Epithelial and Soft Tissue Tumors of the Tracheobronchial Tree

Epithelial and soft tissue tumors of the

tracheobronchial tree

Leslie Litzky, MDDepartment of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center,

6 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA 19104-4283, USA

Most of the tumors described in this article are rare or extraordinarily rare. In

older literature, a number of these entities were incorrectly combined together and

designated as ‘‘bronchial adenomas.’’ This article encompasses a diverse spectrum

of lesions whose pathological classification is relatively straightforward in

relationship to the normal structure and histology of the trachea and major

bronchi. An extensive review of all the literature relating to these unusual tumors

is beyond the scope of this article, but general characteristics of each tumor are

covered with particular reference to the specifics of endotracheal or endobronchial

involvement. Refinements in the pathologic classification in recent literature have

clarified the clinical presentation, therapeutic options, and prognosis of some of

these unusual tracheobronchial tumors. Special attention is directed toward the

nomenclature revisions incorporated within the 1999 World Health Organization/

International Association for the Study of Lung Cancer (WHO/IASLC) histologic

typing of lung tumors [1].

Epithelial tumors of the tracheobronchial tree—benign

Papillomas

A papilloma consists of a central core of connective tissue fronds with an

overlying epithelial surface. The vast majority of tracheobronchial papillomas

have an exophytic growth pattern, but an inverted papilloma pattern has been

reported [2]. Endoscopically and grossly, the papilloma typically appears as

sessile, cauliflower-like or verrucous excrescences that project into the tracheal

or bronchial lumen (Fig. 1). The 1999 WHO Histological Typing of Lung Tumors

subclassifies papillomas by the type of epithelium lining the fibrovascular core [1].

1052-3359/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.

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E-mail address: [email protected]

Chest Surg Clin N Am

13 (2003) 1–40

L. Litzky / Chest Surg Clin N Am 13 (2003) 1–402

Squamous cell papilloma/papillomatosis

The clinicopathologic characteristics of solitary squamous papillomas should

be considered separately from cases of multiple squamous papillomas (squamous

papillomatosis). Most solitary papillomas are not preceded by papillomatosis of

the upper respiratory tract [3,4]. Tracheobronchial papillomatosis usually occurs

in the setting of prior laryngeal disease, and it frequently presents in children

(juvenile papillomatosis) or young adults. Overall, squamous papillomas of the

lung are a rare finding in recurrent respiratory papillomatosis, with a reported

incidence of 5% involving the distal trachea and less than 1% involving the

pulmonary parenchyma [5,6]. Solitary papillomas also are rare. In their series of

3937 patients undergoing bronchoscopy over an 11-year period, Shah et al

identified 53 papillomas (1.3%) [7]. Flieder et al have provided an in-depth

clinicopathologic/in situ hybridization analysis of 14 solitary papillomas in adults

along with a review of 27 cases from the literature [2]. Solitary squamous

papillomas are seen more frequently in men and generally appear in the age

range of 50 to 70 years. When smoking history was available, more than half of

patients were cigarette smokers. A few patients have been asymptomatic;

radiographic abnormalities such as a hilar mass or postobstructive pneumonia

or symptoms such as wheezing, hemoptysis, or recurrent pneumonias are

more common.

Grossly, the lesions are tan, friable, and polypoid. Mass size and gross

inspection are unreliable in excluding an invasive component within the papil-

loma. The squamous epithelium can be keratinizing or nonkeratinizing. The

nonkeratinizing subtype had been reported in older literature as ‘‘transitional’’

because of its phenotypic resemblance to urothelium [8]. A range of squamous

dysplasia can be seen, as well as in-situ or invasive carcinoma. Human papilloma

virus (HPV) has been detected in some solitary papillomas and in cases of

papillomatosis, but its presence in squamous lesions does not appear to correlate

with recurrence or malignancy [2]. HPV 6 and 11 have been found in

histologically benign papillomas [9,10], but HPV 11 also has been correlated

with malignant transformation in the setting of juvenile-onset recurrent respi-

ratory papillomatosis [11]. HPV 16 and 18 have been reported in cases of

papillomas associated with carcinoma [9,10], but the relatively small numbers of

cases in the literature make it difficult to comment on the strength of this

association and the relative risk of malignant transformation. Nevertheless, in all

circumstances complete excision of a solitary papilloma is recommended to

exclude an invasive malignancy and to prevent recurrence.

Fig. 1. (A) Endoscopic photograph of a bronchial papilloma. The exophytic polypoid excrescences

are typical. Microscopically, this proved to be a mixed squamous cell and glandular papilloma.

(Courtesy of Michael A. Grippi, Pulmonary, Allergy, and Critical Care Division, University of

Pennsylvania Medical Center.) (B) Squamous papilloma of the trachea. This low-power photomicro-

graph highlights the branching central fibrovascular cores with a surface lined by benign squa-

mous epithelium.

L. Litzky / Chest Surg Clin N Am 13 (2003) 1–40 3

Glandular papilloma (columnar cell papilloma)/ mixed squamous cell and

glandular papilloma

Glandular papilloma is a papillary tumor lined by glandular epithelium. Less

than 20 of these tumors have been reported in the literature [2,12–14]. The

glandular cell types include ciliated columnar cells, nonciliated columnar cells,

cuboidal cells, and goblet cells. These tumors are solitary and central. Equal

numbers of men and women have been reported with a somewhat older median

age than the median age for solitary squamous papillomas (68 years versus

54 years, respectively) [2]. There does not appear to be a significant correlation

with tobacco use. Recurrence has been reported in one incompletely resected

lesion [13]. Cytologic atypia or malignant transformation has not been reported to

date in glandular papillomas. As the name implies, mixed squamous cell and

glandular papilloma contains a mixture of squamous and glandular epithelium.

These papillomas are usually solitary. The squamous epithelium can be dys-

plastic, therefore progression to squamous carcinoma can occur [2,14].

Adenomas of salivary gland-type tumors

Mixed seromucinous glands and ducts are found in the tracheal and large

bronchial submucosa. These glands are believed to give rise to a variety of

salivary gland-like tumors that are histologically indistinguishable from their

major salivary gland counterparts. The category of salivary gland-like tumors

includes benign and malignant lesions. Although rare, salivary gland-type tumors

of the lung are an important subgroup of tracheobronchial tumors because of their

distinctive morphology, growth pattern, and clinical presentation. In general,

patients tend to present with symptoms such as wheezing or hemoptysis, which

are caused by tumor growth within the larger airways. Although the adenomas

described in this article are benign, complete excision is required to prevent

recurrence. The location might therefore necessitate bronchoplastic surgery.

Mucous gland adenoma

Mucous gland adenoma is rare, with less than 30 cases reported to date

[15–17]. In the largest series (by England and Hotelier), about half of the tumors

presented as solitary endobronchial lesions and half presented as coin lesions. The

majority of mucous gland adenomas arise in the main lobar and segmental

bronchi. The tumors range in size from a little less than 1 cm to 7 cm. They are

well circumscribed with a predominantly helophytic growth pattern. Grossly, they

are soft, partially cystic, and mucinous. Histologically, the tumor is composed of

benign-appearing, mucus-filled cysts, tubules, glands, and papillae. The glandular

epithelium consists of tall columnar, flat, cuboidal, goblet, oncocytic, or clear

cells, but there should not be a squamous cell or intermediate cell component

admixed within the tumor. Heard et al, however, reported seven cases of mucous

gland adenoma, four of which contained a small amount of squamous differenti-

ation [18]. Neither invasion of the pulmonary parenchyma nor hilar lymph nodes

metastases has been reported.


Pleomorphic adenoma (benign mixed tumor)

Mixed tumors (pleomorphic adenomas) of the salivary gland are the most

common histologic type of salivary gland tumor, but they are seen rarely in the

lung. Like its salivary gland counterpart, pleomorphic adenomas consist of

varying proportions of epithelial and connective tissue elements. Myoepithelial

cells are prominent within the epithelial component. The associated stroma has a

myxoid or focally chondroid matrix. There is a wide spectrum of histologic

features and a range of clinical behavior. Malignant salivary gland-type mixed

tumors are discussed later in this article. Primary mixed tumors of the lung are

histologically indistinguishable from mixed tumors that occur in other sites;

clinical correlates are therefore essential to exclude a metastasis from another site

such as the salivary gland or breast.

