7

Selected Non–Central Nervous System Solid Tumors

A solid tumor is “an abnormal mass of tissue that usually does not contain cysts or liquid areas” (NCI, 2020b). Solid tumors can occur almost anywhere in the body, including in bones, muscles, and organs. The most common type of solid tumor found in children is a brain tumor. Brain and spinal cord tumors are discussed in Chapter 6. This chapter addresses selected types of pediatric solid tumors found in other areas of the body, often referred to as “extracranial solid tumors,” as follows:

• Bone: osteosarcoma, Ewing sarcoma family of tumors;
• Soft-tissue: rhabdomyosarcoma (RMS), non-rhabdomyosarcoma;
• Neural crest cell (adrenal and paraspinal nerves): neuroblastoma;
• Kidney: Wilms tumor, renal cell carcinoma (RCC), rhabdoid tumor, clear cell sarcoma;
• Liver: hepatoblastoma, hepatocellular carcinoma (HCC), undifferentiated embryonal sarcoma of the liver (UESL);
• Germ cell: malignant, teratoma;
• Eye: retinoblastoma;
• Skin: melanoma;
• Thyroid: thyroid cancer;
• Colon: colorectal carcinoma (CRC);
• Adrenal gland: adrenocortical carcinoma (ACC).

The epidemiology of the solid tumors included in this chapter is discussed in Chapter 2 and Appendix B.

OVERVIEW

This section provides a general description of several important aspects of the extracranial solid tumors reviewed in this chapter, including the information sources for these tumors and a general approach to their diagnosis, staging, risk assignment, and treatment.

A main source of information on the solid tumors discussed in this chapter is the National Cancer Institute’s Physician Data Query® (see Appendix C). This chapter also relies on a number of resources, including several treatment protocols, from the Children’s Oncology Group (COG) (see Appendix C) and other published literature.

The general approach to the treatment of an extracranial solid tumor begins with a tumor biopsy to establish the pathologic diagnosis. The relative risk faced by a person with a particular type of cancer is driven by multiple factors, including the age of the patient, pathologic and biologic features of the tumor, and the tumor’s location and stage. Since pediatric extracranial solid tumors differ significantly in their biology and clinical presentation, each tumor type has its own risk categorization, but in general, these tumors are divided into low-, intermediate-, and high-risk groups to determine the treatment approach and assign a prognosis.

For patients with newly diagnosed solid tumors in the United States, participation in clinical trials conducted through the COG is considered the standard of care. Multidisciplinary COG disease committees develop new clinical trials based on knowledge gained from completed trials. This approach has led to changes in risk assessment and treatment and to better-tolerated therapies and improved outcomes. When clinical trials are not available at a given time, treatment of solid tumors frequently is based on the treatment from the most recent disease-specific trial using the superior arm if the results are available, or the standard arm if the study has yet to reach a conclusion. Some solid tumors are so rare that prospective clinical trials have not been conducted for them, and treatment decisions are then based on description of outcomes in individual patients or small case series.

Response to therapy for solid tumors is assessed with imaging studies, such as computed tomography (CT) or magnetic resonance imaging (MRI), by measuring the size of the tumor and assessing the number and size of metastatic lesions. In addition, nuclear medicine imaging studies, such as fluoro-deoxy-glucose positron emission tomography (FDG-PET) and metaiodobenzylguanidine (MIBG) scans, have utility in assessing solid tumors by measuring not only the size of tumors but also their metabolic activity. FDG-PET can help differentiate high-grade from low-grade tumors, and MIBG is highly specific for neuroblastomas. Response criteria are (1) complete response (disappearance of all visible disease), (2) partial response (shrinkage by at least 30 percent), (3) progressive disease (growth by at least

20 percent), and (4) stable disease (minimal shrinkage or growth that does not fit the definitions of partial response or progressive disease). These rigorous definitions, along with specific methodology for the measurement of tumor size, must be used in the context of a clinical trial (Eisenhauer et al., 2009), but the terms are often used more loosely to describe the response of a patient’s tumor burden to any prescribed course of therapy. Of note, somewhat counterintuitive and in contrast with many of the hematologic malignancies, rapid early response to chemotherapy is not always predictive (prognostic) of long-term failure-free outcomes in pediatric solid tumors (Rosenberg et al., 2014; Vaarwerk et al., 2018).

The prognosis for solid tumors is described using several different terms. Overall survival (OS) refers to whether the patient is alive or deceased after a specified period of time (e.g., 5 years), usually from the date of diagnosis, but sometimes from the initiation of a new treatment. Progression-free or failure-free survival describes the time interval between diagnosis or new treatment initiation and growth or regrowth of the tumor. Event-free survival (EFS) can reflect a combination of outcomes, since “events” can be defined as and generally include death, tumor progression, tumor relapse, and the development of a second malignancy. For the purposes of this chapter, all outcomes relate to the day of diagnosis (or first treatment initiation) unless otherwise specified. With a few exceptions, the presence of distant metastasis is associated with a very poor prognosis for most solid tumors outside of the central nervous system (CNS). Localized tumors that can be successfully resected or treated with radiation therapy have the best outcomes.

DIAGNOSIS, PROGNOSIS, TREATMENT, AND OUTCOMES BY TUMOR TYPE

For the selected solid tumor types included in this chapter, this section reviews (1) the classification of the tumor types and subtypes, (2) the diagnostic approach (methods for staging and assigning risk category), (3) prognosis, and (4) standard therapies and duration of treatment. The acute, chronic, and late effects of the different treatment modalities are summarized in Chapter 3, and the associated functional limitations are discussed in Chapter 4. Annex Tables 7-1 and 7-2 summarize the diagnostic, prognostic, and treatment information for each type of tumor discussed below.

Bone Tumors

Primary bone cancers fall in the category of sarcomas. Osteosarcoma and the Ewing sarcoma family of tumors are the main types of primary bone cancers that occur in children.

Osteosarcoma

Osteosarcoma is the most common type of pediatric bone cancer. It usually starts in osteoblasts, a type of bone cell that becomes new bone tissue. Pediatric osteosarcoma most commonly occurs near the growth plates around the knee, arms, legs, and pelvis; more than 50 percent of these tumors arise from the long bones around the knee (PDQ Pediatric Editorial Board, 2020j). Almost all patients have tumor cells called micrometastases in the lungs at the time of diagnosis. While osteosarcoma can metastasize to any organ, the most common sites of metastasis include lung, bone, and rarely, the brain. The staging and diagnosis of osteosarcoma are standardized and summarized in Annex Tables 7-1 and 7-2. Antero-posterior and lateral radiographs of the local site are obtained. MRI is obtained to assess the local extent of the disease; the presence or absence of a soft-tissue mass; and if present, its relationship to the surrounding neurovascular bundles. Chest radiographs, CTs of the chest, and bone scans are obtained to assess for metastatic disease. Blood laboratory tests obtained include a complete blood count; liver function tests; and tests to measure electrolytes, calcium, and coagulation. Although not needed to diagnose osteosarcoma, high levels of alkaline phosphatase and lactate dehydrogenase (LDH) can be of prognostic significance (PDQ Pediatric Editorial Board, 2020j).

The majority of osteosarcomas arise sporadically, but a small percentage are associated with hereditary cancer syndromes. Several factors suggest that an osteosarcoma has developed secondary to genetic predisposition, including early-onset, bilateral, multifocal, or metachronous tumors. These hereditary syndromes include Li-Fraumeni syndrome, retinoblastoma, Rothmund-Thompson syndrome (RTS Type 2), Werner syndrome, and Bloom syndrome (see Table 2-3 in Chapter 2). Each of these syndromes is associated with several different mesenchymal and epithelial cancers, but each is associated as well with the development of osteosarcoma. The inheritance patterns can be autosomal dominant or recessive (Hameed and Mandelker, 2018).

Osteosarcomas may be high-grade, intermediate-grade, or low-grade, depending on their histology. High-grade osteosarcomas are the fastest-growing, while low-grade osteosarcomas are less aggressive and typically have better prognoses (Lindsey et al., 2017). The most common type of osteosarcoma, the so-called “conventional” osteosarcoma, begins as a high-grade intraosseous lesion. Depending on the predominant cellular component, conventional osteosarcomas can be classified as osteoblastic, chondroblastic, or fibroblastic. In addition to conventional osteosarcoma, there are two high-grade variants: telangiectatic and small-cell. All high-grade osteosarcomas receive the same kind of treatment. Infrequently, osteosarcomas can occur on the surface of the bone, sometimes referred to

as juxtacortical (next to bone cortex). There are two types of juxtacortical osteosarcomas. Parosteal osteosarcoma is a low-grade surface osteosarcoma, treated with surgery alone, while periosteal osteosarcomas are intermediate-grade tumors, treated with surgery and frequently chemotherapy. High-grade surface osteosarcomas are quite rare and are treated in the same manner as high-grade intraosseous tumors (Bertoni et al., 2005).

Patients with high-grade osteosarcomas receive a combination of chemotherapy and surgery. Radiation, for primary localized disease, is not indicated. For newly diagnosed patients, the optimal timing to begin chemotherapy (i.e., preoperative versus postoperative) can be controversial. However, most centers in the United States administer chemotherapy both before and after surgery. Not only does preoperative chemotherapy eradicate pulmonary micrometastases, simplify the resection/limb salvage, and afford time for surgical planning, but it also provides prognostic information. Assessment of the tumor’s response to chemotherapy, or necrosis, informs prognosis. The extent of tumor necrosis (cell death) provides prognostic information, with <90 percent necrosis portending a worse outcome (Bielack et al., 2002). After resection of the tumor, the patient receives more chemotherapy. In the past, postoperative chemotherapy agents were changed in patients with inadequate tumor response or poor necrosis following preoperative chemotherapy; however, recent studies using the known active agents currently available to treat osteosarcoma have shown this approach not to be beneficial (Marina et al., 2016). In the United States, most children receive MAP therapy (i.e., methotrexate [M], doxorubicin [Adriamycin (A)], and cisplatin [P]) as a standard regimen for 10 weeks prior to surgery and 18 weeks after surgery, regardless of response. Other active chemotherapeutic agents are etoposide, ifosfamide, and carboplatin.

The outcome for patients with osteosarcoma is dependent on the tumor’s grade, location, and treatment. The EFS for patients with high-grade intraosseous osteosarcoma differs depending on location. Patients with extremity osteosarcoma have a 5-year OS of 70–80 percent (Smeland et al., 2019); those with spine osteosarcoma have a 5-year OS of 40–60 percent (Schwab et al., 2012; Zils et al., 2013); those with osteosarcoma of the pelvis have a 5-year OS of 38 percent (Fuchs et al., 2009; Isakoff et al., 2012); and those with macroscopic metastatic disease have significantly lower long-term survival rates. As with the primary disease, the location of the metastatic disease confers prognostic significance. Patients with only pulmonary metastases have a better long-term EFS (20–30 percent) relative to those with bone metastases, a condition that is almost uniformly fatal (Harrison et al., 2018; Meyers and Gorlick, 1997). Surgical resection of all metastatic sites may or may not be feasible without loss of form or function, but should be considered. For long-term disease-free survival, surgical resection of lung metastases is essential. Thoracotomy is the preferred method for resection of

lung metastases, as the surgeon is able to palpate the lung and identify very small metastases. Another surgical approach, thoracoscopy, is a less invasive option, but has not been proven equivalent to thoracotomy.

