Case report: rapid and durable response to PDGFR targeted therapy in a child with refractory multiple infantile myofibromatosis and a heterozygous germline mutation of the PDGFRB gene

Abstract

BackgroundInfantile myofibromatosis belongs to a family of soft tissue tumors. The majority of these tumors have benign behavior but resistant and malignant courses are known, namely in tumors with visceral involvement. The standard of care is surgical resection. Observations suggest that low dose chemotherapy is beneficial. The treatment of resistant or relapsed patients with multifocal disease remains challenging. Patients that harbor an actionable mutation in the kinase domain are potential subjects for targeted tyrosine kinase inhibitor therapy.Case presentationAn infant boy with inborn generalized infantile myofibromatosis that included bone, intracranial, soft tissue and visceral involvement was treated according to recent recommendations with low dose chemotherapy. The presence of a partial but temporary response led to a second line of treatment with six cycles of chemotherapy, which achieved a partial response again but was followed by severe toxicity. The generalized progression of the disease was observed later. Genetic analyses were performed and revealed a PDGFRB gene c.1681C>A missense heterozygous germline mutation, high PDGFRβ phosphokinase activity within the tumor and the heterozygous germline Slavic Nijmegen breakage syndrome 657del5 mutation in the NBN gene. Targeted treatment with sunitinib, the PDGFRβ inhibitor, plus low dose vinblastine led to an unexpected and durable response without toxicities or limitations to daily life activities. The presence of the Slavic NBN gene mutation limited standard chemotherapy dosing due to severe toxicities. Sister of the patient suffred from skull base tumor with same genotype and histology. The same targeted therapy led to similar quick and durable response.ConclusionProgressive and resistant incurable infantile myofibromatosis can be successfully treated with the new approach described herein. Detailed insights into the biology of the patient’s tumor and genome are necessary to understand the mechanisms of activity of less toxic and effective drugs except for up to date population-based chemotherapy regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3115-x) contains supplementary material, which is available to authorized users.

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas

“…other clinical disparities, such as the single occurrence of odontogemic myxoma, in contrast to multicentric lesions reported in some patients with myofibroma. 2,19,28,31 Our data also do not support the hypothesis that the myofibroma of gnathic bones and odontogenic myxoma represent different spectra of the same entity. Although the majority of myofibromas present specific histopathologic features that are usually sufficient for the final diagnosis, the molecular investigation of PDGFRB mutations may be helpful in intra-osseous myofibroma cases with myxoid areas and in those in which the biphasic component is not evident.…”

“…Our results show that odontogenic myxoma does not share the same recurrent driver mutation of soft tissue and intra‐osseous myofibroma. Their distinct molecular pathogenesis is in line with other clinical disparities, such as the single occurrence of odontogemic myxoma, in contrast to multicentric lesions reported in some patients with myofibroma . Our data also do not support the hypothesis that the myofibroma of gnathic bones and odontogenic myxoma represent different spectra of the same entity.…”

“…These genetic alterations were detected not only in the soft tissue tumors, but also in the intra-osseous lesions (Table 1). 16,19,[28][29][30] Herein, we did not detect such mutations in any of the 15 odontogenic myxoma samples evaluated, suggesting that these PDGFRB mutations do not play a role in its tumorigenesis.…”

“…Agaimy et al reported PDGFRB somatic mutations as molecular driver events in the majority of sporadic infantile and adult solitary myofibromas (75% and 69%, respectively). These genetic alterations were detected not only in the soft tissue tumors, but also in the intra‐osseous lesions (Table ) . Herein, we did not detect such mutations in any of the 15 odontogenic myxoma samples evaluated, suggesting that these PDGFRB mutations do not play a role in its tumorigenesis.…”

“…The age of the patients in our cohort varies from 21 to 81 years old. Most of the studies that analyzed PDGFRB mutations in myofibroblastic single or multiple lesions included samples from children or newborn patients . However, such mutations have also been reported in sporadic myofibroma cases from adult individuals …”