Squamous Cell Carcinoma

Probably because of changes in the smoking habits of the public, with a greater preference for filtered cigarettes in the last 35 years,⁷ SCC is no longer the most common type of lung cancer and has been eclipsed by ACA in recent years.^25,31 However, SCC has retained its classic clinicopathologic attributes. These include a tendency for multifocal but clonal in situ disease in the bronchial mucosa, often preceding the appearance of a discrete mass by several years, and a propensity to arise in large central airways proximal to the subsegmental bronchi. Because of the common presence of an endobronchial tumor mass, obstructive pneumonia is a relatively common accompaniment of this neoplasm, but it is not pathognomonic. “Pure” SCC may originate in the peripheral pulmonary parenchyma as well, and rare examples are even subpleural.³

Squamous cell cancer of the lung has an irregular, often friable, gray-white cut surface, commonly showing a large area of central necrosis, with or without cavitation (Fig. 16-1). The surrounding pulmonary parenchyma is frequently tethered to the mass, giving it a “spiculated” appearance that may be well seen on radiographic images (Fig. 16-2). Microscopically, SCC is defined by its resemblance to stratified squamous epithelium of the upper airway, but with disordered architectural and cytologic maturation (Figs. 16-3 to 16-6). Anucleate keratin and squamous pearls are observed in better differentiated lesions, which account for a minority of pulmonary carcinomas. Poorly differentiated SCC may be extremely difficult for the pathologist to distinguish from high-grade ACAs, small cell carcinomas, or large cell undifferentiated carcinomas (LCCs), because they commonly take the form of rather nondescript proliferations of primitive epithelioid cells of varying size, arranged in nests and sheets, with no other distinguishing features. In the absence of special studies, one may have to use the default terminology of “poorly differentiated carcinoma, not further specified,” in the frozen section laboratory and in small biopsies of such lesions. Recognized and distinct subtypes of poorly differentiated SCC include spindle cell and pleomorphic (sarcomatoid) forms^32–35 (see Chapter 14); adenoid-acantholytic (pseudoglandular) variants (Fig. 16-7)³⁶; a pseudovascular (angiosarcoma-like) subtype (Fig. 16-8)^36,37; “lymphoepithelioma-like” carcinoma (Fig. 16-9)³⁸; and a basaloid form (Fig. 16-10) (“small cell squamous carcinoma” or “basaloid squamous cell carcinoma”)³⁹ that is analogous to primary poorly differentiated SCC of the anorectum, hypopharynx, thymus, and other anatomic sites. Other than presenting special problems in microscopic differential diagnosis, these tumor variants have no singular clinical significance in comparison with other high-grade carcinomas.

Figure 16-1 A, Thoracic computed tomogram showing a large centrally cavitary squamous cell carcinoma (SCC) of the right lung. B and C, Gross photographs of pulmonary SCCs demonstrating characteristic central necrotic cavitation. D, Macroscopic photograph of another SCC, demonstrating central location and lymphangitic growth of tumor centripetally from the main mass.

Figure 16-2 A, Computed tomogram demonstrating prototypical radial “spiculation” of pulmonary adenocarcinoma. B, A gross photograph of resected pulmonary adenocarcinoma demonstrates the irregular (“spiculated”) periphery of the lesion and foci of entrapped anthracotic pigment.

Figure 16-3 A and B, Photomicrographs of well-differentiated squamous carcinoma showing obvious keratinization.

Figure 16-4 A and B, Moderately differentiated squamous cell carcinomas (SCCs) of the lung. The tumor cells have higher nucleocytoplasmic ratios and less keratinization than well-differentiated SCCs do.

Figure 16-5 A, Poorly differentiated squamous cell carcinoma (PDSCC) showing only focal keratinization and predominant composition by primitive epithelial cells. B, PDSCC comprising groups of relatively primitive polygonal cells invading the soft tissue of the chest wall. C, Only very focal keratinization is apparent in this PDSCC. D, PDSCC with sarcomatoid features, presenting difficulty in recognition of the lesion as epithelial (see Chapter 14).

Figure 16-6 A, Fine-needle aspiration biopsy (FNAB) of moderately differentiated squamous cell carcinoma. The tumor contains elongated “tadpole” cells and shows focal cytoplasmic orangeophilia. B, This FNAB of poorly differentiated squamous cell carcinoma manifests high nucleocytoplasmic ratios and cellular monotony; keratinization is inapparent in this photograph. (Images compliments of Dr. Diva Salomao, Austin, MN.)

Figure 16-7 A and B, Adenoid (pseudoglandular/acantholytic) squamous cell carcinoma of the lung demonstrating dyshesion of the tumor cells in such a way that the lesions focally resemble gland-forming neoplasms.

