Theodore B. Moore and Carole G. H. Hurvitz
INCIDENCE AND SURVEILLANCE
I. INCIDENCE AND OVERVIEW. Although cancer is the second leading cause of death in children (12% of deaths), it is still relatively uncommon. The incidence of cancer is increasing, however. Fortunately, with modern aggressive multidisciplinary therapy, 5-year survival rates for children with cancer exceed 75%.
A. Cooperative groups. The treatment of children with cancer is highly specialized. Whenever possible, patients younger than 18 to 21 years of age should be treated in specialized centers related to one of the major pediatric cooperative groups, such as the Children’s Oncology Group. More than 90% of children younger than 10 years of age are treated in such centers, and their mortality has decreased proportionally. Only about 30% of teenagers are enrolled in such centers, however, and the mortality rates in this group have not shown the same improvement.
B. Incidence. Leukemia and lymphoma make up almost half of the cases of malignancy in childhood, followed by central nervous system (CNS) tumors. The mortality rate for CNS cancers now exceeds that for acute lymphocytic leukemia.
There is no formal reporting system for malignant tumors in children in the United States. SEER (Surveillance, Epidemiology, and End Results) reports from the National Cancer Institute indicate that approximately 164 cases of cancer occur per 1 million population <20 years of age in the following incidences per million:
|
Leukemia—43 |
Neuroblastoma—8 |
Bone tumors—9 |
|
CNS tumors—29 |
Wilms tumor—6 |
Retinoblastoma—3 |
|
Lymphomas—22 |
Soft tissue sarcomas—11 |
The COG has recently set up a registry to try and determine the incidence.
II. LONG-TERM SURVIVAL AND SURVEILLANCE. Now that more or most children with cancer are cured, the complications of the disease and its management are becoming increasingly important. In addition, some of the long-term complications are just now being appreciated. The most significant complications are as follows:
A. Neurocognitive development. Radiation to the brain and central nervous systems leads to learning disabilities and school problems. Fortunately, RT has been almost eliminated from leukemia treatment plans. Chemotherapy, especially methotrexate, but other agents also, can lead to learning difficulties.
B. Growth retardation. Radiation to the spine or limbs causes reduced growth in the affected area. Steroids and brain irradiation lead to endocrine and growth problems.
C. Second malignances. Breast cancer is a very significant problem in girls who have had radiation to the chest, especially for Hodgkin lymphoma. The incidence reaches almost 40% by age 40 years. Even the newer reduced-dose regimens are still associated with an increased incidence of breast cancer. Radiation leads to second cancers in the radiated area. Brain tumors were frequently seen in leukemia patients after CNS radiation. Having one cancer may put patients at risk of a second cancer. Cancer survivors are at risk of developing colon and skin cancers, leukemia, and lymphoma.
D. Fertility. High-dose chemotherapy can reduce oogenesis and spermatogenesis. Radiation to the pelvis, as in Wilms tumor, causes increased fetal losses due to damage to the uterus.
E. Cardiovascular and respiratory systems. Anthracyclines cause damage to the heart. Recent studies are showing that even lower doses, thought to be safe, can have long-term effects. The younger the child and the greater the dose, the greater the risk. Pregnant women who were treated for cancer as children may develop heart failure during delivery. Radiation to the lungs and drugs such as bleomycin and cyclophosphamide can damage the lungs and cause decreased respiratory reserve.
F. Recommended surveillance
1. Mammograms, or preferably breast MRI, and breast examination are recommended annually for girls with RT to the chest, especially for Hodgkin lymphoma. They should begin screening at 8 years after irradiation or age 25 years, whichever is first.
2. Echocardiograms are recommended every 2 to 5 years, depending upon the age at treatment and the dose. These recommendations are subject to change.
3. Colonoscopy is recommended beginning age 25 or 10 years after RT for those who have received radiation therapy to the pelvis and abdomen.
4. Skin examinations annually are recommended for patients following radiation and stem cell transplantation.
LEUKEMIA AND LYMPHOMA
I. ACUTE LEUKEMIA (see Chapter 25)
A. Pathology. Acute lymphoblastic leukemia (ALL) accounts for 80% to 85% of leukemias in childhood. Acute myelogenous leukemia (AML) accounts for 15% and chronic myelogenous leukemia accounts for 5% of cases.
