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Primary and Metastatic Lung Tumors in the Pediatric Population

A Review and 25-Year Experience at a Large Children’s Hospital

Megan K. Dishop, MD; Supriya Kuruvilla, MD

Context.—Primary lung neoplasms are rare in children, but they comprise a broad and interesting spectrum of le- sions, 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 pri- mary and metastatic lung tumors in children and adoles- cents 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 chil- dren, and to provide recommendations for handling pedi- atric 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 con- sultation, 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 neo- plasms is 1.4:1:11.6. The common types of lung cancer in adults are exceptional occurrences in the pediatric popu- lation. The most common primary lung malignancies in children are pleuropulmonary blastoma and carcinoid tu- mor. Other primary pediatric lung tumors include congen- ital peribronchial myofibroblastic tumor and other myofi- broblastic lesions, sarcomas, carcinoma, and mesothelio- ma. 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)

P rimary lung neoplasms are rare in children. Lung mas- ses 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 met- astatic tumors to nonneoplastic lesions of 1:5:60. 1 Common malformations forming solid and cystic masses of the pe- diatric lung include bronchogenic cyst, segmental bron- chial atresia, intralobar and extralobar pulmonary seques- tration, congenital pulmonary airway malformation (con- genital cystic adenomatoid malformation), and congenital lobar overinflation. The vast majority of solid parenchymal lung masses in children represent inflammatory, infec- tious, or reactive processes, with a differential diagnosis, including granulomatous inflammation (fungal, mycobac- terial, parasitic, sarcoidosis, vasculitis); abscess; pneumo- nia (bacterial, viral); septic embolus; infarction; or hema- toma. 2 Of the lung neoplasms in children, metastatic tu- mors 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 be- nign tumor of the pediatric lung is inflammatory myofi- broblastic tumor (52%), and the most common primary malignancies are carcinoid tumor and pleuropulmonary blastoma. 3 Based on German registry data, malignant tu- mors of the trachea, bronchus, and lungs represent 0.2% of all malignancies in children. 4 The mortality rate for pri- mary benign lung neoplasms in children is low (8.7%), and the mortality rate for primary malignant tumors is approximately 30% overall. Excluding the ‘‘bronchial ad- enomas,’’ which are associated with a favorable prognosis, the mortality rate of the malignant tumors rises to ap- proximately 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 pro- cesses, resulting in a delay of diagnosis until only after symptoms persist or are unresponsive to conventional therapy. Even if a mass is recognized, endobronchial le- sions and cystic parenchymal lesions may be radiograph- ically indistinguishable from reactive processes or lung malformations. The possibility of a lung neoplasm should be considered clinically in any child presenting with

Accepted for publication January 12, 2008. From the Department of Pathology, Texas Children’s Hospital, Baylor College of Medicine, Houston. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Megan K. Dishop, MD, Department of Pathology, MC 1-2261, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fan- nin St, Houston, TX 77030 (e-mail: mkdishop@texaschildrenshospital. org).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1079


Table 1.

Classification of Primary Pediatric Lung Tumors Based on Histogenesis*






Pleuropulmonary blastoma Type I (cystic) Type II (solid and cystic) Type III (solid) Immature teratoma Malignant germ cell tumor

Mature teratoma


Myofibroblastic tumors IMT CPMT Myofibromatosis Hemangioma Lymphangioma Neurofibroma Leiomyoma/smooth muscle tumor (with or without EBV) Chondroma Granular cell tumor

Synovial sarcoma Rhabdomyosarcoma Ewing sarcoma family of tumors Malignant peripheral nerve sheath tumor Leiomyosarcoma (with or without EBV) Bronchopulmonary fibrosarcoma Angiosarcoma Kaposi sarcoma


Lymphoid neoplasms Lymphoproliferative disorders (with or without EBV), polyclonal Histiocytoses Langerhans cell histiocytosis Non-LCH histiocytosis

Lymphoid neoplasms Lymphoproliferative disorders (with or without EBV), monoclonal Lymphoma Hodgkin Non-Hodgkin


Papilloma/papillomatosis Mucous gland adenoma

Carcinoid tumor Mucoepidermoid carcinoma Adenoid cystic carcinoma Squamous cell carcinoma Adenocarcinoma BAC



* IMT indicates inflammatory myofibroblastic tumor; CPMT, congenital peribronchial myofibroblastic tumor; EBV, Epstein-Barr virus; LCH, Lan- gerhans cell histiocytosis; and BAC, bronchioloalveolar carcinoma.

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 as- sessing cystic lung lesions. Several clinical reviews of pediatric lung neoplasms are available. 1,312 Pathologic features of pediatric lung neo- plasms have also been reviewed previously by Dehner al- most 20 years ago. 13 The objectives of this review are (1) to provide additional relative incidence data for both pri- mary and metastatic lung neoplasms from a single large institutional experience, (2) to provide an update on our current understanding of pathologic features and diag- nostic terminology for these rare tumors, and (3) to pro- vide recommendations for the practicing surgical pathol- ogist on handling cystic and/or solid masses of the pe- diatric 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 se- ries. As a result, cumulative historical data from literature reviews are difficult to interpret due to an uneven repre- sentation of these rare lesions and significant differences in diagnostic criteria and terminology, which have evolved during the decades typically encompassed by such re- views. For example, bronchogenic carcinoma has been re- ported to occur with some frequency in other reviews of pediatric lung tumors, but it appears to be overrepresent- ed in the literature relative to current experience. Other

1080 Arch Pathol Lab Med—Vol 132, July 2008

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 his-

togenesis, 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 tu-

mors in this series included 50% malignant and 50% be- nign lesions: plasma cell granuloma (3), pleuropulmonary blastoma (2), mucoepidermoid carcinoma (1), endobron- chial fibrosarcoma (1), and capillary hemangioma (1). Metastatic tumors included Wilms tumor (16), osteosar- coma (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, in- cluding a 36-bed inpatient hematology-oncology unit and

a 15-bed bone marrow transplant unit. The Texas Chil-

dren’s Cancer Center receives approximately 25 000 out- patient 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 lan- guage search of the anatomic pathology information sys-

Pediatric Lung Tumors—Dishop & Kuruvilla

tem for the dates specified, using terms for site (lung, tra- chea, 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, lymphoprolifer- ative, Hodgkin/Hodgkin’s, leukemia, Wilms, neuroblas- toma, hepatoblastoma, osteosarcoma, rhabdomyosarcoma, fibrosarcoma, chondrosarcoma, leiomyoma, leiomyosar- coma, liposarcoma, lipoblastoma, glioblastoma, clear cell, neuroendocrine, carcinoid, melanoma, myofibroblastic, adenocarcinoma, histiocytosis, mesothelioma, Kaposi/Ka- posi’s, granular cell tumor/myoblastoma, and papilloma/ papillomatosis). Patients with juvenile respiratory papil- lomatosis were included if the excised squamous papillo- mas were specifically designated from tracheal, bronchial, or pulmonary sites. Other patients with papillomas ex- cised only from the larynx/vocal cords, oropharynx, na- sopharynx, 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 re- classified as lipoblastoma, and 2 cases of ‘‘spindle cell sar- coma’’ 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 pri- mary 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 pri- mary lung malignancies (n 14) in our pediatric popu- lation was 0.56 per year. Based on this average annual in- cidence of lung malignancies and the recent average an- nual 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 ma- lignancies 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 malig- nant tumors. The most common benign lesions were squa- mous papillomas associated with human papilloma virus infection ( juvenile respiratory papillomatosis), inflamma- tory myofibroblastic tumor, and Epstein-Barr virus (EBV)– associated smooth muscle tumors. The 8 patients with re- spiratory papillomas often had multiple surgical proce- dures, 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 carci-

Arch Pathol Lab Med—Vol 132, July 2008

noid tumor (14.3%). Pleuropulmonary blastoma accounted for 72% (8/11) of parenchymal malignancies, and carci- noid tumor accounted for 67% (2/3) of tracheobronchial malignancies. One mucoepidermoid carcinoma and one type I pleuropulmonary blastoma have been reported pre-

viously in the medical literature. 14,15 In our patient popu- lation, Wilms tumor and osteosarcoma were the 2 most common solid tumor diagnoses leading to surgical exci- sion 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 osteosar- coma, it should be noted that the 28 patients with osteo- sarcoma 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 tab-

ulated separately from institutional cases (Table 3). These tumors included the following additional diagnoses not represented in our institutional data set: congenital peri- bronchial myofibroblastic tumor, synovial sarcoma, soli- tary fibrous tumor, bronchioloalveolar carcinoma, and pleuropulmonary blastoma type II, as well as Burkitt lym- phoma 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 pe- diatric lung tumors reported in the medical literature are reviewed below, beginning with tracheobronchial lesions and followed by specific benign and malignant parenchy- mal lesions.


Juvenile Respiratory Papillomatosis

Respiratory papillomatosis is caused by human papil- lomavirus 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 pa- renchyma occurs rarely (Figure 1, C and D), and may pro- duce solid nodules or cystic air-filled cavities. 2 Malignant transformation to squamous cell carcinoma has been re- ported, 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, CO 2 laser vaporization, and/or adjuvant antiviral or in- terferon 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 intraparenchy- mal. They are rare in children, but they may present as large parenchymal masses with respiratory distress. Chest computed tomography classically shows fat and ‘‘pop- corn’’ calcifications, which suggest the diagnosis. Micro- scopically, cartilage, fat, and fibrous tissue are typically the most prominent components, although smooth muscle,

Pediatric Lung Tumors—Dishop & Kuruvilla 1081

Table 2.

Pediatric Lung Tumors: 204 Patients With Surgical Pathology Specimens During a 25-Year Period at Texas Children’s Hospital (Houston), June 1982–May 2007*














Squamous papilloma Hemangioma JXG IMT Chondroma EBV-SMT IMT Myofibromatosis Lipoblastoma Lymphangioma Congenital immature mesenchymal tumor Squamous papillomas Total


1–18 y


Carcinoid tumor


11–15 y


5 mo

Mucoepidermoid CA


10 y


7 mo



4 y


13 y



5–11 y


PPB type I PPB type III Spindle cell sarcomas Fibrosarcoma Myofibroblastic


3 mo–2 y 4–11 y 3–8 y


7 y



10 y



1 y



11 y




Squamous cell CA


6 y


3 y







LPD, polymorphous


11 mo–6 y


LPD, monomorphous


2–15 y




6 mo–2 y

NHL (LBCL, other)


4–17 y

Histiocytic, non-LCH


1 mo



9–19 y




4 y



6 y



7 y






Metastatic solid

Wilms tumor


1–11 y 6–26 y 7–18 y 3–14 y 16–19 y 7 mo–13 y 10 mo–1 y 9 y 9 mo–11 y 2 y 9 mo








Germ cell tumor












Cellular MN




20 y

Other sarcomas UDS Synovial sarcoma CCST Angiosarcoma Liposarcoma Fibrosarcoma Myofibrosarcoma MFH ASPS Sarcoma, NOS Other carcinomas NPC ACC AdenoCA, colon Clear cell CA, SC Squamous cell CA Other malignant, NOS Total



11–15 y 10–12 y 10 y 10 y 4 y 14 y, 20 y 10 y 9 y 3 y 17 y












17 y


12 y


9 y


4 y


6 y


3–16 y


* CA indicates carcinoma; JXG, juvenile xanthogranuloma; IMT, inflammatory myofibroblastic tumor; EBV-SMT, Epstein-Barr virus–associated smooth muscle tumor; PPB, pleuropulmonary blastoma; LPD, lymphoproliferative disorder; LCH, Langerhans cell histiocytosis; NHL, non-Hodgkin lymphoma; LBCL, large B-cell lymphoma; HL, Hodgkin lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; EWS/PNET, Ewing sarcoma/primitive neuroectodermal tumor; RMS, rhabdomyosarcoma; NB, neuroblastic tumor; HB, hepatoblastoma; HCC, hepatocellular carcinoma; ATRT, atypical teratoid rhabdoid tumor; CCSK, clear cell sarcoma of the kidney; MN, mesoblastic nephroma; DSRCT, desmoplastic small round cell tumor; UDS, undifferentiated sarcoma; CCST, clear cell sarcoma of soft tissue; MFH, malignant fibrous histiocytoma; ASPS, alveolar soft part sarcoma; NOS, not otherwise specified; NPC, nasopharyngeal carcinoma; ACC, adrenocortical carcinoma; and SC, sacrococcygeal. † No. indicates the number of individual patients with tumor diagnosis on surgical pathology specimens; multiple specimens per patient are not included in numerical data.

