Discussion
PMMTI is a unique and locally aggressive soft-tissue sarcoma seen only
in the pediatric population, with 30 cases published in PubMed to date.
It has a mean age of onset of 6.5 months (range 0 to 36 mo) and there
are no reported cases of metastatic disease at presentation. Since
PMMTI’s discovery, there has been a growing body of genetic and
immunohistochemical data to aid in the diagnosis. Key diagnostic
features include nuclear positivity for BCOR and BCL6, BCOR internal
tandem duplication, and ETV6-NTRK3 rearrangement
negativity.2,3 While the clinical and pathologic
characteristics of this disease have become better understood in recent
years, optimal frontline therapy remains less clear.
Like patients with low-grade non-rhabdomyosarcoma soft tissue sarcomas
(NRSTS), the standard of care for PMMTI is surgery alone when a GTR with
negative margins can be acheived.2,4 If this cannot be
achieved, systemic therapy should be considered given the high rate of
recurrence combined with the morbidity and psychosocial impact of
multiple non-curative surgeries over time. Of the 19 cases of PMMTI with
published treatment and outcome data, all but 2 underwent surgical
resection upfront and 60% had disease progression or recurrence, with a
median time to recurrence of less than 6 months. Among those that did
undergo surgery as initial treatment, half went on to require additional
tumor resections, the majority of which were also not
curative.2
While a PMMTI is currently described as a chemo-resistant malignancy, to
date, a total of only 9 cases, including this one, have been described
in which systemic chemotherapy was attempted.1-3,5-8.Of those 9 cases, two received unspecified chemotherapy regimens; one of
which was alive with disease at time of publication, the other of which
was in remission at 4-year follow up.1 Of the 7
patients with both chemotherapy treatment and outcome data (Table 1), 6
received vincristine and actinomycin (VA) as their initial systemic
regimen, 4 of which concurrently received cyclophosphamide (VAC) and 1
of which concurrently received ifosphamide (VAI). The seventh patient
received a similar regimen of vincristine, doxorubicin and
cyclophosphamide (VDC).2-3,5-8 Progression of disease
or short-duration recurrence was seen in 100% of cases, making a strong
case against the use of a VA/VAC backbone in the treatment of PMMTI.
Six of the 7 patients went on to receive subsequent chemotherapy, with a
wide variation in the regimens used. Two-thirds of these individuals
received one additional chemotherapy regimen, with the remaining 2
patients undergoing 3 or more chemotherapy
regimens.2,5-8 Partial or complete response was seen
with three treatment regimens including ifosphamide/doxorubicin (ID; N=
4/4), VDC with ifosphamide and etoposide (N = 1/1) and vincristine,
cyclophosphamide, and topotecan (VCT; N = 1/1). With the exception of
the individual who received VCT, sustained treatment response was only
seen in patients who received ID-containing
regimens.6-8 Of note, the individual who received VCT,
was already demonstrating a good response to ID, however their treatment
course had to be changed due to receiving a maximum cumulative dose of
anthracyclines.7 Those patients who received
ifosphamide or doxorubicin alone or paired with alternative agents, did
not show a response.2,5,7 While these numbers are
small, these outcomes encourage the utilization of ifosphamide and
doxorubicin together as first line chemotherapy for unresectable disease
over other previously attempted anti-neoplastic agents. Given the risk
of anthracycline-induced cardiomyopathy with this regimen, the
utilization of concurrent dexrazoxane for cardio protection is
warranted. This combination is highly active and widely utilized in the
treatment of soft tissue sarcomas and is the standard chemotherapy
backbone in conjunction with surgical resection and adjunctive
radiotherapy for pediatric patients with non-targetable, advanced NRSTS
in the United States.9
The question of whether to provide consolidation therapy with localized
radiation for patients with unresectable PMMTI is a difficult one,
particularly given the very young age at disease onset. Two patients,
including our own, underwent consolidation therapy with proton
irradiation and both were in remission greater than 2 years off therapy
with limited long-term toxicities to date.8 Although
both PBT and conventional photon-based radiotherapy are similarly
efficacious, the increased precision of proton irradiation significantly
reduces the risk of adverse events including secondary
cancers.10 While not appropriate in many situations,
it should be considered a potential component of multidisciplinary PMMTI
care in the setting of unresectable disease or positive surgical
margins.
In summary, PMMTI is a rare and aggressive disease associated with a
high rate of recurrence after surgery alone. For those unable to achieve
complete surgical resection at a microscopic level, event-free survival
is dismal, and morbidity is high. Here we demonstrated the efficacy and
tolerance of multidisciplinary treatment with ID chemotherapy followed
by delayed GTR and adjunctive PBT in an infant with unresectable PMMTI.
Taken in conjunction with the previously reported cases for which
systemic therapy was attempted, this combination should be considered
for patients unable to negative surgical margins upfront. Further study
in a larger cohort of patients in needed. Additionally, while our
patient did not demonstrate targetable findings on genomic sequencing,
very little data has been reported on this, and targeted solid tumor
genomic sequencing, may prove beneficial for this rare disease.
Conflict of Interest Statement: No conflicts of interest to
declare
Acknowledgements: None