Rare Pediatric Tumors

Etiology and Epidemiology

Primary malignant liver tumors (PMLT) in children are rare malignancies representing approximately 1% of pediatric cancers. They are composed almost entirely of hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). In people under 20 years of age, 67% of PMLTs are HBL and 31% are HCC. Age-adjusted rates show a very slight male-to-female predisposition for both HBL and HCC. HBL has been associated with prematurity, low birthweight, fetal alcohol syndrome, use of maternal oral contraceptives, Beckwith-Weidmann syndrome, hemihypertrophy, and familial adenomatous polyposis. HCC is strongly associated with hepatitis B virus (HBV) as well as α ₁ -antitrypsin deficiency, hereditary tyrosinemia, extrahepatic biliary atresia, Fanconi anemia, ataxia-telangiectasia, Sotos syndrome, glucose-6-phosphatase deficiency, congenital hepatic fibrosis, Byler disease, and Wilson disease.

Biologic Characteristics and Molecular Biology

There is no familial clustering of HBL, although genetic syndromes are associated with approximately 15% of cases. Familial adenomatous polyposis coli (FAP) with the heritable mutation of the adenomatous polyposis coli (APC) gene has been associated with risk of HBL as have been Beckwith–Wiedemann, Sotos syndrome and Simpson–Golabi–Behmel syndrome. Trisomy 18 has been observed in HBL, particularly in females and patients with multifocal tumor. Other cytogenetic findings in HBL include gains of chromosomes 2, 8, or 20 and loss of 18. Mutations of β-catenin and phosphatidylinositol-3-kinase have been reported in sporadic cases as well as differential expression of imprinted genes and altered methylation of gene promoters.

Hepatitis B virus is associated with nearly all cases of HCC in areas endemic for HBV. Molecular hybridization reveals incorporation of viral DNA into both malignant and adjacent benign liver cells. The time to development of HCC in children after HBV infection is known to be shorter in children than in adults.

Pathology and Pathways of Spread

Hepatoblastoma is an embryonal tumor thought to arise from a hepatocyte precursor cell; it accounts for 60% to 75% of PMLTs of childhood. Two subtypes are recognized—epithelial and mixed—with the epithelial type further divided into fetal, embryonal, macrotrabecular, small-cell undifferentiated (SCU) and cholangioblastic variants. The SCU variant has a particularly poor prognosis and is often viewed distinctly for treatment decisions. Within the mixed type, stromal and teratoid variants are identified. Molecular profiling studies continue to elucidate high-risk subtypes. In addition, these studies are leading toward suggested systemic therapies based on their identified mechanisms.

A strong relationship is seen between HCC and preexistent hepatic disease or cirrhosis. Fibrolamellar HCC is a variant found in approximately one-third of pediatric HCC and typically in cases without preexisting liver disease. This variant has sometimes been reported to have a higher rate of resectability and improved clinical outcome, although this was not supported by results of the Pediatric Intergroup Hepatoma INT-0098 trial.

Clinical Manifestations, Patient Evaluation, and Staging

The majority of children with primary malignant liver tumors present with a painless right upper quadrant abdominal mass. Additional findings may include abdominal enlargement, pain, anorexia with associated weight loss, nausea, emesis, fever, and jaundice.

Initial evaluation consists of abdominal ultrasound with characteristic findings of a solid intrahepatic mass. Subsequent evaluation should include dual phase CT of the abdomen and pelvis and/or axial and coronal MRI with gadolinium at arterial, portal venous, and equilibrium phases. CT of the chest is also required because lung metastases are present in approximately 20% of HBL cases and 30% of HCC cases. Bone scan is reserved for patients who are symptomatic. Laboratory evaluation includes CBC, differential, platelets, urinalysis, electrolytes including calcium, phosphate, magnesium, creatinine, ALT/AST, bilirubin, and total protein/albumin. Alpha-fetoprotein (AFP) is elevated in approximately 90% of patients with HBL and between 60% and 80% of those with HCC. AFP levels less than 100 ng/mL have been associated with poor prognosis.

Primary malignant liver tumors of childhood are typically staged using the Children's Oncology Group Staging system ( Table 86.1 ) and the PRETEXT surgical staging system ( Fig. 86.1 ). The PRETEXT staging is based on the number and relative locations of involved liver segments on preoperative imaging. Staging using the same criteria applied after two to four cycles of chemotherapy is referred to as POST-TEXT. Additional staging notations can be made for involvement of the vena cava or all three hepatic veins (+V), involvement of the portal vein bifurcation or both right and left portal veins (+P) , involvement of the caudate lobe (+C), extrahepatic contiguous tumor (+E), and distant metastatic disease (+M).