Figure 16-8 A and B, The adenoid squamous cell carcinoma subtype shown here is called “angiosarcoma-like” or “pseudovascular” because its particular version of intercellular dyshesion simulates the image of an endothelial malignancy.

Figure 16-9 A, Lymphoepithelioma-like carcinoma (LELC) of the lung showing syncytia of polygonal neoplastic cells with vesicular nuclear chromatin and prominent nucleoli, which are interspersed with mature lymphocytes. B, Cytokeratin immunostaining demonstrates a characteristically “interlocking” pattern of cellular reactivity. C, This tumor variant is considered a subtype of large cell undifferentiated carcinoma by some observers, but it has a distinctive cytologic monomorphism. D, A fine-needle aspiration biopsy of LELC shows many “naked” tumor nuclei and “smeared” intratumoral lymphocytes.

Figure 16-10 A, Basaloid squamous cell carcinoma of the lung demonstrating a typically organoid growth pattern with prominent foci of geographic necrosis and a composition dominated by small polyhedral cells. B, Zones of centrilobular necrosis are well seen in this image of basaloid squamous cell carcinoma. C, Deposition of intercellular basal lamina is relatively common in basaloid squamous cell carcinoma, potentially causing confusion with such other tumor entities as adenoid cystic carcinoma. D, Peripheral palisading of nuclei is evident in tumor cell nests of basaloid carcinoma.

For unknown reasons, SCC has a greater association with selected hereditary syndromes than do other forms of lung carcinoma.^11–21 These conditions are extremely rare causes of pulmonary neoplasia, but they include such disorders as Muir-Torre syndrome, von Hippel-Lindau disease, and dysplastic nevus (“atypical mole”) syndrome. In one of them—Muir-Torre syndrome—immunohistochemical analyses can be done for the absence of nucleic acid mismatch repair proteins in the tumor cells. The three most commonly assessed gene products are MLH1, MSH2, and MSH6 (Figs. 16-11 and 16-12).

Figure 16-11 Loss of the DNA mismatch repair protein MLH1 in squamous carcinoma of the lung in a patient with Muir-Torre syndrome. Note the nuclear staining of background normal lymphocytes.

Figure 16-12 Loss of another DNA mismatch repair protein, MSH2, in pulmonary squamous cell carcinoma in the context of Muir-Torre syndrome. Note the nuclear staining of normal epithelium.

Nonbronchioloalveolar Adenocarcinomas

As stated earlier, ACA has now successfully eclipsed SCC as the most common form of monodifferentiated lung cancer. In North America and Europe, most ACAs are predominantly peripheral parenchymal masses; however, interestingly, histologically identical lesions in India and Asia are as likely to be central as peripheral in location. Grossly, ACA typically has an irregularly lobulated configuration, with a gray-white cut surface (Fig. 16-13). Anthracotic pigment is commonly entrapped in the tumor mass as well, but foci of necrosis and hemorrhage are seen only in large (>5 cm) lesions. A relationship to tubular airways is only rarely obvious. Close inspection may also demonstrate the presence of “satellite” nodules around the main tumor mass; however, this phenomenon may be a reflection of the tendency for pulmonary ACA to be synchronously or metachronously multifocal, either in one lobe of the lung or in both lungs. The latter statement applies particularly to a special subtype of ACA, bronchioloalveolar carcinoma (BAC; discussed later). One peculiar and uncommon gross presentation of pulmonary ACA that merits special mention is its “pseudomesotheliomatous” form, wherein the pleurotropic growth of extremely peripheral intrapulmonary tumors creates a “rind” of tumor tissue surrounding the lung (Fig. 16-14). This virtually perfectly simulates the appearance of mesothelioma, both intraoperatively and radiographically.^40–42

Figure 16-13 A, Plain-film chest radiograph showing a solitary peripheral nodular mass in the right lower lung field, representing primary adenocarcinoma. B, This computed tomograph from another patient with primary pulmonary adenocarcinoma shows a “spiculated” mass in the right lung field. C, Peripheral (subpleural) adenocarcinoma of the lung is shown in this gross photograph. Anthracotic pigment has been incorporated into the mass. The tumor “tethers” and puckers the overlying visceral pleura (arrow).

Figure 16-14 A, This gross photograph of a “pseudomesotheliomatous” (pleurotropic) adenocarcinoma of the lung shows a neoplasm that encompasses the lung parenchyma, yielding a macroscopic image that is identical to that of true mesothelioma. B, Glandular arrays of tumor cells are present in the pleura in the absence of a definable intraparenchymal lesion in “pseudomesotheliomatous” adenocarcinoma of the lung. High-magnification view of an infiltrating malignant gland in pleurotropic adenocarcinoma (inset). C, An additional microscopic view of pleurotropic adenocarcinoma (PTA) simulating mesothelioma. D, Immunoreactivity for MOC-31 distinguishes PTA, which is labeled for that marker, from mesothelioma, which is not.

