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years this term has been replaced by primary osseous composite sarcoma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.