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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, diagnosed at our institution, including 20 primary benign
but they comprise a broad and interesting spectrum of le- lesions (9.8%), 14 primary malignant lesions (6.9%), and
sions, some of which are familiar from other tissue sites, 170 secondary lung lesions (83.3%). The ratio of primary
and some of which are unique to the pediatric lung. benign to primary malignant to secondary malignant neo-
Objective.—To determine the relative incidence of pri- plasms is 1.4:1:11.6. The common types of lung cancer in
mary and metastatic lung tumors in children and adoles- adults are exceptional occurrences in the pediatric popu-
cents through a single-institution case series, to compare lation. The most common primary lung malignancies in
these data to reports in the medical literature, to discuss children are pleuropulmonary blastoma and carcinoid tu-
the clinical and pathologic features of primary tumors of mor. Other primary pediatric lung tumors include congen-
the tracheobronchial tree and lung parenchyma in chil- ital peribronchial myofibroblastic tumor and other myofi-
dren, and to provide recommendations for handling pedi- broblastic lesions, sarcomas, carcinoma, and mesothelio-
atric lung cysts and tumors. ma. Children with primary or acquired immunodeficiency
Data Sources.—A 25-year single institutional experience are at risk for Epstein-Barr virus–related smooth muscle
with pediatric lung tumors, based on surgical biopsies and tumors, lymphoma, and lymphoproliferative disorders.
resections at Texas Children’s Hospital from June 1982 to Metastatic lung tumors are relatively common in children
May 2007, an additional 40 lung tumors referred in con- and also comprise a spectrum of neoplasia distinct from
sultation, and a review of the medical literature. the adult population.
Conclusions.—A total of 204 pediatric lung tumors were (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
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-
than a neoplasm, with a ratio of primary tumors to met- nign tumor of the pediatric lung is inflammatory myofi-
astatic tumors to nonneoplastic lesions of 1:5:60.1 Common broblastic tumor (52%), and the most common primary
malformations forming solid and cystic masses of the pe- malignancies are carcinoid tumor and pleuropulmonary
diatric lung include bronchogenic cyst, segmental bron- blastoma.3 Based on German registry data, malignant tu-
chial atresia, intralobar and extralobar pulmonary seques- mors of the trachea, bronchus, and lungs represent 0.2%
tration, congenital pulmonary airway malformation (con- of all malignancies in children.4 The mortality rate for pri-
genital cystic adenomatoid malformation), and congenital mary benign lung neoplasms in children is low (8.7%),
lobar overinflation. The vast majority of solid parenchymal and the mortality rate for primary malignant tumors is
lung masses in children represent inflammatory, infec- approximately 30% overall. Excluding the ‘‘bronchial ad-
tious, or reactive processes, with a differential diagnosis, enomas,’’ which are associated with a favorable prognosis,
including granulomatous inflammation (fungal, mycobac- the mortality rate of the malignant tumors rises to ap-
terial, parasitic, sarcoidosis, vasculitis); abscess; pneumo- proximately 50%.3
nia (bacterial, viral); septic embolus; infarction; or hema- Given the rarity of primary lung neoplasms in children,
toma.2 Of the lung neoplasms in children, metastatic tu- clinical detection remains a challenge. Some cases are
mors far exceed the number of primary lesions. Of the asymptomatic and detected only incidentally on imaging
studies. Other nonspecific respiratory symptoms may be
Accepted for publication January 12, 2008. attributed initially to asthma or other inflammatory pro-
From the Department of Pathology, Texas Children’s Hospital, Baylor cesses, resulting in a delay of diagnosis until only after
College of Medicine, Houston. symptoms persist or are unresponsive to conventional
The authors have no relevant financial interest in the products or therapy. Even if a mass is recognized, endobronchial le-
companies described in this article. sions and cystic parenchymal lesions may be radiograph-
Reprints: Megan K. Dishop, MD, Department of Pathology, MC
1-2261, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fan- ically indistinguishable from reactive processes or lung
nin St, Houston, TX 77030 (e-mail: mkdishop@texaschildrenshospital. malformations. The possibility of a lung neoplasm should
org). be considered clinically in any child presenting with
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*
Benign Malignant
Embryonic Hamartoma Pleuropulmonary blastoma
Mature teratoma Type I (cystic)
Type II (solid and cystic)
Type III (solid)
Immature teratoma
Malignant germ cell tumor
Mesenchymal Myofibroblastic tumors Synovial sarcoma
IMT Rhabdomyosarcoma
CPMT Ewing sarcoma family of tumors
Myofibromatosis Malignant peripheral nerve sheath tumor
Hemangioma Leiomyosarcoma (with or without EBV)
Lymphangioma Bronchopulmonary fibrosarcoma
Neurofibroma Angiosarcoma
Leiomyoma/smooth muscle tumor (with or without EBV) Kaposi sarcoma
Granular cell tumor
Lymphohistiocytic Lymphoid neoplasms Lymphoid neoplasms
Lymphoproliferative disorders (with or without EBV), Lymphoproliferative disorders (with or without
polyclonal EBV), monoclonal
Histiocytoses Lymphoma
Langerhans cell histiocytosis Hodgkin
Non-LCH histiocytosis Non-Hodgkin
Epithelial Papilloma/papillomatosis Carcinoid tumor
Mucous gland adenoma Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Squamous cell carcinoma
Mesothelial Mesothelioma
* 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 than the low-grade neuroendocrine carcinomas (carcinoid
pneumonia. Regardless of the clinical working diagnoses, tumors), primary lung carcinoma is vanishingly rare and
the pathologist should remain vigilant to the possibility a reportable occurrence in children. Table 1 presents a
of a primary lung neoplasm in a child, particularly in as- classification of pediatric lung neoplasms according to his-
sessing cystic lung lesions. togenesis, adapted from Tischer et al.4 A previous review
Several clinical reviews of pediatric lung neoplasms are of 465 pediatric lung specimens from a single institution
available.1,3–12 Pathologic features of pediatric lung neo- (a 250-bed children’s hospital in Cape Town, South Africa)
plasms have also been reviewed previously by Dehner al- during a 31-year period revealed a total of 8 primary lung
most 20 years ago.13 The objectives of this review are (1) tumors (6 originating at this institution and 2 reviewed in
to provide additional relative incidence data for both pri- consultation) and 35 metastatic tumors.1 Primary lung tu-
mary and metastatic lung neoplasms from a single large mors in this series included 50% malignant and 50% be-
institutional experience, (2) to provide an update on our nign lesions: plasma cell granuloma (3), pleuropulmonary
current understanding of pathologic features and diag- blastoma (2), mucoepidermoid carcinoma (1), endobron-
nostic terminology for these rare tumors, and (3) to pro- chial fibrosarcoma (1), and capillary hemangioma (1).
vide recommendations for the practicing surgical pathol- Metastatic tumors included Wilms tumor (16), osteosar-
ogist on handling cystic and/or solid masses of the pe- coma (9), rhabdomyosarcoma (5), neuroblastoma (4), and
diatric lung.
hepatoblastoma (1).1
TEXAS CHILDREN’S HOSPITAL EXPERIENCE: 25 YEARS In an attempt to provide additional relative incidence
OF PRIMARY AND METASTATIC LUNG TUMORS data, a similar review of the experience at Texas Children’s
Incidence data on primary lung tumors in children are Hospital (Houston) was performed for a 25-year period
limited in the medical literature due to the predominance (June 1982–May 2007). Texas Children’s Hospital is a large
of individual case reports and diagnosis-specific case se- tertiary care center with 639 licensed hospital beds, in-
ries. As a result, cumulative historical data from literature cluding a 36-bed inpatient hematology-oncology unit and
reviews are difficult to interpret due to an uneven repre- a 15-bed bone marrow transplant unit. The Texas Chil-
sentation of these rare lesions and significant differences dren’s Cancer Center receives approximately 25 000 out-
in diagnostic criteria and terminology, which have evolved patient visits annually. Based on registry data from 2000
during the decades typically encompassed by such re- to 2004, an average of 289 children were diagnosed with
views. For example, bronchogenic carcinoma has been re- malignancies annually at our institution, including 91 new
ported to occur with some frequency in other reviews of solid tumor diagnoses per year. Primary and metastatic
pediatric lung tumors, but it appears to be overrepresent- lung lesions were identified by performing a natural lan-
ed in the literature relative to current experience. Other guage search of the anatomic pathology information sys-
1080 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
tem for the dates specified, using terms for site (lung, tra- noid tumor (14.3%). Pleuropulmonary blastoma accounted
chea, bronchus, bronchial, pleura); general descriptors for 72% (8/11) of parenchymal malignancies, and carci-
(cancer, tumor, neoplasm, benign, malignant, malignancy, noid tumor accounted for 67% (2/3) of tracheobronchial
mass, nodule, metastatic, juvenile, infantile); and specific malignancies. One mucoepidermoid carcinoma and one
tumor types (carcinoma, blastoma, sarcoma, lymphoma, type I pleuropulmonary blastoma have been reported pre-
hamartoma, adenoma, pleuropulmonary, lymphoprolifer- viously in the medical literature.14,15 In our patient popu-
ative, Hodgkin/Hodgkin’s, leukemia, Wilms, neuroblas- lation, Wilms tumor and osteosarcoma were the 2 most
toma, hepatoblastoma, osteosarcoma, rhabdomyosarcoma, common solid tumor diagnoses leading to surgical exci-
fibrosarcoma, chondrosarcoma, leiomyoma, leiomyosar- sion of metastatic lung disease, accounting for 31.2% and
coma, liposarcoma, lipoblastoma, glioblastoma, clear cell, 20.3% of these patients, respectively. Due to the role of
neuroendocrine, carcinoid, melanoma, myofibroblastic, surgical oncologic management for metastatic osteosar-
adenocarcinoma, histiocytosis, mesothelioma, Kaposi/Ka- coma, it should be noted that the 28 patients with osteo-
posi’s, granular cell tumor/myoblastoma, and papilloma/ sarcoma had a total of 57 thoracic surgeries for excision
papillomatosis). Patients with juvenile respiratory papil- of metastases, ranging from 1 to 6 surgeries per patient.
