Biochemical Assessment of Pheochromocytoma and Paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances.

Carotid Body Tumor - radiological imaging and genetic assessment.

Carotid Body Tumor i.e. Paraganglioma is a challenging entity from the point of multidisciplinary diagnosis. The main treatment option i.e. surgery yields intraoperative risk,related to cranial nerve palsy and vascular morbidity.Bifurcation of Common Carotid Artery especially at the Carotid Body is the place where Head and Neck Paraganglioma is most frequently seen i.e. 60% of incidence [19]. Indeed, the knowledge of genetic germline SDH mutations, which cause deregulation of hypoxia-induced factors yields better understanding of the tumor nature. It is recommended to conduct selective neck dissection in regions IIA, IIB, III to exlude malignant transformation and metastasis, due to malignant potential of Carotid Body Tumors, especially in case of SDHB mutation. SDHD mutation is the main cause of hereditary HNPGLs. Computed tomography (CT), magnetic resonance imaging (MRI) and angiography yield thorough assessment of paraganglioma extension. In large size tumors, embolization of supplying artery under guidance of angiography may be considered. In case of Carotid Body Tumor, differential diagnosis should include: carotid artery aneurysm, lymphadenopathy, Schwannoma of the hypoglossal nerve or acessory thyroid gland.

Screening for phaeochromocytoma and paraganglioma: impact of using supine reference intervals for plasma metanephrines with samples collected from fasted/seated patients.

Background The Endocrine Society Clinical Practice Guideline on Phaeochomocytoma and Paraganglioma recommends phlebotomy for plasma-free metanephrines with patients fasted and supine using appropriately defined reference intervals. Studies have shown higher diagnostic sensitivities using these criteria. Further, with seated-sampling protocols, for result interpretation, reference intervals that do not compromise diagnostic sensitivity should be employed. Objective To determine the impact on diagnostic performance and financial cost of using supine reference intervals for result interpretation with our current plasma-free metanephrines fasted/seated-sampling protocol. Methods We conducted a retrospective cohort study of patients who underwent screening for PPGL using plasma-free metanephrines from 2009 to 2014 at Galway University Hospitals. Plasma-free metanephrines were measured using liquid chromatography-tandem mass spectrometry. Supine thresholds for plasma normetanephrine and metanephrine set at 610 pmol/L and 310 pmol/L, respectively, were used. Results A total of 183 patients were evaluated. Mean age of participants was 53.4 (±16.3) years. Five of 183 (2.7%) patients had histologically confirmed PPGL (males, n=4). Using seated reference intervals for plasma-free metanephrines, diagnostic sensitivity and specificity were 100% and 98.9%, respectively, with two false-positive cases. Application of reference intervals established in subjects supine and fasted to this cohort gave diagnostic sensitivity of 100% with specificity of 74.7%. Financial analysis of each pretesting strategy demonstrated cost-equivalence (€147.27/patient). Conclusion Our cost analysis, together with the evidence that fasted/supine-sampling for plasma-free metanephrines, offers more reliable exclusion of PPGL mandates changing our current practice. This study highlights the important advantages of standardized diagnostic protocols for plasma-free metanephrines to ensure the highest diagnostic accuracy for investigation of PPGL.

Risk assessment of maternally inherited SDHD paraganglioma and phaeochromocytoma.

BACKGROUND: Germline mutations in the SDHD tumour suppressor gene (11q23.1) predispose to phaeochromocytomas and paragangliomas (PPGL) mainly on a paternal transmission. However, PPGL have been recently reported in three carriers of a maternally inherited SDHD mutation. OBJECTIVE: To assess the risk of PPGL occurrence on maternal transmission of SDHD mutation. METHODS: Pedigrees of 80 SDHD-related families have been reviewed. 35 asymptomatic subjects carrying a maternally transmitted SDHD mutation were identified. 20 of them accepted to benefit from a PPGL imaging screening. RESULTS: A unique histologically proven biochemically negative phaeochromocytoma has been diagnosed in a 35-year-old woman. Molecular investigations carried out on tumour tissue revealed that the loss of heterozygosity encompassed the paternally derived q arm and the maternally derived p arm of chromosome 11. CONCLUSIONS: This study demonstrates that the risk of developing PPGL for a subject carrying a germline SDHD mutation on the maternal allele remains a rare scenario but does exist. Our data suggest an adjustment of current genetic counselling and clinical care recommendations for at-risk subjects. A targeted familial genetic test should be proposed from the age of 18 years to every subject having a mother carrying a germline SDHD mutation and a first medical workup, including imaging, should be recommended to SDHD-positive mutation carriers.

