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A case of gangliocytic paraganglioma of the duodenum, the 25th in world medical literature, is reported. The histologic appearance consists of epithelioid cell nests resembling "Zellballen" of carotid body tumors, together with gangliocyte-like elements. Ultramicroscopically, the cytoplasm of the cells contains round electron-dense granules or a large number of filaments. Occasional cells contain both granules and filaments.
A case of gangliocytic paraganglioma of the second portion of the duodenal loop is presented. The tumor was polypoid and, histologically, composed of mature ganglion cells, spindle cells and epithelial-like cells. Immunocytochemical examination demonstrated the presence of neurofilament 200 K and S-100 protein only in the first two types of cells; all the cells were positive for neuron-specific enolase. The reaction for cytokeratin was negative in all neoplastic components. According to morphologic and immunocytochemical findings, we suggest a hamartomatous nature of this entity.
An 11-year-old spayed female domestic long-haired cat presented for surgical removal of a slowly growing and deeply invasive 2.5 x 3.5-cm mass cranial to the base of the tail. Light microscopic examination of surgical biopsy specimens revealed an encapsulated mass composed of packets of polygonal cells of various sizes separated by a delicate fibrovascular stroma. Gömöri's reticulum stain revealed a characteristic endocrine or "Zellballen" pattern. Tumor cells contained diffuse positive reactivity to synaptophysin and neuron-specific enolase, reactions consistent with a neuroendocrine neoplasm. S-100 protein-positive cells reminiscent of sustentacular (support) cells occurred singly or in small clusters within tumor packets. At postmortem examination 3 months later, a 9- x 5- x 4-cm multinodular raised tan mass involving the caudal pelvis, sacrum, and tail-head regions was found. The base of this neoplastic mass originated within the cauda equina region and involved approximately five caudal nerve roots. Numerous 1-3-mm metastatic nodules were identified disseminated throughout the pulmonary parenchyma. The tumor was diagnosed as a malignant paraganglioma of the cauda equina region with pulmonary metastasis.
Surgically correctable causes of hypertension are uncommon. Simultaneous occurrence of 2 such causes in the same individual is extremely rare. The authors describe a 25-year-old woman with congenital erythrocytosis, renal artery stenosis, and a paraganglioma. The possible mechanisms of renal artery stenosis in the presence of a catecholamine-secreting tumor are discussed.
We present a case of a 61-year-old female patient with ectopic corticotropin (ACTH) syndrome, hypopituitarism, and catecholamine excess due to a paraganglioma at the inferior pole of the left kidney. In this article we discuss the hormonal findings in the patient and its consequences, the pitfalls of the endocrine workup, and the results of our immunohistological and molecular studies in more detail.
Genetic understanding of pheochromocytoma (PHEO) and paraganglioma (PGL) syndromes has recently expanded with the identification of the involvement of the mitochondrial complex II peptides, namely the succinate dehydrogenase subunit B (SDHB), subunit C (SDHC), and subunit D (SDHD). In patients with PHEO and/or PGL genetic testing for germline mutations in SDHD and SDHB has been recommended, in addition to the PHEO susceptibility genes VHL and RET. After careful clinical assessment of the patient, suspected familial disease may direct the clinician to the appropriate gene for testing. In the absence of obvious features of familial disease, the decision regarding the appropriate gene for testing is more difficult. Such testing can be costly and time consuming, but a rational prioritization of gene testing can streamline the process. Therefore in order to achieve this for apparently sporadic cases we propose a decision matrix based on site of tumor, functionality, and age at presentation.
The discovery of the SDH genes in 2000/2001 dramatically changed the genetics of pheochromocytoma (PHEO) and paraganglioma (PGL). Five years on, it is widely accepted that all patients with PHEO/PGL, whatever their age, should undergo genetic testing, because 25-30% of PHEOs are caused by a germline mutation in one of the five PHEO susceptibility genes. However, genetic testing should be targeted according to family and clinical history. The identification of a causal mutation modifies the management and follow-up of the patient and provides an opportunity for presymptomatic genetic testing for other family members. Moreover, the demonstration that the SDH genes, are tumor suppressor genes and that their inactivation is involved in the hypoxia-angiogenic pathway activating the transcription factor hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylases (PHDs) may lead to the identification of new therapeutic targets for these rare diseases. We discuss here these recent findings and their clinical consequences for the management of PHEO/PGL families and the future of research in this field.
Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest-derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2-1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3+1G>A) was associated with a malignant PHEO.
