Pathology – Rhabdomyosarcoma
Rhabdomyosarcoma is a malignant tumor of striated muscle origin. According to Rubin, it is derived from primitive mesenchyme that retained its capacity for skeletal muscle differentiation.  Rhabdomyosarcoma of the head and neck is primarily a disease of the first decade of life, and it is the most common soft tissue sarcoma in childhood. Approximately 90% of all cases of rhabdomyosarcoma are diagnosed in individuals younger than 25 years, and within this group, 60-70% are younger than 10 years. Rhabdomyosarcoma represents 3.5% of all malignancies in children aged 0-14 years, with approximately 250 new cases diagnosed each year. The annual incidence of rhabdomyosarcoma in the United States is 4.5 cases per 1 million children younger than 14 years.
The disease has little propensity for any particular geographic location or ethnic group. However, people of Asian descent have a slightly lower prevalence than that of blacks or whites. The male-to-female ratio is approximately 1.5:1.
See the image below.
The head and neck are reportedly the most frequent (35-40%) sites of origin, followed by the genitourinary tract, extremities, trunk, retroperitoneum, and uncommon regions (eg, intrathoracic, GI tract, perianal and anal regions). However, a retrospective study by Ma et al of pediatric patients with rhabdomyosarcoma found the genitourinary system to be the most common primary tumor site (43.5%), with the head and neck being the second most common (31.1%) and the extremities the third most common (11.2%); 6.2% of primary tumors were found in the retroperitoneum. 
In the head and neck, the most common sites of rhabdomyosarcoma are parameningeal and orbital locations, which account for 16% and 9% of all cases of the disease, respectively. Over several decades, great progress has been made in the treatment of rhabdomyosarcoma. As a result, 5-year survival rates increased from 25% in 1970 to 73%, as shown in the Intergroup Rhabdomyosarcoma Study (IRS)-IV reported in 2001. 
In a retrospective study of 28 pediatric patients with head and neck rhabdomyosarcoma published in 2018, Häußler et al found the 5-year overall survival rate to be 91.3%, with the median period of progression-free survival reported to be 46 months. Patients received multimodal treatment, including polychemotherapy (all patients), adjuvant radiation therapy (24 patients), and surgery (12 patients). 
In 2006, the National Collaborating Centre for Cancer published a guideline for improving outcomes in patients with sarcoma.  Additionally, the National Cancer Institute has provided a patient guide to treatment. 
Rhabdomyosarcoma is divided into 5 major histologic categories: embryonal, alveolar, botryoid embryonal, spindle cell embryonal, and anaplastic. 
Embryonal rhabdomyosarcoma is the most common subtype observed in children, accounting for approximately 60% of all cases in this age group. The tumors can occur at any site, but they are most commonly observed in the genitourinary region or the head and neck region. On histologic examination, they have high cytologic variability, which represents several stages of skeletal muscle morphogenesis. They may range from highly differentiated neoplasms containing rhabdomyoblasts with large amounts of eosinophilic cytoplasm and cross striations similar to that of poorly differentiated tumor cells (see the image below). Desmin and muscle specific actin are the typical stains used to identify rhabdomyosarcoma. Newer staining agents, such as myogenin and MyoD1, are more specific for skeletal muscle than older stains. Desmin and actin stain smooth muscle as well.
Embryonal rhabdomyosarcoma has unique molecular characteristics. Embryonal rhabdomyosarcoma cells show a loss of specific genome material from the short arm of chromosome 11. This consistent loss of the material from the 11p15 region may suggest the presence of a tumor suppressor gene, though the actual gene responsible for embryonal rhabdomyosarcoma is not yet known. Another molecular feature is its lack of gene amplification. In addition, the cellular DNA content of embryonal rhabdomyosarcoma is hyperdiploid (1.1-1.8 X normal DNA). 
The alveolar subtype makes up about 31% of all cases of rhabdomyosarcoma. It is most frequently observed in adolescents and in patients whose primary sites involve the extremities, the trunk, and the perianal and/or perirectal region. On microscopy, these tumors have the appearance of club-shaped tumor cells arranged in clumps and outlined by fibrous septa. In the center, the clusters are arranged loosely, and therefore, they appear in an alveolar pattern (see the image below). These cells stain intensely with eosinophilic stain. Cross-striated malignant rhabdomyoblasts are observed in 25% of cases, which is less frequent than what is observed with the embryonal form.