In ALL, 15% to 25% of cases are T-cell, <5% are B-cell, and the remainder are precursor B-cell leukemias. Of the precursor B-cell leukemias, 70% possess the common acute lymphoblastic leukemia antigen (CALLA, CD-10). They are usually also terminal deoxynucleotidyl transferase–positive. Almost all are also CD-19–positive.
B. Treatment of ALL in childhood involves induction of remission, prophylaxis to the CNS, a phase of consolidation and reinduction, and maintenance therapy. Standard treatment for ALL leads to long-term remission in >85% of cases. Induction therapy employs vincristine, prednisone, dexamethasone, and L-asparaginase with the addition of daunomycin or doxorubicin, depending on risk stratification. Intensification therapy includes CNS prophylaxis. During maintenance therapy, oral mercaptopurine is given daily and methotrexate weekly for 2 to 3 years. Many patients receive monthly pulses of vincristine plus prednisone or dexamethasone. One or two cycles of a reinduction regimen are often added in ALL.
Certain prognostic factors at diagnosis affect the outlook of children with ALL, and their treatment is modified accordingly. Children with poorer prognostic features require more intensive treatment than standard therapy.
1. Favorable prognostic factors for ALL. Average risk factors include initial white blood cell (WBC) count of <50,000/μL and age 1 to 9 years. Favorable features include pre-B subtype, L1 morphology, hyperploidy, lack of organomegaly, low bone marrow blasts on day 7 of induction therapy, trisomy of chromosomes 4 and 10, and t(4;11) or Tel/AML1 translocations. It has been shown that lack of minimal residual disease (MRD) at the end of induction gives a better prognosis or at least a positive MRD carries a much poorer prognosis.
2. Poor prognostic factors include WBC >50,000/μL, age <1 year or >10 years, massive organomegaly, lymphoma-like features, CNS involvement at diagnosis, mediastinal mass, failure to achieve remission by day 14 or 28, and certain chromosomal translocations, especially MLL gene rearrangements (11q23) in infants, the presence of the Philadelphia chromosome, and positive MRD at the end of induction or at any other time.
3. AML (Acute Myeloid Leukemia) accounts for 15% to 25% of leukemias in childhood.
In AML, high-risk features include monosomy 7, monosomy 5, 5q deletions, and FLT3 mutations. FLT3/ITD (internal tandem duplication) is a poor prognostic factor. In adults, 20% to 30% are FLT3 positive. Secondary AML is particularly difficult to treat and carries a poor prognosis. In children, only 5% to 17% are positive. Positivity increases with age. Good risk features include inv (16)/t(16;16), t(15;17), and t(8;21) conferring survival exceeding 70%.
Treatment of AML requires intensive chemotherapy. At the present time, hematopoietic stem cell transplantation (HSCT) is recommended for high-risk patients, preferably matched family donor (MFD) if available. MFD is recommended for intermediate risk if available and chemotherapy alone for low-risk patients.
C. Survival. The 5-year survival rate is >85% in children with “good-prognosis” ALL following standard therapy. Even children with poorer risk factors who receive intensive therapy have an overall long-term survival of at least 70%. Sites of relapse include the CNS, testes, and bone marrow. The risk for relapse after 2 years off therapy is very low.
The 5-year survival rate with the best available regimens for children with AML is 65% to 70% in first remission with favorable prognostic factors or when consolidated with a sibling donor HSCT and about 50% for those without. HSCT (allogenic, autologous, or matched unrelated) is also often recommended for patients with ALL and AML who relapse.
II. LYMPHOMA
A. Non-Hodgkin lymphoma (see Chapter 21). In pediatrics, lymphomas can be considered to be lymphoblastic or nonlymphoblastic and localized or nonlocalized. Lymphoblastic lymphomas are usually T cell and, when nonlocalized, may be the same entity as T-cell leukemia; these illnesses are usually treated in the same way. Nonlymphoblastic lymphomas are usually B cell and frequently were previously called Burkitts (or Burkitts-like) lymphoma.
