Etiology and Epidemiology

Primary malignant liver tumors (PMLTs) of childhood are very rare malignancies, comprising between 0.5% and 2% of pediatric tumors.¹ The incidence in the United States is approximately 1.6 per million.² The most common forms are hepatoblastoma (HBL) and hepatocellular carcinoma (HCC), but benign vascular tumors, mesenchymal hamartomas, adenomas, nodular hyperplasia, and hepatobiliary tumors are reported as well.¹ The median age at presentation for HBL is 1 year, and it predominates in males with a ratio of 1.5 : 1. HCC presents at a median age of 12 and is more prevalent in males with ratios varying from 2 : 1 to 11 : 1.

HBL has been associated with prematurity, low birth weight, Beckwith-Wiedemann syndrome, familial adenomatous polyposis, maternal ingestion of oral contraceptives, and fetal alcohol syndrome.³ HCC has a strong association with hepatitis B virus (HBV) and is also associated with α₁-antitrypsin deficiency, hereditary tyrosinemia, extrahepatic biliary atresia, Fanconi anemia, ataxia-telangiectasia, Sotos syndrome, and glucose-6-phosphatase deficiency.

Biologic Characteristics and Molecular Biology

HBL can be associated with several genetic aberrations. These include Beckwith-Wiedemann syndrome, most prominently, with loss of heterozygosity (LOH) at 11p15, as well as familial adenomatous polyposis and Li-Fraumeni syndrome. The most common chromosome aberrations are extra copies of 1q, 2q, 7q, 8, 17q, and 20. LOH of 11p15 is seen in a third of patients with HBL, and LOH of chromosome 1p is seen in an additional third.³ Mutations of β-catenin and activation of Wnt/β-catenin signaling have been associated with HBL. Wilms’ tumor and rhabdomyosarcoma have also been associated with HBL.

Time to development of HCC after HBV infection is much shorter in children than in adults. Molecular hybridization reveals incorporation of viral DNA into both malignant and adjacent benign liver cells.

Pathology and Patterns of Spread

HBL is the most common PMLT of childhood, representing 60% to 75% of cases.³ The most widely used classification system was proposed by Ishak and Glunz.³ It distinguishes two forms of HBL, the epithelial type and the mixed type. The epithelial type encompasses a poorly differentiated embryonal type and a highly differentiated fetal type. The pure fetal hepatoblastoma (PFH) has normal hepatocytes with rare mitoses and is associated with a favorable prognosis. Mixed-type HBL contains both epithelial elements and mesenchymal tissue. The small cell undifferentiated (or anaplastic) histologic subtype of epithelial HBL has a very poor prognosis.

HCC accounts for 25% to 40% of childhood PMLTs. There is a strong relationship with preexistent hepatic disease or cirrhosis. HCC is divided into traditional HCC and a fibrolamellar histologic variant. The fibrolamellar variant tends to occur in noncirrhotic livers of adolescents and is characterized by large polygonal neoplastic cells with lamellar collagen bundles. Historically, this variant was thought to have a higher resection rate and superior outcome compared with traditional HCC. However, a report from the Pediatric Intergroup Hepatoma Protocol INT-0098 found that fibrolamellar histology was not associated with superior response to standard therapies or prognosis.⁵

Clinical Manifestations, Patient Evaluation, and Staging

Most children with PMLTs present with a painless right upper quadrant mass. Generalized abdominal enlargement, right upper quadrant pain, fever, anorexia, vomiting, weight loss, and jaundice also may be noted.

Workup begins with an ultrasound evaluation of the abdomen, which typically reveals a solid hepatic mass. Magnetic resonance imaging (MRI) and computed tomography (CT) are useful to delineate the mass, its vascularity, and the potential for resection. Surgeons may require an angiogram to evaluate the hepatic arteries before determination of resectability. Imaging of the chest with CT should be performed; lung metastases are apparent at diagnosis in 20% of children with HBL and 30% of children with HCC.^6–8 Laboratory evaluation includes routine chemistries as well as determination of the serum alpha-fetoprotein level, which is elevated in over 90% of children with HBL and 60% to 80% of children with HCC.^1,3,7–9 An alpha-fetoprotein value less than 100 ng/mL is associated with a poor prognosis.

The most common staging systems for PMLT are the PRETEXT presurgical system and the Children’s Oncology Group postoperative system (Table 73-1). The PRETEXT system (Fig. 73-1) was created in 1990 by the International Society of Pediatric Oncology Liver Study Group (SIOPEL) and is based on preoperative imaging and the number of affected liver segments.⁶

TABLE 73-1 Children’s Oncology Group Staging System for Hepatoblastoma

From Schnater JM, Kohler SE, Lamers WH, et al: Where do we stand with hepatoblastoma? A review. Cancer 98:668-678, 2003.

Figure 73-1 PRETEXT staging system for hepatoblastoma.

Adapted from Schnater JM, Aronson DC, Plaschkes J, et al: Surgical view of the treatment of patients with hepatoblastoma. Results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Cancer 94:1111-1120, 2001.

Primary and Adjuvant Therapy and Results

Surgical resection is the primary treatment modality for PMLTs of childhood and provides the only potential for cure. HBL is also highly chemosensitive, and most patients are treated with neoadjuvant preoperative chemotherapy. The primary rationale for preoperative therapy is to increase the complete resection rate and decrease surgical morbidity.

The SIOPEL-1 trial reported by the International Society of Paediatric Oncology (SIOP) tested four to six courses of preoperative cisplatin and doxorubicin. Eighty-two percent of patients showed at least a partial response based on imaging and alpha-fetoprotein levels; 83% underwent delayed surgery, and in 77% of cases surgery achieved complete resection. The 5-year event-free survival and overall survival (OS), were 66% and 75%, respectively.⁸ The SIOPEL-3 trial compared cisplatin alone with cisplatin plus doxorubicin for three cycles preoperatively, followed by two postoperative cycles in children with HBL involving three or fewer liver segments with an alpha-fetoprotein level less 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.¹⁰

Children with HCC on the SIOPEL-1 trial tended to have more advanced disease at presentation and fared significantly worse than patients with HBL. Partial response was seen in 49%, and complete resection was achieved in only 36%; 5-year OS and event-free survival were 28% and 17%, respectively.⁷ 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 results between the treatment regimens, and the overall 5-year event-free survival was 17% (75% for stage I, 8% for stage II, and 0% for stage IV).⁵ Subsequent SIOPEL studies evaluated a regimen of cisplatin and carboplatin, with no substantial improvement in outcome.⁷

The current Children’s Oncology Group HBL trial is testing surgery alone for resected tumors with pure fetal histology. Other “low-risk” presentations (resected, no small cell undifferentiated component, alpha-fetoprotein >100 ng/mL) receive postoperative cyclophosphamide, 5-FU, and vincristine. “Intermediate-risk” cases (gross residual, localized with small cell undifferentiated histology, alpha-fetoprotein >100 ng/mL) are testing the addition of doxorubicin to the just-mentioned regimen.

Locally Advanced Disease and Palliation

Children with locally advanced and metastatic disease are treated with aggressive preoperative chemotherapy followed by surgery if possible. Pediatric Oncology Group study 9345 evaluated children with unresectable or metastatic HBL. Neoadjuvant therapy with carboplatin and carboplatin/vincristine/5-fluorouracil was followed by surgery when feasible or with high-dose cisplatin and etoposide. Resection was possible in 68% of patients with stage III disease and 36% of patients with stage IV disease; the 5-year event-free survival for the small number of children achieving resection was 79%.¹¹ Current approaches include orthotopic liver transplantation when disease is unresectable, with documented long-term survival in a limited number of patients.^6,11 The ongoing Children’s Oncology Group trial for locally advanced disease was highlighted previously; for “high-risk” patients with metastatic tumor or alpha-fetoprotein value less than 100 ng/mL, a national trial is testing the addition of irinotecan.

