July 16, 2008
Primary and Metastatic Lung Tumors in the Pediatric Population: A Review and 25-Year Experience at a Large Children’s Hospital
By Dishop, Megan K Kuruvilla, Supriya
* Context.-Primary lung neoplasms are rare in children, but they comprise a broad and interesting spectrum of lesions, some of which are familiar from other tissue sites, and some of which are unique to the pediatric lung. Objective.-To determine the relative incidence of primary and metastatic lung tumors in children and adolescents through a single-institution case series, to compare these data to reports in the medical literature, to discuss the clinical and pathologic features of primary tumors of the tracheobronchial tree and lung parenchyma in children, and to provide recommendations for handling pediatric lung cysts and tumors.
Data Sources.-A 25-year single institutional experience with pediatric lung tumors, based on surgical biopsies and resections at Texas Children's Hospital from June 1982 to May 2007, an additional 40 lung tumors referred in consultation, and a review of the medical literature.
Conclusions.-A total of 204 pediatric lung tumors were diagnosed at our institution, including 20 primary benign lesions (9.8%), 14 primary malignant lesions (6.9%), and 170 secondary lung lesions (83.3%). The ratio of primary benign to primary malignant to secondary malignant neoplasms is 1.4:1:11.6. The common types of lung cancer in adults are exceptional occurrences in the pediatric population. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tumor. Other primary pediatric lung tumors include congenital peribronchial myofibroblastic tumor and other myofibroblastic lesions, sarcomas, carcinoma, and mesothelioma. Children with primary or acquired immunodeficiency are at risk for Epstein-Barr virus-related smooth muscle tumors, lymphoma, and lymphoproliferative disorders. Metastatic lung tumors are relatively common in children and also comprise a spectrum of neoplasia distinct from the adult population.
(Arch Pathol Lab Med. 2008;132:1079-1103)
Primary lung neoplasms are rare in children. Lung masses in children are approximately 10 times more likely to represent a benign developmental or reactive lesion than a neoplasm, with a ratio of primary tumors to metastatic tumors to nonneoplastic lesions of 1:5:60.1 Common malformations forming solid and cystic masses of the pediatric lung include bronchogenic cyst, segmental bronchial atresia, intralobar and extralobar pulmonary sequestration, congenital pulmonary airway malformation (congenital cystic adenomatoid malformation), and congenital lobar overinflation. The vast majority of solid parenchymal lung masses in children represent inflammatory, infectious, or reactive processes, with a differential diagnosis, including granulomatous inflammation (fungal, mycobacterial, parasitic, sarcoidosis, vasculitis); abscess; pneumonia (bacterial, viral); septic embolus; infarction; or hematoma. 2 Of the lung neoplasms in children, metastatic tumors far exceed the number of primary lesions. Of the primary lung tumors in children reported in the literature, malignancies exceed the number of benign neoplasms, with a ratio of approximately 3:1.3 The most common benign tumor of the pediatric lung is inflammatory myofibroblastic tumor (52%), and the most common primary malignancies are carcinoid tumor and pleuropulmonary blastoma.3 Based on German registry data, malignant tumors of the trachea, bronchus, and lungs represent 0.2% of all malignancies in children.4 The mortality rate for primary benign lung neoplasms in children is low (8.7%), and the mortality rate for primary malignant tumors is approximately 30% overall. Excluding the "bronchial adenomas," which are associated with a favorable prognosis, the mortality rate of the malignant tumors rises to approximately 50%.3
Given the rarity of primary lung neoplasms in children, clinical detection remains a challenge. Some cases are asymptomatic and detected only incidentally on imaging studies. Other nonspecific respiratory symptoms may be attributed initially to asthma or other inflammatory processes, resulting in a delay of diagnosis until only after symptoms persist or are unresponsive to conventional therapy. Even if a mass is recognized, endobronchial lesions and cystic parenchymal lesions may be radiographically indistinguishable from reactive processes or lung malformations. The possibility of a lung neoplasm should be considered clinically in any child presenting with wheezing, persistent cough, hemoptysis, or recurrent pneumonia. Regardless of the clinical working diagnoses, the pathologist should remain vigilant to the possibility of a primary lung neoplasm in a child, particularly in assessing cystic lung lesions.
Several clinical reviews of pediatric lung neoplasms are available.1,3-12 Pathologic features of pediatric lung neoplasms have also been reviewed previously by Dehner almost 20 years ago.13 The objectives of this review are (1) to provide additional relative incidence data for both primary and metastatic lung neoplasms from a single large institutional experience, (2) to provide an update on our current understanding of pathologic features and diagnostic terminology for these rare tumors, and (3) to provide recommendations for the practicing surgical pathologist on handling cystic and/or solid masses of the pediatric lung.
TEXAS CHILDREN'S HOSPITAL EXPERIENCE: 25 YEARS OF PRIMARY AND METASTATIC LUNG TUMORS
Incidence data on primary lung tumors in children are limited in the medical literature due to the predominance of individual case reports and diagnosis-specific case series. As a result, cumulative historical data from literature reviews are difficult to interpret due to an uneven representation of these rare lesions and significant differences in diagnostic criteria and terminology, which have evolved during the decades typically encompassed by such reviews. For example, bronchogenic carcinoma has been reported to occur with some frequency in other reviews of pediatric lung tumors, but it appears to be overrepresented in the literature relative to current experience. Other than the low-grade neuroendocrine carcinomas (carcinoid tumors), primary lung carcinoma is vanishingly rare and a reportable occurrence in children. Table 1 presents a classification of pediatric lung neoplasms according to histogenesis, adapted from Tischer et al.4 A previous review of 465 pediatric lung specimens from a single institution (a 250-bed children's hospital in Cape Town, South Africa) during a 31-year period revealed a total of 8 primary lung tumors (6 originating at this institution and 2 reviewed in consultation) and 35 metastatic tumors.1 Primary lung tumors in this series included 50% malignant and 50% benign lesions: plasma cell granuloma (3), pleuropulmonary blastoma (2), mucoepidermoid carcinoma (1), endobronchial fibrosarcoma (1), and capillary hemangioma (1). Metastatic tumors included Wilms tumor (16), osteosarcoma (9), rhabdomyosarcoma (5), neuroblastoma (4), and hepatoblastoma (1).1
In an attempt to provide additional relative incidence data, a similar review of the experience at Texas Children's Hospital (Houston) was performed for a 25-year period (June 1982-May 2007). Texas Children's Hospital is a large tertiary care center with 639 licensed hospital beds, including a 36-bed inpatient hematology- oncology unit and a 15-bed bone marrow transplant unit. The Texas Children's Cancer Center receives approximately 25 000 outpatient visits annually. Based on registry data from 2000 to 2004, an average of 289 children were diagnosed with malignancies annually at our institution, including 91 new solid tumor diagnoses per year. Primary and metastatic lung lesions were identified by performing a natural language search of the anatomic pathology information system for the dates specified, using terms for site (lung, trachea, bronchus, bronchial, pleura); general descriptors (cancer, tumor, neoplasm, benign, malignant, malignancy, mass, nodule, metastatic, juvenile, infantile); and specific tumor types (carcinoma, blastoma, sarcoma, lymphoma, hamartoma, adenoma, pleuropulmonary, lymphoproliferative, Hodgkin/Hodgkin's, leukemia, Wilms, neuroblastoma, hepatoblastoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, chondrosarcoma, leiomyoma, leiomyosarcoma, liposarcoma, lipoblastoma, glioblastoma, clear cell, neuroendocrine, carcinoid, melanoma, myofibroblastic, adenocarcinoma, histiocytosis, mesothelioma, Kaposi/Kaposi's, granular cell tumor/myoblastoma, and papilloma/papillomatosis). Patients with juvenile respiratory papillomatosis were included if the excised squamous papillomas were specifically designated from tracheal, bronchial, or pulmonary sites. Other patients with papillomas excised only from the larynx/ vocal cords, oropharynx, nasopharynx, esophagus, and/or other sites not specified were excluded from tabulation.