Like embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma has distinct molecular characteristics. A unique translocation occurs between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 (70%) or the PAX7 gene on chromosome 1 (30%). Individuals with the PAX7 translocation are younger and may have longer event-free survival than those with the PAX3 translocation. Unlike embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma commonly demonstrates gene amplification, and its DNA content is typically tetraploidy. [9, 10, 11]
Botryoid type, a subset of embryonal rhabdomyosarcoma, accounts for 6% of all cases of rhabdomyosarcoma. This subtype characteristically arises under the mucosal surfaces of body orifices; therefore, it is most commonly observed in areas such as the vagina, bladder, and nares. It is distinguished by the formation of polypoid and grapelike tumor masses. On histologic study, botryoid rhabdomyosarcoma demonstrates malignant cells in an abundant myxoid stroma.
The spindle cell subtype of embryonal rhabdomyosarcoma accounts for 3% of all cases. It has a fascicular, spindled, and leiomyomatous growth pattern and can demonstrate notable rhabdomyoblastic differentiation. Some neoplasms show marked collagen deposition and have a nested, storiform growth pattern. This subtype occurs predominantly in the paratesticular region and is rare in the head and neck.
Anaplastic rhabdomyosarcoma, previously called pleomorphic rhabdomyosarcoma, is the least common of all subtypes. It most often occurs in patients aged 30-50 years. It is rarely observed in children. Anaplastic rhabdomyosarcoma is defined by large, lobate hyperchromatic nuclei and multipolar mitotic figures.
Rhabdomyosarcoma is a disease that can be diagnosed and treated early. Researchers in the IRS-IV reported that 23% of the patients received a diagnosed early enough to receive complete surgical resection, and 15% underwent gross resection with only microscopic residual disease.
Because of the various anatomic constraints of the head and neck, most lesions in this region are obvious at presentation; therefore, they are easily detected. A mass or area of localized swelling usually characterizes the initial presentation. Fewer than half of these patients present with pain.
Other symptoms, which depend on the location of tumor, include nasal discharge or airway obstruction, otorrhea, hearing loss, fetor (foul smell), and rapid proptosis. Cranial nerve palsies or other neurologic deficits indicate extension of the neoplasm into the skull base or CNS. The orbit is involved in nearly one third of head and neck rhabdomyosarcomas, followed by those in the oral cavity and oropharynx (29%), face and neck (24%), and middle ear and/or mastoid and sinonasal cavity (9%). Parameningeal sites include the paranasal sinuses, nasal cavity, and middle ear; rhabdomyosarcomas at these sites are observed in 16% of patients (see the images below).
The initial diagnostic workup must address 2 key issues. First, the nature and extent of the primary disease must be determined. To accomplish this, surgical biopsy is performed early in the diagnostic process. In addition, either CT or MRI is performed to provide accompanying information that is used in planning the approach for surgical resection as well as routes and doses for possible radiation therapy later in the treatment process.
Next, the clinician must evaluate the patient for locoregional or metastatic disease. This evaluation is accomplished by performing a battery of adjunctive studies, including bone marrow biopsy, chest CT, and technetium diphosphonate bone scanning. When the primary site is parameningeal, lumbar puncture is also performed for CSF cytology.
Multiple clinical and biologic factors have been shown to influence the prognosis for a child with rhabdomyosarcoma. These include site of tumor origin, tumor size, nodal involvement, histology, and cellular DNA content. Staging classifications based on these factors allow the clinician to determine an overall prognosis for each patient. 
The site of origin influences the patient’s clinical outcome. For example, patients with head and neck rhabdomyosarcoma affecting the orbit and nonparameningeal area have a prognosis more favorable than that of patients with tumors in other sites in the body. A study by Affinita et al of pediatric patients with nonparameningeal head and neck rhabdomyosarcoma reported that the lesions tended to display favorable characteristics, with 72.7% being under 5 cm, 72.7% being classified as T1, and 80.3% being classified as N0. The 10-year overall and progression-free survival rates for the patients—who underwent primary surgery or received chemotherapy along with delayed surgery and/or radiotherapy—were 74.2% and 65.1%, respectively. 
