Journal of ISSN: 2373-633XJCPCR

Cancer Prevention & Current Research
Case Report
Volume 2 Issue 2 - 2015
Advanced Urethral Paraganglioma Treated With Axitinib; Outcome and Comprehensive Molecular Analysis
Chen X1*, Doger B2, Rodriguez-Moreno JF1, Romero N1 and Garcia-Donas J1
1Clara Campal Comprehensive Cancer Center, Spain
2Universitary Hospital Infanta Cristina, Spain
Received: January 14, 2014 | Published: February 28, 2015
*Corresponding author: Xin Chen, Clara Campal Comprehensive Cancer Center; Oña street 10 (Madrid), Madrid, postal (zip) code 28050, Spain, Tel: +34917567800; Email: @
Citation: Chen X, Doger B, Rodriguez-Moreno JF, Romero N and Garcia-Donas J (2015) Advanced Urethral Paraganglioma Treated With Axitinib; Outcome and Comprehensive Molecular Analysis. J Cancer Prev Curr Res 2(2): 00029. DOI: 10.15406/jcpcr.2015.02.00029

Abstract

Introduction: Paraganglioma is a rare entity that arises from extra-adrenal paraganglia and accounts for less than a quarter of all chromaffin cell-related tumors. There are few cases of urethral paragangliomas reported on the literature. Most of them are hormonally inactive and local excision is curative in localized disease. We present a metastatic urethral paraganglioma in 71 years-old man that underwent a comprehensive search for molecular alterations amenable to pharmacological targeting.
Materials and Methods: The following molecular studies were performed in tumor tissue: HER-2/neu amplification, c-Kit immunohistochemistry, EGFR and BRAF mutations and Foundation MedicineT5a panel (next generation sequencing); in peripheral blood germ line alterations in genes related to familiar paraganglioma were also analyzed.
Results: Though no genetic alteration was found, the patient achieved tumor control with antiangiogenics (first with sunitinib that was later shifted to axitinib because of drug induced hyperbilirubinemia). Here mains asymptomatic 16 months after initiation of therapy.
Conclusion: Paraganglioma should be considered as a tumor constitutively addictive to angiogenesis even in the absence of pathogenic mutations or rearrangements in such pathway.
Keywords: Paraganglioma; Axitinib; Sunitinib.

Abbreviations

131I-MIBG: 131I-Meta Iodo Benzyl Guanidine Scintigraphy; MIBG: Meta Iodo Benzyl Guanidine; SDHB: Succinate De Hydrogenase subunit B Gene

Case Presentation

A 71 year-old-man, with Gilbert’s syndrome as the only medical history, presented in February 2013 recurrent episodes of urinary retention and haematuria. Initial diagnosis was benign hyperplasia of the prostate thus 0.4 mg of tamsulosin hydrochloride once a day was prescribed. Symptoms did not improve and four months later a retro pubic adenectomy was performed. Pathological report described a 4.5 cm length malignant tumor of the prostatic urethra with an immuno-phenotype compatible with paraganglioma (positive chromogranin, synaptophysin and S100; negative CK AE1/AE3, EMA, CK 7, CK 20 and CD10); Ki67 index was 5% and the tumor affected surgical margins.
A body CT scan revealed multiple pelvic adenopathies and implants as well as thickening of the urinary bladder wall. A PET-CT with 18F-FDG confirmed such findings (Figure 1A & 1B). Urinary and serous catecholamines were in normal range and 131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy did not show any uptake. Since this is an infrequent condition where little therapeutic options are available, a comprehensive molecular study was initiated aiming to identify alterations amenable to pharmacological targeting. FISH for HER-2/neu gene amplification and ALK translocations, immunohistochemical staining for c-Kit and sequencing of hotspot mutations in the EGFR gene (by the Cobas® EGFR Mutation Test) and BRAF gene (Cobas® 4800 BRAF V600 Mutation Test) were performed showing no alteration.