During this 25-year period, the total number of surgical pathology specimens was 227 655, with annual specimen numbers ranging from 5309 in 1982 to 14 055 in 2006. We received a total of 3980 surgical specimens designated from the trachea, bronchus, or lung (1.7%), including both biopsies and resections. Of these, 507 specimens were from lung transplant recipients (12.7%), and 3473 were from other patients (87.3%). There were 273 biopsy and resection specimens for primary or metastatic neoplasms of the lung, representing 6.9% of all tracheobronchial and lung specimens. Pathologic slides were examined for the primary benign and malignant tumors to ensure accuracy of diagnosis. Among these, 1 "mesenchymoma" was reclassified as lipoblastoma, and 2 cases of "spindle cell sarcoma" included one with myofibroblastic differentiation and another subclassified as a fibrosarcoma. The spectrum of tracheobronchial or lung parenchymal tumor diagnoses is summarized in Table 2, including the number of individual patients and age distribution for each lesion. Of these lung tumors, 34 (16.7%) were primary lung tumors, and 170 (83.3%) reflected metastatic disease or secondary involvement by a hematolymphoid or histiocytic process. Of the primary tumors, 20 (59%) were benign, and 14 (41%) were malignant. During this 25-year period, the average annual incidence of new primary lung malignancies (n = 14) in our pediatric population was 0.56 per year. Based on this average annual incidence of lung malignancies and the recent average annual incidence of all new malignancies (289 per year) at our institution, we estimate that primary pediatric lung malignancies account for 0.19% of all new pediatric malignancies diagnosed annually.
The ratio of primary benign to primary malignant to secondary (metastatic) malignant tumors was 20:14:162 (or 1.4:1:11.6), indicating that excisions for metastatic tumors were almost 12 times more common than primary malignant tumors. The most common benign lesions were squamous papillomas associated with human papilloma virus infection (juvenile respiratory papillomatosis), inflammatory myofibroblastic tumor, and Epstein-Barr virus (EBV)-associated smooth muscle tumors. The 8 patients with respiratory papillomas often had multiple surgical procedures, ranging from 1 to 5 excisions and averaging 2.9 per patient. The most common primary malignancies of the lung were pleuropulmonary blastoma (57.1%) and carcinoid tumor (14.3%). Pleuropulmonary blastoma accounted for 72% (8/11) of parenchymal malignancies, and carcinoid tumor accounted for 67% (2/3) of tracheobronchial malignancies. One mucoepidermoid carcinoma and one type I pleuropulmonary blastoma have been reported previously in the medical literature.14,15 In our patient population, Wilms tumor and osteosarcoma were the 2 most common solid tumor diagnoses leading to surgical excision of metastatic lung disease, accounting for 31.2% and 20.3% of these patients, respectively. Due to the role of surgical oncologic management for metastatic osteosarcoma, it should be noted that the 28 patients with osteosarcoma had a total of 57 thoracic surgeries for excision of metastases, ranging from 1 to 6 surgeries per patient.
Consultation cases referred from other institutions were also reviewed during a similar time period and were tabulated separately from institutional cases (Table 3). These tumors included the following additional diagnoses not represented in our institutional data set: congenital peribronchial myofibroblastic tumor, synovial sarcoma, solitary fibrous tumor, bronchioloalveolar carcinoma, and pleuropulmonary blastoma type II, as well as Burkitt lymphoma and metastatic juvenile secretory breast carcinoma. A summary of the data is also provided in comparison to prior literature review (Table 4).
Clinical and pathologic features of these and other pediatric lung tumors reported in the medical literature are reviewed below, beginning with tracheobronchial lesions and followed by specific benign and malignant parenchymal lesions.
TRACHEOBRONCHIAL MASSES IN CHILDREN
Juvenile Respiratory Papillomatosis
Respiratory papillomatosis is caused by human papillomavirus infection, typically acquired during delivery, and results in multiple recurrent squamous papillomas (Figure 1, A and B), most often of the larynx and trachea but also involving the distal bronchial tree and esophagus in some cases, especially after longstanding duration of disease. Their clinicopathologic features are distinctive, and there is little difficulty in the differential diagnosis with other types of neoplasms. Spread into the lung parenchyma occurs rarely (Figure 1, C and D), and may produce solid nodules or cystic air-filled cavities.2 Malignant transformation to squamous cell carcinoma has been reported, in some cases related to prior radiation therapy, and is distinguished by marked cellular pleomorphism and atypia, loss of maturation, dyskeratosis, and invasion into the bronchial wall or lymphatic channels. Treatment for squamous papillomas may include surgical excision, CO2 laser vaporization, and/or adjuvant antiviral or interferon therapy.10
Hamartomas contain disorganized tissues intrinsic to the lung and show peak incidence in the fourth to sixth decades.7 They are typically lobulated and encapsulated masses, which may be endobronchial or intraparenchymal. They are rare in children, but they may present as large parenchymal masses with respiratory distress. Chest computed tomography classically shows fat and "popcorn" calcifications, which suggest the diagnosis. Microscopically, cartilage, fat, and fibrous tissue are typically the most prominent components, although smooth muscle, bone, and entrapped respiratory epithelium also may be seen. Tumors with a single dominant component may be diagnosed as a chondroma, fibroma, or lipoma, although careful search may demonstrate foci of other mesenchymal elements.
Chondromas are benign cartilaginous tumors that occur as single or multiple encapsulated lesions that arise in continuity with bronchial cartilage and do not have other mesenchymal elements, as in the hamartomas described above (Figure 1, E). Pulmonary chondromas have been described in the Carney triad, a syndrome almost exclusively seen in young females comprising functioning paraganglioma, epithelioid gastrointestinal stromal tumor, and pulmonary chondroma.16,17 Due to potential complications of the associated lesions, children with pulmonary chondroma may benefit from periodic screening for metachronous development of paragangliomas or gastrointestinal stromal tumors.