Metastatic disease is treated with systemic therapy followed by resection when possible. If local control can be achieved, metastasectomy is recommended. In rare patients with unresectable primary tumors, response to chemotherapy, and complete removal of pulmonary metastases, the SIOPEL-1 trial showed a limited number of children were long-term survivors.⁶

Irradiation Techniques

RT is not routinely used for PMLTs. An earlier series of 15 children with incompletely resected disease reported outcome after preoperative or postoperative irradiation.⁴ Doses ranged from 25 to 40 Gy in conjunction with chemotherapy. Six of eight patients treated postoperatively were disease free at 4 to 83 months, and one of four children with preoperative irradiation had histologic tumor control. The current Children’s Oncology Group HBL study specifically excludes use of RT. There are few current indications for hepatic irradiation or treatment beyond palliation to metastatic sites with HBL or HCC. RT has several technical challenges. Future attempts to incorporate RT for PMLTs in children would need to take advantage of modern radiotherapy techniques, including respiratory gating, given the critical organs surrounding the liver and the impact of combined therapeutic approaches.¹²

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

The cornerstone to treatment for PMLTs is surgical resection, although most children are treated with neoadjuvant and adjuvant platinum-based chemotherapy because of the bulk of disease. Orthotopic liver transplantation can provide long-term cures for patients in whom resection is not possible. Investigational treatments for HBL include chemoembolization for unresectable disease, angiogenesis inhibitors, and biologic agents.

Etiology and Epidemiology

Germ cell tumors (GCTs) are rare tumors in childhood, accounting for approximately 3% of pediatric malignancies.^13–15 Teilium has described these tumors as arising from primordial germ cells that escape normal developmental influences. In the embryo, germ cells migrate from the allantoic stalk to the genital ridge and finally to the appropriate genital site. Therefore, GCTs can be found in the ovary or testis and aberrant migration accounts for the location of these tumors in midline structures such as the sacrococcygeal region, retroperitoneum, mediastinum, and pineal gland.

GCTs are more common in females than males.¹⁶ They have a bimodal age distribution, with extragonadal and testicular tumors occurring most frequently in children younger than 3 years old and gonadal tumors occurring most commonly in pubertal adolescents.

Prevention and Early Detection

GCTs are associated with intersex disorders, including pseudohermaphroditism, androgen insensitivity, and 5α-reductase deficiency. Undescended testis is highly associated with an increased risk of testicular malignancy, with the highest risk occurring in the intra-abdominal testis. This risk approaches 30 to 50 times the normal incidence of testicular cancer and can occur in either testis.¹⁴

Biologic Characteristics and Molecular Biology

Chromosomal abnormalities are common in malignant GCTs. The most frequent is isochromosome 12p [i(12p), which occurs in 75% to 80% of malignant ovarian or testicular GCTs]; other aberrations include loss of chromosome 13 and gain of chromosomes 21, 8, or 1q.¹⁷

Pathology and Pathways of Spread

GCTs span a spectrum of entities from benign to malignant, with elements of multiple histologic types in 25% of cases.¹⁶ The most common pediatric GCT is the teratoma, which is composed of tissue from more than one embryonic layer. Teratomas can be either mature, consisting of well-differentiated tissues, or immature, consisting of immature elements (most commonly neuroepithelial tissue).

Yolk sac or endodermal sinus tumors are highly malignant, occur most commonly in the ovary, testis, and sacrococcygeal region, and secrete alpha-fetoprotein. Histologically they show classic perivascular formations called Schiller-Duval bodies. Embryonal carcinomas are composed of large, pleomorphic undifferentiated cells. They often occur in combination with endodermal sinus tumors. Choriocarcinomas are rare tumors composed of malignant cytotrophoblasts and syncytiotrophoblasts. They typically secrete beta–human chorionic gonadotropin. All three of these GCT types are highly undifferentiated tumors with the propensity to metastasize to lung, liver, bone, and lymph nodes. In a series of 95 patients with sacrococcygeal endodermal sinus tumors,¹⁶ 15% had positive lymph nodes at diagnosis and 35% had distant metastases.

Tumors of undifferentiated germ epithelium are named according to the site of origin: seminomas originate in the testis, dysgerminoma in the ovary, and germinoma in the brain. Seminoma and dysgerminoma are infrequent in childhood.

Clinical Manifestations, Patient Evaluation, and Staging

The most common location for pediatric GCTs is the sacrococcygeal region, followed by the ovary, testis, and mediastinum. Unusual locations include the retroperitoneum, neck, stomach, and vagina. Sacrococcygeal tumors are classified according to Altman’s classification. Type I are predominately external, and type IV are entirely presacral. Neonates typically present with large, external, protruding sacral masses, which are commonly benign teratomas. Older children more commonly present with large pelvic masses, with malignant degeneration commonly apparent in children older than age 6 to 12 months.¹⁴

Clinical symptoms depend on the primary site. Ovarian tumors present as abdominal pain, gastrointestinal symptoms, and/or a palpable mass. Testicular tumors typically present as a painless testicular mass. Sacrococcygeal tumors can present in neonates or in utero on ultrasound examination as a large protruding mass from the sacral region; in infants and older children, the degree of the external extent of the tumor is less, because children typically present with a palpable abdominal mass and symptoms due to compression of the bladder or rectum. Mediastinal masses most often present as cough, dyspnea, or superior vena cava syndrome.

Initial evaluation should include a careful history and physical examination. Laboratory studies should include a complete blood cell count, renal and hepatic function tests, and evaluation of alpha-fetoprotein, beta–human chorionic gonadotropin, and lactate dehydrogenase levels; determination of CA-125 may also be of value, especially in sacrococcygeal teratomas. Tumor marker profiles for different histologies are listed in Table 73-2. Imaging includes ultrasonography of the primary site, CT of the abdomen and pelvis to evaluate for lymphadenopathy and resectability as appropriate, and CT of the chest to evaluate for metastatic disease. For secreting tumors, primary resection may be performed for both diagnosis and treatment if it is deemed that a complete resection can be performed. In nonsecreting and unresectable tumors, an open biopsy should be performed before starting definitive therapy.

GCTs are staged according to the site of origin using the Children’s Cancer Group and Pediatric Oncology Group staging system. The staging systems for ovarian, testicular, and extragonadal sites are outlined in Table 73-3.

TABLE 73-3 Children’s Cancer Group and Pediatric Oncology Group Staging System for Pediatric Germ Cell Tumors

Primary Therapy, Adjuvant Therapy, and Results

Primary therapy is dependent on the histologic subtype and tumor resectability. For most malignant tumors a multidisciplinary approach combining surgery and cisplatin-based chemotherapy (often similar to the adult PEB regimen of cisplatin, etoposide, and bleomycin) is standard.

The optimal surgery for ovarian tumors has been debated, and historically principles of resection were based on the adult epithelial ovarian tumor experience. Recently the Children’s Oncology Group reported a series of children with ovarian GCTs who underwent conservative surgical resection and platinum-based chemotherapy; the 6-year survival rate approximated 95%. These researchers concluded that surgical guidelines should be changed to favor a more conservative approach including collection of ascites; examination and palpation of peritoneal surfaces, retroperitoneal lymph nodes, omentum, and the contralateral ovary with biopsy or excision of suspicious nodules; and complete resection of the ipsilateral tumor with potential sparing of a normal fallopian tube.¹⁸

Surgery for testicular tumors should be performed through a high inguinal incision with occlusion of the vessels at the inguinal ring. If frozen section reveals a teratoma, surgery can be limited to enucleation alone. For malignant lesions, a high inguinal orchiectomy is standard.

