Pediatric Rhabdomyosarcoma Surgery

Rhabdomyosarcoma (RMS) is a malignancy that arises from embryonic mesenchymal cells and is the most common sarcoma in the pediatric population, accounting for 4.5% of all childhood malignancies. It was first described in the English literature in 1937. In 1946, Stout described rhabdomyosarcoma as a tumor with rhabdomyoblasts of round, strap, racquet, and spider forms.[1]

Before the evolution of multimodal treatment for malignancies and the development and recognition of effective chemotherapeutic agents, the primary therapy for pediatric RMS was surgical excision. Unfortunately, this purely surgical approach was often unsuccessful and, even when curative, often proved to be quite morbid.

Formal investigations of the treatment of pediatric rhabdomyosarcoma have subsequently been carried out through the Intergroup Rhabdomyosarcoma Study (IRS) Group (IRSG) and have consisted of five studies: IRS-I (1972-1978), IRS-II (1978-1984), IRS-III (984-1991), IRS-IV (1991-1997), and IRS V (1997-2003).[2, 3, 4, 5, 6, 7, 8] Studies have been initiated by the Soft Tissue Sarcoma Committee of the Children's Oncology Group, which attempts to improve outcome and decrease treatment-related morbidity.[9, 10]

Treatment of RMS, once purely surgical, is now multimodal, involving surgical resection, biopsy only, or surgical staging, combined with chemotherapy and radiation therapy, when necessary.

The prognosis of RMS depends on tumor location, patient age, metastasis, histology, tumor biology, and adequacy of tumor resection. Lymph node evaluation is essential in determining the extent of disease and guiding therapy. With adequate treatment, the 5-year survival rate is higher than 70-80%.

Although most frequently diagnosed in the head and neck[11] or the genitourinary system, RMS may occur anywhere in the body. Embryonal histology is usually found in the head and neck, genitourinary tract, or orbit. Alveolar RMS (see Pathophysiology) is usually encountered in the extremities, trunk, or perineum. The botryoid variant arises in cavitary structures such as the vagina and bladder, and spindle cell RMS is found most commonly in the paratesticular area.

The pathogenesis of RMS is not well elucidated, though it is believed to involve disruption of mesenchymal cell growth.

Five variants of rhabdomyosarcoma are described in the international classification of RMS.[12]  Most cases, however, fall into one of the two major subtypes: embryonal and alveolar. Treatment and prognosis are dependent on histologic subtype and tumor location.

The embryonal subtype is most common, accounting for 55% of all RMS. It is usually found in the head and neck, genitourinary tract, or orbit in younger patients. This subtype is characterized by a loss of heterozygosity at the 11p15.5 locus, the region of the IGFII gene. Anaplasia, which may be a feature of this subtype, adversely affects the likelihood of failure-free survival.

Embryonal RMS (ERMS) has also been subclassified into botryoid and spindle cell variants. The botryoid variant, named after its gross resemblance to a cluster of grapes, arises within a hollow cavitary viscus (eg, vagina, biliary tract, or bladder) and is found more frequently in infants. The spindle cell variant is found most commonly in the paratesticular area.

Alveolar RMS (ARMS) is often seen in older patients, accounting for 20% of all tumors in older children. It usually affects the extremities, trunk, and perineum.

Another, albeit much less common, subtype is undifferentiated RMS.

A translocation involving the PAX3 locus, between the long arm of chromosome 2 and the long arm of chromosome 13, has been identified in RMS patients. This involves the PAX3 and FKHR genes. The FOXO transcription factor gene can fuse with either the PAX3 or the PAX7 transcription factor gene. These fusion proteins have been identified in patients with ARMS.[13, 14]

In these PAX/FOXO fusions, the DNA binding domain of PAX is combined with the regulatory domain of FOXO.[15] This results in increased PAX activity, leading to dedifferentiation and the proliferation of myogenic cells.[16]  PAX3-FOXO fusion is more common than PAX7-FOXO fusion (55% vs 23%) and is associated with worse overall survival.[17]

It has been demonstrated that approximately 25% of ARMS tumors are translocation-negative. By gene array analysis, these fusion-negative ARMS tumors more closely resemble ERMS and have a prognosis similar to that of ERMS.[18] ​ In future studies and treatment protocols, fusion status will replace tumor histology for the classification and stratification of RMS tumors.

