Clinicopathological study of SDHB mutation-related pheochromocytoma and sympathetic paraganglioma

in Endocrine-Related Cancer
Correspondence should be addressed to N Kimura; Email: kimura-path@hnh.hosp.go.jp
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et al. 2011). Of these, succinate dehydrogenase subunit B (SDHB) gene mutation is considered a high-risk factor for malignancy. Loss of heterozygosity at the SDHB locus (1p36) was observed in all tumors with SDHB mutation, and et al. (2003) strongly suggested that SDHB is a tumor suppressor gene. Subsequently, loss of SDHB protein immunoreactivity in SDHB-mutated PCC/PGL (SDHB–PCC/PGL) was reported with 100% sensitivity and 84% specificity (et al. 2009). Thus, SDHB immunohistochemistry can be used to screen

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Pheochromocytoma (PCC) and paraganglioma (PGL) are genetically and phenotypically heterogeneous catecholamine-producing neoplasms. They can occur sporadically or as a part of hereditary disease. Approximately 30% of PCC/PGL are believed to be caused by germline mutations (Welander et al. 2011). Of these, succinate dehydrogenase subunit B (SDHB) gene mutation is considered a high-risk factor for malignancy. Loss of heterozygosity at the SDHB locus (1p36) was observed in all tumors with SDHB mutation, and Gimenez-Roqueplo et al. (2003) strongly suggested that SDHB is a tumor suppressor gene. Subsequently, loss of SDHB protein immunoreactivity in SDHB-mutated PCC/PGL (SDHB–PCC/PGL) was reported with 100% sensitivity and 84% specificity (van Nederveen et al. 2009). Thus, SDHB immunohistochemistry can be used to screen SDHB–PCC/PGL using paraffin-embedded pathological materials. SDHB mutation is the only established factor that indicates future metastasis. Therefore, it is important to analyze the histological characteristics of SDHB–PCC/PGL.

It is generally accepted that it is difficult to distinguish histological differences between benign and malignant PCC/PGL. The current consensus is that a long-term follow-up is required after the surgery to screen for recurrence or metastasis in all PCC/PGL patients, regardless whether hereditary or sporadic in origin. Kimura et al. (2014) proposed a histological grading system called the Grading of Adrenal PCC and PGL (GAPP) classification for predicting metastasis. GAPP is composed of six factors: histological pattern, cellularity, presence or absence of comedo-type necrosis, vascular or capsular invasion, Ki67-labeling index (%), and elevated catecholamine type. Each factor was assigned a point and the number of points was summated. Tumor scores of 0–2, 3–6, and 7–10 were classified into well differentiated (WD), moderately differentiated (MD), and poorly differentiated (PD) types respectively. These types correlate with tumor metastasis and patient survival. Herein, we analyzed the clinicopathological features of patients with SDHB mutation using the GAPP classification and SDHB immunohistochemistry.

Fifteen Japanese patients with SDHB mutation and their tumors were examined. All patients were genetically tested and confirmed to have SDHB germline mutations. Patient clinical data, including age, gender, mutation sites, family history, elevated catecholamines (CA), metastasis, and present status after the initial surgical removal of the tumor, are summarized in Table 1. The same mutations were observed in SDHB exon 2 (c.137G>A) and SDHB exon 5 (c.470delT) in six and four patients respectively. Five of the patients (33%) had family history. The preoperative CA phenotypes of the patients included six norepinephrine plus dopamine, six norepinephrine only, and three nonfunctioning type. Eight of the patients (53%) had multiple distant metastases. Only two patients with multiple metastases died of the disease 37 and 12 years respectively after the initial surgery. The number of survival years from the first operation ranged from 2 to 37 years in eight patients; however, the remaining seven patients were operated upon within a past year and their prognosis could not be evaluated. Notably, four patients survived longer than 20 years with multiple metastases since the initial surgery (20, 25, 26, and 37 years respectively). Pathological data are summarized in Table 2. Nine tumors (60%) showed a pseudorosette pattern, which is histologically rare in ordinary PCC. Histological grading of the tumors was as follows: 1 WD, 13 MD (87%), and 1 PD.

