A SDHB malignant paraganglioma with dramatic response to temozolomide–capecitabine

in European Journal of Endocrinology
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  • 1 Hospices Civils de Lyon, Université de Lyon, Hospices Civils de Lyon, Hospices Civils de Lyon, INSERM, Hospices Civils de Lyon, Hospices Civils de Lyon, Hôpital Edouard Herriot, Fédération des Spécialités Digestives, Pavillon Hbis, Place d'Arsonval, 69437 Lyon cedex 03, France

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.

Abstract

Ten percent of paragangliomas are malignant and one-third occurs in a genetic background. We report a case of succinate dehydrogenase subunit B (SDHB)-related malignant paraganglioma with dramatic response to temozolomide and capecitabine regimen (decrease in tumor size of 70% with RECIST criteria). Tumor cells harbored a new mutation in SDHB gene and showed aberrant hypermethylation of O6-methylguanine-DNA-methyltransferase promoter. Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. This observation points to a possible genotype response to treatment relationships, which could help to design tailor-made treatments in the future.

Case report

In 1991, a 39-year-old man had a simultaneous diagnosis of retroperitoneal paraganglioma, treated by radical surgery, and macroprolactinoma, treated by transphenoidal surgery, dopaminergic agonists, and radiotherapy. There was no family history suggestive of hereditary endocrine neoplasia including pheochromocytoma, paraganglioma, medullary thyroid cancer, cutaneous lesions, or other endocrine tumor.

In April 2009, 18 years later, at the age of 57, the patient was referred for dyspnea and poor performance status (Eastern Cooperative Oncology Group Performance Status (ECOG) PS=3). Computed tomography scan showed bilateral mediastinal lymph nodes with tracheal compression associated with two basithoracic lung nodules. Serum chromogranin A levels were 2550 μg/l. Urinary and plasmatic catecholamines were within normal limits. Metaiodobenzylguanidine (MIBG) showed low activity inside the left hilar lymph nodes. In contrast, the 18FDG-PET scan showed high-grade activity in mediastinal and lung metastases. The histological and immunohistochemical examinations of a mediastinal lymph node biopsy concluded to a metastatic paraganglioma. Ki67 index (MIB-1; Dako, Glostrup, Denmark) was 30%. No staining was observed for O6-methylguanine-DNA-methyltransferase (MGMT) in the tumor (mouse anti-MGMT MAB, clone MT23.2, Invitrogen Corporation) with positive staining in lymphoid cells as internal positive control (Fig. 1). In our technical conditions, no staining was observed for succinate dehydrogenase subunit B (SDHB; rabbit anti-SDHB polyclonal antibody HPA002868, Sigma–Aldrich Corporation) with positive staining in lymphoid cells as internal positive control (Fig. 2A), while staining was positive in normal adrenal cells, as a control (Fig. 2B). SDHB gene mutational analyses demonstrated a novel germline mutation c.412G→A, p.Asp138Asn in exon 4. Aberrant hypermethylation of MGMT promoter was revealed by methylation-specific PCR assay performed on bisulfite-treated DNA.

Figure 1
Figure 1

MGMT immunohistochemistry: tumor of the patient negative for MGMT with positive staining in lymphoid cells as internal positive control. Original magnification ×40. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

Citation: European Journal of Endocrinology 166, 6; 10.1530/EJE-11-1098

Figure 2
Figure 2

SDHB immunohistochemistry: tumor of the patient negative for SDHB with positive staining in lymphoid cells as internal positive control (A); striking positive cytoplasmic staining of adrenal cells, as a control (B). Original magnification ×10 (inset ×20). Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

Citation: European Journal of Endocrinology 166, 6; 10.1530/EJE-11-1098

The patient was successively treated by gemcitabine and oxaliplatin (GEMOX), sunitinib, and temozolomide–capecitabine, using doses previously suggested for neuroendocrine tumors (NETs) (1, 2, 3). Clinical response (improvement of dyspnea, voice, and fatigue), biological response (serum chromogranin A levels), and radiological response (using RECIST criteria) are reported in Fig. 3. First, the patient received eight cycles of gemcitabine (1000 mg/m2 i.v.) combined with oxaliplatin (100 mg/m2 i.v.) every 14 days; he presented with dramatic clinical improvement after three cycles (ECOG PS=0), but with grade 2 paresthesia after eight cycles, and partial response rate (17%) using RECIST criteria. Two months after the end of GEMOX, clinical and radiological progression occurred. Then, sunitinib (37.5 mg p.o., once daily) was started but stopped after 1 month due to the occurrence of severe hemoptysis treated by arterial embolization; tumor response was not assessed at this time. Lastly, he received eight cycles of capecitabine (750 mg/m2 p.o., twice daily, days 1–14) and temozolomide (200 mg/m2 p.o., once daily, days 10–14) every 28 days; filgrastim was given to prevent neutropenia (once daily, days 5–10 after each cycle); dramatic objective response rate (70% with RECIST criteria) occurred. The duration of response was 8 months, but capecitabine–temozolomide failed to undergo a new disease control at the time of tumor progression. External radiotherapy of the mediastinum is ongoing.

