Composite Adrenal Anaplastic Neuroblastoma and Virilizing Adrenocortical Tumor With Germline TP53 R248W Mutation
Hans-Christoph Rossbach, MD,1,4* Dmitry Baschinsky, MD,2 Tung Wynn, MD,1 Dana Obzut, MD,1 Maxine Sutcliffe, PhD,3,5 and Cameron Tebbi, MD
Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia,
sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists. Pediatr Blood Cancer 2008;50:681-683. @ 2007 Wiley-Liss, Inc.
Key words: adrenocortical tumor; codon 248; composite; Li-Fraumeni syndrome; neuroblastoma; p53 mutation; virilizing
INTRODUCTION
Composite malignancies in adrenal glands or other organs are extremely rare. Neuro-blastoma frequently arises from an adrenal gland. In contrast, adreno-cortical tumors (ACT) are rare in childhood [1]. More than 80% of patients with ACT have sporadic mutations in the tumor suppressor gene p53 [2] while patients with NB generally do not. Li-Fraumeni syndrome (LFS) is characterized by germline p53 mutations and predisposes to ACT [3,4]. A weak association with NB has been reported [4]. Rare composite adrenal gland tumors, usually ganglioneuroblastomas (GNB) and pheo- chromocytomas, or similar lesions in other anatomic locations, have been documented, primarily in adults [5-7]. Simultaneous ACT and GNB have been described in contra-lateral adrenal glands in one patient [8] and in the same gland in another [9], who also carried a germline TP53 R248W missense mutation. We provide evidence that R248W may predispose to composite tumors and to NB in individuals with LFS.
CASE REPORT
A 10-month-old female presented with a left abdominal mass and enlargement of her clitoris and labia. An extensive family history of cancer included relatives with choroid plexus carcinoma, glioblastoma multiforme, and early onset, metastatic breast cancer (Fig. 1). She had a normal 46, XX female karyotype but an elevated dihydroepi-androsterone level. Computerized tomography showed a large adrenal lesion but normal chest. Urine catecholamines, chemistries, complete blood counts, bone scan, and marrow analysis were normal. Surgical exploration disclosed a composite neoplasm with two distinct masses (Fig. 2). The larger nodule revealed an ACT with a nested growth pattern, fine background capillary network, abundant eosinophilic cytoplasm, and rounded nuclei with small nucleoli. Mitoses were rare and necrosis was absent. The smaller nodule showed highly malignant cells with scant cytoplasm and pleomorphic hyperchromatic nuclei characteristic of an undiffer- entiated, Schwannian stroma-poor NB with high mitotic karyor- rhectic index. Necrosis and microcalcifications were present. A periaortic lymph node demonstrated histologically identical neo- plasm. Immunohisto-chemical stains supported the presence of two entirely different tumors. Cytogenetic analysis of the NB revealed a near-tetraploid karyotype with extreme heterozygosity. Chromo-
some numbers ranged from 61 to 166 in nine of ten analyzable metaphase spreads; a single cell was normal. The ACT failed to provide dividing cells for analysis.
Interphase fluorescence in situ hybridization (FISH) analysis revealed extra copies of chromosomes 1, 2, and 13 in both tumors, without amplification of the N-MYC gene or loss of heterozygosity (LOH) of the tumor suppressor gene p58 (1p36) and the retinoblastoma gene RB1 (13q14). In contrast, FISH analysis of p53 supported LOH in both tumors as it did in the cousin’s brain tumor. Germline sequence analysis of the coding region of p53 identified a missense mutation in the sequence specific DNA binding domain (742C> T), predicting an amino acid change of arginine to tryptophan at codon 248 (R248W) (DNA Diagnostic Laboratory, Baylor College of Medicine, Houston). Other family members have decided against mutation analysis at this time. Chemotherapy included two cycles of doxorubicin and cyclo- phosphamide and two of etoposide coupled with carboplatin or cyclophosphamide. She remains healthy one year post-therapy.
