Sclerosing and spindle cell rhabdomyosarcoma is a rare histologic subtype, designated in the latest WHO classification as a stand-alone pathologic entity. Three genomic groups have been defined: an ...infantile subset of spindle cell rhabdomyosarcoma harboring VGLL2-related gene fusions, a MYOD1-mutant subset commonly associated with sclerosing morphology, and a subset lacking recurrent genetic abnormalities. In this study, we focus on MYOD1-mutant rhabdomyosarcoma to further define their clinicopathologic characteristics and behavior in a larger patient cohort. We investigated 30 cases of MYOD1-mutant rhabdomyosarcoma (12 previously reported and 18 newly diagnosed) with an age range of 2-94 years, including 15 children. All cases showed morphology within the spectrum of spindle cell/sclerosing rhabdomyosarcoma (8 cases showing pure sclerosing morphology, 8 cases showing pure spindle cell morphology and 14 cases showing a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas). All tumors harbored either homozygous or heterozygous MYOD1 (p.L122R) exon 1 mutations. In 10 (33%) cases, a co-existent PIK3CA mutation was identified. Hot-spot mutations in NRAS and HRAS were each identified in a single case, respectively. Follow-up was available on 22 (73%) patients with a median duration of 28 months. Local recurrence was seen in 12 (55%) and distant recurrence in 12 (55%) cases, despite multimodality chemoradiation therapy. At last follow-up, 15 (68%) patients died of the disease, one patient was alive with disease and five had no evidence of disease. The prognosis was equally poor in pediatric and adult patients. In conclusion, MYOD1 mutation defines an aggressive rhabdomyosarcoma subset, with poor outcome and response to therapy, irrespective of age. Given that this distinct molecular subtype is characterized by an aggressive biologic behavior compared to other genetic subtypes of spindle and sclerosing rhabdomyosarcoma, the MYOD1 genotype should be used as a molecular marker in both subclassification and prognostication of rhabdomyosarcoma.
Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase I protocol.
This study examined safety, ...pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10 mg/m(2) intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity.
Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n = 12), sarcoma (n = 17), or other refractory solid tumors (n = 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5 and 10 mg/kg dose levels. Pharmacokinetics revealed a half-life of 8 to 15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T-cell populations. Six subjects had confirmed stable disease for 4 to 10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma).
Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune-related toxicities had an increased overall survival compared with those who showed no evidence of breaking tolerance.
The inability to control the primary site, either as an isolated event or in concert with regional nodal or metastatic relapse, was the overwhelmingly greatest risk of treatment failure: nearly 60% ...of all events consisted of recurrence or progression of the primary tumour (about 30% of events in each group were due to isolated local relapse, local progression accounted for more than 16% of events, and an additional 13% of events were suboptimal response of the primary tumour at week 9); local recurrence, alone or in combination with regional nodal relapse or metastatic relapse accounted fully for 72% of all events; and an additional 5% of events occurred from recurrence of disease in nearby lymph nodes. Fewer than one-in-five events was an isolated metastatic recurrence (15 16% events in the IVA group vs 17 20% in the IVA plus doxorubicin group), the primary endpoint that adding doxorubicin would be most likely to affect favourably—but the proportion of patients at-risk for this type of event was too small to see any improvement in outcome even if the magnitude of benefit was large. The question of the EpSSG RMS 2005 trial was whether four cycles of doxorubicin given before definitive local control would improve outcomes in children with high-risk localised tumours. ...the factors associated with treatment failure—primarily local treatment failure, including primary radioresistance—are better understood, it is possible that future clinical trials in children with rhabdomyosarcoma focusing primarily or exclusively on chemotherapy questions are likely to also fail to improve outcome.
Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain ...largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS).
Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive. The 10 most common genetic alterations were associated with locoregional control (LC), disease-free survival (DFS), and overall survival (OS). Tumor mutational burden (TMB), defined as the total number of somatic nonsynonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes.
