Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas

Abstract

Background: Medulloblastomas may occur in a predisposition context, including familial adenomatosis polyposis. Medulloblastomas related to a germline pathogenic variant of adenomatous polyposis coli (APC) remain rare and poorly described. Their similarities with sporadic WNT medulloblastomas still require description.

Methods: We performed a multicentric retrospective review of 12 patients treated between 1988 and 2018 for medulloblastoma with an identified or highly suspected (personal or familial history) APC germline pathogenic variant. We report personal and familial history APC gene pathogenic variants whenever available: clinical and histologic characteristics of the medulloblastoma, treatments, and long-term outcome, including second tumor and late sequelae.

Results: Medulloblastomas associated with APC pathogenic variants are mainly classic (11/11 patients, 1 not available), nonmetastatic (10/12 patients) medulloblastomas, with nuclear immunoreactivity for ß-catenin (9/9 tested cases). Ten of 11 assessable patients are disease free with a median follow-up of 10.7 years (range, 1-28 y). Secondary tumors included desmoid tumors in 7 patients (9 tumors), 1 thyroid carcinoma, 2 pilomatricomas, 1 osteoma, 1 vertebral hemangioma, and 1 malignant triton in the radiation field, which caused the only cancer-related death in our series.

Conclusions: Medulloblastomas associated with an APC pathogenic variant have an overall favorable outcome, even for metastatic tumors. Yet, long-term survival is clouded by second tumor occurrence; treatment may play some role in some of these second malignancies. Our findings raise the question of applying a de-escalation therapeutic protocol to treat patients with APC germline pathogenic variants given the excellent outcome, and reduced intensity of craniospinal irradiation may be further evaluated.

Keywords: APC; Gardner syndrome; WNT; familial adenomatosis polyposis; medulloblastoma.

Fig. 1

Characteristics of patients and tumors. (A) Box-plot showing the age distribution at diagnosis, in years; line at median with interquartile range. (B) Distribution of presence (green) or absence (red) of personal (left) or familial (right) history of tumor at time of medulloblastoma diagnosis. (C) Absolute number of metastatic status (upper bar), classic histology (middle bar), and molecular subgroup (lower bar) of cases. NA = not available. (D) Axial (left panels) and coronal (right panel) MRI sections of 2 medulloblastomas from the cerebellopontine angle and the cerebellar peduncle.

Fig. 2

Outcome: survival and second tumors. (A) Relative distribution of second tumors according to histologic subtype (number of patients). (B) Overall survival (OS) and (C) secondary tumor-free survival (STFS) (including desmoid tumor, malignant triton tumor, and thyroid carcinoma) according to the Kaplan–Meier method; time in years.