lomatosis were included if the excised squamous papillo- Consultation cases referred from other institutions were
mas were specifically designated from tracheal, bronchial, also reviewed during a similar time period and were tab-
or pulmonary sites. Other patients with papillomas ex- ulated separately from institutional cases (Table 3). These
cised only from the larynx/vocal cords, oropharynx, na- tumors included the following additional diagnoses not
sopharynx, esophagus, and/or other sites not specified represented in our institutional data set: congenital peri-
were excluded from tabulation. bronchial myofibroblastic tumor, synovial sarcoma, soli-
During this 25-year period, the total number of surgical tary fibrous tumor, bronchioloalveolar carcinoma, and
pathology specimens was 227 655, with annual specimen pleuropulmonary blastoma type II, as well as Burkitt lym-
numbers ranging from 5309 in 1982 to 14 055 in 2006. We phoma and metastatic juvenile secretory breast carcinoma.
received a total of 3980 surgical specimens designated A summary of the data is also provided in comparison to
from the trachea, bronchus, or lung (1.7%), including both prior literature review (Table 4).
biopsies and resections. Of these, 507 specimens were Clinical and pathologic features of these and other pe-
from lung transplant recipients (12.7%), and 3473 were diatric lung tumors reported in the medical literature are
from other patients (87.3%). There were 273 biopsy and reviewed below, beginning with tracheobronchial lesions
resection specimens for primary or metastatic neoplasms and followed by specific benign and malignant parenchy-
of the lung, representing 6.9% of all tracheobronchial and mal lesions.
lung specimens. Pathologic slides were examined for the
primary benign and malignant tumors to ensure accuracy TRACHEOBRONCHIAL MASSES IN CHILDREN
of diagnosis. Among these, 1 ‘‘mesenchymoma’’ was re- Juvenile Respiratory Papillomatosis
classified as lipoblastoma, and 2 cases of ‘‘spindle cell sar-
coma’’ included one with myofibroblastic differentiation Respiratory papillomatosis is caused by human papil-
and another subclassified as a fibrosarcoma. lomavirus infection, typically acquired during delivery,
The spectrum of tracheobronchial or lung parenchymal and results in multiple recurrent squamous papillomas
tumor diagnoses is summarized in Table 2, including the (Figure 1, A and B), most often of the larynx and trachea
number of individual patients and age distribution for but also involving the distal bronchial tree and esophagus
each lesion. Of these lung tumors, 34 (16.7%) were pri- in some cases, especially after longstanding duration of
mary lung tumors, and 170 (83.3%) reflected metastatic disease. Their clinicopathologic features are distinctive,
disease or secondary involvement by a hematolymphoid and there is little difficulty in the differential diagnosis
or histiocytic process. Of the primary tumors, 20 (59%) with other types of neoplasms. Spread into the lung pa-
were benign, and 14 (41%) were malignant. During this renchyma occurs rarely (Figure 1, C and D), and may pro-
25-year period, the average annual incidence of new pri- duce solid nodules or cystic air-filled cavities.2 Malignant
mary lung malignancies (n ⫽ 14) in our pediatric popu- transformation to squamous cell carcinoma has been re-
lation was 0.56 per year. Based on this average annual in- ported, in some cases related to prior radiation therapy,
cidence of lung malignancies and the recent average an- and is distinguished by marked cellular pleomorphism
nual incidence of all new malignancies (289 per year) at and atypia, loss of maturation, dyskeratosis, and invasion
our institution, we estimate that primary pediatric lung into the bronchial wall or lymphatic channels. Treatment
malignancies account for 0.19% of all new pediatric ma- for squamous papillomas may include surgical excision,
lignancies diagnosed annually. CO2 laser vaporization, and/or adjuvant antiviral or in-
The ratio of primary benign to primary malignant to terferon therapy.10
secondary (metastatic) malignant tumors was 20:14:162 (or
1.4:1:11.6), indicating that excisions for metastatic tumors Hamartoma
were almost 12 times more common than primary malig- Hamartomas contain disorganized tissues intrinsic to
nant tumors. The most common benign lesions were squa- the lung and show peak incidence in the fourth to sixth
mous papillomas associated with human papilloma virus decades.7 They are typically lobulated and encapsulated
infection ( juvenile respiratory papillomatosis), inflamma- masses, which may be endobronchial or intraparenchy-
tory myofibroblastic tumor, and Epstein-Barr virus (EBV)– mal. They are rare in children, but they may present as
associated smooth muscle tumors. The 8 patients with re- large parenchymal masses with respiratory distress. Chest
spiratory papillomas often had multiple surgical proce- computed tomography classically shows fat and ‘‘pop-
dures, ranging from 1 to 5 excisions and averaging 2.9 per corn’’ calcifications, which suggest the diagnosis. Micro-
patient. The most common primary malignancies of the scopically, cartilage, fat, and fibrous tissue are typically the
lung were pleuropulmonary blastoma (57.1%) and carci- most prominent components, although smooth muscle,
Arch Pathol Lab Med—Vol 132, July 2008 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*
Benign Malignant
Age Age
No.† Range No. Range
Tracheobronchial Squamous papilloma 7 1–18 y Carcinoid tumor 2 11–15 y
Hemangioma 1 5 mo Mucoepidermoid CA 1 10 y
JXG 1 7 mo
IMT 1 4y
Chondroma 1 13 y
Parenchymal EBV-SMT 3 5–11 y PPB type I 6 3 mo–2 y
IMT 1 7y PPB type III 2 4–11 y
Myofibromatosis 1 10 y Spindle cell sarcomas 2 3–8 y
Lipoblastoma 1 1y Fibrosarcoma
Lymphangioma 1 11 y Myofibroblastic
Congenital immature mesenchymal 1 0d Squamous cell CA 1 6y
Squamous papillomas 1 3y
Total 20 Total 14
Lymphohistiocytic/ LPD, polymorphous 4 11 mo–6 y LPD, monomorphous 3 2–15 y
hematopoietic LCH 3 6 mo–2 y NHL (LBCL, other) 3 4–17 y
Histiocytic, non-LCH 1 1 mo HL 15 9–19 y
ALL 1 4y
AML 1 6y
CML 1 7y
Total 8 Total 24
Metastatic solid Wilms tumor 43 1–11 y
tumors Osteosarcoma 28 6–26 y
EWS/PNET 13 7–18 y
RMS 10 3–14 y
Germ cell tumor 6 16–19 y
NB 6 7 mo–13 y
HB 4 10 mo–1 y
HCC 1 9y
Rhabdoid/ATRT 3 9 mo–11 y
CCSK 1 2y
Cellular MN 1 9 mo
DSRCT 1 20 y
Other sarcomas 14
UDS 3 11–15 y
Synovial sarcoma 2 10–12 y
CCST 1 10 y
Angiosarcoma 1 10 y
Liposarcoma 1 4y
Fibrosarcoma 2 14 y, 20 y
Myofibrosarcoma 1 10 y
MFH 1 9y
ASPS 1 3y
Sarcoma, NOS 1 17 y
Other carcinomas 5
NPC 1 17 y
ACC 1 12 y
AdenoCA, colon 1 9y
Clear cell CA, SC 1 4y
Squamous cell CA 1 6y
Other malignant, NOS 3 3–16 y
Total 138
* 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*
Benign Malignant
Age Age
No. Range No. Range
Tracheobronchial Neuroendocrine CA 1 13 y
Mucoepidermoid CA 1 8y
Parenchymal CPMFT 3 0–2 wk PPB type I 4 8 wk–4 y
Congenital immature mesenchymal 2 2 wk–5 mo PPB type II 2 3y
tumor Bronchopulmonary fibrosarcoma 1 5y
Solitary fibrous tumor 1 Synovial sarcoma 1
Total 6 Total 11
Systemic LPD, polymorphous 4 3 mo–12 y LPD, monomorphous 1 14 y
LCH 2 ND, 13 y Burkitt lymphoma 1 2y
Metastatic Osteosarcoma 5 8–21 y
Wilms tumor 3 5–13 y
GNB 1 6y
Hepatoblastoma 2 1–7 y
Hepatocellular CA 1 8y
Synovial sarcoma 1 15 y
Breast CA, juvenile secretory 1 8y
Total 6 Total 17
* 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 with small nuclei and abundant granular eosinophilic cyto-
seen. Tumors with a single dominant component may be plasm.7,9,19–21 The term bronchial adenoma is a misnomer pre-
diagnosed as a chondroma, fibroma, or lipoma, although viously used to refer collectively to 4 distinct lesions (carci-
careful search may demonstrate foci of other mesenchymal noid tumor, mucoepidermoid carcinoma, adenoid cystic car-
elements. cinoma, and mucous gland adenoma). Bronchial mucous
gland adenoma is the only benign lesion among these, and
Chondroma only 2 cases were described in a literature review up to
Chondromas are benign cartilaginous tumors that occur 1983.7 Histologically, mucous gland adenomas are composed
as single or multiple encapsulated lesions that arise in con- of a well-circumscribed mass of distended mucus-filled cysts
tinuity with bronchial cartilage and do not have other and tubules lined by a single layer of columnar goblet cells.