For additional information, see Rhabdomyosarcoma.

The etiology of pediatric RMS is unknown; however, RMS has been associated with a p53 mutation and Li-Fraumeni syndrome.[19] Li-Fraumeni syndrome is a familial cancer syndrome that exhibits autosomal-dominant inheritance of a germline mutation of the p53 gene.[20] It is characterized by a high incidence of soft-tissue or bone sarcomas, leukemia, brain or adrenal neoplasms, and maternal premenopausal breast cancer.

RMS is also known to occur more commonly in patients with neurofibromatosis type I (NF1) and in patients with Beckwith-Wiedemann syndrome. Tumors associated with syndromes typically present earlier and have family histories of malignancy.[21]

RMS is the most common soft-tissue sarcoma in children and accounts for 50% of pediatric soft-tissue sarcomas and 4.5% of all childhood cancers. This malignancy has a bimodal distribution, with peaks at 2-6 years of age and 10-18 years of age.[21]  Approximately 250 new cases of pediatric RMS are diagnosed in the United States each year.

With appropriate risk-adjusted treatment, the overall 5-year survival rate is in excess of 70%. The use of multimodal therapy and the long-term investigations by the IRSG have led to steady improvement in the prognosis for pediatric patients with RMS. IRS-IV determined that the failure-free survival rate and the overall 3-year survival rate are 77% and 86%, respectively, in patients without metastatic disease. In children with metastatic disease, despite current treatment, 5-year survival remains at approximately 30%.

Current emphasis is on stratification of therapy to provide local control with less impairment in functionality or cosmetics.

The clinical presentation of rhabdomyosarcoma (RMS) varies according to the site of presentation. Most patients, however, present with a painless mass, often discovered after minor trauma. Growth of the mass may impact adjacent structures, thus causing symptoms, including pain. When large, RMS may impinge on adjacent structures and lead to secondary problems such as bowel obstruction or respiratory distress.

Other symptoms are determined by location of the mass. Tumors originating in the head and neck may present as a mass or as signs and symptoms of central nervous system involvement due to intracranial extension of the tumor or infiltration of the cranial nerves, meninges, or brainstem.[22, 23]  RMS of the orbit may result in disconjugate gaze, whereas RMS of the uterus, cervix, or bladder may result in menorrhagia or metrorrhagia or difficulty voiding. 

In many instances, physical examination may be positive only for lymphadenoapathy in the region of the tumor. Other findings are dependent on tumor location. Secondary signs may include anemia, thrombocytopenia and neutropenia. Many patients have no physical examination findings at the time of diagnosis.

Preoperative laboratory analysis is essential for any patient undergoing surgical treatment of rhabdomyosarcoma (RMS). Imaging is also required for operative management. Metastatic disease is evaluated through bone marrow analysis; bone scanning; computed tomography (CT) of the brain, lungs, and liver; and cerebrospinal fluid (CSF) analysis. Positron emission tomography (PET) may be included in the workup of a patient with RMS to evaluate occult metastases and regional adenopathy.

Any child with a suspected RMS requires confirmation by tissue diagnosis as well as surgical staging, including evaluation of regional lymph nodes at the time of surgery (depending on the location of the tumor). Thus, early surgical consultation is mandatory. The surgeon then helps determine, on the basis of the location and stage of the tumor, how best to proceed. Although the recommendation for lymph node biopsy has existed since 2003, surgical compliance with protocols regarding nodal excision has been poor, and this has affected patient outcome and overall survival.[24]   

Laboratory tests used in the workup of RMS include the following:

• Complete blood count (CBC) - Anemia, neutropenia and thrombocytopenia may be seen in patients with RMS
• Electrolytes, blood gases, and protein - Sodium, potassium, chlorine, carbon dioxide, calcium, phosphorus, and albumin should be evaluated before the initiation of chemotherapy
• Renal function tests - Blood urea nitrogen (BUN) and creatinine must be evaluated before chemotherapy
• Liver function tests - Results of these (including aspartate transaminase [AST], alanine transaminase [ALT], and bilirubin) may be altered by metastasis of RMS to the liver
• Urinalysis - Hematuria may be seen in patients with genitourinary RMS

Fluorescence in situ hybridization (FISH) may be utilized to determine translocations t(1;13) or t(2;13), which are often present in alveolar RMS (ARMS), and to direct treatment.