Other Benign Tracheobronchial Lesions
Other benign tracheobronchial tumors reported in children include leiomyoma, granular cell tumor, and mucous gland adenoma. Primary solitary leiomyomas are benign smooth muscle tumors, histologically similar to leiomyomas in other locations, which may be asymptomatic or present as endobronchial masses with obstruction. Leiomyomas associated with EBV infection are discussed below. Multiple fibroleiomyomatous hamartomas (benign metastasizing leiomyomas) have been described in a child with a history of rhabdomyosarcoma.18 Bronchial granular cell tumors are reported rarely and have histologic features similar to those described in the oral cavity, comprising sheets of round cells with small nuclei and abundant granular eosinophilic cytoplasm. 7,9,19-21 The term bronchial adenoma is a misnomer previously used to refer collectively to 4 distinct lesions (carcinoid tumor, mucoepidermoid carcinoma, adenoid cystic carcinoma, and mucous gland adenoma). Bronchial mucous gland adenoma is the only benign lesion among these, and only 2 cases were described in a literature review up to 1983.7 Histologically, mucous gland adenomas are composed of a well-circumscribed mass of distended mucus-filled cysts and tubules lined by a single layer of columnar goblet cells. The differential diagnosis of endobronchial masses in children also includes reactive vascular lesions, including granulation tissue and pyogenic granuloma, chronic foreign body reaction, and granulomatous inflammation, for example, due to histoplasmosis or mycobacteria.10
Carcinoid tumors are considered low-grade neuroendocrine carcinomas due to their potential for locally aggressive growth and low potential for metastasis. These lesions are typically obstructive endobronchial masses of older children and adolescents (Figure 1, F), presenting with symptoms of wheezing, cough, hemoptysis, or pneumonia. 6,7,9,22-24 The carcinoid syndrome caused by production of neurosecretory peptides is very rare in the absence of metastatic disease. Carcinoid tumors have been reported to account for up to 80% to 85% of primary malignant lung tumors in children, although this is likely an overestimate. They may arise from the lobar bronchi (75%), mainstem bronchi (10%), or within the lung parenchyma (15%).6 Microscopic features include sheets, nests, and cords of monotonous small cells with stippled nuclear chromatin and a delicate vascular network in the background (Figure 1, G). Treatment is primarily surgical, and endoscopic resection is not recommended due to risk of hemorrhage and incomplete resection. Depending on location and size, complete excision and removal of involved lymphatics may be achieved with bronchial sleeve resection, lobectomy, or even pneumonectomy. Local invasion or distant metastasis has been reported in a significant percentage of children (27%), and overall survival in children is approximately 90%.6,9
Mucoepidermoid carcinoma (MEC) is reported to represent approximately 10% of malignant lung neoplasms in children. This tumor is rare in children, with just more than 30 cases of tracheobronchial MEC reported in the medical literature. Similar to carcinoid tumors, presenting symptoms may include recurrent pneumonia, respiratory distress, persistent cough, wheezing, or hemoptysis. Mucoepidermoid carcinoma arises in the tracheobronchial tree from the salivary-type mucous cells of the submucosa, most commonly occurring in the mainstem bronchus or a proximal lobar bronchus. These tumors are typically exophytic polypoid masses that cause bronchial obstruction (80% of cases).14,23,24 Grading of MEC in the tracheobronchial tree is similar to that in other salivary gland sites and is divided into low-, intermediate-, and high-grade tumors. Low-grade MEC is composed of predominantly mucous cells arranged in large cystic spaces, and it is the most common type described in the tracheobronchial tree in children.9 Intermediate- grade MEC is composed of predominantly intermediate cells and occasional mucous cells, forming a solid pattern with infrequent cysts and glands (Figure 1, H and I). High-grade MEC contains predominantly epidermoid cells and infrequent intermediate cells arranged in solid sheets, and it is characterized by increased pleomorphism and high mitotic activity. The low-grade tumors tend to have local tissue invasion but only rare metastasis.14 Treatment is primarily surgical, with chemotherapy and radiotherapy reserved for those tumors with incomplete resection.25 The 5-year survival rate of adults with MEC is 88%.25 The prognosis in children appears to be more favorable, with no deaths reported in the literature after surgical resection alone. Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is a slowly growing infiltrative salivary gland-type neoplasm that is rare in the tracheobronchial tree. Histologic features are similar to those seen in the salivary glands, consisting of cribriform, glandular, and solid patterns of small hyperchromatic cells. There is a tendency for submucosal spread, circumferential bronchial involvement, and late local recurrence. At the time of literature review in 1983, only 4 cases were reported in children.7 Treatment is complete surgical excision with or without adjuvant radiation therapy.25 Due to the infiltrative nature and tendency for local recurrence, frozen section examination may be helpful in assuring negative bronchial margins at the time of surgery. Adenoid cystic carcinoma has a higher likelihood of distant metastasis compared with mucoepidermoid carcinoma and has poorer survival (55% 5-year survival).25
Inflammatory Myofibroblastic Tumor
Previously called inflammatory pseudotumor or plasma cell granuloma, inflammatory myofibroblastic tumor is a slowgrowing tumor which shows characteristics of both reactive and neoplastic lesions.26-28 Although theorized to result from a repair response, antecedent injury cannot be documented in most cases. Although many tumors are asymptomatic (30%), others present with symptoms of cough or fever. Excluding respiratory papillomatosis, it is estimated that inflammatory myofibroblastic tumor accounts for approximately 52% to 70% of benign primary lung tumors reported in the literature in children.3,14 Most children with pulmonary inflammatory myofibroblastic tumor are older than 5 years (75%), but cases involving a few infants and young children are reported, and there is an equivalent sex distribution.7 Chest x-ray typically demonstrates a solitary well-circumscribed nodule, ranging in size from 1 to 12 cm. Grossly, these nodular lesions may be either endobronchial (17%; Figure 2, A) or intraparenchymal (83%).3,7 Histologic features include a proliferation of bland spindled and stellate cells with abundant eosinophilic cytoplasm, admixed with scattered inflammatory cells, including lymphocytes and, occasionally, prominent plasma cells and eosinophils (Figure 2, B). Immunohistochemistry for smooth muscle actin and/or muscle-specific actin may be helpful in demonstrating the myofibroblastic nature of these cells. Treatment is primarily surgical, and complete but conservative surgical excision is recommended. Inflammatory myofibroblastic tumors have a tendency for local recurrence if incompletely excised.
Myofibromas are relatively common benign soft tissue tumors in children, most often presenting as a firm nodular mass in the subcutaneous or deep soft tissue. Although most often solitary, they may be multifocal and involve both soft tissue and visceral organs, so-called myofibromatosis (Figure 2, C). Myofibromatosis is more often diagnosed in infants and young children than in older children. The cellularity of these lesions varies, often showing some hypocellular hyalinized zones as well as other zones of hypercellularity. Characteristic protrusion of bland spindled cells into adjacent vasculature is occasionally seen and should not be interpreted as an aggressive feature. Hemangiopericytomatous vasculature may be prominent. Pulmonary involvement by myofibromatosis may be a manifestation of multifocal systemic disease or regional involvement of the chest wall. Multifocality in the lung should not be misinterpreted as aggressive or metastatic disease.
