RMS comprises tumors of mesenchymal origin, arising from pluripotent mesenchymal cells that fail to fully differentiate into skeletal muscle myocytes. The immunohistochemical (IHC) stains used to identify RMS include desmin, myogenin, MyoD1, and muscle-specific actin. The World Health Organization (WHO) classification schemata identifies four distinct histological subtypes of RMS: embryonal, alveolar, spindle cell/sclerosing, and pleomorphic. While these histologic categories are of use prognostically and in predicting the behavior, location, and age of affected patients, their utility in risk group stratification has been supplanted by molecular/genetic testing.

ERMS is the most common histologic variant, comprising up to 75% of RMS in children. ERMS may be further divided into classic, botryoid, spindle cell, and dense histology. The botryoid and spindle cell histology portend a better prognosis. Spindle cell histology is commonly found in paratesticular lesions, and botryoid tumors are often found in hollow visceral organs such as the bladder, vagina, and biliary tree. ERMS is characterized by regions of loose myxoid mesenchymal tissue alternating with dense cellular regions with rhabdomyoblasts in various stages of differentiation ( Fig. 66.1 ). In contrast, in the dense subtype without myogenic differentiation, sheets of primitive cells with scant cytoplasm and ovoid nuclei are seen.

Embryonal rhabdomyosarcoma. Botryoid (grape-like) appearance from an infant (A). Low-power histology (B) corresponds with the gross appearance: squamous nonkeratinizing epithelium of the vaginal mucosa covers nondemarcated ribbon-like layers of the tumor, which is relatively primitive and cellular superficially. (C) Persistent tumor posttreatment with phenotypically “maturing” rhabdomyoblasts (larger cells with greater amount of cytoplasm) highlighted on immunohistochemical stain for desmin.

ARMS is the second most common histologic type, occurring in 20%–25% of children. ARMS is subdivided into classic and solid patterns, and requires more than 50% of the specimen to be alveolar in nature to be classified as such. Classic ARMS cells contain eosinophilic cytoplasm arranged in nests separated by fibrous septae with islands of tumor cells, whereas the solid pattern lacks the dividing septae and is characterized by sheets of monomorphic cells with round nuclei ( Fig. 66.2 ).

Alveolar rhabdomyosarcoma. Core needle biopsy sample from a soft tissue arm mass from a teenage girl (A). A highly cellular “small, round blue cell neoplasm” is seen infiltrating the connective tissue in skeletal muscle (H&E stain). (B) At high power, tumor cells are tightly packed, with variably molding cell membranes, small-to-moderate amount of delicate cytoplasm, relatively uniform round nuclei, delicate to “salt-and-pepper” chromatin, mostly inconspicuous nucleoli, and scattered mitoses (H&E stain). (C) Immunohistochemical stain for myogenin strongly highlights the nuclei of the overwhelming majority of infiltrating densely packed tumor cells. In contrast, nuclei of the collagenous connective tissue in the background remain appropriately negative.

Spindle cell or sclerosing histology are considered to be the same RMS subtype, and are relatively less common, comprising 3%–10% of diagnoses. The fourth and final histologic subtype is pleomorphic RMS—a very rare variant in children, most often occurring in adults.

The four distinct histologic classifications of RMS outlined above correspond to characteristic genetic aberrations. ERMS is characterized by a loss of heterozygosity at the 11p15 locus in up to 80% of patients; this locus contains the insulin growth factor 2 ( IGF-2 ) gene, which can be overexpressed due to paternal allele duplication. ERMS also displays a high frequency of RAS pathway aberrations. Notably, patients with ERMS do not display the fusions PAX3:FOX01 or PAX7:FOXO1 (e.g., they are fusion-negative RMS); these gene fusions instead characterize ARMS. ^, Conversely, the ARMS histologic type is defined by the presence of an aberrant fusion between FOXO1 and PAX3 or PAX 7 (e.g., PAX3:FOX01 or PAX7:FOXO1 ); ARMS displaying this aberration are termed “fusion-positive RMS.” ^, In both cases, the FOXO1 transactivation domain is fused to a DNA-binding domain (e.g., PAX3 or PAX7 ), resulting in dysregulated DNA transcription, and the formation of a potent oncogene. These translocations, rather than the histopathologic categorization, are the main determinant of the poorer outcome noted for patients with the alveolar subtype of RMS. ^, PAX3:FOXO1 fusion-positive RMS comprise 60% of all ARMS, PAX7:FOXO1 fusion-positive RMS comprise an additional 20% of all ARMS, and the final 20% of ARMS are fusion negative (e.g., they do not display these characteristic translocations). These fusion-negative ARMS represent a unique variant of RMS; despite having alveolar histology, which would otherwise predispose to a poorer prognosis than ERMS and necessitate more aggressive treatment, fusion-negative ARMS is instead clinically and molecularly indistinguishable from ERMS, and is treated and classified identically. ^, Moreover, it also has comparable overall survival (OS) and event-free survival (EFS). Spindle cell/sclerosing RMS is defined by the specific mutations in any of the following genes: myogenic differentiation 1 (MYOD1), vestigial-like family member 2 (VGLL2), or nuclear receptor coactivator 2 (NCOA2). Finally, pleomorphic RMS is not defined by any one genetic aberration, but rather by the presence of complex and bizarre karyotypes and unbalanced translocations. These mutations tend to cluster in genes responsible for cell cycle and/or DNA repair, and also the RAS pathway; this latter pathway may provide a means of targeting this aggressive and difficult-to-treat form of RMS.

