from 51-63 to 3-5 years at thyroidectomy (P < .001); from 46-51 to 24-25 years at first adrenalectomy (P ≤ .013; high and moderate-high risk mutations); and from 43.5-66 to 16.5-32 years at parathyroidectomy. MTC diameters were more effectively decreased from 14-32 to 1-4 mm (P ≤ 002) than pheochromocytoma diameters (nonsignificant). These insights into MEN2A presentation, adjusted by birth year, illustrate the shift from reactive to preventative medicine, enabling less extensive risk-reducing 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.

Multiple endocrine neoplasia 2A with RET mutation p.Cys380Arg (GRCh38): A case report

MEN 2A is a complex autosomal dominant inherited syndrome characterized by pheochromocytoma (PC), medullary thyroid carcinoma (MTC) and primary parathyroid hyperplasia (PHP). We report a case of 26 years old female offended with bilateral pheochromocytoma, medullary thyroid carcinoma and primary hyperparathyroidism due to multiple endocrine neoplasia type 2A confirmed by RET gene mutation p.Cys380Arg according to the GRCh38 (Genome Reference Consortium Humain Build 38 Organism - 2013) classification. The mutation with a change of amino acid 380 from Cys (Cysteine) to Arg (Arginin) is found in more than one-half of kindreds with MEN2A.

Multiple Endocrine Neoplasia 2A Detected by Peptic Ulcer Perforation with Hypercalcemia

Multiple Endocrine Neoplasia 2A Detected by Peptic Ulcer Perforation with Hypercalcemia

Multiple Endocrine Neoplasia 2a: Case Report and Review of Literature

Multiple endocrine neoplasia is a hereditary, autosomal dominant disease. It is created predominantly by RET germline mutations and is considered rare, with a frequency of 1 in 30,000 people. In particular, medullary thyroid cancer associated to this pathology presents at a younger age in relation to sporadic cases. Pheochromocytoma is linked to metastatic disease in only 4% of cases and it is a disease which requires high clinical suspicion. The age of presentation when related to multiple endocrine neoplasia is lower than that of the general population, 38 and 47 years of age respectively. RET proto-oncogene mutation on Codon 634 in exon 11 is the most frequent genetic alteration, present in 85% of cases of MEN2A. Its penetrance for pheochromocytoma is 25% at 30 years and 88% at 77. The objective of this article is to present a case of a patient with MEN2A with bilateral pheochromocytoma and medullary thyroid cancer, discovered in a hypertensive man as an incidental finding.

RF07 | PSUN366 An Uncommon Path Leading to Diagnosis of Multiple Endocrine Neoplasia 2A