Primary and Adjuvant Therapy and Results

Surgical resection is the primary treatment modality for PMLTs of childhood and provides the only potential for cure. Approximately half of patients with HBL are able to undergo complete resection at the time of diagnosis. As HBL is highly chemosensitive, many patients are treated with neoadjuvant chemotherapy, which increases resectability to approximately 75%. Patients with HBL undergoing complete resection have an event-free survival (EFS) of approximately 90%.

The SIOPEL-1 trial reported by the International Society of Paediatric Oncology (SIOP) evaluated the use of four to six courses of preoperative cisplatin and doxorubicin. Of patients, 82% showed at least a partial response and 77% achieved complete resection. The 5-year EFS and overall survival (OS) were 66% and 75%, respectively. SIOPEL-3 randomized patients to cisplatin alone versus cisplatin plus doxorubicin for three cycles preoperatively, followed by two postoperative cycles in children with HBL involving three or fewer liver segments and an alpha-fetoprotein level greater than 100 ng/mL. Outcomes at 3 years were identical: 95% and 93% underwent complete resection in the respective chemotherapy arms, and OS was 95% and 93%, respectively. Grade 3 and 4 toxicities were significantly more common in the combination arm.

An analysis of stage I pure fetal histology HBL treated with complete surgical resection only on Children's Oncology Group Study P9645 showed all patients free of disease at a median follow-up of 4.9 years.

Children with HCC on the SIOPEL-1 trial presented with more advanced disease and fared significantly worse than patients with HBL. Partial response to neoadjuvant chemotherapy was seen in 49%, and complete resection was achieved in only 36%; 5-year OS and event-free survival were 28% and 17%, respectively. The Pediatric Intergroup Hepatoma Protocol INT-0098 randomized patients with HCC to postoperative cisplatin/vincristine/5-fluorouracil versus cisplatin and doxorubicin. There was no difference in outcome between the treatment regimens, and the overall 5-year EFS was 17% (75% for stage I, 8% for stage II, and 0% for stage IV). Subsequent SIOPEL studies evaluated a regimen of cisplatin and carboplatin, with no substantial improvement in outcome.

The current Children's Oncology Group (COG) study reduces chemotherapy for low-risk patients with stage I non-pure fetal histology, non-SCU HBL or stage II non-SCU HBL to two adjuvant cycles of cisplatin, 5-flouorouracil and vincristine (C5V). Intermediate-risk cases with stage I SCU, stage II SCU, or any stage III are given six cycles of C5V + doxorubicin (C5VD).

Locally Advanced Disease and Palliation

Patients with high-risk HBL include those patients with stage IV disease as well as patients with any stage of HBL, or initial AFP under 100 ng/mL. The Pediatric Oncology Group study 9345 treated children with nonresectable or metastatic HBL with neoadjuvant carboplatin and carboplatin/vincristine/5-fluorouracil, followed by surgery when feasible, or with high-dose cisplatin and etoposide. Of patients, 36% with stage IV disease were able to undergo subsequent resection. For patients able to undergo resection, 5- years EFS was 79%. The recent SIOPEL-4 trial was a single arm prospective study for high-risk HBL using neoadjuvant dose-dense cisplatin plus doxorubicin. This approach yielded very good outcomes, with 74% of children able to undergo complete resection and an 83% 3-year OS. Other approaches include orthotopic liver transplantation when disease is nonresectable, with documented long-term survival in a limited number of patients.

The approach for patients with metastatic disease uses neoadjuvant chemotherapy followed by surgery, if possible, and consideration of metastectomy if local control is achievable. For patients considered for orthotopic liver transplantation, radiographic clearance of metastatic disease must be confirmed prior to transplant.