Bronchioloalveolar carcinoma is considered as a distinct entity subsequently. Microscopically, there are several other currently recognized subtypes of pulmonary ACA:

Figure 16-15 A, A fine-needle aspiration specimen from acinar-type primary adenocarcinoma of the lung shows a three-dimensional cell group comprising atypical polygonal cells with prominent nucleoli. B, This well-differentiated acinar (usual type) adenocarcinoma of the lung demonstrates easily seen glandular lumina.

Figure 16-16 A to D, Micropapillary adenocarcinoma of the lung, shown here, is now considered an entity distinct from bronchioloalveolar carcinoma. It is distinctive in its potential to synthesize calcific psammoma bodies (B and D).

Figure 16-17 A to C, “Solid” pulmonary adenocarcinoma is composed of large sheets and nests of tumor cells with only very focal formation of glandular lumina. D, This “solid” adenocarcinoma comprises virtually undifferentiated small polygonal cells and contains “staghorn” blood vessels. The histologic differential diagnosis would include synovial sarcoma, among other entities.

Figure 16-18 A, “Fetal” adenocarcinoma of the lung is considered to be in the same general family of tumors as pulmonary “blastoma,” and is shown here in an adult patient as a peripheral nodule in the right upper lung field on a plain-film radiograph. B, The resected tumor is a solid, relatively well-demarcated, and homogeneous mass. C and D, Microscopically, fetal adenocarcinoma comprises closely apposed glandular arrays made up of compact columnar cells, resembling those seen in embryonic lungs. E and F, Fine-needle aspiration specimens of fetal adenocarcinoma show small cells with high nucleocytoplasmic ratios, dispersed chromatin, and a tendency to surround small central spaces. Cytologic differential diagnosis includes neuroendocrine and neuroectodermal lesions (see Chapter 13).

(A and B, Courtesy of Dr. Samuel A. Yousem, Pittsburgh, PA. E and F, Courtesy of Dr. Kim Geisinger, Winston-Salem, NC).

Figure 16-19 A and B, Primary “colloid”-type mucinous adenocarcinoma of the lung shows nests of polyhedral tumor cells that are suspended in pools of copious extracellular mucin. This image is analogous to that seen in primary lesions of the breast, gastrointestinal tract, and skin.

Figure 16-20 A and B, This rare primary pulmonary adenocarcinoma is composed of tumor cells with prominent intracytoplasmic mucin vacuoles, yielding a “signet ring cell” appearance.

Figure 16-21 A and B, “Secretory endometrial–like” adenocarcinoma of the lung. Clear cell change and a tendency for nuclei to assume a basal location within glands are typical.

However, more variants exist, such as clear cell and enteric (intestinal-like; Fig. 16-22).^47–52 In some cases, because of the overlap between these histologic groups and the appearance of metastatic ACAs in the lung, it may be extremely difficult for the pathologist to separate primary from secondary lesions. This is particularly true of enteric and signet ring cell tumors, which can closely imitate the attributes of gastric or colorectal carcinomas (see Chapter 17). Psammoma bodies can also be seen in primary papillary ACAs of the lung,^43,53 and these structures therefore raise the question of whether one is instead viewing a solitary metastasis from an occult tumor of the thyroid, ovary, or another location wherein psammomatous carcinomas are potentially found. Needless to say, in cases featuring multifocality of ACA in more than one lobe, this problem is even more striking. Special studies, including electron microscopy and immunohistology, are helpful in resolving this differential diagnosis. Ultimately, however, diagnostic reliance is also placed on such banal characteristics as peritumoral fibrosis and inflammation, which are more common in primary pulmonary lesions than in metastases.

Figure 16-22 A and B, “Enteric” primary adenocarcinomas of the lung featuring a composition by low-columnar tumor cells with basally oriented nuclei and mucin production. The overall image of the lesions is reminiscent of neoplasms arising in the gastrointestinal tract.

Pulmonary ACA may rarely involve the bronchial epithelium diffusely in a pagetoid fashion (Fig. 16-23).⁵⁴ Whether this represents intraepithelial spread of the tumor or multifocal synchronous growth is an open question, but pagetoid lesions are excruciating management problems because of the difficulty in obtaining tumor-free bronchial margins.

Figure 16-23 A, “Pagetoid” involvement of non-neoplastic but metaplastic-hyperplastic bronchial epithelium by dispersed intramucosal adenocarcinoma cells. B, The tumor cells label with the periodic acid/Schiff stain after diastase digestion, confirming the presence of epithelial mucin. A typical adenocarcinomatous mass lesion was present in the nearby parenchyma.