Table 1

SDHB gene mutations and clinical data of 15 patients

ParameterMutation amino acid changen
Mean age at diagnosis (years)32.3±14.2 (17–61)
GenderMale10
Female5
Exon/mutation cDNA nucleotide changeExon 2/c.137G>AR46Q6
Exon 5/c.470delTL1574
Exon 3/c.268C>TR901
Exon 6/c.641A>GQ214R1
Exon 7/c.649C>TR217C1
Intron2–31
Intron4–5, exon5/c.424-7A>C; 424-6_427del1
Family history of pheochromocytoma and paragangliomaPositive5 (33%)
Negative10
Preoperative excessive catecholamine typeNorepinephrine+dopamine6 (40%)
Norepinephrine 6 (40%)
Nonfunctioning3 (20%)
MetastasesPresence8 (53%)
Absence7
Present statusDied of disease2
Alive with disease5
Alive without disease8
Table 2

Pathological data of pheochromocytomas and paragangliomas from 15 patients with SDHB mutation

Parametern
Tumor locationAdrenal gland4 (27%)
Unilateral2
Bilateral1
With renal pelvis1
Retroperitoneum9 (60%)
Single7
Two2
Urinary bladder1
Mediastinum with pelvic cavity1
Tumor size (cm±S.D.)6.35±2.74
Tumor metastasisPresence8 (53%)
Absence7
Lung3
Location of metastasisBone3
Lymph node3
Liver1
Ovary and pelvic cavity1
Omentum and peritoneum1
Breast1
Histologic typeZellballen4
Irregular zellballen2
Pseudorosette pattern9 (60%)
GAPP score (mean±S.E.M.)4.87±0.99
21
31
43
56
63
71
Histologic gradeWell differentiated1
Moderately differentiated13 (87%)
Poorly differentiated1
SDHB-immunohistochemistryNegative14 (93%)
Positive1

In previous reports, genetic testing of SDHB revealed that the mutation sites were distributed throughout the entire gene (Benn et al. 2006). However, exons 2 and 5 appear to be the preferential mutation sites in the present study of Japanese patients. Patients with SDHB mutations were younger, had extra-adrenal tumors more frequently, and had shorter survival times (Amar et al. 2007). However, extraordinary long-term survivors with SDHB mutations and metastatic tumors have been reported. Young et al. (2002) reported a patient with SDHB mutation-associated familial malignant PGL with long survival, who was diagnosed with metastatic disease within 1 year after the initial presentation. The patient was well 30 years later, with little anti-tumor-specific therapy. Neumann et al. (2004) also reported two patients with malignant SDHB–PCC/PGL that had the disease longer than 20 and 32 years respectively. The present study includes four patients with long survival up to 37 years with multiple metastases since the initial surgery. The reasons for the extraordinarily long survival with multiple metastases are important and should be clarified. Timmers et al. (2007) reported that of the 29 patients with SDHB-PHEO/PGL, the catecholamine hypersecretion profile was norepinephrine plus dopamine in 13 patients (46%), norepinephrine only in 12 patients (41%), dopamine only in 1 patient (3%), and nonfunctioning in three patients (10%). Our present findings are similar to these data. Nonfunctioning PCC/PGL might reflect immature biochemical phenotypes. Dopamine hypersecretion and plasma methoxytyramine, the O-methylated metabolite of dopamine, have been considered as the features of immaturity and a marker for malignant PCC/PGL (Eisenhofer et al. 2012).

A pseudorosette pattern is a peculiar histology that is rarely observed in ordinary PCC/PGL. A pseudorosette pattern is sometimes observed in immature tumors of other organs, including pseudo-papillary tumors of the pancreas, some pituitary tumors, and ependymomas. It is surprising that the pseudorosette pattern was observed in nine (60%) of the 15 tumors in the present study. Thus, both catecholamine phenotype and tumor morphology revealed SDHB–PCC/PGL immaturity. Our histological analyses of SDHB–PCC/PGL revealed that most tumors (87%) are MD, whereas there is only one each of WD and PD tumor. Recent results from our Japanese nationwide survey of PCC/PGL have indicated that the 5-year survival rates were 100, 66.8, and 22.4% for the WD, MD, and PD types respectively (Kimura et al. 2014). Patients with MD type of SDHB–PCC/PGL may live for a long time after the initial surgery, even with multiple tumor metastases.

In conclusion, we would like to emphasize that the pseudorosette pattern in PCC/PGL and elevated norepinephrine plus dopamine or nonfunctioning are the features of SDHB mutations. Based on histopathology, the combination of SDHB-negative immunohistochemistry and the presence of pseudorosette pattern strongly suggest SDHB–PCC/PGL. Genomic analyses should be recommended for such cases.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by grants for a Research on Measures for Intractable Diseases, Research Committee on the Diagnosis and Treatment of Pheochromocytoma from the Ministry of Health, Labour, and Welfare of Japan (M Nakane) for Advancement for Hospital Function from the Japan Health, Labour, and Welfare Organization (N Kimura), and in part from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant number 21591168, K Takekoshi).

