Familial paraganglioma syndromes

Runjan Chetty

ABSTRACTParagangliomas and phaeochromocytomas may occur insyndromic or sporadic forms. The former are wellrecognised with multiple endocrine neoplasia (MEN) type2 and von HippeleLindau syndromes. A few cases areassociated with neurofibromatosis type 1. The familialparagangliomaephaeochromocytoma syndromes areless well recognised, but as more genetic testing isperformed, more cases belonging to this syndrome willbe revealed. These syndromes result from mutations inone of three subunits of the succinate dehydrogenase(SDH) gene. There are four types: type 1 associated withSDHD, type 2 with an unknown gene, type 3 with SDHCand type 4 with SDHB. There are distinctgenotypicephenotypic correlations with each mutation.Patients with SDHB mutations have a positive familyhistory in 33% of cases, present with single tumoursaround 30 years of age and have extra-adrenalparagangliomas mainly in the abdomen and pelvis; 20%may also have phaeochromocytomas, and tumours inthese patients have a great propensity to metastasise.Patients with SDHD and SDHC mutations have a higherpositive family history (66%) and have head and neckparagangliomas. SDHD patients present at 30 years withmultiple tumours, while in SDHC mutation carriers, singletumours appear at around 38 years of age. A smallpercentage of patients with sporadic paragangliomas/phaeochromocytomas may have SDH mutations as well.

DEFINITION AND BASIC ORGANISATION OFPARAGANGLIAParaganglia are groups of cells that are of neuralcrest origin, and two types have been identified: (1)those located in the adrenal medulla (responsiblefor the secretion of epinephrine and norepineph-rine), and (2) those found outside the adrenalglands; these extra-adrenal paraganglia are thoughtto be responsible for the detection of oxygen andcarbon dioxide levels in the blood.An alternative way of categorising paraganglia is

by way of their association with either the sympa-thetic or parasympathetic nervous systems that arelocated throughout the body. In this context, themedulla of the adrenal gland is considered to bea modified sympathetic ganglion as it develops inconcert with the sympathetic nervous system; themedulla and the organ of Zuckerkandl are theprototypical sympathetic paraganglia. Sympatheticphaeochromocytomas/paragangliomas usually se-crete catecholamines that result in the classicalclinical symptoms (hypertension, sweating, palpita-tions, etc). The parasympathetic paraganglia arefound mainly along the supra-diaphragmaticbranches of the vagus and glossopharyngeal nerves.The prototypical parasympathetic paraganglion isthe carotid body. Parasympathetic paragangliomas

usually do not secrete catecholamines. Other para-ganglia are found in small pockets or groups mostlyin the head and neck region.Given the diverse and almost ubiquitous distri-

bution of normal paraganglia, it is not surprisingthat tumours arising from them can be encounteredanywhere in the body. Having said that, the mostfrequent sites are in the carotid body (head andneck region), adrenal medulla and extra-adrenalabdomen. Several cell types have been identified,however; the value of these various types is ofquestionable importance and significance froma pathological point of view. Type I are cells called‘true paraganglia’ and are found along nerve fibresor near ganglia of the central nervous system. TypeII, the so-called ‘free paraganglia,’ do not show anydefinite connection to specific structures, and theyare seen in the adipose tissue of the heart. Type III,the ‘interganglionic paraganglia,’ are located withinthe ganglia, and the type IV cells are the ‘Intra-myocardic paraganglia,’ which are cells that lie nearthe myocardiocyte bundles (excitable myocardiaccell fibres that transmit action potentials).

TERMINOLOGYPhaeochromocytoma versus paragangliomaThese two lesions are basically the same tumourexcept their locations are different. The termphaeochromocytoma is reserved for a tumour of thesympathetic paraganglia located within the adrenalmedulla. The term ‘phaeochromocytoma’ is accre-dited to the pathologist Ludwig Pick who astutelynoted the dark brown colour of the tumour cellswhen in contact with fixatives containing chromicacid salts (‘phaeo’ being a cumulative term em-bracing brown, dun or dusky). Other than for thisnomenclatural quirk, a morphologically identicallesion located outside the adrenal medulla is knownas a paraganglioma. Since this somewhat arbitraryand artificial segregation has been endorsed in theWHO Classification of these tumours, this termi-nology will be retained for the purposes of thisreview.