Abstract Introduction MEN2 is a rare Autosomal Dominant disorder resulting from mutations in the RET proto-oncogene. MEN2 is classified into two distinct syndromes: MEN2A and MEN2B. MEN2A is a syndrome that presents with Medullary Thyroid Carcinoma (MTC) in 90% of adult gene carriers, unilateral or bilateral pheochormocytoma in 50%, and multigland parathyroid tumors in 20-30% of affected individuals. Other rare variants of MEN2 include Familial Medullary Thyroid Carcinoma (FMTC), MEN2A with cutaneous lichen amyloidosis, and MEN2A or FMTC with Hirschprung's disease. We present a patient with incidentally noted elevated calcitonin levels, later diagnosed with MEN2A. Clinical Case 37-year-old Caucasian male was referred to our clinic for elevated calcitonin levels noted on lab work done as part of evaluation and management for weight loss prior to initiating GLP-1 agonists. He was diagnosed with hypothyroidism and multinodular goiter and started on Synthroid. His only symptoms were weight gain, tiredness, soft stools and facial flushing He denied any family history of endocrine disorders. Physical exam was unremarkable. Pertinent labs included serum calcitonin 93 pg/mL (&amp;lt;10 pg/mL), serum CEAg 5.2 ng/mL (0-3 ng/mL), and work up for pheochromocytoma and hyperparathyroidism was negative. USG thyroid showed a left lobe thyroid nodule measuring 7×5×7 mm with macrocalcifications, a right lobe thyroid nodule measuring 8×5×10mm, and an abnormal left lateral level III LN. He underwent left thyroid lobectomy with level VI neck dissection (total thyroidectomy aborted due to hypoxia), and subsequently completion thyroidectomy with right central neck dissection. Pathology showed metastatic MTC with pathologic staging pT1aN1a. Genetic testing showed RET c. 1826G&amp;gt;A (p. C609Y) which is ATA – MOD risk. Patients’ father was also genetically screened and diagnosed with MEN2A and noted to have elevated calcitonin levels. He also subsequently underwent total thyroidectomy, which revealed medullary thyroid microcarcinoma. Conclusion A number of studies support that measurement of serum calcitonin is the most sensitive screening test for detecting occult MTC in individuals with thyroid nodules. Yet, the use of serum calcitonin in the routine evaluation of thyroid nodules is controversial due to absence of uniform calcitonin thresholds, high false positive values and unavailability of pentagastrin stimulation testing. Moreover, there are no recommendations based on the current data to check calcitonin levels prior to initiating GLP-1 agonists but their use is not recommended in patients with personal or family history of MTC/MEN2. Based on the above case, measurement of calcitonin levels should be a part of the work up in patients who present with thyroid nodules and are receiving GLP-1 agonists. Attention should also be paid to the importance of genetic counseling in first-degree relatives of patients with MEN2A. This allows for timely diagnosis and reduces morbidity and mortality. Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Case Report: Bilateral Pheochromocytoma: Clinical Characteristics and Surgical Management

Objective: We would like to report the clinical presentation, surgical treatment and outcomes of this patient with bilateral pheochromocytoma. Introduction: Pheochromocytomas (PHEOs) are rare catecholamine-secreting neuroendocrine tumors of neural crest origin arising from chromaffin cells in the adrenal medulla with estimated incidence of 0.46 to 0.8 cases per 100,000 person-years [1]. Germline pathogenic variants associated with PHEO are now identified in 30-50% of these tumors [2]. Genetic syndromes can predispose to bilateral PHEO, such as multiple endocrine neoplasia (MEN) 2A, MEN 2B, von Hippel-Lindau (VHL), neurofibromatosis type 1 (NF1), as well as mutations in the genes of myc-associated factor X (MAX), transmembrane protein 127 (TMEM127), and mutations in the subunits of the succinate dehydrogenase complex (SDHx) [3]. When we suspect the pheochromocytoma clinically, we should look for biochemical confirmation, by dosing the plasma and urinary catecholamine (adrenaline, noradrenaline) and their metabolites (metanephrine and normetanephrine) [4]. This should be followed by tumor localisation using computed tomography (CT) imaging or magnetic resonance imaging (MRI) of the abdomen and pelvis that are the most commonly used methods and have similar sensitivities (90%-100%) and specificities (70%-80%) for tumor localisation [5]. Surgical resection followed by postoperative monitoring is the safest and the most effective therapeutic intervention for pheochromocytoma [6].

Sex differences in MEN 2A penetrance and expression according to parental inheritance.

