In general, children with alveolar rhabdomyosarcoma have worse survival outcomes compared to

those with embryonal histology. Patients with stage 1 or 2 tumor that is grossly resected (group 1 or 2)

have 5-year failure-free survival of 80% and overall survival of 85%. Stage 1 or 2 (group III) patients

have overall favorable outcomes as well. Children younger than 1 year with alveolar histology have

considerably worse survival outcomes (43%). Patients with stage III tumors with nodal involvement

also have poor survival outcomes (34%). Survival correlates with stage, and patients with high-risk

tumors with distant metastases at diagnosis continue to have the worse expected survival of 25%

despite intensified cytotoxic therapy and radiotherapy.

Treatment

Much of the treatment success of rhabdomyosarcoma is credited to successful clinical trials conducted

by the IRSG and the Soft Tissue Sarcoma Committee of the COG. Multimodal therapy aims to minimize

the risk of relapse and optimize curative outcomes, while also minimizing treatment toxicities. The

INRG has completed five major clinical trials (IRS-I, II, III, IV, V/D) that provide the foundation upon

which the current treatment schema is based for all children diagnosed with rhabdomyosarcoma. IRS-V

or the “D” studies further refined treatment protocols on the basis of prognostic factors and risk

stratification.169–172

7 The mainstay of therapy begins with surgery, either complete excision with adequate margins or

incisional biopsy. The goal for surgical margins is at least 0.5 cm of normal tissue surrounding tumor.

Margins should be marked and oriented to ensure that pathologists can accurately identify each

microscopic margin. Contiguous structures, organs, major blood vessels, or nerves that would result in

major disability should not be resected in the initial operation, rather an adequate biopsy should be

obtained and chemotherapy given upfront. In contrast, lesions that are small and not invading

surrounding structures may be completely resected prior to chemotherapy. Resection of

rhabdomyosarcoma tumors with wide and completely clear microscopic margins is the most ideal initial

procedure for all stages to obtain local tumor control. Pretreatment re-excision is recommended after

the initial operation if there is gross residual tumor or microscopically involved margins prior to the

administration of chemotherapy. This is critical for accurate staging and for optimal clinical group

assignment. Debilitating or highly morbid operations are performed only after chemotherapy and

radiation have been given in attempt to decrease tumor burden and minimize extent of resection.

Lymph node sampling is indicated for patients with lesions that involve the extremity (even if

clinically negative) or for clinically positive lymph nodes for all other sites. Biopsies by open, core, or

sentinel lymph node biopsy techniques are all acceptable on the basis of current COG guidelines.

Staging ipsilateral retroperitoneal lymph node dissection is recommended for paratesticular

rhabdomyosarcoma for all males older than 10 years and for those younger than 10 years with enlarged

lymph nodes appearing on CT scan. In this group, staging ipsilateral retroperitoneal lymph node

dissection is required for adequate staging and risk group assessment. A nerve-sparing ipsilateral

retroperitoneal lymph node dissection is recommended. The boundaries of the dissection begin at the

level of the renal veins surrounding the aorta and the vena cava, extending to the deep inguinal ring.

The procedure may be performed laparoscopically or through an open abdominal incision. Patients with

intermediate-risk tumors may benefit from radical debulking of clinically positive lymph nodes if

feasible.

The addition of chemotherapy and radiotherapy to treatment protocols for rhabdomyosarcoma has

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dramatically improved survival rates. Currently, all children diagnosed with rhabdomyosarcoma receive

adjuvant chemotherapy with or without radiotherapy. Current treatment protocols for patients with

low-risk rhabdomyosarcoma (subgroups A and B) consist of vincristine, actinomycin-D,

cyclophosphamide, and local radiotherapy to sites of residual disease (groups II and III). A recent

clinical trial from the Soft Tissue Sarcoma Committee of COG (D9602) focused on eliminating

cyclophosphamide and reducing radiotherapy doses in patients with lowest risk rhabdomyosarcoma.173