“Pseudomesotheliomatous” (pleurotropic) ACAs are indeed separable from true mesotheliomas using adjuvant pathologic techniques, particularly immunophenotyping and electron microscopy (Figs. 16-24 and 16-25 and Table 16-1).⁵⁵ Nonetheless, whether this exercise has any more than academic significance is an open question. Available therapies for both of these tumor types are suboptimal, and the only real significance of the differential diagnosis may be a medicolegal one. In the absence of asbestosis, pleurotropic ACA has no proven causal relationship to asbestos exposure.

Figure 16-24 The tumor depicted in Figure 16-14 shows diffuse immunoreactivity for carcinoembryonic antigen, as expected in most adenocarcinomas of the lung but not in mesotheliomas.

Figure 16-25 Electron photomicrograph of “pseudomesotheliomatous” adenocarcinoma in the pleura demonstrating short, nonbranching cell surface microvilli, structures typical of adenocarcinoma but not mesothelioma.

Bronchioloalveolar Carcinoma

Bronchioloalveolar carcinoma of the lung was initially described in the 1800s, but was most fully characterized as a distinct entity by Liebow in 1960.⁵⁶ Since that time, BAC has been the subject of intense interest and controversy. In particular, the pathologic criteria that apply to its diagnosis and how its histologic attributes relate to prognosis represent perhaps the two most contentious issues.^57–65

There are no particular distinguishing demographic features associated with BAC vis-à-vis other ACAs of the lung. They tend to occur in elderly individuals, with an essentially equal distribution by sex.^58,65 Contrary to reports in the 1970s⁶³—before such phenomena as “passive” tobacco exposure were recognized—there is a definite relationship between cigarette smoking and the genesis of this tumor, as is true of virtually all pulmonary carcinomas. Nonetheless, BAC is indeed over-represented (with regard to other histotypes of lung cancer) in patients who have never smoked and who have never lived with smokers. This point has raised the issue of whether other etiologic factors—in particular, infection with human papillomavirus—might account for the genesis of some BACs.

Radiologically and clinically, three discrete subsets of patients with BAC are recognized.^65,66 These include individuals who have chest radiographic findings and clinical symptoms suggesting pneumonia (fever, productive cough, and lobar or segmental consolidation; Fig. 16-26) as well as some patients with a solitary peripheral mass lesion (Fig. 16-27) and others with multiple rounded densities throughout one or both lung fields (Fig. 16-28). On computed tomograms, the latter lesions may assume a “Cheerio” shape, in that they commonly demonstrate small central areas of cavitation. Hence, BAC may simulate an infectious disease, represent a nondescript “coin” lesion of the lung, or imitate the pattern of metastases to the lung from an occult visceral neoplasm.

Figure 16-26 A, Pneumonia-like bronchioloalveolar carcinoma is seen as consolidation in the upper lobe of the right lung in this chest radiograph. B, Bilateral reticulonodular and consolidative lesions are seen in this thoracic computed tomogram from another patient with bronchioloalveolar carcinoma, resembling the changes of infiltrative non-neoplastic lung disease. C and D, The permeative, confluent, and consolidative nature of the tumor is evident in these gross photographs of affected lung.

Figure 16-27 A, This solitary ill-defined ground-glass lesion was diagnosed as a bronchioloalveolar carcinoma in this computed tomogram of the left lung. B, A scanning photomicrograph of solitary bronchioloalveolar carcinoma shows features that are similar to those of ordinary pulmonary adenocarcinoma, only lacking solid growth or definite areas of stromal invasion.

Figure 16-28 Multifocal synchronous bronchioloalveolar carcinoma presenting as multiple rounded nodules throughout both lung fields and simulating the radiographic appearance of a metastatic malignant tumor.

Histologically, two distinct cytologic subtypes of BAC are recognized: mucinous and nonmucinous.^57,58,62 These are of importance because of their clinical associations. Mucinous tumors (Fig. 16-29) are those that tend to assume a pseudopneumonic or multifocal/multinodular clinical appearance, whereas nonmucinous BAC (Fig. 16-30) is more commonly a solitary lesion. Furthermore, stage for stage, nonmucinous variants may show a more favorable clinical evolution.^62,67 The criteria for the distinction of BAC from “ordinary” pulmonary ACAs continue to be debated. In accord with current convention, we restrict the use of this diagnosis to neoplasms that demonstrate a mantling of pre-existing air spaces (“lepidic” or noninvasive growth) by single layers or limited strata and micropapillae of only modestly atypical cuboidal or columnar epithelial cells, with or without intracellular or extracellular mucin production. Intranuclear inclusions of cytoplasm containing surfactant proteins are also common.⁶⁸ Save for mucin production, such characteristics are shared by both forms of BAC, mucinous and nonmucinous (serous). Septal widening and sclerosis may be seen, especially with nonmucinous BAC, but there must be no desmoplasia or inflammation within or around the lesion if it is to be considered a bona fide BAC. Caution should be exercised in diagnosing BACs with central sclerosis because this is often a site of subtle early invasion. This demanding definition differs from that of some other observers, who have accepted the existence of a “sclerosing” BAC subtype.⁶⁹ Justification for more narrow requirements is gained from biologic data, which show worse behavior of “sclerosing” or “invasive” BAC than of nonfibrotic tumors.^57,70,71 Indeed, Clayton,⁵⁸ who devoted much attention to BAC, clearly stated that bronchioloalveolar carcinomas with sclerosis should be classified with other peripheral ACAs.

