Alveolar Rhabdomyosarcoma of the Female Genitalia

LARRY J. COPELAND, MD,' NOUR SNEIGE, MD,t C. ALLEN STRINGER, MD,' DAVID M. GERSHENSON, MD,' PATTON 8. SAUL, MD,' AND JOHN J. KAVANAGH, MD'

Eight cases of alveolar rhabdomyosarcoma of the female genitalia were diagnosed from 1%3 to 1983 at The University of Texas M. D. Anderson Hospital. The primary sites were vulva in two, perineum in five, and broad ligament in one patient. When possible, therapy was initiated with local tumor excision (five patients). Surgery was followed by local or regional radiation (six patients) and chemotherapy (seven patients). Of the eight patients, five died within 9 months, one died 27 months after diagnosis, and only two are 5-year survivors. The aggressive behavior of this tumor is evidenced by autopsy findings of widespread metastases. Metastatic disease to the bone was present in four patients and to the breast in three patients. h l disease was controlled in two patients who died of distant metastases. Current therapy recommendations include excisional surgery, local radiation, and combination chemotherapy. A need for more effective chemotherapeutic programs is evident.

Cancer 56:849-855, 1985.

HABWMYOSARCOMA is the most common Soft R tissue sarcoma. Distinctly different neoplasms arising from the rhabdomyoblast have been identified. Horn and Enterline, in their classification of rhabdo- myosarcomas, describe four types: embryonal, botryoid, alveolar, and pleomorphic.' Alveolar rhabdomyosarco- mas were first described by Riopelle and Thkriault' in 1956. Considering that the Intergroup Rhabdomyosar- coma Study (IRS) Report3s4 identified only 18% to 20% of their cases as having the alveolar histologic type and rhabdomyosarcomas arise in the genitourinary tract and perineum in only 15% to 20% of cases,3" it is expected that reports of alveolar rhabdomyosarcoma involving the female genital tract are When such cases are reported, they are usually clustered with either embryonal rhabdomy~sarcomas~~~ or alveolar rhabdo- myosarcomas of extragenital sites." This article on alveolar rhabdomyosarcoma of female genitalia presents The University of Texas M. D. Anderson Hospital (MDAH) experience with respect to presentation, spread pattern, histopathologic features, and treatment.

Materials and Methods

All patients with rhabdomyosarcoma of the female genital tract were identified by a search of the data base of the Department of Patient Studies for patients regis-

From the Departments of *Gynecology and tPathology, The Uni- versity of Texas M. D. Anderson Hospital, and Tumor Institute at Houston, Houston, Texas.

Address for reprints: Lany J. Copeland. MD, Department of Gy- necology, M. D. Anderson Hospital and Tumor Institute, Houston, TX 77030.

Accepted for publication November 13, 1984.

tered at MDAH. Histologic review of all cases confirmed the diagnosis of alveolar rhabdomyosarcoma in eight cases. The lesions were staged according to the IRS classification (Table l)." Information relating to the patients' clinical presentations, treatment, and follow- up results was obtained by a retrospective chart analysis. In each case, slides of the primary tumor and metastases stained with hematoxylin and eosin (H & E) and periodic acid-Schiff (PAS), before and after diastase digestion, were studied.

Results The clinical profiles of the eight patients are summa-

rized in Table 2. Two patients were Hispanic and the remaining six were white. Two patients with vulvar lesions had a primary diagnosis of Bartholin's duct cyst or abscess, and one patient had a preoperative diagnosis of perianal abscess. The chemotherapeutic program usu- ally used is outlined in Table 3. Deviations from this program because of poor patient tolerance or toxicity were frequent. All patients with residual gross disease after initial surgery were nonresponsive to either radio- therapy or chemotherapy. In all patients, except the 15- year-old patient who died 27 months after diagnosis, the clinical course was characterized by rapid tumor growth and widespread metastases. Metastatic disease to the breast was noted in three patients. Two patients who died with extensive metastases appeared to have had their local disease controlled.

Pathologic Findings

All tumors were composed of poorly differentiated cells arranged in solid and alveolar patterns (Figs. 1 and

849

850 CANCER August 15 1985 Vol. 56

TABLE I. Intergroup Rhabdomyosarcoma Study Clinical Staging Classification

Group 1 Localized disease, completely resected 1. Tumor confined to muscle or organ of origin 2. Infiltration beyond site of origin with regional nodes not

involved

Group I 1 Gross excision but either microscopic residual disease or adjacent

organ or regional nodes involved I . Grossly resected but microscopic residual disease (tumor found

by pathologist at margin) 2. Regional disease, completely resected, in which nodes may be

involved or extension of tumor into an adjacent organ present

3. Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual disease

Group 111

Group IV

Incomplete resection or biopsy with gross residual disease

Distant metastatic disease present at onset

Adapted from Maurer.”