Congenital Peribronchial Myofibroblastic Tumor
Congenital peribronchial myofibroblastic tumor is a very rare and distinctive benign lung tumor of the fetus and infant, with only approximately 25 cases reported previously in the medical literature.29-33 It has been described under various terminology, including massive congenital mesenchymal malformation of the lung, hamartoma of the lung, bronchopulmonary leiomyosarcoma, and primary bronchopulmonary fibrosarcoma.29 The tumor is thought to arise from the pluripotent mesenchyme found around the developing bronchi at approximately 12 weeks' gestation, with potential for both smooth muscle and cartilaginous differentiation. Interestingly, congenital peribronchial myofibroblastic tumor is morphologically similar to 2 other types of myofibroblastic tumors presenting in the neonatal period: congenital mesoblastic nephroma (classic type) and congenital spindle cell tumor of the intestinal tract. Congenital peribronchial myofibroblastic tumor typically presents in utero or at birth as a large 5- to 7-cm unilateral lung mass with mediastinal shift and resulting in intrauterine polyhydramnios, hydrops, or immediate respiratory failure at delivery. Grossly, nearly the entire lung or a large portion of the lung is typically enlarged and replaced by a firm rubbery mass with a yellow-tan to gray whorled cut surface containing bands of fibrous-appearing tissue (Figure 2, D). Microscopically, bland spindled cells form large fascicles following the planes of the bronchovascular bundles, interlobular septa, and pleura, often forming a distinctive lobular compartmentalization of the lung parenchyma (Figure 2, E). The tumor fascicles are extrinsic to the airways but surround, displace, and distort the airway structures. Malformed and enlarged cartilage plates adjacent to entrapped airways are a prominent component of some tumors. Occasional foci of extramedullary hematopoiesis may be seen. Mitotic figures may be frequent, but there is no cytologic atypia or atypical mitoses. The lesion tends to be more uniform in cellularity, in contrast to other myofibroblastic tumors. Immunohistochemistry shows diffuse positivity for vimentin and focal desmin, muscle-specific actin, or smooth muscle actin positivity.30,32 Flow cytometric DNA ploidy analysis has shown a normal diploid population.32 Cytogenetic study in 1 case has shown a complex rearrangement of chromosomes 4, 8, and 10.30 Electron microscopy shows spindled cells with dilated rough endoplasmic reticulum, scarce mitochondria, occasional lipid droplets, and scant cytoplasmic filaments, some with dense bodies and attachment plaques, consistent with myofibroblastic differentiation. 29,30,32 Although the lesion is cytologically bland, the large size often results in respiratory or hemodynamic compromise and has resulted in a high mortality rate in reported cases (55% in 1 series).32 If early resection is achieved, typically by pneumonectomy or bilobectomy, long-term survival is expected.30
Neurogenic tumors of the lung may include neurofibroma, schwannoma, malignant peripheral nerve sheath tumors, and mucosal neuromas. A series of intrapulmonary neurogenic tumors has shown 26% (9/34) occurring in children younger than 16 years.34 Of these 9 tumors in children, all were benign, including 4 neurofibromas and 5 schwannomas. Although most pulmonary neurofibromas are nonsyndromic, the possibility of neurofibromatosis should always be considered in a child with a pulmonary neurofibroma.
Infantile hemangioma is a lobular proliferation of small capillaries that typically appears in the first weeks of life and shows a period of involution during the ensuing months (Figure 3, A). The early proliferating lesions may be highly cellular and mitotically active, whereas involuting lesions have less capillary density with more widely spaced and dilated thick-walled capillaries. Both proliferative and involuting lesions are characterized by endothelial positivity for the glucose transporter Glut-1 (Figure 3, B), a marker that distinguishes the infantile hemangioma from most other vascular anomalies, including rapidly involuting and noninvoluting congenital hemangiomas, vascular malformations, and pyogenic granulomas. While infantile hemangiomas are most commonly found in the skin and soft tissue, visceral involvement also occurs, both as isolated lesions and as a component of multifocal systemic distribution of disease (hemangiomatosis).35 Tracheobronchial and parenchymal hemangiomas are identified occasionally due to symptoms of obstruction or recurrent hemoptysis.1,10 Lesions of the subglottis and upper trachea are more common than the distal tracheal or endobronchial lesions.10 Intraparenchymal hemangiomas are very rare, but may be a component of multifocal systemic lesions in diffuse neonatal hemangiomatosis.
It should be noted that pulmonary capillary hemangiomatosis is a different entity than the multifocal infantile hemangiomas of diffuse neonatal hemangiomatosis. Pulmonary capillary hemangiomatosis is a rare, poorly defined lesion associated with pulmonary hypertension and composed of a diffuse proliferation of capillaries within the alveolar walls without formation of a mass lesion.36,37 Primarily seen in adults, pulmonary capillary hemangiomatosis has been associated with pulmonary veno-occlusive disease in some cases, and it may represent a postobstructive reactive proliferation of capillaries distal to thrombosis. Lymphatic Malformations and Lymphangiomatosis
Although lymphatic malformations are common lesions in infants and young children, solitary lymphatic malformations (lymphangiomas) occur rarely in the lung, forming localized multicystic masses (Figure 3, C). In contrast, lymphangiomatosis is a proliferation of lymphatic channels involving the lung more diffusely, typically in a septal and pleural pattern of distribution. Secondary hemorrhage and muscularization of the lymphatic channels in lymphatic malformations may produce confusion with a venous malformation, and the lymphatic marker D2-40 is helpful in confirming the lymphatic origin of the vessels.
Like hemangiomas and lymphatic malformations, venous or mixed vascular malformations may produce mass lesions in the lung parenchyma. Arteriovenous malformations may be multiple and produce right-to-left shunting, resulting in high-output cardiac failure and cyanosis. They are more often diagnosed by imaging techniques and are diagnosed uncommonly in surgical pathology specimens (Figure 3, D and E). The presence of multiple arteriovenous malformations should raise consideration of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).
OTHER BENIGN PARENCHYMAL TUMORS
Teratomas within the lung parenchyma are reported as isolated cases, including only 2 case reports before 1983.7,39-41 Pericardial or anterior mediastinal teratomas are more common, and they may show secondary involvement of the adjacent lung parenchyma by direct extension. Primary teratomas of the lung are typically large cystic and solid masses confined to the lung parenchyma, and most contain derivatives of all 3 germ cell layers. Primary malignant germ cell tumors of the lung are exceedingly rare, although choriocarcinoma has been reported.
Lipoblastoma is a benign tumor of adipose tissue typically characterized by an admixture of immature lipoblast in a vascular myxoid matrix, juxtaposed with zones of mature adipose tissue. Lipoblastomas occur most often in the soft tissue of infants and young children, but they may also involve the viscera, including the lung (Figure 4, A).