PATHOLOGYThe gross and microscopic appearances of phaeo-chromocytoma/paraganglioma are well known anddescribed in standard textbooks. Suffice to say thatthey are typified by large polygonal, epithelioid cellsarranged in a nested (zellballen) pattern with aninvestiture (often discontinuous) of spindled, slendersustentacular cells. The stroma around the nests ofcells is characteristically endowed with a richvascular component. The immunophenotypic profileis also pathognomonic: the large epithelioid cells arepositive for generic neuroendocrine markers, whileS-100 highlights the circumferential sustentacularcells. Recently, tyrosine hydroxylase has been added

Correspondence toProfessor Runjan Chetty,Department of Pathology andGene Regulation, McGregorBuilding, Western Infirmary,Dumbarton Road, Glasgow G116NT, UK;r.chetty@clinmed.gla.ac.uk

Accepted 9 February 2010

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to the panel of marker for phaeochromocytomas. Interestingly,staining for either or both chromogranin A and tyrosine hydrox-ylase tends to be weaker and more variable in parasympatheticparagangliomas than in their sympathoadrenal counterparts, andin fact, tyrosine hydroxylase may actually be absent in some ofthese latter cases.1

SYNDROMES ASSOCIATED WITH PHAEOCHROMOCYTOMAS/PARAGANGLIOMASPhaeochromocytomas and paragangliomas are associated withseveral well-known inherited syndromes:1. Multiple Endocrine Neoplasia (MEN) Syndrome: types 2A

and 2B;2. Von HippeleLindau (VHL) disease;3. neurofibromatosis (NF), type 1;4. familial paragangliomaephaeochromocytoma syndromes.

MENThis is an autosomal dominant condition with affected indi-viduals displaying 94% penetrance and manifestation of theassociated pathology by the age of 50 years.2 These patientshave germline mutations of the MEN-1 tumour suppressor genelocated on chromosome 11q13 with consequent loss of a 610-amino acid-nuclear protein, menin, that normally suppresses cellproliferation.3 The RET (rearranged in transfection) gene encodesa tyrosine kinase receptor for molecules belonging to the glialcell line-derived neurotrophic factor (GDNF) family. RET isregarded as a paradigmatic example of how different mutationsof a single gene can lead to different neoplastic phenotypes.Gene rearrangements, often caused by chromosomal inversions,activate the oncogenic potential of RET in some thyroid papil-lary carcinomas. On the other hand, different point mutationsactivate RET in the MEN syndromes and familial medullarythyroid carcinoma.4

Approximately 95% of families with MEN 2A have a RETmutation in exon 10 or 11. In MEN2B, about 95% of individualshave a single-point mutation in the tyrosine kinase domain ofthe RET gene at codon 918 in exon 16, which substitutesa threonine for methionine. MEN 2 does demonstrate agenotypicephenotypic correlation.5

VHLVon HippeleLindau (VHL) disease is an autosomal dominantcondition due to deletions or mutations in a tumour suppressorgene located on chromosome 3p25.5.6 The disease profile istypified by retinal and central nervous system haemangio-blastomas, cysts in the kidney, epididymis (papillary cystade-noma) and liver, haemangioma of the adrenal, liver and lung,renal cell carcinoma, phaeochromocytoma and endolymphaticsac tumours. A distinct genotypeephenotype correlation existsin VHL, especially with regard to the development of phaeo-chromocytomas.6 Missense mutations are frequently foundmore in patients with phaeochromocytoma (so-called type 2),while those without (type 1) have large deletions or prematuretruncation mutations.6

NFThe NF-1 gene is located on chromosome 17q11.2 and is inheritedas an autosomal dominant trait with complete penetrance andvariable expression. Invariably, signs and/or symptoms present by5 years of age. A multitude of different mutations occur in NF-1at a rate of 1/10 000 births, and new mutations account for 50%of all cases. These usually take the form of nonsense, frameshift,

splice mutations or partial and complete deletions and trans-location. The NF-1 gene functions as a tumour suppressor gene,and the NF-1 protein is a 2818-amino-acid cytoplasmic proteincalled neurofibromin. It contains a 360-residue GAP domaininvolved in Ras/Raf/ERK signalling (the ras pathway is abrogatedin 30% of human cancers). Neurofibromin may also promotesensitivity to apoptosis through Ras-independent pathways.7

