Approximately 5–10% of patients with rhabdomyosarcomas (RMS) are diagnosed during the first year of life, and their clinical characteristics have been well documented. However, because RMS rarely occurs during the neonatal period, little is known about neonatal RMS.
Four patients with neonatal RMS were treated at St. Jude Children's Research Hospital between 1962 and 1999. The authors report the results of a review of these patients and of cases described in the literature. Clinical, radiologic, and pathologic features of these patients and their outcomes were evaluated.
One patient with embryonal RMS was treated successfully with a combination of systemic chemotherapy and local control measures. The other three patients had alveolar RMS. Two of them had multiple skin and subcutaneous metastatic nodules at the time of diagnosis and developed brain metastases early in their course. In one of these patients, the PAX3-FKHR fusion transcript was detected. Three other similar cases of neonatal alveolar RMS with metastases to the skin and brain have been reported in the literature.
Approximately 133 children and adolescents per 1 million are found to have cancer each year,1, 2 and approximately 10% of them are diagnosed within the first year of life.1 Cancer will develop in 183 to 218 infants per 1 million live births.1–3 Some tumors are unique to this age group, but most of the major types of childhood neoplasms have been described in infants age < 6 months. Neuroblastoma, teratoma, acute leukemias, soft tissue sarcomas, brain tumors, and renal tumors are the most common malignancies to involve infants and neonates.3, 4 The clinical behavior of an infantile neoplasm may differ from a histologically similar tumor in an older child. Congenital teratomas,4 neuroblastomas,5, 6 and soft tissue neoplasms, such as infantile hemangiopericytoma and infantile fibrosarcoma,7, 8 tend to be less aggressive in neonates and infants than in older children, whereas patients with acute leukemias9 and brain tumors10 have a worse prognosis.
The incidence of rhabdomyosarcoma (RMS) is higher during the first year of life (6.4 cases per 1 million neonates and infants each year compared with an overall incidence of 4.5 cases per 1 million children and adolescents each year).1, 2 Several authors have analyzed the clinical characteristics of infantile RMS.11–13 Ragab and colleagues,11 in a review of the Intergroup Rhabdomyosarcoma Study Group experience with infantile RMS, found that genitourinary sites and botryoid histology were more common among infants than among children and adolescents. However, these characteristics differed from those reported by Salloum and coworkers,12 who found that site distribution was equal in both age groups and that alveolar and poorly differentiated histologies were more common among infants. In both studies, however, clinical group distribution and overall outcome of infants were similar to those of children and adolescents.
Approximately 20–30% of all infantile soft tissue sarcomas are diagnosed during the first month of life and, thus, are considered neonatal.11–13 It is interesting to note that the histology of soft tissue sarcoma during the first year of life differs from that in older children, in that two-thirds of infants with soft tissue sarcoma have non-RMS soft tissue neoplasms, especially fibrosarcoma and hemangiopericytoma.4, 13–15 A very small proportion of neonatal soft tissue tumors are RMS. Neonatal RMS is very rare, and little is known about it. In an attempt to further describe the clinical characteristics of neonatal RMS, we reviewed all patients with neonatal RMS who were treated at our institution and reported in the literature. We found that neonatal alveolar RMS was associated with the presence of multiple skin metastases and the development of early brain metastases.
MATERIALS AND METHODS
A review of the records of all children with RMS who were treated between March 1962 and November 1999 at St. Jude Children's Research Hospital found that, of a total of 402 patients with RMS, 4 patients were neonates. The clinical characteristics, imaging studies, and histologic sections of the patients' tumors were reviewed. In all patients, histologic sections were prepared from formalin fixed, paraffin embedded tissue and stained with hematoxylin and eosin.
A newborn boy age 3 weeks was referred to St. Jude Children's Research Hospital in February 1978 with a rapidly enlarging prescapular mass. His mother's full-term pregnancy had been uncomplicated. Physical examination detected a palpable 6.0 cm × 6.5 cm mass overlying the right scapula. Computed tomography (CT) images of the chest showed that the soft tissue mass did not involve bone and did not extend into the thoracic cavity. Pathologic examination showed a small, round cell neoplasm with an alveolar pattern of growth consistent with alveolar RMS. The results of chest CT scan, bone scan, liver scan, and bone marrow aspiration were negative for tumor. The patient was enrolled on an institutional protocol, which included weekly chemotherapy with combinations of vincristine (1.5 mg/m2), dactinomycin (0.4 mg/m2), cyclophosphamide (300 mg/m2), and doxorubicin (25 mg/m2) for a total of 79 weeks. Repeated studies after 5 weeks of treatment showed an almost complete regression of the mass. A re-excision of the region showed a residual fibrous mass beneath the rhomboid muscle. Pathologic examination showed fibrosis, atrophic degeneration of skeletal muscle bundles, and no residual tumor. The patient received no radiation therapy and completed the scheduled chemotherapy in September 1979. The patient is currently alive without disease.