Pleomorphic adenomas occur primarily in middle-aged adults, although they

have occurred in pediatric patients and younger adults [19–22]. The incidence in

men and women has been equal. Moran et al has reported the largest series and

review of the literature to date [19,23]. In their series, there were eight patients, six

of which had what were characterized as histologically benign lesions. Follow-up

information was limited. Three of the patients with benign lesions were lost to

follow-up and two patients died of other diseases. All of the histologically benign

lesions were 2.0 cm to 2.5 cm in size and well circumscribed, but only half were

associated with a bronchus. In their summary of the previously published eight

reports [24–28], the size range was slightly wider (1.5–4.5 cm), but the

distribution of polypoid endobronchial tumors to peripheral parenchymal nodules

was roughly equivalent. Grossly, the tumors were soft to rubbery masses with a

gray–white, myxoid, cut surface. Histologically, most of the tumors resembled the

‘‘cellular’’ variant of mixed tumors of the salivary gland in the relative paucity of

duct-like structures and the predominance of myxoid or hyalinized stroma rather

than a cartilaginous matrix. Small foci of necrosis were present in two tumors.

Mitoses were increased in three tumors on the order of 1 per 10 high power fields.

Nevertheless, the authors concluded that small size and circumscription tended to

correlate best with benign behavior, assuming adequate excision.

Monomorphic adenoma/myoepithelioma/epithelial–myoepithelial tumor

The terms monomorphic adenoma, myoepithelioma, and epithelial–myoepi-

thelial tumor are applied to tracheobronchial gland tumors that are composed

exclusively of epithelial elements (monomorphic adenoma), myoepithelial ele-

ments (myoepithelioma), or a mixture of the two (epithelial/myoepithelial tumor).

They are extremely rare, but their behavior is similar to the mixed tumors of

salivary gland type described previously [29–38].

Oncocytoma

An oncocytoma, whether within the lung or in a far more common site such as

the kidney, is composed of tumor cells with abundant granular eosinophilic

cytoplasm. Other tracheobronchial tumors such as carcinoids, pleomorphic

adenomas, acinic cell tumors, or mucoepidermoid carcinomas can have a


similar-appearing granular, eosinophilic cytoplasm; therefore, the diagnosis of

oncocytoma cannot be definitively rendered without supporting immunohisto-

chemical or ultrastructural data [39]. By definition, the granular eosinophilic

cytoplasm in an oncocytoma ultrastructurally corresponds to mitochondrial

hyperplasia. Neurosecretory granules should be absent. Immunohistochemistry

reveals that oncocytic carcinoid tumors are positive for neuroendocrine markers

such as chromogranin and synaptophysin. Oncocytomas are negative for these

markers. In retrospect, the earliest case report of a pulmonary oncocytoma by

Black in 1969 [40] probably represents an acinic cell tumor [39], and other

reports in the literature would be more precisely classified as oncocytic carcinoids

[41,42]. Given these ultrastructural criteria, the first example of a pulmonary

oncocytoma was reported by Fechner and Bentinck in 1973 [43]. Other reported

cases within the English literature that conform to these criteria include Santos-

Briz et al, Warter et al, and Nielsen [44–46]. With the exception of the case

reported by Nielsen, the tumors were well circumscribed and in the size range of

3.0 cm to 3.5 cm. The tumor cells ranged from small ovoid cells to larger

polyhedral cells. The tumor cells were arranged in perivascular arrays, ribbon-

like configurations, or cord-like structures. Necrosis was absent and mitoses were

rare or absent. Aggressive behavior—even in the presence of a partially confluent

growth pattern or peribronchial lymph nodes metastasis—has not been reported

to date in these extremely rare tumors.

Epithelial tumors of the tracheobronchial tree—malignant

Endobronchial/tracheal squamous cell carcinoma

Most squamous cell carcinomas occur in central cartilaginous bronchi,

although up to as many as one third develop as peripheral subpleural tumors

[47]. This central location makes it more likely that the tumor will reach an

appreciable size before detection, exfoliate cells into sputum, and to be accessible

to bronchoscopic biopsy (Fig. 2) [48]. In contrast to squamous papillomas, which

tend to occur in the trachea and mainstem bronchi, squamous cell carcinoma is

seen more frequently in lobar and segmental bronchi [48]. Nevertheless, it should

be noted that squamous cell carcinoma occurs with far greater frequency in the

trachea than any other type of tumor [49,50]. Squamous cell carcinomas are

graded by the extent of keratinization, intercellular bridges, or squamous pearl

formation. The presence of squamous differentiation has some prognostic

significance. Data from Gail et al’s study of prognostic factors in patients with

resected stage I non–small-cell carcinoma highlighted the decreased risk for

recurrence in squamous cell carcinoma in comparison with adenocarcinoma and

large-cell carcinoma [51]. Moreover, the risk for recurrence was correlated with

increasing size (T1 versus T2) rather than nodal disease (N0 versus N1). A

similar survival advantage with squamous differentiation was shown using the

1986 staging classification system and was reported by Mountain et al [52].


Within the subsets of T1N0 and T1N1, patients with squamous cell carcinoma

had a significantly better 5-year survival rate than patients with adenocarci-

noma—83% versus 69% for T1N0 and 75% versus 52% for T1N1, respectively.

In this study, the significance of histologic type as a prognostic factor was

variable in other stages and stage subsets. There was no statistically significant

difference for cell type in T2N0 tumors, suggesting the stronger influence of large

tumor size, pleural involvement, or both on prognosis. Histologic type was

significant in the survival of patients with T2N1 disease (53% for patients with

squamous cell carcinoma versus 25% for patients with adenocarcinoma),

although adenocarcinoma is infrequently diagnosed within this stage subset.

There was no significant difference in survival by histologic cell type in stage III

disease, but this patient subset was more heterogeneous. In general, survival rates

of patients with large-cell, undifferentiated carcinoma and adenosquamous

carcinoma are similar to those of patients with adenocarcinoma.

Papillary variant of squamous cell carcinoma

These tumors are characterized by an extensive or pure exophytic pattern with

delicate fibrovascular papillae projecting into the bronchial lumen. The invasive

component of the tumor can be quite focal; therefore, separation of this tumor

from a squamous papilloma might be difficult on a small biopsy specimen.

Severe cytologic atypia, if present, is a supportive feature of squamous cell

carcinoma; however, many of these tumors are characteristically well differ-

entiated and have histologic features that overlap with dysplastic squamous

papillomas. Dulmet-Brender et al reported a favorable 5-year survival rate in

their series of 34 tumors collected over 35 years [53]. There was a preponder-

ance of male patients with a mean age of 58 years. These tumors were nearly

Fig. 2. Squamous cell carcinoma, right mainstem bronchus. The central location allowed this tumor to

reach an appreciable size before detection.


always T1N0 lesions, but their prognosis did not differ significantly from other

T1N0 lesions.

Basaloid variant of squamous cell carcinoma/basaloid carcinoma

Primary carcinomas of the lung with basaloid features have been reported.

These basaloid histologic features are similar to those seen in other extrapulmo-

nary sites such as the head and neck or the cervix. Most of these tumors develop

within proximal bronchi, and they often have an endobronchial component. A

high percentage of cases will have carcinoma in situ. The key histologic features

are a lobular, trabecular, or palisading growth pattern. The tumor cells are

relatively small with moderately hyperchromatic nuclei, scant cytoplasm, a high

mitotic rate, and absent or focal nucleoli. By WHO/IASLC definition, immuno-

histochemical stains for neuroendocrine markers should be negative [1]. Basaloid

carcinoma can occur as a pure form or it can be mixed with other histologic

subtypes of non–small-cell carcinoma such as squamous cell carcinoma or

adenocarcinoma. In Brambilla et al’s initial series, 21 patients with stage I or

stage II basaloid carcinomas (pure and mixed) were combined in an actuarial

analysis that showed a median survival of 22 months and a 5-year survival

probability of 10% [54]. This study and subsequent reports seem to indicate that

these patients have a significantly shorter survival than those with poorly

differentiated squamous cell carcinoma [55–58].

Endobronchial adenocarcinoma (adenocarcinoma invading into bronchi)

Most pulmonary adenocarcinomas are peripheral and tend to involve the larger

cartilaginous airways secondarily as a consequence of increasing tumor size.

Nevertheless, a small number of endobronchial tumors will prove to be

adenocarcinomas with a histologic growth pattern distinct from the salivary

gland type tumors. As a group, these tumors tend to be grossly polypoid.

Extension along smaller airways or into the parenchyma is variable. A broad

spectrum of histologic patterns has been described. Some tumors have been

papillary with tall columnar cells lining fibrovascular cores [59]. Hirata et al

reported a series of 23 moderately differentiated endobronchial adenocarcinomas

with columnar cells that resembled those seen in the bronchial submucosal gland

[60]. Other unusual histologic patterns have included endometrioid type of cell,

stratified columnar cells with signet ring cells, and clear cells [61–63]. There

does not to appear to be any appreciable difference in prognosis between these

tumors and their more common peripheral counterparts from the limited follow-

up information that is available.