Sacrococcygeal tumors are often resected using an inverted-V incision to spare the levator ani muscle and external sphincter. The entire coccyx must be resected because local recurrences of up to 37% are reported with inadequate surgery.¹⁵

Adjuvant therapy is based on the stage, degree of resection, and histologic subtype (Table 73-4). Currently there is no indication for adjuvant chemotherapy in mature or immature teratomas, and these patients are followed with close observation after surgery. Reported survival with surgery alone varies in the literature from 82% to 100%.¹⁴ In the Pediatric Oncology Group 9048/CCG 8891 trial, children with extracranial immature teratomas (32% with a malignant element) were treated with surgery alone with a 3-year overall event-free survival of 93%. Four of five patients with recurrence were disease free after platinum-based salvage chemotherapy.¹⁹

TABLE 73-4 General Treatment Guidelines for Extracranial Germ Cell Tumors

There has been dramatic improvement in survival for children with stage II or greater malignant GCTs with the addition of cisplatin-based chemotherapy. The most commonly used regimen is PEB (cisplatin/etoposide/bleomycin). Using this regimen, OS has increased to more than 80% for all stages of GCTs.16,18,20,21

Locally Advanced Disease and Palliation

Bulky, locally invasive, and metastatic disease require treatment with neoadjuvant chemotherapy followed by second-look surgery; additional chemotherapy is utilized for residual tumor at the time of surgery. Even in this setting the OS is excellent owing to the chemosensitivity of these tumors. For high-risk patients, a high-dose PEB regimen (HDPEB) has been compared with standard-dose PEB. The Pediatric Oncology Group 9040/CCG 8882 trial²⁰ randomized patients with stage III and IV gonadal and stage I to IV extragonadal GCTs to HDPEB versus PEB, reporting 6-year event-free survival of 89.6% versus 80.5% but no benefit in OS; there were more toxic deaths in the high-dose arm of the trial. Surgery for metastatic foci is usually not indicated because these foci tend to respond to chemotherapy. For relapsed or refractory tumors, chemotherapy with ifosfamide added to platinum and etoposide is recommended.

Irradiation Techniques

The role of RT for GCTs has diminished significantly owing to the effectiveness of current chemotherapy regimens. Historically, RT was used in conjunction with surgery and chemotherapy, with OS rates in the range of 48% to 62%.^13,22,23 Seminomas and dysgerminomas were often cured with limited surgery and RT. Currently, the role of RT is limited to cases with unresectable, refractory, or recurrent disease unresponsive to chemotherapy. Classically, disease control for malignant GCTs has required radiation doses of 40 to 45 Gy or more for residual disease or disease that is resistant to chemotherapy.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Treatment is based on tumor site, type, and grade and is detailed in Table 73-4. Surgical resection is necessary for local control and is preceded and/or followed by PEB chemotherapy. In patients with locally advanced or metastatic disease, survival still approaches 75% owing to the sensitivity of these tumors to platinum-based chemotherapy. With the high curability of these tumors, current protocols are using risk-adapted algorithms based on histology, site, stage, and genetic aberrations to decrease toxicity associated with chemotherapy.

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.24,25 There is an increased incidence of JNA in patients with familial adenomatous polyposis, suggesting a connection to the β-catenin pathway.²⁶

Biologic Characteristics and Molecular Biology I

Both androgen and estrogen receptors have been demonstrated in JNAs.27,28 Recently, estrogen beta-adrenergic receptors have been found in a high percentage of JNAs. Schlauder and associates²⁸ have postulated that the presence of aromatase in tumor cells converts endogenous androgens to estrogens, causing tumor growth via an autocrine-like mechanism.²⁹ Most tumors stain for vascular endothelial growth factor.³⁰

Pathology and Pathways of Spread

JNA is a benign tumor, although its exact nature is controversial. Some have suggested that it is a vascular hamartoma and similar to a hemangioma,³¹ but others believe it is neoplastic.³² Histologically, tumors are composed of fibrous connective tissue with abundant endothelium-lined vascular spaces.³¹ Localization of β-catenin to tumor stromal cells suggests these may be the neoplastic component rather than the endothelial cells.³³ Tumors typically arise from the superior margin of the sphenopalatine foramen and invade laterally through the pterygomaxillary fissure toward the infratemporal fossa.²⁴ Intracranial extension is seen in up to a third of cases, although actual dural invasion is uncommon.^34,35 Tumors can be locally invasive of bone and extend into the parapharyngeal spaces, paranasal sinuses, orbit, and base of skull. This pattern of spread predicts for a high risk of local recurrence.³⁵ 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.²⁵ 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.³⁶ 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 require biopsy confirmation before treatment if clinical and radiographic data are consistent with the diagnosis.³⁷

Several staging systems have been proposed (Table 73-5). Most are designed to guide decisions regarding the resectability and optimal surgical approach to the tumor rather than to predict prognosis.^37,38–41

TABLE 73-5 Staging Systems for Juvenile Nasopharyngeal Angiofibroma

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.²⁴ Gross total removal is usually curative.³⁴ A number of cases prove not to be amenable to complete resection; depending on case selection, there is a rate of local recurrence after surgery that approximates 20% to 40%, with most recurrences occurring in large, incompletely resected lesions.^24,25 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.^42,43 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.^36,44 There are currently no indications for adjuvant chemotherapy after initial resection.

Locally Advanced Disease and Palliation

RT can provide effective control for recurrent or large, unresectable tumors. Objective tumor response after RT is typically slow, but ultimate control rates range from 75% to 92%^45–48; 90% of responders have no residual tumor 3 years after treatment.⁴⁹ 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.^36,50,51 Case reports of chemotherapy for recurrent tumor show efficacy for doxorubicin, dactinomycin, vincristine, cyclophosphamide, and cisplatin in selected patients.^52,53,54

Techniques of Irradiation

No radiation dose-response curve has been reported for JNA. Local control rates greater than 80% are seen with doses ranging from 30 to 50 Gy,37,55,56–59 and a dose 36 Gy is commonly used. Intensity-modulated RT (IMRT) techniques provide high conformality for sparing of normal structures (Fig. 73-2). Stereotactic radiosurgery using single doses of 17 to 20 Gy and hypofractionated RT using 45 Gy in three fractions have been reported effective in small series of patients.^60–62

Figure 73-2 IMRT isodose plan for a patient with juvenile nasopharyngeal angiofibroma.

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.

Etiology and Epidemiology

Pleuropulmonary blastoma (PPB) is a dysontogenetic neoplasm of childhood that originates in the lung and/or pleura.⁶³ Although rare, it is the most common primary lung tumor in children.⁶⁴ It is analogous to other dysontogenetic tumors such as Wilms’ tumor, neuroblastoma, and hepatoblastoma.⁶⁵

PPB 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.⁶⁶ Median age at presentation is 3 years.⁶⁷ Younger children typically present with predominantly cystic tumors, whereas older children are more likely to have significant solid components.⁶⁸ Boys and girls are equally affected.⁶⁸ Siblings of patients with PPB have a higher incidence of PPB than the general population, although a genetic cause has not yet been found.⁶⁹ There is also an increased incidence of other types of dysplasia and neoplasia in relatives of children with PPB.^70,71

Prevention and Early Detection

Cystic PPB is clinically indistinguishable from benign lung cysts, and some authors recommend excision of all such lesions.⁶⁹ Further supporting this approach is evidence that PPB can arise de novo from lung cysts, so that resection of these “precancerous” lesions is indicated.^72,73 Others advocate a policy of watchful waiting for purely cystic lesions, only intervening if radiographic changes suggest progression.

Biologic Characteristics and Molecular Biology

TP53 mutations have been described in PPB and may portend a worse prognosis.⁷⁴ Polysomy of chromosome 8 has also been noted.⁷⁵

Pathology and Pathways of Spread

Histologically, PPB has small, primitive blastemal cells separated by an uncommitted sarcomatous stroma.65,68,76 Tumor cells stain with vimentin and may show myogenic differentiation.⁶⁴ Rhabdomyoblasts and cartilage nodules are reported in 40% to 50% of patients.⁶⁹

Tumors usually arise in the lung parenchyma. Spread to contiguous structures such as the mediastinum and pleura is associated with a poorer prognosis. Invasion into the chest wall is uncommon.⁷⁷ Hematogenous metastases occur, most often to the brain. In one series,⁶³ the incidence of brain metastases was 11% in mixed cystic/solid tumors and 54% in purely solid tumors.