Reverse transcriptase–polymerase chain reaction (RT-PCR) is used to evaluate for translocations associated with ARMS when cytogenetic evaluation is not possible or when results from cytogenetic testing are equivocal.

The goal of the evaluation in a patient with a suspected RMS should be to define the local extent of the tumor (ie, its resectability), the degree of lymph node involvement, and the rpesence or absence of distant metastasis.

CT or magnetic resonance imaging (MRI) of the primary tumor is necessary to assess the size of the tumor and its extension into adjacent structures. These studies also assist in narrowing the differential diagnosis. PET-CT may prove valuable in the staging and preoperative evaluation of pediatric RMS.[25]

A bone scan is performed to rule out metastatic disease to the skeletal structures. CT of the chest is also recommended to rule out metastasis to the pulmonary parenchyma.

Echocardiography should be performed in all patients as a baseline study before the initiation of chemotherapy with cardiotoxic side effects.

The bone marrow should be evaluated by means of bone marrow aspiration to rule out metastatic spread to the marrow.

If complete surgical resection is not feasible, an open incisional biopsy to evaluate histologic characteristics should be performed. Core biopsy is often deemed inadequate because of insufficient tissue sample and sampling error. For suspected tumors of the bladder, prostate, and vagina, endoscopic biopsy may be required.

The diagnosis of RMS should be confirmed through histologic evaluation of a tissue specimen, which may be attained by means of core, incisional, or excisional biopsy. The characteristic histologic finding of RMS is a small, blue, round cell (see the image below); this finding is pathognomonic for the disease. Cross-striations may be seen with light microscopy. Desmin, myogenin, myoD1, and muscle-specific actin are often seen in RMS. (For additional information, see Rhabdomyosarcoma.)

The histologic findings in rhabdomyosarcoma.

Once the diagnosis of RMS has been made, the tumor should be staged. The staging system currently used for RMS is the Lawrence-Gehan staging system, which is initiated preoperatively and then completed after resection.[26] The four stages and the associated primary disease sites may be summarized as follows:

• Stage 1 - Orbit/eyelid, head and neck (excluding parameningeal [PM]), genitourinary (excluding bladder/prostate)
• Stage 2 - Bladder/prostate, extremity, PM, other (eg, trunk, retroperitoneum), smaller than 5 cm
• Stage 3 - Bladder/prostate, extremity, PM, other (eg, trunk, retroperitoneum), larger than 5 cm
• Stage 4 - All others

The staging is explained in greater detail in Tables 1 and 2 below.

Table 1. TNM Classification of Rhabdomyosarcoma (Open Table in a new window)

Table 2. Pretreatment Staging of Rhabdomyosarcoma. (Open Table in a new window)

The Intergroup Rhabdomyosarcoma Study Group (IRSG) postsurgical pathologic grouping is as follows:

• Group I - Localized disease, completely resected (clear margins, negative regional nodes)
• Group II - Microscopic disease remaining (at margins or in regional nodes)
• Group III - Incomplete resection or biopsy findings indicating gross residual disease (locally or in regional nodes)
• Group IV - Distant metastases present at onset

Several studies have suggested that a cutoff tumor size of 5 cm may not be the best tool for staging pediatric RMS. Owing to variations in the body surface area (BSA) of children, the tumor size in relation to the patient’s BSA and volumetric measurements may be more useful in staging.[27]

Any child with a suspected rhabdomyosarcoma (RMS) requires a tissue diagnosis confirmation and surgical staging. Thus, early surgical consultation is mandatory to allow accurate diagnosis and treatment planning.

In general, a small resectable tumor of nongenitourinary origin may be treated initially with complete resection. Contraindications for initial surgical excision include unresectable disease outside of the pelvis or retroperitoneum and disease that would necessitate disfiguring or disabling resection. A tumor that is unresectable or is resectable only through mutilating surgery may be treated with incisional biopsy or core needle biopsy (CNB), followed by chemotherapy, radiation therapy (RT), or both, as well as possible definitive surgical resection.

Wide local excision is avoided in head and neck tumors, particularly if excision will result in a significant cosmetic or functional defect. Orbital exenteration for orbital RMS should be performed only for local recurrence. Vaginal or uterine RMS in the pediatric patient is treated with biopsy, followed by chemotherapy with or without radiation and then second-look surgery. Residual disease may necessitate partial vaginectomy.