1082 Arch Pathol Lab Med—Vol 132, July 2008

Pediatric Lung Tumors—Dishop & Kuruvilla

Table 3.

Pediatric Lung Tumors: 40 Additional Consultation Cases Referred to Texas Children’s Hospital (Houston) During a 25-Year Period*














Neuroendocrine CA Mucoepidermoid CA PPB type I PPB type II Bronchopulmonary fibrosarcoma Synovial sarcoma BAC Total


13 y 8 y 8 wk–4 y 3 y 5 y



CPMFT Congenital immature mesenchymal tumor Solitary fibrous tumor


0–2 wk 2 wk–5 mo

















LPD, polymorphous


3 mo–12 y ND, 13 y


LPD, monomorphous Burkitt lymphoma Osteosarcoma Wilms tumor GNB Hepatoblastoma Hepatocellular CA Synovial sarcoma DSRCT Breast CA, juvenile secretory Total


14 y




2 y



8–21 y


5–13 y


6 y


1–7 y


8 y


15 y




8 y





* CA indicates carcinoma; CPMFT, congenital peribronchial myofibroblastic tumor; PPB, pleuropulmonary blastoma; BAC, bronchioloalveolar carcinoma; LPD, lymphoproliferative disorder; LCH, Langerhans cell histiocytosis; GNB, ganglioneuroblastoma; DSRCT, desmoplastic small round cell tumor; and ND, no data.

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 con- tinuity with bronchial cartilage and do not have other mesenchymal elements, as in the hamartomas described above (Figure 1, E). Pulmonary chondromas have been de- scribed in the Carney triad, a syndrome almost exclusively seen in young females comprising functioning paragan- glioma, epithelioid gastrointestinal stromal tumor, and pulmonary chondroma. 16,17 Due to potential complications of the associated lesions, children with pulmonary chon- droma may benefit from periodic screening for meta- chronous development of paragangliomas or gastrointes- tinal stromal tumors.

Other Benign Tracheobronchial Lesions

Other benign tracheobronchial tumors reported in chil- dren 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 as- sociated with EBV infection are discussed below. Multiple fibroleiomyomatous hamartomas (benign metastasizing leio- myomas) have been described in a child with a history of rhabdomyosarcoma. 18 Bronchial granular cell tumors are re- ported rarely and have histologic features similar to those described in the oral cavity, comprising sheets of round cells

Arch Pathol Lab Med—Vol 132, July 2008

with small nuclei and abundant granular eosinophilic cyto- plasm. 7,9,1921 The term bronchial adenoma is a misnomer pre- viously used to refer collectively to 4 distinct lesions (carci- noid tumor, mucoepidermoid carcinoma, adenoid cystic car- cinoma, 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 chil- dren also includes reactive vascular lesions, including gran- ulation tissue and pyogenic granuloma, chronic foreign body reaction, and granulomatous inflammation, for example, due to histoplasmosis or mycobacteria. 10

Carcinoid Tumor

Carcinoid tumors are considered low-grade neuroen- docrine carcinomas due to their potential for locally ag- gressive 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 pneu- monia. 6,7,9,2224 The carcinoid syndrome caused by produc- tion of neurosecretory peptides is very rare in the absence of metastatic disease. Carcinoid tumors have been report- ed to account for up to 80% to 85% of primary malignant lung tumors in children, although this is likely an over- estimate. 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 back- ground (Figure 1, G). Treatment is primarily surgical, and

Pediatric Lung Tumors—Dishop & Kuruvilla


Table 4.

Primary Lung Tumors in Children: Summary of Data From Literature Review and Single-Institution Data (Texas Children’s Hospital [TCH], Houston)*


Literature Review (Hancock et al 3 ), No. (%)

TCH Surgical Cases, No. (%)

TCH Consult

TCH Total Cases, No. (% of Total, n 51)

Cases, No.

Benign IMT CPMFT Myofibromatosis Hamartoma Neurogenic tumor Leiomyoma/EBV-SMT Mucous gland adenoma Granular cell tumor Benign teratoma Squamous papillomatosis Hemangioma Lymphangioma Chondroma Juvenile xanthogranuloma Lipoblastoma Immature mesenchymal tumor Solitary fibrous tumor Total

48 (52.2)

2 (10)

2 (3.9)



3 (5.9)


1 (5)

1 (2.0)

22 (23.9)

9 (9.8)

6 (6.5)

3 (15)

3 (5.9)

3 (3.3)

3 (3.3)

1 (1.1)


8 (40)

8 (15.7)

1 (5)

1 (2.0)

1 (5)

1 (2.0)

1 (5)

1 (2.0)

1 (5)

1 (2.0)

1 (5)

1 (2.0)

1 (5)


3 (5.9)



1 (2.0)





Malignant Carcinoid tumor Mucoepidermoid CA Adenoid cystic carcinoma ‘‘Bronchial adenoma,’’ NOS Pleuropulmonary blastoma† Bronchogenic carcinoma Bronchopulmonary fibrosarcoma Rhabdomyosarcoma Leiomyosarcoma Other sarcoma Hemangiopericytoma Plasmacytoma Lymphoma Immature teratoma/GCT Total

48 (16.5)

2 (14.3)


3 (5.9)

39 (13.4)

1 (7.1)


2 (3.9)

4 (1.4)

27 (9.3)

57 (19.6)

8 (57.1)


14 (27.5)

49 (16.8)

1 (7.1)


2 (3.9)

28 (9.6)

1 (7.1)

1 (2.0)

11 (3.8)


1 (2.0)

11 (3.8)

3 (0.9)

1 (7.1)


2 (3.9)

4 (1.4)

4 (1.4)

3 (1.0)

3 (1.0)





* IMT indicates inflammatory myofibroblastic tumor; CPMFT, congenital peribronchial myofibroblastic tumor; EBV-SMT, Epstein-Barr virus– associated smooth muscle tumor; CA, carcinoma; NOS, not otherwise specified; and GCT, germ cell tumor. † Pleuropulmonary blastoma includes historic cases in children reported as pulmonary blastoma, mesenchymoma, as well as sarcomas and rhabdomyosarcoma arising in cystic malformations.

endoscopic resection is not recommended due to risk of hemorrhage and incomplete resection. Depending on lo- cation and size, complete excision and removal of involved lymphatics may be achieved with bronchial sleeve resec- tion, lobectomy, or even pneumonectomy. Local invasion or distant metastasis has been reported in a significant percentage of children (27%), and overall survival in chil- dren is approximately 90%. 6,9

Mucoepidermoid Carcinoma Mucoepidermoid carcinoma (MEC) is reported to rep- resent 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. Mu- coepidermoid 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 exo- phytic polypoid masses that cause bronchial obstruction (80% of cases). 14,23,24 Grading of MEC in the tracheobron-

1084 Arch Pathol Lab Med—Vol 132, July 2008

chial 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 pre- dominantly intermediate cells and occasional mucous cells, forming a solid pattern with infrequent cysts and glands (Figure 1, H and I). High-grade MEC contains pre- dominantly 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 chil- dren appears to be more favorable, with no deaths re- ported in the literature after surgical resection alone.

Adenoid Cystic Carcinoma Adenoid cystic carcinoma is a slowly growing infiltra- tive salivary gland–type neoplasm that is rare in the tra-

Pediatric Lung Tumors—Dishop & Kuruvilla

Figure 1. Bronchial tumors. A and B, Respiratory papillomatosis. Often multiple and recurrent, respiratory papillomas

Figure 1. Bronchial tumors. A and B, Respiratory papillomatosis. Often multiple and recurrent, respiratory papillomas are caused by perinatally acquired human papillomavirus infection and are characterized by a squamous epithelial proliferation with papillomatous architecture, fibrovas- cular stroma, and often subtle viral cytopathic effect, including binucleation and perinuclear halos. C and D, Intrapulmonary squamous papillo- matosis. This 2-year-old girl with longstanding respiratory papillomatosis developed multiple small nodules on chest x-ray. The nodules were formed by squamous epithelial proliferations with high-grade atypia extending from the terminal bronchioles into the surrounding alveolar spaces. Direct tissue invasion or overt malignant features were not identified. E, Chondroma. Distinct from chondromatous hamartoma, chondromas are proliferations of benign hyaline cartilage, typically associated with central airways. This example was removed from the right upper lobe of a 13- year-old girl with Carney triad and concurrent diagnosis of an epithelioid gastrointestinal tumor of the stomach. F and G, Carcinoid tumor. An 11- year-old boy presented with hemoptysis and was found to have a 2.7-cm mass occluding the right mainstem bronchus. Histologic features include cords of cells with characteristic uniform round nuclei and stippled chromatin. H and I, Mucoepidermoid carcinoma. Mucoepidermoid carcinoma is graded based on varying degrees of 3 major cell types: glandular, squamoid, and intermediate cells. This intermediate-grade mucoepidermoid carcinoma shows cystic spaces with well-formed mucin-producing cells, admixed with smaller solid areas with squamoid and intermediate cells (gross tumor, bronchial resection [F] and hematoxylin-eosin [A through E, G through I]; original magnifications 20 [A], 200 [B and D], and 100 [C, E, and G]).

cheobronchial tree. Histologic features are similar to those seen in the salivary glands, consisting of cribriform, glan- dular, and solid patterns of small hyperchromatic cells. There is a tendency for submucosal spread, circumferen- tial 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 ex- cision 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. Ade- noid cystic carcinoma has a higher likelihood of distant

Arch Pathol Lab Med—Vol 132, July 2008

metastasis compared with mucoepidermoid carcinoma and has poorer survival (55% 5-year survival). 25

MYOFIBROBLASTIC TUMORS Inflammatory Myofibroblastic Tumor Previously called inflammatory pseudotumor or plasma cell granuloma, inflammatory myofibroblastic tumor is a slow- growing tumor which shows characteristics of both reac- tive and neoplastic lesions. 2628 Although theorized to re- sult from a repair response, antecedent injury cannot be documented in most cases. Although many tumors are asymptomatic (30%), others present with symptoms of

Pediatric Lung Tumors—Dishop & Kuruvilla 1085

cough or fever. Excluding respiratory papillomatosis, it is estimated that inflammatory myofibroblastic tumor ac- counts 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 dem- onstrates 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 intraparen- chymal (83%). 3,7 Histologic features include a proliferation of bland spindled and stellate cells with abundant eosin- ophilic cytoplasm, admixed with scattered inflammatory cells, including lymphocytes and, occasionally, prominent plasma cells and eosinophils (Figure 2, B). Immunohisto- chemistry 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 recommend- ed. Inflammatory myofibroblastic tumors have a tendency for local recurrence if incompletely excised.

