Of the pediatric solid tumors, the soft tissue sarcomas are the fourth most common following central nervous system tumors, Wilm's tumor, and neuroblastoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in children under 15 years of age.1 The annual incidence of this tumor among US white children under 15 years of age is 4.4 per million, and for black children the annual incidence is 1.3 per million. The age distribution was bimodal among the lethal rhabdomyosarcomas that were reported between 1960 and 1969.2 An early peak was observed due to primary tumors located in the head and neck area or in the genitourinary tract and a late peak was seen due to tumors located in the male genital tract.
Approximately 70% of cases present before the age of ten years. The disease is more common among males than females, the male:female ratio being 1.4:1. The primary sites of the tumor are head and neck area 28%, orbit 10%, extremities 18%, genitourinary tract 21%, trunk 7%, retroperitoneum 7%, perineum and anus 2%, and other sites 7%.3'4 Rhabdomyosarcoma may occur in siblings and a higher than expected incidence of brain tumor, breast cancer and adrenal cortical carcinoma have been observed in some families. Its association with neurofibromatosis has been reported.2'5
Rhabdomyosarcomas arise from embryonic mesenchyme. Histologically, they are divided into four subtypes: embryonal, alveolar, botryoid, and pleomorphic.6 Two additional variants have been recognized and referred to as "special undifferentiated cells, types I and II."7
The embryonal type is composed of small, anaplastic round and spindle-shaped cells with little acidophilic cytoplasm and elliptical hyperchromatic nuclei. Cytoplasmic cross-striations can be seen in 40% to 60% of all cases. The embryonal type is the most common type and constitutes 57% of rhabdomyosarcomas.8
The alveolar type is composed of slightly larger, round anaplastic cells with varying amounts of acidophilic cytoplasm. The cells reside in spaces or alveoli lined by tumor cells. Nineteen percent of rhabdomyosarcomas are of the alveolar type, which is most frequently seen in lesions of the extremities.
The botryoid type makes up as many as 6% of rhabdomyosarcomas. It is composed of a layer of small round cells at the periphery of the polypoid tumor followed by a zone of myxoid stroma that is followed by deep multilayers of round and spindle-shaped cells. This type is usually seen in the genitourinary tract and occasionally in the head and neck region.
The pleomorphic type, which is the most differentiated type, is composed of large pleomorphic cells which contain generous amounts of acidophilic cytoplasm and anaplastic nuclei. This type makes up 1% of rhabdomyosarcomas.
The "special undifferentiated cell, type 1," or extra osseous Ewing's tumor, is found in 4% of cases and is composed of uniform, anaplastic small round or oval cells with scanty cytoplasm and dense hyperchromatic nuclei. The "special undifferentiated cell, type II"is composed of uniform anaplastic cells that are larger than cells in Ewing's sarcoma and have a cytoplasmic rim that has a vacuolated appearance.
The last two types, special undifferentiated cell types 1 and II, are frequently seen in rhabdomyosarcomas of the extremities and in patients between 10 and 16 years of age. On the other hand, the embryonal and botryoid types are seen more frequently in children who are under four years of age at diagnosis. All six types may contain cytoplasmic glycogen. The classical four types of rhabdomyosarcomas can be found in pure form or as a mixture of subtypes. Recent electron microscopic studies have also shown that there can be considerable overlap between classical histological types as well as the presence of many fine gradations. Some pathologists believe that all childhood forms of rhabdomyosarcoma are essentially embryonic tumors, varying according to the degree that they have differentiated, to the degree they have responses to microenvironmental factors, or both.9'10
For planning treatment and determining prognosis, staging of the tumor at diagnosis is necessary. Determination of the correct stage is derived by clinical, hematologic, radiologic, and isotopie examinations of the patient for evidence of metastases, by a review of surgical operative reports, and by histopathologic examination of the surgical specimen. Various staging systems have been used in different centers. The one most frequently used is that of the lntergroup Rhabdomyosarcoma Study (I RS)3 which divides patients into treatment groups according to the extent of disease.
Group I includes patients with localized disease completely resected (gross and microscopic) without regional lymph node involvement. The tumor is either: 1) confined to muscle or organ of origin or, 2) there is contiguous involvement with infiltration outside the muscle or organ of origin.
