Epithelial and soft tissue tumors of the tracheobronchial tree

Transcription

1 Chest Surg Clin N Am 13 (2003) 1 40 Epithelial and soft tissue tumors of the tracheobronchial tree Leslie Litzky, MD Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 6 Founders Pavilion, 3400 Spruce Street, Philadelphia, PA , 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]. address: lalitzky@mail.med.upenn.edu /03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S (02)

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3 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 papilloma. 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 respiratory 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 photomicrograph highlights the branching central fibrovascular cores with a surface lined by benign squamous epithelium.

4 4 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 dysplastic, 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 differentiation [18]. Neither invasion of the pulmonary parenchyma nor hilar lymph nodes metastases has been reported.

5 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 ( 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 myoepithelial tumor are applied to tracheobronchial gland tumors that are composed exclusively of epithelial elements (monomorphic adenoma), myoepithelial elements (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

6 6 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 similar-appearing granular, eosinophilic cytoplasm; therefore, the diagnosis of oncocytoma cannot be definitively rendered without supporting immunohistochemical 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, ribbonlike 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].

7 L. Litzky / Chest Surg Clin N Am 13 (2003) Fig. 2. Squamous cell carcinoma, right mainstem bronchus. The central location allowed this tumor to reach an appreciable size before detection. Within the subsets of T1N0 and T1N1, patients with squamous cell carcinoma had a significantly better 5-year survival rate than patients with adenocarcinoma 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 differentiated 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 preponderance of male patients with a mean age of 58 years. These tumors were nearly

8 8 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 extrapulmonary 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, immunohistochemical 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 followup information that is available. Carcinoid tumor typical Carcinoid tumor is one of the most frequently encountered and best characterized 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],

9 L. Litzky / Chest Surg Clin N Am 13 (2003) but much attention has been directed towards this entity because of its overall better prognosis in comparison with other types of pulmonary epithelial malignancy. 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 neuroendocrine 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 neuroendocrine 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 mm 2 and no necrosis [1]. Although it is well recognized that some carcinoid tumors

10 10 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 show cytologic atypia, increased cellularity, or lymphatic invasion, these histologic 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 characteristics 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 mm 2 ), hypercellularity 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 welldifferentiated 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.

11 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 mm 2 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, ]. 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 mm 2 ) versus high (6 10 mitoses/ 2mm 2 ) 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-

12 12 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous 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 smallcell 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 smallcell 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 specimens 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-

13 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 neuroendocrine 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 mm 2, but in actual practice, the mitotic counts are usually much higher, averaging in the range of 75 per 2 mm 2. LCNEC is classified as a variant of largecell 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 neuroendocrine 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 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 [ ]. The discovery of a peripheral lesion should prompt clinical consideration 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

14 14 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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

15 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 predominantly 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; p ; with permission.)

16 16 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 adenosquamous 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]. Nevertheless, 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 Hochholzer 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 unresectable at the time of presentation were all dead of their disease within 16 months

17 L. Litzky / Chest Surg Clin N Am 13 (2003) [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 These tumors are extremely rare, with 15 cases reported in the literature to date [23, ]. 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. Microscopically, 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 histologically atypical lesions [19]. Both tumors were considerably larger (6 cm and 16 cm) than the benign lesions ( cm). Both tumors were poorly circumscribed 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 mm 2. 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

18 18 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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, respectively. 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, carcinosarcoma 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, immunohistochemistry 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 rhabdomyosarcoma. 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

19 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 carcinosarcomas 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 carcinosarcomas 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 predominate, 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 followup 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

20 20 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 endobronchial 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 extraadrenal 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 associated with Carney s triad [1]. Grossly, the tumors are 1 cm to 2 cm in size and have

21 L. Litzky / Chest Surg Clin N Am 13 (2003) irregular polypoid projections along a broad base [48]. On cut surface they are firm and white, often with focal areas of calcification or ossification. Microscopically, 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 [ ]. 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, ] 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 [ ]. 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

22 22 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 [ ]. 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. Microscopically, 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 malformation. 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 [ ]. Multiple hamartomas or endotracheal hamartomas have been reported infrequently [ ]. There is some association of pulmonary chondroid hamartomas with Carney s syndrome [148], hamartomas, and Cowden s syndrome [190].

23 L. Litzky / Chest Surg Clin N Am 13 (2003) 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 nondiagnostic. 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.

24 24 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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 [ ]. 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 [ ]. Leiomyoma/leiomyosarcoma/rhabdomyosarcoma Primary pulmonary leiomyomas are solitary tumors that occur as endotracheal/endobronchial or intraparenchymal lesions with approximately equal frequency [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, ]. 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 [ ]. 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 [ ]. 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 translocations in alveolar rhabdomyosarcoma. It is well documented that rhabdomyosarcomas can arise in locations devoid of striated muscle. Endobronchial,

25 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 [ ]. Nevertheless, 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 [ ]. 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 hemangiopericytoma, 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 appearance 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, ]. 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 L. Litzky / Chest Surg Clin N Am 13 (2003) 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

26 26 L. Litzky / Chest Surg Clin N Am 13 (2003) 1 40 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, ]. Tissue assays for the characteristic 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 pseudotumor [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, lymphocytes, 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

27 L. Litzky / Chest Surg Clin N Am 13 (2003) there is a wide reported age range that includes infants and the elderly [250,251, ]. 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 intraparenchymal 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 proliferation, and extent of collagenization (Fig. 5). The proliferation of names corresponds to microscopic intra- and interlesional variability. Some tumors might have a predominant spindle cell component; these spindle cells are often highlighted 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.