Myofibromatosis Myofibromas are relatively common benign soft tissue tumors in children, most often presenting as a firm nod- ular mass in the subcutaneous or deep soft tissue. Al- though most often solitary, they may be multifocal and involve both soft tissue and visceral organs, so-called my- ofibromatosis (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 occa- sionally seen and should not be interpreted as an aggres- sive 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 met- astatic 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. 2933 It has been de- scribed under various terminology, including massive con- genital 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 my- ofibroblastic 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 intra- uterine polyhydramnios, hydrops, or immediate respira- tory failure at delivery. Grossly, nearly the entire lung or

1086 Arch Pathol Lab Med—Vol 132, July 2008

a large portion of the lung is typically enlarged and re-

placed by a firm rubbery mass with a yellow-tan to gray whorled cut surface containing bands of fibrous-appear- ing tissue (Figure 2, D). Microscopically, bland spindled cells form large fascicles following the planes of the bron- chovascular 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 extramed- ullary hematopoiesis may be seen. Mitotic figures may be frequent, but there is no cytologic atypia or atypical mi- toses. The lesion tends to be more uniform in cellularity, in contrast to other myofibroblastic tumors. Immunohis- tochemistry shows diffuse positivity for vimentin and fo- cal 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 chro- mosomes 4, 8, and 10. 30 Electron microscopy shows spin- dled cells with dilated rough endoplasmic reticulum, scarce mitochondria, occasional lipid droplets, and scant cytoplasmic filaments, some with dense bodies and at- tachment plaques, consistent with myofibroblastic differ- entiation. 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 neurofibro- ma, schwannoma, malignant peripheral nerve sheath tu- mors, 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 neurofibro- mas are nonsyndromic, the possibility of neurofibroma- tosis should always be considered in a child with a pul- monary 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 involut- ing lesions have less capillary density with more widely spaced and dilated thick-walled capillaries. Both prolif- erative and involuting lesions are characterized by endo-

thelial positivity for the glucose transporter Glut-1 (Figure

3, B), a marker that distinguishes the infantile hemangio-

ma 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 sys- temic distribution of disease (hemangiomatosis). 35 Tra-

Pediatric Lung Tumors—Dishop & Kuruvilla

Figure 2. Myofibroblastic tumors. A and B, Inflammatory myofibroblastic tumor. Inflammatory myofibroblastic tumors

Figure 2. Myofibroblastic tumors. A and B, Inflammatory myofibroblastic tumor. Inflammatory myofibroblastic tumors may be intraparenchymal or associated with the bronchial tree. This large bronchial lesion filled the lumen of the right upper lobe bronchus and caused compression of adjacent airways. The lesion is composed of a bland spindle cell proliferation with variable cellularity, including some collagen-rich zones. The spindled cells are admixed with scattered inflammatory cells, predominantly lymphocytes. C, Myofibromatosis. A 10-year-old girl presented with a 3-cm soft tissue mass of the chest wall and was found to have multiple small nodules on the visceral pleura, raising suspicion for metastatic disease. The lesions corresponded to multiple ill-defined proliferations of benign spindled cells and collagen, in some areas associated with slitlike and branching hemangiopericytomatous vessels. D and E, Congenital myofibroblastic tumor. This rare tumor typically results in stillbirth or respi- ratory distress at birth requiring lobectomy. The tumor has a whorled stromal appearance on cut surface, corresponding to broad fascicles of bland myofibroblastic cells traversing the bronchovascular bundles and interlobular septa, producing compartmentalization of the alveolar parenchyma (gross tumor, right upper lobectomy [A]; gross tumor, cut surface [D]; and hematoxylin-eosin [B, C, and E]; original magnifications 200 [B], 40 [C], and 20 [E]).

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Pediatric Lung Tumors—Dishop & Kuruvilla 1087

Figure 3. Vascular lesions. A and B, Infantile hemangioma. This infantile hemangioma of the trachea

Figure 3. Vascular lesions. A and B, Infantile hemangioma. This infantile hemangioma of the trachea shows a proliferation of compact and slitlike

capillaries surrounding and entrapping the submucosal glands. Endothelial expression of the glucose transporter type I (Glut1) is characteristic of infantile hemangioma and distinguishes this diagnosis from vascular malformations and reactive capillary proliferations. C, Lymphatic malformation. Lymphatic malformations (lymphangiomas) occur rarely as mass lesions in the lung and consist of a proliferation of complex anastomosing lymphatic channels, often with small lymphoid aggregates in the walls. Proteinaceous lymphatic fluid may be admixed with red blood cells due to secondary hemorrhage. Lymphatic differentiation may be confirmed by endothelial expression of the lymphatic marker D2-40. D and E, Vascular malformation. A 1-year-old girl presented with thrombocytopenia and anemia and was found to have multiple nodules on chest x-ray. Wedge biopsy showed multifocal vascular lesions consisting of nodular regions of dilated thin-walled blood-filled vessels. The architecture of the lesion

is highlighted by endothelial expression of CD34 (shown), and Glut1 was negative. The distribution of disease and pathologic features suggested

a diagnosis of cutaneovisceral angiomatosis (hematoxylin-eosin [A, C, and D], Glut1 immunohistochemistry [B], and CD34 immunohistochemistry

[E]; original magnifications 100 [A and E], 200 [B], and 40 [C and D]).

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Pediatric Lung Tumors—Dishop & Kuruvilla

cheobronchial and parenchymal hemangiomas are identi- fied occasionally due to symptoms of obstruction or re- current hemoptysis. 1,10 Lesions of the subglottis and upper trachea are more common than the distal tracheal or en- dobronchial 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 hemangi- omatosis is a different entity than the multifocal infantile hemangiomas of diffuse neonatal hemangiomatosis. Pul- monary capillary hemangiomatosis is a rare, poorly de- fined 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 hemangio- matosis has been associated with pulmonary veno-occlu- sive disease in some cases, and it may represent a postob- structive reactive proliferation of capillaries distal to thrombosis.

Lymphatic Malformations and Lymphangiomatosis Although lymphatic malformations are common lesions in infants and young children, solitary lymphatic malfor- mations (lymphangiomas) occur rarely in the lung, form- ing localized multicystic masses (Figure 3, C). In contrast, lymphangiomatosis is a proliferation of lymphatic chan- nels involving the lung more diffusely, typically in a septal and pleural pattern of distribution. Secondary hemorrhage and muscularization of the lymphatic channels in lym- phatic malformations may produce confusion with a ve- nous malformation, and the lymphatic marker D2-40 is helpful in confirming the lymphatic origin of the vessels.

Vascular Malformations Like hemangiomas and lymphatic malformations, ve- nous or mixed vascular malformations may produce mass lesions in the lung parenchyma. Arteriovenous malfor- mations may be multiple and produce right-to-left shunt- ing, 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-Ren- du syndrome).

OTHER BENIGN PARENCHYMAL TUMORS Teratomas within the lung parenchyma are reported as isolated cases, including only 2 case reports before 1983. 7,3941 Pericardial or anterior mediastinal teratomas are more common, and they may show secondary involve- ment 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 typ- ically 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 com-

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a rare entity com- Arch Pathol Lab Med—Vol 132, July 2008 Figure 4. Other benign parenchymal

Figure 4. Other benign parenchymal lung lesions. A, Lipoblastoma. Lipoblastomas may occur in any site of the body, including soft tissue and viscera. This rare lesion replacing the left upper lobe of a 16- month-old boy shows areas of immature mesenchyme with predomi- nantly vascular myxoid tissue containing scattered fat vacuoles and maturing lipoblasts. B and C, Rhabdomyomatous dysplasia, nodular form. Rhabdomyomatous dysplasia refers to ectopic skeletal muscle differentiation within the lung and is most often recognized incidentally within the interstitium of extralobar pulmonary sequestrations. Rarely, rhabdomyomatous dysplasia may form nodular lesions, as in this in- cidental lung nodule in a 1-week-old, 28-week gestation neonate, who died of pulmonary hypoplasia and respiratory failure (hematoxylin-eo- sin, original magnifications 40 [A], 20 [B], and 200 [C]).

Pediatric Lung Tumors—Dishop & Kuruvilla 1089

Figure 5. Pleuropulmonary blastoma. A through C, Type I (cystic). The cystic type of pleuropulmonary

Figure 5. Pleuropulmonary blastoma. A through C, Type I (cystic). The cystic type of pleuropulmonary blastoma is typically characterized by a unilocular or multilocular lung cyst distending the surface of the lung, grossly identical to the large-cyst type of congenital pulmonary airway malformation. Microscopically, the lesion is composed of thick and thin septa with variable cellularity and often containing isolated small islands of immature-appearing cartilage. The diagnosis is confirmed by identifying small primitive round and spindled cells, often with a prominent capillary network. These cells are from a cambium-like layer beneath the alveolar-type epithelium lining the septa, resembling that seen in botryoid rhabdomyosarcoma. Hemorrhage and necrosis may be seen focally. D, Type II (solid and cystic). The higher grade pleuropulmonary blastomas contain sheets of hyperchromatic primitive cells, expanding the broad cyst septa in this type II pleuropulmonary blastoma. E through H, Type III (solid). The solid variant of pleuropulmonary blastoma is easily identified as a malignancy, composed of solid sheets of primitive tumor cells. Myxoid areas resembling cartilaginous differentiation and larger round rhabdomyoblastic cells may be seen in some cases. These tumors often have foci with anaplastic features, including marked pleomorphism, cytologic atypia, multinucleation, and atypical mitotic figures (gross tumor, left upper lobe [A] and hematoxylin-eosin [B through H]; original magnifications 20 [B and D], 100 [C, F, and H], 40 [E], and 200 [G]).

posed of benign skeletal muscle cells within the lung pa- renchyma, most often seen incidentally within lung mal- formations, such as extralobar sequestration. Rarely, rhab- domyomatous 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 de- scribed as a unique entity distinct from pulmonary blas- toma in 1988. 42 In contrast to the adult-type biphasic pul- monary blastoma (PB), PPB is a polyphenotypic mesen-