Different combination chemotherapeutic regimens are necessary for the subtypes of lymphoma. Localized lymphomas respond very well to chemotherapy even when bulky, and have a cure rate of >90%. The prognosis for disseminated T-cell lymphomas is the same as for T-cell ALL. The outlook for disseminated nonlymphoblastic or B-cell lymphoma is about 50%.
B. Hodgkin lymphoma (see Chapter 21). There is no consensus on the treatment of Hodgkin lymphoma in children. Chemotherapy is used for all stages of disease. Staging laparotomy is no longer recommended. Splenectomy is contraindicated in young children because of fatal infectious complications and increased risk for leukemia. The alternation of the COPP and ABVD regimens (defined in Appendix D1) or a hybrid of them is frequently recommended rather than either regimen alone. In children, local-field rather than extended-field radiation is preferred in an effort to reduce long-term side effects, such as growth retardation and second cancers, especially breast cancer in girls.
Second malignancies are a major problem with the risk approaching 40% by age 35 years for girls who have been irradiated. Current Children’s Oncology Group (COG) treatment regimens are evaluating modulation of therapy based on initial response with a goal of minimizing toxicity while maintaining high cure rates.
BRAIN TUMORS
Neurologic malignancies are discussed in Chapter 14.
I. EPIDEMIOLOGY. Brain tumors in children may be associated with certain underlying diseases including neurofibromatosis, tuberous sclerosis, and von Hippel-Lindau angiomatosis. Family clusters of CNS tumors have occasionally been reported.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology. Most CNS neoplasms in children are primary tumors of the brain; the single exception is meningeal metastases, which are common with leukemia and lymphoma. Astrocytomas are the most frequent type (about 50% of all cases). Medulloblastomas account for 25% of cases; ependymomas, 9% and glioblastomas, 9%.
B. Sites of disease. Brain tumors in children tend to occur along the central neural axis (i.e., near the third or fourth ventricle or along the brain stem). Most brain tumors that occur during the first year of life are supratentorial. In patients between 2 and 12 years of age, 85% are infratentorial. In patients >12 years of age, the relative incidence of supratentorial tumors increases.
III. SYMPTOMS AND SIGNS
A. Symptoms. The most common symptoms include headaches, irritability, vomiting, and gait abnormalities. Morning headaches are most characteristic, but drowsiness and abnormal behavior are also common. Symptoms may be intermittent, particularly in very young children who have open fontanelles. A head tilt is a common finding and often missed.
B. Physical findings include enlarged or bulging fontanelles in very young children and cerebellar abnormalities, papilledema, and sixth cranial nerve abnormalities in older children.
IV. TREATMENT AND SURVIVAL. Survival rates for patients with low-grade astrocytomas are high if the tumor can be surgically removed (>90% at 5 years) and low if the tumor is high grade (<10% at 5 years). Survival for medulloblastoma depends on both local recurrence (<25% with surgery and radiotherapy) and spinal metastases (about 35% incidence without prophylactic spinal irradiation); this tumor is invariably recurrent when treated with surgery alone, but average risk patients have approximately 80% survival when treated with surgery, radiation, and chemotherapy.
Chemotherapy is now being used more frequently in children with brain tumors in an attempt to improve survival and to reduce the use of radiation, which has devastating effects in young children. RT is deferred in children <3 years of age and preferably in children <10 years whenever possible. Unlike childhood leukemia, relatively little improvement in survival has been obtained over the years. High-dose therapy with autologous HSCT support has shown promising results in certain disease types. In addition, experimental approaches using targeted therapies, novel chemotherapy and radiation delivery systems, and dendritic cell-based vaccines are currently under investigation.
NEUROBLASTOMA
I. EPIDEMIOLOGY AND ETIOLOGY. Neuroblastoma is the most common congenital tumor and the most common tumor to occur during the first year of life. It rarely occurs in patients >14 years of age. About 40% occur in the first year of life, 35% from 1 to 2 years of age, and 25% after 2 years of age. Rarely, family clusters are reported.
II. PATHOLOGY AND NATURAL HISTORY. Neuroblastoma has the highest incidence of spontaneous regression of any tumor in humans.