DISCUSSION
Composite tumors are extremely rare. Their etiology remains elusive. Injury to adrenal tissues during embryogenesis by toxic or infectious agents as an explanation for the development of composite tumors must remain speculative at this point. Inactivating mutations of p53 may provide an alternative explanation. P53 controls a wide variety of cell cycle regulatory pathways. Gene activation results in cell cycle arrest and DNA repair or, alternatively, in apoptosis [10]. Germline p53 mutations are
1Division of Pediatric Hematology/Oncology, St. Joseph Children’s Hospital, Tampa; 2Division of Pathology, St. Joseph Children’s Hospital, Tampa; 3Division of Cytogenetics, All Children’s Hospital, St. Petersburg; 4Department of Pediatrics, University of South Florida, Tampa, Florida; 5Department of Pathology, University of South Florida, Tampa, Florida
*Correspondence to: Hans-Christoph Rossbach, Department of Pediatric Hematology/Oncology, St. Joseph Children’s Hospital, 3001 W. M. L. King Jr. Blvd., Tampa, FL 33607.
E-mail: hanschristoph.rossbach@baycare.org
Received 28 September 2006; Accepted 20 February 2007
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Breast CA dx ?yrs
Breast CA dx 19yrs
Breast CA dx 35yrs
Breast CA dx 24yrs
Glioblastoma multiforme dx 20yrs
Neuroblastoma Adrenal cortical tumor dx 10mths
Choroid plexus CA dx 4mths
associated with the LFS, predisposing to sarcomas, carcinomas of breast and adrenal cortex, brain tumors, and leukemias [3,4]. Other cancers occur less frequently but at an earlier age than expected in the general population [11]. Multiple primary tumors are common. The cumulative probability of a second cancer 30 years after a childhood malignancy exceeds 80%. Three or more cancers are seen in some, often very young patients [12-14]. Synchronous tumors generally involve different organs [13,15]. A weak association of NB and LFS was recently described [4].
To date, over 370 p53 germline mutations have been identified [16]. Decreased tumor suppressor activity is mostly due to missense mutations, 90% of which occur in the sequence specific DNA
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binding domain (codons 110-286). Families with mutations in this domain have a more highly penetrant cancer phenotype than those with a mutation outside this domain [17]. A p53 genotype- phenotype relationship [17] is supported by the observation of children with ACT in Brazil. All children analyzed carried the R337H mutation within the tetramerization domain, while none of their 240 mutation-positive relatives had an increased cancer risk [18].
The patient reported here carried the R248W mutation as did another young child with composite adrenal ACT and GNB [9]. In their series of pediatric and young adult LFS patients with second malignancies, Malkin et al. included an individual with NB, breast cancer, and R248W [19]. Another boy with LFS, NB, and a mutation at codon 248 has subsequently been identified (unpublished data). In contrast, an additional individual with LFS and NB reported elsewhere carried a mutation at codon 273 [20].
We speculate that a germline p53 mutation may constitute a significant factor in the pathogenesis of composite adrenal malignancies in young children. Our findings and the data cited above support the notion of a link between LFS and NB [4]. Whether R248W in particular is an important etiologic factor for the development of NB in patients with LFS remains currently unclear.
Mutation analysis may be indicated in a child with NB and a close relative with one of the malignancies commonly encountered in LFS families. As the case of the patient with NB and breast cancer [19] indicates, it may be prudent to monitor individuals with a history of NB and/or ACT beyond the pediatric age range for LFS- related cancers later in life.
REFERENCES
1. Rodriguez-Galindo C, Figueiredo BC, Zambetti GP, et al. Biology, clinical characteristics, and management of adrenocortical tumors in children. Ped Blood Cancer 2005;45:265-273.
2. Varley JM, McGown G, Thorncroft M, et al. Are there low- penetrance TP53 alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet 1999;65:995-1006.
3. Li FP, Fraumeni J, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;45:5358- 5362.
4. Birch J, Alston RD, McNally RJQ, et al. Relative frequency and morphology of cancers in carriers of germline TP53 mutations. Oncogene 2001;20:4621-4628.
5. Candanedo-Gonzales FA, Alvarado-Cabrero I, Gamboa-Domin- guez A, et al. Sporadic type composite pheochromocytoma with neuroblastoma: clinicomorphologic, DNA content and ret gene analysis. Endocr Pathol 2001;12:343-350.
6. Fujiwara T, Kawamura M, Sasou S, et al. Results of surgery for a compound adrenal tumor consisting of pheochromocytoma and ganglioneuroblastoma in an adult: 5-year follow-up. Intern Med 2000;39:58-62.
7. Banks E, Yum M, Brodhecker C, et al. A malignant peripheral nerve sheath tumor in association with a paratesticular gang- lioneuroma. Cancer 1989;64:1738-1742.