mesenchymal elements, as in the hamartomas described The differential diagnosis of endobronchial masses in chil-
above (Figure 1, E). Pulmonary chondromas have been de- dren also includes reactive vascular lesions, including gran-
scribed in the Carney triad, a syndrome almost exclusively ulation tissue and pyogenic granuloma, chronic foreign body
seen in young females comprising functioning paragan- reaction, and granulomatous inflammation, for example, due
glioma, epithelioid gastrointestinal stromal tumor, and to histoplasmosis or mycobacteria.10
pulmonary chondroma.16,17 Due to potential complications
of the associated lesions, children with pulmonary chon- Carcinoid Tumor
droma may benefit from periodic screening for meta- Carcinoid tumors are considered low-grade neuroen-
chronous development of paragangliomas or gastrointes- docrine carcinomas due to their potential for locally ag-
tinal stromal tumors. gressive growth and low potential for metastasis. These
lesions are typically obstructive endobronchial masses of
Other Benign Tracheobronchial Lesions older children and adolescents (Figure 1, F), presenting
Other benign tracheobronchial tumors reported in chil- with symptoms of wheezing, cough, hemoptysis, or pneu-
dren include leiomyoma, granular cell tumor, and mucous monia.6,7,9,22–24 The carcinoid syndrome caused by produc-
gland adenoma. Primary solitary leiomyomas are benign tion of neurosecretory peptides is very rare in the absence
smooth muscle tumors, histologically similar to leiomyomas of metastatic disease. Carcinoid tumors have been report-
in other locations, which may be asymptomatic or present ed to account for up to 80% to 85% of primary malignant
as endobronchial masses with obstruction. Leiomyomas as- lung tumors in children, although this is likely an over-
sociated with EBV infection are discussed below. Multiple estimate. They may arise from the lobar bronchi (75%),
fibroleiomyomatous hamartomas (benign metastasizing leio- mainstem bronchi (10%), or within the lung parenchyma
myomas) have been described in a child with a history of (15%).6 Microscopic features include sheets, nests, and
rhabdomyosarcoma.18 Bronchial granular cell tumors are re- cords of monotonous small cells with stippled nuclear
ported rarely and have histologic features similar to those chromatin and a delicate vascular network in the back-
described in the oral cavity, comprising sheets of round cells ground (Figure 1, G). Treatment is primarily surgical, and
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1083
Table 4. Primary Lung Tumors in Children: Summary of Data From Literature Review and Single-Institution Data
(Texas Children’s Hospital [TCH], Houston)*
TCH Total Cases, No.
Literature Review TCH Surgical TCH Consult (% of Total,
(Hancock et al3), No. (%) Cases, No. (%) Cases, No. n ⴝ 51)
IMT 48 (52.2) 2 (10) 2 (3.9)
CPMFT 3 3 (5.9)
Myofibromatosis 1 (5) 1 (2.0)
Hamartoma 22 (23.9)
Neurogenic tumor 9 (9.8)
Leiomyoma/EBV-SMT 6 (6.5) 3 (15) 3 (5.9)
Mucous gland adenoma 3 (3.3)
Granular cell tumor 3 (3.3)
Benign teratoma 1 (1.1)
Squamous papillomatosis 8 (40) 8 (15.7)
Hemangioma 1 (5) 1 (2.0)
Lymphangioma 1 (5) 1 (2.0)
Chondroma 1 (5) 1 (2.0)
Juvenile xanthogranuloma 1 (5) 1 (2.0)
Lipoblastoma 1 (5) 1 (2.0)
Immature mesenchymal tumor 1 (5) 2 3 (5.9)
Solitary fibrous tumor 1 1 (2.0)
Total 92 20 6 26
Carcinoid tumor 48 (16.5) 2 (14.3) 1 3 (5.9)
Mucoepidermoid CA 39 (13.4) 1 (7.1) 1 2 (3.9)
Adenoid cystic carcinoma 4 (1.4)
‘‘Bronchial adenoma,’’ NOS 27 (9.3)
Pleuropulmonary blastoma† 57 (19.6) 8 (57.1) 6 14 (27.5)
Bronchogenic carcinoma 49 (16.8) 1 (7.1) 1 2 (3.9)
Bronchopulmonary fibrosarcoma 28 (9.6) 1 (7.1) 1 (2.0)
Rhabdomyosarcoma 11 (3.8) 1 1 (2.0)
Leiomyosarcoma 11 (3.8)
Other sarcoma 3 (0.9) 1 (7.1) 1 2 (3.9)
Hemangiopericytoma 4 (1.4)
Plasmacytoma 4 (1.4)
Lymphoma 3 (1.0)
Immature teratoma/GCT 3 (1.0)
Total 291 14 11 25
* 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 chial tree is similar to that in other salivary gland sites
hemorrhage and incomplete resection. Depending on lo- and is divided into low-, intermediate-, and high-grade
cation and size, complete excision and removal of involved tumors. Low-grade MEC is composed of predominantly
lymphatics may be achieved with bronchial sleeve resec- mucous cells arranged in large cystic spaces, and it is the
tion, lobectomy, or even pneumonectomy. Local invasion most common type described in the tracheobronchial tree
or distant metastasis has been reported in a significant in children.9 Intermediate-grade MEC is composed of pre-
percentage of children (27%), and overall survival in chil- dominantly intermediate cells and occasional mucous
dren is approximately 90%.6,9 cells, forming a solid pattern with infrequent cysts and
glands (Figure 1, H and I). High-grade MEC contains pre-
Mucoepidermoid Carcinoma dominantly epidermoid cells and infrequent intermediate
Mucoepidermoid carcinoma (MEC) is reported to rep- cells arranged in solid sheets, and it is characterized by
resent approximately 10% of malignant lung neoplasms in increased pleomorphism and high mitotic activity. The
children. This tumor is rare in children, with just more low-grade tumors tend to have local tissue invasion but
than 30 cases of tracheobronchial MEC reported in the only rare metastasis.14 Treatment is primarily surgical,
medical literature. Similar to carcinoid tumors, presenting with chemotherapy and radiotherapy reserved for those
symptoms may include recurrent pneumonia, respiratory tumors with incomplete resection.25 The 5-year survival
distress, persistent cough, wheezing, or hemoptysis. Mu- rate of adults with MEC is 88%.25 The prognosis in chil-
coepidermoid carcinoma arises in the tracheobronchial dren appears to be more favorable, with no deaths re-
tree from the salivary-type mucous cells of the submucosa, ported in the literature after surgical resection alone.
most commonly occurring in the mainstem bronchus or a
proximal lobar bronchus. These tumors are typically exo- Adenoid Cystic Carcinoma
phytic polypoid masses that cause bronchial obstruction Adenoid cystic carcinoma is a slowly growing infiltra-
(80% of cases).14,23,24 Grading of MEC in the tracheobron- tive salivary gland–type neoplasm that is rare in the tra-
1084 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
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 metastasis compared with mucoepidermoid carcinoma
seen in the salivary glands, consisting of cribriform, glan- and has poorer survival (55% 5-year survival).25
dular, and solid patterns of small hyperchromatic cells.
