Rhabdomyosarcoma is the most common soft-tissue sarcoma in children. It represents between 5 and 15 per cent of all malignant solid tumors in children and 4 to 8 per cent of all malignant diseases in children under 15 years old. From the patient accrual rates in national studies - namely, the National Wilms' Tumor Study and the Intergroup Rhabdomyosarcoma Study - rhabdomyosarcoma appears to occur at least as frequently as Wilms' tumor.1"3 Better delineation of the histologic features of the tumor probably accounts for the increase in its recognition. Before the early 1960s, the overall twoyear survival rate was less than 20 per cent. With the change in treatment from surgery or radiation therapy to a multidisciplinary approach utilizing surgery, radiation therapy, and intensive multidrug chemotherapy, twoyear survival rates have increased to approximately 70 per cent overall.
The peak incidence of the disease occurs between the ages of two and five years, with approximately 70 per cent of cases presenting before age 10 years.2 Between ages 11 and 21, rhabdomyosarcoma tends to present primarily in the head-and-neck, extremity, and genitourinary regions. The disease is more common in males than females (male: female ratio 1.4:1). The sites of origin in order of frequency are head-and-neck region (36 per cent), extremities (24 per cent), genitourinary tract (18 per cent), trunk (8 per cent), retroperitoneum (7 per cent), gastrointestinalhepatobiliary tract (3 per cent), intrathoracic region (2 per cent), and perineum-anus (2 per cent).
The most frequent abnormality noted at the time of presentation is a mass (Figures 1, 2. and 3). Signs and symptoms relate primarily either to the location of the primary tumor, which can arise virtually anywhere, or to the metastases. Nasopharyngeal tumors cause airway obstruction, sinusitis, epistaxis, local pain, and dysphagia. Orbital tumors produce proptosis. Lesions in the middle ear display a polypoid mass in the external auditory canal, with pain and chronic otitis media. Masses in nasopharynx and nasal cavity, nasal sinuses, and middle ear may extend directly into the central nervous system, causing cranial nerve palsies, meningeal symptoms, and respiratory paralysis due to infiltration of the brain stem.4
Figure 1. Eight-year-old girl with an embryonal rhabdomyosarcoma of the right eyelid.
Figure 2. Two-year-old boy with an embryonal rhabdomyosarcoma of the jaw. The tumor projected into the mouth and bled. The child's lips are blood-stained.
Figure 3. Seven-year-old boy with an embryonal rhabdomyosarcoma of the abdominal wall. The tumor had been biopsied.
Urinary tract symptoms should raise the suspicion of a lesion in the prostate or bladder. Paratesticular lesions usually present as masses. In girls, rhabdomyosarcoma may present as hemorrhagic grapelike masses protruding from the introitus or cervix uteri, the so-called sarcoma botryoids. Rhabdomyosarcoma extends locally and may involve regional lymph nodes. Margins of tumor growth are frequently indistinct. Metastases result from lymphatic and hematogenous spread. Common sites of metastases include lung, bone, bone marrow, lymph nodes, brain, and heart.
The incidence of carcinoma of the breast is higher in adult relatives of children with rhabdomyosarcoma. Also, a high frequency of soft-tissue sarcoma, brain tumor, and adrenocortical carcinoma occurs among the siblings of affected persons.
In addition to a complete history, physical examination, CBC, and urinalysis, preoperative evaluation should include a chest film, skeletal survey, bone scan, bone-marrow aspiration or biopsy, liver scan, brain scan and CSF examination (for head-and-neck tumors), and lymphangiography (for lower-extremity and genitourinary lesions). Also, for special indications, the diagnostic work-up may include angiography for deep-seated tumors, full-lung tomography, gallium scan, and computerized axial tomography. Blood chemistry determinations should include BUN, LDH, SGOT, uric acid, bilirubin, creatinine, and alkaline phosphatase.
Staging classification. Careful staging is extremely important for treatment planning and for determining prognosis; it cannot be overemphasized. The Intergroup Rhabdomyosarcoma Study has established a clinical staging classification that correlates closely with the duration of remission and survival.2 The determinants of clinical stage to a large extent relate to the amount of residual disease following surgical resection of the tumor plus the presence or absence of metastases in the regional lymph nodes1 (Table 1). Careful microscopic examination of the margins of resection must be carried out to determine the presence or absence of residual tumor. Gross inspection of the postoperative field alone may be totally misleading in the assessment of the amount of unresected tumor.
