Nonseminomatous Germ-Cell Tumor Presenting as Bilateral Adrenal Masses.

OBJECTIVE: Many tumors can metastasize to the adrenal glands, making the diagnosis of adrenal masses challenging. Awareness that rare primary tumors can metastasize to the adrenals and consideration of biopsy for their diagnosis, sometimes at extra-adrenal sites, is essential to prevent unnecessary adrenalectomies and facilitate the right treatment. We report a rare case of bilateral adrenal masses due to metastasis from a nonseminomatous germ-cell tumor of a retroperitoneal lymph node origin. METHODS: The diagnosis of the adrenal masses from the nonseminomatous germ-cell tumor of a retroperitoneal lymph node origin was based on a retroperitoneal lymph node core biopsy. An initial core biopsy of the adrenal gland revealed necrotic tissue and inflammatory cells without evidence of malignancy. Due to nondiagnostic findings, the core biopsy was repeated, which showed degenerating cells with a high mitotic index and immunohistochemical staining positive for vimentin, suggesting the possibility of a high-grade sarcoma. A retroperitoneal lymph node biopsy was performed. The patient was started on chemotherapy. RESULTS: A 34-year-old man presented with acute left upper-abdominal pain of 2 weeks and tenderness on the left upper quadrant of the abdomen, and he was found to have bilateral adrenal masses. Laboratory results showed the following: adrenocorticotropic hormone 41 pg/mL (7-69 pg/mL), metanephrine <0.1 nmol/L (0-0.49 nmol/L), normetanephrine 0.99 nmol/L (0-0.89 nmol/L), and morning cortisol 3.1 µg/dL after a 1-mg dexamethasone-suppression test. His dehydroepiandrosterone sulfate level was 62 µg/dL (120-520 µg/dL), and 17OH progesterone level was 36 ng/dL (<138 ng/dL); androstenedione and serum estradiol levels were normal. Laboratory tests for tumor markers revealed the following: testosterone 21 ng/dL (241-827 ng/dL), prostate-specific antigen 0.57 ng/mL (0-4 ng/mL), alpha-fetoprotein 1.9 IU/mL (0.6-6 IU/ml), and beta-human chorionic gonadotropin 134 mIU/mL (0-1 mIU/mL). CONCLUSION: We report a rare case of rapidly progressing adrenal masses in a young man, found to have metastasized from nonseminomatous germ-cell tumors. Histopathologic confirmation of the metastatic tumor was done, which prevented unnecessary adrenalectomy. The patient received appropriate chemotherapy.

New insights on the pathogenesis of paraganglioma and pheochromocytoma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare chromaffin cell tumors (PPGLs) that at times raise significant challenges in clinical recognition, diagnosis, and therapy and when undiagnosed could associate with severe morbidity. Recent discoveries in PPGL genetics propelled our understanding in the pathophysiology of tumorigenesis and allowed the application of functional classification of pathogenetically distinct groups of PPGLs. This also resulted in a qualitative change in our approach to clinical assessment, diagnosis, and therapy of different subgroups of PPGLs. Establishment of the fact that mutations in multiple components of the PHD-VHL-HIF-2α pathway associate with pseudohypoxia-driven tumorigenesis allowed us not only to better understand the effect of this phenomenon but also to more deeply appreciate the value of functional abnormalities in the physiologic tissue oxygen-sensing mechanism. Mutations in the tricarboxylic acid cycle-related genes opened an additional window into understanding the physiology of one of the basic cellular metabolic pathways and consequences of its disruption. Mutations in the kinase signaling-related genes allow the PPGL field to join a massive innovative process in therapeutic advances in current oncology. New pathophysiologically distinct groups of mutations will widen and deepen our understanding of additional pathways in PPGL tumorigenesis and hopefully introduce additional diagnostic and therapeutic approaches. All of these developments are tremendously important in our understanding of both the normal physiology and pathophysiology of PPGLs and are strong tools and stimuli in the development of modern approaches to all components of medical management.

Clinical utility of chromogranin A in SDHx-related paragangliomas.

