The first description of RMS was by Weber in 1854. However, the "definitive" publication is usually considered to be by Stout in 1946, 92 years later.

	Weber, CO. Anatomische Untersuchung Einer Hypertrophieschen Zunge nebst Bemekugen uber die Nubildung querquestreifter Muskelfsern, Virchow Arch. Pathol Anat. 7:115, 1854.
	Stout AP: Rhabdomyosarcoma of the skeletal muscles, Ann Surg 1946; 123: 447-472.

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Adult Cases

Treatment principles for managing adults with RMS are similar to those for children. The five series mentioned above are from:

1. Instituto Nazionale Tumori, Milan, Italy, 190 patients 18 years of age or older over a 25 year period, (Ref. 1)

2. Memorial Sloan-Kettering Cancer Center, New York City, NY, 84 patients 16 years of age or older over a 17 year period, (Ref. 2)

3. M.D. Anderson Cancer Center, Houston, TX, 82 patients 17 years of age or older over a 28 year period, (Ref. 3)

4. Dana-Farber Cancer Institute, Boston, MA, 39 patients 16 years of age or older over a 23 year period, (Ref. 4)

5. Armed Forces Institute of Pathology (Washington, D.C., 38 patients 21 years of age or older over a 30 year period, all with pleiomorphic RMS, (Ref. 5) 

They highlight several key points about “adult” RMS: (1) they are as intrinsically responsive to chemotherapy as “pediatric” RMS with response rates to chemotherapy as high as 85%;  (2) “unfavorable” histologies, including alveolar and pleiomorphic, are more common than embryonal histology; (3) the proportion of patients with Group I, II, III, and IV tumors are comparable to that seen in “pediatric” seri; and, (4) with appropriate treatment, even accounting for differences in the proportion of patients with “unfavorable” histologies, survival rates comparable to that seen in “pediatric” series can be achieved.

The Clinical Trials News column in this issue of ESUN abstracts a large number of Phase I, II and III clinical trials dealing with RMS. Many of the entries are international in scope. The April issue of ESUN featured an article on Online Sarcoma Support Groups contained links to two groups focused on RMS. The April issue also had a related article on Sarcoma Communities that contained links to two websites having RMS-related information.

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Although the overwhelming majority of cases of RMS occur sporadically, between 10-33% of children who develop RMS are thought to have an underlying genetic risk factor (Ref. 10). The development of RMS has been associated with a number of rare familial “cancer syndromes” such as the Li-Fraumeni syndrome (LFS), which includes familial clustering of RMS and other soft tissue tumors in children, with adrenocortical carcinoma and early-onset breast carcinoma in adult relatives. The LFS has been associated with germline mutations of the p53 tumor suppressor gene (Ref. 11). One study of 33 cases of sporadic RMS, found that three of 13 children younger than three years of age at diagnosis (compared with none of the 20 children older than three years of age) had germline mutations in their p53 gene (Ref. 12). RMS has also been seen in association with Beckwith-Wiedemann syndrome, a fetal overgrowth syndrome associated with abnormalities on 11p15, where the insulin-like growth factor II (IGFII) gene is located.  Studies of children with Costello’s syndrome, likely an autosomal dominant disorder characterized by post natal growth retardation, typical coarse facies, loose skin and developmental delay, have noted an increased risk for development of solid tumors, most commonly rhabdomyosarcoma.  There have been ten cases of RMS reported in approximately 100 known children with Costello syndrome.

For an introduction to the Li-Fraumeni syndrome, the Beckwith-Wiedemann syndrome, the Costello syndrome or neurofibromatosis, click on the respective syndrome.

A 7-year old boy presented with one week of swelling and pain of the left eye, without fever or purulent rhinorrhea.  Intravenous antibiotics were administered for treatment of presumptive peri-orbital cellulitis.A MRI (shown below) was obtained and demonstrated an approximately four cm soft-tissue mass arising in the supero-medial aspect of the left orbit displacing the globe anteriorly and laterally. Biopsy of the mass was accomplished by a small, medially placed incision. The diagnosis of embryonal RMS was confirmed. No distant metastases were found on CT chest, bone scan, or bone marrow biopsy. The patient was Stage 1, Group III and was treated successfully with VA chemotherapy plus 45 Gy local XRT).  

Figure 2: Case 1 A 7-year old boy with orbital RMS. MRI of the orbit shows a soft tissue mass arising in the supero-medial aspect of the left orbit displacing the globe outward and laterally.