The lymph node roundness index in the evaluation of lymph nodes of the neck.

The study assessed the validity of the lymph node "roundness index" (RI) in the evaluation of enlarged lymph nodes of the neck. A total of 107 subjects were included in the prospective study, and 135 enlarged lymph nodes were examined. All the subjects were examined clinically and sonographically, the lymph node roundness index was determined, and soon after the nodes was surgically removed and pathohistologically diagnosed. On the basis of pathohistological diagnosis the study subjects were divided into two groups. The first group consisted of patients with benign lymph nodes, and the second one comprised patients with malignant nodes. The second group was further divided into two sub-groups: those with primary malignant nodes and those with secondary lymph nodes (metastases). The study showed that the lymph node RI statistically differs between the groups. In benign lymphadenopathy the RI was 1.66 ± 0.26, in primary malignant lymphadenopathy it was 1.31 ± 0.25 and in secondary malignant lymphadenopathy 1.13 ± 0.11. The analysis demonstrated that 82.9% of subjects randomly chosen from the group with primary malignant lymphadenopathy and 94.6% from the group with the secondary malignant lymphadenopathy have a smaller RI compared to randomly chosen subjects from the group with benign lymphadenopathy. Sensitivity of the method for primary malignant lymphadenopathy was 66.7% and specificity was 92.9%. For secondary malignant lymphadenopathy the sensitivity was 95.5% and specificity 92.9%. Based on this result we can conclude that the lymph node RI is a valid, simple, cost-effective and non-aggressive method which may "increase the suspicion" for a benign or malignant lymphadenopathy. RI ≤ 1.5 is indicative of malignant lymphadenopathy and RI ≥ 1.5 of benign lymphadenopathy.

Familial pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas are neural crest cell tumors of the adrenal medulla and parasympathetic/sympathetic ganglia, respectively, that are often associated with catecholamine production. Genetic research over the years has led to our current understanding of the association 13 susceptibility genes with the development of these tumors. Most of the susceptibility genes are now associated with specific clinical presentations, biochemical makeup, tumor location, and associated neoplasms. Recent scientific advances have highlighted the role of somatic mutations in the development of pheochromocytoma/paraganglioma as well as the usefulness of immunohistochemistry in triaging genetic testing. We can now approach genetic testing in pheochromocytoma/paraganglioma patients in a very organized scientific way allowing for the reduction of both the financial and emotional burden on the patient. The discovery of genetic predispositions to the development of pheochromocytoma/paraganglioma not only facilitates better understanding of these tumors but will also lead to improved diagnosis and treatment of this disease.

Utility of cardiac CT and MRI for the diagnosis and preoperative assessment of cardiac paraganglioma.

BACKGROUND: Cardiac paragangliomas are rare cardiac tumors that are usually benign. Surgical excision can be curative. METHODS: We report a case of 39-year-old male who, during the work up of acute coronary syndrome with coronary angiography, cardiac computed tomography (CT) and magnetic resonance imaging (MRI), was found to have cardiac paraganglioma. RESULTS: The tumor was intrapericardial, arising at the level of proximal left anterior descending artery. The tumor was completely resected and the postoperative course was uneventful. At 3-months follow-up the patient was asymptomatic with normal ventricular function. CONCLUSION: Cardiac CT and MRI are valuable in characterizing and preoperative planning of primary cardiac paragangliomas.

Gangliocytic paraganglioma of the bronchus: a case report with follow-up and ultrastructural assessment.