Another prognostic factor is tumor burden. Individuals with tumors smaller than 5 cm have an improved prognosis when compared with those with larger tumors. Children with regional nodal involvement do worse than those without nodal disease. Children with metastatic disease have the poorest prognosis. In this group, the most important prognostic factors are histologic subtype and the patient’s age at diagnosis. For patients who are younger than 10 years and who have metastatic disease of embryonal histology, the 5-year survival rate is 60%. Patients older than 10 years with embryonal histology and all patients with alveolar histology have 5-year survival rates of less than 30%. 
Nutritional status also appears to be prognostically significant in children with rhabdomyosarcoma; a literature review by Joffe et al found that in the presence of this disease, pediatric patients with an abnormal body mass index (BMI) trend toward worse overall survival. 
The final clinical factor affecting the patient’s prognosis is the extent of disease following initial surgical resection. As discussed in Staging Information below, the clinical groups established in the IRS-III and IRS-IV are partially based on the extent of disease after initial surgical resection. Patients without residual disease (group I) have a 90% 5-year survival rate. In patients with microscopic residual disease (group II), survival decreases to 80%, and those with gross disease after surgery (group III) have a 5-year survival rate of 70%.
Biologic factors can also influence prognosis. The literature often mentions that the alveolar subtype of rhabdomyosarcoma is associated with a prognosis worse than that of the other types. When the alveolar subtype is compared with the embryonal type, alveolar rhabdomyosarcoma is more common in patients with less favorable clinical features (eg, older age, extremity involvement, distant metastasis). However, when the IRS-I and IRS-II study groups were evaluated, no statistical difference was noted among subtypes when examined independently of other factors.
Cellular DNA content, or ploidy, does appear to have prognostic significance. Patients whose tumor cells have a DNA content 1.5 times higher than normal (hyperdiploid) have a better outcome than those with normal (diploid) or twice-normal (tetraploid) DNA content. Hyperdiploid DNA content is associated with embryonal histology, whereas tetradiploid DNA content is associated with alveolar histology. Also, the incidence of anaplasia in patients with rhabdomyosarcoma may be higher than previously described and may be of prognostic significance in children with intermediate-risk rhabdomyosarcoma, as its presence appears to negatively influence survival. 
In a study of 100 patients under age 21 years (median age 4 years) with large, nonmetastatic primary nongenitourinary embryonal rhabdomyosarcoma of the abdomen, Dantonello et al concluded that children with these tumors have a fair prognosis if tumor resection or irradiation can be performed after induction chemotherapy. In the study, 36 patients underwent resection following induction chemotherapy, and 60 tumors were irradiated. Median follow-up was 10 years, with patients demonstrating 5-year event-free and overall survival rates of 52% and 65%, respectively. According to the investigators, significant patient risk factors included age over 10 years, failure to achieve complete remission, and inadequate secondary local therapy (ie, incomplete secondary resection or absence of radiation therapy). 
Two methods are used to stage rhabdomyosarcoma. The initial staging system, adopted in the first 3 intergroup rhabdomyosarcoma studies, categorizes patients on the basis of the extent of disease and the completeness of their initial surgical resection. Investigators in the IRS-IV attempted to use the tumor, node, and metastasis (TNM) system to standardize the staging system in the United States with those in other parts of the world. Unlike the first system, TNM staging does not take the extent of surgery into account, though it does take size and location into consideration.
The 2 staging systems are combined, and individuals with rhabdomyosarcoma are given 1 of 3 risk classifications: low, intermediate, or high. Treatment options are tailored for these risk classifications.
See the list below:
Group I: Thirteen percent of all patients with rhabdomyosarcoma are in group I. This group is defined by localized disease with complete surgical resection and no evidence of regional nodal involvement.
Group II: Twenty percent of patients with rhabdomyosarcoma are in group II.
Group IIA patients have grossly resected disease with microscopic residual disease and no regional involvement.
Group IIB patients have had complete resection with no residual disease, but they also have regional disease with involved nodes.
Group IIC is a hybrid of groups IIA and IIB, containing patients with microscopic residual disease and regional nodal involvement.
