Adrenal Paraganglioma Research Articles

Loose cell clusters with vascular coats: Zellballen pattern of paraganglioma on cytology

Paragangliomas are uncommon tumors arising in paraganglion tissue, which is well represented in the head and neck. A correct pre-operative cytological diagnosis helps in planning early and optimal surgery. Cytologic features in carotid body tumor and extra adrenal paragangliomas have been well described and documented. In addition to the acinar and discrete arrangement of cells, smears also showed a few large loose clusters of cells enveloped by thin vascular channels-the so-called zellballen pattern, a diagnostic feature on histopathology. Zellballen pattern of paraganglioma on cytology is not a common finding and hence is being reported.

A Not So Simple Retroperitoneal Mass-A Clue from Hypertensive Crisis

Extra adrenal paragangliomas are tumours of chromaffin cells arising from the sympathetic and parasympathetic divisions of the autonomic nervous system. About 75% of them are located between the origin of the inferior mesentric artery and bifurcation of the abdominal aorta known as the organ of Zuckerkandl.1Their clinical presentations are varied and are mostly due to the excessive secretion of catecholamines by the tumour. The incidence of the classic triad of Headache, Palpitations and Diaphoresis is seen in as little as 24% of cases. 2A recent review reports hypertension to be paroxysmal in 48%, persistent in 29% and absent in 13 % of cases. 2 About 49% of cases are incidentally diagnosed during abdominal imaging. 2 These tumours may be confused with other common retroperitoneal neoplasms, especially when the patient is asymptomatic. We report a severe hypertensive crisis in such an asymptomatic patient, which was triggered on induction of anesthesia and manipulation of the tumour and its successful management in a patient with undiagnosed paraganglioma.

Sixty-eight consecutive cases of neuroendocrine tumor treated with somatostatin analogues: A 20-year single-center experience.

e14707 Background: Neuroendocrine tumours (NET) arise from enterochromaffine and related cells found in epithelial organs throughout the body. Hormone related symptoms in neuroendocrine tumours are well treated with somatostatin analogues. Previous experience has demonstrated some antiproliferative activity of somatostatin analogues in the treatment of NET. Methods: In the last 20 years 68 patients with histologically proven NET were treated: primaries in small bowel (27), pancreas (17), rectum (9), appendix (5), lung (4), unknown (3), extra- adrenal abdominal paragangliomas (2) and stomach (1). The mean age of first diagnosis was 56 years. All of them received somatostatin analogues in long acting depot administration (or combination interferon/somatostatin analogues) for a minimum period of two months and a maximum of 139 months. Somatostatin therapy was started in patients with endocrine-active tumours immediately after the diagnosis and in patients with endocrine-inactive tumours after an observation time of 3 months without therapy if progress was observed. Tumor size was assessed every 3 months after begin of therapy. Results: Best responses were a stable disease in 46 of 68 patients (68%) and a partial remission in 2 (3%). Twenty of 68 patients (29%) showed progress. The responses achieved were in small bowel 20/27; pancreas 14/17; rectum 7/9; appendix 4/5 and lung 3/4. The median duration of response was 34 months. Conclusions: Our results document that treatment with somatostatin analogues prolongs time to progression in NET. Stabilisation of tumour mass itself is a relevant outcome for patients with NET. The benefit of somatostin analogues is indipendent to use of chemotherapy. Because of its efficacy and the good tolerability somatostatin analogues can be considered a first line treatment option.

Sixty-six consecutive cases of neuroendocrine tumor treated with somatostatin analogues: A 20-year single-center experience.

374 Background: Neuroendocrine tumours (NET) arise from enterochromaffine and related cells found in epithelial organs throughout the body. Hormone related symptoms in neuroendocrine tumours are well treated with somatostatin analogues. Previous experience has demonstrated some antiproliferative activity of somatostatin analogues in the treatment of NET. Methods: In the last 20 years 66 patients with histologically proven NET were treated: primaries in small bowel (27), pancreas (16), rectum (9), appendix (5), lung (3), unknown (3), extra- adrenal abdominal paragangliomas (2) and stomach (1). The mean age of first diagnosis was 56 years. All of them received somatostatin analogues in long acting depot administration (or combination interferon/somatostatin analogues) for a minimum period of two months and a maximum of 139 months. Somatostatin therapy was started in patients with endocrine-active tumours immediately after the diagnosis and in patients with endocrine-inactive tumours after an observation time of 3 months without therapy if progress was observed. Tumor size was assessed every 3 months after begin of therapy. Results: Best responses were a stable disease in 46 of 66 patients (70%) and a partial remission in 2 (3%). Nineteen of 66 patients (27%) showed progress. The responses achieved were in small bowel 20/27; pancreas 13/16; rectum 7/9; pancreas 7/9 and lung 2/3. The median duration of response was 34 months (range 3-139). Conclusions: Our results document that treatment with somatostatin analogues prolongs time to progression in NET. Stabilisation of tumour mass itself is a relevant outcome for patients with NET. The benefit of somatostin analogues is indipendent to use of chemotherapy. Because of its efficacy and the good tolerability somatostatin analogues can be considered a first line treatment option.