Ectopic tissues occasionally form nodular lesions of the lung. Rhabdomyomatous dysplasia is a rare entity composed of benign skeletal muscle cells within the lung parenchyma, most often seen incidentally within lung malformations, such as extralobar sequestration. Rarely, rhabdomyomatous dysplasia forms a nodular focus of skeletal muscle cells in otherwise normal lung (Figure 4, B and C). Ectopic adrenal gland tissue and ectopic glial tissue have also been reported as nodular lesions in the lung.38
Pleuropulmonary blastoma (PPB) is a rare malignant embryonal mesenchymal neoplasm of the lung and pleura occurring almost exclusively in children that was described as a unique entity distinct from pulmonary blastoma in 1988.42 In contrast to the adult- type biphasic pulmonary blastoma (PB), PPB is a polyphenotypic mesenchymal malignancy without an epithelial component. It has been reported previously in the medical literature under a variety of descriptors, including pulmonary blastoma, mesenchymal cystic hamartoma, malignant mesenchymoma, and sarcomas (myxosarcoma or rhabdomyosarcoma) arising in congenital cystic malformations.43-47 Pleuropulmonary blastoma is diagnosed primarily in infants and toddlers, and rarely beyond age 12 years. Occurrence in adults is reported but extremely rare.48 These lesions may be detected incidentally in utero or postnatally. 15 Symptomatic presentation may result from spontaneous pneumothorax in the cystic lesions.49
Pleuropulmonary blastoma is subclassifed based on the spectrum of gross morphology: purely cystic lesions (type I), solid and cystic lesions (type II), and purely solid lesions (type III).49 Age at presentation varies depending on morphologic type, with the type I lesions most often diagnosed in infancy (average age, 10 months), and the type II and type III lesions more often diagnosed in toddlers (average ages, 34 and 44 months, respectively).50,51 Grossly, the low-grade cystic lesions (type I) are typically peripheral and pleural-based lesions, sometimes protruding from the pleural surface (Figure 5, A). They are entirely cystic, with no solid components or nodules and are grossly indistinguishable from the large-cyst (Stocker type I) congenital pulmonary airway malformation (CPAM). Microscopically, they are virtually identical to what has been described as the peripheral cyst (Stocker type IV) CPAM. Type I PPBs have thin cyst walls lined by predominantly alveolar-type epithelium and containing focal areas of hypercellularity and hypervascularity (Figure 5, B and C). The hypercellular foci are composed of hyperchromatic compact spindled cells and small round cells, often forming a cambium-like layer beneath the epithelium lining the cyst walls. Foci of immature- appearing cartilage are present in some cases. The higher grade lesions (type II and type III) have solid components on gross examination. Although entirely solid, the type III PPB may have areas of necrosis and cystic degeneration. The solid components of both type II PPB (Figure 5, D) and type III PPB (Figure 5, E through H) also show higher grade cytologic features, with sheets of spindled and pleomorphic, sometimes anaplastic cells, resembling rhabdomyosarcoma. Fibrosarcoma-like areas and chondroid nodules are other recognized patterns. It should be noted that type I lesions may progress to the higher grade type II or type III lesions, particularly if incompletely excised.
Immunohistochemistry of PPB demonstrates vimentin in the primitive cell component, as well as myogenic differentiation in some cases, specifically with expression of desmin, muscle specific actin, smooth muscle actin, myogenin, and/or myoglobin. Electron microscopy may also show evidence of rhabdomyoblast differentiation with myofibrils and z-band formation, as well as loose granular matrix and abundant rough endoplasmic reticulum, indicating chondrocytic differentiation.49,50 Cytogenetic analysis of PPB has been described in a small number of cases, primarily of higher grade lesions. Although a tumor-specific translocation has not been identified, there may be a variety of karyotypic abnormalities (trisomy 8, trisomy 2, and 17p deletions), and mutations in p53 have been described. 52-54
Pleuropulmonary blastoma may be solitary or multiple, and additional lesions may be discovered synchronously or metachronously in the same patient. Interestingly, PPB may have familial predisposition, and genetic studies are ongoing through the International Pleuropulmonary Blastoma Registry.55 In approximately 25% of cases, PPB is associated with other extrapulmonary lesions in the same patient or family members.49 The most common associated lesion is cystic nephroma, but other embryonal tumors (sarcomas, medulloblastoma, malignant germ cell tumors), thyroid neoplasms, leukemia, Hodgkin lymphoma, and Langerhans cell histiocytosis (LCH) have been associated with PPB.56
Clinically, the diagnosis of PPB is infrequently entertained preoperatively.15 Pathologists must consider the diagnosis of PPB for any child with a spherical unilocular or multiloculated cystic lesion, mixed solid and cystic lesion, or large solid mass in the lung, particularly if the lesion distorts the contour of the lung, is positioned peripherally, or is found to protrude from the pleural surface. The differential diagnosis includes the more common benign cystic lung malformations, as well as other rare primary sarcomas of the lung. The most common submitting diagnosis and the principal pathologic differential diagnosis for cystic type I PPB is CPAM (also called congenital cystic adenomatoid malformation [CCAM]).57 The large-cyst (Stocker type I) CPAM and the peripheral cyst type (Stocker type IV) CPAM are grossly identical to cystic PPB. The large-cyst CPAM is distinguished easily microscopically by a cyst lining composed predominantly of respiratory type epithelium, with or without focal mucigenic epithelium, often resembling small foci of gastric foveolar epithelium. The respiratory epithelial lining shows interdigitation with surrounding airspaces, which may be secondarily enlarged and maldeveloped. The peripheral cyst (Stocker type IV) CPAM is much more problematic to distinguish from cystic PPB and, in fact, it has been suggested that many examples of type IV CPAM may actually represent unrecognized or insufficiently sampled cystic PPBs.58,59 Stocker describes CPAM type IV as having thin cyst walls lined by alveolar-type epithelium and with increased vascularity of the septa. Cystic PPB has a similar architecture, but it is distinguished by the identification of hypervascular and hypercellular foci of primitive cells in the cyst walls, a focal and subtle finding in many cases due to the low-grade cytology. Any lesion mimicking type IV CPAM on initial microscopic sections requires extensive sampling to exclude the presence of these hypercellular foci. The differential diagnosis of the solid and cystic or purely solid lesions includes other primary sarcomas of the lung, including rhabdomyosarcoma and synovial sarcoma. Some cases initially reported as rhabdomyosarcoma of the lung likely represent highgrade PPB.49,60 The lesion described in the literature as "mesenchymal hamartoma of the lung" in children is also more appropriately classified as PPB.61,62 Finally, as mentioned above, PPB should be distinguished from the rare adult-type PB, a tumor most often presenting in the fourth or fifth decade of life, which has an associated epithelial component not present in the childhood lesion.63,64 Entrapment of alveolar or bronchiolar epithelium by PPB may also mimic PB. In the pediatric population, a sarcomatous lesion with a glandular-appearing epithelial component mimicking biphasic PB should prompt consideration of synovial sarcoma. Treatment for PPB is primarily surgical for the cystic (type I) lesions, although adjuvant chemotherapy may be advantageous in cases with incomplete resection. Certainly, the higher grade (type II and type III) lesions require adjuvant chemotherapy after resection, and radiation therapy is recommended for residual disease. In either case, close clinical follow-up is warranted due to potential for recurrence, metastasis, multifocality, and associated extrapulmonary lesions. Low-grade cystic lesions may recur as a higher grade lesion, and this potential justifies chemotherapy for some type I tumors. Metastasis occurs in approximately 30% of types II and III tumors, and may occur late in the disease course. The most commonly reported sites of metastasis include the central nervous system and bone.50 Five-year survival rate is 83% for type I PPB and 42% for types II and III PPB.50
Although rare, synovial sarcoma is one of the more common primary sarcomas of the lung in children. Diagnostic features are similar to those seen in other sites, and morphology may be monophasic or biphasic (Figure 6, A and B). Immunohistochemistry for cytokeratin, epithelial membrane antigen, CD99, and BCL2 are typically positive. Cytogenetic analysis and/or molecular diagnostic testing is helpful in demonstrating the characteristic t(X;18) translocation, producing an SSX-SYT fusion transcript.
