Rhabdomyosarcoma and other soft-tissue sarcomas

Genetics of RMS

• 1.

  Alveolar RMS (ARMS) has a characteristic translocation of the FOXO1 gene (previously known as Forkhead, or FKHR ) at 13q14 with PAX3 at 2q35 or less commonly PAX7 at 1p36. The fusion protein functions as a transcription factor that activates transcription from PAX-binding sites that are 10–100 times more active than wild-type PAX7 and PAX3 . This alteration in growth, differentiation, and apoptosis results in tumorigenic behavior. Approximately 75% of ARMSs contain the FOXO1–PAX3 translocation; the remaining 25% contain the FOXO1–PAX7 translocation. Recently, PAX–FOXO1 fusion was identified to be a poor prognostic indicator with lower event-free survival for low- and intermediate-risk disease. Of the two translocations, PAX7–FOXO1 appears to have a more favorable outcome. This outcome analysis has led to the novel modification to classification and treatment protocols. In regards to metastatic disease, fusion status was not an independent predictor of outcome (clinical risk factor remains the major predictor).

• 2.

  ERMS has a loss of heterozygosity (LOH) at the 11p15.5 locus. This LOH involves loss of the imprinted maternal genetic information and all that remains is expression of the paternal genetic material. This LOH includes loss of tumor suppressor genes that have been implicated in oncogenesis that results in the overproduction of insulin-related growth factor-II (IGF-II). IGF-II stimulates the growth of RMS and blockade of one of its receptors, insulin like growth factor-I receptor (IGF-IR), inhibits RMS growth both in vitro and in vivo.

• 3.

  “Translocation-negative” ARMSs (i.e., tumors that have an alveolar pattern on routine light microscopy but lack the defining FOXO1–PAX translocation) represent approximately 25% of cases of ARMS and have been demonstrated conclusively to cluster genomically and clinically with ERMS. The subset of cases with low-risk clinical features will be considered low-risk fusion-negative RMS in future Children’s Oncology Group (COG) clinical trials.

• 4.

  Spindle cell/sclerosing RMS constitutes a less common subtype of ERMS that may be seen in children and adults. They appear to have distinctive genetic features and clinical behavior in each group: in children cases occur in the paratesticular region and typically have a favorable prognosis. Recurrent NCOA2 translocations have also been described in cases of infantile/congenital spindle cell RMS with very good outcomes. Conversely, adults typically have more aggressively behaving disease. There is growing evidence that many of these tumors (especially with sclerosing histology) contain MYOD1 (L122R) mutation, which appears to be associated with relatively aggressive clinical course in both populations.

Primary sites

RMS may occur in any anatomic location of the body where there is skeletal muscle, as well as in sites where no skeletal muscle is found (e.g., urinary bladder, common bile duct). RMS in children under 10 years of age generally involves the head and neck or genitourinary areas. Adolescents more commonly develop extremity, truncal, or paratesticular lesions. Table 25.3 lists the relative frequency of the various primary sites and sites of regional spread and distant metastases.

NRSTS can arise in any tissue but are extremely uncommon in bone. Approximately half of NRSTS arise in extremities. The remaining NRSTS are divided between trunk, head and neck, and visceral/retroperitoneal sites.

Signs and symptoms

Most STS present as painless masses. Symptoms depend on the location and invasion of the adjacent normal structures.

Specific clinical manifestations vary with the site of origin of the primary lesion and are outlined in Table 25.4 . About 50% of RMSs of head and neck primary tumors (nasopharynx, sinuses, middle ear) have infiltration of tumor through the skull base with intracranial extension of disease that may manifest as cranial nerve palsies with or without headache and/or other signs of raised intracranial pressure.

Rare primary sites for RMS include the gastrointestinal–hepatobiliary tract (3%), where it presents with obstructive jaundice and a large abdominal mass. These tumors arise in the common bile duct and may extend into both lobes of the liver. Other rare primary sites are the intrathoracic region (2%) and the perineal–perianal area (2%).

Approximately 20% of RMSs have metastatic disease at diagnosis and the most common sites are bone marrow and lung, followed by lymph nodes and bone.

NRSTS rarely presents with systemic symptoms. Up to 15% of patients present with metastatic disease, most commonly to the lung. Nodal spread is rarely seen except with epithelioid sarcoma and clear cell sarcoma. Rarely bone, liver, and subcutaneous and brain metastases are seen, and bone marrow involvement is exceedingly rare.

