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pheochromocytoma Fatemeh Rahmani

pheochromocytoma Fatemeh Rahmani.

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pheochromocytoma Fatemeh Rahmani

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  1. pheochromocytomaFatemeh Rahmani

  2. ● presence of a smaller piece of functional tissue● release of a small amount of unmetabolised catecholamines due to a rapid intratumoural turnover rate●episodically secreting tumours●silent stress-activated tumours●DA-producing pheochromocytomas●familial PCS syndromes screened at early stages●Assay interference

  3. 30-year-old woman presenting with an adrenal incidentaloma that was 7.6 × 5.3× 4.8cm in size on an abdominal CTShe did not have any complaints of episodic headaches,sweating, ,palpitations , chestpain,hypertension, weight gain ,excess hair growth on the body, acne ,proximal muscle weakness ,menstrual irregularity,no cushingoid feature

  4. On examination,BP was 110/70 mmHg ,without postural dropIntraoperatively ,the patient had a spell of hypertensive emergency with a BP of 230/120mmHg.Surgery was postponed, and the patient was prescribed 5mg of prazosin twice daily,followed by 50mg of metoprolol twice daily after testing for the adequacy of α blockade.Two weeks later,with a BPof 140/80mmHg,the patient underwent a laparoscopic tumour resectionThepathology revealed an encapsulated tumour ,which confirmed the pheochromocytoma diagnosis

  5. ●2 diststinct subpopulations of chromaffin cells adrenergic cells contain PNMT and store epinephrine noradrenergic cells don’t contain PNMT and store NE ●most PCS produce predominantly NE ●many produce both NE & E● more rarely produce predominantly E ●some extremely rare cases produce Dopamin●patients with EN secreting tumors often show episodic symptoms with palpitations,anxiety,hyperglycemia, PE more frequently than in patients with tumors secretes NE

  6. ●Dopaminergic phenotype is characterized by high levels of dopamine / 3-MT with normal levels of MNE and NMN ●Tumors are commonly extra-adrenal, primarily located in the head and neck region, especially in the carotid body ●Patients can be asymptomatic or have atypical symptoms like abdominal pain, diarrhea, nausea/vomiting, hypotension and weight loss due to dopamin receptor stimulation●this phenotype has been manifested in biochemically silent patients or in approximately 65% of patients with SDHx mutations, especially in SDHB

  7. Malignant pheochromocytoma●At least 10% of phaeochromocytomas and sympathetic paragangliomas are malignant●Unlike for most tumours, no molecular, cellular or histological markers are available for determining whether a PPGL is malignant●malignancy is defined as the presence of metastasis at presentation or during follow-up●a metastasis being defined as the presence of chromaffin tissue in nonchromaffin organs ●The most frequent sites for metastases are lymph nodes, the skeleton, liver and lungs

  8. ●Extraadrenal tumors are more frequently malignant than PCS●Expression of PNMT is controlled by glucocorticoid receptor –mediated mechanisms●local availability of steroids may explain adrenal PSC often produce EN & extraadrenal tumors typically lack PNMT and produce predominantly NE ●patients with PCS or PGLs who carry SDHB mutations have a high relative risk of developing extraadrenal and/or malignant tumors●There is no clear cut-off of primary tumour size that distinguishes benign from malignant lesions. In our study, a cut-off of 5.7 cm provided the best accuracy (sensitivity: 80%; specificity: 59%)

  9. ●Germline mutations in the SDH genes (SDHA ,SDHB ,SDHC ,SDHD ,SDHAF2)account for half of hereditary PHEO/PGL and can be found in up to 15% of all patients●tumous with SDHB mutation are likely to arise in anintra-abdominal extra-adrenal location and have a very high risk of metastasis●In contrast ,SDHD mutated paragangliomas are more likely to occur in the head and neck ●SDHC mutation ,which is considerably more rare than SDHB and SDHD, is associated particularly with carotid body tumours

  10. ●MN -secreting tumours are rarely malignant, and this secretory status is an independent negative predictor of malignancy ●Less frequent secretion of MN in malignant PCC/PGL may be due to the downregulation of PNMT in dedifferentiated tumours and lack of metanephrine secretion by extradrenal tumours ●Isolated or co-secretion of dopamine is a marker of malignancy●Higher prevalence of malignancy in sPGL may be due to relativeimmaturity of sympathetic ganglia as compared to the adrenal medulla or due to the plausible role of adrenal cortex in the prevention of malignant transformation in PCC

  11. ●Subjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumour●Patients with PPGLs included 190 males and 175 females aged 6 –83years (mean 40)●Plasma concentrations of NMN, MN and methoxytyramine,Twenty- four hour urine samples were collected from 338 patients with PPGLs and 513 subjects without tumours for assays of catecholamines, VMA & deconjugated metanephrines.

