Congenital Rhabdomyosarcoma: a different clinical presentation in two cases

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas of childhood. In 5–10% of cases, it is diagnosed in children aged less than one year old, and may be congential in 0.4–2% [1‐3]. Various reports indicate that, when the diagnosis occurs in the neonatal period, the prognosis is worse than in older children [2‐7]. We retrospectively reviewed the medical records of 89 children affected by RMS treated between 2000 and 2016 at our Department and, among these, we found two congenital cases. We report the clinical, radiological and histological characteristics of these patients, as well as therapeutic approach and outcome, together with a literature review of congenital RMS.

Congenital RMS is a very rare neoplasia, as confirmed by data collected in our Institution over a 16-year period: only 2.24% of all RMS patients were diagnosed with the congenital form. We also performed a comprehensive PubMed search and 33 reports of congenital RMS (16 ERMS and 17 ARMS) published in the last 30 years were found and reviewed (Table 1). ERMS [9‐22] ARMS [23‐32]

The most frequent primary site for ARMS was the extremities, whereas for ERMS it was non-parameningeal head and neck. The two cases we reported represent the two different clinical forms in which the disease may manifest itself. While congenital ERMS is often localized and has the same behavior as that observed in older children, congenital ARMS is a highly malignant tumor, often occurring as a disseminated disease (see Case #1). Moreover, ARMS often evolves with the development of brain metastases despite an initial good response to chemotherapy [23, 24]. For case #1, in order to obtain CNS disease remission, we used intrathecal liposomial cytarabine arabinoside, and given the well-known dismal prognosis of the disease and the absence of other suitable alternatives, we decided to use consolidation high-dose chemotherapy. However, the results with high-dose chemotherapy reported in previous published trials, did not show significant benefits in metastatic RMS [33, 34]. Currently, there are no specific guidelines regarding treatment for neonates and infants with sarcoma, with few exceptions, such as that of infantile fibrosarcoma [35]. Infants with RMS are usually treated according to the same protocols used for older children: mainly alkylating agents, vincristine, actinomycin-D, with or without anthracyclines. However, they require tailored treatments given the physiologic immaturity of various organs. Ragab et al. [2] reported an unacceptable toxicity compared with results in older children (5% versus 1% of treatment-related deaths), when full chemotherapy doses were used in infants treated in the IRSG I and II trials. Chemotherapy dose reduction in infants resulted in less fatal toxicities without affecting the overall outcome [1, 3, 4]. Moreover, to avoid cardiac and renal damage, anthracyclines and ifosfamide are omitted in patients less than 3 and 1 months old respectively. With regards to the management of congenital ARMS, we hypothesized that children affected by this disease, could benefit from early use of chemotherapeutic agents with good blood-brain barrier passage as well as early intrathecal chemotherapy, as one of the main causes of treatment failure is CNS progression. Local control, determined by extended surgery and radiotherapy, also poses special challenges in very young children due to possible sequelae. In the literature (Table 1), only 3 out of 16 patients with congenital ERMS received radiotherapy associated with conservative surgery (one of them was a female with a vaginal primary who underwent brachytherapy) [23]. Given the small number of patients and the lack of follow-up data in about one third of cases (6\16), no conclusion can be drawn concerning the outcome. The Italian Cooperative Group reported a higher local recurrence rate in infants with RMS who did not receive appropriate local treatment [1]. In our ERMS patient, since radiotherapy was not recommended, we decided to prolong treatment with maintenance chemotherapy. In this context, our decision was taken in order to consolidate disease remission. The potential role of maintenance therapy in this setting is intriguing but impossible to define given the anecdotal nature of our case. Few data are available regarding tumor biology and fusion status, being reported in only 13 out of 33 cases (Table 1). Gene profiling, currently mandatory in RMS, is even more important in congenital forms, which present a challenging disease. In fact, it could allow more accurate prognostic predictions, as well as detection of new molecular targets. In this regard, molecular prognostic factors have already been identified for a subgroup of congenital RMS, namely the spindle-cell type [36]; the tumors carrying NCOA2 gene rearrangements indeed showed a more favorable clinical course.

In conclusion, although rarely, RMS can also arise in the neonatal period. In these patients, it is often difficult to establish a balance between the necessity to cure and the risk of long-term effects. A large effort to elaborate guidelines/protocols is desirable to homogenize treatment for this rare tumor occurring within this age group. From experience gathered in the 2 reported cases, early CNS prophylaxis should be considered for the alveolar subtype and prolonged maintenance chemotherapy rather than radiotherapy might be envisaged for the localized embryonal type. Moreover, deeper molecular biology studies are crucial for tumor characterization, treatment stratification and for the discovery of new therapeutic targets.