Group III: Approximately 48% of patients with rhabdomyosarcoma are in group III. This group is marked by incomplete resection or biopsy only; therefore, it is characterized as gross residual disease.
Group IV: Approximately 18% of patients with rhabdomyosarcoma are in group IV. Individuals in group IV have distant metastasis at the time of diagnosis.
See the list below:
Stage I: Disease is localized and involves the orbit, the head and neck region (excluding parameningeal sites), or the nonbladder and/or nonprostate genitourinary region.
Stage II: This stage includes any localized disease of any unfavorable primary site not included in the stage I category. The primary tumor must be less than or equal to 5 cm in diameter.
Stage III: The criteria are the same as in stage II except the primary tumor is larger than 5 cm in diameter and/or it involves regional lymph nodes.
Stage IV: Like group IV, stage IV implies metastatic disease at the time of diagnosis.
See the list below:
Low risk: Patients have embryonal rhabdomyosarcoma at a favorable site (stage I), at an unfavorable site with complete resection (group I), or at an unfavorable site with microscopic residual disease (group II).
Intermediate risk: Patients have embryonal rhabdomyosarcoma at an unfavorable site with gross residual disease (group III), metastatic embryonal rhabdomyosarcoma and are younger than 10 years, or any nonmetastatic alveolar rhabdomyosarcoma at any site.
High risk: Those at high risk include any patient with metastatic disease unless he or she is younger than 10 years and has embryonal metastasis.
Treatment of rhabdomyosarcoma is a multimodality effort. Initial efforts are aimed at surgical resection of the tumor, always followed by chemotherapy and typically ending with a standard course of radiation. The principles of surgical and radiation therapy are based on the site of involvement and the extent of disease, whereas the chemotherapeutic options depend on risk factors.
Unlike other regions of the body where rhabdomyosarcoma can occur, the head and neck region is limited by anatomic constraints; therefore, surgical treatment in this area must be altered accordingly. For superficial nonorbital lesions, wide excision is recommended. A cuff of normal tissue is always resected with the neoplastic tissue; however, narrow margins are accepted because of the anatomic restrictions.
Rhabdomyosarcoma of the orbit does not require surgical exenteration at the time of initial resection. Initial surgery is aimed only at biopsy for diagnosis. Exenteration is reserved for recurrent or locally persistent disease. If evidence suggests microscopic residual disease after initial surgical resection of head and neck rhabdomyosarcoma, a second operation with wide margins before chemotherapy may also improve the prognosis.
Surgery plays a limited role in the treatment of metastatic disease. It is indicated only in the context of persistent pulmonary metastases after chemotherapy and irradiation, and it is considered an option only if pulmonary function can be adequately maintained.
Risk-factor analysis based on a combination of staging and histology is the primary means for determining the appropriate course of chemotherapy.
Patients at low risk and those with the most favorable prognosis include individuals with embryonal rhabdomyosarcoma occurring at favorable sites. These include the orbit, nonparameningeal areas of the head and neck, genitourinary nonbladder or nonprostate regions, and biliary tract (stage I). Also included are patients with embryonal rhabdomyosarcoma at unfavorable sites with completely resected disease (group I) or embryonal rhabdomyosarcoma at unfavorable sites with microscopic residual disease after resection (group II). For patients with this prognosis, the most common regimen is a combination of vincristine and dactinomycin (VA protocol).  In certain subpopulations with preexisting renal abnormality that predispose them to nephrotoxicity, cyclophosphamide is often added (ie, VAC protocol). The overall survival rate for this group is more than 90%. 
Patients with intermediate risk and an intermediate prognosis include those with embryonal rhabdomyosarcoma at unfavorable sites and gross disease, those who are younger than 10 years and who have metastatic embryonal rhabdomyosarcoma, and those with nonmetastatic alveolar rhabdomyosarcoma at any site. Standard treatment for these patients is the VAC protocol with the addition of radiation therapy. The new IRS-V protocol calls for the addition of topotecan to the standard treatment regimen. Survival rates at 5 years after diagnosis are 55-70%.
Patients with metastatic disease (except the subgroup in the intermediate category) have a survival rate of approximately 30% despite both chemotherapy and irradiation and are therefore considered to be at high risk with a poor prognosis. Like the intermediate group, this group most commonly receives the VAC protocol. IRS-V recommendations call for the addition of irinotecan in this group.