There is a tendency for submucosal spread, circumferen- MYOFIBROBLASTIC TUMORS
tial bronchial involvement, and late local recurrence. At Inflammatory Myofibroblastic Tumor
the time of literature review in 1983, only 4 cases were Previously called inflammatory pseudotumor or plasma cell
reported in children.7 Treatment is complete surgical ex- granuloma, inflammatory myofibroblastic tumor is a slow-
cision with or without adjuvant radiation therapy.25 Due growing tumor which shows characteristics of both reac-
to the infiltrative nature and tendency for local recurrence, tive and neoplastic lesions.26–28 Although theorized to re-
frozen section examination may be helpful in assuring sult from a repair response, antecedent injury cannot be
negative bronchial margins at the time of surgery. Ade- documented in most cases. Although many tumors are
noid cystic carcinoma has a higher likelihood of distant asymptomatic (30%), others present with symptoms of
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1085
cough or fever. Excluding respiratory papillomatosis, it is a large portion of the lung is typically enlarged and re-
estimated that inflammatory myofibroblastic tumor ac- placed by a firm rubbery mass with a yellow-tan to gray
counts for approximately 52% to 70% of benign primary whorled cut surface containing bands of fibrous-appear-
lung tumors reported in the literature in children.3,14 Most ing tissue (Figure 2, D). Microscopically, bland spindled
children with pulmonary inflammatory myofibroblastic cells form large fascicles following the planes of the bron-
tumor are older than 5 years (75%), but cases involving a chovascular bundles, interlobular septa, and pleura, often
few infants and young children are reported, and there is forming a distinctive lobular compartmentalization of the
an equivalent sex distribution.7 Chest x-ray typically dem- lung parenchyma (Figure 2, E). The tumor fascicles are
onstrates a solitary well-circumscribed nodule, ranging in extrinsic to the airways but surround, displace, and distort
size from 1 to 12 cm. Grossly, these nodular lesions may the airway structures. Malformed and enlarged cartilage
be either endobronchial (17%; Figure 2, A) or intraparen- plates adjacent to entrapped airways are a prominent
chymal (83%).3,7 Histologic features include a proliferation component of some tumors. Occasional foci of extramed-
of bland spindled and stellate cells with abundant eosin- ullary hematopoiesis may be seen. Mitotic figures may be
ophilic cytoplasm, admixed with scattered inflammatory frequent, but there is no cytologic atypia or atypical mi-
cells, including lymphocytes and, occasionally, prominent toses. The lesion tends to be more uniform in cellularity,
plasma cells and eosinophils (Figure 2, B). Immunohisto- in contrast to other myofibroblastic tumors. Immunohis-
chemistry for smooth muscle actin and/or muscle-specific tochemistry shows diffuse positivity for vimentin and fo-
actin may be helpful in demonstrating the myofibroblastic cal desmin, muscle-specific actin, or smooth muscle actin
nature of these cells. Treatment is primarily surgical, and positivity.30,32 Flow cytometric DNA ploidy analysis has
complete but conservative surgical excision is recommend- shown a normal diploid population.32 Cytogenetic study
ed. Inflammatory myofibroblastic tumors have a tendency in 1 case has shown a complex rearrangement of chro-
for local recurrence if incompletely excised. mosomes 4, 8, and 10.30 Electron microscopy shows spin-
dled cells with dilated rough endoplasmic reticulum,
Myofibromatosis scarce mitochondria, occasional lipid droplets, and scant
Myofibromas are relatively common benign soft tissue cytoplasmic filaments, some with dense bodies and at-
tumors in children, most often presenting as a firm nod- tachment plaques, consistent with myofibroblastic differ-
ular mass in the subcutaneous or deep soft tissue. Al- entiation.29,30,32 Although the lesion is cytologically bland,
though most often solitary, they may be multifocal and the large size often results in respiratory or hemodynamic
involve both soft tissue and visceral organs, so-called my- compromise and has resulted in a high mortality rate in
ofibromatosis (Figure 2, C). Myofibromatosis is more often reported cases (55% in 1 series).32 If early resection is
diagnosed in infants and young children than in older achieved, typically by pneumonectomy or bilobectomy,
children. The cellularity of these lesions varies, often long-term survival is expected.30
showing some hypocellular hyalinized zones as well as
other zones of hypercellularity. Characteristic protrusion NEUROGENIC TUMORS
of bland spindled cells into adjacent vasculature is occa- Neurogenic tumors of the lung may include neurofibro-
sionally seen and should not be interpreted as an aggres- ma, schwannoma, malignant peripheral nerve sheath tu-
sive feature. Hemangiopericytomatous vasculature may be mors, and mucosal neuromas. A series of intrapulmonary
prominent. Pulmonary involvement by myofibromatosis neurogenic tumors has shown 26% (9/34) occurring in
may be a manifestation of multifocal systemic disease or children younger than 16 years.34 Of these 9 tumors in
regional involvement of the chest wall. Multifocality in the children, all were benign, including 4 neurofibromas and
lung should not be misinterpreted as aggressive or met- 5 schwannomas. Although most pulmonary neurofibro-
astatic disease. mas are nonsyndromic, the possibility of neurofibroma-
Congenital Peribronchial Myofibroblastic Tumor tosis should always be considered in a child with a pul-
monary neurofibroma.
Congenital peribronchial myofibroblastic tumor is a
very rare and distinctive benign lung tumor of the fetus VASCULAR LESIONS
and infant, with only approximately 25 cases reported
previously in the medical literature.29–33 It has been de- Hemangiomas
scribed under various terminology, including massive con- Infantile hemangioma is a lobular proliferation of small
genital mesenchymal malformation of the lung, hamartoma of capillaries that typically appears in the first weeks of life
the lung, bronchopulmonary leiomyosarcoma, and primary and shows a period of involution during the ensuing
bronchopulmonary fibrosarcoma.29 The tumor is thought to months (Figure 3, A). The early proliferating lesions may
arise from the pluripotent mesenchyme found around the be highly cellular and mitotically active, whereas involut-
developing bronchi at approximately 12 weeks’ gestation, ing lesions have less capillary density with more widely
with potential for both smooth muscle and cartilaginous spaced and dilated thick-walled capillaries. Both prolif-
differentiation. Interestingly, congenital peribronchial my- erative and involuting lesions are characterized by endo-
ofibroblastic tumor is morphologically similar to 2 other thelial positivity for the glucose transporter Glut-1 (Figure
types of myofibroblastic tumors presenting in the neonatal 3, B), a marker that distinguishes the infantile hemangio-
period: congenital mesoblastic nephroma (classic type) ma from most other vascular anomalies, including rapidly
and congenital spindle cell tumor of the intestinal tract. involuting and noninvoluting congenital hemangiomas,
Congenital peribronchial myofibroblastic tumor typically vascular malformations, and pyogenic granulomas. While
presents in utero or at birth as a large 5- to 7-cm unilateral infantile hemangiomas are most commonly found in the
lung mass with mediastinal shift and resulting in intra- skin and soft tissue, visceral involvement also occurs, both
uterine polyhydramnios, hydrops, or immediate respira- as isolated lesions and as a component of multifocal sys-
tory failure at delivery. Grossly, nearly the entire lung or temic distribution of disease (hemangiomatosis).35 Tra-
1086 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
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]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1087
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]).

1088 Arch Pathol Lab Med—Vol 132, July 2008 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
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).
Teratomas within the lung parenchyma are reported as
isolated cases, including only 2 case reports before
1983.7,39–41 Pericardial or anterior mediastinal teratomas are
more common, and they may show secondary 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 Figure 4. Other benign parenchymal lung lesions. A, Lipoblastoma.
most contain derivatives of all 3 germ cell layers. Primary Lipoblastomas may occur in any site of the body, including soft tissue
malignant germ cell tumors of the lung are exceedingly and viscera. This rare lesion replacing the left upper lobe of a 16-
rare, although choriocarcinoma has been reported. month-old boy shows areas of immature mesenchyme with predomi-
Lipoblastoma is a benign tumor of adipose tissue typ- nantly vascular myxoid tissue containing scattered fat vacuoles and
maturing lipoblasts. B and C, Rhabdomyomatous dysplasia, nodular
ically characterized by an admixture of immature lipoblast form. Rhabdomyomatous dysplasia refers to ectopic skeletal muscle
in a vascular myxoid matrix, juxtaposed with zones of differentiation within the lung and is most often recognized incidentally
mature adipose tissue. Lipoblastomas occur most often in within the interstitium of extralobar pulmonary sequestrations. Rarely,
the soft tissue of infants and young children, but they may rhabdomyomatous dysplasia may form nodular lesions, as in this in-
also involve the viscera, including the lung (Figure 4, A). cidental lung nodule in a 1-week-old, 28-week gestation neonate, who
Ectopic tissues occasionally form nodular lesions of the died of pulmonary hypoplasia and respiratory failure (hematoxylin-eo-
sin, original magnifications ⫻40 [A], ⫻20 [B], and ⫻200 [C]).
