Hereditary Paraganglioma/Pheochromocytoma Syndromes



Hereditary Paraganglioma/Pheochromocytoma Syndromes


Vania Nosé, MD, PhD








Graphic shows paraganglia and neuroendocrine tissues symmetrically distributed along the paravertebral axis in the abdomen, including the organ of Zuckerkandl image and the adrenal medulla image.






This pheochromocytoma (PCC) has the characteristic alveolar pattern (zellballen) with variably sized nests of tumor cells surrounded by thin-walled vessels and thin bands of fibrous tissue.


TERMINOLOGY



Abbreviations



  • Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndromes


  • Paraganglioma (PGL)


  • Pheochromocytoma (PCC)



Definitions



  • PCCs and PGLs are neuroendocrine tumors that arise in adrenal medulla or extraadrenal sympathetic and parasympathetic paraganglia



    • Occur sporadically or as part of different hereditary tumor syndromes


    • Tumors arising within adrenal medulla are known as PCCs; histologically identical tumors arising elsewhere are termed PGLs


  • Hereditary PGL/PCC syndromes are characterized by presence of PGL &/or PCC that occur as part of a familial syndrome



    • > 30% of PCCs and PGLs are currently believed to be caused by germline mutations and several novel susceptibility genes have recently been discovered


    • RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127, and MAX have been associated with hereditary PCC or PGL


  • Hereditary PGL/PCC syndromes should be considered in all individuals with PGL or PCC with the following findings



    • Multiple tumors, including bilateral tumors


    • Multifocal with multiple synchronous or metachronous tumors


    • Early onset (age < 40 years)


    • Family history of such tumors


  • Familial PGL/PCC syndrome is term restricted to tumors from germline mutations in SDHx genes


  • Simplex cases: Many individuals with a hereditary PGL/PCC syndrome may present with solitary tumor of head or neck, thorax, abdomen, adrenal, or pelvis and no family history of the disorder


  • In PGL/PCC that appear to be sporadic based on the absence of a family history, rate of occult germline mutation is said to be ˜ 12% and ranges from 7.5-24%


Syndromes Characterized by Susceptibility to PCC and PGL



  • Most tumors were known to be associated with multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), and neurofibromatosis type 1 (NF1)


  • More recently, mutations in genes encoding different subunits of succinate dehydrogenase (SDH) complex have been linked to familial PGL/PCC syndrome (PGL1, 2, 3, and 4)


  • Small fraction is associated with other syndromes (e.g., Carney triad, Carney-Stratakis syndrome, MEN1)


  • Several other genes have recently been added to the list (associated with unknown hereditary PGL/PCC)



    • Kinesin family member 1B (KIF1B)


    • EGL-9 homolog 1 (EGLN1), also termed PHD2


    • Transmembrane protein 127 (TMEM127)


    • MYC-associated factor X (MAX)


GENETICS


MEN2



  • Autosomal dominant syndrome caused by mutation of RET proto-oncogene


  • Activating RET mutation predisposes to PCC, which is often bilateral and recurrent



    • Low risk of malignancy


  • MEN2 prevalence is estimated at 1:30,000


  • MEN2 often suspected on basis of family history; individuals with PCC infrequently present as simplex cases



  • Clinically, can be divided into 3 types: MEN2A (55% of all cases), MEN2B (5-10%), and familial medullary thyroid carcinoma (FMTC, 35-40%)


  • MEN2A and MEN2B patients have almost 100% risk of developing medullary thyroid carcinoma


  • ˜ 50% of individuals with MEN2A and MEN2B develop PCC


  • Subtype FMTC has medullary thyroid carcinoma as its only feature


Familial PGL/PCC Syndromes



  • Germline mutations in SDHx genes give rise to familial PGL/PCC syndrome, sometimes only referred to as familial PGL


  • Prevalence of PGL/PCC syndrome is unknown, but a review of ˜ 13% of all PGL/PCC cases gives an estimate of 1:50,000 to 1:20,000; majority represented by PGL1 and PGL4