Figure 1: Radiological assessments at diagnosis and along treatment.
Left: pelvic adenopathies (white arrows); Right: Tumoral thickening of the urinary bladder wall (black asterisk) and pelvic implant (white arrow)

1A Baseline CT scan (July 2013)
1B Baseline PET CT scan (July 2013)
1C CT scan (September 2013) after two cycles of cisplatin+etoposide. Enlargement of pelvic nodes and bladder mass compared to baseline
1D CT scan (December 2013) after 2 months on sunitinib
1E CT scan (July 2014) after 3 months on axitinib
1F CT scan (October 2014) after 7 months on axitinib.

Additionally tumor samples were subjected to Foundation Medicine T5a test, an assay based on massively parallel DNA sequencing designed to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes. No relevant findings were made (see extra material for a detailed description of the assay, (Table 1)). Finally germ line DNA was studied through sequencing and multiplex ligation-dependent probe amplification (MLPA) of genes previously related with hereditary paraganglioma (VHL, SDHA, B, C and D, SDHF1 and 2 and MAX). No pathogenic alteration was identified (Table 2). In July 2013 the patient started first line chemotherapy with cisplatin 30mg/m2 and etoposide 100mg/m2 days 1 to 3 every 21 days. Toxicity included grade II nausea, grade III constipation, grade III neutropenia and dysgeusia. After two cycles radiological progression was observed and tumor related symptoms worsened (Figure 1C). In October 2013 the patient started sunitinib (37.5 mg daily) with quick improvement of urinary symptoms. He developed conjunctival jaundice (due to grade II hyperbilirubinemia, total bilirubin up to 2.89 mg/dl), grade II hypertension, grade II hand-foot syndrome and grade II hypothyroidism that required hormonal replacement, leading to a dose reduction to 25 mg daily. After two months on therapy, CT scan showed stable disease by RECIST criteria with a decrease in size of some pelvic adenopathies (Figure 1D). No liver metastasis was observed.