A female infant age 7 weeks was referred to St. Jude Children's Research Hospital in December 1982 with a 4-week history of reddish tissue intermittently protruding from the vagina. Her mother's pregnancy had been complicated by toxemia, and a cesarean section was necessary. Vaginoscopy and polypectomy were performed. Pathologic examination showed embryonal (botryoid) RMS. A staging laparotomy indicated that no lymph nodes were involved. Results of CT scans of the chest, abdomen, and pelvis and results of bone scan and bone marrow aspiration showed no metastatic disease. The patient was enrolled on an institutional protocol. She underwent induction therapy with three consecutive courses of doxorubicin (45 mg/m2 for 1 day) and dacarbazine (250 mg/m2 per day for 5 days) followed by three courses of vincristine (1.5 mg/m2 for 1 day), dactinomycin (1.5 mg/m2 for 1 day), and cyclophosphamide (200 mg/m2 orally for 5 days). Results of vaginal biopsy after induction therapy showed residual tumor. The patient underwent vaginectomy and hysterectomy and received brachytherapy with Cesium-137 implants (50 grays). Maintenance therapy was performed with 13 additional courses of vincristine, dactinomycin, and cyclophosphamide and 3 more courses of doxorubicin and dacarbazine. The patient completed therapy in July 1984 and has remained disease free since then.
A female neonate age 2 weeks was seen at her local hospital in April 1985 with a rapidly enlarging mass in the right thigh and multiple skin and subcutaneous nodules. Pathologic examination of the right thigh mass and a skin lesion showed alveolar RMS, and the patient was subsequently referred to St. Jude Children's Research Hospital for further therapy. She had been born at 36 weeks of gestational age, but her mother's pregnancy was uncomplicated otherwise. Physical examination detected a large mass in the right thigh and enlargement of the inguinal lymph nodes. Examination of the skin detected multiple, small skin nodules and palpable subcutaneous nodules. CT images showed a large mass within the right thigh and a continuum of muscle tumefaction up to the iliopsoas muscle. The results of CT scan of the chest, bone scan, and bone marrow aspiration were negative for tumor. With the diagnosis of metastatic RMS, the patient started treatment on a Phase II institutional study of melphalan (45 mg/m2). After two courses of treatment, complete resolution of the subcutaneous and cutaneous nodules could be documented, with less than 50% reduction of the primary tumor. However, 6 weeks after the initiation of therapy, the patient became irritable and was found to have a bulging fontanelle. Results of lumbar puncture revealed clumps of tumor cells in the cerebrospinal fluid. CT images of the brain (without contrast) showed ventricular dilatation but no definitive lesions. The patient received one dose of intraventricular thiotepa (10 mg/m2) and was then placed on an institutional protocol (described for Patient 2, above). However, her neurologic status deteriorated rapidly, and she died after 2 days of therapy. No postmortem examination was performed.
A female neonate age 4 weeks was referred to St. Jude Children's Research Hospital in October 1998 for evaluation of a mass in her right foot. She was born at 38 weeks of gestational age, but her mother's pregnancy was uncomplicated otherwise. There was no history of medication during the pregnancy. Physical examination showed a large mass in the right foot and palpable lymph nodes in the right popliteal and inguinal regions. Examination of the skin revealed multiple skin nodules (Fig. 1), and gentle palpation detected multiple subcutaneous nodules that were unrelated to the skin lesions (Fig. 2). Magnetic resonance images of the right foot showed a large soft tissue mass with erosion of the metatarsal bones. Results of bone scan, CT scan of the chest and brain, and bilateral bone marrow aspiration and biopsy were negative for disease. Pathologic examination of the mass in the foot and of one of the skin lesions showed alveolar RMS. Polymerase chain reaction studies detected the PAX3-FKHR fusion transcript. The patient was enrolled on the Intergroup Rhabdomyosarcoma Study (IRS)-V pilot study for children with Stage IV RMS. However, the disease progressed during the cyclophosphamide-topotecan window therapy, and the patient subsequently was treated weekly with vincristine (1.5 mg/m2) and every 3 weeks with vincristine (1.5 mg/m2), actinomycin D (1.5 mg/m2), and cyclophosphamide (2.2 g/m2). Partial response of the primary tumor and of the lymph node disease was achieved after 6 weeks of treatment. Because of persistent skin lesions, surgical resection of the primary tumor was postponed. Multiple skin biopsies after 6 months of treatment showed persistent disease. In August 1999, after 9 months of treatment, progression of the primary lesion and enlargement of the skin lesions were documented (Fig. 3). Results of bone scan and CT scan of the chest showed no evidence of disease. Results of bilateral bone marrow aspiration and biopsy (including molecular studies) were negative for metastatic RMS. CT images of the brain showed multiple brain metastases. The patient died 13 months after diagnosis. No postmortem examination was performed.