Clinical Utility of Functional Imaging with 18F-FDOPA in Von Hippel-Lindau Syndrome

Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which patients are at risk of developing multiple tumors in different organs. 6-L-¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) positron emission tomography (PET) is a relatively new metabolic imaging tracer proposed for the use of localizing sites of neuroendocrine tumors. There are limited data on the clinical utility of using ¹⁸F-FDOPA PET for identifying neuroendocrine tumors in a high-risk population such as VHL. The aim of this prospective study was to evaluate the clinical utility of ¹⁸F-FDOPA PET in patients with VHL-related tumors. Radiological findings were prospectively collected from four imaging modalities: computed tomography, magnetic resonance imaging (MRI), ¹⁸F-fluorodeoxyglucose PET, and ¹⁸F-FDOPA PET. ¹⁸F-FDOPA PET findings were compared with those from other imaging modalities, as well as with clinical and laboratory data, and pathology findings if patients underwent an operation. In 52 patients with VHL, 390 lesions were identified by computed tomography (n = 139), MRI (n = 117), ¹⁸F-fluorodeoxyglucose PET (n = 94), and ¹⁸F-FDOPA PET (n = 40). ¹⁸F-FDOPA PET identified 20 pancreatic and 20 extrapancreatic tumors, including lesions in the adrenal gland (n = 11), kidney (n = 3), liver (n = 4), lung (n = 1), and cervical paraganglioma (n = 1). These tumor sites were not seen by conventional imaging studies in 9.6% of patients and 4.4% of lesions. Seven of eight patients who had an ¹⁸F-FDOPA PET-positive lesion underwent resection, and pathology showed a neuroendocrine tumor. Four of 10 patients with positive adrenal uptake had elevated catecholamine levels, and six of 10 patients had a discrete mass on axial imaging. ¹⁸F-FDOPA PET is a useful complementary imaging study to detect neuroendocrine tumors in patients with VHL undergoing surveillance, especially in those suspected to have adrenal pheochromocytoma or unusual ectopic locations.

Paraganglioma: A cause of hypertension in a young patient

Collections of neuroendocrine cells dispersed throughout the body are known as paraganglia and the tumor arising from these paraganglia are known as paragangliomas. Paragangliomas located along side the aorta are associated with the pheochromocytoma and they secrete and store catecholamines. We reported a 29-year-old woman with episodes of headache, palpitations, dizziness and sweats, associated with hypertension. Elevated urine catecholamines were consistent with pheochromocytoma. Nuclear magnetic resonance (NMR) was performed and the symptoms were caused by associated mediastinal and retroperitoneal paragangliomas. The tumors were surgically removed. In a 3-year follow-up period the patient had two recidivate lesions, one of them was surgically removed, and for the last one a 6-month follow-up was recommended, because urine cathecholamine level was not significantly elevated and blood pressure was normal. Clinical and imaging data of patients with extra adrenal paragangliomas are not specific. Many of them may be asymptomatic even when the lesion is large, but if tumor is functional, diagnosis may be easier. Patients should be initially evaluated by determining catecholamine level, followed by computerized tomography (CT) or NMR to locate the primary lesion. Since there are no definite microscopic criteria for the distinction between benign and malignant tumors, radical excision and prolonged follow-up is necessary.

Neoplastic spread after trauma: natural death or manslaughter?

We report an unusual death of a seemingly healthy 26-year-old man due to diffuse metastasization of adrenal paraganglioma caused by rupture of the primitive tumour with subsequent massive haemorrhage after a relatively minor trauma. Our report describes the results of forensic investigation and discusses the possible mechanisms of metastasization.

Clinical aspects of SDHx-related pheochromocytoma and paraganglioma

Paragangliomas (PGLs) derive from either sympathetic chromaffin tissue in adrenal and extra-adrenal abdominal or thoracic locations, or from parasympathetic tissue of the head and neck. Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively. The susceptibility gene for PGL2 on 11q13.1 remains unidentified. Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells. SDHB-, SDHC-, and SDHD-associated PGLs give rise to more or less distinct clinical phenotypes. SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL). SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs. SDHC mutations are a rare cause of mainly HNPGL. Most abdominal and thoracic SDHB-PGLs hypersecrete either norepinephrine or norepinephrine and dopamine. However, only some hypersecrete dopamine, are biochemically silent. The biochemical phenotype of SDHD-PGL has not been systematically studied. For the localization of PGL, several positron emission tomography (PET) tracers are available. Metastatic SDHB-PGL is the best localized by [(18)F]-fluorodeoxyglucose PET. The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.