  12. ●Amongst patients without metastases, 86% had adrenal tumours, compared to 14% with extra-adrenal tumours●Amongst patients with metastatic disease these proportions were reversed (P < 0.001); 32% had adrenal primary tumours and 68% primary tumours with an extraadrenal local●Primary tumours amongst patients with metastases were 3.6-fold larger (P < 0.001) in volume than amongst those without metastases, reflecting mean tumour diameters of 7.2 and 4.7cm●Forty-eight patients were identified with mutations of the SDHB gene, including 41 with and 7 without metastases.

  13. Patients with extra-adrenal primary tumours had plasma concentrations of methoxytyramine that were 274% higher (P < 0.001) and plasma concentrations of metanephrine that were 78% lower (P<0.001) than in patients with adrenal tumours.

  14. ●Amongst the 18 biomarkers examined, plasma free methoxytyramine showed the largest diagnosti signal, with close to 5-fold higher levels in patients with than without metastase●tumoural production of methoxytyramine correlates with presence of SDHB mutations and extra-adrenal location of primary tumours●high malignant risk associated with SDHB mutations largely reflects the predominant extra-adrenal locations of associated tumours.●increased tumour size and extra-adrenal location both contribute additively to increased risk of metastatic disease

  15. ●immature catecholamine biosynthetic phenotypes of PPGLs in patients with SDHB mutations can result in an asymptomatic presentation and a delay in detection until tumours attain a large enough size to cause clinical complications● overlap in distributions in plasma methoxytyramine in patients with and without metastases indicates that these measurements can not be used to accurately predict or exclude the presence of malignancy but may serve to assess the relative likelihood of metastatic disease, supplementing predictive information derived from considerations of tumour size ,location and SDHB mutation status.

  16. Malignant disease management●surgical debulking●medical management to control symptoms ●radionuclide therapy (I-MIBG or somatostatin analogues)●chemotherapy (cyclophosphamide,vincristine,dacarbazin )●Molecular Targeted Therapies●external beam radiation therapy

  17. Surgical Recommendations for Metastatic Disease●resection of metastases should be discussed for patients with very stable or slowly progressive tumors and when resection of at least 90 % of the tumor burden can be achieved together with acceptably low risks of morbidity and mortality.●Surgery should be discussed case by case in a multidisciplinary setting

  18. MIBG-Radiotherapy●The diagnostic value of metaiodobenzylguanidine is based on its structural similarity with noradrenaline and a high affinity to and uptake in chromaffin cells. ●131 MIBG can provide a clinical benefit to patients with advanced  PPGL, as evidenced  by  improved blood pressure control, durable  tumor and  biochemical  tumor marker responses●As with chemotherapy and debulking surgery, treatment with 131I -MIBG is no curative option in the treatment of malignant PCC. But it may play an important role as an adjuvant therapeutic agent, following debulking surgery

  19. Peptide Receptor Radionuclide Therapy (PRRT)●In the last few years, an increasing number of metastatic NETs have been treated with peptide receptor radionuclide therapy with radiolabelled somatostatin analogues like 177 Lutetium (Lu)-DOTA-octreotide and 90 Yttrium (Y)-DOTA-lanreotide.●PGL/PCC were found to express predominantly subtypes 2A and 3 of somatostatin , and therefore, patients with PGL/PCC are suitable candidates for PRRT

  20. ●Not all patients with malignant PGL/PCC are eligible for MIBG therapy, as it depends on whether the tumours exhibit adequate take up of the radiopharmaceutical after intravenous administration●In patients with malignant PGL/PCC with poor 13I-MIBG uptake, but good uptake with SRS, PRRT might be a good alternative treatment for 131IMIBG therapy

  21. Systemic Chemotherapy●Systemic chemotherapy is an important treatment for metastatic PCSand SPGs●for patients with progressive disease or overwhelming symptoms, treatment with chemotherapy may be recommended●Cyclophosphamide-based & dacarbazine-based regimens combined with vincristine or doxorubicin are the best studied regimens● But they are clinically beneficial in approximately 50 % of patient

  22. Molecular Targeted Therapies●VEGFs are pro-angiogenesis molecules that bind to VEGFRs and activating of receptor tyrosine kinase that induces vascular proliferation, a necessary process for tumorigenesis and metastasis.●VEGFs are over-expressed in about 70% PGLs and are also over -expressed in PCS●Mutations in SDHB in PGLs activate cellular hypoxia pathways that stimulate the production of VEGFs●Sunitinib is an oral receptor tyrosine kinase inhibitor with anti angiogenic and antitumor activity that targets the PDGF, VEGF, c-KIT, and FLT3 receptors

  23. Radiation Therapy●External beam radiation therapy has been used to treat patients with inoperable tumors at risk for complications ( patients with large cervical lymph nodes) or to palliate symptoms ( patients with painful bone metastases)●It is, however, unclear if malignant PHs and SPGs are sensitive tumors to radiation therapy●As patients with malignant PHs and SPGs may have a large number of skeletal metastases, it is important to avoid extensive radiation therapy and prevent bone marrow insufficiency

  24. Thanks for your attention

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