Ewing Sarcoma Family of Tumors
The Ewing sarcoma family of tumors includes Ewing sarcoma of bone and soft tissue, as well as peripheral primitive neuroectodermal tumor. These tumors are unified by the rearrangement of the Ewing sarcoma gene with one of a variety of fusion partner genes, most commonly Fli-1, produced by a characteristic t(11;22)(q24 ; q12) translocation. By immunohistochemistry, the Ewing sarcoma family of tumors characteristically demonstrates membranous staining with CD99, an important diagnostic feature in clinical practice. In addition, primitive neuroectodermal tumors show evidence of neural differentiation, either by immunohistochemistry or electron microscopy. On a practical level, distinguishing primitive neuroectodermal tumor from Ewing sarcoma is unnecessary, as treatment is the same for both, and there is conflicting evidence for any prognostic difference between primitive neuroectodermal tumor and Ewing sarcoma. Although the Ewing sarcoma family of tumors may occur anywhere in the body, including soft tissue, bone, and viscera, the chest wall is one site of predilection, so-called Askin tumor of the thoracopulmonary region. Chest wall involvement may result in a mass with intrathoracic growth, lytic destruction, and fusiform expansion of ribs, cortical thickening, little or no periosteal reaction, and pleural effusion. 8 Involvement of the pleural cavity with extension into the lung parenchyma is not uncommon and may lead to partial resection of lung with chest wall resection. Rarely, these tumors may arise primarily in the lung, but they most often originate in the rib or chest wall.
While several cases of pulmonary rhabdomyosarcoma reported in the literature likely actually represent cases of pleuropulmonary blastoma, true primary rhabdomyosarcoma of the lung also occurs, often manifesting as an endobronchial mass.7,65,66 Pulmonary rhabdomyosarcoma is estimated to represent approximately 0.5% of all rhabdomyosarcomas in children.3 After Ewing sarcoma family of tumors, rhabdomyosarcoma is the second most common malignancy of the chest wall in children, and it may produce direct involvement of the thoracic cavity or pulmonary metastasis in this setting.8
A few cases of bronchopulmonary leiomyosarcoma have been reported in children.67-71 Rare cases in newborns may, in fact, represent congenital myofibroblastic tumor, rather than true leiomyosarcoma.67 Potentially arising from either bronchial or vascular smooth muscle, these lesions may be located in the tracheobronchial tree or in the parenchyma. Leiomyosarcoma in older children may show aggressive local invasion, metastasis, and poor prognosis. Nuclear atypia, necrosis, and hemorrhage distinguish leiomyosarcoma from both leiomyomas and the myofibroblastic tumors. Epstein-Barr virus is associated with some lesions in the immunocompromised population (see below).
Primary bronchial fibrosarcoma in children is considered to be the equivalent of congenital infantile fibrosarcoma of soft tissues. It is quite rare, with 26 cases reported in the literature to 1989.1 Grossly, bronchopulmonary fibrosarcoma may form an endobronchial polyp or intraparenchymal mass. Histologically, it is composed of cellular sheets and interlacing bundles of spindle cells, often with focal hemorrhage. The mortality associated with bronchopulmonary fibrosarcoma is 21%, with metastatic disease reported in 2 of 26 cases.72
A number of other types of sarcomas have been reported as primary lung neoplasms in children, including angiosarcoma, Kaposi sarcoma, malignant peripheral nerve sheath tumor, and liposarcoma.73 The spectrum of pulmonary and thoracic sarcomas has been reviewed elsewhere. 74,75
Bronchogenic carcinoma is most common in adults 55 to 75 years of age, and it is rare in individuals younger than 40 years, accounting for 1.2% of all patients with lung cancer.76-88 Patients 18 to 30 years old diagnosed with lung cancer have a higher incidence of female sex, no association with smoking history, and more favorable prognosis.89 Survival in these young patients is associated primarily with stage, but it is not dependent on sex, age younger or older than 30 years, smoking history, histologic type, or degree of differentiation.90 Lung cancer in children and adolescents younger than 18 years is extremely rare, with 0.16% of all lung cancers occurring in the first decade of life and 0.7% in the second decade.91 As of 1983, a review of the medical literature included 47 children reported to have "bronchogenic carcinoma," representing approximately 17% of reported primary lung malignancies in children. 3,7 Almost certainly an overestimate of true incidence, this percentage appears to be inflated by cases in the older medical literature. The actual incidence of bronchogenic carcinoma in children is difficult to determine and is limited to individual case reports and small case series in the modern era.92 A 21-year review of pediatric primary epithelial lung malignancies from Memorial Sloan-Kettering Cancer Center yielded a total of 11 patients (age range, 12-21 years) with pathologic diagnoses of adenocarcinoma (4, including 1 well-differentiated fetal adenocarcinoma), basaloid carcinoma (2), carcinoid tumor (4), and MEC (1).93 A 24-year review of the records from Boston Children's Hospital (1957-1981) revealed 6 primary bronchial tumors in children, with no cases of bronchogenic carcinoma.9 In 1999, Mizushima et al89 reported a large series of young lung cancer patients (26 patients younger than 30 years), none of whom were younger than 18 years. Our current 25- year cumulative experience, including both institutional and consultation cases, includes 23 primary lung malignancies, but only 1 case of bronchial squamous cell carcinoma in a 6-year-old child, and no cases of adenocarcinoma.