CLINICAL GROUPING CLASSIFICATION
Histologic classification. Rhabdomyosarcoma arises from embryonic mesenchyme. The four recognized subtypes of rhabdomyosarcoma are embryonal, alveolar, botryoid, and pleomorphic; these subtypes can be found in "pure" forms or as a mixture of subtypes. Two additional histologic variants of the tumor have recently been recognized by Soule and Newton in review of the pathologic material submitted on the large number of cases entered into the lntergroup Rhabdomyosarcoma Study. These variants have been tentatively referred to as special undifferentiated cells, types I and II.5
The most common form, the embryonal type, is found in approximately 55 per cent of patients. It is highly prevalent in the headand-neck region, including the orbit (75 per cent), and the genitourinary region (65 per cent). The embryonal lesions are composed primarily of small anaplastic round and spindle-shaped cells that exhibit hyperchromatic nuclei and granular acidophilic cytoplasm.
The alveolar type is more often found in the deep tissues of the trunk (45 per cent) and extremities (35 per cent). Overall, it accounts for 1 8 per cent of the rhabdomyosarcomas. This form is composed of slightly larger, round, anaplastic cells with varying amounts of acidophilic cytoplasm. The cells tend to be arranged in clusters or in elongated clefts. A rather dense collagenous network accentuates the so-called alveolar arrangement.
The botryoid type makes up 7 per cent of all rhabdomyosarcomas. It is usually seen in the genitourinary tract, but it is occasionally found in other regions, such as the head and neck. A layer of small round cells is apparent at the periphery of the polypoid tumor. A zone of myxoid stroma is followed by a deeper compact zone composed of round and spindle-shaped cells. Cells in the compact zone can usually be readily recognized as rhabdomyoblasts because of their cytoplasmic cross-striations.
The pleomorphic type (adult form) makes up only 2 per cent of all rhabdomyosarcomas. It occurs most often in the somatic soft parts of the extremities and trunk. It is distinguished by large pleomorphic tumor cells that may exhibit many configurations. The conspicuous amount of acidophilic cytoplasm and the presence of large anaplastic nuclei often result in tumor giant cells.
Cytoplasmic longitudinal and cross-striations are occasionally found in all four tumor types. Cytoplasmic glycogen is usually present. Differential diagnosis in the juvenile forms (embryonal, alveolar, botryoid) includes neuroblastoma, malignant lymphoma, Ewing's sarcoma, and undifferentiated round-cell sarcoma of indeterminate type.
A fifth histologic type of rhabdomyosarcoma has recently been described. This type occurs in soft tissues but is considered histologically indistinguishable from Ewing's sarcoma of bones. It is referred to as "special undifferentiated cell, type I" or "extraosseous Ewing's tumor."6 This type is found in approximately 5 per cent of cases. The tumor is composed of uniform, anaplastic, small, round or oval cells with a scant rim of cytoplasm and a hyperchromatic nucleus that sometimes has a ground-glass appearance. Intracellular glycogen is usually present. The cells are larger than those seen in Ewing's sarcoma and are not clearly identifiable as rhabdomyoblasts.
A sixth type, which makes up 5 per cent of all rhabdomyosarcomas, has also recently been recognized. This type is called "special undifferentiated cell, type II." This tumor is characterized as having uniform anaplastic cells that are also larger than those of Ewing's sarcoma. The cytoplasmic rim is more conspicuous, and the nuclei often exhibit a vacuolated appearance. Intracellular stroma is scant, and cytoplasmic glycogen is often present. This tumor resembles the pattern described for large-cell Ewing's tumor of bone.
Whether there is any prognostic significance to any of the cell types of rhabdomyosarcoma is still unclear. Although the alveolar form has been classically associated with a poorer prognosis than the embryonal form, this may relate to site of tumor origin rather than to cell type itself.
When the diagnosis of rhabdomyosarcoma is questionable, electron microscopy may reveal thin and thick myosin filaments and primitive Z-bands not visible by light microscopy. Antimyosin immunofluorescence can be used to confirm the presence of myosin in the tumor cells.
Surgery. The surgical approach to rhabdomyosarcoma is an area of extreme controversy because of the improvement in survival from combined chemotherapy and radiationtherapy programs. There is evidence, based on relatively small groups of patients, that limited surgical excision with preservation of the organ affected may be all that is required for selected sites of origin - for example, for pelvic primaries. Radical surgical excision, heretofore employed exclusively, may at times not be necessary for disease control. The type of operative procedure employed depends on the site of the primary tumor and the extent of local and distant spread. Preliminary results from the Intergroup Rhabdomyosarcoma Study suggest that patients have a better prognosis if there is no gross residual tumor following surgery. Thus, if a lesion is amenable to gross total excision, simple biopsy alone is not as good even when followed by irradiation and chemotherapy.