A. Histology. Neuroblastoma closely resembles embryonic sympathetic ganglia. The tumors partially differentiate into rosettes or pseudorosettes, mature ganglion cells, or immature chromaffin cells. Although histologically similar to ganglioneuromas and pheochromocytomas, neuroblastomas are clearly distinctive. Electron microscopy shows typical dendritic processes that contain granules with dense bodies, probably representing cytoplasmic catecholamines. The most primitive histologic type of neuroblastoma is composed of small round cells with scant cytoplasm. The ganglioneuroma is composed of larger, more mature ganglion cells with more abundant cytoplasm.
Homogeneously staining regions and double minute chromosomes seen in poor-prognosis neuroblastomas represent amplified N-myc segments. Amplification of N-myc is an intrinsic property of poor-prognosis tumors and can be rapidly detected by fluorescent in situ hybridization (FISH) concordant with Southern blot analysis.
B. Sites. The most common primary site is the adrenal gland (40% of cases); a tumor of the adrenal gland produces an abdominal mass. Involvement of posterior sympathetic ganglion cells results in both intrathoracic and intra-abdominal masses, the so-called dumbbell tumor that causes compression of the spinal cord.
C. Mode of spread. Most cases of neuroblastoma present with widespread metastatic disease. The most common metastatic sites include bone, bone marrow, liver, skin, and lymph nodes.
III. DIAGNOSIS
A. Symptoms. The most common symptoms include abdominal pain and distention, bone pain, anorexia, malaise, fever, and diarrhea. Exopthalmus and “raccoon eyes” are a rare but typical presentation.
B. Physical findings include hepatomegaly, hypertension, orbital mass and ecchymosis, subcutaneous nodules (particularly in infancy), intra-abdominal mass, and Horner syndrome.
C. Laboratory studies
1. Complete blood count (CBC), serum chemistry panel
2. Urine for total catecholamines and metabolites, including vanillylmandelic acid (VMA) and homovanillic acid (HVA)
3. Chest and abdominal radiographs
4. CT scan of the abdomen or thorax (possibly preceded by abdominal and renal ultrasound)
5. Bone scan
6. Bone marrow aspiration and biopsy to look for tumor cells
7. 131I-metaiodobenzylguanidine, which is specific for neuroblastoma and pheochromocytoma.
8. Examination of tumor for amplification of the N-myc gene
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system
B. Survival and prognostic factors. The prognosis for neuroblastoma is closely related to the age of the patient and stage of disease.
1. Age. Patients with congenital tumors have the most favorable prognosis, even with widespread disease, and they also have the highest rate of spontaneous regression without treatment. Patients who are between 1 and 5 years of age do worse than patients younger than 1 year or older than 5 years of age.
2. Stage. Patients with advanced disease, except for stage IVS, have a poor survival rate. The overall 2-year survival is >80% for stages I and II and <40% for stage IV. Stage IVS has a 90% survival rate. Patients with stage III and IV disease who have amplification of the N-myc gene do worse.
3. The urinary VMA:HVA ratio is an indirect measure of dopamine hydroxylase. Absence of this enzyme may convey a poorer prognosis (i.e., if the VMA:HVA ratio is <1.5) and may cast doubt on the diagnosis of neuroblastoma.
V. MANAGEMENT
A. Surgery. Localized disease is managed primarily by surgical resection. For metastatic disease, biopsy or excision of the primary tumor is important for N-myc gene assessment. Complete resection is usually delayed until after chemotherapy is administered but may be done at the time of diagnosis.
B. RT is used for bulky tumor in combination with chemotherapy.
C. Chemotherapy
1. Residual localized or advanced disease. Aggressive multimodal chemotherapy with active agents such as doxorubicin, cyclophosphamide, etoposide, cisplatin, vincristine, and topotecan combined with surgical resection and bone marrow transplantation has improved survival in stage III and IV disease.
2. Congenital disease. In patients with congenital disease, specifically for stage IVS, chemotherapy is not used unless the tumor causes significant symptoms.