Staging for RMS

It is essential to fully stage RMS. The prognosis, selection of systemic therapy, and the design of optimal local therapy depend on the following:

• primary site

• histologic type

• tumor size

• degree of regional spread

• nodal involvement

• distant metastatic disease

• extent of prechemotherapy tumor resection

The RMS staging systems consist of the following:

• Pretreatment clinical stage : the Intergroup Rhabdomyosarcoma Study incorporated the most significant prognostic variables (primary site, invasiveness, size, regional lymph node involvement) into a tumor–node–metastasis. The STS-COG staging system is provided in Table 25.6 .

  Table 25.6

  Soft-tissue sarcoma—Children’s Oncology Group pretreatment tumor–node–metastasis staging of rhabdomyosarcoma.

  Modified from Mandell (1993) with permission.

  Stage	Sites	T invasiveness	T size	N	M a
  I	Favorable sites Orbit, head, and neck (excluding parameningeal), genitourinary (nonbladder/nonprostate)	T1 or T2	a or b	N0 or N1 or NX	M0
  II	Unfavorable sites Bladder/prostate, extremity cranial parameningeal other (includes trunk and retroperitoneum)	T1 or T2	a	N0 or NX	M0
  III	Unfavorable sites Bladder/prostate, extremity cranial parameningeal other (includes trunk and retroperitoneum)	T1 or T2	a, b	N1 N0 or N1 or NX	M0
  IV	Any sites	T1 or T2	a or b	N0 or N1	M1

  T=tumor N=regional nodes M=metastasis

  T1=confined to anatomic site of origin; N0=not clinically involved; M0=no distant metastasis

  T2=extension and/or fixation to surrounding tissue; N1=clinically involved; M1=distant metastasis present

  a tumor size ≤5 cm in diameter; NX=clinical status unknown; M1 includes positive CSF cytology, pleural and/or peritoneal fluid and distant nodes

  b tumor size > 5 cm in diameter

  a Distant metastatic disease consists of lung, liver, bones, bone marrow, brain, and distant muscle and nodes. The presence of positive cytology in CSF, pleural, or abdominal fluids, as well as implants on pleural or peritoneal surfaces, also constitutes stage IV disease.

• Postoperative clinical group : this is based on the extent of the surgical resection and takes into account the lymph node evaluation ( Table 25.7 ). In some locations, when complete resection is possible with negative margins, overall survival is improved.

  Table 25.7

  Postoperative clinical grouping system (Intergroup Rhabdomyosarcoma Study).

  Group	Definition (incidence)
  I.	No residual disease (16%)
  	A. Localized, completely resected, confined to site of origin
  	B. Localized, completely resected, infiltrated beyond site of origin
  II.	Microscopic residual disease (20%)
  	A. Margins positive, lymph nodes negative
  	B. Margins negative, lymph nodes positive
  	C. Margins positive, lymph nodes positive
  III.	Gross residual disease (48%)
  	A. Biopsy only
  	B. Grossly visible disease after 50% resection of primary tumor
  IV.	Distant metastasis present at diagnosis (16%)

• Risk group classification ( Table 25.8 ): the risk group classification and treatment has been based on the combination of pretreatment stage, postoperative clinical group, and histology. In the most recent COG trial (ARST-1431), fusion status was also included in the risk group classification.

  Table 25.8

  Rhabdomyosarcoma Risk Group classification and outcome for rhabdomyosarcoma (RMS) from soft-tissue sarcoma—Children’s Oncology Group.

  Risk group	Fusion status	Pretreatment stage	Postoperative clinical group	EFS (%)
  Low	(FN-RMS)	1 (all favorable sites)	I or II	85–95
  	(FN-RMS)	1 (orbit only)	III
  	(FN-RMS)	2 (unfavorable sites ≤5 cm)	I or II
  Intermediate	(FN-RMS)	1 (nonorbit only)	III	70–85
  		2, 3	III	65–75
  		3 (unfavorable sites >5 cm, or unfavorable site, any size, with regional nodal involvement)	I or II	70–85
  		4 (under 10 years of age)	IV	50–60
  	(FP-RMS)	1, 2, 3	I, II, III	50–60
  High	(FN-RMS)	4 (over 10 years of age)	IV	20–40
  High	(FP-RMS)	4	IV	5–20

  Abbreviations: FN-RMS , Fusion-negative rhabdomyosarcoma; FP-RMS , fusion-positive rhabdomyosarcoma.