Clinical Manifestations, Patient Evaluation, and Staging

Presenting symptoms of PPB include cough, dyspnea, wheezing, symptoms of respiratory infection, and, occasionally, spontaneous pneumothorax. Chest CT usually reveals a heterogeneous low-attenuation mass with pleural effusion and mediastinal shift.⁷⁷ Differential diagnosis includes rhabdomyosarcoma, Askin tumor, and nonrhabdoid sarcomas; examination of the cystic fluid or solid tumor is required to make a diagnosis. Bone scintigraphy and MRI of the brain should be performed for staging, especially for tumors with a significant solid component.

PPB has no anatomic staging system but is classified into three morphologic types that have prognostic significance. Type I consists of purely cystic tumors, type III lesions are solid tumors, and type II have mixed cystic and solid components.⁷⁰ Both type II and type III tumors have significantly poorer prognosis than type I, with an incidence of distant metastases at diagnosis approximating 30%.⁶⁷ Recently, a fourth type, type Ir (type I—regressed), has been described for cystic lesions without a neoplastic component, hypothesized to have “regressed” from an earlier type I PPB or, alternatively, represent a genetically determined lung cyst that has not yet evolved along a dysplastic path.⁷⁸

Primary and Adjuvant Therapy and Results

Surgery is the cornerstone of management, although most patients cannot undergo gross total resections owing to involvement of critical structures.^67,76 Neoadjuvant chemotherapy can be used in large tumors to render the tumor resectable; adjuvant chemotherapy is often given postoperatively to patients with type II and III tumors. Chemotherapy may improve survival in type I tumors,^66,78 although it is not widely recommended if the tumor is completely resected.⁶⁷ Drug regimens parallel those used for other pediatric sarcomas and include ifosfamide/carboplatin/etoposide (ICE regimen), and ifosfamide/vincristine/dactinomycin (Actinomycin-D)/doxorubicin (IVADo regimen). Other active drugs include irinotecan⁷⁹ and cisplatin.⁶⁸ RT may be indicated in unresectable tumors, although large treatment volumes and young patient age often hinder the use of this modality.⁸⁰ Five-year survival rates are approximately 80% for patients with type I tumors and 45% for patients with types II and III.^67,68,76

Locally Advanced Disease and Palliation

In patients who experience a recurrence, local relapse is somewhat more common than distant failure.⁶⁷ When type I tumors recur, they usually recur as types II or III.^66,69 Re-resection should be performed when possible, but second-line chemotherapy is often the primary treatment owing to the extent of disease. RT may be useful for brain metastases and palliation of painful bone lesions.

Irradiation Techniques

Fractionated external beam RT using a dose of 44 Gy has been recommended for incompletely resected tumors, although its role in local control is difficult to assess.^67,76 Normal tissue tolerances may preclude this amount of irradiation; use of a lesser dose may be required in circumstances in which volume and dose exceed organ tolerance. Microscopic margins were controlled in one case report using 36 Gy,⁶⁸ but local recurrence was reported after 30 Gy in 10 fractions in a patient with gross tumor.⁸¹ Intracavitary phosphorus-32 has also been used and may contribute to local control in selected patients.⁷⁶

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Initial resection is performed if possible. Neoadjuvant chemotherapy is utilized when initially unresectable, followed by delayed surgery. Adjuvant chemotherapy is indicated for all patients. RT should be considered for microscopic or gross residual tumor after surgery. Children should be followed with chest CT at 3- to 6-month intervals for 2 to 3 years.

Etiology and Epidemiology

Although often considered together, hemangiomas and lymphangiomas are clinically and histologically distinct entities. Many semidescriptive terms have been applied to these lesions (especially the cutaneous hemangiomas), contributing to confusion regarding their study and management. Synonyms for cutaneous hemangioma include “neonatal stain,” “stork bite,” “salmon patch,” “spider angioma,” and “strawberry angioma.”

Hemangiomas occur in about 1% of infants, most often during the first few months of life, with about a third of these presenting in the head and neck.⁸² Lymphangiomas are much less common, with an incidence between 1 in 6,000 and 1 in 16,000 live births.⁸³ Half are congenital; 90% are evident before the age of 2 years. Three fourths of lymphangiomas occur in the neck or head areas.

Pathology and Pathways of Spread

Hemangiomas consist of thin-walled vessels lined by endothelial cells and a discontinuous layer of pericytes and reticular fibers.⁸⁴ They have been reported to occur in a wide variety of locations, including the skin, liver, bone, central nervous system, bladder, trachea, and other soft tissues.⁸⁵ Lymphangiomas are dilated endothelial-lined lymph channels with thick walls containing smooth muscle.⁸⁶ Lymphangiomas can involve the skin, skeletal tissue, spleen, liver, mediastinum, or lung.⁸⁷ Hemangiomas and lymphangiomas classically are malformations or low-grade/benign neoplasms with no capacity for metastasis.

Clinical Manifestations, Patient Evaluation, and Staging

Hemangiomas are classified as capillary, cavernous, or mixed, depending on the size of the vessels involved. When they involve the skin, capillary hemangiomas are often raised, circumscribed red lesions. They usually present early in the first year of life, and the great majority undergo spontaneous involution over the subsequent years. They are distinct from vascular malformations such as port-wine stains, which do not regress.⁸² Clinical manifestations of hemangiomas are largely dependent on the location of the lesion and can include cosmetic deformity, functional impairment, airway obstruction, bleeding, infection, and high-output cardiac failure. Kasabach-Merritt syndrome describes a giant hemangioma causing thrombocytopenia due to consumption coagulopathy.

Lymphangiomas are also categorized according to the size of the abnormal lymph vessels. Lymphangioma circumscriptum contains relatively small-caliber lymph channels and is usually superficial in location. Cystic hygroma or cavernous lymphangioma consists of large, cystic areas of lymph fluid arising in deeper tissues. Unlike hemangiomas, lymphangiomas do not tend to regress spontaneously and may enlarge during adolescence.⁸⁸ Symptoms of lymphangiomas can include disfigurement, pain, infection, and complications of chronic lymph secretion. Lymphangiomas occurring in the mediastinum may cause chylothorax, which can be life threatening.

Classification schemes have been proposed for these lesions, but there is no widely accepted staging system.^84,89

Primary and Adjuvant Therapy and Results

RT was the mainstay of therapy for both hemangiomas and lymphangiomas through the early 1950s and, in some centers, into the 1970s. Subsequently, the use of RT has been all but abandoned as the natural history of spontaneous involution of hemangiomas was recognized and the late morbidities of RT were reported.⁹⁰

Spontaneous involution will occur in 95% of capillary hemangiomas over the course of several years; most require no treatment.⁹¹ Cavernous hemangiomas do not usually regress spontaneously and require treatment if symptomatic.⁸⁵ For symptomatic hemangiomas, topical or intralesional corticosteroids are often the first line of treatment.⁹² Systemic corticosteroids are also effective.⁸² Surgical resection is an effective treatment in appropriate circumstances. Other treatments include interferon, laser ablation, cryotherapy, compression, electrocautery, and embolization. Other pharmacologic interventions include antiangiogenic and antifibrinolytic agents. Irradiation for hemangiomas with life-threatening complications can be performed and is often effective, with improvement or resolution occurring in more than 80% of patients.^85,93

Surgical removal of lymphangiomas is curative, although can be cosmetically or functionally morbid in many anatomic sites. Sclerotherapy using agents such as OK-432 or bleomycin is a common nonsurgical treatment, with complete responses seen in about 40% of patients and partial responses in another 40% to 45%.⁸³ Other nonsurgical therapies include diathermy, cryotherapy, and interferon alfa-2b.⁸⁷ RT has also been used with some efficacy in selected patients.^88,94–96