This study found that the 5-year failure-free and overall survivals were lower than similar ISR-IV

patients receiving cyclophosphamide. Given these results, the COG is currently studying a more modest

dose reduction of cyclophosphamide (ARST0331, closed 2012) for both low-risk subgroups with aims of

maintaining the excellent outcomes of IRS-IV and further reducing toxicity.172

Intermediate-risk tumors are nonmetastatic and include alveolar rhabdomyosarcoma at any site

(stages 1 to 3). Embryonal rhabdomyosarcoma in an unfavorable site that is incompletely excised (stage

2, 3, and group III) is also considered intermediate-risk. The standard chemotherapy for this group is

vincristine, actinomycin-D, and cyclophosphamide with radiotherapy. Improvements in survival have

not progressed as much in this group compared to low-risk tumors. IRS-IV did not show improvement in

outcomes for intermediate-risk group patients by the addition of ifosfamide and ifosfamide/etoposide

substituting for actinomycin-D and cyclophosphamide.174 The COG recent intermediate-risk study

(D9803) compared standard vincristine, actinomycin-D, and cyclophosphamide to a regimen that

alternated standard therapy with vincristine, topotecan, and cyclophosphamide.175 This regimen did not

significantly improve outcomes compared to standard therapy. Results are pending from the COG’s most

recent trial (ARST0531, closed 2013) that randomized patients to receive standard therapy versus

standard therapy alternating with vincristine and irinotecan, and earlier onset radiotherapy.172 The

actions of vincristine and irinotecan are thought to be synergistic with enhanced cytotoxic activity based

on preclinical and pilot studies.

High-risk patients have metastatic disease on presentation with dismal outcomes despite intensive

cytotoxic therapy. Current therapy for high-risk tumors is based on results of the COG high-risk

rhabdomyosarcoma phase II window studies (D9802) and previous IRS-I-IV trials.176 These studies were

the backbone for ARST0431 (closed 2010), which treated patients with multiple combinations of

intensive chemotherapy that included vincristine, actinomycin-D, doxorubicin, irinotecan,

cyclophosphamide, and ifosfamide/etoposide.177 The feasibility of concurrent early administration of

radiotherapy and irinotecan is also being evaluated. Long-term follow-up on the most optimal

combinations of intensified chemotherapy in high-risk patients with rhabdomyosarcoma is needed.

Recently, the COG study (ARST08P1) examined novel biologic agents. Cixutumumab, a monoclonal

antibody against insulin-like growth factor-I receptor (IGF-IR), and temozolomide were added to

intensive chemotherapy backbone regimens. Early results are promising for improved failure-free

survival with cixutumumab but overall survival remains poor.178

Radiotherapy in the form of external-beam radiation is utilized in group II to IV patients and in group

1 alveolar cases to enhance local control.179 Radiotherapy is utilized as the primary means of local

control in rare cases in which surgical excision carries excessive risk or concern for disfigurement

(orbital and vaginal). Parameningeal tumors are treated with radiotherapy because of the high

likelihood of residual disease with surgical excision. The most commonly utilized doses range from 36

Gy to 50 Gy, and higher doses are administered to patients with group III or IV disease (50 Gy given in

28 fractions).179 The IRSG studied a trial of hyperfractionated radiotherapy versus conventionally

fractionated radiotherapy in patients with group III rhabdomyosarcoma and found no differences in

failure rates or survival outcomes.180

Future Directions

Future clinical trials are focused on further tailoring therapies to reduce treatment toxicities and late

adverse effects while improving curative outcomes. The current focus is incorporation of novel biologic

agents to known active backbone chemotherapy regimens, particularly for patients with intermediaterisk and high-risk rhabdomyosarcoma. Human patient tumor-derived xenograft models are guiding

future development of novel targeted therapies for this cancer. The National Cancer Institute supports

the Pediatric Preclinical Testing Consortium, a program to evaluate novel molecules for genomically

characterized solid tumors, including rhabdomyosarcoma

(http://ctep.cancer.gov/MajorInitiatives/Pediatric_Preclinical_Testing_Program.htm).