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chymal malignancy without an epithelial component. It has been reported previously in the medical literature un- der a variety of descriptors, including pulmonary blasto- ma, mesenchymal cystic hamartoma, malignant mesen- chymoma, and sarcomas (myxosarcoma or rhabdomyo- sarcoma) arising in congenital cystic malformations. 4347 Pleuropulmonary blastoma is diagnosed primarily in in- fants and toddlers, and rarely beyond age 12 years. Oc- currence in adults is reported but extremely rare. 48 These lesions may be detected incidentally in utero or postna- tally. 15 Symptomatic presentation may result from spon- taneous 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 le-

Pediatric Lung Tumors—Dishop & Kuruvilla

sions (type III). 49 Age at presentation varies depending on morphologic type, with the type I lesions most often di- agnosed 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 periph- eral 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 predom- inantly alveolar-type epithelium and containing focal ar- eas of hypercellularity and hypervascularity (Figure 5, B and C). The hypercellular foci are composed of hyper- chromatic compact spindled cells and small round cells, often forming a cambium-like layer beneath the epitheli- um lining the cyst walls. Foci of immature-appearing car- tilage are present in some cases. The higher grade lesions (type II and type III) have solid components on gross ex- amination. 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 cy- tologic features, with sheets of spindled and pleomorphic, sometimes anaplastic cells, resembling rhabdomyosarco- ma. 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


lesions, particularly if incompletely excised. Immunohistochemistry of PPB demonstrates vimentin


the primitive cell component, as well as myogenic dif-

ferentiation in some cases, specifically with expression of desmin, muscle specific actin, smooth muscle actin, my- ogenin, 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, indi-

cating chondrocytic differentiation. 49,50 Cytogenetic analy-

sis of PPB has been described in a small number of cases,

primarily of higher grade lesions. Although a tumor-spe- cific 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 de- scribed. 5254 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 Blas- toma 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 tu- mors), thyroid neoplasms, leukemia, Hodgkin lymphoma, and Langerhans cell histiocytosis (LCH) have been asso-

ciated with PPB. 56 Clinically, the diagnosis of PPB is infrequently enter- tained preoperatively. 15 Pathologists must consider the di- agnosis of PPB for any child with a spherical unilocular

or multiloculated cystic lesion, mixed solid and cystic le-

sion, or large solid mass in the lung, particularly if the

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lesion distorts the contour of the lung, is positioned pe- ripherally, or is found to protrude from the pleural sur- face. The differential diagnosis includes the more common benign cystic lung malformations, as well as other rare primary sarcomas of the lung. The most common sub- mitting diagnosis and the principal pathologic differential diagnosis for cystic type I PPB is CPAM (also called con- genital 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 micro- scopically by a cyst lining composed predominantly of respiratory type epithelium, with or without focal muci- genic 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 pe- ripheral cyst (Stocker type IV) CPAM is much more prob- lematic 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 pri- mary sarcomas of the lung, including rhabdomyosarcoma and synovial sarcoma. Some cases initially reported as rhabdomyosarcoma of the lung likely represent high- grade 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 men- tioned 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 Entrap- ment 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 sy- novial sarcoma. Treatment for PPB is primarily surgical for the cystic (type I) lesions, although adjuvant chemotherapy may be advantageous in cases with incomplete resection. Cer tain- ly, the higher grade (type II and type III) lesions require adjuvant chemotherapy after resection, and radiation ther- apy is recommended for residual disease. In either case, close clinical follow-up is warranted due to potential for recurrence, metastasis, multifocality, and associated extra- pulmonary lesions. Low-grade cystic lesions may recur as a higher grade lesion, and this potential justifies chemo- therapy for some type I tumors. Metastasis occurs in ap- proximately 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

Pediatric Lung Tumors—Dishop & Kuruvilla 1091

Figure 6. Sarcomas. A and B, Synovial sarcoma. Although rare, synovial sarcoma is one of

Figure 6. Sarcomas. A and B, Synovial sarcoma. Although rare, synovial sarcoma is one of the most common primary sarcomas of the pediatric lung. It may mimic adult-type pulmonary blastoma due to its biphasic morphology, including compact spindled cells and larger epithelioid cells. CD99 and BCL2 expression are helpful diagnostic features, and the characteristic t(X;18) translocation may be identified by cytogenetic analysis or molecular identification of the SSX-SYT fusion transcript (hematoxylin-eosin, original magnifications 20 [A] and 100 [B].

PRIMARY SARCOMAS Synovial Sarcoma Although rare, synovial sarcoma is one of the more common primary sarcomas of the lung in children. Di- agnostic features are similar to those seen in other sites, and morphology may be monophasic or biphasic (Figure 6, A and B). Immunohistochemistry for cytokeratin, epi- thelial membrane antigen, CD99, and BCL2 are typically positive. Cytogenetic analysis and/or molecular diagnos- tic testing is helpful in demonstrating the characteristic t(X;18) translocation, producing an SSX-SYT fusion tran- script.

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 uni- fied by the rearrangement of the Ewing sarcoma gene with one of a variety of fusion partner genes, most com- monly Fli-1, produced by a characteristic t(11;22)(q24 ; q12) translocation. By immunohistochemistry, the Ewing sar- coma family of tumors characteristically demonstrates membranous staining with CD99, an important diagnostic feature in clinical practice. In addition, primitive neuro- ectodermal tumors show evidence of neural differentia- tion, either by immunohistochemistry or electron micros- copy. On a practical level, distinguishing primitive neu- roectodermal 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 tu- mor of the thoracopulmonary region. Chest wall involve- ment may result in a mass with intrathoracic growth, lytic destruction, and fusiform expansion of ribs, cortical thick- ening, little or no periosteal reaction, and pleural effu- sion. 8 Involvement of the pleural cavity with extension into the lung parenchyma is not uncommon and may lead

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to partial resection of lung with chest wall resection. Rare- ly, 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 rhabdomyosar- coma of the lung also occurs, often manifesting as an en- dobronchial mass. 7,65,66 Pulmonary rhabdomyosarcoma is estimated to represent approximately 0.5% of all rhabdo- myosarcomas 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 pro- duce direct involvement of the thoracic cavity or pulmo- nary metastasis in this setting. 8


A few cases of bronchopulmonary leiomyosarcoma have been reported in children. 6771 Rare cases in newborns may, in fact, represent congenital myofibroblastic tumor, rather than true leiomyosarcoma. 67 Potentially arising from ei- ther bronchial or vascular smooth muscle, these lesions may be located in the tracheobronchial tree or in the pa- renchyma. Leiomyosarcoma in older children may show aggressive local invasion, metastasis, and poor prognosis. Nuclear atypia, necrosis, and hemorrhage distinguish leio- myosarcoma from both leiomyomas and the myofibro- blastic tumors. Epstein-Barr virus is associated with some lesions in the immunocompromised population (see be- low).

Bronchopulmonary Fibrosarcoma

Primary bronchial fibrosarcoma in children is consid- ered to be the equivalent of congenital infantile fibrosar- coma of soft tissues. It is quite rare, with 26 cases reported in the literature to 1989. 1 Grossly, bronchopulmonary fi- brosarcoma may form an endobronchial polyp or intra- parenchymal mass. Histologically, it is composed of cel- lular sheets and interlacing bundles of spindle cells, often

Pediatric Lung Tumors—Dishop & Kuruvilla

with focal hemorrhage. The mortality associated with bronchopulmonary fibrosarcoma is 21%, with metastatic disease reported in 2 of 26 cases. 72

Other Sarcomas A number of other types of sarcomas have been re- ported 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 else- where. 74,75

BRONCHOGENIC CARCINOMA 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. 7688 Patients 18 to 30 years old diagnosed with lung cancer have a higher incidence of female sex, no associa- tion 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 approxi- mately 17% of reported primary lung malignancies in chil- dren. 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 lim- ited to individual case reports and small case series in the modern era. 92 A 21-year review of pediatric primary epi- thelial lung malignancies from Memorial Sloan-Kettering Cancer Center yielded a total of 11 patients (age range, 12–21 years) with pathologic diagnoses of adenocarcino- ma (4, including 1 well-differentiated fetal adenocarcino- ma), 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 bron- chial tumors in children, with no cases of bronchogenic carcinoma. 9 In 1999, Mizushima et al 89 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 ade- nocarcinoma. Reported cases of pediatric lung carcinoma in the med- ical literature are most commonly undifferentiated carci- noma, followed by adenocarcinoma and squamous cell carcinoma. It is difficult to determine whether the histor- ical 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 adenocarci- nomas in the Memorial Sloan-Kettering series all present- ed with stage IV disease, and 2 had rapidly progressive fatal disease within 2 months of diagnosis. 93 Well-differ- entiated fetal adenocarcinoma, also called pulmonary en- dodermal tumor, is an extremely rare variant of adeno-

Arch Pathol Lab Med—Vol 132, July 2008

carcinoma for which there are only isolated reports in chil- dren. 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 conven- tional pulmonary adenocarcinoma, well-differentiated fe- tal 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). 94104 The mucigenic epithelium of the type I CPAM is the purported precursor cell for bronchioloal- veolar carcinoma in this setting. 105107 Squamous cell carcinoma (Figure 7, D) seems to account for a smaller proportion of lung carcinoma cases in chil- dren (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 pro- gression 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 Bas- aloid carcinoma, a rare variant of non–small cell lung car- cinoma 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 mor- tality (90%), and average survival of 7 months after di- agnosis. 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 diag- nosis 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 ma- lignancy following radiation therapy, and there is one re- port of pediatric mesothelioma associated with prenatal isoniazid exposure. 114 Three large series of diffuse malig- nant mesothelioma in children have shown pleural in- volvement 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 pat- terns are similar to those seen in adults, and they have included epithelial, mixed, and fibrous types, as well as papillary, tubuloglandular, solid, and sarcomatoid pat-

terns. 4,113,115

PRIMARY LUNG TUMORS IN IMMUNOSUPPRESSED AND IMMUNOCOMPROMISED CHILDREN Lymphoma and Lymphoproliferative Disorders All immunodeficiency states carry a higher risk of lym- phoma relative to the immunocompetent population, in-

Pediatric Lung Tumors—Dishop & Kuruvilla 1093

Figure 7. Carcinoma. A, Congenital pulmonary airway malformation. A 9-year-old girl presented with spontaneous

Figure 7. Carcinoma. A, Congenital pulmonary airway malformation. A 9-year-old girl presented with spontaneous pneumothorax and was found to have an inflamed complex cystic lesion with focal mucigenic epithelium, yielding a diagnosis of type I congenital pulmonary airway malfor- mation. B and C, Bronchioloalveolar carcinoma, mucinous type, arising in a recurrent congenital pulmonary airway malformation. One year later, she presented again with a recurrent cyst. The resection specimen showed multifocal glandular proliferations extending from the cyst wall and consisting predominantly of mucin-rich columnar cells extending along alveolar septa. Some airspaces contained detached atypical cell groups admixed with abundant mucin. D, Squamous cell carcinoma. A 6-year-old boy presented with a large lung tumor invading the chest wall. Lobectomy showed a squamous cell carcinoma eroding a large bronchus and showing extensive parenchymal infiltration and intrapulmonary lymphatic spread. The bronchial wall demonstrates islands and sheets of squamous cells in the submucosa entrapping benign glands but without glandular differentiation. Extensive keratinization and necrosis were present in many islands of invasive tumor (hematoxylin-eosin, original mag- nifications 100 [A and C], 20 [B], and 40 [D].