lung. Rhabdomyomatous dysplasia is a rare entity com-
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1089
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- chymal malignancy without an epithelial component. It
renchyma, most often seen incidentally within lung mal- has been reported previously in the medical literature un-
formations, such as extralobar sequestration. Rarely, rhab- der a variety of descriptors, including pulmonary blasto-
domyomatous dysplasia forms a nodular focus of skeletal ma, mesenchymal cystic hamartoma, malignant mesen-
muscle cells in otherwise normal lung (Figure 4, B and C). chymoma, and sarcomas (myxosarcoma or rhabdomyo-
Ectopic adrenal gland tissue and ectopic glial tissue have sarcoma) arising in congenital cystic malformations.43–47
also been reported as nodular lesions in the lung.38 Pleuropulmonary blastoma is diagnosed primarily in in-
fants and toddlers, and rarely beyond age 12 years. Oc-
PLEUROPULMONARY BLASTOMA currence in adults is reported but extremely rare.48 These
Pleuropulmonary blastoma (PPB) is a rare malignant lesions may be detected incidentally in utero or postna-
embryonal mesenchymal neoplasm of the lung and pleura tally.15 Symptomatic presentation may result from spon-
occurring almost exclusively in children that was de- taneous pneumothorax in the cystic lesions.49
scribed as a unique entity distinct from pulmonary blas- Pleuropulmonary blastoma is subclassifed based on the
toma in 1988.42 In contrast to the adult-type biphasic pul- spectrum of gross morphology: purely cystic lesions (type
monary blastoma (PB), PPB is a polyphenotypic mesen- I), solid and cystic lesions (type II), and purely solid le-
1090 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
sions (type III).49 Age at presentation varies depending on lesion distorts the contour of the lung, is positioned pe-
morphologic type, with the type I lesions most often di- ripherally, or is found to protrude from the pleural sur-
agnosed in infancy (average age, 10 months), and the type face. The differential diagnosis includes the more common
II and type III lesions more often diagnosed in toddlers benign cystic lung malformations, as well as other rare
(average ages, 34 and 44 months, respectively).50,51 Grossly, primary sarcomas of the lung. The most common sub-
the low-grade cystic lesions (type I) are typically periph- mitting diagnosis and the principal pathologic differential
eral and pleural-based lesions, sometimes protruding diagnosis for cystic type I PPB is CPAM (also called con-
from the pleural surface (Figure 5, A). They are entirely genital cystic adenomatoid malformation [CCAM]).57 The
cystic, with no solid components or nodules and are large-cyst (Stocker type I) CPAM and the peripheral cyst
grossly indistinguishable from the large-cyst (Stocker type type (Stocker type IV) CPAM are grossly identical to cystic
I) congenital pulmonary airway malformation (CPAM). PPB. The large-cyst CPAM is distinguished easily micro-
Microscopically, they are virtually identical to what has scopically by a cyst lining composed predominantly of
been described as the peripheral cyst (Stocker type IV) respiratory type epithelium, with or without focal muci-
CPAM. Type I PPBs have thin cyst walls lined by predom- genic epithelium, often resembling small foci of gastric
inantly alveolar-type epithelium and containing focal ar- foveolar epithelium. The respiratory epithelial lining
eas of hypercellularity and hypervascularity (Figure 5, B shows interdigitation with surrounding airspaces, which
and C). The hypercellular foci are composed of hyper-
may be secondarily enlarged and maldeveloped. The pe-
chromatic compact spindled cells and small round cells,
ripheral cyst (Stocker type IV) CPAM is much more prob-
often forming a cambium-like layer beneath the epitheli-
lematic to distinguish from cystic PPB and, in fact, it has
um lining the cyst walls. Foci of immature-appearing car-
been suggested that many examples of type IV CPAM
tilage are present in some cases. The higher grade lesions
(type II and type III) have solid components on gross ex- may actually represent unrecognized or insufficiently
amination. Although entirely solid, the type III PPB may sampled cystic PPBs.58,59 Stocker describes CPAM type IV
have areas of necrosis and cystic degeneration. The solid as having thin cyst walls lined by alveolar-type epithelium
components of both type II PPB (Figure 5, D) and type III and with increased vascularity of the septa. Cystic PPB
PPB (Figure 5, E through H) also show higher grade cy- has a similar architecture, but it is distinguished by the
tologic features, with sheets of spindled and pleomorphic, identification of hypervascular and hypercellular foci of
sometimes anaplastic cells, resembling rhabdomyosarco- primitive cells in the cyst walls, a focal and subtle finding
ma. Fibrosarcoma-like areas and chondroid nodules are in many cases due to the low-grade cytology. Any lesion
other recognized patterns. It should be noted that type I mimicking type IV CPAM on initial microscopic sections
lesions may progress to the higher grade type II or type requires extensive sampling to exclude the presence of
III lesions, particularly if incompletely excised. these hypercellular foci. The differential diagnosis of the
Immunohistochemistry of PPB demonstrates vimentin solid and cystic or purely solid lesions includes other pri-
in the primitive cell component, as well as myogenic dif- mary sarcomas of the lung, including rhabdomyosarcoma
ferentiation in some cases, specifically with expression of and synovial sarcoma. Some cases initially reported as
desmin, muscle specific actin, smooth muscle actin, my- rhabdomyosarcoma of the lung likely represent high-
ogenin, and/or myoglobin. Electron microscopy may also grade PPB.49,60 The lesion described in the literature as
show evidence of rhabdomyoblast differentiation with ‘‘mesenchymal hamartoma of the lung’’ in children is also
myofibrils and z-band formation, as well as loose granular more appropriately classified as PPB.61,62 Finally, as men-
matrix and abundant rough endoplasmic reticulum, indi- tioned above, PPB should be distinguished from the rare
cating chondrocytic differentiation.49,50 Cytogenetic analy- adult-type PB, a tumor most often presenting in the fourth
sis of PPB has been described in a small number of cases, or fifth decade of life, which has an associated epithelial
primarily of higher grade lesions. Although a tumor-spe- component not present in the childhood lesion.63,64 Entrap-
cific translocation has not been identified, there may be a ment of alveolar or bronchiolar epithelium by PPB may
variety of karyotypic abnormalities (trisomy 8, trisomy 2, also mimic PB. In the pediatric population, a sarcomatous
and 17p deletions), and mutations in p53 have been de- lesion with a glandular-appearing epithelial component
scribed.52–54 mimicking biphasic PB should prompt consideration of sy-
Pleuropulmonary blastoma may be solitary or multiple, novial sarcoma.
and additional lesions may be discovered synchronously Treatment for PPB is primarily surgical for the cystic
or metachronously in the same patient. Interestingly, PPB
(type I) lesions, although adjuvant chemotherapy may be
may have familial predisposition, and genetic studies are
advantageous in cases with incomplete resection. Certain-
ongoing through the International Pleuropulmonary Blas-
ly, the higher grade (type II and type III) lesions require
toma Registry.55 In approximately 25% of cases, PPB is
associated with other extrapulmonary lesions in the same adjuvant chemotherapy after resection, and radiation ther-
patient or family members.49 The most common associated apy is recommended for residual disease. In either case,
lesion is cystic nephroma, but other embryonal tumors close clinical follow-up is warranted due to potential for
(sarcomas, medulloblastoma, malignant germ cell tu- recurrence, metastasis, multifocality, and associated extra-
mors), thyroid neoplasms, leukemia, Hodgkin lymphoma, pulmonary lesions. Low-grade cystic lesions may recur as
and Langerhans cell histiocytosis (LCH) have been asso- a higher grade lesion, and this potential justifies chemo-
ciated with PPB.56 therapy for some type I tumors. Metastasis occurs in ap-
Clinically, the diagnosis of PPB is infrequently enter- proximately 30% of types II and III tumors, and may occur
tained preoperatively.15 Pathologists must consider the di- late in the disease course. The most commonly reported
agnosis of PPB for any child with a spherical unilocular sites of metastasis include the central nervous system and
or multiloculated cystic lesion, mixed solid and cystic le- bone.50 Five-year survival rate is 83% for type I PPB and
sion, or large solid mass in the lung, particularly if the 42% for types II and III PPB.50
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1091
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 to partial resection of lung with chest wall resection. Rare-
Synovial Sarcoma ly, these tumors may arise primarily in the lung, but they
most often originate in the rib or chest wall.
Although rare, synovial sarcoma is one of the more
common primary sarcomas of the lung in children. Di- Rhabdomyosarcoma
agnostic features are similar to those seen in other sites,
and morphology may be monophasic or biphasic (Figure While several cases of pulmonary rhabdomyosarcoma
6, A and B). Immunohistochemistry for cytokeratin, epi- reported in the literature likely actually represent cases of
thelial membrane antigen, CD99, and BCL2 are typically pleuropulmonary blastoma, true primary rhabdomyosar-
positive. Cytogenetic analysis and/or molecular diagnos- coma of the lung also occurs, often manifesting as an en-
tic testing is helpful in demonstrating the characteristic dobronchial mass.7,65,66 Pulmonary rhabdomyosarcoma is
t(X;18) translocation, producing an SSX-SYT fusion tran- estimated to represent approximately 0.5% of all rhabdo-
script. myosarcomas in children.3 After Ewing sarcoma family of
tumors, rhabdomyosarcoma is the second most common
Ewing Sarcoma Family of Tumors malignancy of the chest wall in children, and it may pro-
The Ewing sarcoma family of tumors includes Ewing duce direct involvement of the thoracic cavity or pulmo-
sarcoma of bone and soft tissue, as well as peripheral nary metastasis in this setting.8
primitive neuroectodermal tumor. These tumors are uni- Leiomyosarcoma
fied by the rearrangement of the Ewing sarcoma gene
with one of a variety of fusion partner genes, most com- A few cases of bronchopulmonary leiomyosarcoma have
monly Fli-1, produced by a characteristic t(11;22)(q24 ; q12) been reported in children.67–71 Rare cases in newborns may,
translocation. By immunohistochemistry, the Ewing sar- in fact, represent congenital myofibroblastic tumor, rather
coma family of tumors characteristically demonstrates than true leiomyosarcoma.67 Potentially arising from ei-
membranous staining with CD99, an important diagnostic ther bronchial or vascular smooth muscle, these lesions
feature in clinical practice. In addition, primitive neuro- may be located in the tracheobronchial tree or in the pa-
ectodermal tumors show evidence of neural differentia- renchyma. Leiomyosarcoma in older children may show
tion, either by immunohistochemistry or electron micros- aggressive local invasion, metastasis, and poor prognosis.
copy. On a practical level, distinguishing primitive neu- Nuclear atypia, necrosis, and hemorrhage distinguish leio-
roectodermal tumor from Ewing sarcoma is unnecessary, myosarcoma from both leiomyomas and the myofibro-
as treatment is the same for both, and there is conflicting blastic tumors. Epstein-Barr virus is associated with some
evidence for any prognostic difference between primitive lesions in the immunocompromised population (see be-
neuroectodermal tumor and Ewing sarcoma. Although low).