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NONRHABDOMYOSARCOMA SOFT TISSUE SARCOMA

Epidemiology

Soft tissue sarcomas in children and adolescents occur in approximately 8% of all childhood solid

tumors. Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) represents approximately half of these

cases, occurring in 250 to 300 children per year in the United States.181 Infants and adolescents are

more commonly affected, and there is a slightly higher incidence in males and in African Americans.

NRSTS comprises 27% of sarcomas in infants (<12 months), of which, 24% are fibrosarcomas, 1.7% are

malignant fibrous histiocytoma (MFH), and 1.3% are peripheral nerve sheath tumors.182 The incidence

of NRSTS has not changed in the last several decades. The overall 10-year survival has also remained

steady at 73%. The tumors are distinct from rhabdomyosarcoma in terms of clinical characteristics,

tumor biology, and prognosis. Most cases are sporadic although patients with Li–Fraumeni syndrome,

neurofibromatosis type I (peripheral nerve sheath tumors), Gorlin syndrome (fibrosarcoma and

leiomyosarcoma), and hereditary retinoblastoma have a higher risk of developing soft tissue

sarcomas.183–185 Children who are survivors of childhood cancer are at an increased risk for NRSTS,

particularly those with history of receiving radiation, high-dose anthracyclines, and alkylating agents.186

Pathology and Biologic Features

NRSTS originates from developmental mesenchymal cells with heterogeneous histologic subtypes and

diverse sites of origin. These tumors are classified on the basis of histology-specific cytogenetics of the

tumor. NRSTS may have segmental chromosomal alterations (balanced translocations) or widespread

genomic instability (Table 105-8). Most of the translocations found in NRSTS generate fusion proteins

from two different transcription factors that disrupt normal embryonic development and drive

sarcomagenesis.187 ETV6-NTRK3 found in infantile fibrosarcoma and anaplastic lymphoma kinase (ALK)

found in inflammatory myofibroblastic tumors are tumor cell–specific activated kinases that may have

important roles in pathogenesis.188 Dermatofibrosarcoma protuberans contain the COLIA1-PDGFB fusion

gene.189 Genetic analysis is a powerful tool for the diagnosis of NRSTS and is an important component

of the histopathologic assessment. Detection of tumor-specific chromosomal alterations by RT-PCR,

FISH, or high-throughput sequencing analyses often aids in confirming the diagnosis and in treatment

planning.

Table 105-8 Nonrhabdomyosarcoma Tumor Characteristics

Presentation, Diagnosis, and Staging

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NRSTS typically presents as a painless slow-growing solid mass that may invade surrounding structures.

Approximately 15% of patients present with metastatic disease at presentation, most commonly

lungs.190 Survival for patients presenting with metastatic disease remains poor (35%), and disease-free

progression is only 15% despite aggressive multimodality therapy. In general, diagnostic workup for

NRSTS consists of cross-sectional imaging (MRI) of the primary site along with imaging (CT scan) of

chest, abdomen, and pelvis for surgical planning and adequate staging. Bone scintigraphy is used only

for patients with bone pain or symptoms. Bone marrow biopsy is typically not indicated. Brain imaging

is reserved for patients with CNS symptoms.

An adequate tissue specimen is required to determine the histologic subtype and grade of NRSTS.