The basic principle of wide excision of the primary tumor, with excision of an "envelope" of normal tissue as well, is best adhered to whenever possible. But this approach is generally more applicable to extremity lesions and to certain trunk lesions than to those of the head and neck. If the surgeon leaves "microscopic residual" tumor, as judged by histologic examination of the margins of the excised tumor, a second resection may not be required if chemotherapy and radiation therapy are to follow.
Recent evidence from the lntergroup Rhabdomyosarcoma Study suggests that regional lymph-node involvement occurs with sufficient frequency to justify elective node dissection for genitourinary, extremity, head-andneck, and pelvic primaries.2,7,8 Approximately 50 per cent of patients with paratesticular lesions have involvement of the para-aortic lymph nodes. The variety of anatomic possibilities is too great to establish firm guidelines for elective lymph-node dissection. However, the regional lymph nodes should be considered for biopsy if the surgeon does not plan regional lymph-node dissection as part of the definitive procedure. Unless one considers using computerized axial tomography for follow-up evaluation, metal clips should be placed in areas of lymph-node removal that might prove to be positive. Thus, metal clips should be placed at the periphery of unremoved tumor or at sites of possible residual tumor during operations in the abdomen or thorax to aid in directing subsequent radiotherapy. Pedal lymphangiography may be helpful in staging patients with pelvic, inguinal-canal, and paratesticular lesions.
Guidelines for surgery. Further guidelines for surgery depend on disease site:
Orbit. Simple biopsy followed by radiation therapy and chemotherapy is appropriate. Exenteration is no longer essential for prolonged disease control and survival.
Head and neck. Wide excision is appropriate, but the possibility of excising an "envelope" of normal tissue is quite restricted. Biopsy is often the only procedure possible short of radical surgery.
Extremity. Wide local excision is required to avoid recurrence. If gross excision of the tumor cannot be achieved without amputation, amputation appears to be preferable to simple biopsy followed by radiation and chemotherapy. Preliminary observations from the lntergroup Rhabdomyosarcoma Study suggest that a primary chemotherapy approach, with or without local radiation, with extirpative surgery reserved for the excision of residual disease, may not be as effective as initial gross excision of the tumor and postoperative irradiation and chemotherapy.9
Pelvis. The preservation of one or more of the major pelvic organs, such as the bladder or rectum, is an important goal in therapy. If the tumor is grossly completely removed, it is probable that microscopic residual tumor in the walls of these organs may be controlled by radiation and chemotherapy.10
Paratesticular tumors. Inguinal orchiectomy with high ligation of the spermatic cord is coupled with retroperitoneal lymph-node dissection. The remaining testicle may be spared exposure to radiation by relocating it into the tissues of the ipsilateral thigh, subcutaneously. Following completion of radiation, it is returned to its normal position.
When the tumor recurs in spite of therapy, "curative" surgical procedure should be attempted if this is anatomically feasible and if there are no distant metastases. Persistent metastatic disease in the lung following chemotherapy and radiation therapy should be resected if this can be accomplished and if it is warranted by the general status of the patient.
Radiation therapy. A radiation dose of 5,000 rads in five weeks to 6,000 rads in six weeks to the primary tumor is recommended. In patients with gross or microscopic residual tumor, doses less than 4,000 rads have been associated with a high local recurrence rate even when chemotherapy was given.11 Lower doses of irradiation might be considered in the very young child, especially those under three years of age, when the primary site is to be irradiated. However, no less than 4,000 rads in four weeks should be given in the latter instance. It is important to protect vital structures, such as lung, kidney, liver, etc., whenever possible, so that normal tissue tolerance to irradiation is not exceeded.
"Prophylactic" radiotherapy of uninvolved lymph node areas is not recommended. Radiotherapy of positive lymph node areas (such as the para-aortic nodes) should be considered if subsequent impaired lymphatic drainage will not pose a serious problem to the patient.
When the entire abdomen must be included in the volume for irradiation, the dose to the abdominal contents should be limited to 3,000 rads in four weeks. Local areas of the abdomen that contain the bulk of residual tumor should be "boosted" to the prescribed doses listed above for primary tumors at other sites.
When metastases are present in a lung, bilateral lung irradiation is recommended (1,400-1,800 rads), even when there is total regression of all demonstrable lesions following initial chemotherapy. Localized pulmonary nodules that persist may be treated through coned-down "postage stamp" portals to a total dose of 5,000 rads.
Solitary bone metastasis may also be treated with local irradiation; doses of 5,000 to 6,000 rads in five to six weeks should be used. Other areas of metastases should also be treated whenever possible.
