DISCUSSION
This report
describes a series of patients with no evidence of a primary lesion, and
therefore considered as having RMS with unknown primary site. This is a
rare condition and represents a diagnostic and therapeutic challenge.
The diagnostic difficulties clearly emerge from our study: despite the
usual diagnostic workup (including FDG-PET/CT in 8 cases), clinicians
were unable to identify a clear primary lesion in these 10 patients
registered in the EpSSG MTS2008 protocol. We know that small tumor
lesions localized in the extremities may give widespread dissemination
(4), unfortunately 3 patients in our series were not fully investigated
in this sense and we cannot exclude they had an unrecognized extremity
primary tumor.
Careful clinical examination and whole-body MRI or FDG-PET-CT/MRI
scanning is suggested for all patients with disseminated RMS if the
primary site is not immediately apparent. Another possible limitation of
our study concerns the inclusion of a child with disseminated
leptomeningeal disease and only a cytological diagnosis: we decided to
include this patient in our series because he was considered and treated
like a case of metastatic RMS.
The frequent involvement of the bone marrow (it was the only organ
involved in 2 cases) may support the hypothesis that it could be the
primary tumor site, rather than a site of dissemination. We cannot prove
a primary bone or bone marrow origin, but recent studies found that RMS
can originate from an aberrant development of non-myogenic cells (5).
This would justify the initiation of RMS at sites like the bone marrow
and bone.
The treatment of patients with disseminated disease but unknown primary
tumor presents a series of obstacles. Local control measures are
fundamental in the treatment of RMS, but the absence of a primary lesion
often precludes the use of local surgery or radiotherapy, and it is
difficult to administer radiotherapy as the disease is frequently widely
disseminated and when bone marrow is involved. This is an important
aspect as our recent experience suggests that radiation is associated
with improved survival in metastatic RMS (6). Chemotherapy was the only
treatment modality used in most of our patients, and was unfortunately
not enough: only 3 patients in our series are still alive. The
predictably poor prognosis may explain why clinicians chose to perform
an allogeneic bone marrow transplant in 3 patients, although there is no
clear evidence to indicate that it is effective in RMS. Previous trials
have shown high dose chemotherapy followed by autologous transplant does
not add to survival in metastatic patients (7-8). Since only one of
these patients is still alive, we can draw no firm conclusions regarding
potential efficacy of this procedure, which carries a small but
significant risk of mortality.
The poor prognosis of this group of patients is confirmed by a review of
the medical literature. We found 16 publications (from 1976 to the
present) describing 22 cases of children with RMS and an unknown primary
tumor site (9-24). The characteristics of these patients are summarized
in Table 2. As in our series, this condition seemed to be more typical
of the fusion-positive alveolar subtype of RMS, and occurred mainly in
adolescents. The most often involved sites were the bone marrow, bone
and distant lymph nodes. A lymphoproliferative disease was often
suspected, and the diagnosis was made on analyzing the bone marrow. All
patients were treated with chemotherapy, while radiotherapy and surgery
were performed in a few cases. Only 3 patients out of 17 with outcome
data were reportedly alive with no sign of disease, but the follow-up
was short.
In conclusion, metastatic RMS with no clear evidence of a primary site
is a rare condition, more likely to affect adolescents and to involve
the fusion-positive alveolar histotype. Current treatments are rarely
able to cure these patients, who should be included in investigational
trials along with other very high-risk, metastatic patient groups.