Locally Advanced Disease and Palliation

Mortality from Kasabach-Merritt syndrome can exceed 10%. Large hemangiomas causing coagulopathy or cardiac failure require aggressive treatment.⁹⁷ RT may be useful when other modalities fail.⁹⁸ Fractionated RT to doses of 10 to 20 Gy has been effective in these life-threatening situations.^85,93,97,98 Very rare malignant tumors such as lymphangiosarcoma and malignant hemangioendothelioma are highly aggressive neoplasms and require multimodality treatment.^99,100

Irradiation Techniques

Although the efficacy of RT for these conditions is well established, the availability of other effective treatments and the concern for late effects of irradiation in this young patient population appropriately limit RT to a seldom-used option today.^91,101 No definite dose-response relationship has been established for the treatment of hemangiomas, and fractionated radiation doses ranging from 3 to 40 Gy have been recommended.^85,97 Braun-Falco and colleagues⁹¹ reported a large series of patients with hemangiomas; most were treated with fractionated radiation doses between 12 and 25 Gy. Responses were seen in 73% of patients, with complete responses in 50%. Some have reported good results, with lower doses of 3 to 11 Gy,¹⁰² although others recommend a dose of at least 25 Gy.¹⁰³ Partial improvement after RT can often be noted within a few weeks, but maximum response can take several months to years.

Lymphangioma has been successfully treated with 10 to 20 Gy of fractionated RT.^88,95,96 Responses can be seen much more quickly in lymphangiomas than in hemangiomas.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Observation is usually indicated for hemangiomas. When treatment is required, corticosteroids or locally ablative treatment such as surgery or embolization can be used, as well as systemic agents. RT may be indicated for life-threatening situations. Lymphangioma is usually treated with surgical resection or sclerosing agents such as OK-432. RT, again, is reserved for life-threatening circumstances.

Etiology and Epidemiology

Desmoplastic small round cell tumor (DSRCT) was first characterized by Gerald and associates in 1991¹⁰⁴ as an extremely aggressive neoplasm, usually presenting as an intra-abdominal mass in adolescent males. Age at diagnosis ranges from 6 to 49 years, with a median of 22 years; male-to-female ratios range from 5 : 1 to 20 : 1.¹⁰⁵

Biologic Characteristics and Molecular Biology I

Although the cell of origin remains unknown, DSRCT arises along the serosal lining of body cavities and visceral organs. It demonstrates divergent differentiation and is immunohistochemically reactive with markers for epithelium (epithelial membrane antigen), mesenchyme (vimentin), myogen (desmin), and neurons (neuron-specific enolase, CD56).¹⁰⁶ Grossly, the outer surface of these typically large tumors is bosselated, with the tumor showing areas of necrosis and hemorrhage. Microscopically, it is composed of well-defined nests of small uniform cells with sparse cytoplasm within a predominantly desmoplastic stroma.^107,108

Cytogenetically, DSRCT is characterized by a t(11;22)(p13;q12) translocation. This leads to the fusion of the Ewing’s sarcoma gene (EWS) on chromosome 22 with the Wilms’ tumor gene (WT1) on chromosome 11.^107,109 This EWS-WT1 chimeric fusion is postulated to be the cause of the tumor’s multiply antigenic nature.^110,111

Clinical Manifestations, Patient Evaluation, and Staging

DSRCT is an extremely aggressive neoplasm with a very poor prognosis. It most often presents as a large intra-abdominal mass, although it has been reported to arise in other sites, including paratestes,¹¹² central nervous system,¹¹³ kidney,¹¹⁴ pleura,¹¹⁵ and bone.¹¹¹ Symptoms of the abdominal manifestation of the disease include abdominal pain/cramping, distention, constipation/diarrhea, dysphagia, weight loss, and jaundice. Pathways of spread include direct extension, hematogenous seeding, and nodal involvement (Fig. 73-3). Significant amounts of peritoneal seeding and studding are usually present, and ascites is common. A majority of patients have disease beyond the primary tumor at diagnosis, with lymph node, visceral (liver, lung), or bone metastases.^116–118

Figure 73-3 Desmoplastic small round cell tumor in a 12-year-old boy.

CT and/or MRI of the chest, abdomen, and pelvis should be performed for evaluation; combined imaging with CT and positron emission tomography (CT/PET) may be helpful. Initial open or imaged-guided biopsy is suggested, because extension of disease usually precludes complete resection of disease at presentation.¹¹⁶ There is no accepted staging system for this tumor.

Primary and Adjuvant Therapy and Results

There are no uniform treatment recommendations for DSRCT, and a wide range of treatment regimens have been used. The most common treatment approach is aggressive multimodality therapy with neoadjuvant chemotherapy (typically cyclophosphamide, doxorubicin, and vincristine, with or without ifosfamide and etoposide), second-look surgery with a goal of complete or near-complete (maximal debulking) resection, and whole-abdominopelvic irradiation.116,118,119 In one series, 3-year survival was 58% in patients who underwent aggressive tumor debulking versus 0% for those who did not.¹¹⁸ Other reported treatments include high-dose chemotherapy with autologous bone marrow rescue and continuous hyperthermic peritoneal perfusion with cisplatin.¹²⁰ Despite favorable response and intermediate 2- to 3-year survival, the prognosis is poor, with survival at 5 years rarely above 15%^118,122 (Fig. 73-4).

Figure 73-4 Disease-free and overall survival for desmoplastic small round cell tumor.

Data from Goodman KA, Wolden SL, La Quaglia MP, Kushner BH: Whole abdominopelvic radiotherapy for desmoplastic small round-cell tumor. Int J Radiat Oncol Biol Phys 54:170-176, 2002.

Irradiation Techniques

RT plays an important role in the trimodality treatment of DSRCT. In a series of patients from Memorial Sloan-Kettering Cancer Center (MKSCC), 3-year survival was 55% for those receiving chemotherapy, surgery, and RT versus 27% when fewer than three modalities were used.¹¹⁸ Because of the extensive serosal spread of DSRCT, whole-abdominopelvic irradiation is indicated for consolidation of primary therapy. After the initial MSKCC reports, wide abdominal irradiation is typically delivered in 1.5-Gy fractions to a total of 30 Gy; the large series from MSKCC was based on twice-daily fractionation.¹⁰⁵ Kidneys and liver should be shielded at 15 to 17 Gy and 23 to 25 Gy, respectively, to respect normal tissue tolerances. Whole-abdominal RT has also been delivered using IMRT to spare bone marrow.¹²¹ If the primary disease is intrapelvic or occupies a reasonably confined area of the abdomen, reduced volume “boost” may be continued to 45 Gy as permitted by surrounding structure tolerance.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

The current approach to treatment after biopsy consists of neoadjuvant chemotherapy, second-look debulking surgery, and whole-abdominal RT. Several of these tumors are immunohistochemically positive for markers such as placental alkaline phosphatase, ERBB2, androgen receptor, and c-KIT, which may present options for targeted biologic therapies.¹⁰⁹ Additionally, there are case reports of treatment with bevacizumab¹²² and trastuzumab.¹⁰⁹ Other targeted therapies based on the downstream effects of the EWS-WT1 fusion product are under investigation.¹²³

Etiology and Epidemiology

Langerhans cell histiocytosis (LCH) refers to the spectrum of diseases arising from clonal proliferation of the CD1a- and CD207-positive reticuloendothelial Langerhans cell. The historical name “histiocytosis X” was coined in the 1950s to indicate the histiocytic origin of the disease, with the “X” reflecting the mysterious clinical spectrum of disease presentation.¹²⁴ This designation was replaced by the term LCH in 1987.¹²⁵ Incidence is usually quoted as one to five cases per million children per year. More than 50% of children are diagnosed between 1 and 15 years of age, with a peak incidence between 1 and 4 years of age.^126–128

Biologic Characteristics and Molecular Biology

There has been considerable debate as to whether LCH is a reactive or immune dysregulatory process versus a true neoplasm.¹²⁹ A clonal disorder, it is known to spontaneously regress in some patients and prove fatal in others. Most cases arise spontaneously, although there are rare genetic forms of the disease associated with specific cytokine gene variants that tend to occur early with multifocal disease.¹³⁰

Pathology and Pathways of Spread

The basic lesion of LCH is formed by collections of pathologic Langerhans cells, indeterminate cells, interdigitating cells, and macrophages accompanied by T lymphocytes, with variable numbers of multinucleated giant histiocytes and eosinophils, as well as dendritic cells. Granulocytes and plasma cells, when present, represent reactants.¹³¹ For definitive diagnosis, the Langerhans morphology must be present and Birbeck granules must be visualized by electron microscopy or CD1a expressed on the cell surface. (More recently, CD207 is the most sensitive and specific antibody.)

