Discussion:
The term malignant mesenchymoma was first suggested by Stout in 1948 to define various sarcomas with the common characteristic of being formed by several cell types, excluding fibrosarcoma due to the frequent occurrence of a fibrosarcomatous component associated with most sarcomas (6). Enzinger and Weiss later established the need to clearly differentiate these cell types from a microscopic, immunohistochemical and ultrastructural point of view, also excluding single histologic subtypes as dedifferentiated sarcoma and the combination of osteosarcoma with condrosarcoma (7).
In 1966, Schajowicz described the first case of primary malignant bone mesenchymoma (8), with only about 25 cases reported to date and rarely, cases associated with previous radiation therapy (1-5, 9-18). In recent years this term has been replaced by primary osseous composite sarcoma although this entity is not recognized in the current WHO 2013 classification (5).
Although most malignant soft tissue mesenchymomas are diagnosed at advanced age, primary composite osteosarcoma has a peak incidence in adolescents and young adults, being more frequent in males. The metaphysis of long bones and pelvis are described as the most frequent locations (1-5).
Histologically, these tumors may be derived from a primordial mesenchymal cell with the ability to differentiate into various cell types or they may consist of different cell clones. Previous series have described the combination of areas of liposarcoma with osteosarcoma as the most common pattern (1-5). The present case was diagnosed as an osteosarcoma with rhabdomyosarcoma foci when the entire tumor piece was evaluated. Retrospectively we could demonstrate the focal presence of rhabdoid habit cells with positivity for desmin and myogenin in the diagnostic biopsy that was initially misclassified as conventional osteosarcoma. This histologic variant has been described as the second most common subtype of composite sarcoma, with nine previous cases reported to date. In most of them the diagnosis was not made with the initial biopsy but in the evaluation of the whole tumor specimen, reflecting the diagnostic complexity of these rare forms (1-5, 12-15). The differential diagnosis should incliude dedifferentiated chondrosarcoma, wich is more frequent in older patients, and primary bone rhabdomyosarcoma, another rare entity in children (1, 3, 4, 13).
Our patient presented with a TSC2 mutation wich is one of the most frequently mutated mTOR pathway-related genes. TheTSC2 stop-gain mutation likely interferes with the gene function in suppressing the downstream mTOR activity and may lead to more aggressive tumour behaviour (19). It further provides a potential therapeutic role for mTOR inhibitors demonstrated in other solid tumor types that could not be explored in our patient due to the rapid progression (20). Furthermore, SETD2 missense mutation may be an oncogenic driver mutation in this case (21). Its role is known in multiple cancers, including sarcoma, but has not previously been implicated in primary composite osteosarcoma.
From a clinical and radiological point of view, presentation of primary composite bone sarcoma is similar to conventional osteosarcoma, with osteolytic appearance, cortical erosion and periosteal reaction. Nevertheless, the percentage of patients with metastatic disease at diagnosis reaches 50-60% with pulmonary involvement being the most frequent location (1-5). Our patient presented loco-regional lymph node extension at diagnosis, a rare finding in conventional osteosarcoma related to poor prognosis and not previously described in composite osteosarcoma with rhabdomyosarcoma foci (22-25).
Currently there is not a standar approach on the optimal therapy for primary composite osteosarcoma. It is a highly aggressive pathology with a mortality rate close to 60%, considering that most described cases are treated with chemotherapy schemes for bone or soft tissue sarcoma (1-5).
In conclusion, primary composite osteosarcoma is an exceptional pathology, highly aggressive and intrinsically resistant to chemotherapy, associated with poor prognosis. Tumor sequencing studies may allow the development of targeted treatment strategies in the future. Collaborative efforts are need to gather sufficient biological and clinical information of this condition in children to delineate tailored strategies for them.
Conflicts of interest: none to declare.