the Ewing sarcoma family of tumors may occur anywhere
in the body, including soft tissue, bone, and viscera, the Bronchopulmonary Fibrosarcoma
chest wall is one site of predilection, so-called Askin tu- Primary bronchial fibrosarcoma in children is consid-
mor of the thoracopulmonary region. Chest wall involve- ered to be the equivalent of congenital infantile fibrosar-
ment may result in a mass with intrathoracic growth, lytic coma of soft tissues. It is quite rare, with 26 cases reported
destruction, and fusiform expansion of ribs, cortical thick- in the literature to 1989.1 Grossly, bronchopulmonary fi-
ening, little or no periosteal reaction, and pleural effu- brosarcoma may form an endobronchial polyp or intra-
sion.8 Involvement of the pleural cavity with extension parenchymal mass. Histologically, it is composed of cel-
into the lung parenchyma is not uncommon and may lead lular sheets and interlacing bundles of spindle cells, often
1092 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
with focal hemorrhage. The mortality associated with carcinoma for which there are only isolated reports in chil-
bronchopulmonary fibrosarcoma is 21%, with metastatic dren.93,94 Thought to be related to pulmonary blastoma,
disease reported in 2 of 26 cases.72 this tumor is composed of complex branching tubules and
glands and has been compared with fetal lung in the
Other Sarcomas pseudoglandular stage of development. Unlike conven-
A number of other types of sarcomas have been re- tional pulmonary adenocarcinoma, well-differentiated fe-
ported as primary lung neoplasms in children, including tal adenocarcinoma has a relatively good prognosis, with
angiosarcoma, Kaposi sarcoma, malignant peripheral only 15% mortality.93 Bronchioloalveolar carcinoma has
nerve sheath tumor, and liposarcoma.73 The spectrum of been reported rarely arising from CPAM (Figure 7, A
pulmonary and thoracic sarcomas has been reviewed else- through C).94–104 The mucigenic epithelium of the type I
where.74,75 CPAM is the purported precursor cell for bronchioloal-
veolar carcinoma in this setting.105–107
BRONCHOGENIC CARCINOMA Squamous cell carcinoma (Figure 7, D) seems to account
Bronchogenic carcinoma is most common in adults 55 for a smaller proportion of lung carcinoma cases in chil-
to 75 years of age, and it is rare in individuals younger dren (12%) relative to adults (35%–50%).7 Only 6 cases of
than 40 years, accounting for 1.2% of all patients with lung bronchogenic squamous cell carcinoma were reported in
cancer.76–88 Patients 18 to 30 years old diagnosed with lung children until 1995, with an age range of 1 to 15 years.108
cancer have a higher incidence of female sex, no associa- A pathogenetic relationship with human papillomavirus
tion with smoking history, and more favorable prognosis.89 has been proposed, given the known potential for pro-
Survival in these young patients is associated primarily gression of respiratory papillomatosis to squamous cell
with stage, but it is not dependent on sex, age younger or carcinoma.109 A minute squamous cell carcinoma has also
older than 30 years, smoking history, histologic type, or been reported in the wall of a congenital lung cyst.110 Bas-
degree of differentiation.90 Lung cancer in children and aloid carcinoma, a rare variant of non–small cell lung car-
adolescents younger than 18 years is extremely rare, with cinoma described in 1992, has been reported recently in
0.16% of all lung cancers occurring in the first decade of the pediatric population.93 It is an aggressive tumor
life and 0.7% in the second decade.91 As of 1983, a review thought to arise from the basal bronchial epithelial stem
of the medical literature included 47 children reported to cells and is characterized microscopically by small cells
growing in a characteristic nesting pattern with peripheral
have ‘‘bronchogenic carcinoma,’’ representing approxi-
mately 17% of reported primary lung malignancies in chil-
Primary lung carcinoma in children may be aggressive,
dren.3,7 Almost certainly an overestimate of true incidence,
with frequent metastatic disease at diagnosis, high mor-
this percentage appears to be inflated by cases in the older
tality (90%), and average survival of 7 months after di-
medical literature. The actual incidence of bronchogenic agnosis.3,7 Symptoms may include cough, chest pain,
carcinoma in children is difficult to determine and is lim- pneumonia, or hemoptysis due to local effects, but initial
ited to individual case reports and small case series in the presentation may also be heralded by bone pain, weight
modern era.92 A 21-year review of pediatric primary epi- loss, or anemia due to metastatic disease. Delay in diag-
thelial lung malignancies from Memorial Sloan-Kettering nosis and metastasis at presentation has led to generally
Cancer Center yielded a total of 11 patients (age range, poor survival in the few cases of bronchogenic carcinoma
12–21 years) with pathologic diagnoses of adenocarcino- in children reported.108
ma (4, including 1 well-differentiated fetal adenocarcino-
ma), basaloid carcinoma (2), carcinoid tumor (4), and DIFFUSE MALIGNANT MESOTHELIOMA
MEC (1).93 A 24-year review of the records from Boston Primary pleural neoplasms in the pediatric population
Children’s Hospital (1957–1981) revealed 6 primary bron- are quite rare, representing 2 of 1925 pleural lesions in 1
chial tumors in children, with no cases of bronchogenic series.111 Diffuse malignant mesothelioma is extremely
carcinoma.9 In 1999, Mizushima et al89 reported a large rare in children, with only 4.5% of mesotheliomas in 1
series of young lung cancer patients (26 patients younger series occurring in patients younger than 21 years.112 There
than 30 years), none of whom were younger than 18 years. is no clear causal relationship with asbestos exposure in
Our current 25-year cumulative experience, including both children, although a history of possible asbestos exposure
institutional and consultation cases, includes 23 primary has been reported in isolated pediatric cases.113 Diffuse
lung malignancies, but only 1 case of bronchial squamous malignant mesothelioma may also occur as a second ma-
cell carcinoma in a 6-year-old child, and no cases of ade- lignancy following radiation therapy, and there is one re-
nocarcinoma. port of pediatric mesothelioma associated with prenatal
Reported cases of pediatric lung carcinoma in the med- isoniazid exposure.114 Three large series of diffuse malig-
ical literature are most commonly undifferentiated carci- nant mesothelioma in children have shown pleural in-
noma, followed by adenocarcinoma and squamous cell volvement in 72% of cases (18/25 total patients), with an
age range of 4 to 19 years.113,115,116 Reported mortality in
carcinoma. It is difficult to determine whether the histor-
children ranges from 50% to 71%.113,115,116 Histologic pat-
ical cases of undifferentiated carcinoma truly represent
terns are similar to those seen in adults, and they have
small cell carcinoma or perhaps atypical carcinoid tumors.
included epithelial, mixed, and fibrous types, as well as
Adenocarcinoma may result in consolidation of a lobe or
papillary, tubuloglandular, solid, and sarcomatoid pat-
‘‘white-out’’ of a lung, with or without pleural effusion.92 terns.4,113,115
The 3 patients with conventional pulmonary adenocarci-
nomas in the Memorial Sloan-Kettering series all present- PRIMARY LUNG TUMORS IN IMMUNOSUPPRESSED
ed with stage IV disease, and 2 had rapidly progressive AND IMMUNOCOMPROMISED CHILDREN
fatal disease within 2 months of diagnosis.93 Well-differ- Lymphoma and Lymphoproliferative Disorders
entiated fetal adenocarcinoma, also called pulmonary en- All immunodeficiency states carry a higher risk of lym-
dodermal tumor, is an extremely rare variant of adeno- phoma relative to the immunocompetent population, in-
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1093
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 mon after liver, kidney, or bone marrow transplantation
(HIV) infection, solid organ transplant, bone marrow (1%–3%).117 Lung involvement by PTLD manifests as peri-
transplant, and congenital immunodeficiencies. These airway and parenchymal nodular and interstitial lym-
lymphomas are most often high-grade or intermediate- phoid infiltrate, and primary involvement of the lung is
grade non-Hodgkin lymphomas, typically diffuse large B- highest in lung transplant or heart-lung transplant recip-
cell lymphomas, and often involve extranodal sites. Burk- ients. The pathogenesis of PTLD is related to EBV-stimu-
itt lymphoma, Burkitt-like lymphoma, Hodgkin lympho- lated B-lymphocyte proliferation, which is unopposed due
ma, and human herpesvirus 8–associated primary effu- to iatrogenic inhibition of regulatory T-lymphocyte func-
sion lymphoma also are reported with higher incidence in tion, and the biologic spectrum ranges from polymor-
the HIV-infected population.117 phous to monomorphous and may be polyclonal, oligo-
Epstein-Barr virus–driven lymphoproliferative disor- clonal, or monoclonal. The monoclonal forms most often
ders occur most commonly in immunosuppressed recipi- resemble diffuse large B-cell lymphoma and may be as-
ents of solid organ or bone marrow transplants (posttrans- sociated with regions of necrosis. Epstein-Barr virus DNA
plant lymphoproliferative disorder [PTLD]), as well as probes are positive in most PTLDs but may be negative,
children with primary immunodeficiency (Figure 8, A). In particularly late (more than 5 years) after transplantation.
general, PTLD is most common after heart, lung, or heart- Flow cytometric analysis is an essential component of the
lung transplantation (5%–13% of patients) and less com- diagnostic evaluation of suspected PTLD and allows de-
1094 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
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 munosuppression. Epstein-Barr virus DNA probes are
is the first-line management of these disorders, with or typically strongly positive in these tumors (Figure 8, D).
