Unusual Case of Multiple Endocrine Neoplasia Type 2A Syndrome Without Medullary Thyroid Carcinoma

ObjectiveTo present an unusual case of multiple endocrine neoplasia type 2A (MEN 2A) syndrome and to describe how this case differs from the typical clinical features and usual genetic variations seen in classic MEN 2A syndrome.MethodsWe describe the work-up, diagnosis, and treatment course of a patient who presented with multifocal pheochromocytomas, parathyroid adenoma, thyroid abnormalities, and a RET mutation.ResultsA 65-year-old man with previously treated pheochromocytoma presented with a parathyroid adenoma, multiple thyroid nodules, and a RET polymorphism. C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) occurs with nearly 100% penetrance in patients with MEN 2A syndrome. Our patient did not have CCH or frank MTC, but he expressed the other manifestations of the MEN 2A syndrome.ConclusionMEN 2A syndrome is characterized by the occurrence of MTC, pheochromocytomas, and parathyroid hyperplasia or adenomas. It is inherited in an autosomal dominant fashion, and more than 80% of patients with MEN 2A have a specific substitution on codon 634 of the RET proto-oncogene. Despite the nearly 100% penetrance of MTC or CCH in patients with MEN 2A, our patient did not have this. Additionally, he exhibited a RET mutation that is uncommonly seen in classic MEN 2A syndrome. Our patient may have a MEN 2A variant or a pseudo-MEN 2A syndrome. (Endocr Pract. 2011;17:e4-e7)     

Cushing Syndrome Secondary to A Thymic Carcinoid Tumor Due to Multiple Endocrine Neoplasia Type 1

ObjectiveTo present an Iranian patient with a nonclassic form of multiple endocrine neoplasia type 1 (MEN 1) who presented with ectopic Cushing syndrome (CS) secondary to a corticotropin (ACTH)-producing thymic neuroendocrine tumor (NET), recurrent renal stones, and a giant cell granuloma of the jaw due to primary hyperparathyroidism (PHPT) without involvement of the pituitary or pancreas.MethodsRelevant imaging and hormonal evaluations were performed. The patient was operated on 2 occasions for a thymic NET and on 3 occasions for PHPT. DNA from a peripheral blood sample was extracted for sequencing of the MEN1 gene.ResultHistopathologic evaluation of the thymic tumor removed during the first surgery showed an atypical carcinoid tumor with a Ki-67 labeling index of 5%. Evaluation after the second surgery revealed an invasive carcinoid tumor with a Ki-67 labeling index of 30%.Parathyroid pathology was suggestive of glandular hyperplasia. Menin gene sequencing revealed a novel frameshift mutation c.1642_1648dup in exon 10.ConclusionThis case of MEN 1 is unusual because most thymic NETs in MEN 1 are nonfunctional, and secretion of ACTH or other ectopic hormones rarely occurs. In patients presenting with thymic NETs, the possibility of MEN 1 should be considered, especially in the presence of hyperparathyroidism. This case also demonstrates that the behavior of thymic NETs can change over time from slow-growing tumors to highly invasive neoplasia, and that ectopic ACTH can be produced by these tumors in the context of MEN 1. (Endocr Pract. 2011;17:e92-e96)     

Evolution of Surgical Treatment of Primary Hyperparathyroidism in Patients With Multiple Endocrine Neoplasia Type 2A

ObjectiveTo determine the best surgical strategy for patients with multiple endocrine neoplasia type 2A (MEN 2A) who have primary hyperparathyroidism (PHPT).MethodsWe performed a systematic literature review and conducted a retrospective cohort study that included patients with PHPT identified from the MEN 2A database at the University Medical Center of Utrecht, Utrecht, the Netherlands, between 1979 and 2009.ResultsThe review describes the course of worldwide parathyroid surgical management in MEN 2A PHPT over the past 75 years, which has evolved from aggressive parathyroid resections to minimally invasive parathyroidectomy (MIP). The study cohort included 20 patients. Primary surgery for parathyroid disease in patients with MEN 2A (n = 16) included MIP (n = 6), conventional neck exploration with resection of enlarged parathyroid gland(s) (n = 4), and resection of 1 or more enlarged gland(s) during total thyroidectomy (n = 6). Thirteen patients were initially cured after the primary operation. Five patients experi enced persistent or recurrent PHPT. After MIP, 1 patient had persistent PHPT, but no patient developed recurrent PHPT during 5 years of follow-up. Five patients had hypoparathyroidism after subtotal or total parathyroidectomy with autotransplantation, but only 1 patient had transient hypoparathyroidism after MIP. One patient had transient recurrent laryngeal nerve injury after MIP.ConclusionsSurgery for PHPT in patients with MEN 2A has evolved from aggressive conventional exploration of all 4 glands to focused MIP, which appears to be a feasible approach. MIP has low rates of persistent and recurrent PHPT, and the complications are minimal. (Endocr Pract. 2011;17:7-15)     