At the time of relapse in the lung only, a fraction of patients (20 percent) with a limited number of pulmonary tumor nodules (five or fewer per lung) can be treated with surgery to remove the nodules (“cherry picking”) (Lagmay et al., 2016). A maximum number of five nodules has not been supported as an absolute limit. A longer disease-free interval can be provided if all the pulmonary nodules can be removed without significant loss of lung function. Otherwise, recurrent metastatic osteosarcoma is not considered curable. Overall, there has been little progress in the treatment of osteosarcoma in the past 30 years, and novel therapies for relapsed and metastatic disease are urgently needed.

The type of primary tumor surgery performed for osteosarcoma depends on the tumor’s location and the patient. While the main goal of surgical resection is to resect/remove the tumor en bloc and obtain negative margins, the reconstruction options are plentiful, and which option is employed depends on the tumor’s location and the patient’s expectations and desires. The options range from amputation to different types of limb salvage (reconstruction of the bony architecture with metal or bone or a combination of both). There are several options for each disease site, and each option has benefits and disadvantages. For the best outcome, the decision should be made by the physician, the patient, and the family together. Chapter 4 provides additional information on the types of surgery and functional outcomes.

Functional disabilities from the treatment of osteosarcoma are related primarily to the location of the tumor and the surgical approach required to optimize the potential for cure. For example, bilateral thoracotomies for tumor metastasectomy may lead to exercise intolerance or partial oxygen dependence. Patients also should be monitored for late cardiac effects and renal insufficiency due to maximal use of doxorubicin and cisplatin, respectively.

Ewing Sarcoma Family of Tumors

The Ewing sarcoma family of tumors is a group of highly aggressive cancers that begin in the bones or nearby soft tissues and share some common features. Ewing sarcoma, initially called diffuse endothelioma of bone, is a highly aggressive tumor first described in 1921 by James Ewing. It is the second most frequent pediatric bone tumor and has peak incidence during the second decade of life (PDQ Pediatric Editorial Board, 2020h). Males are slightly more affected than females (sex ratio of 1.3:1.0 [see Appendix B]). Ewing sarcoma is most common in people of European descent, with an

estimated incidence of 1.5 cases per million (Jawad et al., 2009). It is rare in people of Asian and African descent (Jawad et al., 2009).

Ewing sarcoma of bone belongs to a family of tumors wherein the malignant cells share a genetic change termed a translocation, in which a piece of one chromosome breaks off and attaches to a different one or in some cases switches places with a piece of another (PDQ Pediatric Editorial Board, 2020h). The translocation t(11;22), forming the fusion protein EWS-FLI1, is found in about 85 percent of cases, while t(21;22) is found in about 10 percent of cases (PDQ Pediatric Editorial Board, 2020h). This family consists of a spectrum of disease, including osseous Ewing sarcoma, extraosseous Ewing sarcoma, embryonal tumors, and malignant small-cell tumor of the thoracopulmonary region (Askin tumor). Atypical Ewing sarcomas or “Ewing-like” sarcomas histologically resemble Ewing sarcomas of the bone but are now understood to represent a morphologically and molecularly heterogeneous group with a different complement of translocations and, although treated similarly to Ewing sarcomas, are increasingly appreciated as distinct clinical entities.

Ewing sarcoma is a fast-growing tumor typically seen in bone, although it can occur, less commonly, in soft tissue, such as muscle, fat, fibrous tissue, blood vessels, or other supporting tissue (NCI, 2020a). This tumor is aggressive, and as many as 25 percent of patients have metastatic disease at the time of diagnosis (PDQ Pediatric Editorial Board, 2020h). The staging and diagnosis of Ewing sarcoma are summarized in Annex Tables 7-1 and 7-2. The initial evaluation consists of radiographs of the entire bone, MRI of the primary lesion, chest x-ray, CT scan of the chest, and bone scan and/or positron emission tomography (PET) scan. MRI of the spine/pelvis or bone marrow biopsy often is performed to assess for metastatic disease to the marrow, especially in the setting of abnormal blood counts or an elevated serum LDH level, which is prognostic and related to the extent of disease (Bacci et al., 2000).

Approximately 75 percent of patients present with clinically localized disease (Esiashvili et al., 2008). Ewing sarcomas most commonly arise in the pelvis, axial skeleton, and femur, but can arise in any bone. Fifty-four percent arise in the axial (stabilizing) skeleton (pelvis 25 percent, ribs 12 percent, spine 8 percent, scapula 4 percent, skull 4 percent, clavicle 1 percent); 44 percent in the appendicular skeleton (extremities) (femur 16.5 percent, tibia 8 percent, fibula 7 percent, humerus 5 percent, radius and ulna 4 percent, foot 2.5 percent, hand 1 percent); and 1 percent in other bones (Cotterill et al., 2000 [percentages do not sum to 100 because of rounding]). Patients with localized disease have a 5-year OS of 70–80 percent (Grünewald et al., 2018); however, survival rates vary (are lower) depending on tumor location (pelvic tumors), tumor size (large tumors), or poor response to local therapy.

Because micrometastatic disease is presumed to be present in 80–90 percent of localized patients, the treatment for Ewing sarcoma is multimodal, consisting of chemotherapy, surgery, and/or radiation (PDQ Pediatric Editorial Board, 2020h). The sequence is preoperative chemotherapy, local therapy (surgery or radiation), and then postoperative chemotherapy. Standard chemotherapy is vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC/IE). However, there are several other acceptable alternative front-line regimens, including VAI (vincristine, doxorubicin, and ifosfamide) and VIDE (vincristine, ifosfamide, doxorubicin, and etoposide). Patients receive 14–17 cycles, and it has been found that dose intensification by interval compression confers a better prognosis (i.e., every 2 weeks is better than every 3 weeks) (Womer et al., 2012). Chemotherapy alone results in less than 30 percent OS; thus, local therapy (surgery or radiation), generally performed after the sixth cycle, is a critical component of the treatment regimen.

The choice between radiation and surgery as local therapy is one that continues to be controversial and is influenced by the location and size of the tumor and the presence or absence of metastatic disease. The choice may also involve trade-offs among optimal short- and long-term functional results; appearance; and risks of posttreatment morbidities, including functional loss and secondary malignant neoplasms (SMN). At this time, the clinical bias is toward local control with surgery. Several retrospective studies have shown that patients who receive radiotherapy alone have an inferior outcome compared with those who receive surgery. However, these studies are characterized by patient selection bias in that the patients chosen to receive only radiation had worse prognostic factors: larger tumor size and pelvic location (DuBois et al., 2015). For the primary tumor, radiation is unequivocally indicated for those patients who have metastatic disease or unresectable primary tumors following adjuvant chemotherapy, and those whose tumors are resected with close or positive margins.

Staging is one of the predictors of survival and oncologic outcome and can provide risk stratification. Standard-risk patients are those with small tumors and a good response to neoadjuvant chemotherapy (>90 percent necrosis). With standard chemotherapy and surgery, these patients can expect a 3-year EFS of 70–80 percent. Patients with high-risk localized tumors have an unfavorable histologic response (<90 percent necrosis) after chemotherapy or large tumors (>200 ml) and have a 3-year EFS of 50–60 percent (Gaspar et al., 2015). Patients with metastatic disease have high-risk disease and a 6-year EFS and OS of approximately 30 percent. However, those patients with lung-only metastases have a better prognosis relative to patients with other metastatic disease (Miser et al., 2007). The

biology of Ewing sarcoma is increasingly well understood, and there is active research on and hope for the development of therapeutics specifically targeting the driver translocation.

Functional disabilities from the treatment of Ewing sarcoma are related primarily to the location of the tumor and the approach to local control. Patients should be monitored for late cardiac effects and renal insufficiency due to maximal use of doxorubicin and ifosfamide. The intensity of alkylator and etoposide therapy and the use of radiation may also predispose patients to SMN, including therapy-related leukemias and myelodysplastic syndromes.

Ewing-like sarcomas are an emerging category of translocation-driven sarcomas “that share various degrees of morphological, immunohistochemical, molecular, and clinical similarity with Ewing sarcoma” (Renzi et al., 2019, p. 7999). Distinct subgroups within this category of undifferentiated round-cell sarcomas include CIC-DUX4 fusions or BCOR alterations, each carrying unique gene expression signatures. Undifferentiated round-cell sarcomas with BCOR-CCNB3 rearrangements arise most commonly in the bones of the pelvis and extremities, and metastases are seen in approximately 30 percent of cases (PDQ Pediatric Editorial Board, 2020h). Undifferentiated round-cell sarcomas with CIC-DUX4 rearrangements originate from the soft tissues of the trunk and extremities. Historically treated as if they were Ewing sarcomas, BCOR-CCNB3 tumors appear to have a slightly better prognosis and CIC-DUX4 fusions a worse prognosis relative to traditional Ewing sarcomas. The precise natural history and optimal therapy for these diseases are still unknown.

Soft-Tissue Sarcomas

Soft-tissue sarcomas (STS) are cancers that originate in soft tissues such as muscle, tendons, fat, lymph and blood vessels, and nerves. These cancers are found mainly in the arms, legs, chest, and abdomen, but can develop anywhere in the body. Of all STS in children, RMS is the most common. RMS occurs most frequently in children less than 10 years of age, with a second peak among adolescents aged 16–19 (Ingley et al., 2020). The remainder of STS are non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS), a group that includes a variety of rarer soft-tissue tumors.

Rhabdomyosarcoma

RMS, which can occur in many locations throughout the body, usually starts in muscles that are attached to bones. The two most common types of RMS are embryonal and alveolar (PDQ Pediatric Editorial Board, 2020e). Anaplastic or pleomorphic is the least common type of RMS in children

and is not addressed in this report. Embryonal RMS occurs most often in the head and neck area or in the genital or urinary organs, while alveolar RMS occurs most often in the arms or legs, chest, abdomen, genital organs, or anal area. A subset of tumors located at the skull base are termed “parameningeal” RMS and carry a risk of direct spread to the CNS.

Staging and diagnosis of childhood RMS is complex and is best outlined in Annex Table 7-1. Approximately 90 percent of RMS patients in the United States are treated on COG protocols or “as per COG protocol.” For RMS, chemotherapy, radiation therapy, and surgical treatment are based on risk group. Genetic alterations, such as fusion status of PAX3/PAX7-FOXO1, are included in the risk group classification. Surgical and medical impairments resulting from treatment for RMS are organ based and may last well into adulthood (see Annex Tables 3-1 and 3-3 in Chapter 3). The most commonly used chemotherapy drugs are based on the vincristine, actinomycin, cyclophosphamide (VAC) standard treatment, to which other drugs, such as ifosfamide, etoposide, doxorubicin, or irinotecan and temozolomide, are added based on response and risk group. Temsirolimus, a targeted therapy, has been added in a relapsed setting with some success.

