Thereasa A. Rich

Clinical Risk Factors for Malignancy and Overall Survival in Patients with Pheochromocytomas and Sympathetic Paragangliomas: Primary Tumor Size and Primary Tumor Location as Prognostic Indicators

CONTEXT Pheochromocytomas and sympathetic paragangliomas are rare neuroendocrine tumors for which no precise histological or molecular markers have been identified to differentiate benign from malignant tumors. OBJECTIVE The aim was to determine whether primary tumor location and size are associated with malignancy and decreased survival. DESIGN AND SETTING We performed a retrospective chart review of patients with either pheochromocytoma or sympathetic paraganglioma. PATIENTS The study group comprised 371 patients. MAIN OUTCOME MEASURES Overall survival and disease-specific survival were analyzed according to tumor size and location. RESULTS Sixty percent of patients with sympathetic paragangliomas and 25% of patients with pheochromocytomas had metastatic disease. Metastasis was more commonly associated with primary tumors located in the mediastinum (69%) and the infradiaphragmatic paraaortic area, including the organ of Zuckerkandl (66%). The primary tumor was larger in patients with metastases than in patients without metastatic disease (P < 0.0001). Patients with sympathetic paragangliomas had a shorter overall survival than patients with pheochromocytomas (P < 0.0001); increased tumor size was associated with shorter overall survival (P < 0.001). Patients with sympathetic paragangliomas were twice as likely to die of disease than patients with pheochromocytomas (hazard ratio = 1.93; 95% confidence interval = 1.20-3.12; P = 0.007). As per multivariate analysis, the location of the primary tumor was a stronger predictor of metastases than was the size of the primary tumor. CONCLUSIONS The size and location of the primary tumor were significant clinical risk factors for metastasis and decreased overall survival duration. These findings delineate the follow-up and treatment for these tumors.

A current review of the etiology, diagnosis, and treatment of pediatric pheochromocytoma and paraganglioma

CONTEXT Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Diagnosed rarely during childhood, PHEO/PGL are nonetheless important clinical entities, particularly given our evolving understanding of their pathophysiology. EVIDENCE ACQUISITION We identified articles through the U.S. National Library of Medicine by using the search terms pheochromocytoma and paraganglioma. Results were narrowed to manuscripts that included children and studies related to the genetics of PHEO/PGL. Web-based resources for genetic disorders were also used. For all articles, we performed subsequent reference searches and verification of source data. EVIDENCE SYNTHESIS Up to 20% of PHEO/PGL are diagnosed in children. Most are functional tumors, and clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Increasingly, PHEO/PGL are identified during presymptomatic screening in children with genetic syndromes associated with PHEO/PGL (multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and the paraganglioma syndromes). Plasma and/or urine metanephrines are the best diagnostic test for a functional tumor, and the management of pediatric patients is similar to adults. Genetic counseling should be undertaken in all cases. Although most pediatric PHEO/PGL are benign, these tumors can occasionally metastasize, a condition for which no curative treatment exists. CONCLUSIONS Although PHEO/PGL are rarely diagnosed during childhood, the pediatric provider should be able to recognize and screen for such tumors, particularly in the context of a known genetic predisposition. Optimal care of these children includes a multidisciplinary team approach at centers experienced in the evaluation and treatment of these uncommon yet fascinating endocrine neoplasms.

Use of the Tyrosine Kinase Inhibitor Sunitinib in a Patient with von Hippel-Lindau Disease : Targeting Angiogenic Factors in Pheochromocytoma and Other von Hippel-Lindau Disease-Related Tumors

CONTEXT von Hippel-Lindau disease is characterized by highly vascularized tumors of multiple organs. EVIDENCE ACQUISITION We present a patient with von Hippel-Lindau disease with multiple renal and pancreatic tumors and a malignant pheochromocytoma infiltrative of the sacrum and associated with lymph nodule metastases. The pheochromocytoma expressed high protein level of vascular endothelial growth factor and platelet-derived growth factor-beta receptor. The patient presented with a poor performance status, severe pelvic pain, weight loss, and manifestations of catecholamine excess. EVIDENCE SYNTHESIS Treatment against malignant pheochromocytoma with surgery, chemotherapy, or participation in clinical trials was not feasible because of the patients poor performance status, the presence of multiple tumors, and the extension of the pheochromocytoma into the bones. Patient was treated with sunitinib, a potent tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, RET, c-KIT, and FLT-3 receptors. Six months of treatment with sunitinib was associated with normalization of the patients performance status and blood pressure, absence of symptoms of catecholamine excess, weight gain, disappearance of pain, shrinkage of each of the tumors (50% in the largest renal tumor, 38% in the largest islet cell tumor, 21% in the pelvic malignant pheochromocytoma), and reduction of plasma normetanephrines and chromogranin A. CONCLUSION This study provides evidence that targeting tyrosine kinase receptors such as the vascular endothelial growth factor pathway and the platelet-derived growth factor-beta receptor may have value in the treatment of VHL-related tumors including pheochromocytoma.

Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: Insights from the largest single-institutional experience

The objective of this study was to evaluate the clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic paragangliomas by assessing reductions in tumor size and blood pressure and improvements in overall survival (OS).

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

Management of medullary thyroid carcinoma and MEN2 syndromes in childhood

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90–95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype–phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise.

Multiple Endocrine Neoplasia Syndromes

The multiple endocrine neoplasia (MEN) syndromes are rare autosomal-dominant conditions that predispose affected individuals to benign and malignant tumors of the pituitary, thyroid, parathyroids, adrenals, endocrine pancreas, paraganglia, or nonendocrine organs. The classic MEN syndromes include MEN type 1 and MEN type 2. However, several other hereditary conditions should also be considered in the category of MEN: von Hippel-Lindau syndrome, the familial paraganglioma syndromes, Cowden syndrome, Carney complex, and hyperparathyroidism jaw-tumor syndrome. In addition, researchers are becoming aware of other familial endocrine neoplasia syndromes with an unknown genetic basis that might also fall into the category of MEN. This article reviews the clinical features, diagnosis, and surgical management of the various MEN syndromes and genetic risk assessment for patients presenting with one or more endocrine neoplasms.

Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation

BACKGROUND Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. SUMMARY The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy. CONCLUSION A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.

Failure to Recognize Multiple Endocrine Neoplasia 2B: More Common Than We Think?

BackgroundMultiple endocrine neoplasia 2B (MEN2B) has a classic childhood phenotypic presentation characterized by mucosal neuromas and marfanoid habitus. However, the diagnosis of MEN2B is often delayed beyond childhood, at which time medullary thyroid carcinoma (MTC) may be regionally advanced or metastatic. We examined the extent of this delay and its impact on the treatment of MTC.MethodsPatients in the MEN database were retrospectively analyzed to determine the age at first presentation for a MEN2B-related complaint and the subsequent time to correct diagnosis. Operative and pathology reports were reviewed to determine the extent of thyroidectomy and cervical lymphadenectomy during the initial and subsequent neck operations.ResultsWe identified 22 patients with MEN2B, 20 were de novo cases and a M918T RET gene mutation was confirmed in 18 of the 22 patients. Median age at diagnosis of MTC was 13 years (range 6–25 years). The median delay in diagnosis was 26 months (range 0–18 years). Persistent local-regional MTC was present following the initial cervical operation in 12 of 22 patients (55%); including 4 of 13 with MEN2B diagnosed prior to initial surgery and 8 of 9 with MEN2B diagnosed after initial surgery.ConclusionsMost patients displayed phenotypic characteristics of MEN2B long before the correct diagnosis was made. Half of the patients failed to undergo complete resection of MTC at their initial thyroid surgery. Early recognition of the MEN2B phenotype with a thoughtful approach to preoperative staging and surgery will maximize control of MTC and minimize the need for reoperation.

Long-Term Outcomes of Surgical Treatment for Hereditary Pheochromocytoma

BACKGROUND The ideal surgical management of hereditary pheochromocytomas includes planning for a potential metachronous bilateral presentation and the possibility of lifelong steroid dependence if bilateral adrenalectomy is needed. An intact and viable cortical remnant after bilateral pheochromocytoma resection can eliminate the necessity for steroid dependency, but can increase the risk of pheochromocytoma recurrence. STUDY DESIGN We retrospectively reviewed outcomes of all patients with a diagnosis of hereditary pheochromocytomas treated at our tertiary cancer institution from 1962-2011, with subset analysis of patients undergoing a cortical-sparing procedure in the setting of bilateral adrenalectomy. RESULTS Of the ninety-six patients who underwent adrenalectomy for hereditary pheochromocytomas, 47 presented with bilateral disease. In 15 of the 49 patients (30%) who originally underwent unilateral adrenalectomy, pheochromocytoma developed in the contralateral gland at a median of 8.2 years (range 1 to 20 years) after the initial diagnosis. There were 4 recurrences in 55 cortical-sparing remnants (7%) and 3 recurrences in the adrenal bed after 101 intended total adrenal resections (3%) (p = 0.24). Total bilateral adrenalectomy was performed in 25 patients and acute adrenal insufficiency developed in 5 (20%) of those patients. An intended cortical-sparing adrenalectomy was performed in 39 patients and acute adrenal insufficiency developed in 1 (3%). Of these patients with adequate follow-up, 21 of 27 (78%) were steroid independent at 3-year follow-up. Sex, median age, adrenal vein preservation, metachronous adrenal resection, and bilateral cortical-sparing procedures did not predict steroid independence at 3 years. CONCLUSIONS Cortical-sparing adrenalectomy avoids long-term corticosteroid dependence in the majority of patients with hereditary pheochromocytoma with minimal risk of acute adrenal insufficiency. Recurrence occurs in approximately 7% of adrenal remnants.