Synchronous Thymoma and Thymic Carcinoid in A Woman With Multiple Endocrine Neoplasia Type 1: Case Report and Review

ObjectiveTo report a rare case of multiple endocrine neoplasia type 1 (MEN 1) in conjunction with concomitant thymoma and thymic carcinoid.MethodsWe describe a never before reported case involving a 63-year-old female patient with MEN 1 who had synchronous thymoma and thymic carcinoid tumors. A review of the pertinent literature is also undertaken.ResultsAlthough prognosis is stage dependent for patients with thymoma, patients with thymic carcinoids and MEN 1 have been reported to have an extremely poor prognosis, with many patients dying of complications from thymic carcinoid rather than dying of other manifestations of MEN 1. Our patient underwent successful surgical treatment and remains under surveillance for all aspects of the MEN 1 syndrome.ConclusionThymic tumors are rare, and thymic carcinoids, while very rare in occurrence overall, have a definite association with MEN 1. Thus, it is important for practitioners to screen for thymic tumors routinely in patients with MEN 1 and to treat such tumors aggressively when found because they can be a major cause of mortality. Many thymic carcinoids are far advanced before diagnosis, and optimal screening for and treatment of thymic carcinoid are still being developed. (Endocr Pract. 2008;14:713-716)     

Parathyroid Carcinoma in Multiple Endocrine Neoplasia Type 1 with a Classic Germline Mutation

ObjectiveTo report the case of a patient with multiple endocrine neoplasia type 1 (MEN 1) syndrome with concomitant parathyroid carcinoma and a classic MEN1 germline mutation.MethodsWe present the clinical findings, laboratory results, imaging studies, and surgical histopathologic features in a woman with MEN 1 syndrome and concomitant parathyroid carcinoma. We also review the literature regarding patients with similar clinical entities and the use of adjuvant radiotherapy for parathyroid carcinoma.ResultsA 53-year-old woman presented with nausea and severe primary hyperparathyroidism. Computed tomography revealed parathyroid masses, shown later to be bilateral parathyroid carcinomas and adenomas. Magnetic resonance imaging demonstrated a pituitary macroadenoma, and gastrinomas were confirmed by computed tomography and a secretin stimulation test. She was successfully treated with total thyroidectomy, subtotal parathyroidectomy, and adjuvant radiotherapy. Genetic analysis revealed a classic MEN1 germline mutation.ConclusionThis report describes a patient with parathyroid carcinoma occurring in conjunction with MEN 1, further characterizing this rare condition. In contrast to previously described patients, our patient is the first with a classic MEN1 germline mutation, confirming that parathyroid cancer can occur in association with classic MEN 1 genetics. (Endocr Pract. 2009;15:567-572)     

Strongyloidiasis in a Diabetic Patient Accompanied by Gastrointestinal Stromal Tumor: Cause of Eosinophilia Unresponsive to Steroid Therapy

We report here a case of strongyloidiasis in a 72-year-old diabetic patient (woman) accompanied by gastrointestinal stromal tumor receiving imatinib therapy, first diagnosed as hypereosinophilic syndrome and treated with steroids for uncontrolled eosinophilia. She suffered from lower back pain and intermittent abdominal discomfort with nausea and diagnosed with gastrointestinal stromal tumor. After post-operative imatinib treatment eosinophilia persisted, so that steroid therapy was started under an impression of hypereosinophilic syndrome. In spite of 6 months steroid therapy, eosinophilia persisted. Stool examination was performed to rule out intestinal helminth infections. Rhabditoid larvae of Strongyloides stercoralis were detected and the patient was diagnosed as strongyloidiasis. This diagnosis was confirmed again by PCR. The patient was treated with albendazole for 14 days and her abdominal pain and diarrhea improved. This case highlights the need for thorough investigation, including molecular approaches, to test for strongyloidiasis before and during steroid therapies.     