Group II patients have: 1) grossly resected tumor with microscopic residual disease; 2) regional disease with positive nodes or contiguous organ involvement or both, but the tumor is completely resected without microscopic residual or; 3) regional disease, grossly resected, with microscopic residual.
Group III includes patients with incomplete resection of their tumor or biopsy, with gross residual disease.
Group IV includes those with metastatic disease present at diagnosis.
Many patients have advanced disease at diagnosis. Less than half of the patients entered in the lntergroup Rhabdomyosarcoma Study were in Group I and Group II.3 The majority of patients with primary tumors in the head and neck area, trunk, extremities, intrathoracic, or retroperitoneum have unresectable disease and are in Group III and Group IV, while patients with genitourinary primaries are mostly in Group I and Group II.
Figure 1. A child with orbital rhabdomyosarcoma showing proptosis of the left eye.
CLINICAL PRESENTATION AND DIAGNOSTIC EVALUATION
Signs and symptoms of the disease vary according to location of the primary tumor. In the head and neck area the most frequent tumor site is the orbit; therefore, orbital rhabdomyosarcoma is the most common primary orbital tumor of childhood. Orbital tumors usually present with proptosis (Figure 1). Nasopharyngeal tumors may present as sinusitis, airway obstruction or dysphagia. Middle ear tumors may present as polyps in the ear canal, chronic otitis media and hemorrhagic discharge. Due to the proximity of head and neck tumors to the base of the skull, with opportunity for direct extension of the tumor to this area and to the central nervous system, cranial palsies are often observed at the time of diagnosis.
Figure 2. Protrusion of polypoid mass from the vagina in a child with sarcoma botryoides.
Figure 3. Rhabdomyosarcoma presenting as a painfess mass on the right shoulder.
Urinary tract symptoms are usually produced when the tumor causes obstruction of the urinary or fecal pathway. Frequency, dysuria and urinary retention, constipation or hematuria are produced by rhabdomyosarcomas of the bladder and prostate. Frequently, these tumors initially appear as a palpable lower abdominal mass. In girls, sarcoma botryoides of the vagina or uterus may present as protrusion of hemorrhagic polyps from the introitus (Figure 2). In the paratesticular area, the tumor usually presents as an expanding, non-tender mass in the scrotum usually located above and separate from the testis. This may be confused with a hernia and maybe associated with a hydrocele. In the extremities or trunk a painless mass is the most frequent presentation (Figure 3).
The most common sites of metastases are lungs, central nervous system, bones, liver, bone marrow and regional lymph nodes. Head and neck tumors often extend to the base of the skull. All patients with this primary site should have a tomogram, a CT scan, or both, of the tumor and base of the skull.
Pretreatment evaluation should include: hematologic and bone marrow evaluation; radiological examination of the primary tumor site, lungs, and bones; and radioisotope scans of the bones and liver. Other tests such as examination of the cerebrospinal fluid, intravenous pyelogram, cystogram, lymphangiogram, and gallium-67 scan may be done, depending on the primary site of tumor.
Institution of a multidisciplinary approach by surgery, radiation therapy, and multiple drug cycles of chemotherapy for the treatment of childhood rhabdomyosarcoma has resulted in marked improvement in the outcome of therapy. U ntil the late 1 960s, only 20% to 30% of children with early stage operable tumors survived. Now more than half of children treated with multidisciplinary therapy remain alive and disease-free.""13 The treatment of a child with rhabdomyosarcoma is complex. Selection of therapy must be made from multiple options available and based on several factors, including the primary site of the tumor, the size and degree of extension of the tumor, and the age of the patient.
Surgery The initial treatment of rhabdomyosarcomas in most locations is radical surgical excision of the tumor. An attempt must be made to excise all tumor, along with a margin of normal tissue. In addition, regional lymph node dissection should be carried out, if possible, particularly in genitourinary, pelvic and extremity primaries.
For orbital tumors, simple biopsy followed by radiotherapy and chemotherapy is the current treatment of choice. Exenteration or enucleation that yielded 25% to 45% survival before 1968 is now reserved for cases with local failure. Radiotherapy and chemotherapy can control the local disease in 90% of patients.14 For head and neck tumors, accessible tumors, that can be removed without creating any major cosmetic defects, should be excised.