Figure 3
Figure 3

Clinical, biological, and radiological responses of the patient during follow-up. CgA, chromogranin A (reference range, 19.4–98.1 mg/l); GEMOX (gemcitabine and oxaliplatin); Tem–Cap, temozolomide and capecitabine; SD, stable disease; OR, objective response; PD, progressive disease; Clinical res, clinical response. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

Citation: European Journal of Endocrinology 166, 6; 10.1530/EJE-11-1098

Discussion

Paragangliomas are tumors that develop from extra-adrenal chromaffin cells. Approximately 10% of paragangliomas are malignant (4, 5). Until 2002, 10% of pheochromocytoma/paraganglioma were considered to be hereditary. Three possible underlying genetic disorders were identified: multiple endocrine neoplasia type 2 (MEN2), Von–Hippel Lindau (VHL) disease, and neurofibromatose type 1 (NF1). In 2000, mutations in the genes encoding the mitochondrial complex enzyme SDH were discovered (6) and the rate of mutation detection in paragangliomas reached 25–30% (4, 5, 7). New algorithms of genetic testing have been proposed depending on the family/sporadic context, localization of the primary tumor, evidence for bilateral occurrence, biochemical profile of catecholamine secretion, and malignant presentation (4, 8). SDHB mutations were associated with the risk of malignancy and poor prognosis (4, 9), but in contrast with our case, not with tumor response to chemotherapy in preliminary data (10). In our case, SDHB gene was first sequenced because of recurrence of malignant paraganglioma, in a context of negative family history and absence of catecholamine secretion. Indeed, in those patients with malignant disease secondary to an extra-adrenal paraganglioma, almost 50% had SDHB mutations (11). A novel germline mutation, c.412G→A, p. Asp138Asn in exon 4, was identified in our patient. The functional consequences of this mutation were explored by immunostaining of the protein. Loss of expression of SDHB protein was an argument for the loss of wild-type SDHB allele in the tumor, a mechanism already involved in SDHB-related tumors (12, 13).

Surgical resection is considered as the primary treatment when possible. Currently, there is no curative treatment for unresectable malignant paraganglioma. Established treatment modalities include surgery and radionucleotide treatment. Chemotherapy is proposed in patients with rapidly progressing tumors and negative MIBG scintigraphy. The optimal systemic treatment for advanced disease is not assessed, due in part to the lack of agents with proven efficacy. The most used regimen combines cyclophosphamide, vincristine, and dacarbazine (CVD) and can provide tumor regression up to 50% (14). Other regimens have been tested, including gemcitabine alone or with docetaxel (15, 16) or paclitaxel (17) and etoposide–cisplatin (18); however, treatment experience with all these regimens is limited and toxicities are severe, whereas quality of life is an important objective in patients whose survival may be long. Sunitinib appears to be a promising treatment in this malignancy based on a few case reports (19, 20). The mechanism of action is similar to that described in other hypoxia-driven tumors and phase II trials are underway (www.clinicaltrials.gov: NCT00843037 and NCT01371201). The other oral drug experiencing some efficacy in this malignancy is temozolomide (21, 22). Temozolomide is a cytotoxic alkylating agent that was initially developed as an oral and less toxic alternative to dacarbazine for patients with metastatic melanoma. Interestingly, in our case, the MGMT promoter hypermethylation was associated with MGMT silencing. MGMT deficiency has been correlated with the response to temozolomide in NETs (23). In patients with glioblastoma, both MGMT promoter methylation and low levels of immunohistochemical MGMT expression have been associated with improved response to temozolomide in most, but not all, studies (24, 25). However, poor correlation in studies directly comparing these two methods has been reported in glioma (26) and no other correlation between MGMT promoter methylation and MGMT deficiency has been reported in NETs. The mechanism of action of temozolomide involves DNA methylation at the O6-guanine site. The methyl group at O6-site is removed by the DNA repair enzyme MGMT. Thereby MGMT protects DNA from methylation damage. Moreover, in vitro data indicate that the combination of capecitabine and temozolomide may have a synergistic effect (27). Finally, Strosberg et al. (3) recently reported an exceptionally high and durable response rate in a retrospective study of pancreatic NETs with a low rate of toxicity. To our knowledge, we report here the first patient with malignant paraganglioma associated with an impressive clinical and radiological response to this combination. However, temozolomide in paraganglioma has some effect even in monotherapy (21), and a synergistic effect with capecitabine has to be confirmed prospectively. The precise mechanism of this synergism is uncertain; the DNA damage induced by capecitabine may reduce the repair activity of MGMT, thereby potentiating the effect of temozolomide (28). Our report suggests the importance of molecular predictive factors of response for the selection of chemotherapeutic as well as targeted agents. It prompts to the development of a molecular classification of paragangliomas/pheochromocytomas and to the search for molecular predictive factors in other subtypes of these rare tumors. It may be, for instance, hypothesized that a defect in the VHL pathway or similar pseudohypoxic drive may account for the activity of antiangiogenic treatment as sunitinib in some cases (19).