D. HSCT (usually autologous) after intensive radiation and chemotherapy appears to improve the outlook for patients with advanced disease, especially when used in conjunction with posttransplant 13-cis-retinoic acid. The most recent treatment protocol within the COG is examining whether consolidation with tandem high-dose therapy with autologous hematopoietic stem cell support yields superior outcome to a single consolidation.
E. Future directions. Poor survival in the advanced stages of disease has spurred extensive research into targeted therapies. An especially promising target under evaluation is GD2 (disialoganglioside). In early evaluations, Anti-GD2 has shown some efficacy, especially in patients with infiltrating marrow disease. Current protocols also incorporate in disease-responsive drugs such as topotecan into the induction regimen in an attempt to improve response rates.
WILMS TUMOR (NEPHROBLASTOMA)
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Wilms tumor most frequently affects children between 1 and 5 years of age and rarely those >8 years of age. The incidence is about 7 per 1 million in the childhood age group. Familial clusters have been described, particularly in patients with bilateral Wilms tumors.
B. Associated abnormalities. Wilms tumor has been associated with certain congenital anomalies, including genitourinary anomalies, aniridia (absence of an iris), and hemihypertrophy (Beckwith-Wiedemann syndrome). Deletion of the short arm of chromosome 11 has been associated with a syndrome of Wilms tumor, mental retardation, microcephaly, bilateral aniridia, and ambiguous genitalia.
II. PATHOLOGY AND NATURAL HISTORY
A. Histopathologic classification is most accurate for determining the prognosis.
1. Wilms tumor. Tumors that display mature elements and few anaplastic cells have the most favorable prognosis and are termed favorable histology. Unfavorable histology concerns tumors that have focal or diffuse anaplasia, rhabdoid sarcoma, or clear cell sarcoma. Unfavorable histology accounts for 12% of Wilms tumors but almost 90% of deaths.
2. Congenital mesoblastic nephroma is a rare benign tumor that is common in infancy (the most common renal neoplasm during the first month of life) and can be histologically confused with Wilms tumor. This tumor consists of spindle-shaped, immature connective tissue cells that have a distinctive fibroblastic appearance with only minimal nuclear pleomorphism and mitoses.
B. Sites. About 7% of Wilms tumors are bilateral at the time of diagnosis.
C. Mode of spread. The lungs are the principal sites of metastases; liver and lymph nodes are the next most common sites. Bone marrow metastases are extremely rare and tend to be associated with clear cell subtypes of sarcomatous Wilms tumor. CNS metastases are extremely rare.
D. Paraneoplastic syndromes. Wilms tumors have been associated with increased erythropoietin (erythrocytosis) and increased renin (hypertension).
III. DIAGNOSIS
A. Symptoms. The most common symptoms include enlarged abdomen, abdominal pain, and painless hematuria.
B. Physical findings. A palpable abdominal mass is the most common finding. Hypertension is sometimes present.
C. Laboratory studies
1. CBC, serum chemistries, urinalysis
2. Plain radiographs of the chest and abdomen
3. CT or, preferably, MRI scan of abdomen
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system
B. Survival and prognostic factors. The most important prognostic factors are the histopathologic classification and the clinical and surgical staging. Age at diagnosis is of minor importance, although younger patients appear to have a slightly better outcome. The overall 2-year survival rate is >95% for stage I, II, and III disease, with favorable histology, and about 50% for stage IV disease.
V. MANAGEMENT
A. Surgery. All patients must have surgery for both staging and removal of as much tumor as possible. A transabdominal incision is mandatory to examine the vessels of the renal pedicle and the noninvolved kidney. The tumor bed and any residual tumor should be outlined with metallic clips at the time of surgery.
B. RT is useful for treating stage III disease and metastatic disease to bone, liver, or lung.
C. Chemotherapy. Multiple courses of combination chemotherapy are the preferred treatment. The major active chemotherapeutic agents are actinomycin D, vincristine, and doxorubicin. Cyclophosphamide is an effective second-line drug. Cisplatin is active against Wilms tumor and is being used in investigational protocols. The youngest patients are particularly susceptible to serious toxic effects from chemotherapy, particularly hematologic, and drug dosages should be reduced 50% for patients <15 months of age.
