Adult paratesticular rhabdomyosarcoma

Kazunori Haga*, Akira Kashiwagi, Satoshi Nagamori and Katushige Yamashiro About the authors
Correspondence *Department of Medicine, University of California, Los Angeles, 675 Charles E Young Drive South, Los Angeles, CA 90095, USA Email kazunori@ucla.edu

SUMMARY
Background A 29-year-old male patient presented with a history of painless enlargement of the left hemiscrotum. Investigations Laboratory tests for -human chorionic gonadotrophin, -fetoprotein, and lactate dehydrogenase, physical examination, and CT of the chest, abdomen and pelvis. Histologic examination, nerve-sparing retroperitoneal lymph-node dissection. Diagnosis Paratesticular rhabdomyosarcoma with lymph node metastasis. Management Inguinal radical orchiectomy and adjuvant chemotherapy for 48 weeks. Radiotherapy and additional chemotherapy were administered following local recurrence. Keywords: paratesticular rhabdomyosarcoma, retroperitoneal lymph-node dissection
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THE CASE
A 29-year-old man presented with a 3-month history of painless enlargement of the left hemiscrotum measuring approximately 30 mm in diameter. He was otherwise healthy and had no previous history of disease. His WHO PERFORMANCE STATUS was 0. Laboratory tests revealed that serum markers for -HUMAN CHORIONIC GONADOTROPIN and -FETOPROTEIN were within the normal range, although LACTATE DEHYDROGENASE levels were slightly elevated. CT of the chest, abdomen and pelvis revealed no metastasis. Inguinal radical orchiectomy was performed without any complications, and the tumor was macroscopically excised completely. Histologic examination revealed embryonal rhabdomyosarcoma, composed predominantly of poorly differentiated cells and rhabdomyoblasts containing a plump eosinophilic cytoplasm, with necrotic tissues (Figure 1). Immunocytochemical staining was strongly positive for vimentin, desmin, myoglobin and keratin. The final pathologic diagnosis was paratesticular embryonal rhabdomyosarcoma. Figure 1 Histologic findings of the resected tumor.

Embryonal rhabdomyosarcoma mainly composed of poorly differentiated cells and rhabdomyoblasts with plump eosinophilic cytoplasm. Reduced from 400 magnification.

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Since CT scanning of the chest, abdomen and pelvis revealed no evidence of metastatic disease or lymphadenopathy, the patient was diagnosed as clinical stage I, and Group I according to the Intergroup Rhabdomyosarcoma Study (IRS) classification system (Table 1).1 Following consultation with the most current IRS protocol, and after extensive discussion, the patient elected to undergo modified leftnerve-sparing retroperitoneal lymph-node dissection (Figure 2).2 No complications occurred. Histologic examination revealed rhabdomyosarcoma lymph-node micrometastases, and the patient was restaged as IRS Group IIB. Adjuvant chemotherapy was selected, following an IRS-III pediatric protocol.3 A 4-week cycle of IRS-III chemotherapy regimen 36, comprising vincristine, actinomycin D, cyclophosphamide, doxorubicin and etoposide, was administered for 48 weeks (Figure 3).4 During chemotherapy, side effects such as PANCYTOPENIA, emesis, loss of appetite, and alopecia increased progressively, but the patient tolerated the chemotherapy well. After completing the chemotherapy, he was discharged with a WHO performance status of 0. Figure 2 Macroscopic view of the left retroperitoneal lymph node, resected prior to chemotherapy, mapped on the schema of major vessels and ureters.

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Figure 3 Treatment schema for Intergroup Rhabdomyosarcoma Study IRSIII chemotherapy regimen 36

