This article reports a case of giant chondrosarcoma secondary to MS. The patient had a 39-year history of MS and a 2-year history of chondrosarcoma in the left ankle. Due to the large size (40 cm in diameter) and the highly malignant of the left ankle chondrosarcoma, we have to perform an amputation surgery to inhibit the tumor development. The whole exon analysis revealed IDH1 R132C mutation in chondrosarcoma lesions but not in blood DNA, indicating IDH1 somatic mosaic mutation triggers tumorigenesis.
Enchondroma is benign intramedullary chondroma that could occur at any position. In our study, it develops on the bilateral scapula, the right fifth rib, both ilium, the left pubic branch, the left femur, the upper and lower ends of tibia and fibula, and the metacarpal and phalanx. The risk of enchondroma developing into chondrosarcoma approximately 25–30% in patients with MS, usually younger than primary chondrosarcoma patients. Malignant changes frequently occur after 40 years old and could occur in any part of the affected bone. Pelvic and upper limb bones are more prone to malignant changes. The patient in our study deteriorated to chondrosarcoma in the left ankle around 43 years old. Skull base chondrosarcoma accounted for 5–10% of all MS reports. Rarely, it has been reportd a 34-year-old man with tracheal chondrosarcoma and a 39-year-old woman with nasal cavity chondrosarcoma in MS patients[7, 8]. Hemangioma can be seen in many parts, including subcutaneous, mucosal surface, visceral organs, respiratory tract, gastrointestinal tract, aorta, etc. Multiple hemangiomas in both hands were shown in this case.
The IDH1 gene encodes intracytoplasmic nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase, which can catalyze isocitrate to produce α-ketoglutarate (α-KG). However, the mutant IDH1 catalyzes the reduction of α-KG to 2-hydroxyglutaric acid (2-HG), competitively inhibiting the activity of α-KG-dependent dioxygenase and demethylases, resulting in hypermethylation and down-regulation of tumor suppressor. In addition, the mutant IDH1 affects the generation of nicotinamide adenine dinucleotide phosphate (NADPH), which is of great significance in the synthesis of glutathione (GSH). GSH is an essential antioxidant against reactive oxygen species and free radicals, which may also be one of the mechanisms of mutant IDH1 promoting tumor occurrence and development.
Literatures showed that 77% of MS patients carry IDH1 or IDH2 mutations. Moreover, recurrent somatic mutations in IDH1 and IDH2 occurred in about 80% of patients with grade II-III glioma and secondary glioblastoma (GBM), and 10–20% of patients with acute myeloid leukemia (AML), with a low incidence in other cancers; the majority of these lesions involve arginine (R) residue mutations in IDH1 codon 132 (IDH1R132), residue 140 and 172 of IDH2 (IDH2 R140 and IDH2 R172)[14, 15]. It is suggested that somatic heterozygous mutations in IDH1 or IDH2 are also crucial in the development of some malignant tumors, and the increased risk of MS associated with other tumors may be due to common genetic background-mosaic mutations in IDH1 or IDH2.
A MS patient with jugular foramen chondrosarcoma and pituitary adenoma revealed the same IDH1R132C mutation in both tumors. Recently, another literature have shown common IDH1R132C mutations in sellar, brainstem, and skull base tumors in MS patients. Up to now, the IDH1 R132C mutation was only present in the ankle chondrosarcoma tissue but not in the blood of this patient, indicating there will be other tumors in the future. Thereby, it is necessary to carry out the long-term follow-up of the patient and actively recommend further examination and diagnosis.
The treatment of MS aims to alleviate the clinical symptoms of patients and detect malignant lesions early. The essential biochemical indicator of IDH1 and IDH2 mutations in peripheral blood is the abnormal increase of the 2-HG level, which may be a sensitive and specific predictor. Surgery is the primary treatment for bone disease and vascular disease, and amputation should be considered for patients with severely affected functions or malignant changes. The prognostic challenge of MS not only comes from the skeletal deformities and secondary limb length differences caused by itself, as well as the potential risk of malignant transformation into chondrosarcoma. Researchers conducted on 44 patients with endogenic chondroma, 7 cases were diagnosed with MS, and 37 cases were diagnosed with Ollier syndrome, no patient died of skeletal sarcoma, but four of five patients with non-skeletal malignancies died in the study. Therefore, in addition to routine clinical care for MS patients, clinicians should actively detect the development of endogenous chondromas in various parts and do well in tumor detection outside the bone tissue, such as the brain and abdomen.
Given the critical role of mutant IDH1, IDH2, and their products in tumorigenesis and progression, another strategy for MS treatment is targeted therapy for mutant enzymes and products. Small molecules AGI5198 and AGI6780 specifically inhibit the enzyme activity of mutant IDH1 and IDH2, which can inhibit the proliferation of glioma cells and leukemia cells, and successfully induced tumor cell differentiation, confirming the feasibility of mutant enzyme inhibitors for targeted treatment of such tumors[19, 20].