Irradiation Techniques

Radiotherapy is infrequently used in the treatment of PMLTs. Habrand et al. used doses of 25 Gy to 45 Gy in conjunction with chemotherapy in a heterogeneous group of 15 patients; 11 with documented HBL, 2 with HCC, and 2 with unknown pathology. Those with inoperable HBL or minimal (< 2 cm) disease postoperatively showed a possible benefit of radiotherapy. No benefit was seen for patients with HCC. There are few current indications for hepatic irradiation or treatment beyond palliation to metastatic sites with HBL or HCC. The current Children's Oncology Group HBL study specifically excludes use of RT. It is clear that the radiotherapy dose ranges noted above are less than those now known to be necessary in adults with HCC. Modern techniques of respiratory gating and stereotactic techniques may provide for additional options for radiotherapy of pediatric liver tumors in select cases. In addition, experiences with particle therapy and stereotactic body radiotherapy in the treatment of adult HCC have increased in recent years ( Fig. 86.2 ). Although no randomized trials exist, the outcomes appear favorable to conventional radiotherapy. This therapy in the pediatric populations warrants further study in the inoperable setting.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

The cornerstone of treatment for PMLTs is surgical resection. Most children are treated with neoadjuvant and adjuvant platinum-based chemotherapy because of bulky disease. Orthotopic liver transplantation can provide cures for selected patients in whom resection is not possible. Investigational treatments for HBL include chemoembolization, stereotactic radiosurgery to focal liver lesions, angiogenesis inhibitors, and biologic agents.

Etiology and Epidemiology

Juvenile nasopharyngeal angiofibroma (JNA) is a highly vascular tumor that is histologically benign but locally invasive. JNA occurs almost exclusively in adolescent boys and young adult men, suggesting a prominent hormonal role in the tumor's etiology; the average age at diagnosis is 17 years. The incidence of this tumor is approximately 3.7 per million in the population at risk and there is evidence that this incidence has been increasing in recent years. An increased incidence of JNA is seen in patients with familial adenomatous polyposis, consistent with an upregulation of the beta-catenin expression that has been reported in many patients.

Biologic Characteristics and Molecular Biology

Up-regulation of beta-catenin expression is seen in up to 70% of cases, but appears to be limited almost exclusively to patients under the age of 18 years. Increased expression of c-myc, vascular endothelial growth factor (VEGFA), basic fibroblastic growth factor (bFGF), platlet-dervied growth factor subunit A (PDGFA), c-kit, H-Ras, and TP53 have also been reported. The angiogenesis-promoting factor, tenascin-C, has been found to correlate with blood vessel density and tumor stage in JNA and may play a role in tumorigenesis. Most tumors stain for VEGFA, and approximately 40% have a GSTM1 mutation. Increased IL-17 expression has been correlated with increased risk of tumor recurrence.

Both androgen and estrogen receptor expression have been demonstrated in JNAs. Estrogen beta-adrenergic receptors have also been found in a high percentage of JNAs. Schlauder et al. have postulated that the presence of aromatase in tumor cells converts endogenous androgens to estrogens. This could cause tumor growth via an autocrine-like mechanism.

Pathology and Pathways of Spread

Juvenile nasopharyngeal angiofibroma is a benign tumor, although its exact nature is controversial. Some have suggested that it is a vascular hamartoma and similar to a hemangioma, but others believe it is neoplastic. Histologically, tumors are composed of fibrous connective tissue with abundant endothelium-lined vascular spaces. Localization of β-catenin to tumor stromal cells suggests these may be the neoplastic component rather than the endothelial cells. Tumors typically arise from the superior margin of the sphenopalatine foramen and invade laterally through the pterygomaxillary fissure toward the infratemporal fossa. Intracranial extension is seen in up to a third of cases, although actual dural invasion is uncommon. Tumors can be locally invasive of bone and extend into the parapharyngeal spaces, paranasal sinuses, orbit, and skull base. This pattern of spread predicts for a high risk of local recurrence. Blood supply is primarily from the internal maxillary arteries of the external carotid system.

Clinical Manifestations, Patient Evaluation, and Staging

Presenting symptoms include recurrent painless spontaneous epistaxis, nasal obstruction, nasal discharge, a reduced sense of smell, snoring, headache, cranial nerve palsies, and facial swelling. Angiography is essential to define the tumor's blood supply for planning surgery and, typically, for preoperative embolization to decrease surgical blood loss. There are usually multiple tortuous feeding vessels with a dense, homogeneous blush in the capillary phase. CT and MRI help define the anatomic extent of the enhancing tumor. Distant metastases do not occur, so systemic evaluation is not required. Biopsy can be hazardous owing to the tumor's vascularity; not all authors suggest biopsy confirmation before treatment if clinical and radiographic data are consistent with the diagnosis.

Several staging systems have been proposed ( Table 86.2 ). Most are designed to guide decisions regarding the resectability and optimal surgical approach to the tumor rather than to predict prognosis.