We report a case of gangliocytic paraganglioma of bronchus. A 54-year-old woman underwent bronchoscopy following two episodes of right lower lobe pneumonia over the previous 5 months with unresolved chest radiographic changes. A computerized tomographic scan showed a right lower lobe endobronchial lesion, and at bronchoscopy there was a mass partly occluding the lumen of the bronchus. The biopsy and subsequent bronchoscopic resection showed a tumor with morphologic, immunohistochemical, and ultrastructural features of paragangliomatous, gangliocytic, and Schwann cell differentiation consistent with a gangliocytic paraganglioma. The lesion was treated conservatively with bronchoscopic resection and laser therapy. Histopathologic examination of recurrent tumor at 6 months showed features consistent with paraganglioma. Ten months after initial diagnosis, there was no bronchoscopic evidence of residual tumor. The occurrence of gangliocytic paraganglioma in diverse sites gives cause for the reappraisal of the histogenesis of this fascinating lesion. The variable morphology of this lesion may be an expression of the potential for divergent differentiation of a pluripotent stem cell.

[Tumors of the temporal bone and the cerebellopontine angle. Diagnosis, characterization and assessment of extension by using imaging technics]. / Tumori dell'osso temporale e dell'angolo ponto-cerebellare. Diagnosi, caaratterizzazione e bilancio di estensione con le tecniche ad immagini.

We discuss in this paper the reliability of neuroimaging techniques in the diagnosis of neoplastic masses of the posterior-lateral skull base. We also discuss the role of TC and MRI in the evaluation of the extension pattern of these masses.

Vagal paragangliomas: a clinical, pathological, and DNA assessment.

Ten vagal paragangliomas were studied by image analysis and the results correlated with clinicopathologic features to determine if the DNA ploidy pattern could be used to separate benign from malignant paragangliomas. The tumours occurred in 8 women and 2 men ranging in age from 23 to 75 years (average 54 years). Follow-up was available in all 10 patients and ranged from 3 months to 27 years (average 7.8 years). Of the 10 tumours examined for DNA, 5 were diploid, 4 diploid-tetraploid, and 1 aneuploid. Two patients experienced local recurrences. One of these had a diploid tumour that recurred 22 years after excision and the other had an aneuploid tumour which recurred 4 years 4 months later and was associated with cervical lymph node metastasis. Two patients had malignant tumours with histologically confirmed metastases to noncontiguous cervical lymph nodes. One of the malignant tumours was diploid and the other aneuploid. This study concludes that DNA abnormalities are common in vagal paragangliomas and that tumour ploidy can not be used to assess malignant potential.

Paragangliomas: assessment of prognosis by histologic, immunohistochemical, and ultrastructural techniques.

To predict clinical outcome, we studied 42 paragangliomas from 37 patients by routine histology, immunohistochemistry, and electron microscopy. A panel of antisera to neuron-specific enolase (NSE), chromogranin, and met-enkephalin was used to identify chief (type I) cells, and S-100 protein and glial fibrillary acid protein (GFAP) sustentacular (type II) cells. The intensity of staining of type I cells and the density of type II cells were assessed semiquantitatively (0 to 4+) in a total of 38 tumors. A total of 23 of 24 low-grade tumors (solitary, multiple, or associated with other neoplasms; 95.8%) contained type II cells immunoreactive with either S-100 protein or GFAP, and all were positive when S-100 protein and GFAP were used in combination. Five of the nine intermediate-grade (recurrent and/or locally aggressive) tumors were identified as glomus jugulare tumors (GJT). Three intermediate-grade GJTs were devoid of GFAP-reactive type II cells and four GJTs were negative for S-100 protein. Type II cells were identified in only one of five high-grade (malignant) paragangliomas and that tumor contained vanishingly rare cells that were weakly S-100 protein positive but GFAP negative. Sustentacular cell density and chief cell staining intensity were both inversely related to tumor grade. The most sensitive chief cell marker was NSE (92.1%), followed by chromogranin (84.2%). The least sensitive (73.0%) and specific marker was met-enkephalin. Combinations of NSE or chromogranin with met-enkephalin identified chief cells in all cases. Electron microscopy identified neurosecretory granule-containing chief cells, but was of less value in delineating sustentacular cells because of their scarcity and the absence of specific features. By comparison, immunohistochemistry was superior in identifying sustentacular cells. The use of an immunohistochemical panel, in addition to routine histology, can confirm the diagnosis of a paraganglioma and can give an indication of the likely prognosis for a patient.