Figure 16-29 A to D, Mucinous bronchioloalveolar carcinoma shows a “lepidic” growth pattern, with tumor cells mantling pre-existing alveolar septa and production of abundant extracellular mucin.

Figure 16-30 A, This bronchioloalveolar carcinoma (BAC) demonstrates a “crazy-paving” pattern of parenchymal infiltration in a computed tomogram of the chest. B and C, Nonmucinous BAC shows mantling of alveolar septa by well-differentiated low-columnar tumor cells. Intranuclear invaginations of cytoplasm (“pseudoinclusions”) are again potentially visible histologically. D, A fine-needle aspiration biopsy specimen from nonmucinous BAC shows relatively bland and homogeneous polygonal cells that are arranged in three-dimensional profiles. Intranuclear invaginations of cytoplasm are present in some tumor cells.

Another traditional point of discussion pertaining to the microscopic features of BAC (particularly its mucinous form) is that this neoplasm is said to disseminate within the lung by “aerogenous” means. That is to say, tumor cells are believed to detach from a “mother lesion” and spread to other foci in the pulmonary parenchyma by the process of inhalation and exhalation. Some molecular analyses, however, have cast doubt on that premise and instead suggest that the lesions are multiclonal.⁷²

Other lesions that may be confused pathologically with BAC include foci of florid type II pneumocytic hyperplasia surrounding areas of diffuse alveolar damage⁷³ and interstitial fibrosing pneumonitides or organizing pulmonary infarcts⁷⁴; the proliferation known as “atypical adenomatous alveolar hyperplasia” (discussed later)⁷⁵; and the unicentric neoplasms known as “papillary alveolar adenoma” and “sclerosing hemangioma.”⁷⁶ The latter two entities are bland cytologically and show a sharp interface with the surrounding pulmonary parenchyma, unlike BAC. Another point that was often raised in the older literature on BAC concerned the great difficulty with which metastases to the lung could be distinguished from the former neoplasm. Selected immunohistologic markers—especially nuclear labeling for thyroid transcription factor-1 (TTF-1; Fig. 16-31) and cytoplasmic staining for napsin-A—are valuable in distinguishing BAC from metastases of extrapulmonary ACAs,^77–80 but that separation must ultimately rest on careful analysis of conventional clinicopathologic data.

Figure 16-31 Intense nuclear immunoreactivity for thyroid transcription factor-1 is present in this bronchioloalveolar carcinoma.

Prognostically, patients with multifocal or pseudopneumonic BACs have an outlook that is worse than that of patients with unicentric tumors of this type because many of the former lesions are inoperable. Furthermore, mucinous tumors tend to behave more aggressively—with a higher incidence of extrapulmonary metastasis—than nonmucinous BAC when they are matched by size and stage.^57,58 Overall, nonmucinous tumors measuring less than 3 cm in maximum dimension have a good prognosis, approximating 90% at 5 years. Indeed, the current surgical approach to such lesions is limited resection, principally by wedge excision (Fig. 16-32).^81–85

Figure 16-32 Limited wedge excision of small adenocarcinomas, as shown here, is currently used in some instances for solitary bronchioloalveolar carcinomas of less than 2 cm in maximum dimension.

The natural history of BAC is more protracted than that of more conventional pulmonary ACAs, and tumor-related fatalities will continue to accrue even at 10 years after diagnosis.^57,63 Nevertheless, in an often-cited study by Manning and colleagues,⁶² the 5-year survival rate for nonmucinous BAC was 72%, whereas only 26% of patients with mucinous tumors survived at that point.

Atypical Adenomatous Hyperplasia and Its Relationship to Bronchioloalveolar Carcinoma

Kitamura and colleagues⁸⁶ addressed the conceptual mechanistic relationship between topographically small atypical glandular proliferations of the lung—“atypical adenomatous hyperplasia” (AAH)—and BAC. Their model appeared to demonstrate a stepwise progression from AAH to BAC, with further evolution to invasive growth. That concept also had been advanced before, especially by Miller and colleagues,⁸⁷ who postulated that such a stepwise process existed in the lung in analogy to the adenoma-carcinoma sequence in the colon.