Reported cases of pediatric lung carcinoma in the medical literature are most commonly undifferentiated carcinoma, followed by adenocarcinoma and squamous cell carcinoma. It is difficult to determine whether the historical cases of undifferentiated carcinoma truly represent small cell carcinoma or perhaps atypical carcinoid tumors. Adenocarcinoma may result in consolidation of a lobe or "white-out" of a lung, with or without pleural effusion.92 The 3 patients with conventional pulmonary adenocarcinomas in the Memorial Sloan-Kettering series all presented with stage IV disease, and 2 had rapidly progressive fatal disease within 2 months of diagnosis.93 Well-differentiated fetal adenocarcinoma, also called pulmonary endodermal tumor, is an extremely rare variant of adenocarcinoma for which there are only isolated reports in children. 93,94 Thought to be related to pulmonary blastoma, this tumor is composed of complex branching tubules and glands and has been compared with fetal lung in the pseudoglandular stage of development. Unlike conventional pulmonary adenocarcinoma, well- differentiated fetal adenocarcinoma has a relatively good prognosis, with only 15% mortality.93 Bronchioloalveolar carcinoma has been reported rarely arising from CPAM (Figure 7, A through C).94-104 The mucigenic epithelium of the type I CPAM is the purported precursor cell for bronchioloalveolar carcinoma in this setting.105-107
Squamous cell carcinoma (Figure 7, D) seems to account for a smaller proportion of lung carcinoma cases in children (12%) relative to adults (35%-50%).7 Only 6 cases of bronchogenic squamous cell carcinoma were reported in children until 1995, with an age range of 1 to 15 years.108 A pathogenetic relationship with human papillomavirus has been proposed, given the known potential for progression of respiratory papillomatosis to squamous cell carcinoma.109 A minute squamous cell carcinoma has also been reported in the wall of a congenital lung cyst.110 Basaloid carcinoma, a rare variant of non-small cell lung carcinoma described in 1992, has been reported recently in the pediatric population.93 It is an aggressive tumor thought to arise from the basal bronchial epithelial stem cells and is characterized microscopically by small cells growing in a characteristic nesting pattern with peripheral palisading.93
Primary lung carcinoma in children may be aggressive, with frequent metastatic disease at diagnosis, high mortality (90%), and average survival of 7 months after diagnosis. 3,7 Symptoms may include cough, chest pain, pneumonia, or hemoptysis due to local effects, but initial presentation may also be heralded by bone pain, weight loss, or anemia due to metastatic disease. Delay in diagnosis and metastasis at presentation has led to generally poor survival in the few cases of bronchogenic carcinoma in children reported.108 DIFFUSE MALIGNANT MESOTHELIOMA
Primary pleural neoplasms in the pediatric population are quite rare, representing 2 of 1925 pleural lesions in 1 series.111 Diffuse malignant mesothelioma is extremely rare in children, with only 4.5% of mesotheliomas in 1 series occurring in patients younger than 21 years.112 There is no clear causal relationship with asbestos exposure in children, although a history of possible asbestos exposure has been reported in isolated pediatric cases.113 Diffuse malignant mesothelioma may also occur as a second malignancy following radiation therapy, and there is one report of pediatric mesothelioma associated with prenatal isoniazid exposure.114 Three large series of diffuse malignant mesothelioma in children have shown pleural involvement in 72% of cases (18/25 total patients), with an age range of 4 to 19 years.113,115,116 Reported mortality in children ranges from 50% to 71%.113,115,116 Histologic patterns are similar to those seen in adults, and they have included epithelial, mixed, and fibrous types, as well as papillary, tubuloglandular, solid, and sarcomatoid patterns. 4,113,115
PRIMARY LUNG TUMORS IN IMMUNOSUPPRESSED AND IMMUNOCOMPROMISED CHILDREN
Lymphoma and Lymphoproliferative Disorders
All immunodeficiency states carry a higher risk of lymphoma relative to the immunocompetent population, including patients with human immunodeficiency virus (HIV) infection, solid organ transplant, bone marrow transplant, and congenital immunodeficiencies. These lymphomas are most often high-grade or intermediategrade non-Hodgkin lymphomas, typically diffuse large Bcell lymphomas, and often involve extranodal sites. Burkitt lymphoma, Burkitt-like lymphoma, Hodgkin lymphoma, and human herpesvirus 8-associated primary effusion lymphoma also are reported with higher incidence in the HIV-infected population.117
Epstein-Barr virus-driven lymphoproliferative disorders occur most commonly in immunosuppressed recipients of solid organ or bone marrow transplants (posttransplant lymphoproliferative disorder [PTLD]), as well as children with primary immunodeficiency (Figure 8, A). In general, PTLD is most common after heart, lung, or heartlung transplantation (5%-13% of patients) and less common after liver, kidney, or bone marrow transplantation (1%-3%).117 Lung involvement by PTLD manifests as periairway and parenchymal nodular and interstitial lymphoid infiltrate, and primary involvement of the lung is highest in lung transplant or heart-lung transplant recipients. The pathogenesis of PTLD is related to EBV-stimulated B- lymphocyte proliferation, which is unopposed due to iatrogenic inhibition of regulatory T-lymphocyte function, and the biologic spectrum ranges from polymorphous to monomorphous and may be polyclonal, oligoclonal, or monoclonal. The monoclonal forms most often resemble diffuse large B-cell lymphoma and may be associated with regions of necrosis. Epstein-Barr virus DNA probes are positive in most PTLDs but may be negative, particularly late (more than 5 years) after transplantation. Flow cytometric analysis is an essential component of the diagnostic evaluation of suspected PTLD and allows determination of clonality. Reduction of immunosuppression is the first-line management of these disorders, with or without anti-CD20 antibody therapy (rituximab), although cytotoxic chemotherapy may also be necessary for treatment of persistent lesions and the more aggressive monoclonal forms of PTLD.
Smooth Muscle Tumors
(Leiomyoma and Leiomyosarcoma)
Epstein-Barr virus-associated smooth muscle tumors have been described in children with HIV/AIDS (Figure 8, B and C), as well as solid organ transplant recipients and children with primary immunodeficiency.118-122 These tumors may be solitary or multifocal, and site of predilection include the gastrointestinal and respiratory tracts. Similar to the EBV-driven lymphoproliferative tumors, there is a spectrum from benign to malignant morphology, that is, leiomyoma and leiomyosarcoma, and there is potential for regression of tumors with modulation of immunosuppression. Epstein- Barr virus DNA probes are typically strongly positive in these tumors (Figure 8, D).
Kaposi sarcoma associated with human herpesvirus 8 infection may occur in HIV-infected patients and following solid organ transplantation. Although cutaneous Kaposi sarcoma typically predominates clinically, visceral involvement may occur, most often affecting lymph nodes, the gastrointestinal tract, or the lungs. Pulmonary involvement may produce endobronchial or parenchymal violaceous lesions, and it is a cause of pulmonary hemorrhage, cough, and dyspnea in this population.
SECONDARY INVOLVEMENT OF THE LUNG IN SYSTEMIC DISEASE
Langerhans Cell Histiocytosis
In adults, LCH in the lung typically occurs as a solitary nodule in smokers, previously called eosinophilic granuloma.123 In children, LCH in the lung typically reflects involvement by systemic disease rather than isolated lung involvement.124 Langerhans cell histiocytosis occurs most often in infants and young children, and presenting signs may include a rash, bone lesions, or pituitary involvement. Skeletal survey may show punched-out lytic bone lesions of the skull or other long bones. If there is lung involvement, chest computed tomography may show a reticulonodular pattern with nodules ranging from 1 to 10 mm in diameter, larger cavitary nodules, pneumatoceles, bilateral cystic disease, and/or pneumothorax.8 Histologically, LCH typically demonstrates patchy infiltrates involving the interstitium, pleura, and bronchovascular bundles (Figure 9, A). Extension of LCH cells into the alveolar spaces is often associated with the infiltrates expanding the alveolar walls. The histiocytes have typical indented and grooved nuclei and may be admixed with occasional eosinophils. If necessary, confirmation of Langerhans cell phenotype is achieved using immunohistochemistry for CD1a (Figure 9, B) or Langerin (CD207). S100 is also positive but less specific than CD1a or CD207. Electron microscopy demonstrates characteristic pentalaminar rods with bulbous ends (Birbeck granules) formed by internalized invaginations of the cell membrane. The differential diagnosis of interstitial infiltrates and histiocytic nodules includes leukemia, granulomatous processes, and non-LCH, such as juvenile xanthogranuloma (Figure 9, C and D).