The low-risk group includes all nonmetastatic favorable-site ERMS (stage 1, regardless of degree of initial surgical resection) and completely resected (groups I and II) nonmetastatic unfavorable-site ERMS.

The intermediate-risk group includes all nonmetastatic alveolar tumors and embryonal tumors in unfavorable primary sites (stage 2 or 3) that have been incompletely resected (group III). Girls with nonbladder genitourinary tract ERMS treated without local radiation therapy have inferior outcomes and are now considered to have intermediate-risk disease (they had been previously classified as low-risk subset 2) . Their prognosis improves when treated with either intensified systemic therapy (cyclophosphamide at a dose of 2.2 g/m ² /cycle) or “standard-intensity” systemic therapy (cyclophosphamide at 1.2 g/m ² /cycle) combined with appropriate local therapy consisting of some combination of conservative surgery with either vaginal brachytherapy or external beam radiation therapy. In the past, children under the age of 10 years with ERMS and isolated lung metastases were considered in the high-risk group, but due to a more favorable prognosis they can be categorized to have intermediate-risk disease .

The high-risk group includes all metastatic tumors (both alveolar and embryonal) except for children under the age of 10 years with ERMS and isolated lung metastases. Since prognosis is determined by the risk group, the risk group classification determines treatment.

Staging for NRSTS

Staging using the American Joint Committee on Cancer staging system incorporates tumor size (T), depth, nodal (N), and metastatic (M) involvement, and histologic grade (G). Risk stratification is based on tumor size, tumor grade, margins, resectability, and metastatic disease. In pediatric NRSTS, risk stratification with an emphasis on tumor size and resectability predicts outcome.

The low-risk group (~50% of patients) includes those whose primary tumor has been grossly resected, have nonmetastatic disease and whose pathology shows:

• Low-grade tumors regardless of margin status

• High-grade tumors ≤5 cm in size

The intermediate-risk group (~35% of patients) includes those with nonmetastatic disease and:

• High-grade tumors that are grossly resected and greater than 5 cm in size

• High-grade tumors that are unresectable and where a delayed resection is planned

The high-risk group (~15% of patients) includes those who have metastatic disease, irrespective of the pathological grade of the tumor.

Prognosis for RMS

Overall, RMS is curable in the majority of children (70% survival 5 years after diagnosis). The type of treatment failure differs among different risk groups. The failures are typically:

• Local treatment failure for patients with nonmetastatic ERMS.

• Regional and distant treatment failure for patients with nonmetastatic ARMS.

• Distant treatment failure for patients with metastatic RMS.

• Extent of disease is the most important prognostic factor. Children with localized, completely resected disease do better than those with widespread or disseminated disease.

• Patients with gross residual disease after surgery (group III) have a statistically significantly lower 3-year failure free survival (FFS) of 73% compared with 83% and 86% FFS for groups I and II, respectively.

• Patients with smaller tumors (≤5 cm) have improved survival compared to children with tumors greater than 5 cm in size.

• Those with metastatic disease at diagnosis have the worst prognosis. Among those with metastatic disease, two or less metastases are significantly better than three or more.

• Among patients with intermediate-risk disease, patients with alveolar histology have a worse prognosis, and the group with regional nodal involvement has a prognosis that approaches that of patients with conventionally defined “distant metastases.” The alveolar subtype is frequently associated with an extremity site, which is a poor prognostic factor. Of note, fusion-negative alveolar subtype with low-risk clinical features can have a more favorable prognosis.

• Nonparameningeal head and neck sites, nonbladder/nonprostate male and female genitourinary tract sites and biliary tract are “favorable sites”; all other sites are “unfavorable.”

• Children between 1 and 9 years of age have a better prognosis than those older than 9 years of age (83% vs 68% 3-year FFS). This finding might be due to the higher incidence of advanced disease and alveolar type in older children.

The high-risk group of patients has metastatic disease and represents approximately 20% of patients with RMS. Within this group, there is significant diversity of outcome. Patients with ERMS aged 1–9 years of age and lung-only metastases have 50% event free survival (EFS) and those with bone and bone marrow involvement at diagnosis having an overall survival less than 10%. The dominant risk of treatment failure is from the inability to control systemic disease, although local treatment failure also appears to be higher in patients with metastases at diagnosis.