Clinical Manifestations, Patient Evaluation, and Staging

Most clinicians classify LCH in terms of the number of involved sites, because presentation can vary from a solitary bone lesion to multiple-organ system dissemination. The most commonly affected tissues are bone, skin, and lymph nodes, although any organ system can be involved. In general, younger age (≤2 years) and diffuse presentation carry the worst prognosis. LCH is often grouped into three distinct entities that have different clinical presentations and prognoses. These distinctions are somewhat artificial, however, because there is a continuous spectrum of protean disease presentations.

The mildest form of LCH, previously known as eosinophilic granuloma of bone, is usually seen in children between 5 and 15 years of age. Presentation is a purely lytic lesion of bone, most often affecting the skull but occurring anywhere in the skeleton, including the spine, ribs, pelvis, and long bones. Presenting symptoms include pain, swelling, and pathologic fracture.¹³² Classic Hand-Schüller-Christian disease is intermediate in severity, presenting as a triad of exophthalmos, skull lesions, and diabetes insipidus; it generally presents in somewhat younger children between the ages of 2 and 15 years.¹³³ The most aggressive form of LCH, classically identified as Letterer-Siwe disease, usually presents in children younger than age 3 years and carries a very poor prognosis. This form typically involves multiple organ systems, with presentations including splenomegaly, lymphadenopathy, anemia, and blood dyscrasias. The skeleton is frequently diffusely involved, and children may have otitis media, fever, papular rash, and cachexia.

There is no uniform staging system for LCH, thus underscoring the hesitancy of many to associate LCH with a true malignancy. In studies, children are generally grouped by burden of disease or number of systems involved such as single or multiple sites, single or multiple organs, and “non-risk sites” (skin, bone, lymph nodes) versus “risk organs” (liver, spleen, lung, bone marrow).^134–136 Those with “risk organs” involved are now often considered as having “high-risk” LCH versus others with “low-risk” disease. A study of 217 patients from Turkey reported 41.5% with single-system disease, 34.1% with multiple-system disease, and 24.4% with multiple-system disease with organ dysfunction.¹³² Overall, approximately 30% of patients present with unifocal lesions and 70% present with more extensive disease.¹³⁵

Workup includes skeletal survey and bone scintigraphy to evaluate bony lesions. Skeletal survey is necessary because some lesions are purely lytic and not detected on the bone scintiscan. Brain MRI is obtained to screen for involvement of the central nervous system, and CT or MRI of the chest and abdomen are required to evaluate potential visceral disease. PET may be helpful in patients with lymphatic involvement. Bone marrow biopsy is performed to evaluate for marrow involvement. In addition to standard laboratory chemistries, screening for diabetes insipidus should be performed.

Primary and Adjuvant Therapy and Results

For patients with a low burden of disease the goal is to give as little treatment as possible to preserve quality of life with good function. Children with minimal involvement often have spontaneous resolution of their disease and require no active treatment. In cases such as solitary tumor of bone, a simple surgical curettage or injection of corticosteroids may be adequate to control the disease.133,137

Locally Advanced Disease and Palliation

For patients with multifocal disease (with or without organ involvement), chemotherapy is clearly indicated and is risk adapted based on disease severity. Most regimens include vinblastine and prednisone. The purine analogue cladribine is effective for visceral organ involvement, potentially replacing mercaptopurine as a “standard” agent. In nonresponders and refractory disease, stem cell transplantation has been used.^138,139

Irradiation Techniques

LCH is markedly radiosensitive; RT was frequently used in the past for local disease control. Today, RT is used much less frequently because of the good results obtained with other modalities and the risk of late effects after RT in children (primarily the low risk of secondary neoplasms after low-dose irradiation). In cases in which surgical resection would cause loss of function, when a lesion is recurrent or refractory to other local treatment, or a single vertebral body is involved, low-dose RT can be considered.¹³⁴ One series reported 88% long-term local control of bone lesions using RT doses of 6 to 15 Gy (median, 9 Gy).¹⁴⁰ Local control was somewhat less when soft tissues were involved. A German study reported local control of 96% for single osseous lesions and 92% for bone lesions in patients with multiple-organ disease.¹⁴¹ RT using 15 to 20 Gy to the sellar/hypothalamic area has been used in cases of diabetes insipidus secondary to LCH, with modest—in fact, controversial—efficacy.^142,143 In several retrospective series, when RT has been delivered within 1 to 2 weeks of onset, 25% to 35% of patients show improvement in diabetes insipidus.^142,144

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Overall, most patients enjoy a favorable prognosis. Unfortunately, there remain a minority of children (up to 20% to 30%) with extensive organ involvement who succumb to LCH within 5 years. Targeted therapies for LCH are being investigated, and several monoclonal antibodies have been proposed or used in small case studies.145,146,147 The Histiocyte Society¹⁴⁸ serves as a clearinghouse for information regarding LCH as well as for administration of prospective clinical trials.

Etiology and Epidemiology

Pediatric nasopharyngeal carcinoma (PNC) is a rare tumor whose incidence varies significantly depending on geographic location. In endemic areas such as China, Southeast Asia, the Mediterranean, and Alaska there are few children with nasopharyngeal carcinomas. However, in nonendemic areas such as the United States and Europe, PNC represents about 1% of pediatric cancers and accounts for 10% of all nasopharyngeal malignancies. In these areas there is a bimodal age distribution, with a peak in late childhood and adolescence from ages 10 to 20 and another in the 40- to 60-year age group. There is an approximate 2 : 1 male predominance; the median age in children is 13. In the United States, PNC is more common in African-Americans.

Comparisons are often made between the adult and juvenile variants of nasopharyngeal carcinoma, and indeed much of the treatment regimens for PNC has been extrapolated from adult data owing to the rarity of the pediatric tumors. The diseases are similar in their relationship to Epstein-Barr virus infection, to diets containing nitrites and salted fish, and to the male predominance. However, in children, the greatest incidence occurs in the Mediterranean and North America rather than China, Southeast Asia, and Alaska; undifferentiated histology is the most common type; and patients present with significantly more advanced disease at diagnosis. In one retrospective series, 92% of pediatric patients had stage III to IV disease versus 67% of adults with nasopharyngeal carcinoma. Additionally, data show despite higher stage disease that children have a better overall prognosis than adults in both OS and locoregional disease control.149,150,151

Biologic Characteristics and Molecular Biology

Epstein-Barr virus (EBV) is the best established etiologic factor and is associated with 90% of PNCs, particularly the undifferentiated and nonkeratinizing types. The association with EBV was initially based on serologic studies that found high titers of IgG and IgA against the early antigen (D) or viral capsid antigen (VCA). EBV titers of IgG and IgA to these antigens have been shown to be an early predictor of clinical relapse or resistance to treatment in patients in the United States.¹⁵² The relationship between EBV and nasopharyngeal cancer was confirmed when EBV DNA was found in neoplastic epithelial cells but was absent in the surrounding lymphocytes.¹⁵³