Complete surgical resection of all gross diseases is recommended at presentation unless a wide resection

is not feasible or accompanied by high surgical morbidity. Multiple core needle biopsies may be

sufficient though the quality and quantity of specimen must be adequate for histologic and cytogenetic

studies. Fine-needle biopsy is not acceptable for diagnosis. The fresh specimen should be evaluated for

routine histopathology, immunohistochemistry, and molecular studies including DNA and RNA

cytogenetic studies, flow cytometry, and electron microscopy.186 Array technologies are being

increasingly utilized in analysis of NRSTS, allowing measurements of tumor RNA expression and gene

copy number.191 A pathologic tumor grade is assigned to NRSTS on the basis of extent of malignancy

and is an indicator of prognosis. The grading system utilized in pediatric NRSTS was developed by the

Pediatric Oncology Group using concepts of adult grading systems integrating characteristics of

pediatric sarcomas.192 The Pediatric Oncology Group grading system for NRSTS assesses mitotic rate,

extent of necrosis, differentiation, and histologic type and can be used as a predictor of outcome.

The size of the mass is important in initial surgical planning and determines surgical approach.193

Tumor size of 5 cm is utilized by the American Joint Cancer Commission staging system of sarcoma as

standard “cutoff” for resectability, though this has been difficult to translate to children with small body

surface areas. This was addressed by the development of an equivalency factor that is utilized to

calculate prognosis of soft tissue sarcoma based on size of the mass and body surface area.194 Although

tumor size is a key prognostic factor in adult soft tissue sarcomas, the risk is not the same in patients of

different body sizes, and 5-cm cutoff may not pertain to infants and children.

Extent of disease, grade, size, and age, and extent of resection all influence prognosis and survival

outcomes in NRSTS.195 Patients are grouped into low, intermediate, and high-risk (metastatic disease)

categories. High-risk patients have overall survival of approximately 15%, and most patients succumb to

widespread metastatic disease. Intermediate-risk patients have unresectable tumors at presentation with

residual disease or large (>5 cm), high-grade tumors. The survival in this risk group is approximately

50%. Low-risk tumors are completely resectable (<5 cm or equivalent) and are low grade.186 Low-risk

patients have the best prognosis with overall survival of 90%. In general, patients with negative

microscopic margins have the best outcomes, and the addition of radiotherapy minimizes the risk of

recurrence. A pediatric NRSTS staging system has not been validated. The IRSG surgicopathologic

staging system for rhabdomyosarcoma is often utilized as well as the TNM sarcoma staging systems for

adults. The COG is addressing the issue of staging for pediatric NRSTS in ongoing clinical studies.

Treatment

Complete surgical resection is critical in the management of NRSTS because of resistance to

chemotherapy and radiotherapy. Primary tumors that appear grossly resectable should be excised

upfront. If the surgeon anticipates that gross residual disease is likely following surgery or if complete

excision is debilitating or disfiguring, tumor biopsy should be performed. This is typically seen with

large (>5 cm), high-grade regionally invasive or metastatic tumors that will benefit from neoadjuvant

chemotherapy and delayed tumor resection. Tumor debulking is generally not recommended. Large,

potentially morbid resections such as amputation and pelvic exoneration are performed only after

neoadjuvant therapies. In general, incisions on the extremities should be placed longitudinally and

incisions on the trunk are oriented in the axial plane. If the surgeon determines that the mass is not

amendable to full excision upfront, a generous incisional biopsy is required. Primary re-excision of the

primary tumor is recommended if there is gross residual resectable tumor after the initial resection with

at least a 0.5-cm margin. Re-excision is also recommended if the margin status is unknown. Previous

scars or needle tracts should be included en bloc with the specimen. Lymph node sampling is required

for abnormal appearing lymph nodes on clinical examination or imaging. Several histologic subtypes of

NRSTS also require lymph node evaluation for risk assessment and staging purposes, even in patients

without enlarged lymph nodes. These include synovial cell sarcoma, epithelioid sarcoma, and clear-cell

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sarcoma with up to 30% risk of lymph node metastases.193 In these groups, patients without radiologic

evidence of nodal metastases may benefit from sentinel lymph node mapping with technetium 99m and

biopsy rather than traditional lymph node sampling, though results have been mixed.196,197

The most active chemotherapeutic agents for NRSTS are doxorubicin and ifosfamide, though most

