Management of Embryonal Rhabdomyosarcoma in Children

Symposium on Surgical Oncology

Management of Embryonal Rhabdomyosarcoma in Children

Philip R. Exelby, MD.*

Embryonal rhabdomyosarcoma is the commonest soft tissue sarcoma seen in children. It is a highly malignant tumor which previously had a poor prognosis. In recent years combined treatment of surgery, irradiation, and chemotherapy has greatly improved the outlook for children with this disease. 2 ,4-11,14 Due largely to improved chemotherapy and advances in radiation therapy, it is now possible to produce higher cure rates with less extensive surgical procedures. Amputation, which was the treatment of choice for extremity lesions 10 years ago, is no longer carried out as a primary surgical procedure. Less radical operations are currently being proposed for pelvic rhabdomyosarcoma in children: The surgeon, radiation therapist, and chemotherapist are now working together to further improve survival, and to minimize the longterm side effects of treatment. The surgeon's role in the combined management of these children goes beyond the initial surgical removal of the primary tumor. It may be necessary to protect the child's normal organs from the damaging effects of high dose irradiation. Techniques have been developed for collapsing the lung during chest wall irradiation, repositioning pelvic viscera by inserting prosthetic devices, and surgically moving organs such as ovary or testis away from the radiation portal. 3 , 12 Depression of platelets and leukocytes occurring during chemotherapy and radiation therapy may predispose to bleeding, abscess formation, or acute abdominal emergencies. The surgeon must be aware of these complications and correct them surgically where indicated. Lastly the child's nutrition must be maintained during chemotherapy, particularly when combined with irradiation of the abdomen or head and neck areas. Gastrostomy feedings may be the only way to ensure adequate food intake in such patients who cannot tolerate nasogastric feeding tubes. Gastrostomy is carried out before the child's nutritional state deteriorates, often prophylactically before treatment begins. ':'Chief, Pediatric Surgical Service, Memorial Sloan-Kettering Cancer Center, New York, New York

Surgical CLinics of North America- Vol. 54, No.4, August 1974

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Thus the surgeon has multiple roles in the management of these children, and must remain an active member of the combined therapy team throughout all phases of treatment. Pathology Rhabdomyosarcomas are malignant tumors of the rhabdomyoblasts; in children they are predominantly embryonal rhabdomyosarcomas. Two varieties of embryonal rhabdomyosarcoma are seen in children: the solid variety, and the grapelike lesions, so-called sarcoma botryoides. These are really variants of the same tumor, and the difference in gross appearance is accounted for by the site of origin of these tumors. The solid embryonal rhabdomyosarcomas occur in the extremities, trunk, and head and neck region, and the sarcoma botryoides variety occurs in hollow viscera, such as bladder, vagina, and common bile duct. The solid tumor is an irregular, lobulated mass with a soft to rubbery consistency. It is often a red or purple colored lesion, but the color may vary in different parts of the tumor due to areas of hemorrhage and necrosis. The botryoid variety of this tumor, as its descriptive title suggests, gives the appearance of a bunch of grapes growing into the hollow viscus. These grapelike polyps are soft and shiny and arranged in clusters and may grow to enormous size. The surface lining of these polyps is often the normal mucosa of the organ involved. This becomes thinned out and frequently ulcerates and bleeds. The microscopic appearance of the solid embryonal rhabdomyosarcoma and the sarcoma botryoides is essentially the same, the difference being the amount of myxoid ground substance which is markedly increased in the grapelike lesions. The basic cell of the embryonal rhabdomyosarcoma is the rhabdomyoblast. This may vary somewhat in size and maturation. The cells may be small and rounded with or without acidophilic cytoplasm. Sometimes the larger cells may form cross striations or peripherally arranged vacuoles forming the so-called spider web cell. The cells may be elongated with acidophilic cytoplasm and have two or more nuclei. There are often areas of myxoid tissue with stellate cells predominating and only rare differentiated cells. The botryoid tumors generally have a layer of the less differentiated, small, rounded rhabdomyoblasts between two and four cell layers thick with many mitoses. This surface layer is normally covered by the mucosa of the organ involved, such as bladder mucosa or vaginal mucosa. Beneath the layer of the rhabdomyoblasts is an abundance of myxoid tissue with a varying number of the stellate cells. The remainder of the tumor, in its deeper layers, may resemble the solid variety with embryonal rhabdomyoblasts in different stages of maturation and with different amounts of mitotic activity. Incidence It is estimated that rhabdomyosarcoma forms between 5 and 8 per cent of the solid cancers in children, being third only to Wilms' tumor and neuroblastoma in incidence. The age incidence of these tumors varies with location (Fig. 1.). The median age in rhabdomyosarcoma is 5 years. The lesions in the head and neck, extremities, and trunk may be seen at any age and have an even