Low-risk RMS has an excellent OS of at least 90 percent (Raney et al., 2011; Walterhouse et al., 2011, 2014, 2017). However, treatment entails intense chemotherapy, radiation, and surgery. Patients receive chemotherapy for 12 weeks, followed by local control with surgery and/or radiation. After recovery, further chemotherapy is administered for another 12 weeks (total of 24 weeks) (Walterhouse et al., 2014). Relapse is most common within 3 years of therapy, and patients are monitored closely for 5 years (Walterhouse et al., 2014). Failure-free survival is expected at 3 years in 86–93 percent of patients, depending on the site of disease (Walterhouse et al., 2014).

Intermediate-risk RMS, the most common classification, has varied survival based on tumor location and completeness of surgical resection. Relative to low-risk RMS, chemotherapy in general includes more drugs and is more intense, thus potentially causing more episodes that require hospital admission. Evaluation and local control with surgery and radiation therapy occur 13 weeks after initiation of chemotherapy. After local control, chemotherapy continues for a total of 42 weeks. Recently, the duration of therapy has been extended to prevent relapse and improve OS based on an extrapolation of European data (Bisogno et al., 2019). At week 43, maintenance chemotherapy begins, and it continues until 66 weeks after initiation of therapy. After completion of therapy, a 4- or 5-year OS of greater than 70 percent is expected (Bisogno et al., 2019; Hawkins et al., 2018).

High-risk RMS patients have metastatic disease and poor survival. Chemotherapy includes three to six drugs (Weigel et al., 2016). At 19–20 weeks

after the start of chemotherapy, radiation therapy with or without surgery is completed based on the site of the disease and the sites of metastatic disease. Therapy then continues through 54 weeks after diagnosis. Fewer than 50 percent of patients will be alive 5 years after the start of therapy (Breneman et al., 2003; Crist et al., 1995; Rodeberg et al., 2005).

Relapsed RMS has a very poor prognosis and may be treated with many different combinations of chemotherapy, radiation, and surgery, as well as experimental therapy. Survival is not expected for more than 18 months after diagnosis of relapse, and the OS rate is approximately 30 percent at 2 years (Mascarenhas et al., 2019; Setty et al., 2018).

Non-Rhabdomyosarcoma

There are many types of NRSTS (PDQ Pediatric Editorial Board, 2020f), classified by the part of the body in which they started.

Synovial sarcoma

Synovial sarcoma is the most common NRSTS in children and adolescents, accounting for approximately 10 percent of all pediatric STS. It is a malignant mesenchymal tumor with a predilection for the distal extremities, but may also form in the trunk, head, or neck. Staging, outlined in Annex Tables 7-1 and 7-2, consists of imaging of the local site (MRI) and of the lungs (CT), the most common site of metastatic disease. Diagnosis is confirmed by biopsy and identification of the characteristic translocation t(X;18)(p11;q11), resulting in chimeric fusion gene SS18-SSX1, SS18-SSX2, or, rarely, SS18-SSX447.

There are no published standardized treatment or consensus guidelines for pediatric synovial sarcoma (Ingley et al., 2020). Surgery alone is associated with a favorable prognosis in pediatric patients with small (≤5 cm) localized disease, regardless of histologic grade. Large, deep tumors are treated in a multidisciplinary fashion with chemotherapy, radiation, or both (Spunt et al., 2020). Although synovial sarcoma is considered more “chemosensitive” than other histologic subtypes, the role of chemotherapy in its treatment remains controversial. Although often given, several studies have found that chemotherapy provides no significant benefit for localized disease, and only a trend toward better survival for patients less than 18 years of age when compared with adults (Ingley et al., 2020; Palmerini et al., 2009). Chemotherapy does have a role in the management of locally advanced, unresectable, or metastatic disease. Recent clinical trials with an immunotherapy targeting NY-ESO, a marker expressed on the surface of many synovial sarcomas, have shown some promise (D’Angelo et al., 2018).

The size, location, and stage of a synovial sarcoma play a role in prognosis. Patients with a localized synovial sarcoma of less than 5 cm (T1) have

a survival of 82–95 percent at 10 years (El Beaino et al., 2016). Patients with metastatic disease have significantly worse survival—20–30 percent at 5 years (Andrassy et al., 2001; Scheer et al., 2016; Spillane et al., 2000). Functional disabilities from the treatment of synovial sarcoma are related primarily to the location of the tumor and the approach to local control.

Desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) was first described by Gerald and Rosai in 1989 (Gerald et al., 1991). It is a rare, aggressive STS, most frequently of the abdomen, that occurs primarily in children, adolescents, and young adults and affects predominantly males (~85 percent of patients are male) (Hayes-Jordan et al., 2016a). Most major pediatric institutions in the United States may see one patient per year with DSRCT.

The tumor is characterized by a translocation, t(11;22)(p13q;q12), that involves fusion of the Ewing sarcoma gene (EWSR1) and the Wilms tumor gene (WT1). Typically, patients with DSRCT present with advanced disease in the abdomen, with associated peritoneal seeding. The vast majority of patients present with dozens to hundreds of tumors on the organ surfaces within the abdominal cavity, making the site of origin difficult to ascertain. Common sites of metastasis are the liver, lungs, extraperitoneal lymph nodes, and bones. Because of the aggressiveness of the disease, patients with DSRCT usually benefit from multimodal therapy with a combination of neoadjuvant chemotherapy followed by both surgery and radiation therapy. Active chemotherapy agents in DSRCT are highly similar to those known to be effective in Ewing sarcoma, including but not limited to vincristine, ifosfamide, doxorubicin, etoposide, irinotecan, and temozolomide. In addition, tyrosine kinase inhibitors, such as pazopanib, may result in some disease stabilization. OS remains poor, however, and most patients experience relapse (Glade Bender et al., 2013; Subbiah et al., 2018).

DSRCT requires at least 4 months and sometimes up to a year of chemotherapy prior to and following surgical resection. Complete surgical resection of all visible tumors, even those 1–2 mm in size, is necessary for any long-term survival. Cytoreductive surgery and hyperthermic chemotherapy (CRS-HIPEC) may also be used for surgical control of the abdominal disease at highly specialized centers, as described in Chapter 3. This is often followed by whole-abdomen or other targeted radiation for microscopic residual disease. With CRS-HIPEC, a 30–70 percent survival at 3–5 years can be expected based on the extent of metastasis and completeness of surgery (Hayes-Jordan and Anderson, 2011; Hayes-Jordan and Pappo, 2012; Hayes-Jordan et al., 2010, 2016a).

Functional disabilities resulting from the treatment of DSRCT relate to disease dissemination within the abdominal cavity and extensive abdominal surgery, which may cause bowel dysfunction and lead to chronic nutritional

issues. Patients should be monitored for the acute and late effects of intensive chemotherapy. The use of whole-abdomen radiation may also predispose patients to liver and/or other gastrointestinal dysfunction and SMN.

Malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumor (MPNST), also referred to as malignant schwannoma or neurofibrosarcoma, is a rare soft-tissue tumor but is one of the most frequent NRSTS in the pediatric population. It is a spindle-cell sarcoma that arises from or differentiates toward peripheral nerve sheath cells (Ferrari et al., 2007). Approximately 50 percent of all MPNSTs develop in patients with the genetic tumor predisposition syndrome neurofibromatosis type 1 (NF1), and the lifetime incidence of MPNST in patients with NF1 is 15.8 percent (Uusitalo et al., 2016). In patients with NF1, most MPNSTs develop in preexisting histologically benign tumors called plexiform neurofibromas or in histologically borderline tumors called atypical neurofibromatous neoplasms of uncertain biological potential (Higham et al., 2018; Miettinen et al., 2017). Although MPNSTs can arise anywhere in the soft parts of the body, they occur most frequently in the trunk, unlike other NRSTS (Ferrari et al., 2007). Because they can occur in many different locations, their symptoms vary, but pain is present in many patients. MPNSTs can be low-grade or high-grade. The majority are high-grade and behave clinically aggressively, with rapid local growth and development of distant metastases. Low-grade MPNSTs and atypical neurofibromas are characterized by slower growth and lack of metastasis (Higham et al., 2018; Miettinen et al., 2017). Staging of an MPNST is detailed in Annex Tables 7-1 and 7-2. It consists of an MRI of the local site, CT of the chest, and biopsy of the mass. Because of the possibility of tumor seeding, the biopsy is ideally performed under the direction of the surgeon performing the surgical resection of the MPNST. In addition, FDG-PET can assist in differentiating benign from malignant nerve sheath tumors in patients with NF1 (Higham et al., 2018).

The treatment for low-grade MPNSTs and atypical neurofibromas in patients with NF1 is surgery, with the goal of removing the encapsulated-appearing tumor. Wide negative margins are not required, and surgery should aim at maintaining function (Bernthal et al., 2014; Nelson et al., 2019; Reilly et al., 2017; Watson et al., 2017).

For high-grade MPNSTs, complete surgical resection with wide negative margins is the cornerstone of therapy and required for cure. The surgery requires expert orthopedic and sometimes neurosurgeons with experience in the management of patients with NF1. Patients with large (≥5 cm longest diameter) or deep-seated tumors or distant metastases have worse outcomes.

The efficacy of chemotherapy in MPNST is not established, and rates of response to chemotherapy in NF1 MPNST are in most cases less than

20 percent (Carli et al., 2005; Ferrari et al., 2011; Higham et al., 2017). However, front-line neoadjuvant chemotherapy can reduce the tumor sufficiently to allow complete resection and also may help treat micrometastases (Ferrari et al., 2007). The standard sarcoma chemotherapy drugs ifosfamide and doxorubicin have been used most frequently. Radiation prior to or after surgery is another important treatment modality in MPNST. High doses of radiation are required, however, increasing the risk for SMN. Adjuvant radiation therapy is recommended for marginal resections or after wide resection of large tumors.

Many studies describe worse outcomes for patients with NF1-related MPNST (Carli et al., 2005; Ferrari et al., 2011). The 5-year OS for MPNST is 51–62 percent (van Noesel et al., 2019; Watson et al., 2017). Patients with localized completely resected MPNST have much better 5-year OS (59 percent) relative to patients with incompletely resected, unresected, or metastatic MPNST (13 percent) (Watson et al., 2017).

Undifferentiated sarcomas

Undifferentiated sarcomas (also called unclassified sarcomas) are a group of rare, aggressive cancers that differ microscopically from other types of sarcomas (NCI, 2020b). Typically, they develop in muscles that are attached to bones, and some types may form in locations treated previously with radiation therapy (NCI, 2020b; PDQ Pediatric Editorial Board, 2020f). Modern sequencing technology can aid in determining whether an underlying genetic translocation or driver mutation can be identified that might enable tumor classification or direct targeted therapy. Tumors harboring NTRK and ALK fusions, often exquisitely sensitive to such agents as larotrectinib and entrectinib, previously fell under this classification. Children with undifferentiated STS who were treated with risk-adapted multimodal therapy were found to have a 5-year OS of 83 percent (Laetsch et al., 2018).

Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion. These are a heterogeneous group of mesenchymal tumors without evidence of a specific lineage differentiation. UPS in children is rare, representing 2–6 percent of all pediatric sarcomas (Alaggio et al., 2010). These tumors occur most commonly in the pediatric population in the second decade of life. UPS can arise in sites of previous radiation therapy or as a second malignancy. It is a highly aggressive tumor with a high metastatic rate and a 5-year OS of 65–70 percent (Alaggio et al., 2010; Widemann and Italiano, 2018). Staging is delineated in Annex Tables 7-1 and 7-2. It consists of MRI of the primary site and CT of the chest or PET/CT to assess for metastatic disease. The most frequent sites of metastatic disease are the lungs, followed by the lymph nodes, bone, and liver. Survival and the development of metastases are related to tumor depth, size, grade, histologic subtype, and local recurrence. Treatment, as with most STS, is multimodal

and can consist of a combination of surgery, chemotherapy, and/or radiation. Tumors with a favorable prognosis are small and superficial.

Neuroblastoma

Neuroblastoma is a cancer of immature nerve cells (neuroblasts) that derive from the neural crest of the embryo. It often begins in the nerve tissue of the adrenal glands but can also develop in the sympathetic nervous tissues along both sides of the spine in the neck, chest, or abdomen. Neuroblastoma is the most common extracranial solid tumor in childhood, with more than 650 new cases a year in the United States (Howlader et al., 2012), and has one of the most variable clinical manifestations. In some young patients (less than 18 months of age), the tumors can spontaneously regress (shrink) and disappear on their own. In some older patients with widely disseminated disease and adverse biological features, however, the disease is aggressive and difficult to cure, with more than half of patients experiencing disease recurrence and just over 60 percent being alive 3 years after diagnosis (Howlader et al., 2013; PDQ Pediatric Editorial Board, 2020i). While a few hereditable genes and congenital syndromes are associated with neuroblastoma, the vast majority of these tumors are sporadic in nature and occur at a very young age: 37 percent of cases present in infancy, and 90 percent present by 5 years of age (London et al., 2005).

Neuroblastoma can be categorized as very low, low, intermediate, or high risk based on several factors. These factors include the age of the patient; the stage of the disease; and the biological features of the tumor, including how it looks under the microscope (histology), and whether the cells carry many copies of the gene MYC-N (MYC-N amplification) or extra pieces of certain chromosomes (segmental changes), notably loss of 11q. Two staging systems are still in use for neuroblastoma. Historically, the International Neuroblastoma Staging System (INSS) has been used by the COG in North America to determine assignment to one of the above risk groups. The INSS numbers tumors from 1 (localized) to 4 (widely metastatic, usually to bone and bone marrow) (Brodeur et al., 1988). Stage 4S denotes the special pattern arising in infancy where tumors metastasize to skin, liver, and lungs, but minimally to bone marrow (<10 percent) and never to bone, and frequently undergo spontaneous regression (Nickerson et al., 2000). North America and the COG are now moving toward the International Neuroblastoma Risk Group system, which uses the International Neuroblastoma Risk Group Staging System (INRGSS); this system is more universally applicable relative to the INSS as it is used prior to surgery (Cohn et al., 2009). The INRGSS designates four stages: L1 refers to a localized tumor that should be easy to remove

without morbidity; L2 to a tumor with risk factors for surgical morbidity based on imaging; M to metastatic disease; and MS to the 4S tumors of the INSS (Monclair et al., 2009). L2 tumors are most often encountered in the high-risk neuroblastoma group; for these tumors, complete surgical resection is often not feasible without considerable morbidity and may result in a prolonged recovery from the surgery (6–8 weeks). L1 tumors carry a much lower risk of surgical morbidity, and recovery should be expected in 2–4 weeks. The discussion here includes references to both of these staging systems.

Neuroblastoma can present in any number of ways. It can be diagnosed by ultrasound while a baby is still in the womb, or in the first few weeks of life with evidence of “blueberry muffin” skin nodules, an abdominal mass, a rapidly enlarging liver, or weakness in the extremities due to spinal cord compression. If neuroblastoma is diagnosed in the womb or in the immediate newborn period (perinatal), spontaneous regression may occur without therapy. As the infant matures, he or she might present with signs of mass effect, including weight loss, vomiting, abdominal distension, constipation, or urinary retention, and on occasion high blood pressure or diarrhea due to kidney compression or hormonal activity. There are also some rare paraneoplastic syndromes in which cancer-fighting cells in the child’s immune system mistakenly attack normal cells in the nervous system. These syndromes are most often associated with lower-risk disease, with symptoms including intractable watery diarrhea due to vasoactive intestinal peptide secretion (Bourdeaut et al., 2009), or a neurologic condition called opsoclonus myoclonus (“dancing eyes and dancing feet”) that is often chronically debilitating, with neurocognitive sequelae persisting after the tumor has been removed (Mitchell et al., 2002).

In a toddler or young child, one of the most frequent presentations for neuroblastoma is fever and a new limp or refusal to walk, which occurs in the setting of high-risk disease that has already metastasized to bone and bone marrow. These patients may also present with low blood counts from marrow infiltration, which needs to be differentiated from leukemia. The staging evaluation of neuroblastoma is summarized in Annex Table 7-1 and often begins with a sonogram to look for an adrenal mass, the detection of catecholamines (adrenal hormones) in the urine, and anatomic imaging with MRI or CT. It is helpful to have a suspicion of neuroblastoma prior to surgery so that if the tumor is not fully resectable, the surgeon can obtain an adequate amount of tissue at biopsy to study the tumor’s biology, and bone marrow aspirates and biopsies can be performed for complete staging under the same anesthesia. Subsequently, nuclear medicine scans, including the highly specific MIBG scan, can be used to ascertain the presence of distant metastasis to bone.

Perinatal and 4S/MS Neuroblastoma

Localized perinatal neuroblastoma most commonly falls into the low- or very low-risk group. In asymptomatic infants, it is now acceptable to observe the patient for spontaneous regression, often without biopsy, using ultrasound and urine catecholamines, reserving surgical intervention for those who are symptomatic or in whom tumors are growing or catecholamines are rising (Hero et al., 2008; Nuchtern et al., 2012). For babies with 4S/MS “special” patterned metastatic spread who are asymptomatic, a biopsy is generally preferred to ensure favorable tumor biology, including the absence of MYCN amplification. Those with favorable tumor biology can be managed with observation or minimal chemotherapy (Nickerson et al., 2000). Notable exceptions are symptomatic 4S/MS infants under 2 months of age who have large livers with impaired function and are at high risk of surgical morbidity and death. These young, often critically ill babies should be treated with emergent chemotherapy and if adequately supported, should go on to do well (Twist et al., 2019a).

Low-Risk Neuroblastoma

All easily resectable localized tumors (stage 1/L1) are considered low-risk and if not managed with expectant observation (investigational in all but small adrenal tumors), can be managed with surgery followed by observation (Strother et al., 2012). An ongoing COG clinical trial is investigating whether asymptomatic localized tumors that are more difficult to remove (stage 2/L2) and 4S/MS tumors can also be observed in older infants and toddlers (<18 months) after biopsy or partial resection provided they are asymptomatic with favorable histology and genomics (ANBL1232 [NCT021769670]). Chemotherapy is generally reserved for patients who are symptomatic or progressive; treatment rarely can include emergency radiation. Chemotherapy agents include vincristine, cyclophosphamide, doxorubicin, etoposide, cisplatin, and carboplatin.

While formally low-risk, lesions causing acute cord compression and paralysis, including “dumbbell lesions” passing through the spinal canal, lead to permanent secondary effects in the majority of patients regardless of the therapeutic approach utilized (chemotherapy, surgery, and/or radiation). One study found that residual impairments affected up to 72 percent of patients and include paralysis (43 percent), scoliosis (31 percent), bladder dysfunction (26 percent), constipation (19 percent), impaired sensation (17 percent), growth delay (14 percent), and neuropathic pain (5 percent) (Simon et al., 2012). As a group, low-risk localized neuroblastomas have a 5-year OS greater than 95 percent (Strother et al., 2012).

Intermediate-Risk Neuroblastoma

The group of patients with intermediate-risk disease generally comprises patients >18 months of age with localized tumors or those with regional metastasis that cannot be easily removed by surgery (stage 2, 3/L2) and are characterized by one or more adverse biological features but are not MYCN amplified. These patients can achieve excellent outcomes (3-year OS of 95 percent) with 2–8 cycles of moderate-dose chemotherapy and surgery, with the duration of therapy being driven by the tumor’s biological features and response to therapy. This tumor group was recently expanded to include patients with metastatic disease under the age of 18 months with good biology and no MYCN amplification (Baker et al., 2010; Twist et al., 2019b).

High-Risk Neuroblastoma

The cohort of patients with high-risk neuroblastoma includes those with tumors metastatic to bone, bone marrow, and other distant sites (Stage 4/M) over the age of 18 months and all patients with MYCN amplification. These patients require intensive multimodal therapy, including multi-agent induction chemotherapy, extensive surgery, up to two high-dose consolidation therapies with stem cell rescue (autologous transplants), local radiation, and postconsolidation “maintenance” therapy with anti-GD2 immunotherapy and cis-retinoic acid. For patients receiving this therapy, EFS at 3 years is just more than 60 percent (Park et al., 2019). The finding that an additional 5 months of immunotherapy could boost long-term survival over the half-way mark was a groundbreaking discovery (Yu et al., 2010), and some believe intensive anti-GD2 therapy may obviate the need for transplant in selected patients (Kushner et al., 2016). Substantial late effects from tandem myeloablative transplant in young children can be anticipated. These effects include high-frequency hearing loss, affecting 82 percent of survivors, half of whom require hearing aids; dental and bone toxicity; other substantial growth and endocrine deficits; renal, cardiac, and neuropsychological impairments; and increased risk of SMN (Elzembely et al., 2019). This range of late effects highlights the urgent need to use biology and targeted therapies to improve outcomes for these patients while reducing the toxicity of treatment. Current protocols are exploring the broader application of anti-GD2 immunotherapies; the use of ALK inhibition for ALK-mutated disease; and targeted radiotherapy using I-131 MIBG, which is available only at a limited number of centers.

Relapsed and Recurrent Neuroblastoma

While relapsed neuroblastoma, particularly brain recurrence, was previously believed to be universally fatal, there have been some reports of

salvage using radiation, chemotherapy, and/or combined chemo-immunotherapy depending on the pattern of recurrence (Mody et al., 2020). While the true potential for cure after relapse is unknown, many children now survive for years on chronic active neuroblastoma therapy with reasonable quality of life.

Kidney Tumors

Wilms tumor and RCC are the most common kidney tumors in children (PDQ Pediatric Editorial Board, 2020m). There also are many rare types of childhood kidney tumors, including rhabdoid tumors and clear cell sarcoma (PDQ Pediatric Editorial Board, 2020m).