without anti-CD20 antibody therapy (rituximab), al-
though cytotoxic chemotherapy may also be necessary for Kaposi Sarcoma
treatment of persistent lesions and the more aggressive Kaposi sarcoma associated with human herpesvirus 8
monoclonal forms of PTLD. infection may occur in HIV-infected patients and follow-
ing solid organ transplantation. Although cutaneous Ka-
Smooth Muscle Tumors posi sarcoma typically predominates clinically, visceral in-
(Leiomyoma and Leiomyosarcoma) volvement may occur, most often affecting lymph nodes,
Epstein-Barr virus–associated smooth muscle tumors the gastrointestinal tract, or the lungs. Pulmonary involve-
have been described in children with HIV/AIDS (Figure ment may produce endobronchial or parenchymal viola-
8, B and C), as well as solid organ transplant recipients ceous lesions, and it is a cause of pulmonary hemorrhage,
and children with primary immunodeficiency.118–122 These cough, and dyspnea in this population.
tumors may be solitary or multifocal, and site of predilec- SECONDARY INVOLVEMENT OF THE LUNG IN
tion include the gastrointestinal and respiratory tracts. SYSTEMIC DISEASE
Similar to the EBV-driven lymphoproliferative tumors,
there is a spectrum from benign to malignant morpholo- Langerhans Cell Histiocytosis
gy, that is, leiomyoma and leiomyosarcoma, and there is In adults, LCH in the lung typically occurs as a solitary
potential for regression of tumors with modulation of im- nodule in smokers, previously called eosinophilic granulo-
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1095
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- croscopy demonstrates characteristic pentalaminar rods
volvement by systemic disease rather than isolated lung with bulbous ends (Birbeck granules) formed by internal-
involvement.124 Langerhans cell histiocytosis occurs most ized invaginations of the cell membrane. The differential
often in infants and young children, and presenting signs diagnosis of interstitial infiltrates and histiocytic nodules
may include a rash, bone lesions, or pituitary involvement. includes leukemia, granulomatous processes, and non-
Skeletal survey may show punched-out lytic bone lesions LCH, such as juvenile xanthogranuloma (Figure 9, C and
of the skull or other long bones. If there is lung involve- D).
ment, chest computed tomography may show a reticulo-
nodular pattern with nodules ranging from 1 to 10 mm Leukemia and Lymphoma
in diameter, larger cavitary nodules, pneumatoceles, bi- Although pulmonary infiltrates in leukemia patients
lateral cystic disease, and/or pneumothorax.8 Histologi- prompt primary consideration of infection, leukemic infil-
cally, LCH typically demonstrates patchy infiltrates in- tration of the lung may cause a similar pattern radiograph-
volving the interstitium, pleura, and bronchovascular bun- ically. Lung involvement by leukemia usually manifests as
dles (Figure 9, A). Extension of LCH cells into the alveolar patchy interstitial, septal, or pleural infiltrates (Figure 10,
spaces is often associated with the infiltrates expanding A and B), in contrast to non-Hodgkin and Hodgkin lym-
the alveolar walls. The histiocytes have typical indented phoma, which tend to form larger, well-circumscribed
and grooved nuclei and may be admixed with occasional nodules obscuring the background lung parenchyma (Fig-
eosinophils. If necessary, confirmation of Langerhans cell ure 10, C and D). An associated mediastinal mass or hilar
phenotype is achieved using immunohistochemistry for adenopathy are variable features. The differential diag-
CD1a (Figure 9, B) or Langerin (CD207). S100 is also pos- nosis for lymphoma involving the lung in children in-
itive but less specific than CD1a or CD207. Electron mi- cludes primarily Hodgkin lymphoma, non-Hodgkin lym-
1096 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
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]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1097
phoma (acute lymphoblastic lymphoma, Burkitt lympho- provides additional survival benefit. Excision of metastatic
ma [Figure 10, E], diffuse large B-cell lymphoma), and lesions should be complete due to the proven survival
PTLD. Other types of pulmonary lymphoid proliferations benefit, and is indicated even after demonstrated chemo-
have been reviewed by Colby and Yousem.125 therapy response.
Metastatic tumors account for approximately 80% of all The lung is the most common site of metastasis in
lung tumors in children and more than 95% of malignant Wilms tumor (Figure 11, C), the second most common
tumors of the lung in this population.14 Although a wide malignant solid tumor of childhood. Pulmonary metasta-
variety of sarcomas and embryonal tumors of childhood ses are typically detected by imaging rather than by clin-
produce lung metastases in children, Wilms tumor and ical symptomatology. Patients with favorable histology
osteosarcoma are the most frequent.2 Metastases appear Wilms tumor and pulmonary metastasis have a good
as single or multiple circumscribed nodules, often periph- prognosis, with approximately 75% 4-year survival.128 Pul-
eral and preferentially involving the lower lobes in those monary nodules in patients with Wilms tumor may be
with hematogenous spread.2 A reticular or military pat- excised for staging at initial diagnosis, but there is a lim-
tern may occur with those demonstrating lymphangitic ited role for metastasectomy for oncologic management in
spread. Cavitation and pneumothorax are rare but are fea- the United States. Metastasectomy for Wilms tumor is
tures most often associated with Wilms tumor, Hodgkin more commonly used in European centers to spare effects
lymphoma, and osteosarcoma.6 of radiation therapy, but North American centers have not
adopted this approach as standard therapy. Based on Na-
Metastasectomy tional Wilms Tumor Study group data, patients with fa-
While some metastatic lung nodules are excised for di- vorable histology Wilms tumor have excellent survival af-
agnosis and staging, others are removed as a part of on- ter chemotherapy and/or radiation therapy only, with ac-
cologic management to achieve long-term survival and ef- ceptably low rates of radiation pneumonitis. Nevertheless,
fect cure. Kayton126 has recently provided an excellent re- excision of metastases has been used selectively in indi-
view of clinical indications and surgical techniques used vidual Wilms tumor patients with lesions refractory to
for pulmonary metastasectomy in pediatric patients. This chemotherapy or radiation therapy, or in patients prior to
approach began in the 1950s but achieved greater popu- bone marrow transplant.126
larity after 1971, when survival advantage was reported Neuroblastoma
in osteosarcoma patients with excision of metastatic le-
sions (3-year survival of 45% vs 5%, with and without Children with neuroblastoma rarely present with lung
metastasectomy).126 Long-term survival (more than 20 metastases, with an incidence at diagnosis of only 0.4% to
years from diagnosis) can also be achieved in some pa- 3.2%.126 When involving the lung, metastatic neuroblasto-
tients with aggressive and repeated excision of lung nod- ma also typically involves other organs, in which case sys-
ules. It is also now recognized that the effectiveness of temic chemotherapy is more appropriate than pulmonary
surgical management for metastatic tumor is dependent metastasectomy. In the case of isolated pulmonary nod-
on histologic type. Currently, pulmonary metastasectomy ules, however, excisional biopsy may be indicated to con-
remains most common for osteosarcoma due to the dem- firm diagnosis and staging prior to chemotherapy.
onstrated survival advantage of repeated wedge excisions Rhabdomyosarcoma
for metastatic disease. Metastasectomy also plays a central Prognosis for rhabdomyosarcoma patients with pul-
role in management for other tumor types that are resis- monary metastasis is generally poor, and concurrent ex-
tant to chemotherapy and radiation therapy, such as ad- trapulmonary disease is common. Relative to children
renocortical carcinoma and chondrosarcoma. Conversely, with extrapulmonary metastases, children with isolated
surgical management of metastatic disease is uncommon pulmonary disease more commonly have nonalveolar his-
for chemosensitive and radiosensitive malignancies, such tology, parameningeal primary site, and lack of lymph
as Wilms tumor, Ewing sarcoma, neuroblastoma, rhab- node involvement. Overall survival is better for patients
domyosarcoma, thyroid carcinoma, and germ cell tumors. younger than 10 years in this group and for those who
Clinical features and management principles are dis- received radiation therapy. There is currently no standard
cussed briefly below for pulmonary metastasis in selected role for surgical resection of metastases other than for bi-
pediatric solid tumors. opsy confirmation of diagnosis and perhaps resection of
Osteosarcoma isolated lesions.126
In addition to the sporadic cases, osteosarcoma occurs Ewing Sarcoma Family of Tumors
with increased frequency in children with p53 mutations Ewing sarcoma (Figure 11, D and E) is generally sen-
in the Li-Fraumeni syndrome, in children with Rothmund- sitive to both chemotherapy and radiation therapy, and
Thomson syndrome, in retinoblastoma patients, and as a these are the mainstays of management for metastatic dis-
second malignancy in children treated with alkylating ease, as survival advantage after pulmonary metastasec-
agents. Approximately 10% to 15% of children with os- tomy has not been clearly demonstrated. Surgical excision
teosarcoma will have pulmonary metastasis at presenta- of metastatic lesions at this time is typically performed for
tion (Figure 11, A and B).127 Pulmonary metastases are confirmation of diagnosis and remains controversial for
typically asymptomatic and detected by imaging studies. resection of limited pulmonary disease.
