Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors of the autonomous nervous system, which arise in adrenal and extra-adrenal glands respectively, and occur individually or together and are often catecholamine-secreting.199,211,278
PHEO and PGL syndromes are most commonly associated with either succinate dehydrogenase (SDH) gene-related hereditary PGL syndrome, MEN2A and MEN2B, neurofibromatosis 1 (NF-1) or Von Hippel-Lindau disease (VHL) syndromes (Table 6.1).
Hereditary PHEO and PGL syndromes are linked to germline mutations in the SDH gene subunits SDHB, SDHC, SDHD, SDHAF2, SDHA, and in TMEM127 and MAX, respectively (see Table 6.1).219,279 The specific gene mutations and the primary characteristics associated with hereditary PHEO and PGL syndromes are shown in Table 6.1.
|Paraganglia (PGL) / Pheochromocytoma (PHEO) syndromes||Primary characteristics||Genetic mutations||References|
|PGL syndrome type 1||PGL and PHEO||SDHD||Almeida and Stratakis. 2010199; Kantorovich et al. 2010233; Chetty. 2010234|
|PGL syndrome type 2||PGL||SDHAF2 (SDH5)||Kantorovich et al. 2010233|
|PGL syndrome type 3||PGL||SDHC||Almeida and Stratakis. 2010199; Kantorovich et al.233; Chetty. 2010234|
|PGL syndrome type 4||PGL and PHEO||SDHB||Almeida and Stratakis. 2010199; Kantorovich et al. 2010233; Chetty. 2010234|
|PGL syndrome type 5||PGL||SDHA||Karasek et al. 2013208; Kirmani and Young. 2008211|
|MAX-related syndrome||PHEO, possibly PGL||MAX||Kirmani and Young. 2008211; Burnichon et al. 2012219|
|TMEM127-related syndrome||PHEO||TMEM127||Kirmani and Young. 2008211; Qin et al. 2010 235|
|Carney-Stratakis syndrome or Carney-Stratakis dyad (subcategory of SDHx-related PGL)||Extra-adrenal PGL, and gastrointestinal stroma tumors||SDHA, SDHB, SDHC, SDHD||Kirmani and Young. 2008211; Almeida and Stratakis. 2010 100|
Abbreviations: PHEO, pheochromocytoma; PGL, paraganglioma.
The majority (70-75%) of PGL/PHEOs occur sporadically, and genuine sporadic cases are confirmed by the exclusion of germline mutations. Sporadic PHEOs are unicentric, unilateral, and diagnosed later in life than familial cases that are multicentric and bilateral.210 The aetiology of sporadic PGL/PHEO tumors is unknown but thought to be specific alterations in multiple genes. In a 2000 study from the Netherlands, the cause of tumors in PHEO cases (n=29) was speculated to be loss of heterogeneity and possibly involvement of tumor suppressor genes with losses most frequently observed on chromosomes 1p (86%), 3q (52%), 6q (34%), 3p, 17p (31%), 11q (28%), and gains on 9q (38%) and 17q (31%). Malignancy was associated with deletions on 6q (60% malignant, 21% benign) and 17p (50% malignant, 21% benign).280 One 2006 study suggested that chromosome 1p (the most common genetic alteration in sporadic PHEO), was the site of multiple tumor suppressor genes and another study suggested that a region on 22q was also involved.281, 282
A genome-wide high-resolution analysis of 36 sporadic benign PHEOs, showed the loss of a region on chromosome 1p with/without a concomitant loss on 3q in 56% of cases and a second abnormality on 3p with/without concomitant loss on 11q (similar to MEN2-related PHEO) in 31% of cases (similar to VHL-related PHEO). Additional losses on 22q were also reported.283
6.1 PREVALENCE AND INCIDENCE
The worldwide incidence of PGL and PHEO is shown in Table 6.2. A 2010 literature search by Waguespack and colleagues reported that up to 20% of PGL/PHEO tumors were identified in children, and were more frequently familial, bilateral, multifocal, and malignant, relative to those in adults.248 284
Table 6.2. Incidence of familial PGL/PHEO, from literature reviews, worldwide.
|Disease||Annual Incidence (per million)||References|
|PGL/PHEO||3-8||Kirmani and Young. 2008211; Kantorovich et al. 2010233; Lefebvre and Foulkes. 2014210|
|PHEO||2-8||Lefebvre and Foulkes. 2014210|
Note: *, Includes Head-and-neck PGL (HNPGL), abdominal PGL, pelvic PGL.