8. Dahms WT, Gray G, Vrana M, et al. Adrenocortical adenoma and ganglioneuro-blastoma in a child. Am J Dis Child 1973;125:608- 611.
9. Pivnick EK, Furman WL, Velagaleti GVN, et al. Simultaneous adrenocortical carcinoma and ganglioneuroblastoma in a child with Turner syndrome and germline p53 mutation. J Med Genet 1998;35:328-332.
10. Levine AJ. P53, the cellular gatekeeper for growth and division. Cell 1997;88:323-331.
11. Nichols KE, Malkin D, Garber J, et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomark Prev 2001;10:83-87.
12. Hisada M, Garber JE, Fung CY. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;90: 606-611.
13. Khayat CM, Johnston DL. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer 2004;43:683-686.
14. Gutierrez MI, Bhatia KG, Barreiro C, et al. A de novo p53 germline mutation affecting codon 151 in a six year old child with multiple tumors. Human Mol Genet 1994;3:2247-2248.
15. Cavalier ME, Davis MM, Croop JM. Germline p53 mutations presenting as synchronous tumors. J Pediatr Hematol Oncol 2005; 27:441-443.
16. Olivier M, Eeles R, Hollstein M, et al. The IARC TP53 Database: new online mutation analysis and recommendations to users. Hum Mutat 2003;19:607-614. (Database updates in http:// www-p53.iarc.fr/DownloadDatabase.asp?File=TP53Germline&- TypeGraph=Germline).
17. Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li- Fraumeni syndrome. Oncogene 1998;17:1061-1068.
18. Figueiredo BC, Sandrini R, Zambetti GP, et al. Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet 2006;43:91-96.
19. Malkin D, Jolly KW, Barbier N, et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. NEJM 1992;326:1309-1315.
20. Porter DE, Holden ST, Steel CM, et al. A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families. J Bone Joint Surg 1992;74:883-886.
Treatment of Neuroblastoma-Related Opsoclonus-Myoclonus-Ataxia Syndrome with High-Dose Dexamethasone Pulses
Florian Ertle, MD,1 Wolfgang Behnisch, MD,1 Naima Ali Al Mulla, MD,2 Mohammed Bessisso, MD,2 Dietz Rating, MD,3 Gunhild Mechtersheimer, MD,4 Barbara Hero, MD,5 and Andreas E. Kulozik, MD, PHD1*
Opsoclonus-myoclonus-ataxia-syndrome (OMS) represents a rare neuroblastoma-associated paraneoplastic syndrome that com- monly results in neurologic deficits despite tumor resection and immunosuppressive therapy. We describe the response of five such children to high-dose dexamethasone pulses including two patients in whom previous glucocorticoids, rituximab, and cytostatic drugs were not successful. All patients had MYCN non-amplified tumors
that were detected 1 to 7 months after the onset of the OMS or ataxia. This treatment resulted in a good partial response in three and in complete remission in two patients. Our results show that dexamethasone pulses are likely to be useful for both, first-line- and salvage-therapy for OMS-patients. Pediatr Blood Cancer 2008;50:683-687. @ 2007 Wiley-Liss, Inc.
Key words: dexamethasone; neuroblastoma; OMS; paraneoplastic syndrome
INTRODUCTION
Opsoclonus-myoclonus-ataxia-syndrome (OMS) (Kinsbourne syndrome) includes characteristic neurologic symptoms and severe developmental, cognitive, and behavioral deficits that preclude normal schooling and social integration [1]. In most patients, OMS is associated with neuroblastoma (NB), which is usually diagnosed later. With respect to the tumor, patients with OMS have a favorable prognosis [2,3], but the neurologic and developmental deficits often persist and even progress with loss of already obtained devel- opmental milestones.
OMS is thought to be caused by an autoimmune process [4,5] and early immunosuppressive treatment is recommended despite an
“Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany; 2Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar; 3Department of Pediatric Neurology, University Hospital Heidelberg, Germany; 4Institute of Pathology, University of Heidelberg, Germany; 5Department of Pediatric Oncology and Hematology, University of Cologne, Germany Florian Ertle and Wolfgang Behnisch contributed equally.
*Correspondence to: Andreas E. Kulozik, Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 153 69120 Heidelberg, Germany. E-mail: Andreas.Kulozik@med.uni-heidelberg.de
Received 28 June 2006; Accepted 27 October 2006
@ 2007 Wiley-Liss, Inc. DOI 10.1002/pbc.21107
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