Wilms Tumor

Wilms tumor is the most common kidney tumor in children. Most cases (75 percent) occur in children less than 5 years of age, and there are approximately 650 new cases in the United States annually (PDQ Pediatric Editorial Board, 2020m). In most cases, Wilms tumor develops in children with no known predisposition to cancer. However, the disease is associated with a number of genetic conditions, including WAGR and Beckwith-Wiedemann syndromes and other overgrowth syndromes, including isolated hemihypertrophy (overgrowth occurring on only one side of the body) and Denys-Drash syndromes (see Table 2-3 in Chapter 2). In these children with increased risk for Wilms tumor, guidelines for screening include ultrasonography at regular intervals. Wilms tumor typically presents with an abdominal mass, which is frequently asymptomatic; pain, elevated blood pressure, and blood in the urine are less frequent. Diagnostic workup, described in Annex Table 7-1, includes ultrasound and CT of the chest and abdomen. The most frequent distant metastasis of Wilms tumor is to the lungs, followed by liver, bone, brain, and nearby lymph nodes.

Survival for all patients with Wilms tumor collectively is greater than 90 percent (see Annex Table 7-1) as the result of a series of cooperative group clinical trials. This is one of the few solid tumors in which even patients with metastasis to distant sites, such as the lungs, have a high chance for long-term disease-free outcomes. Nearly all children diagnosed with Wilms tumor in the United States are treated on or per COG protocols, which generally call for removal of the entire affected kidney (“radical nephrectomy”) as a diagnostic and therapeutic intervention prior to administration of any chemotherapy. In contrast, studies conducted by the International Society of Pediatric Oncology recommend chemotherapy prior to surgery (Dome et al., 2015; Irtan et al., 2016). A number of prognostic factors have been identified and are used to tailor treatment in COG

protocols (Dome et al., 2014). These include tumor stage (I–V); tumor histology (favorable, focal, and diffuse anaplasia); the patient’s age (younger age is better); tumor weight (less than 500 g is better); the completeness and rapidity of lung nodule response; and adverse genetic features, including loss of heterozygosity at chromosomes 1p and 16q. Additional factors are likely to be incorporated into treatment approaches in the future. Stage I tumors are completely resected, stage II tumors extend regionally beyond the kidney, stage III tumors have residual tumor confined to the abdomen, stage IV tumors have distant metastases, and stage V tumors are characterized by Wilms tumor in both kidneys.

Treatment of Wilms tumor is based on risk groups (see Annex Table 7-2). Patients with very low-risk Wilms tumors undergo surgery alone without chemotherapy or radiation therapy and have a nearly 100 percent 4-year OS (PDQ Pediatric Editorial Board, 2020m). Patients with low-risk tumors receive 22 weeks of “two-drug” chemotherapy with vincristine and dactinomycin after surgery (nephrectomy). And patients with standard-risk tumors are treated with surgery, followed by two- or three-drug chemotherapy (the latter adding doxorubicin), with or without radiation. The 4-year OS for both low- and standard-risk patients is greater than 90 percent (PDQ Pediatric Editorial Board, 2020m). The use of radiation to the tumor bed depends on the extent of the primary kidney tumor; whether it was removed intact or ruptured; and the tumor biology, including loss of heterozygosity. High-risk Wilms patients with anaplastic histology, distant metastases, or poor biology undergo surgery (kidney and sometimes lung) and up to five-drug chemotherapy (the five-drug regimen adding cyclophosphamide and etoposide) for up to 33 weeks. High-risk patients receive radiation to the kidney bed according to the local tumor and/or to the whole lung if metastases are slow to respond to chemotherapy, and have a 4-year OS of about 70 percent (PDQ Pediatric Editorial Board, 2020m). Patients with multifocal/bilateral Wilms tumors are treated up front with intensive chemotherapy and then undergo “nephron-sparing surgery” around week 12, the goal of which is to remove the tumor but leave as much functional kidney as possible. To avoid further kidney damage in these patients, the timing of radiation may vary during the 30-week therapy. Patients with this type of Wilms tumor have an OS of approximately 80–90 percent (PDQ Pediatric Editorial Board, 2020m).

Recurrence occurs in 15 percent of patients with Wilms tumor with favorable histology and 50 percent of those whose tumor has anaplastic histology (PDQ Pediatric Editorial Board, 2020m). Disease sites at relapse are most frequently the lungs and abdomen. Relapsed Wilms is generally treated with a combination of intensive chemotherapy, radiation, and/or surgery depending on the extent and location of the relapsed disease. While the postrelapse OS for children whose tumors have favorable histology is 60

percent, it is very poor for children with recurrent anaplastic Wilms tumor (PDQ Pediatric Editorial Board, 2020m).

Given the inevitable loss of kidney capacity, impaired renal function and, rarely, renal failure can occur as a result of surgery, radiation, and chemotherapy used to treat Wilms tumor. Patients who receive doxorubicin as part of chemotherapy are at risk for cardiotoxicity. Effects from radiation in young children include female infertility, effects on musculoskeletal growth, and, rarely, SMN.

Renal Cell Carcinoma

RCC, a malignant epithelial tumor, accounts for 5 percent of pediatric renal tumors. In contrast with adults, RCC is very rare in children less than 15 years old (4 cases per 1 million children) (PDQ Pediatric Editorial Board, 2020m). Several genetic tumor predisposition syndromes should be considered in children with RCC (see Table 2-3 in Chapter 2), and germline testing is recommended when there is concern for von Hippel-Lindau disease, familial RCC, hereditary leiomyomatosis, or multifocal RCC. Approximately 50 percent of all RCC in children is characterized by translocations involving the TFE3 gene and confers a distinct biology to pediatric RCC.

Pediatric RCC is curable with surgery, but no standard treatment exists for unresectable or metastatic disease in children (PDQ Pediatric Editorial Board, 2020m; Spreafico et al., 2010). Neither radiation nor chemotherapy is particularly effective, and targeted therapies (receptor tyrosine kinase inhibitors) approved for use in adults with RCC show variable, but mostly minimal, response in pediatric patients with TFE3 translocations. Immunotherapy may help control disease, and patients lacking a TFE3 translocation should be tested for ALK aberrations to be considered for ALK inhibitor therapy (PDQ Pediatric Editorial Board, 2020m).

For children with RCC, renal insufficiency and the possible underlying familial tumor predisposition syndrome need to be considered with respect to long-term impairment.

Rhabdoid Tumor

Rhabdoid tumors are very rare and extremely aggressive malignancies that generally occur in infants and young children (Amar et al., 2001). The most common locations are the kidney, the CNS (atypical teratoid/rhabdoid tumor), and other soft-tissue sites (termed malignant rhabdoid tumors). Approximately two-thirds of patients have advanced-stage disease at the time of diagnosis (PDQ Pediatric Editorial Board, 2020m). The possibility of rhabdoid tumor of the kidney should be considered upon presentation with an abdominal mass at a very young age with hematuria and fever.

Rhabdoid tumors of the kidney are most likely to metastasize to the lungs and the brain, with 10–15 percent of patients having CNS lesions as well (PDQ Pediatric Editorial Board, 2020m). Regardless of location, all rhabdoid tumors share a genetic abnormality at chromosome 22q11.2 resulting in the loss of function of the SMARCB1 (INI1/SNF5/BAF47) gene (PDQ Pediatric Editorial Board, 2020m). Germline SMARCB1 alterations, most of which are de novo rather than inherited, are present in approximately one-third of patients with rhabdoid tumors (PDQ Pediatric Editorial Board, 2020m). For this reason, germline analysis and genetic counseling are suggested for affected individuals of all ages. Consensus surveillance guidelines for patients with germline SMARCB1 mutations have been developed and include periodic brain MRI and abdominal/renal ultrasound.

The therapy for rhabdoid tumor of the kidney includes surgery; radiation therapy; and multi-agent chemotherapy, including vincristine, cyclophosphamide, and doxorubicin. In addition, autologous stem cell transplantation following administration of carboplatin, etoposide, and melphalan has been evaluated in case series (Furtwängler et al., 2018; Venkatramani et al., 2014). Patients who experience recurrence or disease progression have very poor survival outcomes. If possible, clinical trials, such as the Pediatric MATCH (Molecular Analysis for Therapy Choice) trial, should be considered for all children with refractory rhabdoid tumor of the kidney. Malignant rhabdoid and other SMARCB1-deleted tumors (epithelioid sarcoma and chordoma) may be sensitive to the agent tazemetostat, newly approved by the U.S. Food and Drug Administration (FDA) (Hoy, 2020; Kurmasheva et al., 2017).

Clear Cell Sarcoma

Clear cell sarcoma of the kidney, seen most often in children under age 3, represents approximately 5 percent of all primary renal malignancies in children and accounts for approximately 20 new cases annually in the United States (PDQ Pediatric Editorial Board, 2020m). Clear cell sarcoma has a higher rate of relapse and death relative to Wilms tumor with favorable histology. Clear cell sarcomas are associated with internal tandem duplications in exon 15 of the BCOR gene in 90 percent of cases (PDQ Pediatric Editorial Board, 2020m), with a smaller subset harboring YWHAE-NUTM2B/E or BCOR-CCNB3 gene fusions (Aw and Chang, 2019). Most patients present with localized stage I–III disease, and 6 percent with metastatic disease. Metastases may be seen in the lungs, bone, brain, and soft tissue. The standard treatment for clear cell sarcoma of the kidney is 1–1.5 years long and includes surgery, “five-drug” chemotherapy, and radiation. With this approach, OS for these patients has increased to 90 percent, and relapse after 3 years is uncommon (Aw and Chang, 2019;

Seibel et al., 2019). When relapse does occur, the brain is a frequent site of recurrent disease. Outcomes for patients with stage IV disease remain poor. Participation in clinical trials should be considered for all patients with clear cell sarcoma of the kidney (PDQ Pediatric Editorial Board, 2020m).

Liver Tumors

Liver cancer is divided into two major subgroups based on histology: hepatoblastoma and HCC (PDQ Pediatric Editorial Board, 2020d). UESL, infantile choriocarcinoma of the liver, and vascular liver tumors are among other, less common types (PDQ Pediatric Editorial Board, 2020d).

Because pediatric liver tumors are rare, participation in clinical trials, when available, should be considered for all children with liver cancer (PDQ Pediatric Editorial Board, 2020d). In addition, treatment invariably includes complex liver surgery, and thus requires planning by a multidisciplinary team of specialists familiar with these diseases and the anatomy of the liver. In lieu of staging, the COG Liver Tumor Committee developed an International Pediatric Liver Tumors Consensus Classification to assist with risk classification, treatment assignment, and international collaborative projects. Tumors are classified by imaging using

• PRETEXT (PRE-Treatment EXTent of disease), in which the extent of liver involvement is defined before therapy; and
• POSTTEXT (POST-Treatment EXTent of disease), in which the extent of liver involvement is defined in response to therapy (Kremer et al., 2014; Lim et al., 2018).

The liver has four sections, and the four PRETEXT and POSTTEXT groups depend on how many sections have cancer in them. In group I, three adjacent sections are cancer free, while cancer is present in one section. In group II, two adjacent sections are cancer free, while cancer is present in one or both of the other two sections. In group III, either one section is cancer free, while cancer is present in three sections, or two nonadjacent sections are cancer free, while cancer is found in the other two sections. In group IV, cancer is present in all four sections.