PARAGANGLIOMA/PHAEOCHROMOCYTOMA SYNDROMES(PPS)SDH geneMost cases of familial paraganglioma/phaeochromocytomaresult from mutations in three genes, SDHB, SDHC and SDHD,that encode subunits of the heterotetrameric succinate dehy-drogenase (SDH) complex, a component of both the mito-chondrial-respiratory chain (complex II) and the Krebs cycle.8 9

The SDH genes encode subunits of the succinate dehydrogenaseSDHA and SDHB together constitute the catalytic domain,while SDHC and SDHD encode membrane anchors thatallow the complex to participate in the respiratory chain ascomplex II.

SDHA and SDHB genesSDHA gene (located on 5p15) and SDHB (on 1p36) encode thetwo catalytic hydrophilic subunits, flavoprotein (70 kDa, 664amino acids) and ironesulfur protein (27 kDa, 280 amino acids),respectively.The SDHA gene consists of 15 exons, a second isoform and at

least one pseudogene (located on chromosome 3q29). SDHB haseight exons and no known pseudogenes.

SDHC and SDHD genesSDHC (located on chromosome 1q21) and SDHD (on chromo-some11q23) encode for hydrophobic transmembrane proteinsthat anchor complex II in the inner mitochondrial membrane,and contain a ubiquinone binding site. SDHC covers six exonsand has three candidate pseudogenes.SDHD has four exons and six reported intronless pseudogenes.The hereditary element in paragangliomas (especially of the

head and neck)/phaeochromocytomas has long been recognisedand was first described in 1989.10 The group of resultant tumoursoccurs along the paravertebral axis from the base of the skull tothe pelvis (paragangliomas) and in the adrenal medulla (phaeo-chromocytomas).Although paragangliomas are well known to pathologists and

clinicians alike, it is only since 2004 that a molecular classifica-tion based on the SDH genes has allowed familial para-ganglioma/phaeochromocytoma to be fully characterised, anddelineated as follows:1. Type 1: SDHD gene is the susceptibility gene for type 1. The

putative genetic locus for type 1 was first mapped in 1992 byHeutink et al,11 12 and then Baysal et al8 reported germlinemutations in the SDHD gene in type 1-linked families.

2. Type 2: the susceptibility gene for type 2 remainsunidentified.

3. Type 3: SDHC gene is the susceptibility gene for type 3.4. Type 4: SDHB gene as the susceptibility gene for type 4.Mutations of SDHA result in a range of clinical abnormalities,

including Leigh syndrome (subacute necrotising encephalo-myelopathy in infants), but have never been reported in relationto paraganglioma or phaeochromocytoma. It is the only subunitto never have shown tumour suppressor behaviour, and evenheterozygous carriers of an SDHA mutation do not develop

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paragangliomas. This appears to be due to the expression of twosimilar SDHA genes (Types I and II) in the paraganglia systemand thus would requite inactivation of all four alleles to result ina paraganglioma.

Thus, heterozygous mutations in SDHD, SDHB and SDHCpredispose to head and neck paragangliomas and adrenal/extra-adrenal phaeochromocytomas/paragangliomas.8 13 14 This is alsocalled the ‘ParagangliomaePhaeochromocytoma syndrome.’15

This inherited syndrome is transmitted in an autosomal domi-nant manner with age-dependent and incomplete penetrance.Interestingly, with SDHDmutations, a ‘parent of origin effect’ ispresent: the mutation is transmitted almost exclusively by thefather, suggesting maternal imprinting of SDHD.10 11

Germline mutations in the SDH genes are encountered inboth sporadic and familial paragangliomas. Sporadic para-gangliomas/phaeochromocytomas have a SDH mutation prev-alence of about 6%.

In PPS, mutations of SDHD are commonest, followed by SDHBand then SDHC.15 It is also noteworthy that 61% of index caseswith SDHD mutations have a positive family history of para-gangliomas; in contrast, 69% of SDHB mutation carriers do nothave an apparent family history of paragangliomas. Patients withSDHC mutations have a positive family history in almost 63% ofcases.15

Sporadic extra-adrenal paragangliomas, malignant cases andthose occurring in children have a much higher prevalence ofSDH mutations, especially SDHB mutations. Thus, there arewell-characterised genotypicephenotypic associations withSDH mutations.

