Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective

Abstract

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS). Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages <14 years diagnosed at the Giannina Gaslini Children's Hospital, Genoa, between 1987 and. Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages V3 years (13 of 25; 52%). In this age group, MBEN was significantly more frequent than desmoplastic MB and classic MB (P < 0.001) and had a good prognosis. MBEN was associated with GS in 5 of 12 cases. Overall, 8 cases occurred in the context of familial tumor predisposition syndromes (5 GS, 1 each NF1, LiFraumeni, and Fragile X) and 7 of these patients were ages V3 years at diagnosis. Desmoplastic histology and a more intensive treatment represented independent favorable prognostic factors in multivariate analysis (P = 0.003 and P = 0.0139, respectively). Metastasis was a predictor of bad outcome (P = 0.0001). Conclusions: Our data indicate that biologically different MB entities warrant risk-adapted treatment and that MBEN is strongly associated with GS. Patients, ages V3 years, with MB and their families should be investigated for tumor predisposition syndromes such as GS. Medulloblastoma (MB) with extensive nodularity (MBEN)occurring in young children is a rare but well-defined entity (1 -3). It is believed to be related to, but distinct from, desmoplastic MB (DMB). However, many aspects of this peculiar entity are still unclear, including its frequency, why it occurs at a very young age, why its prognosis is good, and its association with Gorlin syndrome (GS) or nevoid basal cell carcinoma syndrome. Most of the largest cooperative trials that have been published on MB in infants do not report on the relative frequency of this distinct entity compared with other variants and/or comment on the effect of the diagnosis of this variant on subsequent follow-up and treatment strategies (4 -6). A large prospective study by Eberhart reported that 73 of 330 (22%) cases had various degrees of desmoplasia and 14 of 330 cases were MBEN (4.2%; ref. 7). A more recent, extensive neuropathogical review focused on the morphologic features and biological behavior of 2 large contemporaneous cohorts of patients with MB and showed that DMB represents 5% of all MB and up to 57% of cases in children ages <3 years (3). A recent prospective, cooperative trial reported that desmoplastic histologic variants have a clearly favorable effect on prognosis in infants with MB who are treated with chemotherapy (CT) as first-line therapy. However, it did not mention the frequency of Imaging, Diagnosis, Pro...

Medulloblastoma with Extensive Nodularity Undergoing Post-Therapeutic Maturation to a Gangliocytoma: A Case Report and Literature Review

“…In a large prospective study of MBs, Eberhart et al [18] reported that 14 out of the 330 cases examined were MBEN (4.2%). Diagnostic criteria for MBEN are: >50% of analyzed tissue samples contain prominent nodularity, along with intranodular nuclear uniformity in a desmoplastic background [19]. The nodularity can be so profound that it may be visualized on MRI as a ‘grape-like’ mass.…”

ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome

“…Another example come from the mutations in SUFU (a tumour suppressor gene controlling the Sonic hedgehog signalling) which most remarkably predispose to early onset desmoplastic medulloblastomas, before 3 years of age. 6,7 Peripheral neuroblastic tumours are tumours of neural crest origin that mostly affect children before 5 years of age. The young age at diagnosis lead Knudson and Strong 8 to propose that neuroblastic tumours might frequently arise in a predisposition context.…”

Untitled

“…54 It has been suggested that young children presenting with medulloblastoma of nodular or desmoplastic histology need to be assessed for GS. 54,55 In PTCH1-negative children younger than the age of 3 years with a desmoplastic/nodular medulloblastoma, with and without other manifestations fitting GS, germline mutations in suppressor of fused homolog (SUFU) have been identified. Nontumor CNS manifestations include 56 Both the presence of a germline mutation (in 85% of patients who fulfil the diagnostic criteria of CS a mutation is identified) and the location of the mutation are associated with severity of disease.…”