Hepatoblastoma

Hepatoblastoma is the most common primary liver tumor in children, with approximately 250 new diagnoses occurring annually in the United States (Lim et al., 2018), or an annual incidence of 1.6 cases per 1 million children aged 19 years and younger (PDQ Pediatric Editorial Board, 2020d). Approximately 90 percent of malignant liver tumors in children

aged 4 years and younger are hepatoblastomas, which typically occur before age 3 (PDQ Pediatric Editorial Board, 2020d). Several genetic conditions are associated with hepatoblastoma, including Aicardi syndrome, Beckwith-Wiedemann syndrome, familial adenomatous polyposis, glycogen storage diseases, and Simpson-Golabi-Behmel syndrome (PDQ Pediatric Editorial Board, 2020d). Patients with these conditions should be screened for hepatoblastoma by abdominal ultrasound and determination of alpha-fetoprotein in the blood every 3 months (PDQ Pediatric Editorial Board, 2020d). Likewise, newly diagnosed patients with hepatoblastoma should undergo germline testing for genetic predisposition.

Treatment options for newly diagnosed hepatoblastoma depend on whether the tumor is resectable, without the need for transplant, at diagnosis; tumor histology; the presence of metastases; and response to chemotherapy. Outcomes are best for children with resectable, nonmetastatic tumors at diagnosis, but only 20–30 percent of children meet these criteria (PDQ Pediatric Editorial Board, 2020d). In such patients with well-differentiated fetal histology, surgical resection may be the only therapy required. Patients with other histologies (mixed embryonal) may require two to four cycles of cisplatin-based chemotherapy before or after surgery. The presence of any small-cell undifferentiated elements portends a high risk of tumor recurrence even after surgery and chemotherapy. Approximately 70–80 percent of children with hepatoblastoma have tumors that cannot be surgically resected at diagnosis (PDQ Pediatric Editorial Board, 2020d). For these patients, the standard treatment is four courses of combination chemotherapy—cisplatin/vincristine/fluorouracil or doxorubicin/cisplatin—followed by surgery to attempt complete tumor resection (PDQ Pediatric Editorial Board, 2020d). Surgical options include orthotopic liver transplant, if necessary, but transplantation introduces the need for long-term immunosuppression and all its incumbent adverse effects, including infection, hypertension, and renal insufficiency. If the tumor is completely removed, the patient typically receives two postoperative courses of the same chemotherapy (PDQ Pediatric Editorial Board, 2020d). Transarterial chemoembolization (TACE) can also be used prior to surgery to improve the chances of complete resection. For patients with metastatic disease, treatment algorithms are similar, and include chemotherapy followed by reassessment of the resectability of the primary tumor and all metastatic sites.

Additional chemotherapy, TACE, or radiation therapy may be used when the patient is not a transplant candidate or metastases outside the liver cannot be removed surgically (PDQ Pediatric Editorial Board, 2020d). The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival is possible. Three- to 5-year OS rates range from 20 to 79 percent (PDQ Pediatric Editorial Board, 2020d).

Hepatocellular Carcinoma

The annual incidence of HCC in the United States is 0.8 cases per 1 million children aged 0–14 years and 1.5 cases per 1 million adolescents aged 15–19 years (PDQ Pediatric Editorial Board, 2020d). A number of conditions are associated with HCC, including Alagille syndrome, glycogen storage diseases, hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, progressive familial cholestasis, and tyrosinemia. Fibrolamellar hepatocellular carcinoma is a specific subtype of HCC that generally occurs in adolescents and young adults but is also reported in infants (PDQ Pediatric Editorial Board, 2020d). It is characterized by a distinct genetic change that is unrelated to cirrhosis or HBV or HCV infection.

Like hepatoblastoma, HCC requires gross tumor resection for long-term survival. However, fewer than 30 percent of HCC tumors are resectable (PDQ Pediatric Editorial Board, 2020d). Orthotopic liver transplantation has been successful in some cases and should be considered at the earliest possible time point. Treatment options are similar to those for hepatoblastoma and include surgical resection followed by chemotherapy; chemotherapy followed by surgical resection or transplantation; TACE; and alternative treatments, including experimental clinical trials. Cisplatin and doxorubicin are the preferred chemotherapy agents. Sorafenib, a multitargeted receptor tyrosine kinase inhibitor, can also be considered for advanced or metastatic disease in combination with chemotherapy.

Undifferentiated Embryonal Sarcoma of the Liver

UESL makes up 2–15 percent of pediatric liver cancers (PDQ Pediatric Editorial Board, 2020d). The diagnosis of UESL is made by pathology with distinctive features that separate UESL from other liver tumors. The clinical presentation is typically with an abdominal mass accompanied by pain and feeling ill in children 5–10 years old. At presentation, UESL frequently has spread within the liver and metastasized to the lungs. Treatment of UESL uses a multimodal approach involving surgical resection and chemotherapy to eradicate micrometastasis in all patients. Neoadjuvant chemotherapy is used to try to convert patients with initially unresectable tumors into surgical candidates; liver transplantation is recommended for tumors that remain unresectable. Five-year OS is as high as 92 percent for children receiving combined therapy (Shi et al., 2017).

Germ Cell Tumors

Germ cell tumors (GCTs) derive from the cells that are destined to become eggs in females or sperm in males. Under normal circumstances,

these cells migrate down a central, midline path in the embryo to arrive at their final location in the gonads, which are the testes in males and the ovaries in females. During their migration, germ cells may erroneously be deposited in or near a midline structure such as the sacrum, coccyx, mediastinum, or pineal gland (centered in the brain), ultimately leading to the formation of an “extragonadal” GCT. CNS GCTs are discussed in Chapter 6; this section addresses extracranial GCTs (PDQ Pediatric Editorial Board, 2020c).

GCTs are associated with several congenital syndromes, including cryptorchidism (undescended testes), other genitourinary malformations, and disorders of sex chromosome number and integrity (Klinefelter’s, Swyer, or Turner syndrome). Because germ cells have the potential to form any tissue of the body, GCTs as a group are highly heterogeneous-appearing under the microscope. They may be made up of several different cell types, ranging from mature (hair, cartilage, glands, etc. in teratoma); to embryonal (e.g., yolk sac, choriocarcinoma, and embryonal carcinoma); to fully undifferentiated (e.g., dysgerminoma, seminoma, and germinoma in ovary, testis, and extragonadal sites, respectively) (Shaikh et al., 2016).

GCTs take the name of their most immature component. Teratomas can be mature, immature, or a combination of both. Mature teratomas are often cystic, contain a variety of mature tissues, and can become very large, but are generally considered benign. Immature teratomas, particularly when high-grade with immature neural elements, may behave like cancer and recur locally or spread to other parts of the body. Neither mature nor immature teratomas are believed to respond to chemotherapy, and management is surgical (Pashankar et al., 2016). The embryonal and undifferentiated subtypes of GCT have the capacity to metastasize, and make up the malignant GCTs. Some malignant GCTs produce fetal proteins or hormones that can be measured in the blood and serve as tumor markers that are diagnostic and prognostic and can be followed to detect response and recurrence. Yolk sac tumors classically present with elevation of alpha-fetoprotein and choriocarcinoma with high levels of beta-human chorionic gonadotropin, the hormone elevated in normal pregnancy.

Overall, GCTs make up 3 percent of pediatric cancers, but 15 percent of adolescent cancers (PDQ Pediatric Editorial Board, 2020c). In the early and prepubertal pediatric years (ages 0–14), testicular tumors predominate in boys and sacrococcygeal tumors in girls, with teratoma and yolk sac tumors being the most common subtypes. In postpubertal adolescents, testicular and mediastinal tumors tend to occur in males and ovarian tumors in females, with teratoma, mixed GCT, and dysgerminoma predominating (Fonseca et al., 2019).

GCTs generally present with symptoms that can be painless or intermittently painful. Severe acute pain may be due to trauma; bleeding;

or an ovarian or testicular torsion, a surgical emergency caused by the twisting of the gonad, thereby cutting off its own blood supply. In boys or girls, respectively, a palpable testicular or abdominal mass may be evident. Extragonadal tumors most frequently present with symptoms of urinary obstruction, constipation, or chest tightness. GCTs metastasize most commonly to lung, lymph nodes, and liver and rarely to brain and bone. When a gonadal GCT is suspected, a sonogram and tumor markers are generally obtained and are often adequate to make a preliminary diagnosis. Full clinical staging consists of a chest CT and CT or MRI imaging of the abdomen and pelvis, with brain and bone scan only if clinically indicated. If possible, an up-front complete surgical resection of the testicular or ovarian tumor should be attempted. This surgery entails a radical orchiectomy (removal of the complete testis) using the inguinal approach; removal of the affected ovary; or in the case of sacrococcygeal tumors, resection of the full coccyx, each without violating encapsulated structures. If both gonads are involved, the most affected is removed, and the other is biopsied but left in place to preserve fertility. Several staging systems are used depending on the age of the patient and the location of the tumor (see Annex Table 7-1). Surgical staging of ovarian tumors includes abdominal cavity washings and inspection of all surfaces for implants, as well as palpation of nodes. For older adolescent males with low-stage testicular cancer, a primary nerve-sparing retroperitoneal lymph node dissection may be undertaken, as it substantially decreases risk of relapse when disease is limited to the testis and nodes.

GCTs are among the most curable solid tumors of childhood. Because many localized (stage I) malignant GCTs can be cured with surgery alone, it is important to obtain tumor markers prior to and following surgery to ensure that they normalize after the tumor has been removed. Surveillance using tumor markers and intermittent imaging is generally continued for 3–5 years, although most recurrences will occur in the first year. For standard-risk tumors with persistently elevated tumor markers, evidence of residual tumor, and even metastatic disease, prognosis remains excellent. In fact, disseminated GCT was the first metastatic tumor to be cured by combination chemotherapy in the 1970s, using a platinum-based regimen (Einhorn and Donohue, 1977). The highly effective three-drug regimen of bleomycin, etoposide, and cisplatin for three or four cycles remains the mainstay of GCT treatment, with several other accepted regimens including only minor modifications.

The combination of surgery and chemotherapy delivers long-term disease-free survival rates of more than 95 percent in many cases, particularly in prepubescent patients and good-risk testicular cancer, and more than 80 percent in most other cases (PDQ Pediatric Editorial Board, 2020c). Nevertheless, there remains a group of patients with high-risk malignant GCTs

for whom cure is more challenging, including adolescent girls with stage IV ovarian cancer; adolescent boys with poor-risk testicular cancer (using the International Germ Cell Consensus Classification Criteria accounting for tumor size, markers, and nodal and metastatic sites); and adolescents with metastatic extragonadal tumors, including all tumors in the mediastinum (Frazier et al., 2015). Because of the general chemosensitivity of malignant GCTs, there remains the potential for long-term disease control with salvage chemotherapy, often including high-dose therapy with stem cell rescue, even in the setting of relapse (O’Shaughnessy et al., 2015). In girls, there are options for surgical local control if disseminated abdominal disease recurs. Complete resection of peritoneal and abdominal tumors should be performed. Abdominal radiation has shown little benefit in the relapse setting. Complete surgical resection followed by HIPEC using cisplatin can be an effective local control strategy (Hayes-Jordan et al., 2016b).