Following complete excision of localized tumors, postoperative irradiation to the tumor bed does not appear to enhance local disease control over that afforded by chemotherapy alone. Thus, postoperative irradiation is not recommended for group I tumors when chemotherapy is given. This recommendation is based on recent preliminary data derived from the Intergroup Rhabdomyosarcoma Study.2
Chemotherapy. All rhabdomyosarcoma patients should receive chemotherapy routinely. Heyn and associates, reporting for the Children's Cancer Study Group, have shown that the two-year disease-free survival rate increased from 47 per cent to 82 per cent when 12 months of chemotherapy (vincristine plus dactinomycin) was given after total surgical removal of the primary tumor, supplemented by postoperative radiation therapy.12 The efficacy of such "prophylactic" chemotherapy, better termed chemotherapy of "micrometastases," has been confirmed now by several groups.
The role of chemotherapy in rhabdomyosarcoma is gradually changing from one of adjuvant therapy to one of primary therapy. This change is due to the discovery of effective drugs used in intensive combinations and schedules. In the presence of gross residual or metastatic disease at diagnosis, a six-week course of chemotherapy is appropriate to reduce tumor burden prior to irradiation. The complete response rate with chemotherapy followed by radiation therapy is approximately 50 per cent, with the overall response rate being about 80 per cent.2,13 The median time to response is approximately 11 weeks with "pulse" VAC (vincristine, actinomycin D, cyclophosphamide) induction therapy. When there is gross residual tumor (clinical group III) or metastatic disease (clinical group IV), chemotherapy should be continued for a period of two years. For patients with localized disease that has been completely resected (clinical group I) or microscopic residual disease following surgery (clinical group II), chemotherapy should be continued for one to two years.
"First-line" drugs active against rhabdomyosarcoma are dactinomycin, vincristine, cyclophosphamide, and adriamycin and are best used in two-to- four-drug combinations. Agents that hold promise for the future are DTIC, bleomycin, and cis-platinum. Optimal chemotherapy schedules and doses have not been defined; current recommendations are based on the experience of the lntergroup Rhabdomyosarcoma Study.
For clinical group I disease, VAC chemotherapy should be started as soon after surgery as the clinical condition of the patient permits. The schedule is as follows: vincristine, 2 mg./ sq.m. IV (maximum single dose is 2 mg.) weekly for 12 doses starting at day 0; dactinomycin, (0.015 mg./kg./day IV for five days). The courses are repeated four times in 48 weeks; and cyclophosphamide, 2.5 mg./ kg./day p.o. from day 42 up to 24 months. For this disease group, thus far in the lntergroup Rhabodmyosarcoma Study, it appears that postoperative radiation to the tumor bed does not enhance local disease control over that achieved by VAC chemotherapy alone.
For clinical group II disease, all patients should be treated with postoperative radiation therapy to the tumor bed and given either VAC chemotherapy (as outlined above) or vincristine, 2mgJsq.m. IV weekly for six doses (six courses are given over a 48- week period) and dactinomycin, 0.015 mg./kg./day FV for five days, with courses repeated five times in 45 weeks. The two chemotherapy regimens appear to be equally effective thus far.
For clinical groups III and IV disease, both "pulse" VAC and "pulse" VAC plus adriamycin are being employed in the lntergroup Rhabdomyosarcoma Study, the two combinations being equally effective thus far. "Pulse" VAC consists of vincristine, 2 mg./ sq.m. IV weekly for 12 doses; dactinomycin, 0.015 mg./kg./day IV for five days (course repeated four times during 54 weeks); and cyclophosphamide, 10 mg./kg./day IV (on days 1-5, course repeated orally on days 84-90), then 2.5 mg./kg./day p.o. from day 140 to 24 months. Radiation therapy is delivered to the primary site and sites of metastases beginning at 6 weeks postoperatively. When adriamycin is used, it is given at a dose of 60 mg./sq. m. IV for five doses interspersed during 51 weeks along with "pulse" VAC chemotherapy.