Clonal genomes have also been found in early dysplastic lesions, leading to the hypothesis that infection is an early event in carcinogenesis. The genome is a double-stranded DNA virus encoding 100 genes. However, only 10 of these are expressed in vitro; six are nuclear proteins (EBNAs), two are latent membrane proteins (LMPs), and there are two nontranslated RNA molecules (EBER) that likely aid in cell growth. In nasopharyngeal carcinoma, LMP1 acts as an oncogene, changing growth patterns and up-regulating proteins that inhibit apoptosis, including BCL2.¹⁵⁴ It also binds to various proteins associated with tumor necrosis factor receptors and is involved in activation of transcription factors, cellular adhesion molecules, and cytokines. LMP2 is also expressed in nasopharyngeal carcinoma and acts by preventing reactivation of the virus by blocking phosphorylation of tyrosine kinases. EBERs are not transcribed as proteins but play a role in oncogenesis and resistance to apoptosis.^154,155,156

There is also evidence for genetic predisposition based on human leukocyte antigen (HLA) subtypes. The HLA-A2 Bsin2 haplotype and HLA-Aw19, HLA-Bw46, and HLA-B17 types have been shown to have increased risk of nasopharyngeal carcinoma.^157,158 Several studies have demonstrated deletions of chromosomes 3p and 16q; other aberrations include 9p, 11q, 13q, and 14q. These findings suggest that tumor suppressor genes are located in these regions and that loss of a normal copy of these genes can lead to promotion of PNC.¹⁵⁴

Other well-known molecular changes include inactivation of TP53, rearrangement of the retinoblastoma tumor suppressor genes, and polymorphism of CYP2E1. Genetic gains on chromosome 12 as well as losses on 11q, 13q, and 16q have been associated with invasiveness, whereas TP53 mutation and altered expression of cadherins are associated with metastasis.^{157,159–161} Clinically, molecular markers have been pursued as a means to predict for prognosis and survival. Although there was no predictor for survival found in a study of TP53, BCL2, Ki67, and c-KIT, there was a trend toward a reduced recurrence rate; however, on multivariate analysis, only early stage and young age predicted for good prognosis.¹⁵¹ A small proportion of PNC exhibit t(15;19) with the BRD4-NUT oncogene; the typically midline NUT-rearranged carcinomas are particularly aggressive PNCs.

Thus, the development of PNC is thought to be a multiple-step process involving EBV infection resulting in the expression of LMP1 and overexpression of TP53 in the epithelial tumor cells. BCL2 has been studied in this population and, although it may be significant in adult nasopharyngeal carcinoma, it seems unrelated to the development of the pediatric disease.¹⁶²

Pathology and Pathways of Spread

The World Health Organization (WHO) classification of nasopharyngeal carcinoma includes three histiotypes: keratinizing squamous cell carcinoma (type I), nonkeratinizing squamous cell carcinoma (type II), and undifferentiated carcinoma (type III, earlier called lymphoepithelioma). Lymphoepithelioma (or Schmincke’s tumor) refers to an undifferentiated tumor with prominent nonmalignant lymphocytic infiltration. Type I shows significant keratin production, is usually seen in adults, and is not usually associated with EBV. In type II there can be groups of cells with oval or fusiform nuclei and scant cytoplasm. The Cologne modification of the WHO classification further subdivides types II and III by degree of lymphoid infiltration; type IIa has pleomorphism without lymphoid infiltration, whereas type IIb has significant lymphoid infiltrate. Type IIIa is characterized by larger, eosinophilic nuclei, whereas type IIIb has smaller basophilic nuclei; virtually all PNC cases are type III undifferentiated carcinomas.154,163

Nasopharyngeal carcinoma typically originates in the fossa of Rosenmüller, the space posterolateral to the eustachian tube orifice. Routes of direct spread include the oropharynx or perineural spread along cranial nerves extending to the skull base. The cervical lymph nodes are typically involved early, but the spinal accessory chain and retropharyngeal nodes are at risk as well. Distant metastases at presentation are rare but when they occur are most commonly seen in the bones, lungs, liver, bone marrow, and mediastinum.¹⁶⁴

Clinical Manifestations, Patient Evaluation, and Staging

Painless cervical lymphadenopathy is the most common presenting symptom, occurring in up to 90% of patients. The rich lymphatic supply of the nasopharynx explains this high rate of early nodal metastasis; regional lymphatics include the internal jugular nodes, the spinal accessory nodes, and the retropharyngeal nodes. The midline location of the nasopharynx puts the bilateral nodal basins at risk. Other common symptoms at presentation include nasal obstruction or bleeding, hearing loss, or otitis from obstruction of the eustachian tubes, which can lead to ear pain and tinnitus, headache, facial pain, neck pain, and various cranial neuropathies from invasion of the base of skull.154,157,158,165 Symptom duration before diagnosis ranges from 1 to 24 months, with an average of 5 months.¹⁶⁶ The syndrome of inappropriate antidiuretic hormone secretion has been reported and can cause severe hyponatremia.^154,164,167

The differential diagnosis in a patient presenting with such symptoms should include upper respiratory tract infection, benign adenoidal hypertrophy, rhabdomyosarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and JNA.

Evaluation includes history and physical examination, including nasopharyngoscopy, a complete blood cell count, serum biochemistries including kidney and liver function tests, serum EBV titers, a baseline audiogram, CT or MRI of the head and neck, CT of the chest and abdomen, and bone scintigraphy. Biopsies of the primary site should be performed, and complete dental and endocrine evaluations should be done.

Local extension in PNC is explained by anatomy; the pharyngobasilar fascia acts as a barrier and directs the spread of tumor toward the skull base anterior to the clivus. Indications of local bone and marrow involvement on MRI include decreased T1-weighted signal, increased T2-weighted signal, and postcontrast enhancement. The petroclival fissure may be widened from tumor invasion and is seen best on CT bone windows. In later stages of disease, tumor may cross the pharyngobasilar fascia to invade the parapharyngeal space.¹⁶⁸

Staging is based on the American Joint Committee on Cancer staging system for nasopharyngeal carcinoma for adults (Table 73-6). The nodal staging for nasopharyngeal tumors takes into account the anatomic level of nodal involvement, an important prognostic factor; retropharyngeal lymph nodes, regardless of their laterality, are considered N1.^169,170

TABLE 73-6 Nasopharyngeal Carcinoma Staging: American Joint Committee on Cancer

* Parapharyngeal extension denotes posterolateral spread of tumor.

From Edge SB, Byrd DR, Compton CC, et al, editors: AJCC Cancer Staging Handbook, ed 7, New York, 2010, Springer.

Primary and Adjuvant Therapy and Results

RT is the mainstay of therapy for every stage of PNC. Surgery is limited to biopsy for diagnosis in PNC that is unresectable based on anatomy. However, outcome with RT alone has been unsatisfactory, with local recurrence rates of 20% to 60% and rates of distant metastases that range from 20% to 55%.

Locally recurrent or metastatic disease presents within 1 to 2 years; survival rates approximate 50% to 60%.¹⁵⁴ Systemic therapies have thus been pursued, in the form of neoadjuvant, concurrent, and adjuvant chemotherapy, especially for the majority of patients with locally and/or regionally advanced disease.

Given the rarity of PNC, data have often been extrapolated from adult trials. Caution must be employed when extrapolating these data because PNCs are largely distinct biologic entities. The Intergroup 0099 trial compared chemoradiation with RT alone in adult patients with nasopharyngeal carcinoma, delivering 70 Gy with or without cisplatin, followed by three cycles of adjuvant cisplatin and 5-fluorouracil.¹⁷¹ Three-year progression-free survival was 69% versus 24% favoring the chemotherapy arm of the trial; 3-year OS was 78% versus 47%, also favoring the chemotherapy arm. Additionally, a recent meta-analysis by Langendijk and colleagues¹⁷² reported a significant survival benefit for the group who received concurrent chemoradiation: a 20% survival benefit with chemoradiation versus irradiation alone.