In conclusion, the synergistic effect of temozolomide and capecitabine ought to be evaluated in metastatic paragangliomas. Our observation needs to be confirmed by prospective studies but already points to possible genotype response to treatment relationships, which could help to design tailor-made treatments.

Declaration of interest

C Nozières, M-O Joly, S Giraud, J-P Riou, and C Simon state that there is no conflict of interest. T Walter received consulting fees from Novartis, Ipsen, Roche. J-Y Scoazec was supported by the boards Keocyt and Novartis; received consulting fees from Novartis, Ipsen, and Pfizer, and orator fees from Novartis and Ipsen. F Borson-Chazot was supported by the boards Novartis, Ipsen, and Pfizer and received orator fees from Novartis and Ipsen. C Lombard-Bohas was supported by the boards Novartis, Keocyt, and Roche and received orator fees from Novartis, Ipsen, and Amgen.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

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  • View in gallery

    MGMT immunohistochemistry: tumor of the patient negative for MGMT with positive staining in lymphoid cells as internal positive control. Original magnification ×40. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

  • View in gallery

    SDHB immunohistochemistry: tumor of the patient negative for SDHB with positive staining in lymphoid cells as internal positive control (A); striking positive cytoplasmic staining of adrenal cells, as a control (B). Original magnification ×10 (inset ×20). Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

  • View in gallery

    Clinical, biological, and radiological responses of the patient during follow-up. CgA, chromogranin A (reference range, 19.4–98.1 mg/l); GEMOX (gemcitabine and oxaliplatin); Tem–Cap, temozolomide and capecitabine; SD, stable disease; OR, objective response; PD, progressive disease; Clinical res, clinical response. Full colour version of this figure available via http://dx.doi.org/10.1530/EJE-11-1098.

  • 1

    Cassier PA, Walter T, Eymard B, Ardisson P, Perol M, Paillet C, Chayvialle JA, Scoazec JY, Hervieu V, Bohas CL. Gemcitabine and oxaliplatin combination chemotherapy for metastatic well-differentiated neuroendocrine carcinomas: a single-center experience. Cancer 2009 115 33923399. doi:10.1002/cncr.24384.

    • Search Google Scholar
    • Export Citation
  • 2

    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Horsch D, Hammel P, Wiedenmann B, Van Cutsem E, Patyna S, Lu DR, Blanckmeister C, Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 2011 364 501513. doi:10.1056/NEJMoa1003825.

    • Search Google Scholar
    • Export Citation
  • 3

    Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, Helm J, Kvols L. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011 117 268275. doi:10.1002/cncr.25425.

    • Search Google Scholar
    • Export Citation
  • 4

    Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. Journal of Clinical Oncology 2005 23 88128818. doi:10.1200/JCO.2005.03.1484.

    • Search Google Scholar
    • Export Citation
  • 5

    Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C. Germ-line mutations in nonsyndromic pheochromocytoma. New England Journal of Medicine 2002 346 14591466. doi:10.1056/NEJMoa020152.

    • Search Google Scholar
    • Export Citation
  • 6

    Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW III, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000 287 848851. doi:10.1126/science.287.5454.848.

    • Search Google Scholar
    • Export Citation
  • 7

    Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics 2001 69 4954. doi:10.1086/321282.

    • Search Google Scholar
    • Export Citation
  • 8

    Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 2010 39 775783. doi:10.1097/MPA.0b013e3181ebb4f0.

    • Search Google Scholar
    • Export Citation
  • 9

    Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. Journal of Clinical Endocrinology and Metabolism 2007 92 38223828. doi:10.1210/jc.2007-0709.

    • Search Google Scholar
    • Export Citation
  • 10

    Ayala-Ramirez M, Feng L, Habra MA, Rich T, Dickson PV, Perrier N, Phan A, Waguespack S, Patel S, Jimenez C. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 2012 (In press) doi:10.1002/cncr.26577.

    • Search Google Scholar
    • Export Citation
  • 11

    Brouwers FM, Eisenhofer G, Tao JJ, Kant JA, Adams KT, Linehan WM, Pacak K. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. Journal of Clinical Endocrinology and Metabolism 2006 91 45054509. doi:10.1210/jc.2006-0423.

    • Search Google Scholar
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  • 12

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