A Novel Double Mutation Val648ile and Val804leu of Ret Proto-Oncogene in Multiple Endocrine Neoplasia Type 2

Objective: We report the case of a female patient with multiple endocrine neoplasia type 2A (MEN2A) who was found to have a double mutation in the RET (rearranged during transfection) proto-oncogene.Methods:RET mutational analysis was performed by Sanger DNA sequencing.Results: The proband was a compound heterozygote for the RET germline mutations Val648Ile and Val804Leu on exons 11 and 14, respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except 1 daughter who carried the Val804Leu mutation. However, none of them showed any clinical, biochemical, or histologic signs of neoplastic disease either in the thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not show pathologic evidence of C-cell disease.Conclusions: We hypothesize that the combined effect of the 2 mutations may have induced the development of pheochromocytoma (PHEO) in our patient. Thus, in the presence of single RET-induced mild medullary thyroid cancer (MTC) phenotype, the search for additional genetic anomalies may lead to the discovery of rare but potentially more aggressive double mutation genotypes.Abbreviations: ACTH = adrenocorticotropic hormone ATA = American Thyroid Association CT = calcitonin FMTC = familial medullary thyroid cancer HSCR = Hirschsprung disease MEN2A/B = multiple endocrine neoplasia type 2A/2B MTC = medullary thyroid cancer PHEO = pheochromocytoma RET = rearranged during transfection SDHB/D = succinate dehydrogenase subunits B/D VHL = Von Hippel-Lindau     

Neuroendocrine Thymic Carcinoma Metastatic to the Parathyroid Gland that was Reimplanted into the Forearm in Patient with Multiple Endocrine Neoplasia Type 1 Syndrome: A Challenging Management Dilemma

ObjectiveTo describe a unique case of a metastatic thymic carcinoma to the hyperplastic parathyroid gland and to present a challenging management dilemma.MethodsOur patient is 60-year-old, intellectually disabled man with history of the multiple endocrine neoplasia type 1 (MEN1) syndrome, a surgery in 1985 for hypercalcemia with removal of one parathyroid gland, surgery in 2007 with findings of extensively necrotic well differentiated neuroendocrine carcinoma (carcinoid tumor) of the thymus. In 2012, he presented with persistent hypercalcemia (calcium level 11.7 mg/dL [range, 8.6-10.2]), and a parathyroid hormone (PTH) level of 225 pg/mL (range, 15-65 pg/mL). He underwent a repeat neck exploration with removal of 2 small inferior and a large left superior 4.5 × 2.5 × 1.5cm parathyroid glands, all of which showed hyperplasia on intraoperative frozen section. A small portion of the superior gland was reimplanted into the patient’s forearm. Final pathology showed the presence of a focus of neuroendocrine tumor within the left superior parathyroid gland with immunostain identical to the thymic carcinoma. His postoperative PTH level was 14 pg/mL and calcium 8.5 mg/dL. A positron emission tomography – computed tomography (PET-CT) and octreotide scans revealed an extensive metastatic disease within the lung, mediastinum, and bones.ResultsWe decided to leave a portion of the reimplanted parathyroid gland with possible metastatic thymic carcinoid in his forearm because of the presence a widespread metastatic disease and his intellectual disability that would result in noncompliance with calcium replacement in case of permanent hypocalcemia.ConclusionMetastatic thymic carcinoma to the parathyroid gland has never been reported in the literature. We have described the first case and presented a challenging management dilemma. (Endocr Pract. 2013;19:e163-e167)     

Non-Invasive Prenatal Diagnosis of Multiple Endocrine Neoplasia Type 2A Using COLD-PCR Combined with HRM Genotyping Analysis from Maternal Serum