NRSTSs are relatively chemoresistant. Current treatment strategies are based on protocols from the

COG clinical trial ARST0332 that assigned NRSTS patients to treatment groups on the basis of risk. Lowrisk patients (grossly resected, low grade, any size) receive surgical excision alone with or without

radiotherapy, depending on margins status. Intermediate-risk and high-risk (metastatic disease) patients

are treated with ifosfamide and dose-intensive doxorubicin and radiotherapy either before or after

surgical excision. The outcomes of this trial are pending. Because of the limited efficacy of

chemotherapy in NRSTS, novel targeted therapeutic approaches are warranted, especially for children

with high-grade or relapsed tumors.186,195

HEPATIC TUMORS

Hepatoblastoma

Epidemiology and Genetic Risk

Hepatoblastoma is the most common malignant liver tumor in children, occurring in 0.7 per million to 1

per million children younger than 15 years, yielding approximately 100 cases per year in the United

States.4 The incidence of hepatoblastoma has increased roughly 4% in the last three decades in the

United States.198 Hepatoblastoma occurs most commonly in infants and children between the ages of 6

months and 3 years. A slight male predominance is reported and there does not appear to be significant

differences in incidence among race. The median age at diagnosis is 18 months of age. Hepatoblastoma

is the third most frequent abdominal tumor after neuroblastoma and Wilms tumor. Environmental risk

factors have not been confirmed. Hepatoblastoma has been found in association with prematurity and

low birth weight.199 There is a strong association with very low-birth-weight neonates (<1,500 g)

though the underlying mechanism is not yet unknown.198

Several inherited syndromes are associated with hepatoblastoma. Patients with Beckwith–Wiedemann

syndrome are at risk for developing hepatoblastoma and require routine screening.200 Most cases are

due to defective imprinting on chromosome 11p15.201 Hepatoblastoma may also occur in children with

hemihypertrophy and trisomy 18.202 There is an increased risk of hepatoblastoma in children of families

with familial adenomatous polyposis (FAP) syndrome though no specific genetic alteration in

chromosome 5 has been identified.203 There is a nonrandom association between hepatoblastoma and

children with trisomy 18.204

Sporadic hepatoblastoma has not been characterized by any single chromosomal abnormality and

cytogenetic analyses have not revealed consistent patterns. The most common genetic abnormalities are

trisomies.2,8,19,205 These genetic alterations are thought to have a role in hepatoblastoma pathogenesis,

but the precise molecular mechanism is not understood.LOH of 11p15 has been detected in up to 33% of

children with hepatoblastoma, and it is hypothesized that a tumor suppressor gene may be located in

this region.206 Insulin-like growth factor 2 (IGF-2), a fetal mitogen, is an imprinted gene on 11p15

affected by β-catenin mutations.207 LOH at 11p is most often of maternal origin and commonly found in

patients with Beckwith–Wiedemann syndrome. LOH has also been found at chromosome 1p and 1q and

may have a role in tumorigenesis.208 Translocations involving the NOTCH2 gene at chromosome 1 have

been detected in hepatoblastoma tumors.209

Pathology and Biologic Features

Hepatoblastoma displays a combination of histologic patterns that range from epithelial and

mesenchymal elements. This tumor is thought to originate from undifferentiated embryonal hepatic

cells that maintain pluripotency and have potential to develop into both hepatocytes and biliary

epithelial cells.210,211 Hepatoblastoma may be classified by five different histologic subtypes that carry

prognostic value: well-differentiated fetal (pure fetal), embryonal, macrotrabecular (epithelial fetal or

embryonal), small cell undifferentiated, and cholangioblastic (bile ducts predominate) (Table 105-

9).212,213 Of these, the most favorable outcomes are seen with well-differentiated fetal subtypes. Small

cell undifferentiated tumors (anaplastic subtype) carry the worse prognosis.214 Small cell

undifferentiated tumors are often associated with low or normal serum α-fetoprotein (AFP) levels

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