Atypical adenomatous hyperplasia must be differentiated from reactive or regenerative pneumocytic lesions, at one end of the spectrum, and from small bona fide ACAs, at the other. With regard to separation of AAH from various reactive lesions, Kitamura and co-workers⁸⁶ have emphasized the tendency of reactive lesions to include multiple cell types, including type II pneumocytes, ciliated cells, and mucinous cells, and they have described the relatively more conspicuous interstitial inflammation and edema in localized interstitial pneumonitis. Additional criteria that are found to be helpful in this context involve assessment of the lesional borders and patterns of fibrosis. There is a tendency for lesions of AAH to be more sharply circumscribed and for the mild interstitial fibrosis and inflammation to stop at the same boundary as the atypical alveolar cells. Conversely, reactive lesions tend to be less well defined, and the interstitial scarring extends beyond the areas of alveolar cell atypia. The individual cells in AAH, although less homogeneous than those in BAC, also tend to be more uniformly atypical than those of reactive hyperplasias (Figs. 16-33 and 16-34).

Figure 16-33 Atypical adenomatous hyperplasia, low power. There is mild interstitial thickening.

Figure 16-34 Aytpical adenomatous hyperplasia, higher power. The nuclei are less atypical, less crowded, and smaller than the cells of bronchioloalveolar carcinoma.

Gupta and colleagues⁸⁸ identified factors that favored the diagnosis of BAC over reactive changes in an evidence-based construct: multiple growth patterns; anisocytosis; nuclear atypia in 75% or more of the lesional cells; macronucleoli; and atypical mitoses. Conflicting information has emerged on the use of p63 immunostains to make this diagnostic distinction. Sheikh and colleagues⁸⁹ suggested that p63 positivity was restricted to reactive processes and absent in nonmucinous BAC, whereas Saad and coworkers⁹⁰ found p63 reactivity in 89% of cases of BAC.

A variety of chemotherapeutic agents can induce striking degrees of cytologic atypia, and this phenomenon is a well-documented pitfall in exfoliative cytology.^74,91 We have also seen several examples of pneumocytes with intranuclear cytoplasmic inclusions in clear-cut cases of organizing phase diffuse alveolar damage; hence, their presence should not be viewed as pathognomonic of neoplasia.

It is our view that the distinction between AAH and small nonmucinous BAC is conceptually arbitrary. Standard criteria that have been cited as useful in this distinction include uniformly atypical nuclei, large lesional size (>5 mm), and complex growth, with budding or tufting of tumor cells in the alveolar spaces in BAC but not AAH.^75,92 Kitamura and coworkers⁸⁶ suggested that a nuclear area of less than 40 μm² and a lesional diameter of less than 5 mm could effectively identify AAH as opposed to small BAC. Miller⁹³ also proposed a limit of 5 mm to separate “bronchioloalveolar cell adenoma” from BAC.

Nevertheless, morphometric and immunohistologic analyses have shown a synonymity rather than a disparity between AAH and nonmucinous BAC.^94,95 Similarly, molecular studies, which show some differences in statistical groups, have demonstrated many more shared features than differences.^96–100

The most important consideration of this discussion concerns the clinical significance of AAH. In practice, this lesion is often not appreciated until microscopic sections arrive on the pathologist’s desk, and they are seen in four main contexts:

To provide some understanding of the importance of atypical lesions, several points must be kept in mind. First, because most AAH lesions are found in patients undergoing resection of an obvious cancer, it is nearly an insurmountable challenge to arrive at any conclusions concerning their biology. The outcome of these cases will be determined by the characteristics of the grossly obvious tumors. Alveolar AAH lesions tend to be multifocal throughout both lungs but may be inapparent on gross examination, and can be easily missed, even with current radiologic imaging techniques. Therefore, short of bilateral lung transplantation, it is impossible to say what would constitute adequate surgical resection of such lesions. Given these realities, it is best for pathologists to be pragmatically conservative in the diagnosis of clinically inapparent AAH lesions as small BACs, despite the conceptual considerations noted earlier. It is important to emphasize, however, that such lesions can be multifocal and may have a relationship with subsequent multicentric BACs, underscoring the need for close follow-up to identify the possible appearance of metachronous tumors. On the other hand, proliferations that represent grossly observed lesions with compellingly atypical cytology should be designated as outright carcinomas.