851

MANAGEMENT OF EMBRYONAL RHABDOMYOSARCOMA IN CHILDREN

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24 22

20 18 .l!l <:

16

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14

:! "E

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Z

12 10 8

6

4 2 0 2

4

5

6 8 Age in years

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11

12

13

14

Figure 1. Age distribution of embryonal rhabdomyosarcoma, 1960 to 1969.

spread through the childhood years. Sarcoma botryoides in the bladder, prostate, and vagina has a peak incidence in the infancy years. Seventyfive per cent of the vaginal lesions will be seen before the age of 2. The paratesticular lesions seen in the boys are primarily seen after the age of 9 and reach a peak incidence between 14 and 17. Location of Tumors Embryonal rhabdomyosarcoma tends to present in certain areas of the body more commonly than others and is relatively rare outside these areas of predilection (Table 1). Approximately 50 per cent of embryonal rhabdomyosarcomas occur in the head and neck area. The commonest site in this region is the orbit, followed by nasopharynx, parotid, and neck. Twenty per cent of the tumors occur in the extremities as the solid variety, and 20 per cent will occur in the lower genitourinary tract, either as sarcoma botryoides of the bladder or vagina or the solid paratesticular rhabdomyosarcoma. The remaining 10 per cent of the tumors in children will be found on the trunk or chest wall, or within the abdominal cavity. Course of the Disease In contrast to many sarcomas, the initial spread of embryonal rhabdomyosarcoma is often to regional lymph nodes. The tumor may remain Table 1. Location of Embryonal Rhabdomyosarcoma in Children Head and neck Extremities Genitourinary tract Intraabdominal } Chest wall Trunk

50 per cent 20 per cent 20 per cent 10 per cent

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localized to lymph nodes for a considerable period of time. The tumor also spreads hematogenously and may metastasize simultaneously to lymph nodes and lungs. Late metastases may occur to almost any organ in the body, including liver, bone, and brain. Embryonal rhabdomyosarcoma in all locations is extremely aggressive and infiltrates tissue planes and connective tissue barriers without difficulty. Management GENERAL. The initial treatment in most locations is radical surgical excision of the tumor. An attempt must be made to excise all tumor with a margin of normal tissue. In addition we carry out a regional node dissection, if possible, in continuity with the primary excision. Irradiation is given to the primary site if margins of resection contain tumor. If regional nodes are positive for tumor, the primary site and regional lymph drainage areas are treated by postoperative irradiation. Radiation therapy is used as primary treatment in most head and neck lesions where surgery would be mutilating, and in grossly inoperable lesions at other sites. All children would then receive 2 years of chemotherapy consisting of a four-drug protocol of dactinomycin, adriamycin, vincristine, and cyclophosphamide (Fig. 2.). This would be continued as a cyclic regimen for a period of 2 years and then stopped. The evaluation and initial treatment vary somewhat depending on the location of the tumor. HEAD AND NECK EMBRYONAL RHABDOMYOSARCOMA. These tumors usually present as a mass in the orbit, parotid, or neck. In the nasopharynx they present as nasal obstruction, nose bleeds, or chronic upper respiratory infection. Disease in the head and neck region may spread to regional lymph nodes in the neck before spreading to lungs. Primary treatment of the head and neck lesions would depend on their location. All suspected lesions have a surgical biopsy prior to definitive therapy.

