Christian A. Koch

Pheochromocytoma in von hippel-lindau disease: distinct histopathologic phenotype compared to pheochromocytoma in multiple endocrine neoplasia type 2.

Pheochromocytomas are rare neuroendocrine tumors that arise from chromaffin tissue. In a small subset of patients, pheochromocytomas occur as a manifestation of von Hippel-Lindau (VHL) disease. The histology of VHL-associated pheochromocytomas has not been reported in detail. In this article, we describe histopathologic features of 14 pheochromocytomas in eight patients with VHL disease and demonstrate that VHL-associated pheochromocytomas have a distinct histologic phenotype as compared with pheochromocytomas in patients with multiple endocrine neoplasia type 2 (MEN 2). VHL tumors are characterized by a thick vascular tumor capsule; myxoid and hyalinized stroma; round, small to medium tumor cells intermixed with small vessels; predominantly amphophilic and clear cytoplasm; absence of cytoplasmic hyaline globules; and lack of nuclear atypia or mitoses. In contrast to MEN 2, there is no extratumoral adrenomedullary hyperplasia in the VHL adrenal gland. Our findings of a distinct histologic phenotype of VHL phenochromocytoma may further help in subdividing patients who clinically present with multiple, bilateral pheochromocytomas.

New Insights into the Genetics of Familial Chromaffin Cell Tumors

Abstract: We review genetic aspects and recent advances in our understanding of the molecular pathogenesis of familial chromaffin cell tumors (pheochromocytoma, paraganglioma). About 10 percent of pheochromocytomas are familial and occur as part of multiple endocrine neoplasia type 2 (MEN 2), von Hippel‐Lindau (VHL) disease, and neurofibromatosis type 1 (NF 1). A subset of paragangliomas, tumors that can also produce and secrete catecholamines, are also familial and occur in patients with germline mutations in genes that encode subunits of the mitochondrial complex II. The precise molecular mechanisms underlying the pathogenesis of chromaffin cell tumors remain widely unknown, although recent studies in hereditary tumors help elucidate their development. In MEN 2, overrepresentation of mutant RET in selected adrenomedullary cells may be an important mechanism in initiating the formation of a pheochromocytoma. In VHL disease, pheochromocytoma development appears to occur according to Knudsons two‐hit model, a VHL germline mutation and wildtype allelic deletion. Tumorigenesis of NF1‐associated pheochromocytomas remains unknown, as does tumor formation (i.e., carotid body tumor) in patients with germline mutations in SDHB, SDHC, and SDHD, genes that encode subunits of the mitochondrial complex II, the smallest complex in the respiratory chain. Many genetic alterations have been found in sporadic chromaffin cell tumors. However, at present such genetic changes are difficult to place into context with regard to tumor formation and progression.

Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion

The majority of patients with Von Hippel-Lindau (VHL) disease are affected by a VHL germline mutation involving one copy of the VHL gene. Loss of heterozygosity of the second VHL allele can be consistently demonstrated in tumor tissue from these patients, suggesting that allelic deletion is a very early or even initiating event for tumorigenesis. Approximately 20% of VHL disease patients, however, exhibit germline deletion of one entire copy or at least a substantial part of the VHL gene. To investigate the nature of the ‘second genetic hit’ in this patient population, we analysed two renal cell carcinomas and one CNS hemangioblastoma from three unrelated patients for genetic changes of the second copy of the VHL gene. All three tumors showed retention of one VHL allele by FISH. Single-strand conformation polymorphism and mutation analysis of microdissected tumor DNA revealed somatic point mutations of the wild-type VHL copies in each of the three tumors. The results indicate that the ‘two hit model’ is equally applicable to patients with VHL germline mutation and VHL germline deletion. In contrast to tumors from patients with VHL germline mutation, however, point mutations of the wild-type allele can be detected in tumors from patients with VHL germline deletion.

Chronic Hypercortisolemia Inhibits Dopamine Synthesis and Turnover in the Nucleus accumbens: An in vivo Microdialysis Study