Several new chemotherapeutic agents, including doxorubicin, cisplatin, etoposide, ifosfamide, topotecan and melphalan, have been tested in various combinations with and without the standard VAC protocol. However, none of these is superior to VAC alone. With high-dose chemotherapy with reconstitution of stem cells, high-risk patients with metastatic disease have a relapse-free survival rate of 19-44%. However, 1 comparison of this therapy to standard VAC chemotherapy with radiation therapy showed no significant survival advantage to stem cell reconstitution.
The location and extent of disease after surgical management largely determine the doses for radiation treatment. In general, a margin of 2 cm around the tumor and involved nodes is the guideline for the treatment volume.
Chemotherapy is typically administered for 2-3 months before the start of radiation therapy. Radiation treatment is then administered for approximately 5-6 weeks. The only exception to this rule involves patients with parameningeal disease and evidence of meningeal spread. In this circumstance, radiation is started at the time of diagnosis. During radiation treatment, doses of chemotherapy are altered to avoid the use of radiosensitizing agents (eg, dactinomycin, doxorubicin). Patients with encranial meningeal extension of parameningeal rhabdomyosarcoma should receive whole-brain irradiation in addition to radiotherapy of the primary tumor.
In general, irradiation is good for patients with evidence of gross or microscopic residual disease after resection. Patients in group I (complete resection) typically do well without irradiation. However, radiation therapy may be of some benefit in patients with alveolar histology, who may otherwise have a less favorable prognosis.
Patients in clinical group II typically receive total radiation doses of 4100 cGy. Individuals in group III receive approximately 5000 cGy. Although this dose is associated with a relapse rate of more than 30%, the long-term toxic effects of increasing the total dose make more aggressive treatments unfeasible. Current investigators are examining hyperfractionization and brachytherapy as alternatives to current treatment methods. In addition, newer studies indicate that improved risk stratification enables decreased therapy intensity for selected patients without compromising survival. 
A study by Clement et al indicated that long-term survivors of pediatric head and neck rhabdomyosarcoma are at a significantly increased risk of developing pituitary dysfunction, owing to treatment with radiation therapy. The study, of 80 survivors of head and neck rhabdomyosarcoma, reported pituitary dysfunction in 24 of them (30%) after a median 11-year follow-up period, with risk factors for such dysfunction including external beam radiation therapy (EBRT), a parameningeal tumor site, and embryonal rhabdomyosarcoma subtype. Children treated with the AMORE (ablative surgery, moulage technique brachytherapy, surgical reconstruction) protocol were less likely than those treated with EBRT to develop pituitary dysfunction. 
A study by Mattos et al indicated that chemoradiotherapy in children with head and neck rhabdomyosarcoma can significantly impact dental and craniofacial features. The investigators found 603 dental alterations—most frequently, root shortening—among the study’s 27 patients, with 377 such changes (62.5%) appearing in patients aged 5 years or younger. The study also reported the presence of facial asymmetry (74% of patients), reduced facial depth (70.4% of patients), short-sized mandibles (48.4% of patients), and reduced facial height (77.8% of patients). 
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Amelia F Drake, MD ND Fischer Distinguished Professor of Otolaryngology, Executive Associate Dean of Academic Programs, Director, Craniofacial Center, Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill School of Medicine
Amelia F Drake, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Cleft Palate-Craniofacial Association, American Society of Pediatric Otolaryngology, North Carolina Medical Society
Disclosure: Nothing to disclose.
Steve C Lee, MD, PhD Assistant Professor, Head and Neck Oncologic Surgery and Skull Base Surgery, Department of Otolaryngology-Head and Neck Surgery, Loma Linda University School of Medicine
Steve C Lee, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Arlen D Meyers, MD, MBA Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;Preacute Population Health Management;The Physicians Edge<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; for: Rxblockchain;Bridge Health.
Daniel J Kelley, MD Consulting Staff, Eastern Shore ENT and Allergy Associates and Peninsula Regional Medical Center
Daniel J Kelley, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Head and Neck Society, The Triological Society
Disclosure: Nothing to disclose.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Michael O Ferguson, MD, to the development and writing of this article.
Pathology – Rhabdomyosarcoma
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