ABL1

GID4

CUL4B

FGF23

IRF4

MSH6

PDGFRA

RUNX1

WISP3

AKT1

CARD11

CYP17A1

FGF3

IRS2

MTOR

PDGFRB

RUNX1T1

WT1

AKT2

CASP8

DAXX

FGF4

JAK1

MUTYH

PDK1

SETD2

WTX

AKT3

CBFB

DDR2

FGF6

JAK2

MYC

PIK3C2G

SF3B1

XPO1

ALK

CBL

DIS3

FGF7

JAK3

MYCL1

PIK3C3

SH2B3

XRCC3

ALOX12B

CCND1

DNMT3A

FGFR1

JUN

MYCN

PIK3CA

SMAD2

ZNF217

APC

CCND2

DOT1L

FGFR2

KDM5A

MYD88

PIK3CG

SMAD4

ZNF703

APCDD1

CCND3

EGFR

FGFR3

KDM5C

MYST3

PIK3R1

SMARCA4

AR

CCNE1

EMSY

FGFR4

KDM6A

NBN

PIK3R2

SMARCB1

ARAF

CD79A

EP300

FLT1

KDR

NCOR1

PMS2

SMARCD1

ARFRP1

CD79B

EPHA3

FLT3

KEAP1

NF1

PNRC1

SMO

ARID1A

CDC73

EPHA5

FLT4

KIT

NF2

PPP2R1A

SOCS1

ARID2

CDH1

EPHB1

FOXL2

KLHL6

NFE2L2

PRDM1

SOX10

ASXL1

CDK12

ERBB2

GATA1

KRAS

NFKBIA

PRKAR1A

SOX2

ATM

CDK4

ERBB3

GATA2

LMO1

NKX2-1

PRKDC

SPEN

ATR

CDK6

ERBB4

GATA3

LRP1B

NOTCH1

PRSS8

SPOP

ATRX

CDK8

ERG

GNA11

MAP2K1

NOTCH2

PTCH1

SRC

AURKA

CDKN1B

ESR1

GNA13

MAP2K2

NOTCH3

PTEN

STAG2

AURKB

CDKN2A

EZH2

GNAQ

MAP2K4

NOTCH4

PTPN11

STAT4

AXL

CDKN2B

FAM46C

GNAS

MAP3K1

NPM1

RAD50

STK11

BACH1

CDKN2C

FANCA

GPR124

MAP3K13

NRAS

RAD51

SUFU

BAP1

CEBPA

FANCC

GRIN2A

MCL1

NSD1

RAD51B

SYK

BARD1

CHEK1

FANCD2

GSK3B

MDM2

NTRK1

RAD51C

TBX3

BCL2

CHEK2

FANCE

HGF

MDM4

NTRK2

RAD51D

TET2

BCL2L2

CHUK

FANCF

HLA-A

MED12

NTRK3

RAD52

TGFBR2

BCL6

CIC

FANCG

HRAS

MEF2B

NUP93

RAD54L

TIPARP

BCOR

CRBN

FANCI

IDH1

MEN1

PAK3

RAF1

TNFAIP3

BCORL1

CREBBP

FANCL

IDH2

MET

PAK7

RARA

TNFRSF14

BLM

CRKL

FANCM

IGF1

MITF

PALB2

RB1

TOP1

BRAF

CRLF2

FAT3

IGF1R

MLH1

PARP1

REL

TP53

BRCA1

CSF1R

FBXW7

IGF2

MLL

PARP2

RET

TRRAP

BRCA2

CTCF

FGF10

IKBKE

MLL2

PARP3

RICTOR

TSC1

BRIP1

CTNNA1

FGF12

IKZF1

MPL

PARP4

RNF43

TSC2

BTG1

CTNNB1

FGF14

IL7R

MRE11A

PAX5

RPA1

TSHR

BTK

CUL4A

FGF19

INHBA

MSH2

PBRM1

RPTOR

VHL

Rearrangements

ALK

BRAF

ETV4

EWSR1

NTRK1

RARA

TMPRSS2

BCL2

EGFR

ETV5

MLL

PDGFRA

RET

BCR

ETV1

ETV6

MYC

RAF1

ROS1

Table 1:List of 287 genes studied in the Foundation Medicine T5a assay.

Gene

Molecular study

Technic

SDHA

sequencing

PCR and direct sequencing was performed of the coding region and flanking intronic region (8bp) of the genes:

SDHA (reference sequence NM_004168.2*; chromosome 5)

SDHB (reference sequence NM_003000.2; chromosome 1)

SDHC (reference sequence NM_003001.3; chromosome 1)

SDHB

sequencing

SDHD (reference sequence NM_003002.2; chromosome 11)

VHL (reference sequence NM_000551.3; chromosome 3)

SDHC

sequencing

Capture target regions using oligonucleotide probes (Next era rapid, Ilumina) and subsequent realization of next generation sequencing (Miseq, Ilumina) was completed. The alignment and identification of bases were performed using the Burrows / Wheeler Aligher, BWA Miseq reporter), followed by analysis with Next Gene (Soft Genetics) program. When necessary, the Sanger sequencing was performed in the regions in which bases were insufficient cover aged. average coverage lower than 100X or minimum coverage lower than 20X *

SDHC

sequencing

VHL

sequencing

deletions /duplications

MLPA analysis (MRC Holland ) of the chromosomal region comprising the genes:

SDHA

SDHA (cr5) Reference sequence NM_004168.2 (SDHA)

SDHB

SDHB (cr1) Reference sequence NM_003000.2 (SDHB)

SDHC

SDHC (cr1) Reference sequence NM_003001,3 (SDHC)

SDHD

SDHD (cr11) Reference sequence NM_003002,2 (SDHD)

SDHAF1

SDHAF1 (cr19) Reference sequence NM_001042631.2 (SDHAF1)

SDHAF2

SDHAF2 (cr11) Reference sequence NM_017841.2 (SDHAF2)