Over 60% of patients with Cushing’s syndrome suffer from major depression, which frequently abates after correction of the hypercortisolism. The mesolimbic and mesocortical dopaminergic (DAergic) systems are thought to participate in psychiatric disorders. In this study, we investigated whether hypercortisolemia affects indices of DAergic activity in the nucleus accumbens (NAc) and the prefrontal cortex (PFC) of freely moving rats. Cortisol (CORT, 25 mg/kg/day) was infused subcutaneously for 7 days via an osmotic minipump. Microdialysate collection (30-min periods, 2 µl/min) began 24 h after probe placement. Concentrations of dihydroxyphenylalanine (DOPA) in interstitial fluid in the nucleus accumbens (NAc) and perifrontal cortex (PFC) were measured before and after local perfusion with NSD-1015, an irreversible inhibitor of L-aromatic amino acid decarboxylase, to assess local dopamine (DA) biosynthesis. The sum of microdialysate DA, dihydroxyphenylacetic acid, and homovanillic acid was used as an index of local DA turnover. DOPA accumulation after NSD-1015 was markedly attenuated in CORT-treated compared with saline-treated animals (5,703 ± 1,849 vs. 10,902 ± 2,454 pg/ml; p < 0.01). In contrast, the two groups did not differ in DOPA accumulation in the PFC. Values for the turnover index of DA were also significantly lower in CORT-treated animals in the NAc but not in the PFC. The results indicate that CORT inhibits DA synthesis and turnover in the NAc but not in the PFC. Region-specific CORT-induced inhibition of DAergic activity may help to explain depressive symptoms in patients with chronic hypercortisolemia and normalization after medical or surgical correction of hypercortisolism.

Do Glucocorticoids Cause Spinal Epidural Lipomatosis? When Endocrinology and Spinal Surgery Meet

Here, we report pathogenetic aspects of spinal epidural lipomatosis (SEL) based on a literature review. SEL is a rare entity but can cause significant morbidity. Its symptoms can be identical to those of more common disorders such as vertebral and disc disease, and cord lesions (for example, transverse myelitis, multiple sclerosis and syringomyelia). Therefore, it often goes undiagnosed. In addition, SEL occurs in patients on glucocorticoid therapy, which can lead to myopathy, thereby mimicking the motor symptoms of SEL. Glucocorticoids seem to play a major role in the development of SEL, although idiopathic SEL has also been reported. The latter occurs almost exclusively in obese individuals who may have concurrent hypercortisolism. Once clinically suspected, SEL is best diagnosed by magnetic resonance imaging (MRI). Treatment of SEL is directed at reducing body weight in patients with idiopathic SEL, and at decreasing glucocorticoid excess in patients with endogenous or exogenous hypercortisolism. In severe cases, decompressive laminectomy might become necessary to alleviate the neurological symptoms caused by spinal cord compression.

Allelic imbalance of the mutant and wild-type RET allele in MEN 2a-associated medullary thyroid carcinoma

Germline mutations of the RET proto-oncogene are responsible for the familial tumor syndrome called multiple endocrine neoplasia type 2 (MEN 2) that includes medullary thyroid carcinoma (MTC). Although inherited mutations of RET lead to tumor formation in patients with MEN 2, it is not understood why only selected cells develop into tumors. We have recently shown that duplication of the mutated RET allele or loss of the wild-type allele might represent mechanisms of tumorigenesis in patients with MEN 2A-related pheochromocytoma. We now analysed 19 DNA samples of MTC (15 of which were non-microdissected, four of which were microdissected) from patients with MEN 2A. Using polymorphic marker and phosphorimage densitometry analyses, we found allelic imbalance of the mutated and wild-type RET allele in six of 19 DNA MTC samples. Of note, two of the four microdissected tumor DNA samples showed allelic imbalance of RET, whereas only four of the 15 non-microdissected MTC samples did. These results underscore the significance of microdissection in the analysis of tumor DNA. In our study, some of the non-microdissected tumor DNA samples may have failed to display allelic imbalance of RET, because of contamination of tumor DNA with nonneoplastic DNA or noninformative microsatellite marker analysis. Taken together, our results suggest allelic imbalance between mutated and wild-type RET as a possible mechanism for tumor formation in some patients with MEN 2A-related MTC.

RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed?

OBJECTIVE To describe a kindred with a rare RET germline mutation in codon 791 and discuss potential management strategies. METHODS We present clinical and biochemical data as well as results of mutation analysis in our study subjects and provide an overview of related published reports. RESULTS Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid hyperplasia or adenoma. Germline mutations in RET are responsible for this autosomal dominant syndrome. Familial MTC is a variant of MEN 2A and can be caused by RET mutations in codon 791. Deaths from gene carriers with mutations in these codons have not yet been reported. In general, gene carriers with these RET mutations have late-onset MTC. Because only a few kindreds with this specific mutation have been identified and no long-term follow-up data are available, management of these patients can be a challenge. We illustrate the difficulties with decisions about not only when to perform thyroidectomy in these patients but also whether thyroidectomy should even be considered in such gene carriers with a benign course. Our reported kindred included four carriers with a codon 791 RET germline mutation, one of whom had the rare concomitant occurrence of acromegaly and MEN 2A. The 70-year-old mother had acromegaly and hyperparathyroidism but normal serum calcitonin levels and normal findings on thyroid ultrasound examination. She refused pentagastrin testing and any surgical intervention. The 37-year-old daughter had hypothyroidism, a small thyroid gland, and negative results of pentagastrin stimulation testing of calcitonin. The 18-year-old grandson also had a negative pentagastrin test result and normal thyroid ultrasound findings. The 5-year-old granddaughter had normal results of thyroid ultrasonography. In all patients, we recommended thyroidectomy. CONCLUSION Prospective studies are needed to clarify which patients with codon 791 RET germline mutation should undergo thyroidectomy.

