Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is a soft tissue tumor originating from immature mesenchymal cells that form any tissue except bone. It is the most common soft tissue sarcoma in children and adolescents, accounting for approximately 50% of soft tissue sarcomas. The overall survival (OS) of RMS patients has improved to 71% as a result of the Intergroup Rhabdomyosarcoma Study Group (IRSG; established in 1972), which is now continued by the Children’s Oncology Group Soft Tissue Sarcoma (COG-STS) committee.1,2
RMS is the third most common childhood extracranial solid tumor, after neuroblastoma and Wilms tumor.3 Approximately 350 new cases of RMS are diagnosed annually in the USA, corresponding to an incidence of 4.5 cases per million children aged 20 years or younger.4,5 RMS has a bimodal distribution with approximately 65% of cases occurring in children <6 years and the remaining cases developing in children aged 10–18 years.6 More than 80% of cases are diagnosed before the age of 14 years.7 Outcomes are worse in adolescents who usually present with alveolar RMS, lymph node involvement, delay in diagnosis, and metastases.8 Poor outcomes are also seen in infants usually due to failure to achieve adequate local control.9
Approximately one-third of RMS occurs in the head and neck (including parameningeal locations). Genitourinary locations are found in 22–31% of cases; trunk and extremities are the next most common sites.1,5
RMS is classified as a small, round, blue cell tumor of childhood, a category including neuroblastoma, Ewing sarcoma, small cell osteogenic sarcoma, non-Hodgkin lymphoma, and leukemia. Six major pathologic subtypes of RMS are outlined by the International Classification of RMS in order of decreasing 5-year survival): (1) embryonal (botryoid); (2) embryonal (spindle cell); (3) embryonal, not otherwise specified (NOS); (4) alveolar, NOS or solid variant; (5) anaplasia, diffuse; and (6) undifferentiated sarcoma.10 Botryoid RMS is associated with a superior 5-year survival rate of 95% and most commonly occurs in the bladder or vagina in infants and young children, and in the nasopharynx in older children.11 Spindle cell RMS is commonly found in the paratesticular area, head and neck, extremities, or orbit.12 Embryonal and embryonal variants account for approximately 60–70% of all pediatric RMS cases in younger patients.5,11,13,14 Alveolar, anaplastic, and undifferentiated variants of RMS account for approximately 35% of all new cases, and generally have the worst prognosis. The incidence of alveolar RMS is increasing with an annual per cent change (APC) of 4.09%.5 The alveolar subtype is seen more commonly in older patients.11 A ‘solid alveolar’ variant lacks the characteristic alveolar septations but behaves similarly to the alveolar subtype.15 The prognostic value of each specific histologic subtype has varied somewhat in different studies.14–16 However, in IRS-IV, 3-year failure-free survival (FFS) was 83% for embryonal, 66% for alveolar, 55% for undifferentiated, and 66% for unclassified sarcoma (P < 0.001).1
Staging
Two classification schemes have been used to categorize RMS. The clinical grouping system was devised by the IRSG and is a surgicopathologic system based on the initial operative assessment (Table 70-1).11 Stratification of survival was based on the ability for complete resection; thus, an initial surgical approach was required, which varied by institution.13 Clinical grouping has consistently been an independent prognostic indicator as shown in Figure 70-1.
TABLE 70-1
Intergroup Rhabdomyosarcoma Study Group Clinical Grouping Classification of Rhabdomysarcoma
From Qualman SJ, Coffin CM, Newton WA, et al. Intergroup Rhabdomyosarcoma Study: Update for pathologists. Pediatr Dev Pathol 1998;1:550–61.
FIGURE 70-1 Overall survival according to clinical group assignment (Intergroup Rhabdomyosarcoma Study [IRS] I to IV). Survival of patients treated on IRS-I, IRS-II, IRS-III/IV-P (IV pilot), and IRS-IV by clinical group at diagnosis is shown. A significant difference is seen in outcome by the extent of initial surgical resection, with the best outcome among the patients with completely resected tumors (group I), followed by those with microscopic residual (group II) and gross residual (group III) disease. Patients with metastatic disease (group IV) at diagnosis fare poorly. (Anderson JR. Personal communication, 2000; from Pizzo PA, Poplack DG, editors. Principles and Practice of Pediatric Oncology. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2002.)
