Molecular alterations in a case of bilateral adrenal neuroblastoma.

Abstract

*Neuroblastoma, the most common extracranial solidtumor of childhood, presents heterogeneous molecularand clinical characteristics. To date few molecular studieshave been reported for multifocal neuroblastoma, a modeof presentation of this tumor that occurrs in about 2% ofthe cases and reflects the complex pathogenesis of thisneoplasm [1–3]. Herein, we report a case of bilateraladrenal synchronous neuroblastoma. Our studies revealedthe presence of molecular and cytogenetic heterogeneityand suggest that a clonal evolution might have occurredin one of the primary tumors.A 7› year-old girl was admitted in June 1995 to theGaslini Children’s Hospital (Genova, Italy) for abdom-inal pain. Ultrasonography revealed a round nonhomo-geneous adrenal mass on the right (R) and a smalleradrenal mass on the left (L). Urinary catecholamineexcretion, serum lactate dehydrogenase, and ferritinlevels were abnormally elevated. Both tumors and severallymph nodes were resected. Histopathologic and clinicalevaluation led to a diagnosis of bilateral synchronousneuroblastoma, both stroma-poor [1]. The right-sidedtumor was of the undifferentiated subtype with high MKIaccording to Shimada et al. [4]. This tumor was morpho-logically heterogeneous and presented a differentiating(R1) and an undifferentiated (R2) area. The L tumor wasof the differentiating subtype, with low MKI. Six monthsafter surgery, the tumor recurred retroperitoneally, andthe patient was treated with six cycles of chemotherapyand irradiation. Fourteen months later, multiple relapseswere detected in distant lymph nodes and in the 9th rightrib. A biopsy from a lymph nodal metastasis (M) wasavailable for molecular studies. The patient was treatedwith aggressive chemotherapy, but died of diseaseprogression in 1997.Histopathologic data suggested that the R1, R2, and Ltumor areas had different biologic characteristics. In fact,immunohistochemical analysis showed a high level ofexpression of the proliferation marker Ki-67 in R2. Onthe contrary, in R1 and L an intermediate and a lownumber of cells were positive for Ki-67 (Fig. 1, A–C).The DNA index was 1.00 in all three areas. Comparativegenomic hybridization (CGH) and fluorescent in situhybridization (FISH) showed an additional copy ofchromosome 7 in R1, R2, and M, but not in L (Fig. 1,D–I). MYCN gene amplification, chromosome 1p dele-tion, and additional chromosomal aberrations were notobserved. Microsatellite analysis of 16 chromosome 1pmarkers demonstrated the presence of replication errorsat the adjacent loci D1S496 and D1S197 only in R1 andexcluded the presence of small 1p deletions (data notshown).Neuroblastoma generally presents as a sporadic singlelesion. However, the occurrence of multiple primarytumors in young children has been described and couldunderline a genetic predisposition of this disease [1–3,5].Unlike other cases described in the literature [3], ourpatient developed the tumors at an older age and herdisease progressed rapidly. In Figure 2, we report thebiologic and molecular characteristics and the possibleevolution of the tumors.In conclusion, although other interpretations arepossible, our findings suggest that two independenttumors (R and L) developed in this patient in agreementwith the concept of ‘‘multiple foci of disease’’ [3]. Thishypothesis is supported by the chromosome 7 trisomy,