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