For extremity tumors, wide local excision of the tumor mass and surrounding normal tissue is required. This means muscle group resection as well as regional node dissection. However, due to the extent of the disease and involvement of vital structures, often gross removal of tumors is impossible, but attempts should be made to excise as much tumor as possible and still have a functionally viable extremity. Residual local disease can be treated by irradiation and chemotherapy. Regional nodes are involved in 17% of patients and in these radiotherapy to the involved lymphatic area is also necessary. Amputation is rarely recommended unless other modalities have failed.
Paratesticular tumors grow rapidly and in 40% of cases they metastasize to regional lymph nodes.15 Transinguinal biopsy of the mass, with clamping of the spermatic cord, is necessary for diagnosis. Definitive surgery consists of radical orchiectomy, hemiscrotectomy combined with ipsilateral pelvic and para-aortic node dissection. Radiotherapy is given postoperatively if the margin of resection or regional lymph nodes are positive on histopathological examination.
Radical en bloc surgical procedures have been recommended as optimum therapy for pelvic rhabdomyosarcomas since local excision or segmental resection alone, as performed in the past, were followed by prompt local recurrence.16 For rhabdomyosarcomas of the bladder and prostate, some16 advocate cystoprostatectomy and regional lymph node dissection followed by radiotherapy and chemotherapy for patients who have localized microscopic residual disease. Others have reported that improvement in disease-free survival of patients can be obtained without radical surgery.17 In a limited number of patients with localized tumor, chemotherapy was administered initially, and if the tumor persisted or was found to be growing, radiotherapy was given. Radical surgery did not become necessary in any patient and the majority of patients remained without evidence of disease.17 This scheme of multidisciplinary therapy, to avoid radical surgery and yet obtain local control, is being investigated in a larger number of patients.18'19 Definitive surgery for tumors of the bladder and prostate involves radical cystectomy or prostatectomy or both, with ileal conduit urinary diversion.
In females, partial cystectomy may be adequate provided it is followed by chemotherapy; when residual local microscopic disease is present, radiotherapy is required. For vaginal tumors, radical surgery consists of anterior or posterior or total pelvic exenteration with preservation of the ovaries. For intra-abdominal, chest wall and trunk tumors, excision of the primary tumor with as much surrounding margin as possible is recommended.
Radiotherapy Radiotherapy delivered without concomitant chemotherapy, in a dose of 5000 to 6000 rad over five to six weeks has achieved local control in approximately 70% to 90% of children with rhabdomyosarcoma.20'21 When lower doses of irradiation were given (less than 4000 rad in four weeks) a high rate of local recurrence was observed.20 Chemotherapeutic agents enhance the effects of radiation both on the tumor and on normal surrounding tissues. This may result in acute or delayed local adverse side effects of radiotherapy.22
Since all the various multidisciplinary treatment protocols have contained irradiation-enhancing drugs, attempts have been made to avoid radiotherapy if possible or to modify the dose of irradiation without decreasing local control of the disease. An early study12 confirmed by the lntergroup Rhabdomyosarcoma StudyI3'21 demonstrated that for patients with localized, completely resected tumor, radiotherapy is not necessary. It is suggested that for patients with microscopic residual disease, 3000 to 4000 rad delivered with concomitant chemotherapy may be sufficient to achieve local control.23 For patients with gross tumor who receive intensive chemotherapy, the dose of 4000 to 5000 rad is necessary, the dose being adjusted for the size of the tumor and age of the patient. Radiotherapy to involved lymph node areas is given when histologic involvement of the nodes is demonstrated.
Chemotherapy Rhabdomyosarcoma is a malignant tumor, in addition to Wilms' tumor and osteosarcoma, in which chemotherapy has significantly altered the outcome of the therapy and has increased survival rate of the patients. The use of single chemotherapeutic drugs, such as dactinomycin, vincristine, cyclophosphamide, adriamycin, dimethyltriazino-imadozole carboxamide (DTIC), and cis-dichlorodiammine-platinum can produce temporary regression of the demonstrable tumor in 30% to 50% of cases.
All patients with rhabdomyosarcoma should receive chemotherapy. The justification for chemotherapy has been based upon the assumption that even in the early stages of tumor, occult metastases are present and chemotherapy can arrest their growth. Furthermore, the addition of chemotherapy to radiation therapy increases both the chances of tumor regression and the likelihood of complete response to therapy. The efficacy of chemotherapy can be augmented by the concurrent administration of several drugs with different mechanisms of action and minimal overlapping toxicity.