Pheochromocytoma: an update on genetics and management

Pheochromocytomas (PHEOs) are rare neoplasms that produce catecholamines and usually arise from the adrenal medulla and are considered to be an adrenal paraganglioma (PGL). Closely related tumors of extraadrenal sympathetic and parasympathetic paraganglia are classified as extraadrenal PGLs. Most PHEOs are sporadic, but a significant percentage (approximately 25%) may be found in patients with germline mutations of genes predisposing to the development of von Hippel-Lindau disease, neurofibromatosis 1, multiple endocrine neoplasia type 1 (MEN1) and 2 (MEN2), and the PGL/PHEOs syndrome, based on the described mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC). As one out of four PHEOs turns out to be a hereditary clinical entity, screening for genetic alterations is important, as it provides useful information for a rational diagnostic approach and management. This review discusses the genetics, the pathophysiology of hypertension, the clinical picture, the biochemical and imaging diagnosis, and the preferred therapeutic approach for PGLs/PHEOs. Furthermore, it emphasizes the need for genetic testing in cases with apparently sporadic PHEOs.

Malignant Paragangliomas Associated with Mutations in the Succinate Dehydrogenase D Gene

Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate dehydrogenase D (SDHD) gene. The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in five patients with SDHD (D92Y) mutations observed in approximately 200 SDHD (D92Y) mutation carriers followed in our institution. Metastasis and/or local tumor invasion was documented 0 (n=2), 1, 18, and 30 yr after the initial diagnosis of paraganglioma. Malignancy was proven by paraganglioma bone metastases (n=2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone, and locally invasive paraganglioma of the bladder with lymph node metastases. Four of the five patients developed catecholamine excess during follow-up due to intraadrenal paraganglioma (pheochromocytoma) (n=1), extra adrenal paraganglioma (n=2), and presumed subclinical disease (n=1). SDHD mutations (D92Y) are associated with malignant paragangliomas and catecholamine excess with remarkable interindividual variations despite the same mutation. We estimate that the prevalence of malignancy in carriers of D92Y mutations is at least 2.5%.

Hepatocyte Paraffin 1 Expression in Human Normal and Neoplastic Tissues: Tissue Microarray Analysis on 3,940 Tissue Samples

Hepatocyte paraffin 1 (Hep Par 1) is a monoclonal antibody developed from hepatic tissue from a failed liver allograft. Several studies have shown that Hep Par 1 is a useful marker to differentiate hepatocellular carcinoma (HCC) from other types of adenocarcinoma metastatic to the liver. The aim of our study was the systematic investigation of the epidemiology of Hep Par 1 expression in 3,940 tissue samples using the tissue microarray technique. Strong Hep Par 1 expression was found most frequently in 35 (73%) of 48 HCCs. In nonhepatic tumors, strong Hep Par 1 expression was detected in adenocarcinoma of the lung (2/50), gallbladder (3/31), pancreas (2/48), stomach (3/74), small intestine (1/11), adenoma of the colon with high-grade dysplasia (1/49), adrenal gland carcinoma (1/6), paraganglioma (1/9), and malignant melanoma (2/48). Our data suggest that Hep Par 1 is a highly specific marker for HCC, although several nonhepatic tumors occasionally can show some Hep Par 1 positivity.

A mini review of paragangliomas with presentation of two cases

Paragangliomas are rare tumours of the paraganglion system, which may, in approximately 80% of cases, be hormonally active with potentially lethal consequences. In this mini review, the classification, pathology, pathophysiology and clinical management are described. An attempt is also made to evaluate the relative advantages and disadvantages of the most commonly used diagnostic imaging modalities, viz. Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and radionuclide scintigraphy. Paragangliomas are divided into four anatomical classes:1. Paragangliomas arising from the adrenal medulla2. Aortico-sympathetic paragangliomas3. Parasympathetic and visceroautonomic paragangliomas4. Paragangliomas not otherwise specified. They occur sporadically or in families, and have recognised associations with other diseases. The majority are benign. Ninety percent of tumours are adrenal and 1O% are extra-adrenal. Patients commonly present with hypertension or paroxysmal crises and the laboratory diagnosis hinges on the demonstration of elevated catecholamine levels. Initial management involves stabilisation with alpha-blockade followed by preoperative tumour localisation.MRI has similar accuracy to CT in diagnosis of adrenal tumours. MRI surpasses metaiodobenzylguanidine (MIBG) scanning in detecting adrenal disease and non-functional paragangliomas. MIBG has greater sensitivity and specificity than MRI in the detection of extra-adrenal tumours, although both are superior to CT. MRI is currently the investigation of choice, with MIBG being used in cases of disease recurrence, metastases or equivocal MRI. Surgical cure is possible in up to 85% of cases. The recurrence rate is between 5 and 10%, with a 5 year survival rate of 80 to 95%.