D. Treatment according to stage of disease. Surgery and chemotherapy are used for all stages of disease.
1. Stage I. RT is not necessary.
2. Stages II and III. RT is not needed for stage II with favorable histology but is used for unfavorable histology and stage III.
3. Stage IV or recurrent disease. If possible, surgery can be used. Chemotherapeutic agents can be restarted if they were discontinued or changed if relapse occurred during treatment. RT is useful for metastatic disease. Intensive chemotherapy with autologous HSCT may be beneficial in recurrent disease.
4. Stage V. Bilateral Wilms tumor necessitates a special effort to preserve as much renal tissue as possible. Initially, biopsy is done, and then chemotherapy followed by judicious resection of the remaining tumor. Bilateral nephrectomy followed by chemotherapy, and renal transplantation is a last resort. The 3-year survival rate is 75% for these patients.
RHABDOMYOSARCOMA
I. EPIDEMIOLOGY AND ETIOLOGY. Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children; there are about eight cases per million population. Suggestive evidence of C-particle viruses in these tumors has been observed with electron microscopy, but the viruses have not been isolated.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Four major histologic categories of this striated muscle neoplasm have been described: embryonal (including sarcoma botryoid), alveolar, pleomorphic, and mixed. Z bands can be seen with electron microscopy. Rhabdomyoblasts have acidophilic cytoplasm, which is often periodic acid–Schiff stain (PAS)–positive. There are characteristic genetic alterations that can be observed. Embryonal RMS may have a characteristic loss of heterozygosity at the 11p15 locus. The majority of alveolar RMS have a characteristic t(2;13) resulting in a chimeric PAX3 and FKHR fusion gene product with a smaller percentage having t(1;13) involving PAX7 and FKHR.
B. Sites. The head and neck are involved in 35% of cases, the trunk and extremities in 35%, and the genitourinary tract in 30%.
C. Mode of spread. These tumors have a great tendency to recur locally and to metastasize early through the venous and lymphatic systems. Any organ may be involved with metastases, but the lungs are most frequently affected.
III. DIAGNOSIS
A. Symptoms. The most common presenting symptom is a painless, enlarging mass. Hematuria and urinary tract obstruction are seen with primary tumors of the genitourinary tract. The painless swelling is often noticed after minor trauma that calls attention to the enlarging mass.
B. Physical findings include mass lesions, urinary tract obstruction, and a “cluster of grapes” protruding through the vaginal canal (sarcoma botryoid). Exophthalmos or proptosis occurs with head and neck primaries.
C. Laboratory studies
1. CBC, liver function tests
2. Plain radiographs and MRI or CT scans of involved areas
3. Bone marrow aspiration and biopsy
4. Gallium (and perhaps thallium) scans
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Intergroup rhabdomyosarcoma study staging system
B. Survival and prognostic factors. Survival is closely correlated with stage. The 5-year survival rate with the standard VAC chemotherapy regimen (vincristine, actinomycin D, and cyclophosphamide) is almost 100% for stage I and II disease, >60% for stage III disease, and about 40% for stage IV disease. The overall survival rate is 70%.
V. MANAGEMENT. The treatment of RMS should be aggressive, even with localized disease. Surgery, RT, and chemotherapy should be used for all cases with any residual disease.
A. Surgery should include total excision, if possible, but radical surgery is unnecessary and unwarranted. Lymph node dissection is useful for staging in extremity or genitourinary tract tumors.
B. RT usually consists of 5,000 to 6,000 cGy given over 5 to 6 weeks to the primary tumor site with wide ports to include margins of all dissected tumors.