The multiple endocrine neoplasia type 2A (MEN2A) is a monogenic disorder characterized by an autosomal dominant pattern of inheritance which is characterized by high risk of medullary thyroid carcinoma in all mutation carriers. Although this disorder is classified as a rare disease, the patients affected have a low life quality and a very expensive and continuous treatment. At present, MEN2A is diagnosed by gene sequencing after birth, thus trying to start an early treatment and by reduction of morbidity and mortality. We first evaluated the presence of MEN2A mutation (C634Y) in serum of 25 patients, previously diagnosed by sequencing in peripheral blood leucocytes, using HRM genotyping analysis. In a second step, we used a COLD-PCR approach followed by HRM genotyping analysis for non-invasive prenatal diagnosis of a pregnant woman carrying a fetus with a C634Y mutation. HRM analysis revealed differences in melting curve shapes that correlated with patients diagnosed for MEN2A by gene sequencing analysis with 100% accuracy. Moreover, the pregnant woman carrying the fetus with the C634Y mutation revealed a melting curve shape in agreement with the positive controls in the COLD-PCR study. The mutation was confirmed by sequencing of the COLD-PCR amplification product. In conclusion, we have established a HRM analysis in serum samples as a new primary diagnosis method suitable for the detection of C634Y mutations in MEN2A patients. Simultaneously, we have applied the increase of sensitivity of COLD-PCR assay approach combined with HRM analysis for the non-invasive prenatal diagnosis of C634Y fetal mutations using pregnant women serum.     

Genomic and Yeast Artificial Chromosome Long-Range Regular Article Linking Six Loci in 10q11.2 and Spanning the Multiple Endocrine Neoplasia Type 2A (MEN2A) Region

Multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited cancers that have in common the clinical feature of medullary thyroid carcinoma (MTC). We have performed both genomic long-range restriction mapping and yeast artificial chromosome (YAC) contig assembly and restriction mapping to establish physical linkage, order, and distances between six loci in 10q11.2 near the genes responsible for these hereditary cancers. RET, D10S94, D10S182, and D10S102 have been mapped in genomic DNA. RET, D10S94, D10S182, D10F3853, and the 10q11.2 sequences detected by DNA marker DM124 are encompassed by a 1-Mb YAC contig. Six physically linked loci are within 1.4 Mb and have an order and orientation of 10cen, D10F38S3, DM124, RET, D10S94, D10S182, D10S102, 10qter. Mutations in the RET proto-oncogene have recently been demonstrated to be associated with MEN 2A and FMTC. RET is located within a genetically defined MEN2A candidate interval between D10S141 and D10S94; MEN2B has been mapped to a larger, overlapping region between D10S141 and a more distal locus, RBP3. Both our genomic physical map and our YAC contig span the entire MEN2A candidate region and overlap with that of MEN2B . These maps will facilitate the identification of genes that can be considered candidates for MEN2B and the identification of tumor-specific alterations important in sporadic MTC.     

Disease-Specific Mortality and Secondary Primary Cancer in Well-Differentiated Thyroid Cancer with Type 2 Diabetes Mellitus

Background

Increased body mass index is related to the incidence of thyroid cancer. However, the presentation and therapeutic outcomes of different thyroid cancers and type 2 diabetes mellitus (DM) have not been studied. This study investigated the effect of type 2 DM on the clinical presentations and therapeutic outcome of well-differentiated thyroid cancer.

Methods and Findings

A retrospective analysis of adult thyroid cancer patients with or without type 2 DM admitted between January 2001 and December 2010 was performed at an institution. A total of 1,687 well-differentiated thyroid cancer patients with different histological patterns were enrolled. Among these subjects, 122 were type 2 DM patients. Patients with thyroid cancer and type 2 DM were significantly older than non-DM patients. After a mean follow-up period of 5.6±0.1 years, patients with thyroid cancer and type 2 DM showed a higher percentage of disease progression than non-DM patients (24.6% vs. 17.4%). In addition, disease-specific mortality was higher in the type 2 DM group (10.7% vs. 3.8%). Thyroid cancer patients with type 2 DM showed a higher percentage of secondary primary cancers than those without DM (10.7% vs. 4.9%). Thyroid cancer-specific survival rates in the type 2 DM and non-DM groups were 82.2% and 94.9% at 5 years, 72.9% and 91.4% at 10 years, and 36.5% and 61.3% at 20 years, respectively. Multivariate analysis showed that type 2 DM was independent of thyroid cancer-specific mortality.

Conclusion

Patients with type 2 DM and well-differentiated thyroid cancer had an advanced tumor-node-metastasis stage at the time of diagnosis and an increased disease-specific mortality. Aggressive surgical procedures and close follow-up for well-differentiated thyroid cancer patients with type 2 DM are therefore necessary.     