2). The latter is characterized by ill-defined nests of cells showing central loss of cellular cohesion and formation of irregular “alveolar” spaces. The individual nests were separated by a framework of dense, frequently hyalinized fibrous septa. The cells at the periphery of the alveolar spaces adhered in a single layer to the fibrous septa, whereas the cells in the center tended to be more loosely arranged or “freely floating” (Fig. 3). The individual cells in both alveolar and solid portions of the tumor were small, round, or oval with scanty, sometimes acidophilic, ill-defined cytoplasm containing hyperchro- matic nuclei with or without inconspicuous nucleoli. Mitotic figures ranged from I to 20 mitosis per high- power field. Occasionally, arrangement of the cells about incomplete trabecular or vascular structures resulted in indistinct “papillary formation” (Fig. 4).

In two cases, neoplastic rhabdomyoblasts with pro- nounced stringy or granular, deeply eosinophilic cyto- plasm were present among the less-differentiated cells, especially in the solid areas (Fig. 2). Multinucleated giant cells with prominent acidophilic cytoplasm and peripherally placed multiple “wreathlike” nuclei were noted in four cases. In one case, there were solid areas in which the cells had abundant pale-staining cytoplasm vaguely resembling a carcinoma. The alveolar pattern was also maintained in the metastases (Fig. 4). No cross- striation was seen with certainty in any of our cases. All tumors contained glycogen, especially in the solid com- ponent.

Discussion

Alveolar rhabdomyosarcoma of the female genital tract is a tumor that the gynecologist encounters rarely. Subsequently, early diagnosis and planning comprehen-

sive therapy is frequently delayed. In 1969, Enzinger and Shiraki reported 110 cases of alveolar rhabdomyo- sarcoma that were accessioned at the Armed Forces Institute of Pathology (AFIP).” Most of these cases were neoplasms of the muscles and soft tissues of the upper and lower extremities; only 16 (14.5%) of the I10 cases involved the perineum, perianal, or perirectal region. In a report from Memorial Sloan-Kettenng Cancer Center, Lloyd and associates presented 54 cases of rhabdomyo- sarcoma in adults.’* Five cases were of the alveolar pattern, and only one of these occurred in the genitouri- nary area. In a recent British review of 55 childhood nonovanan female genital tract cancers, there were 2 cases of alveolar rhabdomyocoma, both in girls younger than 5 years.’

This neoplasm of the vulva and perineum occurs predominantly in the adolescent age group. Character- istically presenting as either a painless or mildly tender mass, this neoplasm is frequently misdiagnosed as a cyst of the Bartholin’s duct or a perirectal abscess (Fig. 5). When the clinician encounters atypical granular or spongy tissue in what was expected to be a cyst or abscess in the vulvar or perineal area, rhabdomyosarcoma should be suspected.

Likewise, pathologists may have difficulty diagnosing this tumor. A tumor with a prominent pseudoalveolar pattern can be mistaken for poorly differentiated ade- nocarcinoma, synovial sarcoma, or malignant heman- gioma.6 Areas of closely packed, poorly differentiated cells are occasionally confused with other small cell malignant neoplasms, including reticulum cell sarcoma, neuroblastoma, Ewing’s sarcoma, Wilms’ tumor, neu- rogenic sarcoma, or liposarcoma.” A careful search for longitudinal and cross-striations may confirm the rhab- domyomatous origin.’ Awareness of the typical micro- scopic appearance of this tumor is important because recognition of the histologic pattern permits, in most instances, a positive diagnosis, even in the absence of rhabdomyblasts. Characteristically, tumor cells in a single layer line “alveolar” spaces. The presence of free-floating cells in the alveolar spaces also aids in alveolar rhabdo- myosarcomas identification. The alveolar rhabdomyo- sarcoma should not be confused with alveolar soft part s a r c ~ m a ’ ~ which, although similar in name, has distinctly different histopathologic features and a better prognosis. Neither should the alveolar rhabdomyosarcoma be con- fused with the embryonal rhabdomyosarcoma (or sar- coma botryoid variant) which, when it occurs in the adolescent, is usually located higher in the genital tract, involving the upper vagina or cervix.