Leukemia and Lymphoma
Although pulmonary infiltrates in leukemia patients prompt primary consideration of infection, leukemic infiltration of the lung may cause a similar pattern radiographically. Lung involvement by leukemia usually manifests as patchy interstitial, septal, or pleural infiltrates (Figure 10, A and B), in contrast to non- Hodgkin and Hodgkin lymphoma, which tend to form larger, well- circumscribed nodules obscuring the background lung parenchyma (Figure 10, C and D). An associated mediastinal mass or hilar adenopathy are variable features. The differential diagnosis for lymphoma involving the lung in children includes primarily Hodgkin lymphoma, non-Hodgkin lymphoma (acute lymphoblastic lymphoma, Burkitt lymphoma [Figure 10, E], diffuse large B-cell lymphoma), and PTLD. Other types of pulmonary lymphoid proliferations have been reviewed by Colby and Yousem.125
METASTATIC SOLID TUMORS OF CHILDHOOD
Metastatic tumors account for approximately 80% of all lung tumors in children and more than 95% of malignant tumors of the lung in this population.14 Although a wide variety of sarcomas and embryonal tumors of childhood produce lung metastases in children, Wilms tumor and osteosarcoma are the most frequent.2 Metastases appear as single or multiple circumscribed nodules, often peripheral and preferentially involving the lower lobes in those with hematogenous spread.2 A reticular or military pattern may occur with those demonstrating lymphangitic spread. Cavitation and pneumothorax are rare but are features most often associated with Wilms tumor, Hodgkin lymphoma, and osteosarcoma.6
While some metastatic lung nodules are excised for diagnosis and staging, others are removed as a part of oncologic management to achieve long-term survival and effect cure. Kayton126 has recently provided an excellent review of clinical indications and surgical techniques used for pulmonary metastasectomy in pediatric patients. This approach began in the 1950s but achieved greater popularity after 1971, when survival advantage was reported in osteosarcoma patients with excision of metastatic lesions (3-year survival of 45% vs 5%, with and without metastasectomy).126 Long-term survival (more than 20 years from diagnosis) can also be achieved in some patients with aggressive and repeated excision of lung nodules. It is also now recognized that the effectiveness of surgical management for metastatic tumor is dependent on histologic type. Currently, pulmonary metastasectomy remains most common for osteosarcoma due to the demonstrated survival advantage of repeated wedge excisions for metastatic disease. Metastasectomy also plays a central role in management for other tumor types that are resistant to chemotherapy and radiation therapy, such as adrenocortical carcinoma and chondrosarcoma. Conversely, surgical management of metastatic disease is uncommon for chemosensitive and radiosensitive malignancies, such as Wilms tumor, Ewing sarcoma, neuroblastoma, rhabdomyosarcoma, thyroid carcinoma, and germ cell tumors. Clinical features and management principles are discussed briefly below for pulmonary metastasis in selected pediatric solid tumors. Osteosarcoma
In addition to the sporadic cases, osteosarcoma occurs with increased frequency in children with p53 mutations in the Li- Fraumeni syndrome, in children with Rothmund-Thomson syndrome, in retinoblastoma patients, and as a second malignancy in children treated with alkylating agents. Approximately 10% to 15% of children with osteosarcoma will have pulmonary metastasis at presentation (Figure 11, A and B).127 Pulmonary metastases are typically asymptomatic and detected by imaging studies. Large studies have demonstrated a strong correlation between complete resection of primary and metastatic lesions at presentation and overall survival.126 Repeated excision of additional lung metastases is often necessary and provides additional survival benefit. Excision of metastatic lesions should be complete due to the proven survival benefit, and is indicated even after demonstrated chemotherapy response.
The lung is the most common site of metastasis in Wilms tumor (Figure 11, C), the second most common malignant solid tumor of childhood. Pulmonary metastases are typically detected by imaging rather than by clinical symptomatology. Patients with favorable histology Wilms tumor and pulmonary metastasis have a good prognosis, with approximately 75% 4-year survival.128 Pulmonary nodules in patients with Wilms tumor may be excised for staging at initial diagnosis, but there is a limited role for metastasectomy for oncologic management in the United States. Metastasectomy for Wilms tumor is more commonly used in European centers to spare effects of radiation therapy, but North American centers have not adopted this approach as standard therapy. Based on National Wilms Tumor Study group data, patients with favorable histology Wilms tumor have excellent survival after chemotherapy and/or radiation therapy only, with acceptably low rates of radiation pneumonitis. Nevertheless, excision of metastases has been used selectively in individual Wilms tumor patients with lesions refractory to chemotherapy or radiation therapy, or in patients prior to bone marrow transplant.126
Children with neuroblastoma rarely present with lung metastases, with an incidence at diagnosis of only 0.4% to 3.2%.126 When involving the lung, metastatic neuroblastoma also typically involves other organs, in which case systemic chemotherapy is more appropriate than pulmonary metastasectomy. In the case of isolated pulmonary nodules, however, excisional biopsy may be indicated to confirm diagnosis and staging prior to chemotherapy.
Prognosis for rhabdomyosarcoma patients with pulmonary metastasis is generally poor, and concurrent extrapulmonary disease is common. Relative to children with extrapulmonary metastases, children with isolated pulmonary disease more commonly have nonalveolar histology, parameningeal primary site, and lack of lymph node involvement. Overall survival is better for patients younger than 10 years in this group and for those who received radiation therapy. There is currently no standard role for surgical resection of metastases other than for biopsy confirmation of diagnosis and perhaps resection of isolated lesions.126
Ewing Sarcoma Family of Tumors
Ewing sarcoma (Figure 11, D and E) is generally sensitive to both chemotherapy and radiation therapy, and these are the mainstays of management for metastatic disease, as survival advantage after pulmonary metastasectomy has not been clearly demonstrated. Surgical excision of metastatic lesions at this time is typically performed for confirmation of diagnosis and remains controversial for resection of limited pulmonary disease.
Other Soft Tissue Sarcomas
Metastasectomy is a component of therapy for other types of sarcomas, including alveolar soft part sarcoma, synovial sarcoma, chondrosarcoma, fibrosarcoma, and malignant fibrous histiocytoma, and the approach is generally similar to that used for osteosarcoma.126 In particular, alveolar soft part sarcoma has a high incidence of lung metastasis (60% of pediatric patients), and because it shows incomplete response to chemotherapy, surgical resection is a necessary component of oncologic management. 126
Pulmonary metastases of hepatoblastoma may completely respond to chemotherapy, allowing long-term survival. For unresponsive or partially responsive tumors, however, extended survival may be achieved by pulmonary metastasectomy following chemotherapy, leading to a combined approach in such patients.
Mortality is very low for pediatric thyroid cancer. Despite frequent lymph node metastasis, prognosis is generally favorable, and very few patients develop distant metastasis. When present, pulmonary metastases tend to produce a miliary pattern of disease which would not allow resection by metastasectomy. Instead, the primary therapeutic modality for pulmonary metastases of thyroid carcinoma is radioactive iodine (131I) treatment, and it allows complete radiographic resolution of disease and long-term survival in many cases. Metastasectomy is reported for diagnostic purposes, but otherwise it is not a routine component of oncologic management.
Pulmonary metastases are relatively frequent in patients with stage IV adrenocortical carcinoma (Figure 11, F) and, based on experience with adults, excision of these lesions results in dramatically increased 5-year survival (71% vs 0%, with and without metastasectomy).126Metastasectomy is recommended early after detection and should be complete, preventing recurrence and/or tumor spillage into the thoracic cavity.
If a metastatic nodule is removed after chemotherapy, evidence of treatment effect may include necrosis, fibrosis, or hemosiderin deposition. Cytodifferentiation after chemotherapy occurs in some embryonal neoplasms, for exampl