Acknowledgements

The authors thank K Terashima and T Moriyama for their dedication and cooperation in preparation of pathological materials.

References

  • AmarLBaudinEBurnichonNPeyrardSSilveraSBertheratJBertagnaXSchlumbergerMJeunemaitreXGimenez-RoqueploAP2007Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. Journal of Clinical Endocrinology and Metabolism9238223828. (doi:10.1210/jc.2007-0709).

  • BennDEGimenez-RoqueploAPReillyJRBertheratJBurgessJBythKCroxsonMDahiaPLElstonMGimmO2006Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism91827836. (doi:10.1210/jc.2005-1862).

  • EisenhoferGLendersJWSiegertGBornsteinSRFribergPMilosevicDMannelliMLinehanWMAdamsKTimmersHJ2012Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. European Journal of Cancer4817391749. (doi:10.1016/j.ejca.2011.07.016).

  • Gimenez-RoqueploAPFavierJRustinPRieublandCCrespinMNauVKhau Van KienPCorvolPPlouinPFJeunemaitreX2003Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research6356155621.

  • KimuraNTakayanagiRTakizawaNItagakiEKatabamiEKakoiNRakugiHIkedaYTanabeANigawaraT2014Pathologic grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-Related Cancer21405414. (doi:10.1530/ERC-14-0494).

  • van NederveenFHGaalJFavierJKorpershoekEOldenburgRAde BruynEMSleddensHFDerkxPRivièreJDannenbergH2009An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncology10764771. (doi:10.1016/S1470-2045(09)70164-0).

  • NeumannHPPawluCPeczkowskaMBauschBMcWhinneySRMuresanMBuchtaMFrankeGKlischJBleyTA2004Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association292943951. (doi:10.1001/jama.292.8.943).

  • TimmersHJKozupaAEisenhoferGRaygadaMAdamsKTSolisDLendersJWPacakK2007Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism92779786. (doi:10.1210/jc.2006-2315).

  • WelanderJSöderkvistPGimmO2011Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer18R253R276. (doi:10.1530/ERC-11-0170).

  • YoungALBaysalBEDebAYoungWFJr2002Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. Journal of Clinical Endocrinology and Metabolism8741014105. (doi:10.1210/jc.2002-020312).

N Kimura and K Takekoshi contributed equally to this work

 

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References

AmarLBaudinEBurnichonNPeyrardSSilveraSBertheratJBertagnaXSchlumbergerMJeunemaitreXGimenez-RoqueploAP2007Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. Journal of Clinical Endocrinology and Metabolism9238223828. (doi:10.1210/jc.2007-0709).

BennDEGimenez-RoqueploAPReillyJRBertheratJBurgessJBythKCroxsonMDahiaPLElstonMGimmO2006Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism91827836. (doi:10.1210/jc.2005-1862).

EisenhoferGLendersJWSiegertGBornsteinSRFribergPMilosevicDMannelliMLinehanWMAdamsKTimmersHJ2012Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. European Journal of Cancer4817391749. (doi:10.1016/j.ejca.2011.07.016).

Gimenez-RoqueploAPFavierJRustinPRieublandCCrespinMNauVKhau Van KienPCorvolPPlouinPFJeunemaitreX2003Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research6356155621.

KimuraNTakayanagiRTakizawaNItagakiEKatabamiEKakoiNRakugiHIkedaYTanabeANigawaraT2014Pathologic grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocrine-Related Cancer21405414. (doi:10.1530/ERC-14-0494).

van NederveenFHGaalJFavierJKorpershoekEOldenburgRAde BruynEMSleddensHFDerkxPRivièreJDannenbergH2009An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncology10764771. (doi:10.1016/S1470-2045(09)70164-0).

NeumannHPPawluCPeczkowskaMBauschBMcWhinneySRMuresanMBuchtaMFrankeGKlischJBleyTA2004Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association292943951. (doi:10.1001/jama.292.8.943).

TimmersHJKozupaAEisenhoferGRaygadaMAdamsKTSolisDLendersJWPacakK2007Clinical presentations, biochemical phenotypes, and genotype–phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. Journal of Clinical Endocrinology and Metabolism92779786. (doi:10.1210/jc.2006-2315).

WelanderJSöderkvistPGimmO2011Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine-Related Cancer18R253R276. (doi:10.1530/ERC-11-0170).

YoungALBaysalBEDebAYoungWFJr2002Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. Journal of Clinical Endocrinology and Metabolism8741014105. (doi:10.1210/jc.2002-020312).

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