Pheochromocytomas and paragangliomas are rare neural crest-derived tumors of sympathetic (generally catecholamine producing) or parasympathetic (rarely catecholamine producing) origin. Patients affected by these tumors present with a variable clinical picture, often making diagnosis troublesome. Surgery is the treatment of choice, but requires appropriate medical management before, during, and after tumor resection. Appropriate follow-up of patients is particularly important to identify recurrences, remaining disease, or developing malignancy. Currently, however, no firm guidelines exist about what form follow-up should take. There is also a general lack of prospective studies establishing the best approaches for management and treatment of the tumor. Choice of the many available different therapeutic options instead usually depends on institutional experience and clinical setting, which may vary for different groups of patients. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts addressed and discussed the many therapeutic options and problems associated with management and treatment of patients with pheochromocytoma, reporting their personal experience and sharing their opinions with those of patient representatives. The aim of this special Discussion Session was to reconcile differences of opinion and reach agreement about appropriate management and therapeutic options. This article summarizes the discussion and the recommendations derived from that session.
Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high-dose 131I-MIBG. Patients were 11-62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I-MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I-MIBG was synthesized on-site, by exchange-labeling 131I with 127I-MIBG in a solid-phase Cu2+-catalyzed exchange reaction. 131I-MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I-MIBG therapy. After the first 131I-MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High-dose 131I-MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty-three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I-MIBG uptake on diagnostic scanning, high-dose 131I-MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.
PURPOSE: To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl). PATIENTS AND METHODS: We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria. RESULTS: We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant. CONCLUSION: Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.
We report a family with malignant sympathetic paragangliomas (PGL) exhibiting a new type of germline mutation in the succinate dehydrogenase subunit B (SDHB) gene. Two affected brothers, presenting with symptoms at the ages of 25 and 52 yr, suffered from malignant abdominal extraadrenal sympathetic PGL. They died of their disease at ages 43 and 61 yr. Their mother had the same history of signs and symptoms, suggesting a catecholamine-producing tumor at the age of 55 yr. Analysis of the germline DNA from these three patients revealed a novel mutation in exon 4 (H132P) of the SDHB gene. This mutation was absent in 160 control chromosomes. Loss of heterozygosity analysis of the tumors showed a loss of one SDHB allele, and RT-PCR-based expression analysis confirmed the exclusive expression of the mutated allele in both tumors. A review of the published PGL families revealed malignant tumors in seven of 12 well-documented families with SDHB mutation-associated extraadrenal PGL. These findings, as well as findings of the family reported here, suggest a strong causal relationship of SDHB germline mutations with malignant extraadrenal abdominal PGL and imply the necessity of a close follow-up of affected individuals and family members.
More than 30% of adrenal pheochromocytomas are hereditary. These neuroendocrine tumors are major components of three inherited cancer syndromes: multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and pheochromocytoma/paraganglioma syndrome (PC/PGL). Germline mutations in RET; VHL; and SDHB, SDHC, and SDHD are associated with multiple endocrine neoplasia type 2, VHL, and PC/PGL, respectively. The majority (>70%) of hereditary extraadrenal PCs [catecholamine-secreting paragangliomas (PGL)] are accounted for by germline intragenic mutations in SDHB, SDHC, or SDHD. Therefore, a subset of hereditary PGL is not accounted for. Here we report two unrelated hereditary PGL families, one with a germline whole-gene deletion of SDHD (family 4194), the other a partial deletion of SDHB (family BRZ01). Although they were initially designated mutation negative for all of the PC-associated genes after PCR-based analysis, we suspected that a large deletion or rearrangement might be present. Genotyping around the PC-associated genes demonstrated that both families were consistent with linkage with one of these genes. Using fine structure genotyping and semiquantitative duplex PCR analysis, we identified an approximately 96-kb deletion spanning SDHD in family 4194 and an approximately 1-kb deletion involving the 5' end of SDHB in family BRZ01. Thus, including SDHB and SDHD deletion analysis could increase gene-testing sensitivity for PGL patients, which would aid in genetic counseling and management of patients and families.
Pheochromocytoma or secreting paraganglioma may recur after initial surgery. Diagnostic methods have improved in recent decades. We determined whether features at presentation have changed over time and are associated with long-term outcome. In 192 patients with pheochromocytoma/paraganglioma seen between 1975 and 2003, we compared time from onset of hypertension to first operation, total metanephrine excretion, tumor size and site, the proportion of cases presenting as incidentalomas, and the probability of recurrence according to date of operation (divided into quartiles). The duration of hypertension and tumor size at first operation decreased significantly over time. Right-sided adrenal tumors were more frequent and larger, excreted greater amounts of metanephrines, and presented more frequently as incidentalomas than left-sided tumors. Age, familial disease, and tumor site and size were independent predictors of recurrence. The risk of recurrence was 3.4-fold higher in patients with familial disease than in those with sporadic tumors; it was, respectively, 3.1- and 11.2-fold higher in patients with right adrenal and extraadrenal tumors than in patients with left adrenal tumors. In conclusion, pheochromocytomas/paragangliomas can now be diagnosed earlier, with smaller tumors, and more frequently as incidentalomas. Familial, right adrenal, and extraadrenal tumors recur more frequently than left adrenal tumors.
