Rhabdomyosarcomas Flashcards
What is the epidemiology of Rhabdomyosarcoma?
Rhabdomyosarcoma (RMS) is the most common form of soft tissue sarcoma, accounting for 5% of all childhood cancers.
It is the third most common pediatric extracranial solid tumor after Wilms tumor and neuroblastoma.
RMS is a malignant tumor of mesenchymal origin and along with neuroblastoma, primitive neuroectodermal tumors (PNETs), and lymphoma form the group of small, round blue cell tumors of childhood. Its incidence is estimated at 350 cases each year in the United States with approximately 6 cases per 1,000,000 population per year.
RMS has a Caucasian male predominance and presents with a bimodal age of distribution with peaks between ages 2 and 6 years and again between 10 and 18 years.
However, more than 80% of cases are diagnosed before 14 years of age.
This bimodal incidence correlates with the occurrence of the two major histologic subtypes of RMS: embryonal rhabdomyosarcoma (ERMS) for early childhood, which typically presents in the head, neck, and genitourinary (GU) regions, and alveolar RMS (ARMS) for the later childhood and adolescent years and is commonly located in the trunk and extremities.
The overall incidence of the two subtypes is approximately 65–75% (ERMS) and 25–32% (ARMS). In terms of site, greater than one-third (35%) of RMS occurs in the head and neck, followed by GU and extremity presentations.
Most cases of RMS are sporadic; however, RMS has been associated with familial syndromes, including Li Fraumeni and neurofibromatosis type 1 (NF1).
Li Fraumeni patients with RMS are linked to a germline mutation of the tumor suppressor gene p53 and activation of the RAS oncogene. These patients present with disease at an early age and may develop other malignancies, including premenopausal breast cancer, leukemia, and adrenocortical carcinoma.
NF1 patients also have an increased risk of malignant nonneurofibroma tumors, including RMS, and, like Li Fraumeni patients, they have an early age at presentation.
Other syndromes associated with RMS include BeckwithWiedemann, Noonan, Costello, and hereditary retinoblastoma.
The use of marijuana or cocaine during pregnancy has been linked to the development of RMS.
Finally, up to one-third of children with RMS have congenital abnormalities found during autopsy.
What is the tumor biology of RMS?
RMS is thought to arise from pluripotent mesenchymal cells with disrupted cell growth and differentiation.
However, its exact pathogenesis remains unclear.
Causal relationships have been suggested for the MET proto-oncogene, macrophage migration inhibitory factor (MIF), and p53 with regard to oncogenic transformation and tumor progression.
The immunohistochemical (IHC) stains used to identify RMS include desmin, myogenin, MyoD1, and muscle specific actin.
ERMS is characterized by a loss of heterozygosity at the 11p15 locus in up to 80% of patients. The insulin growth factor 2 (IGF-2) gene lies within this locus12 and can be overexpressed due to paternal allele duplication.
ERMS has been associated with other genetic aberrations, including fibroblast growth factor receptor 1 (FGFR1) and neuroblastoma RAS viral oncogene homolog (NRAS), and has high cytologic variability representing progressive states of muscle morphogenesis.
Mutations of MYCN and CDK-4 are more common in ARMS, and its appearance resembles pulmonary parenchyma in IHC stains.
The molecular diagnosis of chromosomal translocations has transformed tumor diagnostics. Specifically, reversetranscription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) for the detection of fusion proteins have been essential in progressing beyond simple IHC.
Patients with ARMS are noted to express fusion proteins arising from the fusion of the FOXO transcription factor gene with either PAX3 (55%) or PAX7 (23%) transcription factors. In these fusions, the DNA binding domain of PAX is combined with the regulatory domain of FOXO, resulting in increased PAX activity leading to dedifferentiation and proliferation of myogenic cells.
The PAX7-FOXO fusion results in worse overall survival (OS).
Twenty percent of ARMS cases that do not express fusion status are known as fusion-negative and have similar biologic behavior to ERMS tumors with the same loss of heterozygosity at 11p15.5, and also have comparable OS and event-free survival (EFS).
Studies have shown that these translocations, rather than what is seen on histopathologic examination, appear to determine the poorer outcome noted for patients with alveolar subtype.
Fusion-positive ARMS patients have been shown to have a higher rate of metastasis compared with those who are fusion-negative.
Myogenin expression is also associated with alveolar histology and thus carries a worse prognosis.
Fusion status will replace tumor histology for the classification of RMS in future treatment protocols.
How is RMS subdivided by histologic findings?
The two major groups of RMS are further subdivided according to histologic findings.
ERMS includes botryoid, spindle cell, and dense patterns.
Having the botryoid and spindle cell histology portends a better prognosis.