Initial involvement of lymph nodes at the time of diagnosis is seen in approximately one quarter of patients, and in some cases portends a poorer prognosis than those without lymph node involvement. ^, Specific primary sites with a higher incidence of nodal disease include the perineum, trunk, head and neck, retroperitoneum, extremity, bladder, and parameningeal and paratesticular regions. In fusion-positive ARMS, the presence of positive lymph nodes represents an independent predictor of poorer prognostic for OS and failure-free survival (FFS). However, lymph node positivity does not appear to be prognostic for fusion-negative ERMS patients, provided they receive radiation therapy.

Clinical and radiographic assessment of both local and distant lymph nodes should be performed in all patients prior to the initiation of treatment to guide staging and treatment. In particular, tumor node metastasis (TNM) staging defines clinical nodal involvement as being >1 cm in size based on CT or MRI imaging, or PET-avid.

Indications for nodal evaluation include positive clinical nodes and extremity, trunk, and paratesticular tumors in patients >10 years old. ^, It has also been advocated that all head and neck RMS should undergo nodal evaluation due to the difficulty in detecting micrometastatic lymph node involvement; local lymph node recurrence has been documented in up to 57% of these cases, of which 75% had been reported as clinically negative at the time of diagnosis. ^,

Biopsy is necessary to confirm local and disseminated metastatic disease. In the absence of palpable nodes, sentinel lymph node (SLN) biopsy should be performed to assess nodal involvement, particularly for patients with extremity or trunk RMS ( Fig. 66.4 ). In this procedure, technetium-99 ( ^99m Tc) sulfur microcolloid is injected intradermally at the site of the tumor and then mapped using nuclear medicine lymphoscintigraphy to identify sentinel lymph nodal basins. Intraoperatively, blue dye, such as isosulfan blue, is injected and utilized to assist with the visual identification of lymphoid tissue. Indocyanine green (ICG) has been gaining popularity as an off-label agent in adult oncology to assist with sentinel lymph node mapping. While limited data in the pediatric malignancy population exists, ICG has been found to be a more sensitive adjunct at identifying lymphoid tissue in general, when compared with isosulfan blue, as well as possessing increased sensitivity for identifying histopathologically positive nodes when used together with ^99m Tc. Complete lymph node dissection is unnecessary and does not improve outcome. Extremity tumors with positive transit nodes (e.g., epitrochlear and brachial nodes for upper-extremity tumors and popliteal nodes for lower-extremity tumors) require evaluation as well, as failure to include these nodal groups in the radiation field increases the chances for local and regional tumor failure. While PET-CT has been proposed as an alternative to SLN biopsy, it does not appear sufficiently sensitive to eliminate the need for biopsy.

Axillary sentinel lymph node biopsy from a child with a trunk rhabdomyosarcoma. Blue dye can be appreciated in the sample. The arm is extended to the left under the sterile towels.

Multiple steps are involved in determining the extent of a patient’s disease:

• 1.

  Determination of Stage using Tumor Node Metastasis (TNM) classification

• 2.

  Determination of a Clinical Group

• 3.