BACKGROUND: Measurement of plasma/urinary catecholamine metabolites--especially normetanephrine (NMN)--represents a gold standard in biochemical detection of succinate dehydrogenase subunit B (SDHB) and D (SDHD)-related pheochromocytomas (PHEO) and paragangliomas (PGL). This study was designed to assess diagnostic utility of chromogranin A (CgA) alone or in combination with NMN in patients with PHEO/PGL related to mutations in SDHB and SDHD. MATERIALS AND METHODS: A retrospective study of SDHB and SDHD NIH patients' cohort, which included 41 patients with SDHB mutation-related PHEO/sPGL and 18 patients with either SDHD or SDHB mutation-related head and neck PGL (HNPGL) with both CgA and NMN measured at the time of diagnosis at NIH. RESULTS: In the SDHB group, CgA showed sensitivity of 73.2% and specificity of 95.9%, while for NMN they were 70.7% and 98.6%, respectively. Elevations in CgA and NMN were complementary in 92.7% of patients with proven tumors. Both tests performed well on receiver operating characteristic curve analysis. CgA levels were elevated in 76.9% of SDHB patients and in 80% of patients with metastatic disease and normal NMN levels. CgA values in patients with HNPGL were significantly lower than in patients with PHEO/sPGL. CONCLUSION: CgA is a valuable complementary biomarker in work-up of SDHB-related PHEO/sPGL. In combination with plasma NMN, CgA further enhances tumor detection by 22.0% with minimal loss in specificity. Although non-specific for PHEO/PGL, CgA may well supplement plasma NMN to facilitate diagnostic evaluation of SDHB-related PHEO/sPGL, especially where the measurement of plasma metanephrines could otherwise be delayed by decreased availability or cost restriction.

Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations.

PURPOSE: To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. PATIENTS AND METHODS: From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. RESULTS: Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. CONCLUSION: The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

Hypertension in pheochromocytoma: characteristics and treatment.

Pheochromocytoma is a tumor of the chromaffin cells in the adrenal medulla and sympathetic paraganglia, which synthesizes and secretes catecholamines. Norepinephrine, epinephrine, and dopamine all act on their target receptors, which causes a physiologic change in the body. High circulating levels of catecholamines can lead to severe hypertension and can have devastating effects on multiple body systems (eg, cardiovascular, cerebrovascular), and can lead to death if untreated. Although surgical treatment represents the only modality of ultimate cure, pharmacologic preoperative treatment remains the mainstay of successful outcome.

SDH-related pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma are rare tumors of adrenals as well as the sympathetic and parasympathetic paraganglia. Clinical presentation of these tumors depends on localization, secretory profile and malignant potential. Four distinct syndromes--PGL1-4--are related to mutations in the succinate dehydrogenase gene--mitochondrial complex involved in electron transfer and Krebs cycle. Here we describe etiology, genetics, as well as clinical aspects of SDH-related tumors. We also describe recent discoveries in HIF-related pathway of tumorigenesis and mutations in new SDH-related genes that have improved our understanding of this disease.

Pheochromocytoma and paraganglioma.

Pheochromocytoma is a very special kind of tumor full of duplicity. On the one hand it represents its own microworld with unique clinical, biochemical and pathological features, while on the other it constitutes a tremendously significant part of whole body system, playing a vital role for practically every organ system. It has a very special character - sometimes like a child it can be sweet and predictable, while at times it can behave like a deadly wild beast, crashing and tearing everything on its path in a fierce rage. It also consists of the amazingly intelligent neuroendocrine cells that possess a magical ability to make miraculous substances of many kinds. But most of all, it is a system that is able to drive our curiosity and the itch of "Cogito, ergo sum" to limitless depths and year by year it still amazes us with new and unexpected discoveries that move our understanding of multiple pathways and metabolic events closer to the ultimate truth. Recent discoveries of succinate dehydrogenase (SHD) and prolyl hydroxylase (PHD) mutations, for example, propelled our understanding of neuroendocrine tumorigenesis as a whole, as well as physiology of mitochondrial respiratory chain and phenomenon of pseudohypoxia in particular. Good old discoveries make their way from dusty repositories to shine with new meaning, appropriate for the current level of knowledge. This acquired wisdom makes us better physicians - knowing the specific expression makeup of catecholamine transporters, GLUTs and SRIFs allows for better tailored imaging and therapeutic manipulations. There are still long ways to go, keeping in mind that pheochromocytoma is but so very special, and we are optimistic and expect many great things to come.