The second classification scheme is a pretreatment staging system based on the tumor/node/metastasis (TNM) system, which was introduced by the COG-STS committee (Table 70-2).17 The system includes primary tumor site, lymph node involvement, distant metastatic disease, and size. Favorable primary sites include the orbit, eyelid, other nonparameningeal head/neck sites, and nonbladder, nonprostate genitourinary structures. Unfavorable primary sites include extremities (including buttock), trunk, retroperitoneum, perineum, urinary bladder and prostate, and cranial parameningeal sites. IRS-IV was the first study to use this staging system to classify patients prospectively. FFS data for patients with local or regional tumors, according to stage, are shown in Figure 70-2. For these tumors, pretreatment staging is a more accurate predictor of outcome than the clinical grouping classification system.
TABLE 70-2
Rhabdomyosarcoma Tumor/Node/Metastasis (TNM) Pretreatment Staging Classification
aTumor: T1, confined to anatomic site of origin. T2, extension and/or fixation to surrounding tissue.
ba, <5 cm in diameter; b, ≥5 cm in diameter.
cRegional nodes: N0, regional nodes not clinically involved; N1, regional nodes clinically involved by neoplasm; Nx, clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation).
dMetastasis: M0, no distant metastases present; M1, distant metastases.
Molecular Biology
Mutations in certain tumor suppressor genes, including TP53, predispose individuals to RMS. Patients with Li–Fraumeni syndrome and neurofibromatosis type 1 are more likely to develop RMS, and approximately 10% of patients with RMS have one of these syndromes.18,19
Embryonal RMS is characterized by loss of heterozygosity (LOH) with loss of maternal genetic information and duplication of paternal genetic information at the 11p15 locus.20 This genetic locus is the site of the insulin-like growth factor-2 (IGF-2) gene and LOH results in overexpression, which can lead to RMS through several different possible pathways.13,18 The etiology of RMS can also be linked to the loss of 9q22, which corresponds to a tumor suppressor gene in embryonal RMS patients.20
In approximately 70% of alveolar RMS, a common translocation between chromosomes 2 and 13, t(2;13)(q35;q14), is present.21 This translocation usually involves the PAX3 gene that regulates transcription driving neuromuscular development and the FOXO1 gene that is involved in the differentiation process of myoblasts.22 Less commonly, the translocation involves the PAX7 gene located at 1p36 to the same location on chromosome 13.23 PAX3/FOXO1 expression can increase IGF-2 expression and an IGF-binding protein, providing a common pathway for both embryonal and alveolar RMS. These known molecular disturbances are now being adopted and studied clinically. Several studies have demonstrated a worse prognosis with the presence of a PAX3/FOXO1 fusion gene in alveolar subtypes of RMS, and an improved prognosis with PAX7/FOXO1.18,24,25 Additionally, the t(2;13) translocation has been shown to characterize alveolar RMS with a poor prognosis, whereas the t(1;13) translocation is associated with improved outcome.26 The ELMO1 gene has been implicated in alveolar RMS metastasis.27 Another recent study has correlated a 34-metagene with COG risk classification groups.28 The exact molecular pathway leading to the development of alveolar RMS potentially caused or exacerbated by these translocations remains to be found.
Clinical Presentation
The clinical presentation of RMS is variable and depends largely on tumor site, patient age, and the presence of distant metastases. Most symptoms are secondary to the local mass effect. RMSs involving the head and neck region including orbits, parameningeal tissues (middle ear, nasal cavity, paranasal sinuses, nasopharynx, and infratemporal fossa), and nonparameningeal tissues (scalp, face, oral cavity, oropharynx, hypopharynx and neck) are most commonly embryonal subtype and rarely involve regional lymph nodes. Symptoms can include proptosis, ophthalmoplegia, nasal/sinus obstruction with or without discharge, cranial nerve palsies, meningeal symptoms, or a painless, enlarging mass. Paratesticular RMS may present as a painless swelling in the scrotum or inguinal canal, and have a high rate of lymph node spread to the retroperitoneum.