Carcinoid tumor—typical

Carcinoid tumor is one of the most frequently encountered and best charac-

terized of the unusual tumors that occur in the tracheobronchial tree. The reported

incidence generally varies between 1% and 4% of all primary lung tumors [64,65],


but much attention has been directed towards this entity because of its overall

better prognosis in comparison with other types of pulmonary epithelial malig-

nancy. It should be emphasized from the outset that carcinoid tumors are not

‘‘benign’’ tumors (or ‘‘adenomas’’ as they were termed in older literature); they are

best regarded as a low-grade malignant neuroendocrine carcinoma with a capacity

for invasion and metastasis. On average, the tumor occurs in a younger age group

(< 50 years) than those with the much more common lung cancers, but carcinoid

tumors have been reported in the young and elderly [66–73]. In the previously

cited reports, the incidence is approximately equal between men and women. The

tumor is not associated with cigarette smoking or any other known toxic exposure

[48]. Davila et al reported that 75% of bronchial carcinoid tumors arose in the

lobar bronchi, with 10% originating in the main stem bronchi and 15% arising in

the periphery of the lung [74]. Given their relatively slow growth within a large

bronchus, it is common for patients to present with symptoms or radiographic

evidence of bronchial obstruction [75,76]. Patients with pulmonary carcinoids

usually do not have symptoms of carcinoid syndrome, which is most frequently

reported in patients with liver metastases [72]. Similarly, Cushing’s syndrome is a

rare but well-documented presentation [77–79]. Carcinoid tumors have been

associated with multiple endocrine neoplasia syndrome-type 1 (MEN 1) [80–82].

Grossly, central carcinoids are fleshy, polypoid masses that often have a

cherry-red color that reflects its vascularity. This gross polypoid configuration

can present a problem in accurately determining the margin of resection in a

lobectomy specimen [48]. Attention to the tumor’s characteristic growth pattern,

by surgeons and pathologists alike, can prevent additional unnecessary surgery.

The standard transverse section of the proximal bronchial margin, which is often

appropriate in other types of lung cancer, can create a false-positive appearance to

the margin if a carcinoid is protruding in polypoid configuration proximally in the

lumen, as is often the case. Careful dissection of the true proximal bronchial

margin in a circumferential manner usually proves that the margin is free and that

the base of tumor attachment is really centimeters away. Another characteristic

gross configuration in which there is an obstructing central endobronchial lesion

along with a deeply invasive parenchymal component has been termed ‘‘iceberg’’

by Ishida et al [83].

The histologic appearance of central carcinoids is characteristic of a neuro-

endocrine tumor and recognizable by light microscopy alone. The tumor cells are

arranged in organoid, trabecular, insular, palisading, or ribbon- or rosette-like

patterns. The cells might be round or spindle shaped, but the cell size is generally

uniform and they have moderate amount of eosinophilic, finely granular

cytoplasm and the finely granular nuclear chromatin pattern typical of a neuro-

endocrine tumor. A number of unusual patterns (papillary, sclerosing, follicular,

or glandular), cytologic features (oxphilia, mucin or melanin production), or

stromal changes (bone, cartilage, dense fibrosis, amyloid) have been documented

[1], but their significance is mainly as potential pitfalls in pathologic recognition.

By WHO/IASLC criteria, the tumor must have fewer than two mitoses per 2 mm2

and no necrosis [1]. Although it is well recognized that some carcinoid tumors


show cytologic atypia, increased cellularity, or lymphatic invasion, these histo-

logic features are not invariably associated with a more aggressive clinical course.

Overall, carcinoid tumors have an excellent prognosis, with 5-year survival rates

in the range of 90% to 100% consistently reported over several decades and from

various institutions [66,68,72,84,85]. There are currently no histologic character-

istics that reliably predict which tumors will behave aggressively, although some

correlation with large tumor size has been noted. In Thunnissen et al’s series,

tumor size predicted for regional lymph node metastasis in 80% of the cases [86].

Hilar and mediastinal lymph node metastases occur in 5% to 10% of cases, but

they do not necessarily indicate a poor prognosis [73]. Recurrences and

metastases tend to occur considerably later than they do in atypical carcinoids

or other types of lung cancer [73]. Some of the earlier analyses were performed

before the 1999 WHO/IASLC revisions. MEN 1-associated genetic alterations

have been reported in sporadic lung carcinoids [87–95]. The group of tumors in

Debelenko et al’s original series [87] was re-reviewed following the 1999 WHO/

IASLC revisions and reclassified as atypical carcinoids (see definition in

following section) [96]. Further investigations are needed to elucidate potential

risk factors.

Carcinoid tumor—atypical

Arrigoni et al were the first to refine the criteria for ‘‘atypical carcinoid’’ in

1972 [97]. Since that time there has been some controversy regarding what

pathologic characteristics define this tumor, how reproducible the diagnosis is,

what the overall prognosis is, and what nomenclature is appropriate for this tumor

given its clinical behavior. Arrigoni et al’s original series described 23 tumors

(out of a total of 215 carcinoid tumors) that appeared to have a general

resemblance to carcinoid tumors but that also had a focally disorganized growth

pattern, areas of tumor necrosis, increased mitoses (5–10/2 mm2), hypercellu-

larity and cellular pleomorphism. Criticism of the use of the word ‘‘atypical’’

soon followed, given the aggressive biologic behavior described in this initial

series, with 30% of patients dead of disease at 3 years, a 70% incidence of

metastases, and an average survival time of 27 months. It was for this reason that

the alternate designation ‘‘well-differentiated neuroendocrine carcinoma’’ [98]

was proposed for the same entity to avoid any confusion with the considerably

better prognosis of carcinoid tumors. Some authors objected to the term ‘‘well-

differentiated’’ given the ultimately fatal outcome for many patients within a

relatively short span of time. Other terms were introduced into the literature in

1980s as more published reports detailing this entity appeared. These terms

included peripheral small-cell carcinoma of lung resembling carcinoid tumor [99]

and Kulchitsky cell carcinoma II [100]. The tumors described in this older

literature are a heterogeneous group in regard to staging and pathological

classification. This was (in part) because of the subjective interpretation of

features such as ‘‘architectural distortion’’ and the lack of generally accepted

criteria for increased mitotic rate and necrosis.


The reproducibility of the diagnosis will (hopefully) in the future be less of an

issue, not just among pathologists. The 1999 WHO/IASLC classification retained

the original nomenclature and defines an atypical carcinoid tumor as a carcinoid

tumor with between two and ten mitoses per 2 mm2 or foci of coagulative necrosis

[1]. The necrosis typically is punctate. Other features such as cytologic atypia,

disorganized architecture, increased cellularity, lymphatic invasion, and nucleoli

have been described in these tumors, but these features are not required for the

diagnosis. It should be noted that the defining characteristics of necrosis or an

increased mitotic rate can be focal; therefore, it might be difficult to distinguish an

atypical carcinoid tumor from a typical carcinoid tumor on a cytology specimen,

small biopsy, or grossly at the time of resection. From a practical point of view,

however, it is not necessary to make the distinction preoperatively because

complete resection remains the treatment of choice for both tumors. A potential

role for chemotherapy or radiation therapy remains to be proven.

The prevalence rate of atypical carcinoid tumors, as estimated from various

series in the literature, ranges from about 10% to 20% of all pulmonary carcinoid

tumors [68,101–103]. The clinical presentation is essentially identical to that of

typical carcinoid tumors. In one recent series, about one third were asymptomatic;

the remainder had the usual common symptoms of cough, hemoptysis, or

evidence of bronchial obstruction [68]. In published reports that conform to this

entity, there appears to be slight male predominance and an overlap of age

incidence with other neuroendocrine tumors. Smoking has proved to be a

consistent association in this tumor in most cases. Central and peripheral

locations have been reported, with patients presenting at all tumor stages. The

incidence of nodal metastases ranges from 30% to 75%. Beasley et al have

published a recent series that examines prognostic indicators for 106 atypical

carcinoid tumors using the 1999 WHO/IASLC criteria [104]. They reported

overall 5- and 10-year survival rates as 61% and 35%, respectively. Five-year

survival rates were significantly better for stage I (71%) than for stage II (46%)

and stages III/IV (37%). Of the clinical features, higher stage and a tumor size of

3.5 cm or greater were associated with a worse prognosis. For unclear reasons,

female gender was also associated with a worse prognosis. Patients were further

subdivided in subgroups of low (2–5 mitoses/2 mm2) versus high (6–10 mitoses/

2 mm2) mitotic rates. When patients were stratified by stage, patients with a

higher mitotic rate had a significantly worse survival. As referenced in the

previous discussion of genetic alterations associated with carcinoid tumors, the

results from studies of atypical carcinoids have been variable, but they tend to

show a higher rate of allelic losses within chromosomal region 11q13 when

compared with carcinoid tumors [92]. Some overlap does exist, and further

investigation will be needed to elucidate these differences and their significance.