This study aimed to delineate the age-dependent clinical penetrance and expression of heterozygous rearranged during transfection (RET) missense mutations associated with multiple endocrine neoplasia 2A (MEN2A) according to parental inheritance. This was an observational study of RET carriers operated for MEN2A-associated tumors between 1985 and 2021. Kaplan-Meier time-to-event and multivariable Cox proportional hazards regression analyses were performed on node metastases from medullary thyroid cancer, pheochromocytoma, bilateral pheochromocytoma, and primary hyperparathyroidism. Some 405 (70.1%) of 578 patients carrying heterozygous MEN2A RET missense mutations had information about the parental inheritance of the trait. On Kaplan-Meier analysis, offspring who inherited the trait from the father developed node metastases (Plog-rank= 0.007), pheochromocytoma (Plog-rank= 0.029), bilateral pheochromocytoma (Plog-rank= 0.002), and primary hyperparathyroidism (Plog-rank= 0.018) at a significantly younger age than offspring who inherited the trait from the mother. On multivariable Cox regression, controlling for index status, offspring sex, and (where feasible) mutational risk, parental inheritance was consistently associated with each MEN2A-associated tumor (hazard ratios (HR) = 1.7-1.8 for the earlier manifestations node metastases and pheochromocytoma vs HR of 2.9-3.4 for the late manifestations bilateral pheochromocytoma and primary hyperparathyroidism). Herein, node metastases were 3.1- and 1.7-fold more closely associated with mutational risk (HR of 5.3 for high and 2.9 for moderate-high risk mutations vs low-moderate risk mutations) than parental inheritance (HR = 1.7). These findings illustrate the importance of considering not just mutational risk but also parental inheritance when it comes to personalization of screening for and early detection of the various components of MEN2A-associated tumors.

Comparison of Parathyroid Autofluorescence Signals in Different Types of Hyperparathyroidism.

There are scant data in the literature regarding whether parathyroid autofluorescence (AF) signal patterns vary based on the etiology of hyperparathyroidism. The aim of this study was to compare AF signals of parathyroid glands across different etiologies of hyperparathyroidism. As a prospective institutional review board-approved study between 2016 and 2019, AF intensities and heterogeneity indexes (HIs) of parathyroid glands in patients who underwent parathyroidectomy using AF were calculated and compared using Chi-square, Kruskal Wallis, Mann Whitney U, and logistic regression tests. Of the total of 183 patients, 127 patients had sporadic classic primary hyperparathyroidism, 30 patients had sporadic normohormonal primary hyperparathyroidism, 10 patients had sporadic normocalcemic primary hyperparathyroidism, 12 patients had tertiary hyperparathyroidism, and 4 patients had familial primary hyperparathyroidism related to multiple endocrine neoplasia (MEN) 2A. There were no statistical differences in AF signals of abnormal parathyroid glands in classic, normohormonal or normocalcemic sporadic hyperparathyroidism. Parathyroid glands in patients with tertiary hyperparathyroidism were similar in intensity, but more homogenous compared to those in sporadic primary hyperparathyroidism. The pattern of AF exhibited by abnormal parathyroid glands was similar across different spectrums of primary hyperparathyroidism, in accordance with observations in the literature. However, parathyroid glands in tertiary hyperparathyroidism were more homogeneous, despite exhibiting a similar intensity of AF compared to those in sporadic primary hyperparathyroidism. These differences should be kept in mind when using the AF pattern as an adjunct to visual assessment in parathyroid exploration.

Medullary thyroid carcinoma in children: current state of the art and future perspectives.

Medullary thyroid carcinoma (MTC) is a distinct type of malignant thyroid tumor in cell origin, biological behavior, and natural history. It accounts for 1.6% of all thyroid cancers and presents either sporadically or as a hereditary disease, the latter occurring as a part of multiple endocrine neoplasia (MEN) 2A and MEN2B syndromes or as a familial MTC disease with no other manifestations. The gene responsible for the hereditary form is the rearranged during transfection (RET) gene, a proto-oncogene located to human chromosome 10. Most pediatric MTC cases have been discovered after genetic testing investigations, leading to the concept of prophylactic surgery in presymptomatic patients. Therefore, the genetic status of the child, along with serum calcitonin levels and ultrasonographic findings, determine the appropriate age for prophylactic surgical intervention. Nevertheless, a diagnosis at an early stage of MTC warrants total thyroidectomy and central lymph node dissection with the addition of lateral/contralateral lymph node dissection depending on the tumor size, ultrasonographic evidence of neck disease, or calcitonin levels. Conversely, locally advanced/unresectable or metastatic MTC is primarily treated with multikinase inhibitors, while more specific RET inhibitors are being tested in clinical trials with promising results.