In light of the current availability of biologic agents that can be used to treat lung cancer, it is appropriate to mention the genotypes of nonmucinous and mucinous BAC. In general, nonmucinous lesions demonstrate mutations in the epidermal growth factor receptor (EGFR) molecule, to which tyrosine kinase inhibitor (TKI) therapeutic agents are directed.^101,102 On the other hand, mucinous BAC manifests preferential aberrations in the K-ras gene and accordingly does not show a response to TKIs.¹⁰¹ Mutant EGFR protein overexpression, as indicated indirectly by strong cell membrane immunoreactivity in tumor cells, correlates to some degree, but very imperfectly, with in situ hybridization studies or polymerase chain reaction-based assays.¹⁰³

“Micropapillary” ACA of the lung was formerly considered by many observers to be a subtype of nonmucinous BAC. That nosologic approach has now changed,⁴³ occasioned by the demonstrably worse prognosis of micropapillary carcinoma.^104,105 Accordingly, the latter neoplasm is now regarded as a pathologic entity unto itself. In analogy to the diagnostic approach to BAC, a conclusive interpretation of micropapillary carcinoma should be avoided in cytologic specimens. Rudomina and colleagues¹⁰⁶ have shown that papillary profiles in the latter samples do not correlate well with a final diagnosis of micropapillary ACA.

Adenocarcinomas Associated with Scars

In the relatively recent past, it was taught that fibrous scarring in the lung—seen as a consequence of pneumonia, interstitial fibroproliferative diseases, or pneumoconioses—predisposed to ACA and had a directly causative role in the genesis of that tumor type.¹⁰⁷ Nevertheless, several investigators have concluded that the central fibrosis seen in “scar adenocarcinomas” (Fig. 16-35) is formed after initiation of the carcinoma and that it is the product of the tumor cells themselves.^108–110 At a practical level, there is no reason to suspect that localized fibrosing conditions in the lung are, in and of themselves, preneoplastic. However, it appears that an increased frequency of lung carcinoma may exist in patients with diffuse interstitial fibrosis—as seen in late-stage “usual interstitial pneumonia,” for example—over and above that associated with smoking alone.¹¹¹ Nevertheless, the relative weights of those potentially causal elements are still unclear.

Figure 16-35 A broad zone of fibroelastotic “scarring” is seen in the center of this pulmonary adenocarcinoma. Matrical changes such as this are a product of the tumor rather than a pre-existing condition.

With particular reference to asbestosis and silicosis, special forms of pulmonary interstitial fibrosis, our review of the aggregated literature leads to the conclusion that the risk of pulmonary carcinoma may (debatably) be increased by those conditions of the lung, although such an association does not prove causation. It is clear that cigarette smoking is, by far, the most significant carcinogenic factor in this specific context.¹¹²

Adenosquamous Carcinoma

Adenosquamous carcinoma (ASC) is a “composite” tumor, exhibiting simultaneous squamous and glandular differentiation in the same mass (Fig. 16-36). It accounts for no more than 5% of all lung cancers in most surgical series.^113–115 The clinical, radiographic, and gross pathologic attributes of ASC are most similar to those of “pure” ACAs of the lung. A point of contention with regard to this lesion is whether it is synonymous with high-grade mucoepidermoid carcinoma of the salivary glandular type. Our opinion is that those two neoplasms are typically separable. Salivary gland analog tumors in the lung, as considered subsequently, tend to arise in the large central airways, in contrast to the propensity for ASC to be peripheral. In addition, foci of lower-grade mucoepidermoid carcinoma are often present in the former, but not the latter, of these tumor types. The prognosis of pulmonary ASC is said to be adverse. In studies reported by Ishida and colleagues,¹¹³ Takamori and colleagues,¹¹⁵ and Cakir and co-workers,¹¹⁶ the survival of patients with adenosquamous tumors was statistically worse than that of individuals with “pure” ACAs or SCCs.

Figure 16-36 A, Low-power photomicrograph of adenosquamous carcinoma of the lung with a configuration like that of other non–small cell lung cancers. B, Closer inspection shows a bifid composition by obviously keratinizing squamous elements and gland-forming tumor cells, which are intimately admixed. C, Multiple glandular lumina, containing secretions, are present in the middle of an otherwise squamoid focus in adenosquamous carcinoma. D, A digested periodic acid/Schiff stain demonstrates the presence of epithelial mucin in another similar area of the tumor.

Large Cell Carcinoma

Large cell undifferentiated carcinomas account for approximately 15% of all lung cancers.¹¹⁷ As mentioned earlier, diagnostic use of the term “non–small cell carcinoma” has produced some confusion among poorly differentiated SCC, poorly differentiated ACA, poorly differentiated ASC, and true LCC. Accordingly, it has been suggested that the designation of “large cell carcinoma” should be employed restrictively as a synonym for LCC. An even more extreme point of view is that current pathologic tools for cellular analysis have made this diagnosis completely obsolete.^118,119

Large cell carcinomas are typically larger than 5 cm in maximum dimension, have a white-gray cut surface (which may be lobulated and resemble “fish flesh,” thus potentially simulating the appearance of a sarcoma or a hematolymphoid lesion; Fig. 16-37), and are rarely multicentric. Internal necrosis is a relatively common feature. Approximately 50% demonstrate a connection to a large tubular airway.