  Assignment to a Risk Group, based on the Stage, Clinical Group, and fusion status

The clinical group classifies a patient’s disease status as one of four clinical groups (I to IV), depending on the extent of disease at diagnosis and the amount of disease that remains after initial surgical resection. Patients are assigned to a clinical group according to the pathologic evaluation of the specimen, which encompasses the completeness of excision (including residual disease and margin status) and evidence of tumor metastasis to lymph nodes or distant sites. The clinical group assigned refers to the pathologically determined extent of tumor after resection or biopsy of the primary lesion, along with the lymph node evaluation and the patient’s status prior to the initiation of systemic therapy ( Table 66.2 ).

The Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS-COG) created the risk stratification system to tailor therapy to patient outcomes. Following categorization using Stage and Clinical Group, a Risk Group is assigned based on these two factors, as well as the FOXO1 fusion status. Patients are divided into low, intermediate, and high risk (the “risk” referring to the risk of relapse/recurrence). ^, This comprehensive stratification process has shown to be an accurate predictor of outcomes ( Table 66.3 ). Current COG protocols use fusion status and molecular findings rather than histology to define Risk Groups. ^,

Systemic chemotherapy is administered to all patients with RMS, irrespective of group. However, the duration and intensity varies with Risk Group assignment. The standard chemotherapy regimen includes vincristine and actinomycin-D (VA), with or without cyclophosphamide (VAC), and forms the backbone of all modern RMS treatment regimens. For patients with low-risk RMS (LRRMS), current COG-based best practices have resulted in a 4-year EFS of approximately 90% by utilizing a regimen comprised of 48 weeks VA, or 12 weeks of VAC followed by 12 weeks of VA. ^, The current front-line COG study (ARST2032) for LRRMS seeks to maintain these outcomes, while further deintensifying therapy in a subset of patients with low risk disease.

In children with intermediate-risk RMS (IRRMS), the most recent major COG study (ARST0531) added irinotecan (I) in the form of VAC/VI, as it had been shown to provide benefit with metastatic and recurrent RMS. However, it did not improve EFS or OS compared with VAC alone, but the lower rate of toxicity and cumulative dose of cyclophosphamide in the VAC/VI regimen supported its use as the current standard therapy for IRRMS. This study found a 4-year EFS of 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year OS of 73% for VAC and 72% for VAC/VI ( P = .80). A separate study, however, found different results when decreasing the total cyclophosphamide dose for patients with subset 2 low-risk RMS who did not receive radiotherapy. These patients had a decrease in FFS and an increase in local recurrence when the total dose of cyclophosphamide was decreased.

Significant advances have been made in improving the outcomes of the low-risk RMS (LRRMS) and intermediate-risk (IRRMS) groups. ARST1431 recently examined the addition of temsirolimus to the VAC backbone for intermediate risk patients, finding that it did not appear to affect outcome (unpublished results).

In children with high-risk RMS (HRRMS), some progress has been made, but outcomes remain dismal. The two recent most HRRMS COG trials (ARST0431 and ARST08P1) utilized all known active agents (vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide, and VAC) in an interval-compressed intensified backbone; several additional novel agents were also added (irinotecan, temozolomide, or cixutumumab). ^, Using this approach, Stage 4 ERMS patients under 10 years of age achieved superior outcomes compared to other HRRMS patients, with a 3-year EFS of 60%–64%. However, in children over 10 years of age the 3-year EFS for children with Stage 4 ERMS was only 32%–48%. Among children with ARMS overall, outcomes remained very poor, with a 3-year EFS of 6%–16%. Unfortunately, the addition of the novel agents irinotecan, temozolomide, or cixutumumab did not improve outcomes. ^, The current front-line COG study ARST2031 is therefore attempting a somewhat modified approach, with an initial vinorelbine, dactinomycin, and cyclophosphamide (VINO-AC) phase, followed by a vinorelbine and oral cyclophosphamide (VINO-CPO) maintenance phase: 24 weeks of VINO-AC followed by 24 weeks of VINO-CPO maintenance therapy, versus 24 weeks of VAC followed by 24 weeks of VINO-CPO maintenance therapy.