Tumors involving the bladder, urinary tract, or prostate can cause obstruction, hematuria, constipation, and/or urinary frequency. Vaginal tumors are more common in very young patients and may present as vaginal bleeding, discharge, or a mass. Tumors involving the uterus more commonly present in older girls with extensive tumor at diagnosis. RMSs involving the extremity usually present as a mass, tend to be more aggressive, and most are alveolar subtype. They have an approximately 50% incidence of regional lymph node involvement and around 15% of patients present with metastatic disease. Presentation in the neonate is extremely rare with most babies having the embryonal/botryoid/undifferentiated subtypes (0.4%).14,29–34
Diagnosis
The diagnosis of RMS may be suspected clinically, but needs to be confirmed by biopsy. Depending on location, this may require endoscopy, needle biopsy, or excisional/incisional biopsies. Biopsy incisions should be made so that complete excision is possible if a subsequent wide local excision is necessary. Prior to the definitive operation, a full evaluation including imaging, laboratory studies, and bone marrow evaluation should be performed (Box 70-1).7
Surgical Treatment
Primary Resection
Prognosis in rhabdomyosarcoma patients is linked to the amount of residual disease present after resection (see Fig. 70-1). Complete tumor resection, with no microscopic residual disease, offers the best chance for cure. However, in many sites such as the orbit, bladder, prostate, vagina, uterus, complete tumor resection is not feasible while still preserving function of vital organs and avoiding a mutilating procedure. Over the last 35 years, organ salvage rates have increased without adversely affecting OS. The operative approach depends on the primary tumor site, size, presence or absence of lymph node involvement, and distant metastases. These decisions must be made in the context of a multidisciplinary team, including the surgeon, oncologist, pediatric radiologist, and radiotherapist to allow optimal patient care. A tissue biopsy and biologic studies are recommended for definitive diagnosis if resection of the primary tumor site with negative margins is not possible.
Primary Re-excision
Primary re-excision (PRE) of a tumor includes any repeat attempt at complete resection before the initiation of any other form of therapy. As with the primary tumor resection, PRE is performed to allow a clinical group I classification without sacrificing vital structures or organs causing impaired function or poor cosmesis. PRE is recommended in patients whose initial resection had positive or unknown margin status, or was performed for presumed benign disease. If not feasible, reliance on adjuvant irradiation and chemotherapy is advisable. PRE has been shown to improve survival by converting a significant proportion of patients from group IIa to group I in patients with extremity tumors and perineal RMS.17,35,36 The Italian Cooperative Study Group concluded that PRE is the treatment of choice for children with RMS and nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) who are age 3 years or younger and cannot receive radiation therapy (RT). It is also preferred for paratesticular sites as well.35 PRE and postoperative irradiation showed equivalent results in achieving local control in extremity and trunk sites. PRE was not effective for tumors >5 cm.
Lymph Node Evaluation
RMS frequently spreads to regional lymph nodes early in the disease and lymph node involvement significantly worsens the prognosis. However, involved nodes can go undetected by sophisticated imaging techniques. Any clinically or radiographically suspicious lymph node requires histologic confirmation. It is important to determine regional lymph node status to determine if more aggressive treatments such as RT are needed. Pediatric surgeons may be asked to evaluate the regional lymph node status, but lymphadenectomy serves a diagnostic purpose only.7
Specific recommendations regarding regional lymph node evaluation will be reviewed according to the specific site. However, in general, it is recommended that RMS patients with primary tumors of the extremity, primary tumors of the perineum, and paratesticular tumors in children older than 10 years old undergo operative evaluation of regional lymph node status even if there is no clinically apparent disease.19,37 If disease is found, then distal lymph nodes should be sampled to determine metastatic disease.19 Additionally, during the course of tumor resection for genitourinary and retroperitoneal tumors, lymph node sampling should be performed if feasible.
Lymphatic mapping with sentinel lymph node biopsy may allow adequate staging while limiting operative morbidity.37,38 Most experience with this technique has been gained with extremity and truncal tumors, and with adult breast cancer and melanoma.19 Typically, lymphoscintigraphic mapping is performed before the planned operation. Intraoperatively, vital blue dye is injected at the primary tumor site and a detector is used to identify the sentinel lymph node. Through a small incision and limited dissection, a blue sentinel lymph node(s) with evidence of the radioactive tracer is excised. These techniques often limit the extent and morbidity of the operation when compared with formal lymph node dissection as was previously performed.
Second-Look Operations
At the initial operation, the size, invasion, or location of RMS tumors frequently prohibits complete resection to achieve group I or II status. In IRS-IV, among all patients without metastatic disease (n = 883), 62% were classified as group III.1 After intensive multiagent chemotherapy with or without irradiation, these patients usually benefit from a second-look operation. Clinical and radiographic assessments are often inaccurate. The goals of the second-look operation are to remove residual tumor and determine response prior to additional therapy. This approach has been shown to improve patient survival and/or to classify patients as complete responders.19,39,40 Alternatively, a negative biopsy (i.e., no tumor) at second-look operation does not exclude or diminish the possibility of recurrence.39,41
Surgical Treatment for Recurrent Disease
Despite the successes of primary therapy for RMS, survival after relapse remains very poor. Approximately 30% of RMS patients will experience relapse, and between 50% and 95% of these will die of progressive disease.42