CONTEXT: Mutations of the gene encoding succinate dehydrogenase subunit B (SDHB) predispose to malignant paraganglioma (PGL). Recognition of the SDHB phenotype in apparently sporadic PGL directs appropriate treatment and family screening. OBJECTIVE: The objective of the study was to assess mutation-specific clinical and biochemical characteristics of SDHB-related PGL. DESIGN: The study design was retrospective descriptive. PATIENTS: PATIENTS included 29 patients (16 males) with SDHB-related abdominal or thoracic PGL. INTERVENTION: There was no intervention. MAIN OUTCOME MEASURES: Clinical presentations, plasma and urine concentrations of catecholamines and O-methylated metabolites, and genotype-phenotype correlations were measured. RESULTS: Mean +/- sd age at diagnosis was 33.7 +/- 15.7 yr. Tumor-related pain was among the presenting symptoms in 54% of patients and was the sole symptom in 14%. Seventy-six percent had hypertension, and 90% lacked a family history of PGL. All primary tumors but one originated from extraadrenal locations. Mean +/- sd tumor size was 7.8 +/- 3.7 cm. In this referral-based study, 28% presented with metastatic disease and all but one eventually developed metastases after 2.7 +/- 4.1 yr. Ten percent had additional head and neck PGLs. The biochemical phenotype was consistent with hypersecretion of both norepinephrine and dopamine in 46%, norepinephrine only in 41%, and dopamine only in 3%. Ten percent had normal catecholamine (metabolite) levels, consistent with biochemically silent PGL. No obvious genotype-phenotype correlations were identified. CONCLUSIONS: SDHB-related PGL often presents as apparently sporadic PGL with symptoms related to tumor mass effect rather than to catecholamine excess. The predominant biochemical phenotype consists of hypersecretion of norepinephrine and/or dopamine, whereas 10% of tumors are biochemically silent. The clinical expression of these tumors cannot be predicted by the genotype.
Pheochromocytomas are neural crest-derived tumors that occur mostly sporadically, but may also be part of inherited syndromes. The molecular pathogenesis of sporadic pheochromocytomas remains unknown. Recently, the susceptibility gene for familial paraganglioma syndrome, a disorder embryologically related to pheochromocytomas, was characterized and shown to encode the small subunit of succinate dehydrogenase (SDHD), which is part of the mitochondrial complex II. This complex regulates oxygen-sensing signals. Importantly, hypoxic signals also appear to be related to the pathogenesis of pheochromocytomas associated with von Hippel-Lindau syndrome. We sequenced the entire coding region of the SDHD gene in a series of pheochromocytomas. Although we did not find mutations in the gene, we identified a new intronic single nucleotide polymorphism in 15% of the samples (g.97739A-->G). We also confirmed the existence of a sequence highly homologous to the SDHD complementary DNA in chromosome 1p34--36, a region commonly deleted in pheochromocytomas. Full analysis of this sequence revealed a heterozygous single base substitution in 70% of our samples that was also present in the germline. This sequence does not appear to be transcribed and is probably a processed pseudogene. Therefore, despite its chromosomal location, it is unlikely that this sequence is a target of loss of heterozygosity in pheochromocytomas. In conclusion, mutations of the SDHD gene are not a common event in this series of sporadic pheochromocytomas. The existence of SDHD pseudogenes should be considered when analyzing complementary DNA-based samples.
A pheochromocytoma, a glomus jugulare tumor, and multiple pulmonary paragangliomas were found in a patient with neurofibromatosis. We review the literature and add this case to the growing number of case reports of neurocutaneous disease in association with neuroendocrine tumors.
Primary paraganglioma of the external auditory canal is a rare otological finding. To date, only three cases have been reported in the world-wide literature. Such a tumour is now described in a 42-year-old female. The clinical and histopathological features of the case are discussed. The role of immunocytochemistry in defining diagnosis, from a large list of differentials, is illustrated. We present the first magnetic resonance images of this rare tumour and highlight the benefit of intra-operative frozen section in limiting surgery to canal excision.