  • Associated with germline mutations in genes encoding subunits of SDH enzyme complex in context of familial PGL syndromes; PGL1, PGL2, PGL3, and PGL4 caused by mutations in SDHD, SDHAF2, SDHC, and SDHB genes, respectively



    • PGL2 is caused by mutations in SDHAF2/SDH5, which encodes for a molecule that is an accessory to the function of the SDH enzyme and its SDHA subunit


  • Mutations were recently found in SDHA subunit in a limited number of patients with PGL &/or PCC


  • SDHB mutations in particular may also predispose to thyroid and renal cancer, and possibly other tumors



    • Patients harboring SDHB mutation are at increased risk of malignancy


  • Genotype–phenotype correlation



    • People with SDHB, SDHD, and SDHC mutations can develop PCCs or PGLs anywhere in paraganglia



      • Genotype-phenotype correlations guiding diagnostic testing and patient care


      • Germline mutations in SDHB are strongly associated with extraadrenal sympathetic PGL


      • Chromaffin tumors in people with germline SDHB mutations are 6x more likely to be extraadrenal than chromaffin tumors in general


      • PGL in people with germline SDHB mutation are more likely to become malignant than sporadic PGL or in those with germline SDHD and SDHC mutations


      • SDHB mutations also predict shorter survival


      • Up to 50% of people with malignant extraadrenal PGL have a germline SDHB mutation PGL


      • People with a germline SDHD mutation are more likely to develop head and neck and abdominal PGL compared with people with a germline SDHB mutation


      • Germline SDHC mutations appear to be primarily associated with head and neck PGL


von Hippel-Lindau Syndrome (VHL)



  • Autosomal dominant disorder caused by mutation of VHL


  • Features include retinal angiomas, central nervous system hemangioblastomas, clear cell renal cell carcinoma, pancreatic endocrine tumors, endolymphatic sac tumors, renal, pancreatic and epididymal cysts, and PCCs


  • Occurs in ˜ 1/36,000 individuals


  • ˜ 10-26% of VHL patients develop PCC or PGL, but risk varies between families



    • Frequency of PCC in individuals with VHL is 10-20%


  • Mean age of onset of PCC in VHL is ˜ 30 years



    • PCCs occur in only 6-9% of individuals with VHL type 1


    • Prevalence of PCC rises to 40-59% in individuals with VHL type 2


    • In type 2C VHL, PCCs are sole manifestation of the syndrome (simplex cases)


  • VHL mutations predispose to unilateral or bilateral PCCs and, much less frequently, to sympathetic or parasympathetic PGLs



    • ˜ 50% of PCCs are bilateral


  • PCCs in VHL secrete primarily norepinephrine and normetanephrine


  • ˜ 5% Of VHL-related catecholamine secreting tumors become malignant, most commonly extraadrenal sympathetic PGL



    • Only 3% displayed malignant tumors


    • Bilateral PCC was seen in 44% of the patients


    • Mean age at diagnosis of PGL/PCC is 29 years


    • PCC or PGL is 1st manifestation of VHL disease in 30-55% of cases


    • VHL can be distinguished from other hereditary PGL/PCC syndromes clinically


NF1



  • Autosomal dominant disorder caused by mutation of NF1


  • Major features of NF1 include neurofibromas, café au lait spots, iris hamartomas, and axillary and inguinal freckling


  • Gastrointestinal stromal tumors (GISTs) and carcinoid tumors may also occur


  • PCCs and PGLs are not among most common manifestations of NF1 but occur in 0.1-5.7% of patients


  • PCCs occur in 20-50% of individuals with NF1 and hypertension


  • NF1-associated PCCs and PGLs typically have characteristics similar to those of sporadic tumors, with a relatively late mean age of onset and ˜ 10% risk of malignancy