Endobronchial small-cell carcinoma/combined small-cell carcinoma

The 1999 WHO/IASLC classification defines small-cell carcinoma as a

malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-


defined cell borders, finely granular nuclear chromatin, and absent or incon-

spicuous nucleoli [1]. The previous 1981 WHO categories of oat cell carcinoma/

small-cell carcinoma, intermediate cell type/combined oat cell carcinoma, and the

1988 IASLC category of mixed small-cell/large-cell carcinoma have been

dropped because subsequent studies did not confirm their clinical significance

or interobserver reproducibility. The 1999 WHO/IASLC definition of combined

small-cell carcinoma defines the tumor as a small-cell carcinoma with an

additional component that consists of any of the histological types of non–

small-cell carcinoma. The classic common and advanced presentation of small-

cell carcinoma is familiar to all thoracic surgeons and will not be reviewed here.

The diagnosis is more challenging when the occasional small peripheral or

endobronchial nodule is encountered. Small-cell carcinoma remains a diagnosis

by light microscopy. Immunohistochemical demonstration of neuroendocrine

differentiation is of limited utility and can be variable, with about 25% of cases

negative for markers such as chromogranin, synaptophysin, and Leu-7 [1];

however, immunohistochemical stains are reasonable, particularly in a smaller

sample, when the histology suggests a broader differential diagnosis that might

include lymphoma or other small, blue-cell tumors. The tumor cells can be round,

oval, or spindle-shaped. The mitotic rate is high and nuclear molding is

prominent. A few histologic pitfalls can make the diagnosis difficult, especially

in small biopsy specimens obtained by fiberoptic bronchoscopy [71]. There is no

absolute size criterion for the tumor cells, though it is often stated that the general

size should be less than the size of three small resting lymphocytes. Cell size can

be larger in well-fixed specimens, resections, and frozen sections. Similarly,

necrosis is common and often extensive, but it is not an invariable feature,

particularly in small specimens. It might be more difficult to appreciate a high

mitotic rate in small specimens, and this feature is critical in distinguishing small-

cell carcinoma from typical and atypical carcinoid tumors. Finally, although crush

artifact might well preclude a definitive diagnosis (and this is often frustrating

from a pathological and clinical perspective), it is not pathognomic of small-cell

carcinoma or even of malignancy. It is therefore essential given the therapeutic

and prognostic implications of the diagnosis that the complete clinical and

radiographic presentation be taken into consideration and that suboptimal speci-

mens be accepted as nondiagnostic.

Endobronchial large-cell carcinoma/large-cell neuroendocrine carcinoma

Large-cell carcinoma is a diagnosis of exclusion that is based on light

microscopy. By definition, large-cell carcinoma is a malignant epithelial tumor

that lacks squamous or glandular differentiation and lacks the cytologic features of

small-cell carcinoma. Lung tumors are histologically heterogenous, and this

heterogeneity is also expressed in to what degree they show neuroendocrine

differentiation [96]. Neuroendocrine differentiation is usually suggested by

morphologic features such as organoid nesting, trabeculae, rosette-like structures,

and palisading patterns. It can be confirmed by electron microscopy or immuno-


histochemistry, the latter technique being more widely employed in routine

diagnostic work. There is a general acknowledgment that there are some lung

tumors that are not classic small-cell carcinomas, yet they do suggest neuro-

endocrine differentiation that might or might not be confirmed by special stains. In

1991 Travis et al set forth criteria for what was termed large-cell neuroendocrine

carcinoma (LCNEC) [105]. These tumor cells are generally large with moderate to

abundant cytoplasm and the nuclear chromatin ranges from vesicular to finely

granular. Nucleoli are frequent and often prominent, and they remain the definitive

feature for the separation from small-cell carcinoma. Large areas of necrosis are

also common. By 1999 WHO/IASLC criteria, mitotic counts must be at least

11 per 2 mm2, but in actual practice, the mitotic counts are usually much higher,

averaging in the range of 75 per 2 mm2. LCNEC is classified as a variant of large-

cell carcinoma. The nomenclature is extremely complicated in the 1999 WHO/

IASLC classification because of the current uncertainty as to what effect, if any,

neuroendocrine features have on differences in survival or therapeutic response.

Large-cell neuroendocrine carcinoma has neuroendocrine morphology and

neuroendocrine markers by electron microscopy or immunohistochemistry.

Large-cell carcinoma with neuroendocrine morphology is applied to tumors that

have neuroendocrine morphology but lack neuroendocrine markers by electron

microscopy or immunohistochemistry. Large-cell carcinomas with neuroendo-

crine differentiation lack neuroendocrine morphology but have neuroendocrine

markers by electron microscopy or immunohistochemistry. Large-cell carcinoma

lacks neuroendocrine morphology or neuroendocrine differentiation by special

studies. Complete resection remains the treatment of choice for all of these

tumors. Though there are conflicting reports in the literature, a potential role for

adjuvant or neoadjuvant therapy has yet to be determined. The reproducibility of

the histologic criteria for neuroendocrine tumor subclassification continues to be

an issue [106].

Carcinomas of salivary gland-type

Adenoid cystic carcinoma

Adenoid cystic carcinoma is the most common of the tracheobronchial

salivary gland-type tumors [107,108]. The majority of these tumors arise in large

bronchi, but peripheral primary adenoid cystic carcinomas have been reported

[109–111]. The discovery of a peripheral lesion should prompt clinical consid-

eration of metastasis from a previous or occult head and neck primary. Most

patients are adults, but there are pediatric cases [112,113]. The reported age of

adults at presentation is wide (18–82 years). The tumor occurs in both women

and men, but there is a slight male predominance in some series [23]. There is no

correlation with cigarette smoking. By comparison with other lesions such as

carcinoid tumors and mucoepidermoid carcinomas (which usually present as

intralumenal masses), adenoid cystic carcinomas have a more variable growth

pattern. Typical presenting symptoms such as wheezing, progressive dyspnea,

cough, and hemoptysis tend to reflect tumor size and the extent of intralumenal


tumor growth [23]. The size of the tumors has generally ranged from about 1 cm

to 4 cm. Some tumors are grossly nodular with minimal invasion of the bronchus,

whereas others have a mixed nodular/infiltrative or predominantly infiltrative

growth pattern [114]. More infiltrative tumors appear as small nodules within the

airway or cause a generalized constriction of the airway. Some tumors have a

tendency to radially spread into the adjacent parenchyma rather than along the

airways. The microscopic level of invasion nearly always exceeds that which is

grossly apparent, and negative resection margins often are difficult to achieve.

Complete resection can be difficult and can require multiple frozen sections to

confirm clear surgical margins. Long-term disease control has been reported with

positive surgical margins [115].

Adenoid cystic carcinoma tumor cells are small with a relatively high nuclear/

cytoplasmic ratio, but nuclear pleomorphism and mitoses are rare. The histologic

pattern varies, with some tumors entirely composed of cells arranged in tubular

and cribriform (cylindromatous) patterns. Some tumors have a significant

component of solid tumor nests [116]. In a large series by Moran et al [117],

prognosis correlated with stage rather than with these variations of cell type. As is

characteristic of their salivary gland counterparts, adenoid cystic carcinomas are

notorious for perineural spread. There can be lymph node involvement, usually

by direct extension. Long-term survival can be achieved with adequate resection,

but local recurrence can occur even late (> 10 years) following resection [50,118].

Mucoepidermoid carcinoma

Mucoepidermoid carcinoma is characterized by an admixture of mucus-filled

cysts and solid areas of transitional (non–mucin-secreting, nonkeratinizing cells)

or squamoid (nonkeratinizing but epidermoid) cells. Mucoepidermoid carcinoma

is distinguished from the bronchial mucous gland adenoma previously described

by the finding of these transitional or intermediate cells in the mucoepidermoid

carcinoma. These tumors are rare, with the reported incidence varying between

0.2% and 1.2% of all lung tumors [119,120]. Unlike its salivary gland counterpart,

mucoepidermoid carcinomas of the lung are divided into low or high-grade

lesions. An intermediate grade variant has not been characterized. This simple

two-grade separation correlates well with clinical presentation, general pathologic

features, and prognosis. The distinction between low-grade and high-grade tumors

is based on nuclear pleomorphism, mitotic activity, the presence of necrosis, and

the degree to which undifferentiated or transitional cells predominate.