In 1974, the Children's Cancer Study Group reported on the role of adjuvant chemotherapy in preventing growth of metastases. An increase in disease-free survival from 53% to 82% was observed when dactinomycin and vincristine were given fora period of one year after initial complete surgical removal of the primary tumor and postoperative radiotherapy.24 In a subsequent study, cyclophosphamide was added to the chemotherapy regimen of dactinomycin and vincristine. The survival rate of patients with microscopic residual disease at the site of the primary tumor was increased to 70%. In patients with gross residual or metastatic disease, the survival rate was 43% and 27% respectively.2" When the same three drugs (vincristine, dactinomycin, and cyclophosphamide) were used simultaneously for two years, the overall response and survival rates were over 50% in patients with unresectable or metastatic disease at diagnosis.13
In our experience, the addition of adriamycin to the three drugs resulted in an overall survival rate of 76%, as compared to 24% in a historical group.26 But for unresectable or metastatic disease, the survival rates were 50% and 20% respectively.
In our subsequent study utilizing six drugs administered in pulses concomitantly with radiation therapy in patients with unresectable or metastatic disease, we were unable to demonstrate statistically significant improvement in survival rate over that obtained in four-drug sequential therapy.27
A multi-institution, multidisciplinary, randomized study (namely, Intergroup Rhabdomyosarcoma Study-I), which began in 1972 resulted in clarification of many points in biologic behavior and treatment of childhood rhabdomyosarcoma. 3,4,28 These results may be summarized as follows.
In Group I patients (those with localized, completely resected tumor), the addition of local radiation therapy to a 24-month regimen of vincristine, dactinomycin, and cyclophosphamide (VAC) did not improve local disease control. Therefore, radiotherapy can be omitted in this group. The survival rate at three years is 87% to 92%.
In Group II patients (those with resected localized or regional tumor and microscopic residual disease) who received radiation therapy, there was no difference in relapse rate or disease- free survival between the group who received VAC as compared to those who received only two drugs. The three-year survival rate was 70% to 74%.
In Group III patients (those with incompletely resected tumors) and Group IV patients (metastatic disease), pulse VAC, or pulse VAC plus adriamycin were equally effective in producing an initial response in 85% of the patients. All patients received radiotherapy. In Group III the three-year survival rate was 57%, and in Group IV the three-year survival rate was 29%.
These results indicate that there is a correlation in prognosis between the extent of disease at diagnosis and survival, but there is no significant difference between the regimens investigated within each clinical group. Therefore, the extent of disease or clinical group at diagnosis is the single most important factor.3,25,26,29 In addition, other factors have lesser degrees of influence on the outcome of therapy29 and survival of the patient.
Patients with alveolar rhabdomyosarcoma have the least favorable prognosis, particularly those in clinical Group I.29 Patients with orbital31 or genitourinary rhabdomyosarcomas have the most favorable prognosis, whereas those with extremity rhabdomyosarcomas have an unfavorable prognosis.29,30 In Intergroup Rhabdomyosarcoma Study-I, patients with primary tumor in the head and neck area, that is adjacent to the meninges, in "parameningeal sites" (middle ear, mastoid, ear canal, nasal cavity, paranasal sinuses, nasopharynx and infra-temporal fossa), showed a high recurrence rate and a poor survival rate.32 However, similar observations have not been made by other investigators.33,34 In their view, the prognostic significance of local meningeal involvement associated with recurrence of an adequately irradiated primary tumor is unclear.
The Intergroup Rhabdomyosarcoma Study-II (IRS-II) was designed in 1978 to refine therapy for those patients with a high survival rate and to intensify the therapy for patients with a poor survival rate. However, efforts to intensify therapy for poor responders still continues. The preliminary results of IRS-II indicate that improvement in the survival rates of group III and group IV patients has been achieved.
Complications of Therapy Investigators at various centers have reported marked improvement in the duration of disease-free survival of patients treated with the combination of surgery, irradiation, and chemotherapy. This success has led to the recognition of increased numbers of patients with delayed side effects of therapy and the significant risk for development of additional neoplasms.35-38 Future investigations should be aimed at maintaining the excellent survival rates while minimizing the morbidity and other long-term problems caused by the therapy.
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