Multiple Endocrine Neoplasia 2A with Late-onset Medullary Carcinoma Thyroid and Bilateral Pheochromocytoma: A Complex Presentation

Multiple Endocrine Neoplasia 2A with Late-onset Medullary Carcinoma Thyroid and Bilateral Pheochromocytoma: A Complex Presentation

Breast metastasis from medullary thyroid carcinoma: a report of a case

BackgroundMetastasis to the breast is rare. We herein report a patient with metastatic medullary thyroid carcinoma to the breast for whom measuring the calcitonin level was an important clue to the correct diagnosis.Case presentationA 54-year-old woman visited our hospital for the treatment of recurrent metastatic medullary thyroid carcinoma due to multiple endocrine neoplasia 2A and breast cancer. Positron emission tomography performed before the operation for metastatic medullary thyroid carcinoma recurrence in the neck showed the accumulation of 18F-fluorodeoxyglucose in the bilateral breast at sites other than the disease in the neck. Ultrasonography revealed multiple tumors in both breasts. A core needle biopsy of three breast tumors was performed. Microscopically, the tumor cells showed solid growth and did not show a tubular structure. She was diagnosed with triple-negative invasive ductal carcinoma. Post-operative positron emission tomography was performed as the serum calcitonin level increased after the operation. The accumulation of 18F-fluorodeoxyglucose in the bilateral breast tumors and lymph nodes in the neck was noted. The possibility of the breast tumors being metastasis of metastatic medullary thyroid carcinoma was considered. Needle aspiration was performed for three breast tumors. The calcitonin level of the washout fluid was measured and found to be ≥ 17,500 pg/mL. Immunohistochemistry showed that the tumor cells were calcitonin-positive and gross cystic disease fluid protein-15-negative. Vandetanib was started as recurrent metastatic medullary thyroid carcinoma with breast metastasis was finally diagnosed. The serum calcitonin level decreased after 1 month.ConclusionAlthough breast metastasis of medullary thyroid carcinoma is rare, a correct diagnosis is indispensable for appropriate treatment. When a breast tumor shows atypical morphological features for breast cancer according to the histopathology in a patient with a history of cancer, metastasis to the breast should be considered. Calcitonin measurement of the needle washout fluid was useful for confirming metastatic medullary thyroid carcinoma.

Bilateral Posterior Retroperitoneoscopic Adrenalectomy with Cortical Sparing on Right Side

Cortical sparing adrenalectomy allows for resection of adrenal tumor(s) while preserving unaffected adrenal tissue to prevent adrenal insufficiency. This is especially important in patients affected with bilateral adrenal tumors, typically pheochromocytomas. Posterior retroperitoneoscopic adrenalectomy (PRA) allows for a minimally invasive approach to adrenal gland resection compared to the more traditional laparoscopic transabdominal adrenalectomy and open approaches. The PRA technique is increasingly used by high-volume endocrine surgeons throughout the world. This approach is ideal to address patients with bilateral disease and was utilized in this case of a patient presenting with bilateral pheochromocytomas in the setting of multiple endocrine neoplasia 2A syndrome.