VHL

VHL (cr3) Reference sequence NM_000551.3. (VHL)

MAX

MAX (cr 14) Reference sequence NM_002382,4 (MAX)

Table 2:Table 2: Description of direct sequencing and Multiplex Ligation-dependent Probe.
Amplification performed on germ line DNA.
Side effects were properly controlled but hyperbilirubinemia, which rose again up to 3.38 mg/dl. Treatment was held and reintroduced at an intermittent schedule (daily sunitinib 25 mg, 3 weeks on, one week off). After six months on treatment stable disease was confirmed in CT scan but sunitinib was definitely discontinued because of recurrent hyperbilirubinemia. On April 2014 the patient started axitinib 5mg every 12 hours but a dose reduction to 5 mg daily was again required because of hyperbilirubinemia (serum bilirubin 2.88mg/dl). Currently the patient remains asymptomatic and on treatment, 16 months after initiation of antiangiogenics (Figure 1E & 1F).

Discussion

Paraganglioma is an infrequent tumor that arises from extra-adrenal paraganglia and accounts for less than a quarter of cases of all chromaffin cell-related tumors. There are few cases of urethral paragangliomas reported on the literature. Most of these tumors are hormonally inactive. Although haematuria may be the presenting symptom, it is important to exclude additional more common and possibly more sinister lesions such as transitional cell carcinoma. Local excision appears to be curative in most of reported cases [1,2].
Surgery and metaiodobenzylguanidine (MBIG) are cornerstones of treatment for advanced disease [3,4]. Unfortunately our case was deemed as unresectable due to multiple pelvic implants and no MIBG uptake was observed at diagnosis. Chemotherapy was initially administered but demonstrated to be useless and toxic. A comprehensive search for molecular alterations amenable to pharmacological targeting failed to guide treatment choice thus; antangiogenic therapy was initiated based on recently communicated data with sunitinib [5-9]. Though tumor control and clinical improvement were achieved, recurrent hyperbilirubinemia, likely related to Gilbert’s syndrome led to a switch to axitinib. Recently a link between this syndrome and hyperbilirubinemia along sunitinib or pazopanib treatment has been shown. This is the first report to communicate clinical benefit of a malignant paraganglioma treated with axitinib.
Around 50% of metastatic paraganglioma is caused by hereditary germ line mutations of the mitochondrial enzymatic complex II succinate dehydrogenase subunit B gene (SDHB) which finally produces a downstream activation of angiogenesis. Additionally vascular endothelial growth factors and their receptors 1 and 2 are known to be over expressed in metastatic pheocromocitomas and paragangliomas regardless of SDHB mutations [10].
Other genes involved in hereditary paragangliomas (VHL, SDHA, C and D and their cofactors SDHAF and MAX) are known to cause a similar stimulation of angiogenesis. These findings have led to the design of two clinical trials assessing the utility of both sunitinib and axitinib in pheochromocitoma and paraganglioma (NCT00843037 and NCT01967576, respectively) [11]. Interestingly our case, despite a comprehensive molecular analysis, did not present alterations in neither the mentioned genes nor additional 287 cancer related genes included in the Foundation Medicine T5a test [12]. These studies cover all the recommended genes regarding screening of familiar paraganglioma [13]. However we did not study epigenetic alterations that have been described as major contributors to some related pathologies as renal carcinoma, nor mutations in any additional genes. Thus, activators of angiogenesis could be present in the tumor but undetected by our techniques.

Conclusion

Paraganglioma should be considered as a tumor constitutively addictive to angiogenesis even in the absence of pathogenic mutations or rearrangements.

References

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  11. clinicaltrials.gov, visited on November 2014.
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  13. Cascon A, Pita G, Burnichon N, Landa I, Lopez-Jimenez E, et al. (2009) Genetics of Pheochromocytoma and Paraganglioma in Spanish Patients. J Clin Endocrinol Metab 94(5): 1701-1705.
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