Primary alveolar rhabdomyosarcoma of the bone: two cases and review of the literature

A 17-year-old male with Crohn’s disease in his medical history, presented with fever, weight loss and lower back pain; experienced over a period of 1–2 weeks. He was found to have elevated inflammatory markers and serious hypercalcemia with impaired renal function. Bone scintigraphy, lumbar spine and pelvic MRI revealed disseminated, diffuse infiltration of the bone marrow which primarily raised the suspicion of lymphoma (Fig. 1a). Repeated bone marrow biopsies (iliac crests) confirmed ARMS (Grade III). A primary soft tissue tumor was never found. During chemotherapy according to CWS-2012 Protocol’s metastatic arm, dose reduction and modifications of cytostatic drugs, intensive care and hemodialysis were required several times due to serious arrhythmias and renal insufficiency caused by osteolysis-induced hypercalcemia. Despite the appropriate, aggressive chemotherapy, his disease showed progression that could be delayed temporarily by RANKL inhibitor denosumab monotherapy for a four month period. We lost him seven months after the initial symptoms.

Histological examination of the second bone marrow biopsy (iliac crests) revealed solid sheets of tumor cells infiltrating the entire bone marrow replacing and expelling the normal hematopoietic cells. The highly cellular infiltrate showed no special arrangement, although fine fibro-vascular stroma could focally be identified. The monomorphic, poorly differentiated tumor cells had round, vesicular nuclei with fine chromatin content and were localized at the periphery of the cells, in an eccentric position (Fig. 1b). The cytoplasm of most of the tumor cells possessed either an eosinophilic appearance or abundant intracytoplasmic vacuoles could be seen. While tumor cells did not show striation, the overall morphology suggested rhabdomyoblast-like differentiation (Fig. 1b). Although, by examining a HE specimen, a hematological malignancy could be ruled out, further immunohistochemical (IHC) tests were needed to characterize the phenotype of the tumor cells. The results of IHC showed diffuse vimentin positivity as well as the cells gave substantial cytoplasmic and nuclear labelling with both rhabdomyogen markers, desmin and Myf-4, respectively (Fig. 2a–c). The pan-cytokeratin and TFE-3 reactions were negative as well as INI-1 was retrained; by which alveolar soft part sarcoma or rhabdoid tumor as a differential diagnostic possibility could be ruled out. As the overall pattern of the tumor was not typical for neither embryonal nor alveolar RMS, we further performed a FOXO-1 break-apart FISH probe as the aforementioned gene is known to be involved and is consistently associated with the alveolar subtype of RMS. Indeed, we detected the translocation and break-apart signals involving FOXO-1 (Fig. 2d). Based on the histological and molecular findings as well as extended radiological examinations not proving a primary soft tissue tumor, the diagnosis of primary ARMS (solid variant) of the bone was made.

A 9-year-old male was admitted to the hospital presented with recurrent fever, lower back and right lower limb pain, experienced over the period of a month. He was found to have mild anemia and elevated inflammatory markers. Imaging studies revealed disseminated multiplex bone lesions involving the entire vertebral column, pelvic bones, ribs, skull, the distal part of the right femur and the proximal part of the right tibia (Fig. 3a). These findings and the lack of primary soft tissue manifestation raised the possibility of Ewing-sarcoma or malignant lymphoproliferative disease. Initially, the patient required intensive therapy for serious hypercalcemia and its complications due to osteolysis. The initial histological diagnosis was mesenchymal chondrosarcoma (Grade III), but the atypical clinical findings made histological revision necessary which, in turn, confirmed alveolar rhabdomyosarcoma with bone marrow involvement. A primary soft tissue tumor could not be identified. The therapeutic response was excellent in relation to the first-line chemotherapy given according to CWS-2009 Protocol’s metastatic arm as control MRI and PET/CT revealed complete remission. Seven months after finishing the first-line therapy, a relapse of the primary disease was confirmed, localized to the distal femur and proximal tibia on the right side. Second-line therapy was given according to CWS-2012 relapse protocol and based on the proven ALK-positivity of the tumor, ALK inhibitor crizotinib was permitted as an off-label drug for maintenance therapy for 10 months. In the fourth month of crizotinib treatment multiplex metastases were confirmed. Based on the proven increased mTOR activity of the previous biopsy specimen (iliac crests), mTOR inhibitor temsirolimus was given for 3 months. Due to disease progression, both targeted therapies were stopped and 30 months after the primary diagnosis, we lost the patient.

The biopsy sample that was taken from the tibia showed different morphological patterns and areas that made the overall histological picture misleading: among the bony trabeculae, a cellular tumor infiltrate could be identified and the cells were arranged in solid sheets replacing the normal hematopoiesis. Other foci of the tumor showed intramedullary cartilage islands around which spindle or ovoid shape tumor cells formed a cohesive structure; allowing mesenchymal chondrosarcoma diagnosis. Besides this, however, some areas of the tumor formed solid sheets of tumor islands that were divided by fine fibro-vascular stroma (Fig. 3b–d). The cytomorphology was identical with a so called “small round blue cell tumor”. Considering that neither the age nor the dissemination of the process (multiplex bony lesions) were typical for mesenchymal chondrosarcoma, we further evaluated the phenotype of the tumor cells with several IHC tests. The cells showed cytoplasmic positivity with vimentin as well as intensive and diffuse cytoplasmic desmin and nuclear Myf-4 reactions being observed (Fig. 3e–f). To further characterize the subtype of RMS without an identifiable soft tissue component, we performed a FOXO-1 break apart FISH DNA probe that evaluated the translocation involving FOXO-1. Concerning the clinical and pathological findings, the final diagnosis of primary alveolar rhabdomyosarcoma of the bone was made.