Median age at diagnosis was 16.4 years and median follow-up, 2.1 years. Patients with fusion-negative RMS had more genomic alterations and a higher TMB than those with fusion-positive RMS (mean number of genomic alterations, 6.0 vs. 2.9;
= 0.007 and mean TMB, 2.6 vs. 1.0;
= 0.01). Genetic alterations in
were associated with worse OS (
= 0.03). High TMB (defined as the top quartile ≥ 2.8) was associated with worse LC (
= 0.05), DFS (
= 0.04), and OS (
= 0.01), with significance retained on multivariable analysis after controlling for risk group, fusion status, and receipt of chemotherapy as per pediatric protocols.
High TMB was associated with worse clinical outcomes in patients with RMS. With further validation, TMB and other genomic classifiers may be combined with traditional clinicopathologic risk factors to guide risk stratification and ultimately treatment decisions.
Malignant peripheral nerve sheath tumors (MPNST) are aggressive neoplasms, arising either sporadically, in the setting of neurofibromatosis type I (NF1) or post radiation. Most MPNST occur in adults ...and their pathogenesis is driven by the loss of function mutations in the PRC2 complex, regardless of their clinical presentation. In contrast, pediatric MPNST are rare and their pathogenesis has not been elucidated. In this study, we investigate a large cohort of 64 MPNSTs arising in children and young adults (younger than the age of 20 years) to better define their clinicopathologic and molecular features. Sixteen (25%) cases were investigated by MSK‐IMPACT, a targeted NGS panel of 505 cancer genes. Most patients (80%) were aged 11–20 years. A history of NF1 was established in half of the cases. Mean tumor size was 8.5 cm. The most common locations included the extremities (34%) and abdomen/pelvis (27%). Histologically, 89% of high‐grade MPNST showed conventional features, while the remaining three cases showed a predominant epithelioid phenotype. Heterologous differentiation occurred in 25% of high grade cases, with half showing rhabdomyoblastic differentiation. Tumors arose in a background of a plexiform neurofibroma (16%), neurofibroma (13%), and schwannoma in two cases (3%). Immunohistochemically, H3K27me3 expression was lost in 82% of conventional high‐grade MPNST analyzed, while loss of SMARCB1 expression was seen in one epithelioid MPNST. Genomically, all cases showed more than one genetic abnormality, with 53% showing mutations in EED / SUZ12 genes, and 47% of cases harboring alterations in NF1 and CDKN2A/CDKN2B genes. At the last follow‐up, 30% patients died of disease, 28% were alive with disease and 42% had no evidence of disease. NF1 status did not correlate with overall survival. In conclusion, half of pediatric and young adult MPNST were NF1‐related and showed loss of function alterations in PRC2 complex, NF1, and CDKN2A, similar to the adult counterpart. Thus, H3K27me3 loss of expression may be used in the diagnosis of high grade MPNSTs in children. Moreover, a small subset of pediatric MPNST have an epithelioid morphology with different pathogenesis.
Background
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of adolescence and childhood. Although most patients with localized RMS are cured, outcome of those with metastatic disease ...remains unsatisfactory. RMS with bone marrow (BM) metastasis accounts for approximately 6% of all cases with RMS and has a 3‐year event‐free survival of 14%. Our study aims to describe our institution's experience of patients with metastatic RMS with BM involvement.
Methods
This was a single‐institution retrospective study from Memorial Sloan Kettering Kids, a tertiary pediatric oncology center. Patients with RMS who were diagnosed with BM metastasis between 1998 and 2018 were identified from pathology reports.
Results
For patients with RMS and BM positivity at diagnosis (N = 27), the median survival was 1.5 years. The 1‐, 2‐, and 3‐year overall survival (OS) were 81%, 32%, and 20%, respectively. There is one long‐term (defined as >4 year) survivor who is still alive 14.9 years after diagnosis despite two metastatic recurrences. An Oberlin status of 4 that included BM metastasis portended a 3‐year OS of 0%.
Conclusions
Although most patients will respond to initial therapy, BM metastasis at the time of diagnosis lends a near‐fatal diagnosis in pediatric patients with RMS. Novel therapies are desperately needed to consolidate their initial remission.
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