SURGERY RADIATION

•

CHEMOTHERAPY

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70

80

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Figure 2. Multidiscipline protocol (T2) for childhood tumors at Memorial Sloan· Kettering Cancer Center.

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Rhabdomyosarcomas in the nasopharynx and orbit are then treated by radiation therapy. A dosage of between 5000 and 6000 rads is usually recommended to eradicate this tumor by radiation therapy. If the tumor is accessible to surgical excision, such as in the parotid or in the neck, then a wide excision of the primary tumor would be carried out with in-continuity radical neck dissection. In those children treated by surgery, radiation therapy would only be given where margins of resection were microscopically positive or lymph node metastases were proven by histologic examination . TRUNK AND EXTREMITY EMBRYONAL RHABDOMYOSARCOMA. These tumors commonly present as a palpable tumor mass, usually deep seated but occasionally involving the skin. They are soft to firm tumors relatively fixed to underlying musculature. They are not painful and rarely produce any other symptom but the mass. These tumors spread to regional lymph nodes and to the lungs. The primary management of trunk and extremity lesions is surgical; if possible, a wide excision of the tumor mass and surrounding normal tissues is carried out. This means a muscle group resection in the extremities and a wide excision in all directions in the trunk lesions combined with a regional lymph node dissection. There are circumstances where gross removal of tumor is impossible due to extent of disease or involvement of vital structures in the extremity. An attempt should be made to excise as much tumor as possible and still leave a viable extremity. Residual disease would then be treated by irradiation. Amputation would only be carried out where surgery and irradiation fail to control local tumor. When surgery removes all tumor, radiation therapy would not be given postoperatively. Where microscopic or gross disease is left after surgery, or regional nodes are histologically positive for tumor, irradiation is given to tumor bed and nodal areas. All children receive four-drug chemotherapy as outlined above. SARCOMA BOTRYOIDES OF THE VAGINA, BLADDER, AND PROSTATE. These lesions form a special category because of the nature of the tumor and because they are largely diseases of infancy. Vagina. In the vaginal lesions the commonest presenting symptom is vaginal bleeding and will be seen in about half the children. The other half present with a polypoid mass protruding from the vagina or passage of tissue from the vagina. These tumors spread by direct extension to other pelvic structures, such as bladder, rectum, and pelvic wall. They also metastasize to the pelvic and paraaortic lymph nodes. Pain is remarkably absent in this lesion until the tumor is far advanced locally. Ob.struction of the ureters or bladder outlet is only seen in advanced cases. Prior to definitive treatment a complete evaluation of the pelvis is carried out under anesthesia. This includes proctosigmOidoscopy, cystoscopy, and pelvic and vaginal examination with multiple biopsies. Once the diagnosis is confirmed and extent of disease determined, treatment is either radical surgical excision or radiation followed by four-drug chemotherapy. At the present time surgery involves anterior, posterior, or total pelvic exenteration with preservation of one ovary. There is some evidence that less radical surgery, preserving bladder and rectal function, may be possible as more effective chemotherapy and radiation therapy become