A 14-year old girl presented with a two week history of rapidly worsening right-sided proptosis and “swollen glands” on the right side of her neck.  MRI demonstrated a multi-compartmental nearly seven cm soft tissue mass (shown below) centered in the sinonasal cavity and extending through the cribriform plate into the anterior cranial fossa. No edema was seen within the frontal lobes to suggest direct parenchymal extension of the tumor.  Multiple enlarged lymph nodes were also seen in the right lateral retropharyngeal region and in the right anterior cervical chain. Physical examination was notable for marked right-sided proptosis and ophthalmoplegia with preserved vision. A mass was visible in the right nares.  Rock-hard cervical lymphadenopathy was present. A fine needle aspiration (FNA) of the cervical nodes revealed a small, round blue cell tumor suspicious for RMS. A biopsy of the mass in the nasal cavity demonstrated the characteristic “alveolar” appearance of alveolar RMS.  Immunostains were strongly positive for desmin, vimentin, and myogenin. RT-PCR confirmed the presence of a t(2;13) PAX3-FKHR translocation. CSF cytology was negative for malignant cells. No evidence of distant metastases was found on CT chest, bone scan, PET scan, or bone marrow biopsy. A diagnosis of Stage 3, Group III alveolar RMS with a paramengingeal primary (likely the ethmoid sinus) with intracranial extension was made. All sites of initially visible tumor disappeared completely on follow-up MRI and PET scan following just two cycles of chemotherapy.  Despite the administration of additional chemotherapy and full-dose (50.4 Gy) XRT to the primary site and all involved lymph nodes, rapidly progressive and ultimately fatal leptomeningeal recurrence was documented within the radiation field six months from the start of therapy.

Figure 3: Case 2 A 14-year old girl with parameningeal RMS. MRI of the sinuses shows a large, invasive soft tissue mass centered in the sinonasal region invading into both the right and left orbits and extending intra-cranially through the base of the skull.

A 18-year old college student developed erectile dysfunction, acute abdominal pain, right-sided flank pain, urinary frequency, hesitation, and decreased stream. Oral antibiotics were administered without improvement.  A CT scan demonstrated a 10 x 6.5 x 7.3 cm pelvic mass arising in the vicinity of the prostate, inseparable from the posterior wall of the bladder and anterior wall of the rectum, obstructing the right ureter and causing right hydronephrosis, with associated bilateral external and left internal iliac adenopathy.  Similar findings were seen on MRI (shown below).  A transrectal needle biopsy yielded material that was comprised of a densely cellular small round blue cell tumor, strongly positive for desmin, vimentin, actin, and myogenin on immunostaining, and containing a t(2;13) PAX3-FKHR translocation on RT-PCR. A temporary percutaneous nephrostomy tube was placed to relieve the right-sided hydronephrosis.  No distant metastases were seen on CT chest, bone scan, or bone marrow biopsy.  A diagnosis of Stage 3, Group III alveolar RMS of the prostate was made and aggressive, multi-agent chemotherapy was commenced to which the patient achieved a complete response.  Erectile function returned to normal.  Additional chemotherapy and full-dose (50.4 Gy) pelvic XRT was administered; treatment was complicated by the development of hemorrhagic cystitis and radiation enteritis.   The patient returned to college less than three months after the completion of eight months of treatment and remains in continuous complete remission 18 months from diagnosis.

Figure 4: Case 3 An 18-year old man with prostate RMS. MRI of the prostate showing a large soft tissue mass on the right side of the pelvis compressing the posterior wall of the urinary bladder and the anterior wall of the rectum.

A 7-year old boy was found to have a firm, painless “lump” in his left calf while being bathed. Physical examination confirmed a rock-hard mass in the calf with obviously enlarged lymph nodes in the popliteal and inguinal regions. MRI demonstrated a large soft-tissue mass in the calf with evidence of hemorrhage (shown), extending cephalad through the popliteal fossa. CT scan of the chest abdomen and pelvis demonstrated the presence of inguinal and pelvic lymphadenopathy, and “suspicious” para-aortic lymphadenopathy; PET scan confirmed that these nodes were hypermetabolic, consistent with metastases. An incisional biopsy of the calf mass and inguinal node demonstrated a “classic” alveolar RMS; RT-PCR confirmed the presence of a “consensus” PAX-FKHR translocation.  Except for the nodal metastases, no other distant metastases were found in the lung, bones, or bone marrow. A diagnosis of Stage 4, Group IV alveolar RMS of the extremity with regional (popliteal and inguinal) and distant (pelvic and para-aortic) nodal metastases was made.  Within one week of starting chemotherapy, the calf tumor had shrunk by more than 50% and the hypermetabolic nodal disease had resolved. Treatment is ongoing on a MSKCC single-institutional pilot protocol for “high-risk” patients.