Primary bladder tumors are no longer treated with anterior pelvic exenteration. Instead, chemotherapy and, occasionally, RT for persistent disease are used.[28] This therapy has allowed a functional bladder to be retained in 60% of patients 4 years after diagnosis, with a survival rate of 89%.

Whereas earlier studies suggested that prognosis was not improved by a resection that did not remove all gross disease, subsequent studies suggested that pretreatment debulking of 50% or more of the tumor volume in patients with retroperitoneal and pelvic RMS may result in superior failure-free survival.[23]

The surgeon should evaluate the draining lymph node basin for selected sites (eg, extremity, trunk, or paratesticular location). The Intergroup Rhabdomyosarcoma Study (IRS) Group (IRSG) recommends aggressive nodal sampling; however, the surgeon may also consider lymph node mapping and sentinel lymph node biopsy (SLNB) with preoperative lymphoscintigraphy.[29, 30]

Certain sites (eg, extremity, trunk, and paratesticular) have a predilection for lymphatic metastases. Accordingly, SLNB with preoperative lymphoscintigraphy is recommended for these sites and has been found to be superior to positron emission tomography (PET) alone. However, these recommended protocols often are not followed, and this failure of procedure has an impact on patient survival.[24]

Investigations are under way through the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. These studies seek to verify the stratification-based treatment algorithm. Future studies will aim to continue to improve survival while minimizing the morbidity and mortality resulting not only from the malignancy but also from its treatment.

In addition, it should be remembered that local control is achieved by a combination of resection and RT. Outcomes are best when both modalities are employed. If RT is to be held or diminished out of concern for long-term morbidity, it is important for the surgeon to utilize resection as the primary form of local control.

Novel therapies, including oncolytic viruses, dendritic-cell vaccines, and monoclonal antibodies, are under current clinical investigation.

Current recommendations stem from IRS-V, in which treatment is stratified according to risk—low, intermediate, or high—on the basis of risk of disease recurrence and overall survival. Patients are then staged on the basis of the primary tumor site. Favorable sites include the orbit, nonparameningeal head and neck sites, and genitourinary nonbladder/nonprostate sites; all other sites are unfavorable.[13]

Staging is further refined on the basis of primary tumor size (< 5 cm or ≥5 cm), regional lymph node involvement, distant metastases, and histologic subtype (see Staging). Alveolar subtypes are now stratified according to gene fusion status.

Chemotherapy

Low-risk patients receive vincristine weekly for nine doses and actinomycin D with or without cyclophosphamide (VAC regimen) and granulocyte colony-stimulating factor (G-CSF) for four doses every 12 weeks (at weeks 0, 12, 24, and 36). RT is added in patients with residual localized disease.

The protocol for intermediate-risk patients includes RT and either VAC or VAC plus topotecan (according to randomized assignment) for nearly 1 year. For patients with intermediate-risk disease, VAC-VI (irinotecan) has been shown to be as effective as VAC while decreasing the dose of cyclophosphamide. A currently open intermediate-risk RMS trial is examining the use of temsirolimus with a VAC-VI backbone.

High-risk patients begin therapy with irinotecan, which is followed by VAC and RT. Newer chemotherapeutic agents and molecular therapies are frequently tried in high-risk, relapse, and disease-progression patients in the hopes of improving outcomes. 

Radiation therapy

RT is administered to patients who are at increased risk for local tumor recurrence. It is used in almost all RMS patients (except clinical group I embryonal RMS [ERMS]) to improve local control and outcome. Candidates for RT primarily include patients with group I alveolar RMS (ARMS; 36 Gy), group II RMS (41.4 Gy), or group III RMS (50.4 Gy).

The impact of therapy is determined by the location of the primary and the degree of residual disease remaining after surgical resection when RT is initiated[31] . RT dosing can be adjusted on the basis of either the completeness of resection before chemotherapy (clinical grouping) or the completeness of a delayed primary excision after adjuvant chemotherapy. RT in very young children with RMS poses a unique therapeutic challenge because of concerns about long-term toxicity.[9]

Outcomes and local control are worse for for infants than for older children because the former are frequently undertreated. Intensity-modulated RT (IMRT) and proton-beam RT can help reduce the total dose and decrease late effects.[32, 33]

Patients with group II disease (microscopic residual disease) have a high risk of local recurrence if prescribed RT is omitted or reduced. Million et al noted that more than half of the patients who experienced relapse at the original tumor site received nonstandard RT and that three quarters of these patients died of their disease.[34]

The aim of surgical treatment is to remove the tumor in its entirety, including a surrounding margin of normal tissue, when the tumor is resectable without the patient experiencing functional or cosmetic impairment. At present, there is no role for tumor debulking in surgical therapy for RMS.