Traditionally, ~ 10% of PHEO cases were thought to be inherited, however, it is currently estimated that in fact one-third of cases may have a genetic predisposition.210,285 In a series of 71 patients with PHEO and/or PGL in Italy, 28% were inherited/familial cases. Of these inherited cases, 11% (n=8) had originally been misdiagnosed as apparently sporadic cases.286 In another study of 329 patients in Spain, germline mutations were detected in 14%, and found at a higher prevalence in PGL (28.7%) than PHEO (4.5%). Somatic mutations were detected in 43% of patients, with a higher prevalence in PHEOs (48.5%) than in PGLs (32.3%). Both these studies recommended prioritizing genetic screening.287
In a study of 190 PHEO/PGL cases (1993-2008), 127 of the 202 tumors were apparently sporadic, with no identifiable mutations, while somatic mutations in VHL or RET genes were identified in 14% of cases.215
Approximately 25-30% of apparently sporadic cases of PGL and PHEO have been linked to germline or somatic mutations in the genes RET, VHL, NF1, MAX, HIF2A, HRAS and BRAF. The prevalence of detectable mutations has increased in recent years due to improved detection sensitivity with newer technologies such as next-generation sequencing (NGS). In 2015, Luchetti and colleagues identified a number of novel somatic mutations in PHEO and PGL by sequencing mutation hotspots in 50 known human cancer genes. Overall, 8.9% of sporadic cases had HRAS/BRAF mutations in PHEO/PGL.289 The three main studies reported a prevalence of 5.5% in all PHEO/PGL (n=438), 8.9% in sporadic PHEO/PGL (n=269), and 9.9% in sporadic PHEO (n=233), respectively.278,289,290
In a 1998 retrospective study from Spain, sporadic patients with MEN2A PHEO had later age at presentation (47 years +/- 16 years) than familial cases (38 years +/- 11 years). All sporadic cases were unilateral while familial cases were bilateral.291
Somatic mutations in the RET proto-oncogene were identified in up to 31% of benign sporadic PHEO cases. In a 1998 study of 29 malignant and 27 benign paraffin-embeded tissue samples of PHEO cases, a mutation was detected in 1 in 29 malignant and 4 of 27 benign tumors. The mutations were not associated with aggressive tumors in sporadic PHEO.292
6.2 COST BURDEN OF DISEASE
Due to the rarity of PHEO and PGL syndromes, cost benefit and cost-effectiveness analyses are not available.
6.3 DEMOGRAPHIC DIFFERENCES
In general, it is important to note that although gender differences may exist with regards to associated tumor risks, most studies are small and may be influenced by small sample sizes and ascertainment bias.
A South Korea study evaluating 23 male and 35 female PHEO patients reported more headaches, dizziness, anxiety, tremor, weight change, numbness and energy-level changes in females than in males, but no significant difference between the sexes in biochemical phenotypes.293
Retrospective studies of asymptomatic PHEO have shown no demographic differences or differences in pathological characteristics in sporadic tumors.294,295 No demographic differences were detected in a 2013 study (SEER database, 1988-2009) of 287 patients with malignant PHEO and 221 with malignant PGL from the SEER database. However, PHEO appeared to present more aggressively, and more likely to present with distant metastases and larger tumors.296
6.4 LIFE EXPECTANCY AND MORTALITY
In the above-mentioned 2013 study of malignant PHEO (n=287) and PGL (n=221) patients, over a 5-year follow-up period, PHEO patients had lower overall survival (54.4%) than PGL patients (73.3%). This was more independently associated with not having surgery for PHEO and having metastatic disease for PGL.296
It is recommended that familial PHEO patients have clinical, imaging, and biochemical assessment throughout their lives for recurrence and for other syndromic neoplasms, and sporadic PHEO cases, with a recurrence rate of 17%, also be followed up indefinitely as there is no way of distinguishing between benign and malignant tumors.295,297,298
In a study in France of 51 patients with famlial (n=25) or sporadic (n=26) abdominal extra-adrenal PGL, who had been initially operated on, 14% underwent operative resection after a median of 47 months. The estimated incidence of recurrence was 15% at 5 years and 23% at 10 years. The new lesions were ~10-times more likely to be associated with lymph node metastasis than the primary lesion (43% vs. 4%). Vascular invasion, positive nodes and malignancy were more common at reoperation (43% for all three) than the primary surgery (24%, 4%, 8% respectively), while synchronous distant metastasis was found in 4% of primary surgeries, and was absent from reoperations.299
6.5 KEY TRENDS AND HEALTH OUTCOMES
Most PHEO/PGL are benign and can be completely excised by surgery. The effects of catecholamine secretion need to be controlled with α-adrenergic blockers prior to surgery. While PHEO/PGL disorders are rare in children, 10-20% are diagnosed during childhood, with an average age of 11 years. Early detection (and confirmation by genetic testing if in a familial context) and treatment by a multidisciplinary team produces the best outcomes.248
For metastatic disease, meta-iodobenzylguanidine (MIBG) therapy had limited results, although all patients were alive after median follow-up of 5 years.300,301 Chemotherapy, traditionally a regimen of cyclophosphamide, vincristine, and dacarbazine (CVD) can aid in tumor regression and symptom relief, but does not prolong overall survival. More recently, targeted therapies such as tyrosine kinase inhibitor sunitinib appear to hold more promise. Medical records (December 2007-December 2011) of 17 patients with progressive metastatic PHEO/PGL (including 8 with apparently sporadic tumors) treated with sunitinib were retrospectively reviewed. Of the 17 patients, 47% showed reduced tumor size or disease stabilization (median PFS of 4.1 months). Most of the patients that experienced no treatment benefits had sporadic tumors.302
An adrenalectomy is the most common treatment for unilateral tumors in PHEO. Pre-operation treatment includes a- and b-adrenoceptor antagonists, calcium channel blockers, and/or drugs that inhibit catecholamine synthesis to prevent hypertensive crisis during surgery. Usually, phenoxybenzamine, a non-competitive a-receptor blocker is administered. In some cases b-blocking agents or calcium channel blockers may be used prior to surgery.242
In a 2009 study from Japan, of 32 patients with metastasized malignant PHEO, primary tumors had been surgically excised in 25. The 50% survival rate in the 32 patients was estimated at 14.7 years. Younger patients had a longer survival. Of the 25 patients, 16 were treated with CVD and 9 were untreated. The survival rate was worse in the CVD group than in the untreated group, when diagnosed after metastases. Being female and an adrenal origin of tumor were negative factors for CVD chemotherapy.303 Treatments and outcomes for PGL and PHEO are highlighted in Table 6.3.