C. Chemotherapy. The VAC regimen is most commonly given. Studies that compared doxorubicin, etoposide, and ifosfamide with VAC for advanced disease showed no survival advantage, although the combination may be useful in recurrent or resistant disease. Chemotherapy is necessary for patients with the following indications:
1. Adjuvantly with stage I disease
2. With RT for stage II disease
3. To shrink the primary tumor either before or after surgery for stage III and IV disease and continued as adjunctive therapy
EWING SARCOMA AND PRIMITIVE NEUROECTODERMAL TUMOR (EWING FAMILY TUMORS)
I. EPIDEMIOLOGY AND ETIOLOGY. The incidence of Ewing family tumors (EFT), Ewing sarcoma, and primitive neuroectodermal tumor (PNET) is about 1.5 cases per 1 million population. The disease is very rare among black children. Seventy percent of patients are <20 years of age. The peak incidence is at 11 to 12 years of age for girls and 15 to 16 years of age for boys. The male-to-female incidence ratio is 2:1. A reciprocal translocation between chromosomes 11 and 22 in about 85% of tumors creates a chimeric ews-fli1 fusion gene.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. EFT is a small cell tumor of bone or soft tissue characterized by islands of anaplastic, small, round blue cells (see Appendix C4, Section II, for immunophenotypes of small blue cell tumors). The spectrum of EFT includes Ewing sarcoma of bone, extraosseous Ewing sarcoma, and PNET. Ewing sarcoma and PNET carry the same chromosomal translocation.
B. Sites of disease. These tumors occur predominantly in the midshaft of the humerus, femur, tibia, or fibula, but they also occur in the ribs, scapula, pelvis, or extraosseous sites. PNETs in the chest are called Askin tumors.
C. Mode of spread. At the time of diagnosis, 20% to 30% of these tumors have metastasized. Most metastases are to the lung. Metastases to other bones or lymph nodes can also occur. CNS metastases, particularly meningeal, have been reported but are rare.
III. DIAGNOSIS
A. Symptoms. Pain that is followed by localized swelling is the most frequent manifestation.
B. Physical findings include tenderness and a palpable mass over the tumor site.
C. Preliminary laboratory studies may show an elevated erythrocyte sedimentation rate and lytic bone lesions on radiograph (frequently, the lesions have an “onion-skin appearance”). A chest radiograph and CT should be obtained in all patients.
D. Special diagnostic studies
1. Bone scan
2. MRI or CT scans of involved sites
3. Gallium scan
4. Positron emission tomography
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging. The two major stages for Ewing sarcoma and PNET are simply
1. Localized disease
2. Metastatic disease
B. Survival and prognostic factors. Patients with a primary tumor in a central location have a higher incidence of local recurrence and a generally poorer prognosis than do patients with tumors in other primary sites. The prognosis for patients with metastatic disease at the time of diagnosis remains grave; bone metastases have the worst prognosis. High WBC count and fever at diagnosis also are associated with a poor prognosis. The disease-free survival depends on the response to chemotherapy.
V. MANAGEMENT
A. Treatment according to stage of disease
1. Localized disease. All patients with localized disease should receive intensive chemotherapy followed by complete surgical resection, if possible. If resection is not feasible or complete, RT is given. RT is not needed if the tumor can be removed with >1 cm margin.
2. Metastatic disease is treated with intensive chemotherapy followed by surgical resection (if possible) or RT.
B. Chemotherapy involves multiple drugs given in multiple cycles. The most active agents include vincristine, actinomycin D, high-dose cyclophosphamide, doxorubicin, ifosfamide, and etoposide; combinations of these drugs are effective. Carmustine, methotrexate, and bleomycin also have activity against this disease and are useful in combination with the more active agents. The optimal combination of agents is controversial. High-dose chemotherapy with autologous HSCT is often used for consolidation in advanced stage disease with variable success.
C. Surgery. The initial procedure should be biopsy only. Open biopsy is preferred in children. Control of the primary tumor site is essential. Surgery is used in selected patients with localized disease and in patients with bulky metastatic disease. The total removal of tumor is not necessary in instances in which severe disabilities could result. Concerted efforts at limb preservation should be made.
D. RT is aimed at eradicating all disease while preserving limb function. The optimal volume of bone to be irradiated has not been determined.
1. Nonbulky lesions. When combined with chemotherapy, delivering 4,000 to 5,000 cGy of RT to the entire bone with an additional 1,000 to 1,500 cGy coned down to the involved site yields good results.
2. Leg-length discrepancies. In the past, when the probabilities for leg-length discrepancies were excessive (e.g., for younger children with lesions near the knee), patients underwent primary amputation plus chemotherapy. Expandable endoprosthetic reconstruction now makes surgical resection an option for younger children. This regimen usually results in better extremity function than limbs treated with orthovoltage irradiation. Limb-salvage procedures using chemotherapy are also frequently performed when appropriate.