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available. 2 • 10, 11, 13 Extensive inoperable tumors are treated by irradiation and chemotherapy. Bladder and Prostate. These tumors are usually located low down on the posterior wall of the bladder or in the prostate, and cause urinary retention as an early symptom. In some cases both bladder and prostate are involved and the exact site of origin cannot be determined. Intravenous pyelograrn wili usually outline the polypoid lesions in bladder tumors. A cystogram is carried out in all cases to determine extent of bladder involvement. Panendoscopy, cystoscopy, and proctosigmoidoscopyare carried out to determine extent of disease. Multiple biopsies are performed from any suspicious areas during endoscopy. Surgical treatment consists of radical cystectomy or prostatectomy, or both with ileal conduit urinary diversion. Postoperative irradiation is given to the entire pelvis where margins of resection contain tumor cells or lymph nodes contain disease. Chemotherapy is given for 2 years as outlined above. PARATESTICULAR RHABDOMYOSARCOMA. These tumors present with an expanding, non tender mass in the scrotum usually lying above and separate from the testis. The tumor tends to grow rapidly and metastasizes early to regional lymph nodes. Whereas testis tumors in children rarely involve regional nodes, paratesticular rhabdomyosarcoma spreads to pelvic and retroperitoneal lymph nodes. A secondary hydrocele may be present associated with a para testicular rhabdomyosarcoma. In the late cases, it may be impossible to distinguish these tumors from primary testis tumors. The management of paratesticular rhabdomyosarcoma involves a transinguinal biopsy of the mass with the cord clamped. If the diagnosis of paratesticular rhabdomyosarcoma is confirmed, definitive surgery then consists of hemiscrotectomy, radical orchiectomy, combined with an ipsilateral pelvic node dissection, and paraaortic node dissection. , ,6 Postoperatively, radiation therapy would only be given if margins of resection were involved with tumor microscopically or if regional lymph nodes were diseased. All the children would get the fourdrug chemotherapy for 2 years. INTRAABDOMINAL RHABDOMYOSARCOMA. Rhabdomyosarcoma may occur almost anywhere within the abdominal cavity. The problem is really differential diagnosis of an abdominal mass. Management of rhabdomyosarcoma within the abdominal cavity is excision of the primary tumor with as much surrounding margin as is possible. Following excision, radiation therapy would only be given if the margins of resection were involved with tumor. Four-drug chemotherapy would be given as in other locations. Fortunately, intraabdominal rhabdomyosarcoma is rare in children because it has the worst prognosis of any location. CHEST WALL RHABDOMYOSARCOMA. Occasionally a tumor arising on the chest wall presents special problems. Small lesions are best excised and treated similarly to trunk tumors. Larger tumors or those extending into the neck from the chest wall are treated by radiation therapy. The problem of damaging irradiation to the underlying lung has been successfully handled by collapsing the lung by artificial pneumothorax.~ A small catheter is placed into the pleural space and air introduced until the lung is completely collapsed. The pneumothorax is maintained for 5 days

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B

c Figure 3. A, Roentgenogram of patient with rhabdomyosarcoma in upper chest wall and supraclavicular region . B, Same patient with 100 per cent right pneumothorax, induced during irradiation to the chest wall. C, Normal chest roentgenogram after 5100 rads to chest wall.

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Table 2. Results of Treatment of Embryonal Rhabdomyosarcoma NO. OF YEAR OF DIAGNOSIS

1960 to 1966 1967 to 1969 1970 to 1973

TREATMENT

Surgery and/or radiation therapy Surgery and/or radiation therapy + chemotherapy Surgery and/or radiation therapy + chemotherapy

PATIENTS

PER SURVIVORS

CENT

38

13 14

36

25

21*

84

73

18

"Living Free of Disease 9 patients more than 2 years (off chemotherapy) 7 patients 1 to 2 years 5 patients less than 1 year

while irradiation is delivered. At weekends the lung is re-expanded, allowing the child to go home. Pneumothorax is reintroduced the following Monday, and the cycle repeated until radiation therapy is complete. This procedure is safe and well tolerated by the children. Using this technique, there has been no impairment of pulmonary function in these children despite high dose irradiation to large portions of the chest wall (Fig. 3). Results of Treatment At Memorial Hospital from 1960 to 1966, the 2-year survival of lOS children with embryonal rhabdomyosarcoma was IS per cent (Table 2). From 1967 to 1969, a period in which chemotherapeutic agents were first used extensively, approximately 36 per cent of the patients are surviving more than 2 years. Since 1970, when surgery and radiation therapy were combined with intensive four-drug chemotherapy, results have shown even greater improvement. Twenty-five patients have been treated by this combined approach, and 21 (S4 per cent) are living between 5 months and 3 years free of disease. Of these survivors, nine are off all treatment and are surviving more than 2 years. Seven others are still on chemotherapy free of disease more than 1 year, and the remaining five children are free of disease but less than 1 year from diagnosis. The five children who died of disease all had advanced recurrent or metastatic tumor when first seen. Ten years ago SO per cent of children with rhabdomyosarcoma died; now it seems that SO per cent will live with current combined treatment methods.