With regard to the radiotherapy element of the protocol, patients with Group I (alveolar histology only) or Group II tumors received 41.4 Gy; patients with Group III or Group IV tumors received 41.450.40 Gy depending on age and tumor size. Doses to metastatic sites depended on specific tissue tolerance. In this patient, a 4-week cycle of this regimen was administered for 48 weeks. A, intravenous actinomycin D 0.015 mg/kg/day (maximum single dose 0.5 mg) 5; A2, intravenous actinomycin D 1.2 mg/m2; C3, intravenous cyclophosphamide 10 mg/kg/day 3; C4, intravenous cyclophosphamide 20 mg/kg (week 6 and 9 doses were omitted in patients who received radiation to the bladder or had large volumes of bone marrow irradiated); CR,

complete response; D, intravenous doxorubicin 60 mg/m2; D2, intravenous doxorubicin 30 mg/m2/day 2; DTIC, imidazole carboximide 200 mg/m2/day 5; E, intravenous etoposide 100 mg/m2/day 3; EVAL, surgical evaluation with biopsy or tumor resection; Mx, mixed response; NR, no response or progressive disease; P, intravenous cisplatin 90 mg/m2; PR, partial response; q, every; RT, radiation therapy; V, intravenous vincristine 2 mg/m2 (maximum single dose 2 mg); V2, intravenous vincristine 2 mg/m2/day (maximum single dose 2 mg) on days 1 and 4. Adapted from reference 1 (2001) American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. Full figure and legend (15K)Figures & Tables indexDownload Power Point slide (225K)
Table 1 Intergroup Rhabdomyosarcoma Study tumor grouping system.

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After 4 months, the patient had a local recurrence at the left inguinal region, between the primary resected site and the site of the retroperitoneal lymph-node dissection. This region was resected and the patient received local radiotherapy; 50 Gy to the retroperitoneal region, followed by adjuvant chemotherapy (etoposide, nedaplatin, and ifosfamide) for 3 months. The patient currently remains disease-free, 24 months postoperatively.
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DISCUSSION
Adult paratesticular rhabdomyosarcoma is extremely rare and has highly malignant potential. On the other hand, rhabdomyosarcoma is one of the most common tumors found in children:5 two incidence peaks occur, the first between 2 and 6 years of age and the second between 15 and 19 years of age. About 70% of all cases occur before 10 years of age. Paratesticular rhabdomyosarcoma is extremely rare in adults; soft tissue sarcomas make up less than 1% of all adult malignancies, and rhabdomyosarcoma accounts for only 3% of all soft tissue sarcomas. Paratesticular rhabdomyosarcoma arising from the mesenchymal tissue of the spermatic cord, epididymis, testis and testicular tunic occurs in approximately 7% of all known rhabdomyosarcoma cases and tends to have a better prognosis than other forms of rhabdomyosarcoma. However, this tumor spreads rapidly and thus needs to be diagnosed accurately and treated as early as possible.
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DIFFERENTIAL DIAGNOSIS AND HISTOLOGIC EXAMINATION

Clinically, paratesticular rhabdomyosarcoma usually presents as an intrascrotal mass, sometimes reaching the external inguinal ring. Pain is associated with the tumor in only 7% of cases. Paratesticular rhabdomyosarcoma compresses the testis and epididymis, and is sometimes misdiagnosed as a hydrocele or a testicular tumor. There are no specific serum markers for this tumor, and the patient had normal levels of -human

chorionic gonadotropin and -fetoprotein, but slightly elevated lactate dehydrogenase levels. Although macroscopically the tumor may appear circumscribed, on microscopic examination paratesticular rhabdomyosarcoma often extends well beyond the margins seen by the naked eye and, therefore, it should be completely removed. Thorough histologic examination is also essential. All histologic subtypes of rhabdomyosarcoma can occur in the paratesticular region, although the most common subtype seen is embryonal, followed by alveolar, pleomorphic, and mixed. In this case, the presence of poorly differentiated cells and rhabdomyoblasts containing eosinophilic cytoplasm indicated embryonal rhabdomyosarcoma. Cytogenetically, partial monosomy of chromosome 11 often characterizes embryonal rhabdomyosarcoma, although this was not examined in this case. Spindle-cell rhabdomyosarcoma is a variant of embryonal rhabdomyosarcoma that has an excellent prognosis. Histologic examination reveals bundles of spindle cells with eosinophilic and clear cytoplasm, and rhabdomyoblasts with plump eosinophilic cytoplasm. Desmin, myoglobin and myoblast determination protein 1 immunostains confirm skeletal muscle differentiation. Histologic examination revealed no elements of spindle-cell rhabdomyosarcoma in this case.
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TREATMENT AND MANAGEMENT