The earliest series of PNCs were published in the 1980s and generally included small numbers of patients treated with RT alone,173–175,176 noting OS of 50% to 55% with relapse-free survival in the range of 36% to 75%, following irradiation to 35 to 86 Gy.

Reports of PNCs published in the past 2 decades used better staging and improved RT techniques, including evolution of three-dimensional and IMRT volume-based therapy. Cisplatin-based chemotherapy regimens were also introduced in this era. Studies by Ayan and associates¹⁷⁷ and Wolden and colleagues¹⁷⁸ showed improved outcome after chemoradiation, particularly in the neoadjuvant setting; data suggested a benefit primarily when radiation doses exceeded 60 Gy, with OS in the most aggressively treated cohort as high as 76%.

Laskar and colleagues¹⁷⁹ explored prognostic factors correlated with disease-free survival (DFS) and noted age, nodal stage, TNM stage, node size, node fixation, radiation dose, and response to chemotherapy to be significant. In comparing concurrent cyclophosphamide versus concurrent modified vincristine, cyclophosphamide, epirubicin, and dactinomycin (Actinomycin-D) versus neoadjuvant cisplatin in conjunction with 46 to 76 Gy to the nasopharynx and regional lymph nodes, Kupeli and colleagues¹⁸⁰ documented the benefit of cisplatin, with OS 80% versus 63% with AVAC and 31% with cyclophosphamide. Parallel to the experience in adults, 10-year survival was 88% without lymph node involvement compared with 39% with nodes larger than 3 cm and 0% with supraclavicular node involvement. Ozyar and colleagues¹⁵⁰ reported a large, multi-institutional international review of PNC over a 25-year interval documenting overall 5-year survival of 77.4% and DFS of 68.8% after combined irradiation and chemotherapy; the only significant negative prognostic factor for OS and DFS was N3 disease. RT doses less than 66 Gy adversely affected locoregional control, and RT without chemotherapy decreased locoregional control and DFS.

A German prospective pediatric trial tested three cycles of cisplatin, 5-fluorouracil, methotrexate, and leucovorin followed by RT (59.4 Gy) for stage III/IV PNC; patients were then maintained on interferon-beta for 6 months. The 108-month DFS was 91%; OS was 95%. The excellent outcome was hypothesized as due, in part, to the administration of interferon-beta during a period of relative immune suppression in EBV-positive nasopharyngeal carcinoma.163,181

The Pediatric Oncology Group 9486 study showed 4-year event-free and OS of 77% and 75%, respectively, following neoadjuvant chemotherapy (cisplatin, 5-fluorouracil, methotrexate, and leucovorin) and RT (50.4 Gy to the upper neck, 45 Gy to the lower neck, and a boost to the primary tumor to a total dose of 61.2 Gy).¹⁸²

There is significant toxicity using doses of 50 to 70 Gy in children and adolescents. Xerostomia, neck fibrosis, dental caries, chronic sinusitis, chronic serous otitis, trismus, hypopituitarism, stunted growth, hypothyroidism, hypoplasia of facial bones or clavicles, and second malignancies have been well documented154,178,180 (Table 73-7).

TABLE 73-7 Incidence of Treatment-Related Toxicity in Nasopharyngeal Cancer

The optimal dose of RT for disease control has been controversial, especially in the setting of effective systemic therapy. Although earlier reports suggested improved locoregional control with doses greater than 60 Gy, recent studies have explored lower-dose, response-adapted RT. Habrand and associates¹⁸³ reported outcome after sequential cisplatin-based regimens and response-adapted RT (50 Gy after marked response and 65 to 70 Gy after poor chemoresponse).^177,183 Five-year event-free survival and OS were 64% and 68%, respectively; locoregional failures were similar between the groups, but the low RT dose group actually had significantly improved OS and event-free survival, with apparent reduction in late toxicities. Orbach and colleagues¹⁸⁴ reported results following one of three chemotherapy protocols (both neoadjuvant and adjuvant chemotherapy). Objective response to preirradiation chemotherapy was apparent in 78% of cases; those with complete response or very good partial response received an attenuated RT (median dose 47 Gy to the clinically negative cervical nodes and 59.4 Gy to the primary tumor); those with less response received a 60-Gy median dose to all involved sites. OS for the entire group was 73% at 5 years, and local failure rate was 10% with regional failure rate of 3% and distant failure rate of 18%. The 5-year OS did not correlate with radiation dose; no patient demonstrated isolated cervical nodal relapse.

Irradiation Techniques

The principles of RT for PNC require delivering a tumoricidal dose to the primary tumor and clinically involved nodes, as well as a prophylactic dose to nodal areas clinically at risk. The optimal doses for tumor eradication are not yet known, but there is emerging evidence that radiation dose can be adapted based on clinical response to neoadjuvant chemotherapy.183,184 Recent data suggest that IMRT with sparing of normal tissues offers reduced toxicity and superior target coverage; experience with both acute and long-term tolerance suggest IMRT may be the treatment of choice, recognizing concerns regarding an increased risk of secondary malignancies in a pediatric population due to an increase in integral dose with IMRT. This risk has been projected to be 2% for patients treated with IMRT compared with 1% for patients treated with conventional radiation techniques.¹⁸⁵

Simulation should be CT based, with appropriate immobilization and localization techniques. The Children’s Oncology Group currently recommends delineation of the gross tumor volume based on primary tumor and involved nodes as seen on MRI or as determined clinically; lymph nodes larger than 1.5 cm or of any size with a necrotic center are included in the gross tumor volume. The clinical target volume includes the gross tumor volume plus a 1-cm margin, the entire nasopharynx, retropharyngeal nodes, skull base, pterygoid fossa, parapharyngeal space, inferior sphenoidal sinus, and posterior third of the nasal cavity and maxillary sinuses as well as the bilateral cervical lymphatic levels I to V. The lower half of levels IV and V can be excluded in patients with early-stage disease. A boost, or second clinical target volume, may include the nasopharynx and residual enhancing disease after chemotherapy.

A typical dose to the primary tumor and gross disease is between 60 and 70 Gy, with at-risk nodal areas receiving 45 to 50 Gy. IMRT techniques are strongly encouraged, but if three-dimensional conformal techniques are used, parallel opposed fields with successive cone downs and electron fields to treat the posterior cervical regions after 45 Gy are commonly utilized.

Critical normal structures include the spinal cord and brainstem, mandible/temporomandibular joint, temporal lobes, and optic apparatus. Other structures at risk are the parotid gland, oral cavity, larynx, eyes, lens, cochlea, and pituitary.

Treatment Algorithms, Controversies, Challenges, and Future Possibilities

Standard treatment for PNC is currently defined as three to four cycles of platinum-based chemotherapy followed by high-dose RT to the primary tumor and regional lymphatics (60 to 70 Gy). Future dose reduction studies require exquisite monitoring because further tests of decreased radiation dose based on response to initial chemotherapy need to ensure excellent local disease control and measurable reduction in both acute and long-term toxicities. The Children’s Oncology Group is currently studying the adaptive-RT dose concept in conjunction with further attempts to diminish toxicities by using amifostine. Patients with stage I and II disease receive RT alone with daily amifostine to 61.2 Gy for stage I disease and 66.6 Gy for stage IIa disease. Patients with stage III to IV disease receive three cycles of cisplatin/5-fluorouracil followed by concurrent RT with amifostine and cisplatin for two additional cycles. Based on response to chemotherapy, patients with a complete or partial response then receive 45 Gy to the cervical nodes with a 16.2-Gy boost to the primary tumor for a total dose of 61.2 Gy. Patients with no response to chemotherapy receive 45 Gy to the cervical nodes, with a 25.2 Gy boost to the primary and involved lymph nodes.