  • Up to 84% of PCC are unilateral


  • Extraadrenal sympathetic PGL can occur


  • 95% of patients with NF1 had PCC and 6% had PGL; all PGLs were sympathetic


  • 14% of patients displayed bilateral PCC


  • 9% developed malignant disease


Carney Triad (CT)



  • Rare multitumoral syndrome of unknown etiology



    • Some SDH-deficient GISTs are driven by classical SDH mutations, but precise mechanisms of tumorigenesis in those associated with Carney triad remain unknown



  • Usually occurs in young women


  • Neoplasms affect stomach, lungs, paraganglionic system, adrenal cortex, and esophagus



    • Triad: Gastric stromal tumor, PGL, and pulmonary chondroma


    • PCC, adrenal cortical adenoma, and esophageal leiomyoma are also associated


    • Multifocal tumors develop in affected organs


  • Mean age at presentation with PGL/PCC is 28 years


  • 92% present with PGL, including both sympathetic and parasympathetic tumors, and ˜ 16% present with PCC


  • Multiple PGLs are found in 22% of patients and bilateral PCC in 3%


  • Metastasis occurs in 11% of patients


Carney-Stratakis Syndrome



  • Mutations in SDHB, SDHC, and SDHD can give rise to Carney-Stratakis syndrome, characterized by dyad of PGLs and GISTs


  • 100% of patients had PGL and 1 patient also presented with unilateral PCC, with a mean age of 33 years at presentation


  • PGLs occur in head and neck, thorax, and abdomen


  • Multiple PGLs, which could be both sympathetic and parasympathetic, were seen in 73% of patients


  • None of the tumors were malignant


MEN1



  • Caused by mutations in MEN1 gene


  • MEN1 gene is a 10-exon gene that encodes 610-amino acid protein, menin


  • Mutation spectrum



    • > 1,300 different mutations of MEN1 gene have been characterized


    • Penetrance of MEN1 is high: 45% by age 30, 82% by age 50, 96% by age 70


    • Spread over entire coding and intronic sequence



      • > 60% truncating mutation, 20% missense mutation, 10% frame deletions or insertions, 10% others


    • Most are inactivating


  • Function is unknown; may act as regulator of gene transcription, cell proliferation, apoptosis, and genome stability


  • No cases of PGL and only 7 cases of PCC in MEN1 syndrome have been reported in the literature



    • Reported tumors were unilateral in all cases and malignant in 1 case


Other Genes Involved in PGL/PCC



  • Several other genes have recently been added to the list (associated with unknown hereditary PGL/PCC)



    • Kinesin family member 1B (KIF1B); EGL-9 homolog 1 (EGLN1), also termed PHD2; transmembrane protein 127 (TMEM127); and MYC-associated factor X (MAX)


  • No specific syndrome has been attributed yet, but patients with germline KIF1Bβ mutations seem to be predisposed to at least PCCs and neuroblastomas



    • Ganglioneuroma, leiomyosarcoma, and lung adenocarcinoma have also been reported in a family with KIF1Bβ mutations


  • Only 1 PGL patient, suffering from recurrent PGL and erythrocytosis, has been reported to have a germline mutation in EGLN1



    • Presentation with sympathetic PGL and a recurrent tumor was diagnosed 3 years later, but no metastases have been reported


  • So far, no specific syndrome has been described for TMEM127



    • TMEM127 mutations were identified in 2% of the cases considered sporadic, all of which had PCC


    • 96% of patients have PCC and 39% have bilateral PCC


  • MAX mutations segregate with disease in families with PCC, but no specific syndrome has been described yet



    • Usually bilateral tumors, early age of onset, &/or familial antecedents with the disease


    • Notably, 25% of patients showed metastasis at diagnosis, suggesting that MAX mutations are associated with high risk of malignancy


    • So far, no studies on PGLs have been reported


CLINICAL IMPLICATIONS AND ANCILLARY TESTS

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Hereditary Paraganglioma/Pheochromocytoma Syndromes

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