Radiotherapy is an essential part of local control except for those patients with clinical group I ERMS (those who have had successful complete resection). The anatomic location, extent of residual disease after surgical resection, and lymph node involvement will dictate dosing and timing of therapy. Radiotherapy is generally given 6–12 weeks after the beginning of chemotherapy, except for patients with parameningeal RMS with intracranial extension, in whom an earlier start confers better local control. Radiotherapy dosing ranges between groups: group I ARMS (36 Gy), group II (41.4 Gy), and group III (50.4 Gy). Studies have shown that conservative surgery plus brachytherapy can conserve vital structures and function without compromising outcomes. Unlike children and adolescents, infants are a significant challenge secondary to long-term toxicity, which can include facial growth retardation, neuroendocrine dysfunction, visual/orbital problems, hearing loss, hypothyroidism, developmental delay, esophageal stenosis, leukemia, and brain hemorrhage. ^, Current strategies are targeting local control with intensity-modulated radiation therapy (IMRT) and proton beam radiotherapy, which can avoid undertreatment while providing more focal radiotherapy with decreased adverse effects. A recent large prospective cohort showed that proton radiotherapy represents a safe and effective radiation modality for pediatric RMS patients with improved 5-year local control (81%), EFS (69%), and OS (78%).

Patients who present with suspected RMS should undergo thorough surgical evaluation, as local surgical control is an important determinant of outcome. Local recurrence is the most common cause of treatment failure among patients with localized disease. For tissue diagnosis, open biopsy or percutaneous core biopsy is generally recommended to obtain sufficient tissue for histologic and genetic/molecular analyses. If core-needle biopsies are performed, multiple passes (up to 20 or more) may be necessary to avoid a sampling error.

Complete surgical excision should be performed initially, provided that an R0 resection is anticipated, and resection will not result in major functional impairment. This is particularly challenging in sites such as the orbit, bladder, prostate, vagina, and uterus. The goal is to achieve complete resection with normal tissue margins of at least 0.5 cm surrounding the tumor. Margins should be marked and oriented for adequate histopathologic review. Debulking does not have a role in current management of RMS, and outcomes have been shown to be similar between patients with gross residual disease following resection, versus those who did not undergo resection, or who undergo biopsy alone. Additionally, radiation dosing remains the same in the setting of gross residual disease, and therefore debulking should not be performed.

In cases where complete excision is not possible and residual disease remains, the surgical bed should be marked with small titanium clips to guide radiotherapy and future reexcisions if needed. Tumors that are removed piecemeal are considered group II even if all gross tumor is removed. It is important to emphasize that surgical planning of RMS should include a thorough and multidisciplinary approach including radiation oncology, medical oncology, pathology, and surgery, all within a tumor board evaluation.

Pretreatment reexcision (PRE) is defined as complete wide local resection with negative margins performed prior to the initiation of chemotherapy. PRE of RMS should be considered in cases in which only a biopsy was taken initially, if an R1 resection was performed, or if a nononcologic excision was performed. PRE should only be performed if an R0 resection is likely and will not result in a debilitating outcome. In instances of prior biopsy, the PRE should incorporate any and all biopsy tracts. PRE is most commonly performed in cases of extremity, trunk, and paratesticular RMS.

Patients who undergo PRE with negative margins are categorized as group I. Outcomes are similar for those who undergo initial R0 primary excision and for those who undergo biopsy followed by R0 PRE. PRE has shown to improve FFS and OS.

Delayed primary excision (DPE) is the resection of residual tumor following chemotherapy. Response is generally evaluated with CT/MRI after induction chemotherapy at approximately week 12 after initiation of therapy, but this has been shown not to correlate with FFS for either ERMS or ARMS. However, the pathologic response (amount of viable tissue found at the DPE) has a direct association with prognosis. In one series, 79% of pathology specimens after DPE contained viable tumor after 12 weeks of systemic therapy, and these patients had lower FFS rates. A DPE should be considered in patients with residual disease after chemotherapy, if complete gross resection can be achieved without significant morbidity. The goal of DPE is to achieve local control, thereby reducing the radiotherapy dose and the associated morbidity. Recent studies have proposed tailoring radiotherapy dosing based on completeness of excision (36 Gy for complete excision, 41.4 Gy for microscopic residual disease, and 50.5 Gy for gross residual disease). Another study showed that almost 75% of patients with IRRMS were eligible for a dose reduction without compromising local control compared with historical controls. ^, Debulking surgery, in which gross residual tumor is left behind, does not improve outcomes and is therefore not recommended for any site.

Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is performed at select centers of expertise for children with abdominal RMS. Patients with a lower burden of disease, quantified by the peritoneal cancer index (PCI), who undergo CRS-HIPEC have demonstrated improved disease-free survival, as well as improved OS. Patients who may be candidates for this approach should be referred to these specialized centers for evaluation. ^{, ,}

Residual masses after completion of therapy are found in approximately one third of children who receive radiotherapy for local control without initial resection. This is most common in tumors that are fusion-negative and large (more than 5 cm in diameter). Despite this, they do not have worse OS compared with those who have previously undergone partial resection. Group III patients who have undergone resection of residual masses following completion of therapy have not been shown to have improved overall or failure-free survival. Therefore, current recommendations do not include resection of residual masses following the conclusion of therapy as not only are these resections rarely complete, but the residual masses are unlikely to contain viable tumor.

RMS surgical principles described previously should be applied to all patients to achieve the best outcome possible. However, certain site-specific principles are also important.

Head and Neck

Primary intracranial RMS is rare, and its prognosis is poor compared with other primary sites. Patients with orbital RMS should undergo biopsy for diagnosis followed by chemotherapy and radiotherapy. Orbital exenteration is usually not advised. A recent retrospective study evaluated outcomes after orbital RMS treated with excision, chemotherapy, and radiotherapy after biopsy confirmation of disease. This study showed a good prognosis with localized disease, but found significant complications including decreased visual acuity, cataracts (50%), and local tumor recurrence (35%), with a 7% mortality rate. Nonorbital RMS of the head, including parameningeal disease, is treated with biopsy, radiotherapy, and chemotherapy ( Fig. 66.5 ). Studies have shown that intensity-modulated radiation therapy provides excellent local control after chemotherapy. Surgical resection is only advised for recurrent or residual disease after chemotherapy and radiation. The management of nonorbital and nonparameningeal tumors of the head and neck includes wide excision when possible ( Fig. 66.6 ). Isolated cases of pineal RMS have been reported with improved outcomes after high-dose adjuvant chemotherapy, radiotherapy, and subsequent autologous peripheral blood stem cell transplantation.

13-year-old patient with stage IV parameningeal alveolar RMS. Left image shows MRI T1-weighted image coronal plane with a heterogeneous mass centered within the right ethmoid air cells ( arrow ) and superior nasal cavity mildly displacing the orbit. Right image shows right neck lymphadenopathy with high uptake in a PET scan image.

(A) MRI primary tumor. Coronal T1-weighted image following intravenous contrast administration shows a heterogeneous mass ( asterisk ) centered within the left ethmoid air cells and superior left nasal cavity, with extension into the adjacent left orbit, maxillary sinus, and through the cribriform plate into the anterior cranial fossa ( arrow ). (B) MRI neck. Coronal fast inversion recovery-weighted image shows a large lymph node ( curved arrow ) inferior to the left parotid gland. A smaller lymph node is seen in the right neck ( straight arrow ). (C) Lymphoscintigraphy. Axial image of the neck from an SPECT/CT lymphoscintigraphic study obtained following the injection of filtered technetium-99m sulfur colloid into the left paranasal sinus mass shows a focus of activity within the right neck ( straight arrow ). Additional activity is present in the pharynx secondary to dripping from the injection ( curved arrow ). (D) Sentinel lymph node from the right neck showed a microscopic focus of metastatic tumor (outlined by the arrows ) (H&E 200×).

Biliary Tree

While biliary RMS represents only 1% of all RMS, it is still the most common biliary tumor in children. Patients with RMS of the biliary tree typically present before 5 years of age and this location is classified as an unfavorable site. The presenting clinical picture mimics that of choledochal or hepatic cysts with abdominal pain, pruritis, acholic stools, and/or jaundice. While biliary RMS can arise from any site along the biliary tree, the common bile duct is the most common location. The diagnosis is typically made retrospectively, upon final histopathologic examination after excision. In these cases, complete oncologic excision is rarely achieved. The standard treatment is chemotherapy and radiation with overall favorable outcomes, therefore the role of surgery remains controversial. ^{, ,} Biliary RMS represents the most common cause of neoplastic biliary obstruction in childhood. Biliary drainage procedures, such as ERCP with stent placement or percutaneous transhepatic external biliary drainage, may be combined with biopsies. If liver resection is considered, a transhepatic approach for biopsy and/or drainage should be within the liver segments that are anticipated to be resected. Due to the controversy surrounding the modality for local control, surgery versus radiotherapy, assessment for complete R0 resections should be made by surgeons with hepatobiliary expertise in concert with a multidisciplinary team. Biliary RMS has an estimated 5-year survival rate of 80% despite the frequent presence of residual disease ( Fig. 66.7 ).

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