cluding patients with human immunodeficiency virus (HIV) infection, solid organ transplant, bone marrow transplant, and congenital immunodeficiencies. These lymphomas are most often high-grade or intermediate- grade non-Hodgkin lymphomas, typically diffuse large B- cell lymphomas, and often involve extranodal sites. Burk- itt lymphoma, Burkitt-like lymphoma, Hodgkin lympho- ma, and human herpesvirus 8–associated primary effu- sion lymphoma also are reported with higher incidence in the HIV-infected population. 117 Epstein-Barr virus–driven lymphoproliferative disor- ders occur most commonly in immunosuppressed recipi- ents of solid organ or bone marrow transplants (posttrans- plant lymphoproliferative disorder [PTLD]), as well as children with primary immunodeficiency (Figure 8, A). In general, PTLD is most common after heart, lung, or heart- lung transplantation (5%–13% of patients) and less com-

1094 Arch Pathol Lab Med—Vol 132, July 2008

mon after liver, kidney, or bone marrow transplantation (1%–3%). 117 Lung involvement by PTLD manifests as peri- airway and parenchymal nodular and interstitial lym- phoid infiltrate, and primary involvement of the lung is highest in lung transplant or heart-lung transplant recip- ients. The pathogenesis of PTLD is related to EBV-stimu- lated B-lymphocyte proliferation, which is unopposed due to iatrogenic inhibition of regulatory T-lymphocyte func- tion, and the biologic spectrum ranges from polymor- phous to monomorphous and may be polyclonal, oligo- clonal, or monoclonal. The monoclonal forms most often resemble diffuse large B-cell lymphoma and may be as- sociated 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 de-

Pediatric Lung Tumors—Dishop & Kuruvilla

Figure 8. Lung tumors in immunocompromised children. A, Lymphoproliferative disorder, Epstein-Barr virus associated.

Figure 8. Lung tumors in immunocompromised children. A, Lymphoproliferative disorder, Epstein-Barr virus associated. Epstein-Barr virus–driven lymphoproliferative disorders in immunosuppressed patients may be monomorphous or polymorphous, and they typically produce nodular and interstitial infiltrates of lymphocytes. This monotonous lymphoid infiltrate in a 4-year-old girl with a congenital T-cell immunodeficiency showed a clonal population of B lymphocytes by flow cytometric analysis. In situ hybridization for Epstein-Barr virus (Epstein-Barr virus–encoded RNA [EBER]) demonstrates numerous cells with strong nuclear positivity. B through D, Smooth muscle tumor, Epstein-Barr virus associated. An 11-year- old boy with human immunodeficiency virus/AIDS was found to have 2 nodules of the right upper lobe. The nodules consisted of bland prolif- erations of whorled smooth muscle cells similar to conventional leiomyomas (shown). In situ hybridization for Epstein-Barr virus (EBER) shows strong nuclear expression in the majority of cells (hematoxylin-eosin [A and C]; gross tumor, right upper lobe [B]; and EBER DNA probe in situ hybridization [D]; original magnifications 40 [A], 200 [C], and 100 [D]).

termination of clonality. Reduction of immunosuppression is the first-line management of these disorders, with or without anti-CD20 antibody therapy (rituximab), al- though 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. 118122 These tumors may be solitary or multifocal, and site of predilec- tion include the gastrointestinal and respiratory tracts. Similar to the EBV-driven lymphoproliferative tumors, there is a spectrum from benign to malignant morpholo- gy, that is, leiomyoma and leiomyosarcoma, and there is potential for regression of tumors with modulation of im-

Arch Pathol Lab Med—Vol 132, July 2008

munosuppression. Epstein-Barr virus DNA probes are typically strongly positive in these tumors (Figure 8, D).

Kaposi Sarcoma Kaposi sarcoma associated with human herpesvirus 8 infection may occur in HIV-infected patients and follow- ing solid organ transplantation. Although cutaneous Ka- posi sarcoma typically predominates clinically, visceral in- volvement may occur, most often affecting lymph nodes, the gastrointestinal tract, or the lungs. Pulmonary involve- ment may produce endobronchial or parenchymal viola- ceous 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 granulo-

Pediatric Lung Tumors—Dishop & Kuruvilla 1095

Figure 9. Histiocytic lesions. A and B, Langerhans cell histiocytosis. The histiocytic disorders tend to

Figure 9. Histiocytic lesions. A and B, Langerhans cell histiocytosis. The histiocytic disorders tend to produce patchy regions of interstitial infiltration. Langerhans cell histiocytosis is characterized by cells with ovoid, folded, and coffee-bean–shaped nuclei, sometimes accompanied by eosinophil infiltrates. Langerhans cell phenotype is confirmed by immunohistochemical expression of CD1a or CD207 (Langerin). C and D, Juvenile xanthogranuloma. This example of juvenile xanthogranuloma produced an intraluminal obstructive mass in the trachea of a 7-month-old boy. It is characterized by sheets of histiocytic cells, some with foamy xanthomatous cytoplasm and including scattered multinucleate giant cells (he- matoxylin-eosin [A, C, and D] and CD1a immunohistochemistry [B]; original magnifications 400 [A], 100 [B], 40 [C], and 200 [D]).

ma. 123 In children, LCH in the lung typically reflects in- volvement 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 involve- ment, chest computed tomography may show a reticulo- nodular pattern with nodules ranging from 1 to 10 mm in diameter, larger cavitary nodules, pneumatoceles, bi- lateral cystic disease, and/or pneumothorax. 8 Histologi- cally, LCH typically demonstrates patchy infiltrates in- volving the interstitium, pleura, and bronchovascular bun- dles (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 pos- itive but less specific than CD1a or CD207. Electron mi-

1096 Arch Pathol Lab Med—Vol 132, July 2008

croscopy demonstrates characteristic pentalaminar rods with bulbous ends (Birbeck granules) formed by internal- ized 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 infil- tration of the lung may cause a similar pattern radiograph- ically. 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 lym- phoma, which tend to form larger, well-circumscribed nodules obscuring the background lung parenchyma (Fig- ure 10, C and D). An associated mediastinal mass or hilar adenopathy are variable features. The differential diag- nosis for lymphoma involving the lung in children in- cludes primarily Hodgkin lymphoma, non-Hodgkin lym-

Pediatric Lung Tumors—Dishop & Kuruvilla

Figure 10. Lymphoid and hematopoietic lesions. A and B, Acute myeloid leukemia. Leukemic infiltrates in

Figure 10. Lymphoid and hematopoietic lesions. A and B, Acute myeloid leukemia. Leukemic infiltrates in the lung tend to produce ill-defined interstitial infiltrates, in contrast to the nodular masses produced by metastatic solid tumors. This example of acute blast crisis of juvenile myelo- monocytic leukemia shows sheets of blasts producing a pleural plaque with subpleural parenchymal and peribronchial infiltrates. C and D, Hodgkin lymphoma. This Hodgkin lymphoma metastatic to the lung demonstrated destruction of a bronchial wall and large zones of necrosis. Characteristic Reed-Sternberg cells and Hodgkin variant cells are distributed within the background infiltrate of small mature lymphocytes and eosinophils. E, Burkitt lymphoma. Burkitt lymphoma forms both nodular infiltrates and more diffuse interstitial infiltrates of lymphoma cells. The ‘‘starry sky’’ pattern produced by apoptotic cells in the infiltrate is apparent even in this metastatic lesion and reflects the high proliferative rate of this tumor (hematoxylin-eosin, original magnifications 40 [A], 200 [B through D], and 20 [E]).

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Pediatric Lung Tumors—Dishop & Kuruvilla 1097

phoma (acute lymphoblastic lymphoma, Burkitt lympho- ma [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 periph- eral and preferentially involving the lower lobes in those with hematogenous spread. 2 A reticular or military pat- tern may occur with those demonstrating lymphangitic spread. Cavitation and pneumothorax are rare but are fea- tures most often associated with Wilms tumor, Hodgkin lymphoma, and osteosarcoma. 6

Metastasectomy While some metastatic lung nodules are excised for di- agnosis and staging, others are removed as a part of on- cologic management to achieve long-term survival and ef- fect cure. Kayton 126 has recently provided an excellent re- view of clinical indications and surgical techniques used for pulmonary metastasectomy in pediatric patients. This approach began in the 1950s but achieved greater popu- larity after 1971, when survival advantage was reported in osteosarcoma patients with excision of metastatic le- sions (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 pa- tients with aggressive and repeated excision of lung nod- ules. 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 dem- onstrated survival advantage of repeated wedge excisions for metastatic disease. Metastasectomy also plays a central role in management for other tumor types that are resis- tant to chemotherapy and radiation therapy, such as ad- renocortical carcinoma and chondrosarcoma. Conversely, surgical management of metastatic disease is uncommon for chemosensitive and radiosensitive malignancies, such as Wilms tumor, Ewing sarcoma, neuroblastoma, rhab- domyosarcoma, thyroid carcinoma, and germ cell tumors. Clinical features and management principles are dis- cussed 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 os- teosarcoma will have pulmonary metastasis at presenta- tion (Figure 11, A and B). 127 Pulmonary metastases are typically asymptomatic and detected by imaging studies. Large studies have demonstrated a strong correlation be- tween complete resection of primary and metastatic le- sions at presentation and overall survival. 126 Repeated ex- cision of additional lung metastases is often necessary and

1098 Arch Pathol Lab Med—Vol 132, July 2008

provides additional survival benefit. Excision of metastatic lesions should be complete due to the proven survival benefit, and is indicated even after demonstrated chemo- therapy response.

Wilms Tumor 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 metasta- ses are typically detected by imaging rather than by clin- ical symptomatology. Patients with favorable histology Wilms tumor and pulmonary metastasis have a good prognosis, with approximately 75% 4-year survival. 128 Pul- monary nodules in patients with Wilms tumor may be excised for staging at initial diagnosis, but there is a lim- ited 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 Na- tional Wilms Tumor Study group data, patients with fa- vorable histology Wilms tumor have excellent survival af- ter chemotherapy and/or radiation therapy only, with ac- ceptably low rates of radiation pneumonitis. Nevertheless, excision of metastases has been used selectively in indi- vidual Wilms tumor patients with lesions refractory to chemotherapy or radiation therapy, or in patients prior to bone marrow transplant. 126

Neuroblastoma 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 neuroblasto- ma also typically involves other organs, in which case sys- temic chemotherapy is more appropriate than pulmonary metastasectomy. In the case of isolated pulmonary nod- ules, however, excisional biopsy may be indicated to con- firm diagnosis and staging prior to chemotherapy.