Many of pelvic rhabdomyosarcomas fail to identify the alveolar subpopulation; this makes inter- pretation of treatment programs for the alveolar subtype difficult. Possibly because of the profound lack ofsuccess (only 2 survivors of 102 evaluable cases), a description

No. 4 ALVEOLAR RHABDOMYOSARCOMA - Copeland el al. 85 1

TABLE 2. Alveolar Rhabdomyosarcoma of Female Genitalia

Treatment* CaSe no. Age Si te/stage Surgery Chemotherapy Radiation status Comments

I 13 Perineum and inguinal lncisional biopsy PNS, 6-MP, Head* Dead 7 Metastases to Sc, S, nodes Group Ill CTX mo B, Br, K, P, L, H,

VINC, A, Ln (autopsy) ACTD, HN2

2 18 Left labium majus lncisional biopsy Arterial VINC 4700 rad pelvis, Dead 4 Metastases to Lu, Group 111 during XRT 1500 rad mo Abdominal Ln, V,

perineum Bm, Pt, T, A, P, K, H (autopsy)

3 15 Vulva/Group I Excision: Right pelvic VAC* 4500 rad pelvis,* Living Recurrence 2 mo: mass excised* and lo00 rad 12 yr Right pelvic mass new vulvar lesion perineum* and vulvar lesion excised’

4 16 Pelvis, right broad Right salpingo- VAC 2600 rad strip to Dead 4 Recurred during ligament/Group 111 oophorectomy pelvis mo therapy: Metas-

and excision of mass and lower tases Sc, Ln, Lu abdomen (no autopsy)

5 15 Perineum and Excision VAC and 5500 rad to Dead 27 Recurrence at 19 ischiorectal fossa/ ADR, left pelvis, mo mo: Metastases to Group 1 ADR,* iridium Br and axillary Ln

ALK,* needles (no autopsy) DTlC* (3000 rad)

6 14 Perineum with extension Excision VAC 4400 rad to Living Left external nodes

1000 rad to on pretreatment tumor site lymphangiogram

to left buttock/Group I pelvis plus 7.5 yr called “suspicious”

7 20 Perianal and perineum/ lncisional biopsy VINC, CTX, 4000 rad to Dead3 MetastasesV Group III ADR, pelvis, mo (no autopsy)

DTIC I 0 0 0 rad perineum, 1000 rad inguinal

8 13 Perineum, isochiorectal Incomplete excision VAC, VINC,* 5000 rad to Dead 8 Metastases to Kn, fossa, and pelvic and ADR* pelvis mo V, SP, Br nodes/Group IV (no autopsy)

* For persistence or recurrence. Chemotherapy-ACTD dactinomycin; ADR: doxorubicin; ALK:

melphalan; CTX: cyclophosphamide; DTIC dimethyltriazene: HN2: nitrogen mustard; 6-MP: 6-meraptopurine; PNS: prednisone; VAC vincristine + dactinomycin + cyclophosphamide; VINC: vincristine.

of treatment methods is omitted from Enzinger’s large review of alveolar rhabdomyosarcomas.”

A wide local excision, with clear margins, may reduce the risk of local recurrences. The tendency of the tumor toward early metastases encourages the use of adjuvant therapy, radiotherapy for the local disease in either adjacent soft tissue or lymph nodes, and chemotherapy for occult systemic disease. Many rhabdomyosarcoma tumors respond well to preoperative chemotherapy, which may limit the extent of subsequent surgery.18

For the last 10 years, the predominant chemothera- peutic program for embryonal rhabdomyosarcomas has been the combination of vincristine, dactinomycin, and cyclophosphamide (VAC) in a variety of dosage schedules and corn bin at ion^.^*^^"-^^ This regimen may require dosage adjustments because of myelosuppression and peripheral neurotoxicity. The addition of do~orubicin,~ methotrexate, or bleomycin’2 has not demonstrated superiority to the VAC regimen. Rhabdomyosarcomas,

Metastatic sites: A: adrenals; B: brain; Bm: bone marrow; Br: breasts; H: heart; K: kidney; Kn: knee; L liver, Ln: lymph nodes; Lu: lung; M: mandible: P pancreas; Pt: pituitary; S: skull; SC: subcutaneous; Sp: scapula; T thyroid; V: vertebrae.

TABLE 3. Vincristine Plus Dactinomycin Plus Cyclophospharnide Chemotherapy

. Drug Dose Frequency

Vincristine 2 mg/m2, I v Weekly for 12 weeks (maximum (given concurrent dose 0.5 mg) with radiation;

limited by neurotoxicity)

D actinomycin 15 pg/kg/day, IV Daily for 5 days, (maximum dose given at 4- to 6- 0.5 mg) week intervals as

tolerated (inter- rupted during radiation therapy)

Cyclophosphamide 10 mg/kg/day* Daily for 5 days, given at 4- to 6- week intervals as tolerated (inter- rupted during radiation therapy)

For long-term (2-year) maintenance dose often converted to con-

IV: intravenously. tinuous daily dose of 2.5 mg/kg/day, orally.

852 CANCER August 15 1985 Vol. 56

No. 4 ALVEOLAR RHABDOMYOSARCOMA - Copeland et al. 853

FIG. 1. Tumor cells forming “alveolar” spaces separated by fibrous septae (H & E, X 120).