REFERENCES J. D.: Rhabdomyosarcoma of the paratesticular tissues in children. Report of eight cases. J. Pediat. Surg., 4:503-510, 1969. 2. Clatworthy, W. H., Jr., Braren, V., and Smith, J. P.: Surgery of bladder and prostatic neoplasms in children. Cancer,32:1157-60, 1973. 3. D'Angio, G. J., Exelby, P. R., Ghavimi, F., Cham, W. G., and Tefft, M.: Protection of certain structures from high doses of irradiation. Amer. J. Radiol. Nucl. Med., (in press). 1. BUrrington,

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4. Donaldson, S. S., Castro, J. R., Wilbur, J. R., and Jesse, R. H.: Rhabdomyosarcoma of head and neck in children. Combination treatment by surgery, irradiation and chemotherapy. Cancer, 31 :26-35, 1973. 5. Exelby, P. R.: Soft part sarcomas in children-1972. Seventh National Cancer Conference Proceedings. J. B. Lippincott Co., 1973, pp. 619-625. 6. Ghavimi, F., Exelby, P. R., D'Angio, G. J., and Murphy, M. L.: Combination therapy in children· with embryonal rhabdomyosarcoma. Proc. Assoc. Cancer Res., 14:54, 1973 (abstr.). 7. Ghavimi, F., Exelby, P. R., D'Angio, G. J., Whitmore, W. F., Jr., Lieberman, P. H., Lewis, J. L., Jr., Mike, v., and Murphy, M. L.: Combination therapy of urogenital embryonal rhabdomyosarcoma in children. Cancer, 32: 1178-1185, 1973. 8. Grosfeld, J. L., Smith, J. P., and Clatworthy, H. W., Jr.: Pelvic rhabdomyosarcoma in infants and children. J. UroL, 107:673-675, 1972. 9. Grosfeld, J. L., Clatworthy, H. W., Jr., and Newton, W. A., Jr.: Combined therapy in childhood rhabdomyosarcoma. An analysis of 42 cases. J. Pediat. Surg., 4:637-645. 1969. 10. Heyn, R. M., Holland, R., Newton, W. A., Jr., Tefft, M., Breslow, N., and Hartmann, J.: The role of combined chemotherapy in the treatment of rhabdomyosarcoma in children. For Children's Cancer Study Group A. Cancer (in press). 11. Kilman, J. W., Clatworthy, H. W., Jr., Newton, W. A., Jr., and Grosfeld, J. L.: Reasonable surgery for rhabdomyosarcoma. A study of 67 cases. Ann. Surg., 178:3:346-351, 1973. 12. Nahas, W. A., Nisce, L. Z., D'Angio, G. J., and Lewis, J. L., Jr.: Lateral ovarian transposition. Obstet. Cynec., 38: 785-788, 1971. 13. Tefft, M., and Jaffe, N.: Sarcoma of the bladder and prostate in children. Cancer, 32:11611177, 1973. 14. Wilbur, J. R., Sutow, W. W., Sullivan, M. P., Castro, J. R., and Taylor, H. C.: Successful treatment of rhabdomyosarcoma with combination chemotherapy and radiotherapy. Amer. Soc. CUn. Oncology, 7:56, 1971 (abstr.). Memorial Hospital for Cancer and Allied Diseases 444 East 68th Street New York, New York 10021