Rhabdomyosarcoma Prognosis for rhabdomyosarcoma patients with pul- monary metastasis is generally poor, and concurrent ex- trapulmonary disease is common. Relative to children with extrapulmonary metastases, children with isolated pulmonary disease more commonly have nonalveolar his- tology, 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 bi- opsy confirmation of diagnosis and perhaps resection of isolated lesions. 126

Ewing Sarcoma Family of Tumors Ewing sarcoma (Figure 11, D and E) is generally sen- sitive to both chemotherapy and radiation therapy, and these are the mainstays of management for metastatic dis- ease, as survival advantage after pulmonary metastasec- tomy 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,

Pediatric Lung Tumors—Dishop & Kuruvilla

Figure 11. Metastatic solid tumors of childhood. A and B, Osteosarcoma. Metastatic osteosarcoma may be

Figure 11. Metastatic solid tumors of childhood. A and B, Osteosarcoma. Metastatic osteosarcoma may be excised for staging and also for surgical oncologic management, and is therefore a common diagnosis in lung wedge excisions in adolescents. This example of osteoblastic osteosarcoma shows atypical polygonal cells with focal necrosis and delicate osteoid production. C, Wilms tumor. Wilms tumor (nephroblastoma) produces nodular masses composed of variable blastemal, stromal, and epithelial elements. This example shows predominantly blastemal cells with focal epithelial tubule formation (upper right). D and E, Ewing sarcoma. The Ewing sarcoma family of tumors most often involves the lung by direct extension from the chest wall, or distant metastasis from a soft tissue or bone primary, as in this case. Sheets of monomorphous small, round cells show focal cytoplasmic clearing. Strong membranous expression of CD99 is typical of this tumor. F, Adrenocortical carcinoma. Adrenocortical carcinoma is very rare in children, but it is one of the tumor types for which metastasectomy has a role in oncologic management. This example from a 15-year-old boy with Li-Fraumeni syndrome shows mild pleomorphism with focal nuclear enlargement and atypia, features also seen in many adrenocortical adenomas (hematoxylin-eosin [A through D and F] and CD99 immunohistochemistry [E]; original magnifications 40 [A and C], 200 [B and E], and 100 [D and F]).

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Pediatric Lung Tumors—Dishop & Kuruvilla


synovial sarcoma, chondrosarcoma, fibrosarcoma, and malignant fibrous histiocytoma, and the approach is gen- erally similar to that used for osteosarcoma. 126 In partic- ular, alveolar soft part sarcoma has a high incidence of lung metastasis (60% of pediatric patients), and because it shows incomplete response to chemotherapy, surgical re- section is a necessary component of oncologic manage- ment. 126

Hepatoblastoma Pulmonary metastases of hepatoblastoma may com-

pletely respond to chemotherapy, allowing long-term sur- vival. For unresponsive or partially responsive tumors, however, extended survival may be achieved by pulmo- nary metastasectomy following chemotherapy, leading to

a combined approach in such patients.

Thyroid Carcinoma Mortality is very low for pediatric thyroid cancer. De- spite frequent lymph node metastasis, prognosis is gen- erally favor able, and very few patients develop distant me- tastasis. When present, pulmonary metastases tend to pro- duce a miliary pattern of disease which would not allow resection by metastasectomy. Instead, the primary thera- peutic modality for pulmonary metastases of thyroid car- cinoma is radioactive iodine ( 131 I) 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 com- ponent of oncologic management.

Adrenocortical Carcinoma 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). 126 Metastasectomy

is recommended early after detection and should be com-

plete, preventing recurrence and/or tumor spillage into the thoracic cavity.

Chemotherapy Effect If a metastatic nodule is removed after chemotherapy, evidence of treatment effect may include necrosis, fibrosis, or hemosiderin deposition. Cytodifferentiation after che- motherapy occurs in some embryonal neoplasms, for ex- ample, mature skeletal muscle fibers in rhabdomyosarco- ma. A mixed germ cell tumor may show only residual mature teratomatous components after therapy.

RECOMMENDATIONS FOR GROSS EXAMINATION OF PEDIATRIC LUNG CYSTS AND TUMORS The possibility of unsuspected malignancy should be considered for both solid masses and cystic lesions of the lung in children. These specimens should be received fresh from the operating room, without prior formalin fix- ation or prior incision into the lesion. Examination of the gross specimen should include photography and routine gross description, as well as consideration of sampling of fresh lesional tissue for special studies. Solid masses or mixed solid and cystic lesions warrant tissue collection for electron microscopy (glutaraldehyde), cytogenetic analysis (RPMI or other cell culture medium), and molecular di- agnosis (frozen tissue). Additional tissue may be retained frozen for research studies, with the consideration that the

1100 Arch Pathol Lab Med—Vol 132, July 2008

child may later be enrolled in a biology or treatment pro- tocol (eg, Children’s Oncology Group, International Pleu- ropulmonary Blastoma Registry). Recommended histolog-

ic sections include sampling of at least one section of tu-

mor per centimeter greatest tumor dimension, with pref- erential sampling of heterogeneous areas and junction to normal parenchyma. Sampling of resection margins should include the bronchial margin(s), as well as paren- chymal margins in the case of wedge excisions, partial lobectomies, and lobectomies from lungs with an incom- plete fissure, in which case there may be a stapled paren- chymal margin at the point of division from the adjoining lobe. Evaluation of surgical margins is not necessary for most metastasectomy specimens obtained for diagnosis and staging, but it should be reported for lesions removed for surgical oncologic management (for example, osteo- sarcoma). The purely cystic lesions of the pediatric lung have a broader differential diagnosis and require greater delib- eration in the process of initial tissue handling. Although cystic developmental anomalies are much more frequent than the rare cystic type I PPB, the surgical pathologist should be alert to the possibility of malignancy and con- sider collecting tissue as described above in cases where diagnosis is not clear from gross features. Knowledge of the clinical and diagnostic imaging characteristics is ex- tremely helpful in guiding the proper approach to the specimen. For example, a new cystic lesion identified only after medical illness, such as pneumonia or respiratory distress, would suggest an acquired cyst, such as a pneu- matocele or persistent pulmonary interstitial emphysema. Chest computed tomography provides information on an- atomic characteristics that might suggest a developmental anomaly, such as systemic arterial supply (extralobar and intralobar pulmonary sequestration), anomalous bronchial anatomy (bronchial atresia, intralobar sequestration), or lobar or segmental distribution (congenital lobar overin-

flation, bronchial atresia, intralobar sequestration). A clin- ical or diagnostic imaging impression of a large-cyst (Stocker type I) CPAM typically indicates the presence of

a large unilocular or multilocular purely cystic lesion,

with or without surrounding hyperinflation. Because as- sociated bronchial or vascular anatomy is not always fully characterized by computed tomography imaging, the ab- sence of specific features does not exclude bronchial atre-

sia or intralobar sequestration from the differential diag- nosis. At this point, the surgical pathologist should ex- amine the lung externally for the same anatomic clues, which would suggest a developmental anomaly: segmen- tal or lobar parenchymal hyperinflation, aberrant systemic arterial supply, a mucocele, or aberrant bronchial anatomy. The hilar bronchi are probed in all directions to determine their anatomic distribution and to identify any regions that do not appear to be connected to the central airways.

If specific diagnosis is not established after review of the

diagnostic imaging and gross pathologic features, and if

large-cyst CPAM still remains a diagnostic consideration, then the specimen should be treated as if it may be a PPB type I, and fresh tissue collection is recommended prior

to transbronchial and transpleural injection inflation with

formalin. These large cystic lesions require extensive his- tologic sampling to exclude foci of primitive cells, partic- ularly for cysts lined by alveolar-type epithelium, mim- icking the lesion described as peripheral cyst (Stocker type IV) CPAM.

Pediatric Lung Tumors—Dishop & Kuruvilla

The rarity of PPB and other primary malignancies of the pediatric lung underscores the need for thoughtful dis- section and, if indicated, fresh tissue collection for biologic studies. Such studies will allow further definition of the cytogenetic and molecular characteristics of these rare tu- mors, and it will likely enhance not only our diagnostic capabilities in the future, but also help to determine prog- nosis and optimal therapy for these children.

SUMMARY In this institutional review of pediatric lung biopsies and resections, the ratio of primary benign to primary ma- lignant to metastatic lung tumors in children is 1.4:1:11.6. Metastases to the lung are approximately 12 times more common than primary lung malignancies in children, and they may be excised for diagnosis, staging, or therapeutic purposes. The most common metastatic tumors excised in the pediatric population are Wilms tumor and osteosar- coma. Primary lung malignancies represent only approx- imately 0.19% of all pediatric malignancies, and are often not clinically suspected due to lack of symptoms or non- specific nature of presenting symptoms. The spectrum of primary tumors of the lung in children shows little over- lap with the types of lung tumors seen in adults. The most common primary lung malignancies in children are pleu- ropulmonary blastoma and carcinoid tumor, and broncho- genic carcinomas are exceptionally rare. The relationship of neoplasia to CPAM remains unclear, as some malig- nancies reported to arise in this setting are, in fact, cystic forms of PPB. Bronchioloalveolar carcinoma arising from congenital cysts has been observed rarely, primarily in older children and adults. Immunosuppressed children are susceptible to EBV-associated tumors, including lym- phoproliferative disorders and smooth muscle tumors. Given the rarity of primary lung neoplasms in children and the high incidence of sarcomas and embryonal tu- mors, consideration should be given for sampling of fresh tissue for cytogenetic analysis, electron microscopy, mo- lecular diagnostics, and tumor banking for research pro- tocols.


1. Cohen MC, Kaschula ROC. Primary pulmonary tumors in childhood: a re-

view of 31 years’ experience and the literature. Pediatr Pulmonol. 1992;140:222–


2. Eggli KD, Newman B. Nodules, masses, and pseudomasses in the pediatric

lung. Radiol Clin North Am. 1993;31:651–666.

3. Hancock BJ, DiLorenzo M, Youssef S, Yazbeck S, Marcotte JE, Collin PP.

Childhood primary pulmonary neoplasms. J Ped Surg. 1993;28:1133–1136.

4. Tischer W, Reddeman H, Herzog P, et al. Experience in surgical treatment

of pulmonary and bronchial tumors in childhood. Prog Pediatr Surg. 1987;21:


5. Sane SM, Girdany BR. Cysts and neoplasms in the infant lung. Semin Roent-

genol. 1972;7:122–148.


McCahon E. Lung tumours in children. Paediatr Respir Rev. 2006;7:191–



Hartman GE, Shochat SJ. Primary pulmonary neoplasms of childhood: a

review. Ann Thorac Surg. 1983;36:108–119.

8. Crisci KL, Greenberg SB, Wolfson BJ. Cardiopulmonary and thoracic tumors

of childhood. Radiol Clin North Am. 1997;35:1341–1366.

9. Lack EE, Harris GBC, Eraklis AJ, Vawter GF. Primary bronchial tumors in

childhood: a clinicopathologic study of six cases. Cancer. 1983;51:492–497.

10. Scott KJ, Darrow D, Greinwald JH, Smith RJH. Endobronchial tumors in

children: an uncommon clinical entity. Ann Otol Rhinol Laryngol. 2001;110:63–

14. Welsh JH, Maxson T, Jaksic T, Shahab I, Hicks J. Tracheobronchial muco-

epidermoid carcinoma in childhood and adolescence: case report and review of the literature. Int J Pediatr Otorhinolaryngol. 1998;45:265–273.

