In contrast to other soft tissue sarcomas which metastasize primarily to the lung, MRCL is associated with an unusual pattern of metastasis. Previous reports have shown metastases of MRCL to extrapulmonary sites, including the retroperitoneum, subcutaneous soft tissue and bone [
2,
3,
5,
6]. Antonescu and Blair reported that MRCL in particular tends to spread to other soft tissue sites including retroperitoneum, thorax, and extremity before metastasizing to the lung [
4,
5,
7]. Also, in the previous large series of MRCL, extrapulmonary metastatic rate in MRCL was 17–30% and common sites of extrapulmonary metastases were bone, soft tissue of extremity, retroperitoneum, abdomen, and chest wall [
2,
6,
8,
9]. Skeletal metastasis has recently been reported as the most common site of metastasis in MRCL [
2]. Schwab et al. identified 8 patients with skeletal metastases on radiographic findings in a population of 184 patients with MRCL, an incidence of 4.3% [
2]. Schwab et al. reported that more than half (56%) of the total metastatic sites represent skeletal metastases, 70% in the absence of pulmonary spread, and a high incidence of metastasis to the spine [
2].
MRCL contains the specific
t (12; 16) chromosomal translocation, which results in rearrangement of the
TLS and
CHOP genes that is clone specific at DNA level [
10–
12]. Three common forms of the
TLS-CHOP fusion have been described, differing by the presence or absence of
TLS exons 6–8 in the fusion product. Type
I includes
TLS exon 6 and 7 in the fusion, type
II consists of
TLS exon 1–5 fused to
CHOP exon 2, and type
III fuses
TLS exons 1–8 to
CHOP exon 2 [
5]. A specific
TLS-CHOP fusion gene resulting from the
t (12; 16) is present in at least 95% of MRCL [
5]. 85% of the patients who developed bone metastases showed a type
II TLS-CHOP fusion transcript [
2]. Ogose et al. reported that the reason for the high incidence of extrapulmonary metastases in MRCL is unclear, but an abundance of fat cells in metastatic sites, such as subcutaneous tissue, retroperitoneum, bone marrow, and epidural space, may contribute to the high incidence of these unusual metastases [
13]. In our study, extrapulmonary metastases rate in MRCL was 14%. Common locations for extrapulmonary metastases were bone and soft tissue of extremities, similar to the previous studies ().
| Table 3Comparison between previous and current study. |
MRCL patients have been reported to present more commonly with multifocal disease, either synchronous or metachronous, compared to other soft tissue sarcomas [
7]. Multifocal presentation, defined as the presence of tumor at two or more anatomically separate sites, before the manifestation of disease in sites where sarcomas usually metastasize (e.g., lungs) occurs in about 1% of extremity soft tissue sarcomas [
7].
An interesting question is whether these extrapulmonary tumors in fact represent metastatic disease versus sites of synchronous or metachronous primary disease [
8]. Tedeschi proposed the concept of a “pluricentric anlage” or “incidental stimulation of undifferentiated mesenchymal cells” due to altered lipid metabolism [
10] as an explanation to why patients he observed had multiple lipomatous tumors in fat-bearing soft tissue locations. An analogy has been drawn between this phenomenon and the clinical presentation of multiple subcutaneous nodules in patients with neurofibromatosis [
11]. Smith et al. analyzed the genomic rearrangements of
TLS,
CHOP, or
EWS in six patients and confirmed the monoclonal origin of multifocal MRCL [
4]. They concluded that this unusual clinical phenomenon most likely represents a pattern of presumably hematogenous metastasis to other soft tissue sites, by tumor cells seemingly incompetent to seed the lungs [
4]. Definitive differentiation between metastatic disease and synchronous or metachronous primary disease is elusive and likely will become possible only by molecular biologic analysis of tumor clonal heterogeneity [
12].
Prognostic factors of MRCL have been described in several previous studies. Age (>45 years) [
6], large tumor size (≥10
cm) [
14,
15], percentage of round cell differentiation (≥5%) [
4,
15], and presence of tumor necrosis [
6] were associated with a poor prognosis. Antonescu et al. also sought to evaluate the potential impact of
TLS-CHOP fusion transcript structure on clinical outcome in 82 cases of localized MRCL [
5]. They concluded that in contrast to some other translocation associated sarcomas, such as Ewing sarcoma, synovial sarcoma, and rhabdomyosarcoma, the molecular variability of
TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in localized MRCL [
5]. However, high histological grade (≥5% round cell component), presence of necrosis, and P53 overexpression were independent predictors of unfavorable outcome in localized MRCL [
5]. To our knowledge, parameters that influence the pattern of metastases have not been reported to date. Our results suggest that tumor size, histological grade, and implementation of chemotherapy have significant influence on metastatic patterns. Large tumor size and low histological grade were significantly associated with extrapulmonary metastasis. Also, presence of chemotherapy was significantly associated with metastasis, but there is a bias here in that higher rate of chemotherapy was performed on patients with high-grade tumors: 15 of 20 patients (75%) compared to patients with low-grade tumors: 14 of 38 patients (37%). Chemotherapy was not effective in reducing disease-free survival rate.
In conclusion, extrapulmonary metastasis was observed in 14% of the cases with MRCL. The bone was the most common location for extrapulmonary metastasis. Large tumor size and low histological grade were significantly associated with extrapulmonary metastasis. These findings might lead to new diagnostic and treatment options for MRCL.