Neonatal RMS is very rare. The four patients reported here comprise only 1% of the total patients with RMS who have been treated at our institution over a 37-year period, a proportion in agreement with that reported in the literature.11, 12, 16 The most interesting finding of our review is that two of our four patients had tumors of alveolar histology with multiple skin and subcutaneous nodules, and both patients eventually died of brain metastases. Three other similar cases have been reported previously. All of those patients had alveolar RMS with multiple skin or subcutaneous metastases, and brain metastases developed early in the course of the disease (Table 1). 17, 18
Table 1. Clinical Features of Neonatal Alveolar Rhabdomyosarcoma with Skin Metastases
Neonatal RMS has not been described fully in the literature: Only a few reports have analyzed its features. Lobe et al.16 reviewed 14 cases of neonatal RMS (0.4% of the total cases of RMS) occurring in patients enrolled in IRS studies I–IV. Two-thirds of the patients were embryonal; the rest were undifferentiated. No cases of alveolar histology were reported. In a review of the Children's Cancer Group experience with neonatal soft tissue sarcomas, Dillon and colleagues15 reported 11 cases of neonatal RMS. Seven tumors were of embryonal histology, three were undifferentiated, and only one tumor was of alveolar histology. In these studies, neither the stage nor the outcome seemed to differ from those of cases of RMS in children or adolescents.
Only one of our patients with alveolar RMS was tested for gene fusions, and the PAX3-FKHR fusion transcript was detected. In a recent report, Kelly and colleagues19 described the clinical phenotypes associated with both the PAX3-FKHR and the PAX7-FKHR fusion transcripts in children and adolescents with alveolar RMS. Patients with the PAX7-FKHR fusion transcript usually were younger, had lesions on the extremities, and, generally, had a better outcome than patients with the more common variant, PAX3-FKHR. The latter variant usually was associated with older age and central tumors. The patterns of metastatic disease at the time of diagnosis also were different. RMS with the PAX3-FKHR fusion transcript involved more sites, including brain and skin.
The presence of multiple cutaneous or subcutaneous nodules in a young infant usually is associated with the diagnosis of neuroblastoma20 or, less frequently, with the diagnoses of infantile myofibromatosis,21 infantile capillary hemangioma,22 or congenital disseminated rhabdoid tumor.23 Neonatal alveolar RMS, as shown here, also needs to be included in the differential diagnosis of skin nodules in neonates. However, metastasis of RMS to the skin is extremely uncommon in older children, even in the last stages of the disease. For example, a review of 263 patients who died of progressive RMS and were examined postmortem found no evidence of cutaneous involvement.24 The rarity of this phenomenon also is documented by other studies.25, 26 Although it is rare, primary RMS of the skin is a well-recognized entity.27, 28 The experience of Orozco-Covarrubias and coworkers28 showed that RMS was one of the most common skin malignancies of children.28 All of the 13 cases they reported involved primary tumors, and two-thirds of these tumors developed during the first 2 years of life (one patient was a neonate). Unfortunately, histologic subtypes were not reported. Of the seven cases of RMS of the skin described by Schmidt and colleagues,27 five involved primary tumors, and two involved metastatic disease: It is noteworthy that six of the seven tumors were of alveolar histology. Even more interesting is the fact that one of the two patients with metastatic disease was a neonate with alveolar RMS; the presenting symptom was described as multiple bluish skin nodules.27
Brain metastases are a rare but well-described complication of RMS. In our experience, brain metastases develop in approximately 2.4% of patients with embryonal or alveolar RMS.29 This low incidence rate corresponds with the experience of other institutions,30, 31 although the continued improvement in outcome and longer survival for patients with RMS may lead to an increase in its incidence.31–34 In the last stages of the disease, brain metastases develop in as many as 20% of patients with RMS, as demonstrated by postmortem examinations.24, 33 It is interesting to note that this incidence rate is even higher for patients with RMS of the extremities (37%), probably because this type of disease has more aggressive biologic features.24 In general, metastases of RMS usually are supratentorial (70% of patients) and often multiple.29, 30, 32 However, in 90% of the children with RMS metastasis to the brain, metastatic disease to other sites, such as lungs or bone, already has occurred.29, 30, 33 This finding indicates that metastasis of RMS to the brain is a sign of widespread tumor dissemination.
In light of the natural history of RMS in children and adolescents, it is even more surprising that one of the main features of our patients with neonatal alveolar RMS was the presence of multiple skin metastases and the development of brain metastases relatively early in the course of the disease with no evidence of metastatic disease to more common sites, such as lungs, bone, or bone marrow. The RMS cells disseminated with an unusual trophism for tissues of neuroectodermal origin; this finding suggests that the malignant cells of neonatal patients with alveolar RMS are present during fetal development and probably before the blood-brain barrier is developed.
When our findings and the reports on three other patients are combined, a distinct syndrome of neonatal RMS appears. It is characterized by alveolar RMS (possibly with the PAX3-FKHR fusion transcript) with multiple skin and subcutaneous metastases, the early development of brain metastases, and a fatal outcome. This syndrome should be included in the differential diagnosis of neonatal soft tissue sarcomas and in the differential diagnosis of newborns with multiple skin nodules.
The authors are indebted to Flo Witte for editorial assistance.