A chemotherapy regimen of vincristine, actinomycin D, and cyclophosphamide is reported to be effective for childhood rhabdomyosarcoma.4 However, adult patients have a poorer prognosis than children, with a 5-year event-free survival and 5-year overall survival of 28% and 40%, respectively.6 Many trials have been carried out to compare different treatment options for rhabdomyosarcoma.7 In the IRS classification system for this condition, metastasis is the critical point, as with most other cancers. Paratesticular rhabdomyosarcoma patients in IRS Group IV have an extremely poor prognosis, with a 5-year survival rate of 22.2%, while patients in Groups IIII have a 5-year survival rate of 94.6%.8 In this case, the patient's clinical stage was initially thought to be Group I, since the CT scan revealed no evidence of metastasis. However, following retroperitoneal lymph-node dissection, lymph-node metastasis was found and the patient was reclassified as Group IIB. Because adult rhabdomyosarcoma is so rare, therapy protocols have not yet been established. Therefore, a pediatric protocol was followed and the patient was initially treated with a vincristine, actinomycin D, and cyclophosphamide chemotherapy regimen.9, 10 The literature states that retroperitoneal lymph-node dissection is not necessary in children younger than 10 years with clinically negative nodes, as determined by preoperative imaging studies. Chemotherapy is able to control micrometastases of retroperitoneal nodes once the primary tumor has been completely resected, but paratesticular rhabdomyosarcoma patients older than 10 years have a higher likelihood of nodal involvement and should therefore receive unilateral nerve-sparing retroperitoneal lymph-node dissection.2 The role of retroperitoneal lymph-node dissection for paratesticular rhabdomyosarcoma is controversial;4, 8 however, this procedure is important for both accurate staging and local treatment, since lymphnode involvement is a crucial prognostic factor. In this case, it was decided that the advantages in terms of diagnosis and treatment outweighed the operative risks of the procedure. Radiation is recommended for patients with lymph-node metastasis. Univariate analysis of 28 cases of rhabdomyosarcoma revealed that parenchymal metastasis and unresectability were the most important predictors of mortality, and multivariate analysis has shown that unresectability is the most important predictor of a fatal outcome.11 Consequently, retroperitoneal lymph-node dissection is mandatory for the accurate staging of adult paratesticular rhabdomyosarcoma patients, and could

determine whether adjuvant abdominal radiotherapy is required for patients belonging to IRS Group II.2 Adult paratesticular rhabdomyosarcoma is a rare tumor and takes time to diagnose and to determine the pathologic stage. In this case, the chemotherapy protocol had been started by the time a diagnosis was reached. It was therefore decided not to administer radiation therapy at this point. Patients with paratesticular rhabdomyosarcoma should be treated with a combined approach including inguinal radical orchiectomy, local radiotherapy (in the case of microscopic or macroscopic residual tumor after initial or delayed surgery), and multiple sequential or cyclic chemotherapy.2 An adjuvant chemotherapy regimen of vincristine, actinomycin D and cyclophosphamide has been reported to improve survival in group I rhabdomyosarcoma. Therefore, the patient in this case was treated using an IRS protocol. Since therapy protocols for adult rhabdomyosarcoma have still not been established, and the IRS study showed few differences between the IRS-III and IRSIV protocols,12 the patient was treated with IRS-III protocol 36. Following chemotherapy, the patient had a local recurrence. The region was resected again, and the patient was subjected to radiotherapy and chemotherapy. The treatments were well tolerated and the patient has shown no further evidence of disease in the 24 months following the operation.
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CONCLUSION
Paratesticular rhabdomyosarcoma tumors may grow rapidly, and thus need to be diagnosed and treated as early as possible. Retroperitoneal lymph-node dissection is crucial for both accurate staging and treatment, particularly in adult patients, as demonstrated in this case where the procedure allowed accurate restaging of the patient. Surgical resection is necessary and combined chemotherapy is the standard treatment. In the absence of protocols designed specifically for adult patients, it is necessary to follow therapeutic guidelines in pediatric protocols. REFERENCES
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