Pheochromocytoma: an endocrine stress mimicking disorder.

A pheochromocytoma is an endocrine tumor that can uniquely mimic numerous stress-associated disorders, with variations in clinical manifestations resulting from different patterns of catecholamine secretion and actions of released catecholamines on physiological systems.

Genetic determinants of osteoporosis susceptibility in a female Ashkenazi Jewish population.

PURPOSE: To determine the heritability of low bone mineral density (BMD) at the hip in Ashkenazi Jewish families. METHODS: BMD at hip was accessed by dual x-ray absorptiometry (DEXA) in 166 female subjects from 61 families. Variance component analysis was used to estimate genetic contributions. RESULTS: We observed significant genetic contributions to age-adjusted BMD at the femoral neck as measured by heritability 0.67 (P < 0.0001). CONCLUSION: There is significant genetic determination in decreased BMD at the femoral neck in an Ashkenazi Jewish female population. These results warrant further gene mapping studies in this population to identify osteoporosis susceptibility loci.

Vitamin D-mediated hypercalcemia in lymphoma: evidence for hormone production by tumor-adjacent macrophages.

Nearly one-half of all hypercalcemic patients with lymphoma present with inappropriately elevated circulating concentrations of the active vitamin D metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3). However, the cellular source of the vitamin D hormone in lymphomas remains unclear. To address this, we report the case of a 75-year-old man with hypercalcemia associated with raised circulating concentrations of 1,25(OH)2D3 and suppressed parathyroid hormone (PTH) levels. Positron emission tomographic (PET) and computed tomographic (CT) imaging revealed the presence of a large lymphoma that was confined to the spleen; subsequent pathological analysis showed that this was an intermediate grade B-cell lymphoma. After surgical removal of the spleen, serum calcium and 1,25(OH)2D3 levels became normalized within 24 h. Immunolocalization of the vitamin D-activating enzyme 25-hydroxyvitamin D3-1alpha-hydroxylase (la-hydroxylase) in sections of resected spleen showed that staining was negative in the lymphoma cells but positive in neighboring macrophages. This case study indicates that the hypercalcemia associated with lymphomas may be due, in some instances, to excessive extrarenal production of 1,25(OH)2D3. Furthermore, by using immunohistochemistry to assess the distribution of la-hydroxylase, we have been able to show for the first time that tissue macrophages, rather than actual tumor cells, are the most likely ectopic source of this enzyme. Based on this case study, we propose that the abnormal synthesis of 1,25(OH)2D3 associated with some lymphomas is because of paracrine regulation of tumor-associated macrophages.

Genetic heterogeneity in familial renal magnesium wasting.

Isolated hereditary renal magnesium (Mg) wasting may result from mutations in the renal tubular epithelial cell tight junction protein paracellin-1 gene or the tubular Na(+),K(+)-ATPase gamma-subunit gene FXYD2. The FXYD2 gene mutation was discovered in two Dutch families as an autosomal dominant disorder. It is characterized by isolated renal Mg wasting with resultant symptomatic hypomagnesemia. The defective FXYD2 gene in these families mapped to chromosome 11q23. Here, we describe an American family with a similar phenotype but without linkage to the 11q23 locus; in testing 22 individuals in the pedigree multipoint LOD scores for five different loci from the 11q23 region were equal to -2.97. Compared with unaffected family members and normal controls, affected family members harbored significant reductions in the serum and lymphocyte Mg concentrations and in the serum immunoreactive PTH level with a 4-fold increase in the mean fractional urinary Mg excretion rate during a normomagnesemic clamp. Bone mineral density at the lumbar spine and proximal femur was significantly reduced in affected family members. In conclusion, our data demonstrate locus heterogeneity for the phenotype of isolated renal Mg wasting with hypomagnesemia and suggest that hypomagnesemia, at least in this pedigree, may be associated with low bone mass.