The late effects of greatest concern for GCTs are the risks of pulmonary fibrosis and hearing loss from the bleomycin and platinum, respectively, as well as SMN in those who receive radiotherapy. Pulmonary function tests and audiometry should be monitored prospectively. Because platinum can also cause renal damage and renal failure, survivors of GCTs are at increased risk for renal dysfunction in addition to sensory peripheral neuropathy, hypogonadism, decreased fertility, psychosocial issues, early-onset cardiovascular disease, and SMN (Travis et al., 2010).

Retinoblastoma

Retinoblastoma arises in the retina and is the most common neoplasm of the eye in childhood (Ortiz and Dunkel, 2016; Rodriguez-Galindo et al., 2015). It is a rare tumor occurring predominantly in children less than 2 years old (PDQ Pediatric Editorial Board, 2020l). It can occur in one eye (unilateral) (75 percent) or in both eyes (bilateral or multifocal) (25 percent) (Rodriguez-Galindo et al., 2015). Trilateral retinoblastoma refers to the development of an intracranial tumor in conjunction with retinoblastoma, which occurs in 5–15 percent of children with heritable retinoblastoma (PDQ Pediatric Editorial Board, 2020l). Heritable disease is characterized by a germline mutation in the RB1 gene, which either is inherited from a parent (25 percent) or arises from a new mutation in utero (75 percent) (Rodriguez-Galindo et al., 2015). The presence of heritable disease is suggested by a family history of retinoblastoma or bilateral or multifocal disease (PDQ Pediatric Editorial Board, 2020l). Once a diagnosis of retinoblastoma has been established, genetic counseling and testing of family members are critical to establish whether the retinoblastoma is sporadic or heritable for purposes of family planning and cancer screening for family members at risk for the development of other cancers, most

notably osteosarcoma. Detailed screening guidelines have been developed for children with a family history of retinoblastoma and include detailed dilated eye exam under anesthesia at regular intervals.

The presentation of retinoblastoma is most commonly with leukocoria and strabismus and, when the disease is advanced, pain, cellulitis, and glaucoma. Bilateral retinoblastoma typically presents in children less than 12 months old when the absence of a “red reflex” has been noted. The diagnostic evaluation for retinoblastoma includes an eye exam under anesthesia, ultrasound of the eye, and an MRI. Evaluation for metastatic disease, which occurs in about 5 percent of patients (Ali et al., 2013), includes bone scan, bone marrow aspiration and biopsy, and lumbar puncture. The diagnosis is typically made without pathologic confirmation. Several staging systems for retinoblastoma have been developed. The International Classification of Intraocular Retinoblastoma classifies intraocular tumors in groups based on the extent of the tumor within the retina and vitreous body. The groups range from A to E, with A denoting the least tumor extent and very low risk, and E the most tumor extent and very high risk (Ortiz and Dunkel, 2016; Rodriguez-Galindo et al., 2015). The International Retinoblastoma Staging System (IRSS) is a relatively new system developed by an international consortium of experts. In the IRSS, stage 0 tumors are treated conservatively; stages I and II denote eye enucleation without (stage I) or with (stage II) microscopic residual disease; stage III tumors have regional extension (e.g., to the orbit or lymph nodes); and stage IV denotes tumors with metastatic disease (hematogenous IVa, CNS IVb).

The goal of treatment for retinoblastoma is not only to cure the patient but also to preserve vision and reduce long-term toxicities and SMN. Retinoblastoma requires treatment by a multidisciplinary team with varied expertise in this rare disease. A risk-adapted individualized approach includes any single or combination of the following treatment options: enucleation, focal treatments such as cryotherapy, chemotherapy into the vitreal body, intra-arterial chemotherapy into the ophthalmic artery, systemic chemotherapy, or radiation therapy. Chemotherapy agents used for advanced disease typically include combinations of vincristine, etoposide, and carboplatin alone or alternating with cyclophosphamide and an anthracycline (PDQ Pediatric Editorial Board, 2020l). For patients with bilateral retinoblastoma, chemotherapy is typically administered to reduce tumor burden and then followed by focal therapies, with the goal of retaining vision without sacrificing cure (Berry et al., 2013). Enucleation is curative in 85–90 percent of patients with intraocular unilateral retinoblastoma without extraocular disease (Rodriguez-Galindo et al., 2015). With the use of intra-arterial and systemic chemotherapy as well as focal therapy, however, many intraocular retinoblastomas can be treated successfully without the need for enucleation. For bilateral retinoblastomas, the administration of

chemotherapy and focal therapies to both eyes can also allow salvage of the eyes. Trilateral retinoblastoma has had a very poor prognosis in the past (Ortiz and Dunkel, 2016). Recent studies have demonstrated that high-dose chemotherapy followed by autologous hematopoietic stem cell rescue may be the most effective therapy for these rare tumors (de Jong et al., 2014; Dunkel et al., 2010). The outcome for patients with intracranial extension of the retinoblastoma or with extracranial metastases is poor, and long-term disease control can rarely be achieved (Rodriguez-Galindo et al., 2015).

Because of the risk of SMN as well as other late effects, radiation is avoided if at all possible. Survivors of retinoblastoma, particularly those with germline RB1 mutation, are at high risk of developing SMN. Proton therapy is being used in an attempt to reduce the risk of SMN (Mouw et al., 2014), which are the most common cause of death in retinoblastoma and contribute to 50 percent of deaths among patients with bilateral, hereditary retinoblastoma up to six decades after completion of therapy (Kleinerman et al., 2019). Survivors also suffer from late effects that include diminished orbital growth after enucleation, visual field defects, and chemotherapy-associated hearing loss.

Other Tumors

This section reviews unusual cancers that are extremely rare in children. Because of their rarity, the available information on efficacious treatments for these cancers may be limited and based on the follow-up of a single child or a small group of children who received the same type of treatment (PDQ Pediatric Editorial Board, 2020k).

Melanoma

The two main types of primary skin cancer are melanoma and nonmelanoma (basal cell and squamous cell carcinomas of the skin). Even though malignant melanoma is rare in children, it is by far the most common pediatric skin cancer, representing less than 1 percent of cancer in young children but up to 7 percent of cancer in adolescents aged 15–19 (Howlader et al., 2013; Pappo, 2003; PDQ Pediatric Editorial Board, 2019). Age is a significant determinant of the behavior of melanoma, such that pediatric differs from adult melanoma and prepubescent from adolescent melanoma in terms of both biology and clinical behavior (Lange et al., 2007).

Two rare and almost uniformly fatal forms of prepubescent melanoma are congenital melanoma, acquired through the placenta of an affected mother, and melanomas commonly associated with a congenital skin disorder, such as xeroderma pigmentosum or congenital melanocytic nevus syndrome. But the vast majority of cases of melanoma in young children

actually are not congenital but a low-grade variant, termed pediatric spitzoid melanoma, that may involve regional lymph nodes but almost never metastasizes (Lallas et al., 2014). Adolescents may also develop spitzoid melanoma, but they are often “atypical,” and their course is less predictable relative to young children, making it difficult to differentiate the disease clinically from conventional adult malignant melanoma, which begins to appear in this age group. Increasingly, however, an understanding of the distinct microscopic and genetic characteristics of spitzoid melanoma and conventional malignant melanoma has allowed for better classification and determination of prognosis (Bahrami and Barnhill, 2018). While the incidence of conventional malignant melanoma had been rising steadily in adolescents since the 1970s, it appears that this trend has been reversed over the past two decades, potentially as a result of educational programs regarding sun protection (Campbell et al., 2015; Wong et al., 2013).

Pediatric melanomas are diagnosed by skin exam followed by biopsy, typically a punch or shave biopsy, performed by a general or pediatric dermatologist. All melanomas should undergo surgical reexploration and complete excision following biopsy to achieve adequate negative margins as determined by the site, size, and thickness of the initially biopsied lesion. Prepubertal children with noncongenital melanoma tend to have a higher rate of lymph node metastasis (as identified by sentinel lymph node biopsy) but a lower chance of death as compared with adolescents and adults (Moore-Olufemi et al., 2011). Noncongenital melanomas can often be nonpigmented in the prepubertal child, so the diagnosis can be delayed, but 5-year OS is approximately 99 percent. For spitzoid tumors, a repeat excision to ensure negative margins is generally all that is required. Sentinel node biopsy, wherein radiolabeled dye is injected into the area of the lesion and followed to the draining node bed to be sampled, is controversial in spitzoid melanoma because metastasis is frequently detected (up to 40 percent), but clinical outcome is excellent without complete node dissection or adjuvant therapy (Lallas et al., 2014). Spitzoid tumors usually carry novel fusion kinases that would theoretically be targetable with a kinase inhibitor (see Chapter 3) should the tumors recur, but this has yet to be reported. The rare patients with spitzoid melanoma with poor prognosis appear to have a specific genetic mutation in the promoter of the TERT gene (Bahrami and Barnhill, 2018). PET/CT is the most sensitive test for metastatic work-up but can be problematic because of high false-positive rates. The use of imaging for surveillance is generally reserved only for spitzoid patients who are positive for the TERT-promoter mutation (Kaste, 2019).

For adolescents with localized nonmetastatic malignant melanoma, the same diagnostic and treatment algorithms used in medical oncology are followed. However, these patients tend to do better than their adult counterparts, with more than 90 percent alive 5 years after diagnosis (Howlader

et al., 2013; PDQ Pediatric Editorial Board, 2019). Adolescents with lymph node metastases often present late in the course of disease and have a very poor prognosis that mimics that of adults at about 55 percent 5-year survival (Moore-Olufemi et al., 2011). Surgical excision with adequate negative margins is the mainstay of therapy for localized melanoma. Patients with thick lesions and/or ulceration should have sentinel node biopsy and be considered for complete lymph node excision if positive. Staging should include PET/CT or PET/MRI. Immunotherapy (immune check point inhibitors) and targeted therapy using BRAF and MEK inhibitors (see Chapter 3) are now the standard of care for adult melanoma in the adjuvant setting or as treatment for disseminated disease, but are still in early development for children. It will be important for pediatric patients with malignant melanoma to receive these therapies in the context of clinical trials or registries, if possible, to enable better understanding of the response, behavior, and long-term prognosis of these rare patients.

Thyroid Cancer

Thyroid cancers account for 1.5 percent of all pediatric cancers, with adolescents most frequently affected (PDQ Pediatric Editorial Board, 2020g). The incidence of thyroid carcinoma has been increasing annually by 3.8 percent among children and adults in the United States (Prasad et al., 2020). In addition, genetic tumor predisposition syndromes have an important role in a subset of thyroid carcinomas (see Table 2-3 in Chapter 2). Thyroid cancer is also the most common SMN in children, adolescents, and young adults who are survivors of childhood cancer.

Thyroid tumors can be histologically benign (adenomas) or cancerous (carcinomas). Carcinomas are classified as differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Papillary thyroid carcinoma (PTC) is the most frequent DTC in children (90 percent), typically presenting as multifocal disease (Prasad et al., 2020) that spreads most frequently to regional lymph nodes and the lungs (25 percent). Prior radiation exposure is an important risk factor for PTC. The other form of DTC, follicular thyroid carcinoma (FTC) is uncommon in children. MTC accounts for 10 percent of thyroid carcinomas in children. The cells of origin are parafollicular C cells. These cells secrete the hormone calcitonin, which can be measured in the blood and serve as a marker of disease activity. In children, MTC is associated with the hereditary tumor predisposition syndrome multiple endocrine neoplasia (MEN) type 2 (MEN2A and MEN2B) (see Table 2-3 in Chapter 2). Patients have different types of germline mutations in the RET oncogene, with the type of mutation being associated with differing risks for developing MTC and for

metastatic spread (Wells et al., 2015). ATC is exceedingly rare in children (1 percent of pediatric thyroid carcinomas).