|Paraganglioma (PGL)/Pheochromocytoma (PHEO) syndromes||Treatment||Outcome||References|
|PGL/PHEO||121 patients (75% sporadic tumors, 16% MEN2-related tumors, von Recklinghausen’s disease in 9%) surgically treated over 47 years; in one referral center in Sweden, 1950-1997.||Patients successfully treated for PHEO/PGL still have higher mortality than the general population. Over 15±6 year observation, 42 patients died vs. 23.6 in general population. 85% hypertensive at diagnosis, and >50% still hypertensive 1 year after surgery. No intra- or post-operative mortality.||Khorram-Manesh et al. 2005304|
|PGL/PHEO||221 patients with malignant PGL, 287 patients with malignant PHEO, US, SEER 18, diagnosed 1988-2008. Surgery had been performed in 74.3% of PHEO and 78.9% of PGL; external beam radiation administered in 8% PHEO and 28.1% PGL.||Lower overall survival for PHEO (54%) than PGL (73.3%); disease-specific survival were similar for PHEO (73.5%) and PGL (80.5%); the 5-year overall and disease-specific survival rates were 58.1% and 71.1% for PHEO, and 80% and 86.3% for PGL. Metastasis at diagnosis and failure to undergo surgery compromised survival.||Goffredo et al. 2013296|
|metastatic PHEO/PGL||123I-MIBG treatment for ~30% of patients who respond to scintigraphy.||Biochemical response rates up to 67% and symptom response rates up to 89%. To be proven in multicenter studies.||Chen et al. 2010279; Gedik et al. 2008305|
|Chemotherapy: combination cyclophosphamide, vincristine, and dacarbazine (CVD), especially if rapidly growing tumors.||Temporary tumor regression and symptom relief in up to 50% of patients; response rates in ~30% of patients||Chen et al. 2010279; Averbuch et al. 1988306|
|Metastatic PHEO or sympathetic extra-adrenal PGL (excluding HNPGL)||Systemic chemotherapy (doxorubicin or non-doxorubicin-based or other-platins; cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone or prednisolone; temozolomide; etoposide; imatinib; ifosfamide; and thalidomide), patients (n=52) diagnosed January 1979- March 2010. The University of Texas MD Anderson Cancer Center.||33% responded to front-line chemotherapy (treated with cyclophosphamide and dacarbazine), 17% had reduced tumor size, 8% had normalized blood pressure and 8% had both. The OS response rate was 51% at 5 years in all 52 patients. In the 33% that were chemotherapy-responsive, median OS time was 6.4 years and for non-responders it was 3.7 years. Patients who had surgery for primary tumor and chemotherapy, had survival of 6.5 years compared with 3 years for those with chemotherapy only.
None of the 4 patients with SDHB mutations responded to chemotherapy. 1 patient with SDHC mutation did respond to treatment.
|Ayala-Ramirez et al. 2012307|
|PGL||Operative excision of EAPs can lead to prolonged remission, sporadic (n=26) and inherited (n=25) EAPs, France.||Local regional recurrence of 15% at 5 years, 23% after 10 years; all were secreting; 38% provoked clinical symptoms. New lesions were smaller than primary EAP and more associated with lymph nodes (43% vs. 4%). Operative excision complete in n=5 and clinical remission maintained in n=4 after a 57 month follow-up.||Van Slycke et al. 2009299|
|PHEO: organ-contained and unilateral||Open surgery and laparoscopic procedures in a large institutional patient series (n=101) in India with large (>6cm) PHEOs, 1990-2010.||While cure and hypertension outcomes were no different, morbidity was more frequent in open surgery (n=12) than laparoscopic patients (n=4).||Agarwal et al. 2012308|
Abbreviations: PGL, paraganglioma; PHEO, pheochromocytoma.