Low-grade mucoepidermoid tumors are more common; they occur both in

children and adults. Yousem and Hochholzer have reported the largest series of

adult mucoepidermoid carcinomas of the lung to date [121]. In their series of

58 tumors, 45 tumors were low-grade. There were 18 men and 27 women. The

ages ranged from 9 to 78 years, but 25 of the patients were 30 years of age or

younger. Smoking history was available for only 22 patients, but fewer than half

reported cigarette use. Most of the patients were symptomatic, often with cough

and hemoptysis. A solitary mass was the most common radiographic finding

(29 patients) followed by postobstructive pneumonia (14 patients) and lobar


atelectasis (seven patients). Although peripheral mucoepidermoid carcinomas

have been reported, they are extremely rare [122]. Low-grade mucoepidermoid

carcinomas characteristically are exophytic and polypoid. The tumors are pre-

dominantly endobronchial with limited involvement of the bronchial submucosa

and infrequent extension into the pulmonary parenchyma (Fig. 3). In Yousem and

Fig. 3. (A) Left mainstem bronchus resection for an endobronchial mucoepidermoid carcinoma. (B) The

same mucoepidermoid carcinoma in cross-section, demonstrating an attachment to the bronchus, but

invasion is limited to the superficial portion of the submucosa. (From Litzky LA. The pathology of

non–small cell lung carcinomas. In: Fishman AP, Elias JA, Fishman JA, et al, editors. Pulmonary

diseases and disorders, 3rd edition. New York, NY: McGraw-Hill; 1998. p. 1739–58; with permission.)


Hochholzer’s series, four tumors were located in the main stem bronchi, but the

rest were in lobar bronchi. The size range was 0.8 cm to 0.6 cm. On cut section,

these tumors are variably cystic and solid lesions. By comparison, the tumors

might appear to be more mucoid or cystic than the more common carcinomas of

the lung. Histologically, there are numerous dilated glandular spaces within the

tumor interspersed with solid areas. Columnar and goblet cells line the cysts, and

these cells also might be scattered through the solid areas. By definition, the solid

areas are composed of transitional and squamoid cells without significant

cytologic atypia, increased mitotic activity, or necrosis. Intermediate cells have

a polygonal shape and eosinophilic cytoplasm, but they lack obvious squamous

or glandular differentiation. Forty-four of the 45 patients in this series had no

nodal involvement and were without evidence of disease at 7 years of follow-up.

The single patient with a low-grade mucoepidermoid carcinoma and a lymph

node metastasis was lost to follow-up. Heitmiller et al’s smaller series of

12 patients with low-grade mucoepidermoid carcinoma showed similar results

following complete resection [119].

By contrast, patients with high-grade mucoepidermoid carcinomas are at

higher risk for recurrent disease and death from disseminated disease. There is

some variation in the reported risk for recurrence and death, but the prognosis

clearly differs from the better outcome in low-grade mucoepidermoid carcinoma

and from the generally worse prognosis in most reported series of adenosqua-

mous carcinoma of the lung if histologic criteria are strictly applied. In Yousem’s

and Hochholzer’s series, there were six men and seven women with an age range

of 13 to 67 years (mean age 45 years). Ten of the 13 patients were symptomatic

with cough, hemoptysis, weight loss, or fatigue. Smoking history was available

for only five patients, but four of the five were cigarette smokers. Radiographic

findings included atelectasis, postobstructive pneumonia, and nodules with a

distal pneumonic infiltrate. All of the tumors were within lobar bronchi and they

ranged in size from 1.5 cm to 4.0 cm. There was an exophytic component to the

tumors, but six of the 13 patients also had invasion of the pulmonary

parenchyma. Histologically, areas of low-grade mucoepidermoid carcinoma were

identified, but solid areas were more conspicuous than in the low-grade tumors.

The tumor cells had high-grade cytologic features with nuclear enlargement,

anaplasia, mitoses, and necrosis. Frank keratinization of cells is not seen in

mucoepidermoid carcinomas; this is a significant feature used in distinguishing

high-grade mucoepidermoid carcinoma from adenosquamous carcinoma [123]. It

is clear from the literature that high-grade mucoepidermoid carcinoma has a

higher incidence of nodal involvement, unresectabilty, and inoperability because

of disseminated disease at the time of presentation [119,121,124,125]. Never-

theless, the magnitude of risk varies from study to study. Three of the 13 patients

(including the two with hilar lymph node metastases) in Yousem and Hochholz-

er’s series died of their disease [121]. A fourth patient had a lobectomy for

recurrent disease 4 years after the initial operation. In Heitmiller et al’s series,

the three patients with high-grade mucoepidermoid carcinoma that was unresect-

able at the time of presentation were all dead of their disease within 16 months


[119]. All 12 of the patients reported by Turnbull et all were dead in less than

1 year, but eight of these patients presented with disseminated disease or

unresectable lesions [124].

Acinic cell carcinoma

Fechner first described an acinic cell carcinoma of the lung in 1972. These

tumors are extremely rare, with 15 cases reported in the literature to date

[23,126–135]. Most of the tumors have been reported in adults with an

approximately equal male/female incidence and an age range of 27 to 75 years.

There was one pediatric case in a 12-year old girl [128]. The nodules ranged in

size from 1.2 cm to 4.0 cm with some propensity for the right middle lobe.

Tracheal, endobronchial, and intraparenchymal locations have been noted. The

lesions lack sharp circumscription, but proximity or connection to a major

bronchus is usually present. This tumor has the diverse histologic growth patterns

of its salivary gland counterpart, and special attention must be paid to excluding a

salivary gland metastasis by clinical history. The tumor can also be confused with

other tumors such as oncocytic carcinoids or granular cell tumors. Microscop-

ically, the tumors have been predominantly solid with focal acinar or microcystic

areas. Organoid or lobular patterns have also been described. The tumor cells are

cytologically bland with round hyperchromatic nuclei and granular eosinophilic

or clear cell cytoplasm. This cytoplasm is periodic acid Schiff (PAS)-positive in

most cases and ultrastructural studies have confirmed the large, membrane-bound

granules that are typical of serous secretory cells. The tumor cells should be

positive for cytokeratin but negative for chromogranin, synaptophysin, or S-100.

All of the patients reported have been alive and without evidence of recurrence

following surgical resection. One patient with interlobar lymph node metastasis

who underwent radiation therapy was without evidence of disease at 20 months

of follow-up care [130].

Malignant salivary gland-type mixed tumors

In Moran et al’s series of benign and malignant salivary gland-type tumors of

the lung, there were two patients who had what were characterized as histolog-

ically atypical lesions [19]. Both tumors were considerably larger (6 cm and

16 cm) than the benign lesions (2.0–2.5 cm). Both tumors were poorly circum-

scribed and infiltrative, and one patient had satellite nodules within the lobe. The

hilar and regional lymph nodes at the time of initial resection were negative in

both patients. In these two histologically malignant lesions, the tumors grew

predominantly as slender cords and trabeculae of cells within an abundant

myxoid matrix. Angioinvasion was prominent in one patient, and both tumors

had conspicuous areas of hemorrhage and necrosis. Mitotic counts averaged 5 to

10 per 2 mm2. Both patients had recurrent disease within the thorax within 2 to

3 years and one had died of the disease. In their summary of the previous

literature, the authors noted that a high mitotic rate was present in all of the

patients with aggressive disease, although clinical follow-up information was

available for only four of the eight previous reports. Three out of four of these


patients had late recurrences at 4 years [27], 8 years [136], and 9 years [26].

These data suggest the potential for late recurrence or metastasis, although some

patients have lived for an extended period of time with recurrent disease. It

should also be re-emphasized that clinical history and examination are essential to

exclude a metastasis from another site such as the salivary gland or breast.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements (including

carcinosarcoma and pulmonary blastoma)

The classification of these poorly differentiated, primary, non–small-cell lung

tumors that contain a component of sarcoma or sarcoma-like elements has been a

matter of some controversy, and these tumors have been described under a

variety of names. Designations include spindle cell carcinoma, carcinosarcoma,

sarcomatoid carcinoma (monophasic and biphasic), pleomorphic carcinoma,

giant cell carcinoma, and pulmonary blastoma. Despite the fact that these tumors

might represent a continuum of epithelial and mesenchymal differentiation, the

1999 WHO/IASLC classification set forth criteria for the classification of these

tumors in an attempt to foster uniform classification and potentially provide

more refined prognostic information in the future [1]. Carcinomas with spindle

cells or giant cells are classified as pleomorphic carcinoma, spindle cell

carcinoma, or giant cell carcinoma depending on the predominance of spindle

cells or giant cells. Tumors that are composed exclusively of spindle cells or

giant cells are termed spindle cell carcinoma and giant cell carcinoma, respec-

tively. These pure forms are extremely rare. The more frequently encountered

tumor, which consists of a poorly differentiated squamous cell carcinoma,

adenocarcinoma, or large-cell carcinoma admixed with spindle cells or giant

cells (comprising at least 10% of the tumor) is now termed a pleomorphic

carcinoma. Although the separation is acknowledged as arbitrary, carcinosar-

coma is defined as a malignant tumor having a mixture of carcinoma and

sarcoma containing heterologous elements (ie, differentiated mesenchymal

elements) such as malignant cartilage, bone, or skeletal muscle. In addition to

the histologic recognition of these malignant heterologous elements, immuno-

histochemistry with epithelial markers is often used to confirm epithelial

differentiation. It should be noted that the WHO/IASLC classification relies

on histologic criteria using routine light microscopy and does not require the

demonstration of positive immunohistochemical staining for cytokeratin. When

keratin stains are negative, however, it might be difficult to separate these tumors

from primary or metastatic sarcoma. Pulmonary blastoma is defined as a

biphasic tumor containing a primitive epithelial component that can resemble

well-differentiated fetal adenocarcinoma and a primitive mesenchymal stroma

that occasionally has foci of osteosarcoma, chondrosarcoma, or rhabdomyosar-

coma. This tumor presents mainly in adults [137] and should be distinguished

from pleuropulmonary blastoma, a tumor that occurs almost exclusively in

children of 6 years old or younger at diagnosis [138,139].