The clinical presentation of DTC is typically a thyroid mass, and sometimes enlarged lymph nodes. Elucidating a family history of thyroid cancer is critical given the genetic tumor predisposition in some patients. Presentation at younger age and larger tumor size are associated with more aggressive disease behavior. MTC presents with more aggressive disease relative to DTC, and 50 percent of children with MTC have distant metastases, including to liver, lungs, or bone, at diagnosis (PDQ Pediatric Editorial Board, 2020g). Children with the germline RET M918T, associated with MEN2B, have the highest risk for MTC development at an early age. These children also have mucosal neuromas and marfanoid habitus, which can alert care providers to the possibility of MEN syndrome and MTC. In addition, 50 percent of these children develop pheochromocytomas (PDQ Pediatric Editorial Board, 2020g), hormonally active tumors arising from the adrenal glands. Pheochromocytomas can result in potentially life-threatening hypertension, heart palpitations, chest pain, and other symptoms. Measurement of plasma-free metanephrines, which are produced by these tumors, in the blood is very helpful in establishing a diagnosis and in managing the hormonal activity with medications, including those for controlling blood pressure, prior to surgery.

Diagnostic evaluation of thyroid tumors includes ultrasound of the thyroid and measurements of serum thyroid-stimulating hormone (TSH) levels and serum thyroglobulin. Fine-needle aspiration, open biopsy, and resection can help establish the pathologic diagnosis. A number of molecular alterations have been described in PTC, FTC, and ATC. These include aberrations in BRAF, RAS, RET-PTC, NTRK, DICER1, ALK, and TP53, which can be assessed in tumor samples and if present, may offer opportunities for targeted therapies (Prasad et al., 2020). Additional imaging studies to evaluate for extent of disease include neck ultrasound and CT/MRI of the neck/chest/abdomen and pelvis. Thyroid nuclear scintigraphy (nuclear medicine scan) may also be performed in patients with suppressed TSH to look for metastatic deposits.

Treatment of PTC and FTC includes surgery, radioactive iodine ablation, and targeted therapies (Francis et al., 2015). Total thyroidectomy is the treatment of choice, and should be performed by a surgeon with expertise in endocrine surgeries in children at a specialized center offering the full spectrum of pediatric specialty care. If thyroid carcinoma has spread to the neck lymph nodes, central or lateral neck dissection is performed. For patients with persistent local or nodal disease that cannot be resected or known metastases, 131I therapy is administered. Treatment and dosing should be performed by experts in pediatric thyroid carcinoma. Overall, children with DTC have excellent survival outcomes (>95 percent OS at

10 years) (Francis et al., 2015; Prasad et al., 2020; Sugino et al., 2015). However, in addition to a lifelong requirement for thyroid hormone supplementation, the long-term potential side effects of 131I treatment include dysfunction of the salivary glands, damage to the lung (pulmonary fibrosis), and SMN.

Most cases of pediatric MTC are associated with hereditary MEN. In these patients, prevention of MTC is the primary goal. Accordingly, the American Thyroid Association has recommended prophylactic thyroidectomy, depending on the type of RET mutation (Wells et al., 2015); for the most frequent RET mutation, M918T, which also poses the highest risk of MTC, prophylactic thyroidectomy is recommended in the first months of life. For established MTC, surgery is the mainstay of therapy, with serum calcitonin monitoring for disease recurrence. For patients with unresectable or metastatic advanced disease, targeted therapies are an option. Two tyrosine kinase inhibitors, vandetanib and cabozantinib, which block the RET oncogene and other kinases, have been approved by FDA for adults with advanced MTC. These agents have also been evaluated in children with MTC and have demonstrated activity in clinical trials (Chuk et al., 2018; Fox et al., 2013). Selpercatininb is a more specific RET inhibitor recently approved by FDA for adolescents with RET-driven MTC. Current recommendations are to initiate these therapies in patients with clearly progressing disease as opposed to stable metastatic disease, as these tumors can be quite indolent and slow-growing.

Colorectal Carcinoma

The colon (large bowel), rectum, and anal canal are parts of the large intestine. CRC is very rare in pediatric patients (PDQ Pediatric Editorial Board, 2020b). Although its diagnosis and treatment are presently the same as for adults, the outcomes are much different in that stage for stage, pediatric patients with CRC have a poorer prognosis (Hayes-Jordan et al., 2020). Specifically, for each stage besides stage I, pediatric patients have a 5–6 times higher risk of death from colon cancer (Hayes-Jordan et al., 2020). As in adults, stage I pediatric patients are treated with surgery alone and monitored closely. Stage II and III patients are treated with surgery, followed by 6–9 months of chemotherapy. Patients with mucinous histology, T4 tumors, positive lymph nodes, Signet ring, and intestinal perforation have the worst prognosis. Drug therapy for stage II and III patients may include cytotoxic chemotherapy (5-fluorouracil and irinotecan), antiangiogenic therapy, and/or immunotherapy. In addition to colectomy, surgery may include HIPEC and/or liver resection. Stage IV patients may be offered chemotherapy and/or surgery; their survival is usually less than 2 years (Hayes-Jordan et al., 2020).

Adrenocortical Carcinoma

Adrenocortical tumors in children can be histologically benign (adenomas) or malignant (carcinomas) (PDQ Pediatric Editorial Board, 2020a). Adrenocortical tumors are very rare in children, with only 25 new cases seen in the United States annually. Germline TP53 mutations are present in most pediatric adrenocortical tumors. Several genetic tumor predisposition syndromes in addition to Li-Fraumeni syndrome predispose to adrenocortical tumors (see Table 2-3 in Chapter 2). Differentiating between adenomas and carcinomas can be difficult; however, the majority of these tumors in pediatric patients are carcinomas and are functional, producing hormones that result in a number of endocrine abnormalities, including virilization, hypoestrogenism, and Cushing syndrome, and provide clues to the diagnosis (Erickson et al., 2014; Gupta et al., 2018).

Prognostic features of ACC for patients with and without TP53 mutations include metastatic disease (most frequent sites are liver, lung, and retroperitoneal lymph nodes), large tumor size, older age, and incomplete tumor resection. Five-year survival for patients with stage I resectable disease is more than 80 percent, compared with less than 20 percent for patients with stage IV metastatic disease (PDQ Pediatric Editorial Board, 2020a). In a recently reported single institution series, the majority of children presented with stage IV disease (Gupta et al., 2018).

The treatment of pediatric ACC is similar to that of adult disease. Surgery is the mainstay of therapy, with complete resection, including enlarged retroperitoneal lymph nodes, being required for cure. At the time of diagnosis, two-thirds of pediatric ACCs are resectable. Surgery should be performed by surgeons with expertise in pediatric endocrine surgery because of the risk of tumor rupture and spillage. Chemotherapy is another important treatment modality. Mitotane, a chemotherapeutic agent approved by FDA for adults with ACC, can also be used in children in the adjuvant setting, often in combination with etoposide, doxorubicin, and cisplatin (Mihai, 2015). Mitotane has significant side effects, including malaise, and lower doses may be better tolerated. Most recently, immune checkpoint inhibitors have demonstrated activity in pediatric ACC (Geoerger et al., 2020).

In patients with functioning tumors, in addition to drugs targeting the tumor, antisteroidogenic drugs—including ketoconazole and steroid receptor antagonists, such as spironolactone—may have to be administered. Ultimately effective therapy may ablate the adrenals, rendering patients dependent on physiologic and stress steroid replacement for life.

FINDINGS AND CONCLUSIONS

Findings

7-1 Non–central nervous system (CNS) tumors make up a heterogeneous group of tumors with distinct diagnostic characteristics, treatments, survival rates, and prognoses.

7-2 For many non-CNS pediatric solid tumors, the majority of patients achieve long-term disease-free survival. However, they require intensive multimodal therapy that is tailored to the specific diagnosis and risk group, which puts them at risk for acute and chronic functional impairments.

7-3 Risk stratification within a diagnosis permits reduction in therapy for patients with good prognoses and intensification of therapy for those with poor prognoses.

7-4 The greatest progress in treatment, survival, and reduction of late effects for pediatric non-CNS solid tumors has been achieved in the chemotherapy-sensitive pediatric embryonal tumors: rhabdomyosarcoma, neuroblastoma, Wilms tumor, hepatoblastoma, and germ cell tumors.

7-5 With rare exceptions (e.g., Wilms tumor, young patients with good-risk germ cell tumors), metastatic pediatric non-CNS solid tumors have a poor prognosis.

7-6 Almost all recurrent pediatric non-CNS solid tumors have a poor prognosis, with the exception of those that did not require maximal therapy at diagnosis (e.g., low-risk rhabdomyosarcoma, Wilms tumor, low- and intermediate-risk neuroblastoma, and low- and standard-risk germ cell tumors).

7-7 Immunotherapy as maintenance therapy has been a major breakthrough in the treatment of neuroblastoma.

7-8 The survival benefits and long-term consequences of newer therapies (e.g., targeted and immunotherapy) for non-CNS solid tumors remain unknown.

Conclusions

7-1 Pediatric non-CNS malignant tumors must be considered individually, with distinct periods of treatment and recovery, survival rates, and long-term outcomes.

7-2 For children with metastatic or relapsed malignant non-CNS solid tumors for which an effective salvage therapy is not known, participation in investigational clinical trials is critical to the identification of effective therapies.

7-3 Participation in clinical trials is warranted for children with non-CNS solid tumors for which outcome and survival have plateaued.

7-4 Because advances in pediatric cancer are made incrementally through clinical trials in which the control arm or backbone represents the standard of care, participation in trials is considered the standard of care for patients newly diagnosed with non-CNS solid tumors.

7-5 Further evaluation of tumor biology and genomics will likely result in future modifications of risk stratification and aid in identifying additional therapeutic targets and treatment options for pediatric non-CNS solid tumors.

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ANNEX TABLE 7-1
Selected Non-Central Nervous System (CNS) Solid Tumors: Diagnostic and Prognostic Information

NOTE: With the exception of low-risk rhabdomyosarcoma, Wilms tumor, low- and intermediate-risk neuroblastoma, and low- and standard-risk germ cell tumors, almost all recurrent tumors have poor long-term survival.

^a In contrast with other cancers, OS for Wilms tumor is reported as 4 years.

^b PDQ Pediatric Editorial Board (2020d); see description of PRETEXT in Chapter 7.

^c See PDQ Adult Editorial Board (2020) for staging.

ANNEX TABLE 7-2
Selected Non-Central Nervous System Solid Tumors: Treatment Information

* In addition to the treatment durations listed, which are based on standard treatment protocols, the committee estimates, based on the members’ clinical expertise, that patients typically require an additional 3–18 months to recover from the acute effects of treatment with radiation and/or chemotherapy

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