Large studies have demonstrated a strong correlation be-
tween complete resection of primary and metastatic le- Other Soft Tissue Sarcomas
sions at presentation and overall survival.126 Repeated ex- Metastasectomy is a component of therapy for other
cision of additional lung metastases is often necessary and types of sarcomas, including alveolar soft part sarcoma,
1098 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
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]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1099
synovial sarcoma, chondrosarcoma, fibrosarcoma, and child may later be enrolled in a biology or treatment pro-
malignant fibrous histiocytoma, and the approach is gen- tocol (eg, Children’s Oncology Group, International Pleu-
erally similar to that used for osteosarcoma.126 In partic- ropulmonary Blastoma Registry). Recommended histolog-
ular, alveolar soft part sarcoma has a high incidence of ic sections include sampling of at least one section of tu-
lung metastasis (60% of pediatric patients), and because it mor per centimeter greatest tumor dimension, with pref-
shows incomplete response to chemotherapy, surgical re- erential sampling of heterogeneous areas and junction to
section is a necessary component of oncologic manage- normal parenchyma. Sampling of resection margins
ment.126 should include the bronchial margin(s), as well as paren-
chymal margins in the case of wedge excisions, partial
Hepatoblastoma lobectomies, and lobectomies from lungs with an incom-
Pulmonary metastases of hepatoblastoma may com- plete fissure, in which case there may be a stapled paren-
pletely respond to chemotherapy, allowing long-term sur- chymal margin at the point of division from the adjoining
vival. For unresponsive or partially responsive tumors, lobe. Evaluation of surgical margins is not necessary for
however, extended survival may be achieved by pulmo- most metastasectomy specimens obtained for diagnosis
nary metastasectomy following chemotherapy, leading to and staging, but it should be reported for lesions removed
a combined approach in such patients. for surgical oncologic management (for example, osteo-
Thyroid Carcinoma The purely cystic lesions of the pediatric lung have a
Mortality is very low for pediatric thyroid cancer. De- broader differential diagnosis and require greater delib-
spite frequent lymph node metastasis, prognosis is gen- eration in the process of initial tissue handling. Although
erally favorable, and very few patients develop distant me- cystic developmental anomalies are much more frequent
tastasis. When present, pulmonary metastases tend to pro- than the rare cystic type I PPB, the surgical pathologist
duce a miliary pattern of disease which would not allow should be alert to the possibility of malignancy and con-
resection by metastasectomy. Instead, the primary thera- sider collecting tissue as described above in cases where
peutic modality for pulmonary metastases of thyroid car- diagnosis is not clear from gross features. Knowledge of
cinoma is radioactive iodine (131I) treatment, and it allows the clinical and diagnostic imaging characteristics is ex-
complete radiographic resolution of disease and long-term tremely helpful in guiding the proper approach to the
survival in many cases. Metastasectomy is reported for specimen. For example, a new cystic lesion identified only
diagnostic purposes, but otherwise it is not a routine com- after medical illness, such as pneumonia or respiratory
ponent of oncologic management. distress, would suggest an acquired cyst, such as a pneu-
matocele or persistent pulmonary interstitial emphysema.
Adrenocortical Carcinoma Chest computed tomography provides information on an-
Pulmonary metastases are relatively frequent in patients atomic characteristics that might suggest a developmental
with stage IV adrenocortical carcinoma (Figure 11, F) and, anomaly, such as systemic arterial supply (extralobar and
based on experience with adults, excision of these lesions intralobar pulmonary sequestration), anomalous bronchial
results in dramatically increased 5-year survival (71% vs anatomy (bronchial atresia, intralobar sequestration), or
0%, with and without metastasectomy).126 Metastasectomy lobar or segmental distribution (congenital lobar overin-
is recommended early after detection and should be com- flation, bronchial atresia, intralobar sequestration). A clin-
plete, preventing recurrence and/or tumor spillage into ical or diagnostic imaging impression of a large-cyst
the thoracic cavity. (Stocker type I) CPAM typically indicates the presence of
a large unilocular or multilocular purely cystic lesion,
Chemotherapy Effect with or without surrounding hyperinflation. Because as-
If a metastatic nodule is removed after chemotherapy, sociated bronchial or vascular anatomy is not always fully
evidence of treatment effect may include necrosis, fibrosis, characterized by computed tomography imaging, the ab-
or hemosiderin deposition. Cytodifferentiation after che- sence of specific features does not exclude bronchial atre-
motherapy occurs in some embryonal neoplasms, for ex- sia or intralobar sequestration from the differential diag-
ample, mature skeletal muscle fibers in rhabdomyosarco- nosis. At this point, the surgical pathologist should ex-
ma. A mixed germ cell tumor may show only residual amine the lung externally for the same anatomic clues,
mature teratomatous components after therapy. which would suggest a developmental anomaly: segmen-
tal or lobar parenchymal hyperinflation, aberrant systemic
RECOMMENDATIONS FOR GROSS EXAMINATION OF arterial supply, a mucocele, or aberrant bronchial anatomy.
PEDIATRIC LUNG CYSTS AND TUMORS The hilar bronchi are probed in all directions to determine
The possibility of unsuspected malignancy should be their anatomic distribution and to identify any regions
considered for both solid masses and cystic lesions of the that do not appear to be connected to the central airways.
lung in children. These specimens should be received If specific diagnosis is not established after review of the
fresh from the operating room, without prior formalin fix- diagnostic imaging and gross pathologic features, and if
ation or prior incision into the lesion. Examination of the large-cyst CPAM still remains a diagnostic consideration,
gross specimen should include photography and routine then the specimen should be treated as if it may be a PPB
gross description, as well as consideration of sampling of type I, and fresh tissue collection is recommended prior
fresh lesional tissue for special studies. Solid masses or to transbronchial and transpleural injection inflation with
mixed solid and cystic lesions warrant tissue collection for formalin. These large cystic lesions require extensive his-
electron microscopy (glutaraldehyde), cytogenetic analysis tologic sampling to exclude foci of primitive cells, partic-
(RPMI or other cell culture medium), and molecular di- ularly for cysts lined by alveolar-type epithelium, mim-
agnosis (frozen tissue). Additional tissue may be retained icking the lesion described as peripheral cyst (Stocker type
frozen for research studies, with the consideration that the IV) CPAM.
1100 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
The rarity of PPB and other primary malignancies of 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 pediatric lung underscores the need for thoughtful dis- the literature. Int J Pediatr Otorhinolaryngol. 1998;45:265–273.
section and, if indicated, fresh tissue collection for biologic 15. Miniati DN, Chintagumpala M, Langston C, et al. Prenatal presentation
studies. Such studies will allow further definition of the and outcome of children with pleuropulmonary blastoma. J Pediatr Surg. 2006;
cytogenetic and molecular characteristics of these rare tu- 16. Carney JA. The triad of gastric epithelioid leiomyosarcoma, functioning
mors, and it will likely enhance not only our diagnostic extra-adrenal paraganglioma and pulmonary tumor. Cancer. 1979;43:374–382.
capabilities in the future, but also help to determine prog- 17. Dajee A, Dajee H, Hinrichs S, Lillington G. Pulmonary chondroma, extra-
adrenal paraganglioma, and gastric leiomyosarcoma: Carney’s triad. J Thorac Car-
nosis and optimal therapy for these children. diovasc Surg. 1982;84:377–381.
18. Hull MT, Gonzalez-Crussi F, Grosfeld JL. Multiple pulmonary fibroleio-
SUMMARY myomatous hamartoma in childhood. J Pediatr Surg. 1979;14:428–431.
In this institutional review of pediatric lung biopsies 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–
and resections, the ratio of primary benign to primary ma- 202.
lignant to metastatic lung tumors in children is 1.4:1:11.6. 20. Kramer R. Myoblastoma of the bronchus. Ann Otolaryngol. 1939;48:1083.
Metastases to the lung are approximately 12 times more 21. Kommel RM, Bernstein J. Granular cell myoblastoma of the bronchus: re-
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common than primary lung malignancies in children, and 22. Broaddus RR, Herzog CE, Hicks MJ. Neuroendocrine tumors (carcinoid
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23. Hause DW, Harvey JC. Endobronchial carcinoid and mucoepidermoid car-
the pediatric population are Wilms tumor and osteosar- cinoma in children. J Surg Oncol. 1991;46:270–272.
coma. Primary lung malignancies represent only approx- 24. McDougall JC, Unni K, Gorenstein A, O’Connell EJ. Carcinoid and mu-
imately 0.19% of all pediatric malignancies, and are often 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
not clinically suspected due to lack of symptoms or non- cancer: spectrum of clinical presentation, histopathologic and prognostic factors.
specific nature of presenting symptoms. The spectrum of Cancer. 2007;110:2253–2259.
primary tumors of the lung in children shows little over- 26. Coffin CM, Dehner LP. Soft tissue tumors in first year of life: a report of
lap with the types of lung tumors seen in adults. The most 190 cases. Pediatr Pathol. 1990;10:509–526.
27. Coffin CM, Dehner LP. Fibroblastic-myofibroblastic tumors in children and
common primary lung malignancies in children are pleu- adolescents: a clinicopathologic study of 108 examples in 103 patients. Pediatr
ropulmonary blastoma and carcinoid tumor, and broncho- Pathol. 1991;11:569–588.
genic carcinomas are exceptionally rare. The relationship 28. Tomashefski JF Jr. Benign endobronchial mesenchymal tumors. Am J Surg
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