Hypercalcemia in Pheochromocytoma: From MEN to VHL

Background: Co-occurrence of phaeochromocytoma and primary hyperparathyroidism is usually seen in patients of Multiple Endocrine neoplasia 2A(MEN2A) and is rare in Von Hippel Lindau disease (VHL). Parathyroid adenoma with pheochromocytoma in a genetically confirmed VHL has been reported only once till date (1). Clinical Case: A 30-year male was admitted for evaluation of hypertension and incidentally diagnosed adrenal mass on ultrasound. 9-years back, he was diagnosed as a case of VHL (right renal clear cell carcinoma, pancreatic cystadenoma, spinal hemangioblastoma and epididymal cysts). Right nephrectomy and pancreatic cyst excision had been done and past work-up for pheochromocytoma was normal. He also had been operated twice for recurrent renal calculi. Family history revealed surgery in mother for pancreatic mass. Current imaging revealed right adrenal mass (4.7*4.6 cm) with left renal cysts and calculi, pancreatic cysts and spinal- medullary hemangioblastoma and epididymal cysts. Fundus examination was normal. 24-hours urinary fractionated normetanephrines were elevated (2062 mcg/24 hours) and I131MIBG scan showed 4.7*4.6cm concentrating lesion in right renal fossa suggestive of right adrenal pheochromocytoma. However his biochemical evaluation revealed hypercalcemia (12.1 mg/dl), low phosphorus (3.2 mg/dl), low 25(OH) D (24.84 nmol/l), and raised PTH (121pg/ml). Ultrasound neck and Tc99m-Sestamibi localized left inferior parathyroid adenoma. DEXA scan showed severe osteoporosis. Genetic analysis confirmed VHL mutation in exon-1. Calcitonin and RET mutation were normal (ruled out MEN2A). Therapeutic approach was surgical excision of adrenal pheochromocytoma followed by parathyroidectomy. We report a case of pheochromocytoma with primary hyperparathyroidism (cause: left inferior parathyroid adenoma) in a patient of VHL (Renal clear cell carcinoma, pancreatic cystadenoma, epidydymal cysts and medullary and spinal hemangioblastoma). Hypercalcemia seen in patients of VHL is either due to bone metastasis/PTHrP/IL-6 secretion from RCC or due to PTHrP/PTH/calcitonin secretion from pheochromocytoma and rarely due to associated parathyroid adenoma. Literature search revealed four case reports of parathyroid adenoma with VHL. In only one of these, VHL had pheochromocytoma associated with parathyroid adenoma (1). Conclusion: Ours is the 2nd such case reported in literature of primary hyperparathyroidism in a genetically confirmed case of VHL with pheochromocytoma. This case highlights the overlap of tumorigenesis in two rare genetically divergent syndromes and importance of long-term follow-up for sequential development of new tumors. Reference: Arao T, Okada Yet al. A case of VHL disease with bilateral pheochromocytoma, renal cell carcinoma, pelvic tumor, spinal hemangioblastoma and primary hyperparathyroidism. Endocr J. 2002 Apr;49(2):181–8.

Recurrent Pheochromocytoma, as Component of Multiple Endocrine Neoplasia

Background: Pheochromocytoma is a rare neuroendocrine tumor from the adrenal medulla’s chromaffin cells that secrete catecholamines. The mainstay of treatment is surgery. Although rare, it has a recurrence rate of 6.5-16.5% even after adequate surgical removal with a notable increase in prevalence among genetic syndromes, extra-adrenal tumors, larger tumor size, and younger age of diagnosis. Case: A 23-year-old Filipino male with no known familial disease presented with episodic headache, palpitations, diaphoresis, and resistant hypertension. Two masses in the left adrenal gland, with the larger one measuring 6.0cm x 5.0cm x 3.0cm, were surgically removed. Histologic examination revealed pheochromocytoma. Post-operatively, there was the normalization of urinary metanephrines and the resolution of the signs and symptoms. He was lost to follow-up and returned five years later with an abdominal ultrasound demonstrating a right adrenal mass. He had no accompanying signs and symptoms; the physical examination was unremarkable. On workup, biochemical testing revealed two 24-hour urinary metanephrine levels were markedly elevated, 14.49 and 19.97 (NV:0-1mg/24 hours). Calcitonin: 644 (NV:0-18pg/ml) and carcinoembryonic antigen (CEA): 23.52 (NV:<5ng/ml) were also elevated. Mild hypercalcemia was noted with elevated intact PTH 101.74 (NV:0-65pg/ml). Parathyroid scintigraphy was normal. The neck ultrasound showed multiple bilateral thyroid nodules, with the largest measuring 1.2cmx0.9cm (TIRADS IV). The abdominal CT scan showed two well-defined, homogenous right adrenal masses, with the largest measuring 6.3cm x 5.6cm x 7.4cm. He underwent right adrenalectomy, and histopathology showed pheochromocytoma with Pheochromocytoma of the Adrenal Scale Score (PASS) of 3. One month later, he underwent total thyroidectomy with neck dissection and inferior parathyroid gland resection. Histopathology confirmed medullary thyroid cancer with nodal metastasis and parathyroid adenoma. The patient recovered well without complications. Biochemical tests normalized eight weeks post-surgery. The presence of synchronous recurrent pheochromocytoma, medullary thyroid cancer (MTC), and primary hyperparathyroidism is consistent with multiple endocrine neoplasia 2A (MEN2A) syndrome. Conclusion: Lifelong follow-up is essential in patients treated for pheochromocytoma despite the complete removal of the adrenal masses due to recurrence risk. Recurrence should likewise raise the suspicion of MEN2, a genetic syndrome. In addition, the pheochromocytoma has malignant characteristics, and the MTC has metastases to the cervical lymph nodes. Early detection and prompt intervention are essential for the treatment of the disease.