15. Miniati DN, Chintagumpala M, Langston C, et al. Prenatal presentation

and outcome of children with pleuropulmonary blastoma. J Pediatr Surg. 2006;


16. Carney JA. The triad of gastric epithelioid leiomyosarcoma, functioning

extra-adrenal paraganglioma and pulmonary tumor. Cancer. 1979;43:374–382.

17. Dajee A, Dajee H, Hinrichs S, Lillington G. Pulmonary chondroma, extra-

adrenal paraganglioma, and gastric leiomyosarcoma: Carney’s triad. J Thorac Car- diovasc Surg. 1982;84:377–381.

18. Hull MT, Gonzalez-Crussi F, Grosfeld JL. Multiple pulmonary fibroleio-

myomatous hamartoma in childhood. J Pediatr Surg. 1979;14:428–431.

19. Oparah SS, Subramanian VA. Granular cell myoblastoma of the bronchus:

report of 2 cases and review of the literature. Ann Thorac Surg. 1976;22:199–


Kramer R. Myoblastoma of the bronchus. Ann Otolaryngol. 1939;48:1083.

Kommel RM, Bernstein J. Granular cell myoblastoma of the bronchus: re-

port of a case. Harper Hosp Bull. 1960;18:20.

22. Broaddus RR, Herzog CE, Hicks MJ. Neuroendocrine tumors (carcinoid

and neuroendocrine carcinoma) presenting at extra-appendiceal sites in child- hood and adolescence. Arch Pathol Lab Med. 2003;127:1200–1203.

23. Hause DW, Harvey JC. Endobronchial carcinoid and mucoepidermoid car-

cinoma in children. J Surg Oncol. 1991;46:270–272.

24. McDougall JC, Unni K, Gorenstein A, O’Connell EJ. Carcinoid and mu-

coepidermoid carcinoma of bronchus in children. Ann Otol. 1980;89:425–427.

25. Molina JR, Aubry MC, Lewis JE, et al. Primary salivary gland-type lung

cancer: spectrum of clinical presentation, histopathologic and prognostic factors. Cancer. 2007;110:2253–2259.

26. Coffin CM, Dehner LP. Soft tissue tumors in first year of life: a report of

190 cases. Pediatr Pathol. 1990;10:509–526.

27. Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors in children and



adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr Pathol. 1991;11:569–588.

28. Tomashefski JF Jr. Benign endobronchial mesenchymal tumors. Am J Surg

Pathol. 1982;6:531–540.

29. Warren JS, Seo IS, Mirkin LD. Massive congenital mesenchymal malfor-

mation of the lung: a case report with ultrastructural study. Pediatr Pathol. 1985;


30. Alobeid B, Beneck D, Sreekantaiah C, Abbi RK, Slim MS. Congenital pul-

monary myofibroblastic tumor: a case report with cytogenetic analysis and review of the literature. Am J Surg Pathol. 1997;21:610–614.

31. Kuhnen C, Harms D, Niessen KH, Diehm T, Muller KM. Congenital pul-

monary fibrosarcoma: differential diagnosis of infantile pulmonary spindle cell tumors. Pathology. 2001;22:151–156.

32. McGinnis M, Jacobs G, El-Naggar A, Redline RW. Congenital peribron-

chial myofibroblastic tumor (so-called ‘‘congenital leiomyosarcoma’’): a distinct neonatal lung lesion associated with nonimmune hydrops fetalis. Mod Pathol.


Robb D. A case of neonatal fibrosarcoma of lung. Br J Surg. 1958;46:173–


Bartley TD, Arean VM. Intrapulmonary neurogenic tumors. J Thorac Car-

diovasc Surg. 1965;50:114–123.

35. Rohana J, Boo NY, Hayati AR, Baizura J. Diffuse neonatal haemangioma-

tosis: a rare cause of haemorrhagic shock and refractory coagulopathy in the newborn. Med J Malaysia. 2002;57:364–367.

36. Whittaker JS, Pickering CAC, Heath D, Smith P. Pulmonary capillary he-

mangiomatosis. Diagn Histopathol. 1983;6:77–84.

37. Oviedo A, Abramson LP, Worthington R, Dainauskas JR, Crawford SE. Con-

genital pulmonary capillary hemangiomatosis: report of two cases and review of

the literature. Pediatr Pulmonol. 2003;36:253–256.



38. Armin A, Castelli M. Congenital adrenal tissue in the lung with adrenal

cytomegaly: case report and review of the literature. Am J Clin Pathol. 1984;82:


39. Jamieson MP, McGowan AR. Endobronchial teratoma. Thorax. 1982;37:


40. Prauer HW, Mack D, Babic R. Intrapulmonary teratoma 10 years after

removal of a mediastinal teratoma in a young man. Thorax. 1983;38:632–634.

41. Pound AW, Willis RA. A malignant teratoma of the lung in an infant. J

Pathol. 1969;98:111–114.

42. Manivel JC, Priest JR, Watterson J, et al. Pleuropulmonary blastoma: the

so-called pulmonary blastoma of childhood. Cancer. 1988;62:1516–1526.

43. Mark EJ. Mesenchymal cystic hamartoma of the lung. N Engl J Med. 1986;


44. Weinberg AG, Currarino G, Moore GC, Votteler TP. Mesenchymal neopla-

sia and congenital pulmonary cysts. Pediatr Radiol. 1980;9:179–182.



Bove KE. Sarcoma arising in pulmonary mesenchymal cystic hamartoma.


Al-Qahtani AR, DiLorenzo M, Yazbeck S. Endobronchial tumors in chil-

Pediatr Pathol. 1989;9:785–792.

dren: institutional experience and literature review. J Pediatr Surg. 2003;38:733–

46. Ueda K, Gruppo R, Unger F, Martin L, Bove K. Rhabdomyosarcoma of


lung arising in congenital cystic adenomatoid malformation. Cancer. 1977;40:


Augustin N, Hofmann S, Wurnig P. Endotracheal and endobronchial tu-


mors in childhood. Prog Pediatr Surg. 1987;21:136–144.

13. Dehner LP. Tumors and tumor-like lesions of the lung and chest wall: clin-

ical and pathologic review. In: Stocker JT, ed. Pediatric Pulmonary Disease. New York, NY: Hemisphere; 1989:207.

Arch Pathol Lab Med—Vol 132, July 2008

47. Hedlund GL, Bisset GS, Bove KE. Malignant neoplasms arising in cystic

hamartomas of the lung in childhood. Radiology. 1989;173:77–79.

48. Hill DA, Sadeghi S, Schultz MZ, Burr JS, Dehner LP. Pleuropulmonary

blastoma in an adult: an initial case report. Cancer. 1999;85:2368–2374.

Pediatric Lung Tumors—Dishop & Kuruvilla 1101

49. Dehner LP, Watterson J, Priest J. Pleuropulmonary blastoma: a unique in-

trathoracic-pulmonary neoplasm of childhood. In: Askin FB, Langston C, Rosen-

berg HS, Bernstein J, eds. Pulmonary Disease. Perspectives in Pediatric Pathology. Vol 18. Basel, Switzerland: Karger; 1995:214–226.

50. Priest JR, McDermott MB, Bhatia S, Watterson J, Manivel JC, Dehner LP.

Pleuropulmonary blastoma: a clinicopathologic study of 50 cases. Cancer. 1997;


51. Priest JR, Hill DA, Williams GM, et al, and the International Pleuropul-

monary Blastoma Registry. Type I pleuropulmonary blastoma: a report from the International Pleuropulmonary Blastoma Registry. J Clin Oncol. 2006;24:4492–



Novak R, Dasu S, Agamanolis D, Herold W, Malone J, Waterson J. Trisomy

8 is a characteristic finding in pleuropulmonary blastoma. Pediatr Pathol Lab Med.


53. Yang P, Hasegawa T, Hirose T, et al. Pleuropulmonary blastoma: fluores-

cence in situ hybridization analysis indicating trisomy 2. Am J Surg Pathol. 1997;


54. Barnard M, Bayani J, Grant R, Teshima I, Thorner P, Squire J. Use of mul-

ticolor spectral karyotyping in genetic analysis of pleuropulmonary blastoma. Pe- diatr Dev Pathol. 2000;3:479–486.

55. The International Pleuropulmonary Blastoma Registry. Available at: http://

www.ppbregistry.org. Accessed March 18, 2008.

56. Priest JR, Watterson J, Strong L, et al. Pleuropulmonary blastoma: a marker

for familial disease. J Pediatr. 1996;128:220–224.

57. Stocker TJ, Madewell JE, Drake RM. Congenital cystic adenomatoid mal-

formation of the lung. Hum Pathol. 1977;8:155–171.

58. Holland-Moritz RM, Heyn RM. Pulmonary blastoma associated with cystic

lesions in children. Med Pediatr Oncol. 1984;12:85–88.

59. Hill DA, Dehner LP. A cautionary note about congenital cystic adenoma-

toid malformation (CCAM) type 4 [letter]. Am J Surg Pathol. 2004;28:554–555.

60. Pai S, Eng HL, Lee SY, et al. Correction: pleuropulmonary blastoma, not

rhabdomyosarcoma in a congenital lung cyst. Pediatr Blood Cancer. 2007;48:


61. Meza MP, Newman B, Dickman PS, Towbin RB. Pediatric case of the day:

pulmonary mesenchymal cystic hamartoma. Radiographics. 1992;12:843–844.

62. Haller JO, Kauffman SL, Kassner EG. Congenital mesenchymal tumour of

the lung. Br J Radiol. 1977;50:217–219.

63. Dehner LP. Pleuropulmonary blastoma is THE pulmonary blastoma of

childhood. Semin Diagn Pathol. 1994;11:144–151.

64. Kodaira Y, Akiyama H, Morikawa M, Shimizu K. Pulmonary blastoma in a

child. J Pediatr Surg. 1976;11:239–241.

65. Schiavetti A, Dominici C, Matrunola M, Capocaccia P, Ceccamea A, Cas-

tello MA. Primary pulmonary rhabdomyosarcoma in childhood: clinico-biologic

features in two cases with review of the literature. Med Pediatr Oncol. 1996;26:


66. Fallon G, Schiller M, Kilman J. Primary rhabdomyosarcoma of the bron-

chus. Ann Thorac Surg. 1971;12:650–654.

67. Jimenez JF, Uthman EO, Townsend JW, Gloster ES, Seibert JJ. Primary bron-

chopulmonary leiomyosarcoma in childhood. Arch Pathol Lab Med. 1986;110:


68. Killingsworth WP, Reynolds GS, Harrison AW. Pulmonary leiomyosarcoma

in a child. J Pediatr. 1953;42:466–470.

69. Lawson EE, Goldstein IR. Bronchial leiomyosarcoma in a child. J Pediatr

Surg. 1971;6:179.