Diagnosis by Serendipity: Cushing Syndrome Attributable to Cortisol-Producing Adrenal Adenoma as the Initial Manifestation of Multiple Endocrine Neoplasia Type 1 Due to a Rare Splicing Site Men1 Gene Mutation

ObjectiveTo report a case that highlights the potential for Cushing syndrome to be the first manifestation of multiple endocrine neoplasia type 1 (MEN 1) syndrome and to describe the rare underlying genetic mutation and the heterogeneous manifestations of the syndrome within the same family.MethodsWe present a case report including biochemical and radiologic findings, review family data, and discuss the results of genetic analyses.ResultsA 16-year-old girl who was not known to have any medical illness and had no known family history of MEN 1 syndrome presented with Cushing syndrome attributable to a cortisol-producing adrenal adenoma. During her evaluation, she was found to have primary hyperparathyroidism and a pituitary microprolactinoma. These findings raised the possibility of MEN 1 syndrome. She did not have clinical, biochemical, or radiologic evidence of islet cell pancreatic tumors. Family screening showed that her father had evidence of primary hyperparathyroidism, mild hyperprolactinemia, normal findings on magnetic resonance imaging of the pituitary, and a 1.2- cm nodule in the tail of the pancreas in conjunction with slight elevation of serum insulin and normal gastrin levels. The patient’s 5 siblings had evidence of primary hyperparathyroidism, and 2 of them also had mild hyperprolactinemia. Genetic screening confirmed the presence of a MEN1 gene missense G to A mutation in the patient, her father, and her siblings at the splicing site of intron 6 (IVS6 + 1G > A). This mutation leads to frameshift and truncation of the MEN1 gene.ConclusionIn MEN 1, Cushing syndrome is an extremely rare and usually late manifestation. Most cases are due to corticotropin-producing pituitary adenomas. Although Cushing syndrome generally develops years after the more typical manifestations of MEN 1 appear, it may be the primary manifestation of MEN 1 syndrome. There is considerable heterogeneity in the manifestations of MEN 1, even within a family having the same genetic mutation. (Endocr Pract. 2008;14:595-602)     

Inhibition of KIT-Glycosylation by 2-Deoxyglucose Abrogates KIT-Signaling and Combination with ABT-263 Synergistically Induces Apoptosis in Gastrointestinal Stromal Tumor

Positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose (FDG) is frequently used for visualizing gastrointestinal stromal tumors (GIST), which are highly glucose-avid tumors. Dramatic metabolic responses following imatinib treatment indicate a high, KIT-dependent glucose turnover which has been particularly helpful for predicting tumor response to imatinib. The glucose analogue 2-deoxyglucose (2DG) inhibits glucose metabolism in cancer cells that depend on aerobic glycolysis for ATP production. We show that 2DG inhibits proliferation in both imatinib-sensitive and imatinib-resistant GIST cell lines at levels that can be achieved clinically. KIT-negative GIST48B have 3-14-fold higher IC50 levels than KIT-positive GIST cells indicating that oncogenic KIT may sensitize cells to 2DG. GIST sensitivity to 2DG is increased in low-glucose media (110mg/dl). 2DG leads to dose- and glucose dependent inhibition of KIT glycosylation with resultant reduction of membrane-bound KIT, inhibition of KIT-phosphorylation and inactivation of KIT-dependent signaling intermediates. In contrast to imatinib, 2DG caused ER-stress and elicited the unfolded protein response (UPR). Mannose but not pyruvate rescued GIST cells from 2DG-induced growth arrest, suggesting that loss of KIT integrity is the predominant effect of 2DG in GIST. Additive anti-tumoral effects were seen with imatinib and BH3-mimetics. Our data provide the first evidence that modulation of the glucose-metabolism by 2DG may have a disease-specific effect and may be therapeutically useful in GIST.     

Mouse Ovarian Cancer Models Recapitulate the Human Tumor Microenvironment and Patient Response to Treatment

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Synchronous RCC and TCC of the Kidney in a Patient With Multiple Recurrent Bladder Tumors

Development of concomitant renal TCC and RCC is an uncommon occurrence, yet many interesting issues can be addressed with this model. The possibility of misdiagnosing a renal TCC for an RCC, the options and importance of treating a retained ureteral stump after performing a radical nephrectomy for a renal TCC, and the risk of developing lower tract TCC in patients with upper tract TCC are some of the issues raised in this case review.