Metastatic Thyroid Cancer After Thyroidectomy in Patient With Neuroendocrinal Tumor

Abstract Background: Multiple endocrine neoplasia type 2 is an autosomal dominant disorder with an estimated prevalence of 1 per 30,000 in the general population. Classical multiple endocrine neoplasia 2A is the most common variant. It is a heritable predisposition to medullary thyroid cancer, pheochromocytoma, and primary parathyroid hyperplasia. The respective frequency of these tumors in classical MEN2A is over 90 percent for MTC, approximately 10 to 50 percent for pheochromocytoma, and 10 to 20 percent for multigland parathyroid hyperplasia. Discussion: our interesting patient is a 67-year-old patient with past medical history of prophylactic total thyroidectomy at the age of 25 years after a positive pentagastrin test (sister was diagnosed with MTC, pheochromocytoma),niece with metastatic kidney cancer.at that time, patient had benign pathology. Patient presented to the ED with a complain of shortness of breath after being referred by her PCP for evaluation of possible pneumonia. In the ED, her vitals were within normal, chest X-ray was done and didn’t show pneumonia but the patient was found to have elevated procalcitonin of 22.7 ng/mL(0.09 ng/mL) CT chest was done and showed enlarged necrotic cervical lymphadenopathy which was confirmed by obtaining CT of the neck. Patient had right cervical LN core biopsy, pathology was positive for medullary thyroid cancer with Immunohistochemical studies positive for TTF-1, chromogranin, synaptophysin and calcitonin, testing for pheochromocytoma came back within normal, CEA 70.7ng/ml (&amp;lt;0.25 ng/ml), calcitonin 2949 pg/ml (5 pg/mL) Chromogranin was high at 453 ng/ml (25 - 140 ng/mL) had PET CT with multiple low right cervical and supraclavicular lymph nodes with internal calcifications and abnormal FDG activity, which were suspicious for medullary thyroid cancer metastases, she eventually had radical neck dissection with pathology from inferior parathyroid gland positive for medullary thyroid cancer and 12/15 regional LN positive for malignancy, after the procedure her calcitonin dropped nicely to 194pg/ml, CEA dropped to 4.0, chromogrannin to 394, she was referred to genetic testing and tested positive for pathogenic variant within RET (c.1859G&amp;gt;T, p.Cys620Phe), which is known to be associated with multiple endocrine neoplasia type 2A, she is currently being evaluated for Lutathera treatment. Conclusion: In contrast to MEN1, in which the long-term benefit of early diagnosis by genetic screening is not well established, early diagnosis by screening of “at-risk” family members in MEN2 with positive RET mutation kindreds is essential because MTC is a life-threatening disease that can be cured or prevented by early thyroidectomy. Total thyroidectomy has been recommended for patients as young as 3 years for MEN2A if they contain the genetic mutation.