A thorough knowledge of drug toxicities is essential before initiation of therapy with these combinations of drugs, since they can produce life-threatening or fatal toxicity. Complications of dactinomycin include myelosuppression, abdominal pain, nausea, vomiting, ulceration of the buccal mucosa, and alopecia. Erythema of the skin in the radiation portals has been induced by this agent. Vincristine causes constipation, alopecia, and a constellation of neuromuscular problems including paresthesias in the fingers and toes, jaw or throat pain, muscle weakness, ptosis, and eventual disappearance of the deep tendon reflexes. Hyponatremia is also a possible complication. Adriamycin causes alopecia, myelosuppression and, at total doses above 600 mg./sq.-m, cardiac toxicity. Each of these agents is given intravenously and can cause severe skin and subcutaneous irritation when extravasation occurs. Cyclophosphamide causes bladder toxicity, myelosuppression, and gastrointestinal disturbances. "Pulse" VAC therapy can produce substantial myelosuppression, leading to septicemia. Ten to 14 days of careful observation of patients receiving this combination is essential in minimizing the risk of lifethreatening or fatal toxicity.
Children below the age of seven years have a better prognosis than those above age seven, according to Sutow and associates.14 Young children also tend to have less advanced disease at diagnosis, which possibly accounts for their better prognosis.2
Outcome also varies with the location of the primary tumor. Orbital and genitourinary-tract lesions have a comparatively good prognosis, as they tend to infiltrate locally, metastasize late, and give rise to signs and symptoms early. Tumors originating in the middle ear, prostate, and extremity have a poorer outlook. Extremity lesions tend to metastasize to the central nervous system. Head-and-neck lesions, particularly those in the nasopharynx, nasal cavity, nasal sinus, and middle ear, invade the central nervous system by direct extension.
The prognostic value of histologic type has yet to be. determined. The historically "unfavorable" types (alveolar, pleomorphic) tend to occur in older children, who as a group tend to have more advanced disease at diagnosis.
The extent of disease at diagnosis, clinical group, is the single most important factor. At the present time, the two-year survival rate is approximately 90 per cent for clinical group I, 85 per cent for clinical group II, 75 per cent for clinical group III, and 35 per cent for clinical group IV disease.2
1. Maurer, H. M. The Intergroup Rhabdomyosarcoma Study; objectives and clinical staging classification. J. Pediatr. Surgery 10 (1975), 977-978.
2. Maurer, H. M-, et al. The Intergroup Rhabdomyosarcoma Study; preliminary report. Cancer In press.
3. Maurer, H. M., for the Intergroup Rhabdomyosarcoma Study Committee. Intergroup Rhabdomyosarcoma Study; progress report. Proc. Am. Soc. Clin. Oncol. Toronto, May 4-5, 1976, p. 24 (Abstr.).
4. Tefft, M-, et al. for the I.R.S. Committee. Incidence of meningeal involvement by rhabdomyosarcoma of the head and neck. Proc. Am. Assoc. Can. Res., Denver, May, 1977, (Abstr.).
5. Seule, E. H., and Newton, W. A. Intergroup Rhabdomyosarcoma Study (I.R.S.): identification of a histologic subgroup, Ewing's tumor of soft tissue. Proc. Am. Soc. Clin. Oncol., Toronto, May 4-5, 1976, p. 301 (Abstr.).
6. Angervall, L., and Enzinger, F. M. Extraskeletal neoplasm resembling Ewing's sarcoma. Cancer 36 (1975), 240-251.
7. Lawrence, VV., Jr., Hays, D. M., and Moon, T. E. Lymphatic metastasis with childhood rhabdomyosarcoma. Cancer 39 (1977), 556-559.
8. Raney, B., et al. for the I.R.S. Committee. Paratesticular rhabdomyosarcoma in childhood. Proc. Am. Soc. Clin. Oncol. Denver, May, 1977. (Abstr.).
9. Hays, D. M., et al., for the Intergroup Rhabdomyosarcoma Study Committee: Rhabdomyosarcoma; a review of therapy in the extremity lesions of children. In preparation.
10. Hays, D. M., and Ortega, J. Primary chemotherapy in the management of pelvic rhabdomyosarcoma in infancy and early childhood. Proceedings of the International Conference of Adjuvant Therapy of Cancer. Tucson, Arizona, May 2-5, 1977.
11. Tefft, M.. for the I.R.S. Committee. Local control of rhabdomyosarcoma by radiation in patients receiving concomitant chemotherapy; review of the data from the Intergroup Rhabdomyosarcoma Study. Proc. Am. Soc. Therap. Rad. Denver, November, 1977 (Abstr.).
12. Heyn, R. M., et al. The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. Cancer 34 (1974), 2128.
13. Tefft, M., Fernandez, C H., and Moon, T. E. Rhabdomyosarcoma response with chemotherapy prior to radiation in patients with gross residual disease. Cancer 39 (1977), 665-670.
14. Sutow, VV. W., et al. Prognosis in childhood rhabdomyosarcoma. Cancer 25 (1970), 1385-1390.
CLINICAL GROUPING CLASSIFICATION