Figure 5: Case 4 A 7-year old boy with extremity RMS. MRI of the lower extremity showing a soft tissue mass arising in the calf and extending through the popliteal fossa.

The following table summarizes how the combination of site, tumor size, regional nodal status, distant metastases, age at diagnosis, and histology is used to generate risk-stratified therapy for patients with RMS.  The Column entitled “Risk” stratifies patients into one of four risk group (Low-A, Low-B, Intermediate, and High) that is used to assign the appropriate treatment on the Fifth Intergroup Rhabdomyosarcoma Study (IRS-V).  The specific protocol number is indicated in the parentheses as the letter “D” followed by a four-digit figure. 

D9602 is the “low-risk” study consisting of approximately eleven months of chemotherapy treatment on either Arm A (2-drug chemotherapy with vincristine plus dactinomycin [VA], with or without radiation therapy) or Arm B (3-drug chemotherapy with vincristine plus dactinomycin plus cyclophosphamide [VAC], with radiation for almost all patients); D9803 is the “intermediate-risk” study consisting of a randomization between chemotherapy according to Arm A (14 cycles of VAC) or Arm B (eight cycles of VAC alternating with six cycles of vincristine plus topotecan plus cyclophosphamide), plus radiation therapy; D9802 is the “high-risk” study consisting of a “phase II window” with irinotecan administered on the “daily x 5 x 2 schedule” developed in the Houghton lab at St. Jude Children’s Research Center (Ref. 13) either as a single-agent or in combination with vincristine, followed by either eight cycles of VAC plus four cycles of vincristine plus irinotecan for patients responding to irinotecan, or 12 cycles of VAC chemotherapy for patients not responding to irinotecan, plus radiation therapy.  The various IRS-V studies are expected to complete accrual by the end of 2004. Successor studies are planned to open in 2005-2006.  

Rhabdomyosarcoma risk groups definition.

Favorable = Orbit/eye lid, head and neck (excluding parameningeal), genito-urinary (not bladder or prostate)

Unfavorable = Bladder, prostate, extremity, parameningeal, other (trunk, retroperitoneal, etc)

a = Tumor size <= Five cm in diameter

b = Tumor size > Five cm in diameter

EMB = Embryonal, botryoid or spindle variants or ectomesenchymomas with embryonal features

ALV = Alveolar or undifferentiated sarcomas, or ectomesenchymomas with alveolar features

N0 = Regional nodes not clinically involved

N1 = Regional nodes clinically involved

NX = Node status unknown

Table 2: Risk-stratification for patients with newly diagnosed RMS. The combination of Stage, Group, Site, Size, Age, Histologic Subtype, and the presence or absence of regional nodes or distant metastases is used to stratify patient into one of four “risk-groups”.

The following tables contain the detailed site-modified TNM staging system and surgico-pathologic Clinical Group system used to categorize patients with RMS.  These “short-hand” systems are one of the more confusing aspects of caring for children with RMS.  Any tumor that arises in one of the favorable locations is Stage 1 as long as it has not visibly spread to another “distant” part of the body (see below).  Any tumor that has visibly spread to another “distant” part of the body is always Stage 4. Tumors that arise in any of the unfavorable locations will either be Stage 2 (if they are “small” and have not spread to the lymph nodes) or Stage 3 (if they are “big” or have spread to the lymph nodes).   Most children with RMS have Stage 2 or Stage 3 tumors.  Since the TNM “staging” system does not require pathologic confirmation of imaging abnormalities, problems with accurately classifying patients can arise when, for example, a patient would be Stage 4 based on the presence of a pulmonary nodule on CT scan that is believed to represent a metastasis but is then found to not contain tumor when surgery is done to remove it.

Table 3: Site-modified Tumor, Nodes, Metastasis (TNM) Staging System for patients with newly diagnosed RMS. The combination of site (favorable versus unfavorable), size, and the presence or absence of regional nodes or distant metastases is used to classify patients into one of four Stages. This system is a Clinical staging system that relies upon physical examination and radiologic imaging to determine the extent of disease.

T1 = tumor confined to anatomic site of origin;  T2 = extension and/or fixation of tumor to surrounding tissues/structures; other abbreviations as above in the “Risk Stratification” table, Table 2)

An introduction to various cancer staging systems can be found on the Surveillance, Epidemiology and End Results (SEER) Program "Training" website.  The TNM staging system is discussed on the American Joint Committee on Cancer link.  Information about the IRSG staging system can be found here.

CT, MRI, PET and bone scans are described in the "A Caregivers Notes" column in this issue of ESUN.  Links are also provided to additional web resources describing these tests in the Q&A section of the colu