In light of this review of changing nomenclature and given that the routine use

of immunohistochemistry has been employed for barely two decades, it is


somewhat difficult to sort through the literature on these rare tumors. The lack of

adequate staging information that conforms to the current TNM classification

system in older literature adds to this confusion. The most recent series of

carcinosarcomas that utilizes the 1999 WHO/IASLC criteria and provides staging

information is that of Koss et al [140]. In this same series, the 66 carcinosarcomas

were compared with the largest previously published series of pleomorphic

carcinomas [141]. Several generalizations appear to be true from their series.

Pulmonary carcinosarcomas affect men more frequently than women and tend to

present in more elderly patients. The median age in Koss et al’s series was

65 years, but there was a wide patient age range (from 38 to 81 years). When

smoking history is obtained, all are smokers. Frequent symptoms include cough,

chest pain, hemoptysis, and dyspnea, but a substantial number of patients (about

one third in Koss et al’s series) are asymptomatic or have their tumors identified

on a routine chest radiograph. Although the tumors range in size from 2 cm to

16 cm, most are between 3 cm and 11 cm. The tumors are usually gray–white,

and areas of hemorrhage or necrosis are frequent. In an appreciable number of

instances, the large size of the tumor or the lack of information prevented an

accurate assessment of endobronchial or peripheral location. Some carcinosarco-

mas present with an endobronchial component or largely as central, polypoid,

endobronchial masses. Koss et al report a 34% incidence in their series and a 46%

incidence in the literature of tumors that contain an endobronchial component.

They report a 12% incidence and a 17% incidence in the literature of carcino-

sarcomas that were purely polypoid or largely polypoid endobronchial tumors.

Previously published reports and their histologic analysis of these tumors

underscore the need for careful sampling. The malignant stroma is often the

predominant component in the carcinosarcoma, and the foci of carcinoma are

small. Similarly, the poorly differentiated spindle cell component can predom-

inate, and a careful search is required to identify the heterologous elements. The

overall 5-year survival rate was 21%. There was no statistical significance in

5-year survival rates between the patients with carcinosarcomas and patients with

pleomorphic carcinomas (15%). Carcinosarcoma tumor size of greater than 6 cm

correlated with reduced survival. Although stage did not appear to be related to

outcome in this series, nearly one fourth of the cases did not have staging

information. It is still unclear whether or not the distinctly primitive histologic

appearance of pulmonary blastomas makes a prognostic difference. Although

about two thirds of patients have died of their disease within 2 years of diagnosis,

staging information has not always been complete and has lacked statistical

power. Overall, a larger number of cases with more complete staging and follow-

up information will be required to determine whether or not these histologic

differences correlate with clinical behavior.

Metastatic carcinoma

Most tumors metastatic to the bronchus represent intrathoracic spread from

primary pulmonary adenocarcinomas; however, metastases from extrathoracic


organ sites and intrathoracic tumors like malignant pleural mesothelioma do

occur. Endobronchial metastases from extrapulmonary solid malignant tumors

are rare. Many types of primary tumor have been reported, but breast, colon, and

renal cell adenocarcinomas are the most common [142,143]. Epithelial tumors

predominate, but melanoma and a wide variety of mesenchymal tumors have also

been documented. This latter group of tumors in particular can lead to diagnostic

difficulties because of a long latency period between the initial primary tumor

diagnosis and the development of pulmonary metastases [144]. Symptoms such

as wheezing or cough or radiological findings such as atelectasis can be

indistinguishable from those of primary lung cancer [145,146]. Invasion of the

bronchial wall, the more common pattern of bronchial metastatic spread,

manifests itself as submucosal irregularity or nodularity. Actual polypoid endo-

bronchial masses are quite rare, but they closely mimic a primary bronchogenic

tumor. The histologic diagnosis will be straightforward in most circumstances,

but a history of previous primaries helps to avoid pathologic misinterpretation.

Soft tissue tumors of the tracheobronchial tree—benign and malignant

The supporting fibroconnective tissues of the trachea and bronchi include

cartilage, smooth muscle cells, fibroblasts, adipocytes, nerves, lymphatics, and

blood vessels. These fibroconnective tissues can give rise to a variety of benign

and malignant soft tissue tumors. In comparison with the epithelial tumors

previously described, most of these tumors are exceedingly rare. From a clinical

and pathological perspective, it is essential to recognize that metastases and

epithelial carcinomas far exceed the incidence of primary soft tissue tumors.

Tumors that are initially thought to represent a true primary sarcoma of the lung

often prove upon further inquiry into patient history to represent late metastasis

from a primary soft tissue tumor or to be a carcinosarcoma upon further sampling.

Chondroma/chondrosarcoma

It is common diagnostic error to use the term chondroma for hamartomas that

have a dominant cartilaginous component. True chondromas are quite rare, with

an incidence of three cases in 40,000 autopsies [48]. Chondromas arise in the

cartilaginous rings of the large bronchi or trachea and, by definition, they have a

connection to the rings or with their perichondrium [48]. Chondromas have been

reported in a broad age range of patients, including pediatric patients [147].

Patients typically present with obstructive symptoms. There continues to be a

debate regarding whether true chondromas occur in the setting of Carney’s triad

(pulmonary chondromas, gastric epithelioid smooth muscle tumors, and extra-

adrenal paragangliomas) [148]. Some authors support the notion that the

‘‘chondromas’’ described in Carney’s triad are chondroid hamartomas [48],

whereas others include chondromas within the epidemiologic pathology associ-

ated with Carney’s triad [1]. Grossly, the tumors are 1 cm to 2 cm in size and have


irregular polypoid projections along a broad base [48]. On cut surface they are

firm and white, often with focal areas of calcification or ossification. Micro-

scopically, the tumor is composed entirely of mature cartilage without cytologic

atypia. Given the intimate connection with the cartilaginous rings, complete

resection might require bronchoplastic surgery.

The distinction between chondroma and chondrosarcoma is based upon the

cytologic atypia of the cartilaginous proliferation. Chondrosarcomas are

extremely rare, but endobronchial and peripheral locations have been described

[149–153]. The central tumors tend to be discovered at an earlier stage and

appear to have a relatively good prognosis until tumor size precludes complete

resection [150,151,153].

Glomus tumor

Glomus tumors are of presumed glomus cell origin or differentiation and have

features of modified smooth muscle by immunohistochemistry or electron

microscopy. Tracheal tumors [132,154–162] and lung tumors with endobronchial

or parenchymal growth have both been reported [154,158,159,162,163]. In

instances in which a detailed description of the tracheal location was reported,

the tumors were described as polypoid lesions arising from the posterior

membranous portion of the trachea [156,157]. Gaertner et al reported four cases

of primary pulmonary glomus tumors and reviewed the literature on four

additional previously reported cases [163]. The average age at presentation was

45 years. The majority of the tumors measured less than 2.5 cm in size. The

behavior of these tumors has been indolent, without evidence of recurrence

following resection. Gaertner et al also reported one patient with a malignant

glomus tumor (glomangiosarcoma) who developed widespread metastases and

died within 10 months after initial therapy.

Vascular tumors—hemangioma/angiosarcoma/Kaposi’s sarcoma

Capillary hemangioma, a benign vascular tumor, is much more frequently

reported in the pediatric literature. The tumor is typically discovered in early

infancy when patients present with respiratory distress and airflow obstruction

[164–167]. There are a few reports of this tumor in adults, who presented with a

chief complaint of hemoptysis or cough [168,169]. Bronchoscopic examination

revealed circumscribed submucosal lesions with an overlying vascularized surface

protruding into the airway. Complete removal has been achieved by bronchoscopy.