Genotypicephenotypic correlations of SDH mutations1. A positive family history is most often seen with carriers of

SDHC and SDHD mutations (approximately two-thirds ofcases). Only one-third of SDHB mutation carriers havea positive family history.

2. The mean age of tumour manifestation for SDHD and SDHBmutations is around 30 years of age; SDHC mutation carriershave tumours later, at about 38 years.

3. Almost 80% of SDHD mutation carriers have multipletumours; the vast majority (>65%) of patients with SDHBand SDHC mutations have a single tumour.

4. Patients with SDHB germline mutations commonly haveextra-adrenal paraganglioma in the abdomen, pelvis, retro-peritoneum and cervical mainly; less commonly thoracicand mediastinal; 20% of these patients have head andneck paragangliomas only, and a further 20% can haveadrenal phaeochromocytomas alone or with an associatedparaganglioma.

5. Paragangliomas/phaeochromocytomas in patients with SDHBmutations tend to behave in a malignant fashion with a highrate of distant metastases. Therefore, this mutation serves asa marker of malignant disease. These patients may also be atrisk for the development of renal cell cancer and papillarythyroid cancer.13

6. The vast majority (almost 80%) of patients with SDHDmutations present with multiple or single head and neckparagangliomas only. Phaeochromocytomas and paragan-gliomas of the abdomen are uncommon in this cohort ofpatients.

7. SDHCmutation carriers have a similar phenotypic expressionas SDHD mutation carriers with almost 90% of patientsmanifesting just head and neck paragangliomas.

Hereditary paragangliomaepheochromocytoma syndromes shouldbe considered in all individuals with paragangliomas and/or

phaeochromocytomas, particularly those with the followingfindings:16

1. multiple tumours (ie, more than one separate tumour ortumour type), including bilateral tumours;

2. multifocal with multiple synchronous or metachronoustumours;

3. recurrent tumours;4. early onset of tumours (ie, age <40 years);5. a family history of such tumours (See table 1).

CarneyeStratakis dyad (CarneyeStratakis syndrome)This is the association of paragangliomas and GISTs described byCarney and Stratakis.17 The CarneyeStratakis dyad appears tobe distinct from the Carney triad. They described five familieswith paragangliomas and GISTs that appeared to be inherited inan autosomal dominant manner with incomplete penetrance.Paragangliomas (both secretory and non-secretory) occurredin the head, neck, thorax and abdomen. In six individuals fromsix unrelated families with the CarneyeStratakis dyad,McWhinney et al reported mutations in SDHB in three, SCHC intwo and SDHD in one.18

Note: in Carney ’s triad (pulmonary hamartoma, gastric GISTand extra-adrenal paraganglioma), SDH mutations have notbeen demonstrated in the paragangliomas.

ConclusionPhaeochromocytomas and paragangliomas may be encounteredin MEN type 2, VHL, NF type 1, Carney ’s triad and CarneyeStratakis dyad. It is only in the latter and the Para-gangliomaePhaeochromocytoma Syndromes in which SDHgene mutations are encountered. Depending on the subunit ofthe SDH gene that is mutated, very characteristic genotypicephenotypic expressions emerge. While they are uncommon,there is increasing awareness of this subset of inherited para-gangliomas and phaeochromocytomas.

Table 1 Genotypicephenotypic correlations

SDHmutations

Familyhistory (%)

Age (years) ofpresentation

No oftumours Sites

SDHB 33 30 Single Abdomen, pelvis,retroperitoneum andadrenal

SDHD 66 30 Multiple/single Head and neck

SDHC 66 38 Single Head and neck

Take-home messages

< Phaeochromocytomas/paragangliomas may be associatedwith MEN 2, VHL, NF1, paraganglioma syndromes, Carney’striad and CarneyeStratakis dyad.

< The paragangliomas syndromes are associated with muta-tions in the SDH gene.

< Type 1 has SDHD mutations and these patients have single ormultiple head and neck paragangliomas.

< Type 3 has SDHC mutations and is characterised by singlehead and neck paragangliomas.

< Type 4 has SDHB mutations and patients have singleparagangliomas in the abdomen, pelvis, retroperitoneum andadrenal gland.

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Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

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doi: 10.1136/jcp.2010.076257 2010 63: 488-491J Clin Pathol

 Runjan Chetty Familial paraganglioma syndromes

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