3. Pelvic primaries. Moderate doses of RT (4,000 cGy) with limited surgery are used for pelvic primary tumors because excessive morbidity is associated with large doses of radiation delivered to bowel and bladder. Chemotherapy must be used as well.
RETINOBLASTOMA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Retinoblastoma occurs in about 3 per 1 million children annually. The average age of patients is 18 months, and >90% are <5 years old. The incidence in Asians is four times that in whites. Patients have a high risk for other neoplasms, particularly radiation-induced osteosarcomas that arise in treatment portals.
B. Familial retinoblastoma. About 40% of cases are hereditary. These have bilateral multifocal involvement, early age at diagnosis, secondary tumors, and a positive family history. Siblings have a 10% to 20% chance of developing retinoblastoma if the affected child has bilateral disease and about 1% if unilateral. The offspring of a patient who survived bilateral retinoblastoma have about a 50% chance of developing the disease.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Retinoblastoma is a malignant neuroectodermal tumor. It appears histologically as undifferentiated small cells with deeply stained nuclei and scant cytoplasm. Large cells are sometimes seen forming pseudorosettes, particularly in bone marrow aspirates.
B. Mode of spread. Multiple foci of tumor in the retina are typical at the outset. Most patients die from CNS extension through the optic nerve or widespread hematogenous metastases.
III. DIAGNOSIS
A. Symptoms. The disease typically presents with a “cat’s eye” (white pupil or leukokoria). A squint or strabismus is occasionally noted. Orbital inflammation or proptosis rarely occurs.
B. Physical findings are usually limited to the eye, but patients must have a complete neurologic examination. Ophthalmologic examination under anesthesia is essential for infants and small children, for both those with symptoms and those at high risk for developing the disease. Two pathognomonic features are as follows:
1. The typical pattern of fluffy calcifications in the retinas
2. The presence of vitreous seeding by tumor cells
C. Preliminary laboratory studies
1. CBC, liver function tests
2. MRI or CT scans of head and orbit (both scans performed with contrast)
D. Special diagnostic studies
1. Lumbar puncture with cerebrospinal fluid by cytocentrifuge
2. Bone marrow aspiration and biopsy
3. Serum levels of carcinoembryonic antigen and α-fetoprotein, which are frequently elevated in this disease
4. Urinary catecholamine levels, which are infrequently elevated
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The Reese-Ellsworth classification is most frequently used:
B. Survival and prognostic factors. The prognosis is related to both stage and the interval between discovery of clinical signs and the initiation of treatment. The survival rate is virtually 100% for groups I to IV and 83% to 87% for group V. After disease has invaded the orbit, the mortality rate exceeds 80% despite aggressive chemotherapy.
V. MANAGEMENT
A. Surgery is the primary modality of treatment. Prompt enucleation in unilateral disease and enucleation of the most extensively involved eye in bilateral disease are most commonly employed. Another approach has been to enucleate only those eyes with optic nerve involvement and to treat the remaining disease with RT. When enucleation is performed, as long a segment of the optic nerve as possible should be removed. Chemotherapy, photocoagulation, cryotherapy, and plaque radiotherapy may be used in selected cases.
B. RT is given, in most cases, to either the tumor bed or the nonremoved involved eye. Usually, the dose given is about 3,500 cGy in nine fractions over a 3-week period to the posterior retina. This technique, particularly when using megavoltage irradiation, is used to attempt to spare the anterior chamber and avoid cataract formation; it is unsuitable for tumors at or beyond the midpoint of the eye.
1. Radiocobalt applicators have been used for single lesions or discrete groups of small lesions.
2. RT without surgery is usually reserved for patients with advanced disease in both eyes, residual tumor after surgery, or tumors involving the optic nerve. Most patients should not have RT without surgery.
3. Light coagulation and cryotherapy have been used for discrete lesions, particularly for small recurrences.
C. Chemotherapy is useful for metastatic disease. Adjuvant therapy for localized disease has not been shown to increase longevity. Many chemotherapeutic agents are active (vincristine, actinomycin D, cyclophosphamide, and doxorubicin).
Suggested Reading
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