Primary pulmonary angiosarcomas are exceeding rare, even within the select

group of primary pulmonary sarcomas or otherwise rare tumors [120,170]. These

patients typically present with late-stage disease. Angiosarcoma in the lung is far

more likely to represent metastatic disease [171].

Kaposi’s sarcoma can present as purple–red, raised nodules along the

tracheobronchial tree or as diffuse bronchial wall thickening, but the most

common patterns of lung involvement are nodular and interstitial infiltrates and


pleural effusion [172,173]. In most instances, thoracic involvement presents late

in the course of the disease, but the lung might be the primary disease site in 10%

to 15% of AIDS patients [172,174]. Predominant pulmonary involvement

without skin lesions is also seen in rare instances in the sporadic European form

of the disease [175,176] or in the transplant population [177].

Granular cell tumor

Granular cell tumors (GCTs) that are histologically identical to those found in

other anatomic sites have been reported in the lung [178–181]. Deavers et al

reported the largest series on pulmonary granular cell tumors [178]. The patients

were adults with an average age of 45 years and an equal proportion of men to

women. In this study of 23 lesions from 20 patients, two tumors were peripheral,

but the remainder involved large, cartilaginous bronchi. Ten cases presented as

obstructing endobronchial lesions and three others had hemoptysis. Most of the

lesions were solitary, but two patients had multiple lung masses. Pulmonary

GCTs are typically small, with a mean size of 1 cm. The endobronchial lesions

are unencapsulated and polypoid with a tan–white to yellow color. Microscop-

ically, the tumor cells are large, round, or somewhat fusiform cells that have

abundant granular eosinophilic cytoplasm. The nuclei are small, with minimal

atypia and rare—if any—mitoses. The tumor cells can infiltrate peribronchial

structures including nerves and lymph nodes, but this extension is limited. The

overlying bronchial epithelium might show squamous metaplasia or ulceration,

but the characteristic pseudoepitheliomatous hyperplasia that is seen in other sites

has not been reported. The tumor cells are strongly positive for S-100 protein and

negative for cytokeratins. Malignant behavior has not been reported in pulmonary

granular cell tumors, even for those with multicentric involvement. Incompletely

resected lesions appear to be stable over time.

Hamartoma

Hamartoma is a benign, slow-growing mesenchymal tumor consisting of

varying proportions of adipose tissue, loose myxoid fibrous tissue, and cartilage.

Within the tumor are intersecting clefts lined by respiratory epithelium, but these

epithelial elements are not neoplastic and represent passive glandular entrapment

[182,183]. Hamartomas might be more accurately termed fibrolipochondromas

[48], but the historical designation of hamartoma has persisted despite its

misleading implication that these tumors are somehow a congenital malforma-

tion. Hamartoma is the most common benign tumor of the lung. The estimated

incidence of pulmonary hamartomas in the general population is 0.25% [64].

Hamartomas are more frequently intraparenchymal, but roughly 10% will present

in an endobronchial location, often with obstructive symptoms [183–185].

Multiple hamartomas or endotracheal hamartomas have been reported infre-

quently [186–189]. There is some association of pulmonary chondroid hamarto-

mas with Carney’s syndrome [148], hamartomas, and Cowden’s syndrome [190].


Endobronchial hamartomas are substantially represented (24%) in Shah et al’s

series of 185 benign tumors identified endoscopically and treated with laser

resection [7]. Initial endoscopic biopsies of these lesions are sometimes non-

diagnostic. The overlying benign surface epithelium, the mesenchymal elements

(especially the cartilage), and the frequent surrounding obstructive changes can

make bronchoscopic biopsy difficult. The gross appearance, however, is quite

characteristic. Hamartomas are well circumscribed and often lobulated or

papillary when they project into the airway lumen (Fig. 4). On average,

endobronchial hamartomas are smaller in size than their peripheral counterparts,

which can range from a few millimeters up to 20 cm; this size difference is no

doubt related to obstructive symptoms that lead to earlier detection [48].

Hamartomas are often firm on palpation—even hard—depending on the amount

of cartilage or the extent of calcification or ossification. They range from white to

yellow in color, depending on the proportion of adipose tissue or cartilage. There

is some potential for histologic confusion between this tumor, true chondromas

(as discussed previously), and mixed tumors of salivary gland-type, particularly

with limited sampling. In a cartilagneous hamartoma, the chondroid elements are

Fig. 4. Endobronchial hamartoma. This low-power photomicrograph demonstrates the characteristic

circumscription and lobulated architecture. There is a predominance of cartilaginous elements in this

tumor that might lead to a misdiagnosis of chondroma.


well developed and are usually the predominant component. Moran et al have

observed that this is not typically the case with mixed tumors. In addition, the

epithelial elements of a mixed tumor appear to be an integral part of the lesion

rather than entrapped glandular elements, as in a hamartoma [19]. Chromosomal

abnormalities in pulmonary hamartomas have been reported [191–194]. The

most recent reports center on high-mobility group proteins and show interesting

specific genetic alterations shared by pulmonary hamartomas and other benign,

slow-growing tumors such as lipomas, endometrial polyps, and uterine myomas

[195–198].

Leiomyoma/leiomyosarcoma/rhabdomyosarcoma

Primary pulmonary leiomyomas are solitary tumors that occur as endotra-

cheal/endobronchial or intraparenchymal lesions with approximately equal fre-

quency [107]. Leiomyomas comprise approximately 2% of benign lung tumors

[199]. Although a wide age range that includes pediatric cases has been reported,

most of the tumors tend to occur in individuals in the third and fourth decades of

life [200,201]. Females appear to be affected more commonly than males.

Pulmonary leiomyomas are similar in gross and histologic appearance to

leiomyomas of other common sites such as the uterus or gastrointestinal tract.

Tumors within the tracheobronchial tree appear as fleshy, polypoid masses that

protrude intralumenally and are attached by a wide base [48]. By definition,

leiomyomas do not have significant cytologic atypia, a high mitotic rate, or

necrosis. The prognosis is excellent with complete resection. The location of the

tumor and secondary lung destruction might limit options such as laser therapy or

bronchoplastic surgery.

Excluding those that arise within the pulmonary artery, primary pulmonary

solitary leiomyosarcomas are about as rare as pulmonary leiomyomas. They tend to

be larger tumors and they occur, on average, about a decade later [200,202–205]. It

should be emphasized that the possibility of metastasis from the genital tract should

be rigorously excluded in women who present with what appears to be a primary

pulmonary leiomyosarcoma. Most of these tumors are intraparenchymal, but they

often have an endobronchial component by direct extension. In the small number of

reports that have examined pathologic attributes and prognosis, histologic grade

(ie, lower versus higher mitotic rates and absence or presence of necrosis) in

addition to size (3 cm) seemed to correlate with prognosis [204–206]. Yellin et al

reported an overall 45% 5-year survival rate in patients who underwent complete

surgical resection.

Primary pulmonary rhabdomyosarcomas are extremely rare, but they have

been reported occasionally in children and adults [207–219]. By definition, the

tumor must show evidence of striated muscle differentiation by light microscopy

(ie, cytoplasmic cross-striations), immunohistochemistry, or electron microscopy.

In addition, there are now molecular assays for specific chromosomal trans-

locations in alveolar rhabdomyosarcoma. It is well documented that rhabdomyo-

sarcomas can arise in locations devoid of striated muscle. Endobronchial,


intraparenchymal, and pulmonary trunk sites have been reported. Most of the

adult patients died within 2 years of diagnosis. Many of the patients presented

late in the course of their disease or at autopsy. As with other rare types of

pulmonary sarcoma, it is important to consider the possibility of metastasis from

another primary site or the more common carcinosarcoma.

Lipoma/liposarcoma

Most lipomas of the lung that have been reported are endobronchial, but it is

not clear to what extent some of these reported cases actually represent

hamartomas with a predominant component of adipose tissue [220–226]. Never-

theless, from a clinical perspective, these tumors are benign and a conservative

approach to excision is indicated. Primary liposarcomas are among the most rare

of the subtypes of pulmonary sarcoma [227–229].

Fibrosarcoma/hemangiopericytoma/malignant fibrous histiocytoma

As Suster asserts in his review of primary sarcomas of the lung, the majority of

the previously reported cases of fibrosarcoma or hemangiopericytoma are

probably intrapulmonary, localized, fibrous tumors or, in the instance of heman-

giopericytoma, primary synovial sarcomas [229]. The most common of the

spindle cell sarcomas without specific differentiation is therefore malignant

fibrous histiocytoma. Most of these tumors have been located in the lung

periphery. Histologically, malignant fibrous histiocytomas are identical in appear-

ance to their soft tissue counterparts. There is a broad differential diagnosis for

this pleomorphic spindled cell tumor that includes more common entities such as

intrathoracic extension from a chest wall primary, extrathoracic metastasis from a

soft tissue primary, pleomorphic carcinoma, and inflammatory pseudotumors.