Spindle cell histology is commonly found in paratesticular lesions, and botryoid tumors are often found in hollow viscus 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.
In contrast, in the dense subtype without myogenic differentiation, sheets of primitive cells with scant cytoplasm and ovoid nucleus are seen.
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.
What is the clinical presentation of rhabdomyosarcomas?
Symptoms of RMS will depend on the location and size of the primary disease. However, most patients present with an asymptomatic mass.
Patients can also have signs and symptoms secondary to mass effect on adjacent structures and complications due to compression.
RMS involving the head and neck are most commonly embryonal subtype and can present with proptosis, ophthalmoplegia, cranial nerve palsies, and meningeal symptoms.
Paratesticular RMS can present with painless swelling in the scrotum and is known to have a high rate of retroperitoneal lymph node metastases particularly among boys >10 years of age.
Tumors involving the GU tract can present with obstruction, constipation, or urinary frequency.
Patients with vaginal RMS are usually younger and present with bleeding, discharge, or fullness secondary to the mass effect.
Uterine involvement usually has extensive disease at diagnosis.
Perineal/perianal RMS most commonly has alveolar histology, frequently involves regional lymph nodes, and has a poor prognosis with a 5-year OS around 45%.
Extremity RMS usually presents as a painless mass. These tumors are more aggressive and are usually ARMS. Almost half of them will involve regional lymph nodes at presentation.
Neonatal presentation of RMS is extremely rare, with most cases presenting with the embryonal botryoid subtype.
What are the necessary diagnostics for patients with RMS?
All patients with suspected RMS require a complete workup prior to initiation of treatment, including laboratory examination with complete blood count, electrolytes, renal and liver function tests, coagulation panel, and urinalysis.
Cross-sectional imaging studies should be performed on the primary tumor with computed tomography (CT) or magnetic resonance imaging (MRI) to assess its true size and involvement of surrounding structures or vital organs.
For most patients, staging generally includes bone marrow biopsy; whole-body bone scan; CT of the brain, chest for lung evaluation, and abdomen with triple-phase contrast for liver assessment; and lumbar puncture for cerebrospinal fluid evaluation.
However, recent studies have shown that RMS without evidence of local invasion has a low rate of metastatic disease, and bone marrow biopsy and bone scan are unnecessary in these patients.
The use of metabolic imaging with 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) in the pediatric RMS population has limited experience and is not yet part of the first-line imaging.
Evaluation of occult metastases, regional adenopathy, and persistent or recurrent disease may be improved with PET/CT compared with CT/MRI alone.
It is important to note that PET findings during staging or as follow-up imaging after therapy do not correlate with disease burden or outcomes, and can have a positive predictive value up to 90% but a negative predictive value close to 70%.
How is lymph node status evaluated for RMS patients?
Clinical and radiographic assessment of regional and distant lymph nodes should be performed in all patients prior to the initiation of treatment as this will guide staging and therapeutic management.
Positive regional nodes are irradiated, and positive distant nodes are considered metastatic disease, which upstages the disease and alters therapy.
Nodal disease is present in up to 25% of all RMS patients, with a higher incidence in specific primary sites such as the perineum, retroperitoneum, extremity, bladder, and parameningeal and paratesticular regions.
Positive lymph node status is also an independent poor prognostic factor for OS and failure-free survival (FFS) in patients with fusionpositive ARMS, but does not appear to be as prognostic for fusion-negative ERMS patients, provided they receive radiation therapy (RT).
Indications for nodal evaluation include positive clinical nodes and extremity, trunk, and paratesticular tumors in patients >10 years old, and is recommended in all patients with fusion-positive ARMS given its poor outcome and high incidence of false negative imaging.
Biopsy is necessary to confirm local and disseminated metastatic disease.
In the absence of palpable nodes, sentinel lymph node (SLN) biopsy is the technique of choice and should be performed to assess involvement, particularly for patients with extremity or trunk RMS.
Completion lymph node dissection is unnecessary and does not improve outcome.
Extremity tumors within transit nodes require aggressive evaluation since the incidence of involvement is higher than anticipated, and failure to include these nodal groups in the radiation field increases the chances for local and regional tumor failure.
What are indications for nodal evaluation In RMS patients?
Indications for nodal evaluation include positive clinical nodes and extremity, trunk, and paratesticular tumors in patients >10 years old, and is recommended in all patients with fusion-positive ARMS given its poor outcome and high incidence of false negative imaging.
How is pre treatment staging done for RMS?
Staging of RMS follows the classic tumor/node/metastasis (TNM) classification and defines a pretreatment system determined by site and size of the primary tumor, degree of invasion, nodal status, and the presence or absence of metastatic disease.
It is based on the preoperative physical examination and imaging studies.
How is clinical grouping done post treatment for RMS?