Somatic VHL gene deletion and point mutation in MEN 2A-associated pheochromocytoma.

Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome that includes pheochromocytoma. Germline mutations in RET are responsible for MEN 2 but the precise pathogenetic mechanisms of tumorigenesis are unknown. We have recently identified possible mechanisms of tumor formation in patients with MEN 2A-related pheochromocytoma. Two of nine tumors investigated, however, did not reveal either of these mechanisms. In the present study, we therefore searched for other possible mechanisms underlying the pathogenesis of MEN 2A-related pheochromocytoma. Hereditary pheochromocytoma also occurs in patients with von Hippel-Lindau (VHL) disease, a syndrome consisting of tumors caused by inactivation of the VHL tumor suppressor gene. A subset of sporadic pheochromocytomas have somatic mutations in RET or VHL, suggesting that both genes contribute to pheochromocytoma pathogenesis in a subset of tumors. It is unknown, however, whether VHL gene alterations would be associated with tumorigenesis in hereditary, MEN 2-related pheochromocytoma. We therefore investigated four pheochromocytomas from patients with MEN 2A and RET germline mutations for the presence of allelic deletion and/or somatic mutation of the VHL gene. LOH analysis using the polymorphic markers D3S1038 and D3S1110 that map to the VHL gene locus 3p25/26, revealed evidence for somatic VHL gene deletion in all four MEN 2A-related pheochromocytomas. Mutation analysis of the VHL gene showed frameshift mutations in two tumors and a splice acceptor mutation in one tumor. The remaining tumor did show LOH but not mutation of the VHL gene. These results suggest that somatic genetic alterations of the VHL gene may play a role in the tumorigenesis of some MEN 2A-related pheochromocytomas.

The spectrum of thyroid diseases in childhood and its evolution during transition to adulthood: natural history, diagnosis, differential diagnosis and management.

In this contribution, we review current knowledge on the pathogenesis, diagnosis and differential diagnosis of thyroid disorders in childhood and adolescence, as well as present an update on therapy methods and management guidelines for these disorders. This overview is conceptually divided into two parts, one focusing on thyroid functional disorders, i.e. conditions leading to hyper- and hypothyroidism, and another one pertinent to structural abnormalities of the thyroid gland, i.e. nodular disorders and thyroid cancer. Currently, congenital hypothyroidism is diagnosed in a much more timely fashion rather than in the past, rendering hypothyroidism-related mental retardation and developmental deficits very rare in newborns and children and, hence, diminishing significantly its public health impact. At the same time, considerable advances have occurred in our understanding of the molecular basis of several genetic conditions affecting the thyroid gland in childhood, such as familial non-autoimmune hyperthyroidism, as well as of the pathways leading to thyroid neoplasia.

Ectopic Cushing's syndrome caused by an esthesioneuroblastoma.

OBJECTIVE To report a case of florid Cushings hormone (ACTH) secretion related to the presence of an esthesioneuroblastoma (ENB). METHODS We present clinical, laboratory, and pathologic findings in a 36-year-old Caucasian man presenting with Cushings syndrome. Results of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and somatostatin receptor scintigraphy are presented, along with tumor pathology findings. RESULTS After initial biochemical studies suggestive of ectopic Cushings syndrome, CT of the chest and abdomen revealed multiple cavitated pulmonary lesions, an ischiorectal mass, and bilateral adrenal hyperplasia. MRI of the pituitary gland revealed normal findings. Both PET scanning with [18 F]-flurodeoxyglucose (FDG) and somatostatin receptor scintigraphy with 111 indium-penetetreotide (Octreoscan) revealed strong tracer uptake in the ethmoid region. CT and MRI of the sinuses and brain subsequently localized a 5-cm mass in the ethmoid sinuses with intracranial extension. On biopsy, pathology results were consistent with a diagnosis of ENB, and immunohistochemical analysis revealed that tumor cells were strongly positive for ACTH, synaptophysin, and S-100, providing definitive diagnosis of ACTH-producing ENB. Hypercortisolemia was initially controlled by metyrapone, then by external beam radiation therapy (RT). CONCLUSION This case illustrates the usefulness of nuclear imaging in the diagnosis of ENB, and the importance of prompt control of hypercortisolemia in Cushings syndrome.