Benign and malignant nerve sheath tumors—neurofibroma/schwannoma

(neurilemoma)/neurogenic sarcoma

It is far more common to encounter nerve sheath tumors within the posterior

mediastinum or paravertebral region, but a few endotracheal/endobronchial or

intraparenchymal cases have been reported [202,230–239]. Neurofibromas and

schwannomas are more common than malignant tumors. The incidence is equal

among women and men. Although some of these cases involve patients with

neurofibromatosis, other patients do not appear to have any evidence of the

disease. Obstructive symptoms have been noted with intraluminal tumor growth.

Endoscopically, the tumors have a polypoid appearance similar to other types of

tumor. These nerve sheath tumors are histologically identical to similar tumors in

other anatomic sites and have a similar clinical behavior.

Osteosarcoma

Primary osteosarcoma is a rare tumor, with only a handful of cases reported in

the literature [206,240,241]. As Suster cautions in his summary of primary


pulmonary sarcomas, occasional tumors that were initially felt to be primary lung

osteosarcomas proved to be carcinosarcomas upon additional sampling

[229,240]. The prognosis for these tumors is poor.

Synovial sarcoma

Recent investigations using molecular analysis have confirmed that synovial

sarcomas arise in the lung and are more common among the primary pulmonary

sarcomas than previously thought [170,242–247]. Tissue assays for the char-

acteristic t(X;18) translocation and SYT/SSX fusion genes are available in

specialized laboratories; therefore sufficient tissue should be obtained at the time

of biopsy or resection if sarcoma is a consideration. The largest series to date has

been reported by Zeren et al [247]. In their series of 25 cases, there were an

approximately equal number of men and women, with an age range from 16 to

77 years. The most common symptoms were chest pain, cough, dyspnea, and

hemoptysis. The tumors were solitary and varied in size from 0.6 cm to 20.0 cm.

Two lesions involved the bronchial wall. Follow-up information was available for

18 patients. Six died of the disease, eight were alive with the disease, and four

had no evidence of the disease. The authors emphasize that because of its

distinctive biologic behavior, synovial sarcoma should be distinguished from a

variety of malignant and metastatic lesions.

Miscellaneous tumors

Inflammatory pseudotumor/inflammatory myofibroblastic tumor

Historically, a wide variety of names have been applied to inflammatory

pseudotumor/inflammatory myofibroblastic tumors (or, perhaps, entities). In

addition to inflammatory myofibroblastic tumor [248] or inflammatory pseudo-

tumor [249], these names include plasma cell granuloma [250,251], xanthoma

[252], xanthomatous pseudotumor [253], fibroxanthoma, histiocytoma [254],

fibrous histiocytoma, pseudosarcomatous myofibroblastic tumor, invasive fibrous

tumor of the tracheobronchial tree [255], mast cell tumor [256], and mast cell

granuloma [257]. It is easier to make sense of this bewildering proliferation of

names if one understands that the lesion itself is composed of a variety of cellular

components, and the nature of this lesion (reactive versus neoplastic) is still a

matter of some controversy. These lesions frequently occur in the lung, but many

other extrapulmonary sites have been reported. The 1999 WHO/IASLC criteria

define the entity as ‘‘a spectrum of fibroblastic or myofibroblastic proliferations

with a varying infiltrate of inflammatory cells, typically plasma cells, lympho-

cytes, or foamy histiocytes’’ [1]. The definition encompasses lesions that have a

predominant myofibroblastic or fibroxanthomatous appearance and lesions with a

heavy infiltrate of plasma cells. This lesion is commonly seen in the pediatric age

group, and is encountered more frequently in patients under 40 years old, but


there is a wide reported age range that includes infants and the elderly

[250,251,258–260]. The incidence in men and women is equal. About 50% of

patients will be asymptomatic; the other half present with cough, hemoptysis, and

dyspnea, and some will have systemic symptoms. The lesions are usually solitary,

but multiple lesions have been reported. The lesion can be entirely intraparen-

chymal or form a polypoid endobronchial/endotracheal mass [250,253,254,261].

Some lesions have mediastinal or chest wall extension. Grossly, the mass is

usually well circumscribed but unencapsulated with variations in color and

consistency that depend upon the degree of inflammation, fibroblastic prolifera-

tion, and extent of collagenization (Fig. 5). The proliferation of names corre-

sponds to microscopic intra- and interlesional variability. Some tumors might

have a predominant spindle cell component; these spindle cells are often high-

lighted by positive vimentin and actin immunohistochemical stains [248].

Cytokeratin stains are positive in about one third of cases. Inflammatory areas

might be alternate with the fibrohistiocytic areas or they might predominate. The

plasma cell areas have been demonstrated to be polyclonal [262]. Although it is

not entirely clear that some authors have excluded other tumors such as malignant

fibrous histiocytoma or deceptively bland sarcomatoid carcinomas, atypical

features such as mitoses, necrosis, vascular invasion, and invasion into adjacent

thoracic structures have been reported. There have been rare instances of

spontaneous regression [259]. Complete excision is generally associated with

an excellent prognosis [259,263,264]. Partially resected lesions might show

slowly infiltrative growth that results in death caused by compromise of adjacent

vital structures [262,265]. In terms of etiology, some authors have suggested a

Fig. 5. Inflammatory myofibroblastic tumor. The lesion is well circumscribed with variegations in

color and consistency. This lesion might easily be mistaken for a more common lung carcinoma on

radiographs and initial gross examination.


reactive process [266,267]. Other authors regard these lesions as benign but

locally invasive tumors and have suggested a similarity to fibromatoses

[248,268]. Recent studies have demonstrated cytogenetic evidence for a clonal

origin [269] in addition to anaplastic lymphoma kinase expression [270,271]. In

the end, one might question whether this is truly one lesion with a diverse

histologic appearance or several distinct reactive or neoplastic entities with

overlapping histologic features [272,273].

Malignant lymphoma

The immunologically specialized bronchial associated lymphoid tissue is an

important component of the larger mucosal associated lymphoid tissue and, as

such, it can give rise to a variety of benign and malignant lymphoproliferative

disorders. Although it is more common to see secondary airway involvement or

disseminated disease from a nodal lymphoma, primary pulmonary lymphomas

have been well characterized. Low-grade lymphomas of the bronchial-associated

lymphoid tissue represent the vast majority of all primary pulmonary lymphomas

[274], but nearly every type of lymphoma has been reported, including primary

Hodgkin’s disease [275] and anaplastic large-cell lymphoma [276]. From a

practical point of view, lymphoid disorders must be considered within the

differential diagnosis of crushed endobronchial biopsies that consist of ‘‘small

blue cells’’ or undifferentiated large cells. By definition, there should be no

histologic evidence of nodal or systemic involvement for the diagnosis of primary

pulmonary lymphoma to be rendered.

Primary pulmonary melanoma

Metastatic melanoma is far more common than primary pulmonary melanoma,

but both lesions can present in an endobronchial location and patients tend to

be symptomatic on the basis of this endobronchial involvement [120,142,

144,277,278]. The tumor can be confused with other more common lung tumors

such as carcinoids or non–small-cell lung cancer, especially when the evaluation

is made on small biopsy samples [48,279]. The diagnosis of primary pulmonary

melanoma is based upon the absence of a melanoma of the skin, eye, or other site

and the finding of a solitary tumor that has at least some endobronchial

component. As Wilson and Moran point out in their review of eight cases, these

criteria for diagnosis—in particular the demonstration of an in situ component—

can be difficult to fulfill [279]. Age of patients in these series has ranged from the

30s to the 80s, and there has been an equal incidence in men and women. Some

of the lesions had a large, central, endobronchial component [278,279]. The

overall prognosis for primary pulmonary melanoma is poor in most circum-

stances, but there have been some reported exceptions. In Wilson and Moran’s

series, one out of eight patients was alive with no evidence of disease at

108 months of follow-up care. Jennings et al reported a 30% survival rate after

complete resection.


Summary

This article provides a broad overview of tumors that can involve the tra-

cheobronchial tree. For the most part, the clinical, radiographic, and endoscopic

presentation of these rare tumors does not differ significantly from the more

common tumors of the lung. Appropriate classification of many tracheobronchial

tumors ultimately requires complete sampling and a thorough microscopic

evaluation. The introduction of ancillary diagnostic techniques such as immuno-

histochemistry and molecular analysis will continue to refine tumor classification.

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Epithelial and Soft Tissue Tumors of the Tracheobronchial Tree