One of the most important prognostic factors in RMS is the extent of residual disease after initial resection.
After the initial surgical procedure, the patients are assigned to a clinical group according to the pathologic evaluation of the specimen, which encompasses the completeness of excision (residual disease including 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.
How is risk group stratification done for RMS patients?
The Soft Tissue Sarcoma Committee of the Children’s Oncology Group (STS-COG) created the risk stratification system in an effort to tailor therapy to patient outcomes.
It incorporates pretreatment staging (including site and TNM status), clinical group, and histology. It also classifies patients into low-, intermediate-, and high-risk groups.
This comprehensive stratification process has shown to be an accurate predictor of outcomes.
What is the standard chemotherapy regimen for RMS?
Systemic therapy should be part of the treatment plan for all RMS patients.
The standard chemotherapy regimen includes vincristine, actinomycin-D, and cyclophosphamide (VAC).
For the low-risk group (LRRMS), the duration of chemotherapy and the dosing of cyclophosphamide can both be decreased from the current regimen dosing while maintaining good outcomes, thereby limiting its toxicity.
Irinotecan (I) was added in a recent randomized control trial to the intermediate-risk (IRRMS) group in the form of VAC/VI since it has shown significant benefit with metastatic and recurrent RMS.
Although it did not improve EFS or OS compared with VAC alone, the lower rate of toxicity and cumulative dose of cyclophosphamide in the VAC/ VI regimen supports its use as the current standard therapy for RMS.
A recent study, however, found different results when decreasing the total cyclophosphamide dose for patients with subset 2 low-risk RMS who did not receive RT. 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 LRRMS and IRRMS groups.
However, for high-risk patients, slow progress has been made in ongoing prospective trials despite the use of new chemotherapeutic agents and molecular therapies.
Currently a randomized phase III trial is comparing standard chemotherapy with standard chemotherapy and temsirolimus in treating patients with IRRMS, hypothesizing that temsirolimus (an inhibitor of the mammalian target of rapamycin [mTOR]) may improve survival in conjunction with standard chemotherapy.
What is the recommended radiotherapy regimen for RMS?
Except for clinical group I ERMS, RT along with surgical resection is an essential part of local control.
The anatomic location, extent of residual disease after surgical resection, and lymph node involvement will dictate dosing and timing of therapy.
RT is generally given 6–12 weeks after the beginning of chemotherapy except for patients with parameningeal RMS with intracranial extension, in which an earlier start confers better local control.
RT 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 RT, which can avoid undertreatment while providing more focal treatment with decreased adverse effects.
A recent large prospective cohort showed that proton RT represents a safe and effective radiation modality for pediatric RMS patients with improved 5-year local control (81%), EFS (69%), and OS (78%).
What are principles for surgical excision of RMS?
Patients who present with suspected RMS should have a thorough surgical evaluation since local surgical control is an important determinant of outcome.
Local recurrence is the most common reason for treatment failure for patients with localized disease.
For tissue diagnosis, open biopsy is generally recommended to obtain enough tissue for biology and chromosomal analyses.
If core needle biopsies are performed, multiple passes are needed to avoid sampling error.
Complete surgical excision should be performed initially as long as there will be no major functional impairment or disfiguring cosmetic result.
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.
Although debulking procedures are generally not indicated, they may have some benefit for advanced-stage retroperitoneal embryonal tumors.
In cases in which complete excision is not possible and residual disease is left, the surgical bed should be marked with small titanium clips to guide RT and future re-excisions 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 within a tumor board evaluation.
When should pretreatment re-excision be considered for RMS?
Pretreatment re-excision (PRE) of RMS should be considered in cases in which the surgical margins are positive, when a nononcologic excision was performed, or when only a biopsy was taken, if the surgeon thinks that complete resection with negative margins is feasible prior starting chemotherapy.
It is most commonly performed in extremity and trunk RMS.
Patients who undergo PRE are then categorized as group I and have the same outcome as patients with negative margins following initial excision.
PRE has shown to improve FFS and OS.
When should delayed primary excision be considered In RMS?
Response to therapy is generally evaluated with CT/MRI after induction chemotherapy around week 12, but it has been shown that it does not correlate with FFS for either ERMS or ARMS.
However, the pathologic response (amount of viable tissue found at the delayed primary excision [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 resection can be achieved without significant morbidity.
The goal of DPE is to achieve local control, thereby reducing the RT dose and the associated morbidity.
Recent studies propose tailoring RT dosing based upon 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.
DPE should not be mistaken for resection of residual masses after completion of standard therapy. Second look operation (SLO) should be considered for local control, during or after adjuvant therapy, for tumors that are initially unresectable but show a significant response to induction chemotherapy and RT and can be completely resected.