70. Guccion JG, Rosen SH. Bronchopulmonary leiomyosarcoma and fibrosar-

coma: a study of 32 cases and review of the literature. Cancer. 1972;30:836–


Ownby D, Tyon G, Spock A. Primary leiomyosarcoma of the lung in child-

hood. Am J Dis Child. 1976;130:1132–1133.

72. Pettinato G, Manivel JC, Saldana MJ, Peyser J, Dehner LP. Primary bron-

chopulmonary fibrosarcoma of childhood and adolescence: reassessment of a low-grade malignancy: clinicopathologic study of five cases and review of the literature. Hum Pathol. 1989;20:463–471.

73. Wu JP, Gilbert EF, Pellett JR. Pulmonary liposarcoma in a child with ad-

renogenital syndrome. Am J Clin Pathol. 1974;62:791–796.

74. Salter DM. Pulmonary and thoracic sarcomas. Curr Diagn Pathol. 2006;


75. Crist WM, Raney RB, Newton W, Lawrence W Jr, Teft M, Foulkes MA.

Intrathoracic soft tissue sarcomas in children. Cancer. 1982;50:598–604.

76. Jubelirer SJ, Wilson RA. Lung cancer in patients younger than 40 years of

age. Cancer. 1991;67:1436–1438.


77. Putnam JS. Lung carcinoma in young adults. JAMA. 1977;238:35–36.

78. DeCaro L, Benfield JR. Lung cancer in young persons. J Thorac Cardiovasc

Surg. 1982;83:372–376.

79. Pemberton JH, Nagorney DM, Gilmore JC, Taylor WF, Bernatz PE. Bron-

chogenic carcinoma in patients younger than 40 years. Ann Thorac Surg. 1983;

84. Green LS, Fortoul TI, Ponciano G, Robles C, Rivero O. Bronchogenic can-

cer in patients under 40 years old: the experience of a Latin American country.

Chest. 1993;104:1477–1481.

85. Rocha MP, Fraire AE, Guntupalli KK, Greenberg SD. Lung cancer in the

young. Cancer Detect Prev. 1994;18:349–355.

86. Niitu Y, Kubota H, Hasegawa S, et al. Lung cancer (squamous cell carci-

noma) in adolescence. Am J Dis Child. 1974;127:108–111.

87. Cayley CK, Caez HJ, Mersheimer W. Primary bronchogenic carcinoma of

the lung in children. Am J Dis Child. 1951;82:49–60.

88. Shelly BE, Lorenzo RL. Primary squamous cell carcinoma of the lung in

childhood. Pediatr Radiol. 1983;13:92–94.

89. Mizushima Y, Yokoyama A, Ito M, et al. Lung carcinoma in patients age

younger than 30 years. Cancer. 1999;85:1730–1733.

90. Icard P, Regnard JF, de Napoli S, Rojas-Miranda A, Darteveelle P, Levasseur

P. Primary lung cancer in young patients: a study of 82 surgically treated patients. Ann Thorac Surg. 1992;54:99–103.

91. Fontenelle LJ. Primary adenocarcinoma of lung in a child: review of the

literature. Am Surg. 1976;42:296–299.

92. Epstein DM, Aronchick JM. Lung cancer in childhood. Med Pediatr Oncol.


93. Lal DR, Clark I, Shalkow J, et al. Primary epithelial lung malignancies in

the pediatric population. Pediatr Blood Cancer. 2005;45:683–686.

94. Kantar M, Cetingul N, Veral A, Kansoy S, Ozcan C, Alper H. Rare tumors

of the lung in children. Pediatr Hematol Oncol. 2002;19:421–428.

95. Ramos SG, Barbosa GH, Tavora FR, et al. Bronchioloalveolar carcinoma

arising in a congenital pulmonary airway malformation in a child: case report

with an update of this association. J Pediatr Surg. 2007;42:E1–E4.

96. Lantuejoul S, Ferretti GR, Goldstraw P, Hansell DM, Brambilla E, Nichol-

son AG. Metastases from bronchioloalveolar carcinomas associated with long- standing type 1 congenital cystic adenomatoid malformations: a report of two cases [letter]. Histopathology. 2005;48:200–219.

97. Ioachimescu OC, Mehta AC. From cystic pulmonary airway malformation,

to bronchioloalveolar carcinoma and adenocarcinoma of the lung. Eur Resp J.


98. Sudou M, Sugi K, Murakami T. Bronchioloalveolar carcinoma arising from

a congenital cystic adenomatoid malformation in an adolescent: the first case

report from the Orient. J Thorac Cardiovasc Surg. 2003;126:902–903.

99. Granata C, Gambini C, Balducci T, et al. Bronchioloalveolar carcinoma

arising in congenital cystic adenomatoid malformation in a child: a case report

and review on malignancies originating in congenital cystic adenomatoid mal- formation. Pediatr Pulmonol. 1997;25:62–66.

100. Kaslovsky RA, Purdy S, Dangman BC, McKenna BJ, Brien T, Ilves R. Bron-

chioloalveolar carcinoma in a child with congenital cystic adenomatoid malfor- mation. Chest. 1997;112:548–551.

101. Ribet ME, Copin MC, Soots JG, Gosselin BH. Bronchioloalveolar carci-

noma and congenital cystic adenomatoid malformation. Ann Thorac Surg. 1995;


102. Sheffield EA, Addis BJ, Corrin B, McCabe MM. Epithelial hyperplasia and

malignant change in congenital lung cysts. J Clin Pathol. 1987;40:612–614.

103. de Perrot M, Pache JC, Spiliopoulos A. Carcinoma arising in congenital

lung cysts. Thorac Cardiov Surg. 2001;49:184–185.

104. West D, Nicholson AG, Colquhoun I, Pollock J. Bronchioloalveolar car-

cinoma in congenital cystic adenomatoid malformation of lung. Ann Thorac Surg.


105. MacSweeney F, Papagiannaopoulos K, Goldstraw P, Sheppard MN, Cor-

rin B, Nicholson AG. An assessment of the expanded classification of congenital

cystic adenomatoid malformations and their relationship to malignant transfor- mation. Am J Surg Pathol. 2003;27:1139–1146.

106. Stacher E, Ullmann R, Halbwedl I, et al. Atypical goblet cell hyperplasia

in congenital cystic adenomatoid malformation as a possible preneoplasia for pulmonary adenocarcinoma in childhood: a genetic analysis. Hum Pathol. 2004;


107. Lantuejoul S, Nicholson AG, Sartori G, et al. Mucinous cells in type I

pulmonary congenital cystic adenomatoid malformation as mucinous bronchio-

loalveolar carcinoma precursors. Am J Surg Pathol. 2007;31:961–969.

108. Keita O, Lagrange JL, Michiels JF, et al. Primary bronchogenic squamous

cell carcinoma in children: report of a case and review of the literature. Med Pediatr Oncol. 1995;24:50–52.

109. Dallimore NS. Squamous bronchial carcinoma arising in a case of mul-

tiple juvenile papillomatosis. Thorax. 1985;40:797–798.

110. Usui Y, Takabe K, Takayama S, Miura H, Kimula Y. Minute squamous cell

carcinoma arising in the wall of a congenital lung cyst. Chest. 1991;99:235–236.

111. Young JL Jr, Miller RW. Incidence of malignant tumors in U.S. children.

J Pediatr. 1975;86:254–258.

112. Brenner J, Sordillo PP, Magill GB, Golbey RB. Malignant mesothelioma



the pleura: review of 123 patients. Cancer. 1982;49:2431–2435.


Larrieu AJ, Jamieson WRE, Nelems JMB, et al. Carcinoma of the lung in


Fraire AE, Cooper S, Greenberg SD, Buffler P, Langston C. Mesothelioma

patients under 40 years of age. Am J Surg. 1985;149:602–605.


childhood. Cancer. 1988;62:838–847.

81. Roviaro GC, Varoli F, Zannini P, Fascianella A, Pezzuoli G. Lung cancer

in the young. Chest. 1985;87:456–459.

82. Antkowiak JG, Regal AM, Takita H. Bronchogenic carcinoma in patients

under age 40. Ann Thorac Surg. 1989;47:391–393.

83. Capewell S, Wathen CG, Sankaran R, Sudlow MF. Lung cancer in young

patients. Respir Med. 1992;86:499–502.

1102 Arch Pathol Lab Med—Vol 132, July 2008

114. Tuman KJ, Chilcote RR, Berkow RI, Moohr JW. Mesothelioma in a child

with prenatal exposure to isoniazid. Lancet. 1980;2:362.

115. Coffin CM, Dehner LP. Mesothelial and related neoplasms in children

and adolescents: a clinicopathologic and immunohistochemical analysis of eight cases. Pediatr Pathol. 1992;12:333–347.

116. Brenner J, Sordillo PP, Magill GB. Malignant mesothelioma in children:

Pediatric Lung Tumors—Dishop & Kuruvilla

report of seven cases and review of the literature. Med Pediatr Oncol. 1981;9:


117. Cadranel J, Naccach JM, Wislez M, Mayaud C. Pulmonary malignancies

in the immunocompromised patient. Respiration. 1999;66:289–309.

118. Chadwick EG, Connor EJ, Hanson IC, et al. Tumors of smooth muscle

origin in HIV-infected children. JAMA. 1990;263:3182–3184.

119. Jenson HB, Leach CT, McClain KL, et al. Benign and malignant smooth

muscle tumors containing Epstein-Barr virus in children with AIDS. Leuk Lym-

phoma. 1997;27:303–314.

120. McClain KL, Leach CT, Jenson HB, et al. Association of Epstein-Barr virus

with leiomyosarcomas in children with AIDS. N Engl J Med. 1995;332:12–18.

121. Lee ES, Locker J, Nalesnik M, et al. The association of Epstein-Barr virus

with smooth muscle tumors occurring after organ transplantation. N Engl J Med.


122. Reyes C, Abuzaitoun O, DeJong A, et al. Epstein-Barr virus associated

Arch Pathol Lab Med—Vol 132, July 2008

smooth muscle tumors in ataxia-telangiectasia: a case report and review. Hum Pathol. 2002;133:133–136.

123. Colby TV, Carrington CB, Mark GJ. Pulmonary involvement of malignant

histiocytoses: a clinicopathologic spectrum. Am J Surg Pathol. 1981;5:61–73.

124. Chu T, D’Angio GJ, Favara B, Ladisch S, Nesbit M. Histiocytosis syn-

dromes in children. Lancet. 1987;1:208–209.

125. Colby TV, Yousem SA. Pulmonary lymphoid neoplasms. Semin Diagn

Pathol. 1985;2:183–196.

126. Kayton ML. Pulmonary metastasectomy in pediatric patients. Thorac Surg

Clin. 2006;16:167–183.

127. Kager L, Zoubek A, Potschger U. Primary metastatic osteosarcoma: pre-

sentation and outcome of patients treated on neoadjuvant Cooperative Osteosar- coma Study Group protocols. J Clin Oncol. 2003;21:2011–2018.

128. Gatta G, Capocaccia R, Coleman MP, et al. Childhood cancer survival

in Europe and the United States. Cancer. 2002;95:1767–1772.

Pediatric Lung Tumors—Dishop & Kuruvilla 1103