First, the surgeon must obtain a tissue diagnosis. The initial surgical intervention may consist either of wide local excision or of incisional or excisional biopsy. Incisional biopsies should be planned to ensure that the scar does not impede later attempts at resection, particularly in the case of extremity tumors. Thus, biopsy incisions on the extremity should always be longitudinal. (See the image below.) Patients in whom margins are positive or of unknown status should be considered for reexcision.

Proper orientation of the biopsy allows complete resection at second operation.

Anesthetic administration should be planned to incorporate any procedures that the child will need. For example, the surgeon should discuss the possible need for a central venous line, bone marrow aspiration, lymph node evaluation, and biopsy with the oncologist, the patient, and the family, so that, if necessary, all procedures can be performed on the same day.

Thorough preoperative planning is essential because of the various surgical options that may be necessary in children with RMS, and the surgeon should take into consideration the possibility of obtaining clear margins when determining the initial surgical approach. In the event of resection after chemotherapy and RT, if the surgeon is unsure that complete excision can be achieved safely, placement of brachytherapy catheters or administration of intraoperative RT may be discussed before operative intervention.

Unlike adult sarcoma, pediatric RMS may be present in the lymphatics in approximately 40% of cases. Accordingly, it is important to evaluate the lymphatics in all children with RMS. This is best performed at the time of the initial procedure, particularly if lymphatic mapping with SLNB is planned, because prior biopsy or excision may disrupt the lymphatics.

Surgical options for evaluating the lymphatics include aggressive node sampling and SLNB (see the image below). Formal lymph node dissection is not recommended, because it has not been shown to significantly improve survival, even in patients with histologically positive nodes.

Sentinel node biopsy after lymphatic mapping in a child with rhabdomyosarcoma. Notice that the incision is oriented to allow extension or incorporation of the incision should further dissection be necessary. The sentinel node should be blue and should have high counts of radioactive tracer signal when checked with the gamma probe.

Exceptions to wide local excision include head and neck tumors, vaginal/uterine tumors, and bladder tumors.

Operative details

Preoperatively, all radiographic studies should be reviewed for evidence of metastases or signs of local invasion that may complicate resection. The surgeon should be prepared to perform a complete resection, when indicated, in order to afford the child the best possible prognosis.

If surgical margin status in unclear or a biopsy was initially performed for the tumor and the surgeon believes that it is possible to achieve complete tumor excision prior to chemotherapy, pretreatment reexcision (PRE) is recommended, including a wide reexcision of the operative site with adequate margins. This is most commonly seen with extremity and trunk lesions, and if negative margins can be obtained, the patient would be considered group 1.

Regardless of the tumor site, the surgeon should strive for a complete resection, without causing mutilation or disability. When the margins are in doubt, frozen sections should be sent for analysis. Frequently, major neurovascular structures are in the resection field. When these structures are essential, a careful resection should be undertaken to remove as much of the tumor as possible. In these cases, brachytherapy, intraoperative RT, or postoperative RT may be beneficial. Studies suggest that debulking has no advantage over biopsy in terms of survival.[35]

Patients should be observed postoperatively to ensure adequate wound healing and to examine for signs of local or distant recurrence.

Postoperatively, the tumor is graded on the basis of the extent of resection. This should be determined once the pathology is completed to determine the need for additional medical or surgical therapy. When possible, tumors with positive margins should be reexcised.

Complications vary according to the site of the primary tumor. Because of the frequency of preoperative RT, the surgeon should be aware of the possibility of impaired wound healing.

Multiple issues arise in long-term survivors of RMS. Late effects include pituitary dysfunction, secondary malignancies, hearing loss, and thyroid complications in those with head and neck RMS, as well as bony defects and growth in those with RMS of the extremities. This underscores the need for long-term follow-up in survivors.