FIG. 2. Solid cellular portion of alveolar rhabdomyosarcoma with many differentiated deeply eosinophilic rhabdomyoblasts (H & E, X300).

resistant to conventional chemotherapy have responded to cisplatin (3-4.5 mg/kg 8-hour infusion at 3-week

The Intergroup Rhabdomyosarcoma Study 3 and others22 have failed to demonstrate benefit from adjunc- tive radiation in Group I patients. When known residual microscopic tumor (Group 11) exists, adjunctive radiation in moderate doses (4000-5000 rad) has been credited with aiding in the control of local disease.23 The risks of using radiation therapy in the management of female genital tract rhabdomyosarcomas include slipped capital femoral epiphysis, nonfusion of the pubic rami, and hypoplasia of the female genital organs, including radia- tion ~ a s t r a t i o n . ~ ~ . ~ ~ There was no apparent therapeutic benefit of radiation in our patients with gross visible residual tumor. However, in one of our reported cures, the pretreatment staging evaluation revealed “suspi- cious,” but histologically unconfirmed, pelvic lymph- adenopathy.

Of the rhabdomyosarcomas encountered in children, the alveolar type has the worst progno~is.~.’ Reported

survivors of alveolar rhabdomyosarcoma are rare. In a review, Milkulowski and Berge’“ reported that 28 of 30 patients died from their tumor. In the two surviving patients, the female genitalia were not the site of the primary tumors. Enzinger and Shiraki reported that only 2 of 102 evaluable patients were alive beyond 5 years of diagnosis.” Both of these survivors were young boys with extremity lesions. None of their 16 patients with perineal, perianal, or penrectal lesions were iden- tified as cured. Neither the sex of the patient nor the site of the lesion is given in the one 5-year survivor of seven cases reported by Anel and Bri~eno.~’ Horn and Enterline reported no survivors among their patients with alveolar rhabdomyosarcoma.’ The recent IRS-I report of their alveolar histologic subtype describes no patients with the primary in the female genital tract. One third of the nine patients with perineal lesions are reported ~urviving.~

Early lymphatic and hematogenous spread is the rule rather than the exception. The AFIP review noted that at autopsy, lymph node, lung, pancreas, and bone

FIG. 3. Alveolar spaced with a single layer of viable tumor cells attached to the intervening fibrous septa. Some rhabdomyoblasts appear free in the alveolar space (H & E, X300).

854 CANCER August 15 1985 Vol. 56

FIG. 4. Metastatic alveolar rhabdomyosarcoma in breast tissue. Notice the alveolar pattern with focal papillary formation (left) (H & E. Xl50).

metastases were present in more than 50% of cases." Other sites, including heart, adrenals, testes, ovaries, and kidney had metastases in at least 25% of cases.

FIG. 5. Alveolar rhabdomyosarcoma of leR labium majus.

Three of six patients with recurrent tumor in our series had breast metastases; this concurs with the high incidence of breast involvement in a study from St. Jude's Children's Research Hospital.28 They reported 6 cases of breast metastases among 18 patients with alveolar rhabdomyosarcoma. Five of their 18 patients were fe- male, and 4 of the 5 developed breast metastases. The breast metastases in all six patients reported by Howarth and associates developed when the patients were 13 years of age or older. For these reasons Howarth and associates suggested that the physiologic state of the breast was an important determining factor in the development of such metastases.28 The three cases of breast metastases in our series were in adolescent girls undergoing breast growth. Lloyd and associates' review12 of rhabdomyosarcomas in adults described five patients with alveolar type tumors, and none were reported to have breast metastases, lending support to the concept that the developing breast is at higher risk for being involved with metastases.

The unexplained high incidence of pancreas, bone, heart, and adrenal metastases reported by the AFIP is uncommon in other neoplasms of the vulva or sarcomas of the female genital tract.29 In this review, the autopsy in two cases demonstrated metastases to all of these sites.

No. 4 ALVEOLAR RHABDOMYOSARCOMA * Copeland et al. 855

When planning staging workups, the numerous sites at risk should be evaluated. Quddus and associates3’ have noted that skeletal surveys by means of x-ray are superior to bone scans in detecting metastatic bone involvement in patients with rhabdomyosarcomas.

In summary, this rare neoplasm occasionally involves the vulvar and perineal tissue. Since the lesion often mimics benign vulvar entities, delays in diagnosis are both common and critical. The dismal survival rates reported for alveolar rhabdomyosarcoma are the sequelae of early disease dissemination. Hope for improving survival lies in early diagnosis and new therapeutic approaches. Results of current therapy, consisting of excision, local radiotherapy, and systemic chemotherapy, should be improved upon. New, more effective chemo- therapeutic programs are needed, since the regimens used to date, including VAC, have demonstrated limited activity against this tumor.

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