Familial pheochromocytoma associated with a novel mutation in the von Hippel-Lindau gene.

We report a three generation, 25 member kindred with familial pheochromocytoma. Seven subjects of generations I and II had pheochromocytoma, in five of the seven, the tumors were bilateral, and in two of the seven, the tumors were both adrenal and extraadrenal. One patient also had a carotid body chemodectoma, and one patient had a malignant adrenal tumor and abdominal paraganglioma. In the patient with the chemodectoma, a cerebellar hemangioblastoma became manifest 25 yr after his initial diagnosis with pheochromocytoma, leading only then to a clinical diagnosis of von Hippel-Lindau disease (VHL). A mutational analysis of the VHL gene revealed a novel nucleotide 709 G-->T transversion present in all affected subjects and in four presymptomatic children. In familial pheochromocytoma the diagnosis of VHL should be considered, even when the formal criteria for diagnosis of the syndrome are lacking.

ABSENCE OF OVER-EXPRESSION OF P53 PROTEIN IN BENIGN AND MALIGNANT PARAGANGLIOMAS

Expression of abnormally stable mutant forms of the protein encoded by the gene known as p53 is an extremely common event in human neoplasms, a fact reflecting its crucial role in the regulation of cell turnover. Although widely investigated in a range of tumours from a variety of sites, there do not, to our knowledge, appear to have been any studies of its expression in paragangliomas. Abnormal expression of p53 protein was absent from 15 morphologically typical adrenal (2) and extra-adrenal(13) paragangliomas, 3 were overtly malignant, when sought for using the DO-7 antibody (Dako), whilst colon adenocarcinomas known to abnormally express the protein and used as controls were consistently positive. These results suggest that the mechanism of any dysfunction of the p53 encoding gene in paragangliomas might differ from that in tumours from other sites such that its detectable overexpression does not result.

MR imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas.

To compare the potential of magnetic resonance (MR) imaging and scintigraphy performed with radiotracer-labeled metaiodobenzyl-guanidine (MIBG) in localization and characterization of functioning paragangliomas, the authors analyzed results of both modalities in 33 patients. Overall sensitivity for detection was 91% for MR imaging and 80% for MIBG scintigraphy. MR imaging demonstrated 100% of adrenal paragangliomas and 75% of extraadrenal paragangliomas, whereas MIBG scintigraphy revealed 75% and 88%, respectively. MIBG scintigraphy was more specific in the characterization of paragangliomas than MR imaging (100% vs 82%). However, MR imaging demonstrated nine other lesions not seen on scintigrams. On the basis of their results and other considerations, the authors believe MR imaging is the preferred initial technique when a functioning paraganglioma is suspected.

The value of the clonidine-suppression test in the diagnosis of pheochromocytoma.

AbstractWe assessed the clinical value of a clonidine‐suppression test in the diagnosis of pheochromocytoma. Three different groups were investigated: group I, 10 patients with operatively verified catecholamine‐secreting tumors (1 extra adrenal paraganglioma); group II, 34 patients with “neurogenic” hypertension; and group III, 14 normotensive, healthy subjects.Clonidine, 300μg given orally at time zero, significantly reduced mean systolic/diastolic blood pressure (MBP) in all 3 groups: group I, maximum MBP fall ‐19/0 mm Hg; group II, ‐43/21 mm Hg; and group III, ‐25/9 mm Hg, respectively. The maximal MBP fall was seen between 2 and 3 hours after administration of clonidine. Mean plasma concentrations of noradrenaline/norepinephrine (NA) decreased in groups II and III, in group II from 2.6±0.3 to 0.7±0.05 nmol/l (p<0.001), and in group III from 1.3±0.2 to 0.6±0.06 nmol/l, respectively. Plasma concentrations of adrenaline/epinephrine (A) were low < 0.2 nmol/l and remained unchanged during the test. In contrast, in patients with pheochromocytoma (group I), NA and A mean plasma concentrations were high before clonidine, 7.7±2.2 nmol/l for NA and 4.0±1.7 nmol for A, and remained high or somewhat elevated during the 3 hours of observation. No patient showed a decrease in plasma catecholamines during the test.After successful operation for the catecholamine‐secreting tumors, all 10 patients achieved normal BP (mean 135/83 mm Hg supine) and had normal basal plasma catecholamine concentrations (NA 2.8± 0.5 nmol/l, A<0.2 nmol/l) with normal suppression of NA after clonidine to 1.1± 0.2 nmol/l (p<0.01 compared with basal values). We conclude that the clonidine‐suppression test is a safe and simple diagnostic method for verification or exclusion of pheochromocytomas, especially in patients with normal resting (baseline) catecholamine levels (4 patients in the present study). No significant or clinically relevant side effects were noted during the test apart from some sedation and dry mouth.