Primary and Adjuvant Therapy and Results

Surgical removal, often preceded by tumor embolization, is the primary treatment for JNA. A craniofacial approach is used for locally advanced tumors. Endoscopic techniques have less morbidity and are effective for earlier-stage lesions. Gross total removal is usually curative. A number of cases prove not to be amenable to complete resection; depending on case selection, the rate of local recurrence after surgery is approximately 20% to 40%, with most recurrences occurring in large, incompletely resected lesions. Moderate doses of RT may be indicated for postoperative residual tumor, although observation is more often considered because spontaneous involution of tumor is a well-recognized phenomenon. Most recurrences present within a year of surgery. The risk of recurrence is greatest in patients with large tumors that erode the skull base, young age at presentation, and irradiated tumors that are slow to regress. Currently no indications exist for adjuvant chemotherapy after initial resection.

Locally Advanced Disease and Palliation

Radiotherapy can provide effective control for recurrent or large, nonresectable tumors. Objective tumor response after RT is typically slow, but ultimate control rates range from 71% to 92% ; 90% of responders have no residual tumor 3 years after treatment. Given the strong association of JNA with hormonal receptors, there has been interest in hormonal manipulation for patients with advanced disease. Diethylstilbestrol and flutamide have been used, but results have been inconsistent. A prospective trial supported the use of flutamide in postpubertal patients with 13 of 15 patients showing a partial radiographic response to this agent. Case reports of chemotherapy for recurrent tumor show efficacy for doxorubicin, dactinomycin, vincristine, cyclophosphamide, and cisplatin in selected patients.

Techniques of Irradiation

Local control rates greater than 80% are seen with doses ranging from 30 Gy to 50 Gy, and a dose of 36 Gy is commonly used. One series reported improved local control of 91% when a dose of 35 Gy to 36 Gy was used, compared with local control of 77% for 30 Gy to 32 Gy. Intensity-modulated RT (IMRT) techniques provide high conformality for sparing of normal structures ( Fig. 86.3 ). Stereotactic radiosurgery using single doses of 17 Gy to 20 Gy and hypofractionated RT using 45 Gy in three fractions have been reported effective in a small series of patients.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Preoperative embolization is followed by maximal surgical resection. Postoperative residual tumor can be observed or treated with RT. Recurrent tumor can be managed with RT. Hormonal manipulation and cytotoxic chemotherapy may be tried for recurrent, refractory disease. The elevated levels of vascular endothelial growth factors in these tumors also suggests a potential role for inhibitors of angiogenesis.

Etiology and Epidemiology

Pleuropulmonary blastoma (PPB) is a dysontogenetic neoplasm of childhood that originates in the lung and/or pleura. Although rare, it is the most common primary lung tumor in children. It is analogous to other dysontogenetic tumors such as Wilms tumor, neuroblastoma, and hepatoblastoma.

Pleuropulmonary blastoma is thought to progress through a distinct sequence of clinical and pathologic changes beginning as a relatively nonaggressive cystic lesion and subsequently developing into the more malignant mixed cystic/solid and purely solid morphologies. Median age at presentation is 3 years. Younger children typically present with predominantly cystic tumors, whereas older children are more likely to have significant solid components. Boys and girls are equally affected. Siblings of patients with PPB have a higher incidence of PPB than the general population, and mutations in DICER1 have been found in many of these families. An increased incidence of other types of dysplasia and neoplasia is also seen in relatives of children with PPB, and siblings and first-degree relatives of patients should be screened for associated pulmonary and extrapulmonary benign and malignant conditions.

Prevention and Early Detection

All children with known DICER1 mutations should undergo chest x-ray screening at an early age for PPB, as well as screening for other DICER1-associated neoplasms. The incidence of PPB in apparently benign lung lesions such as congenital cystic adenomatoid malformations is approximately 4%. However, cystic PPB is clinically indistinguishable from benign cysts, and some authors recommend excision of all such lesions. Further supporting this approach is evidence that PPB can arise de novo from lung cysts, so that resection of these “precancerous” lesions is indicated. Others advocate a policy of watchful waiting for purely cystic lesions, only intervening if radiographic changes suggest progression.

Biologic Characteristics and Molecular Biology

Over 70% of patients with PPB have an autosomal-dominant germline mutation of DICER1 , a gene coding for an endoribonuclease involved in regulation of mesenchymal proliferation, and a second, tumor-specific DICER1 missense mutation in the RNase IIIb domain leading to deregulation of numerous target messenger RNAs. TP53 mutations have been described in PPB and may portend a worse prognosis. Polysomy of chromosome 8 has also been noted.