Figure 16-37 A, Gross photograph of large cell carcinoma of the lung showing a fleshy tan-pink mass with no other distinguishing features. B, In another patient with large cell undifferentiated carcinoma, the gross tumor has a “fish-flesh” appearance and surrounds the great vessels in the mediastinum.

Histologically, LCCs show a composition of large polygonal cells with vesicular chromatin, prominent nucleoli, discernible cytoplasmic borders, and by definition, a lack of glandular differentiation or keratinization (Fig. 16-38). They are typically arranged in sheets or large clusters, potentially exhibiting foci of central necrosis. Two distinctive subtypes also exist—giant cell carcinoma and clear cell carcinoma.

Figure 16-38 A to C, Large cell carcinoma of the lung showing formless sheets of pleomorphic polygonal cells with no evidence of keratinization or gland formation. D, A cohesive group of large pleomorphic cells is seen in this fine-needle aspiration biopsy specimen of large cell undifferentiated carcinoma.

Giant cell carcinoma was initially believed to be a separate clinicopathologic entity,^120,121 but that philosophy is no longer considered valid.¹²² Microscopically, this variant of LCC is composed of extremely pleomorphic large tumor cells, which are often multinucleated (Fig. 16-39). There is a regular admixture of polymorphonuclear leukocytes with the neoplastic elements, even in the absence of necrosis, suggesting tumoral synthesis of leukocyte cytokines, such as granulocyte colony–stimulating factor.¹²³ Parenthetically, this phenomenon can also be associated with systemic neutrophilia in association with the giant cell subtype of LCC. Neoplastic “cannibalism” may also be observed, wherein the giant tumor cells appear to engulf one another. One subtype of pulmonary giant cell carcinoma bears a close resemblance to choriocarcinoma of the gonads, complete with tumor synthesis of beta-human chorionic gonadotropin.¹²⁴

Figure 16-39 Giant cell carcinoma (GCC) of the lung. A, Sheets of undifferentiated tumor cells. B, Large neoplastic multinucleated cells. C, Gigantiform nuclei are apparent with numerous intratumoral neutrophils. D, A fine-needle aspiration biopsy specimen of GCC shows dyshesive tumor cells with a markedly variable cytologic appearance. Inflammatory cells are also abundant in this specimen.

Primary clear cell carcinoma of the lung (CCCL) is a diagnosis of exclusion, and it is likely that tumors with both squamous and glandular differentiation are included in that group. A number of other clear cell neoplasms of the lung, including some “carcinoids,” the benign “sugar tumor,” metastatic renal cell carcinoma, and metastatic “balloon cell” melanoma, must also be considered before making the diagnosis of CCCL.^50,125–129 This can be accomplished by a combination of radiographic, electron microscopic, and immunohistologic evaluations. The overall clinicopathologic attributes of CCCL are comparable to those of LCC, not otherwise specified.

In the last two decades, it has been suggested that a subset of pulmonary large cell carcinomas that show occult neuroendocrine differentiation—as detected only by electron microscopy or immunohistology—should be nosologically separated from truly undifferentiated large cell tumors.^130–133 Hence, the terms “exocrine large cell carcinoma” (another synonym for LCC) and “endocrine large cell carcinoma” have entered use.¹³² In our opinion, “endocrine large cell carcinomas” are best specified as either high-grade “pure” neuroendocrine carcinomas, large cell type, or LCCs with occult neuroendocrine differentiation; those two entities are considered in more detail in another chapter on neuroendocrine neoplasms of the lung (see Chapter 13).

Selected large cell lung cancers have a “rhabdoid” phenotype¹³⁴ with eosinophilic hyaline inclusions in the cytoplasm and large vesicular nuclei with prominent nucleoli (Fig. 16-40). It is likely that this image represents a final common pathway of clonal evolution (“dedifferentiation”) in carcinomas of the lung, as in several other neoplasms demonstrating a rhabdoid configuration.¹³⁵ That conclusion is supported by the fact that other forms of carcinoma may be admixed with the rhabdoid elements (“composite” extrarenal rhabdoid tumors).¹³⁵ Moreover, nuclear expression of the INI1 gene—a tumor suppressor—is retained in “composite” extrarenal rhabdoid tumors (Fig. 16-41), but is consistently deleted in prototypical rhabdoid tumor of the kidney in children.^136–138

Figure 16-40 A to C, Large cell lung carcinoma with a “rhabdoid” phenotype in which globular eosinophilic cytoplasmic inclusions displace the nuclei of the tumor cells. D, A fine-needle aspiration biopsy specimen contains similar cells, which are dyshesive. The cytopathologic differential diagnosis includes metastatic neoplasms with a potentially rhabdoid appearance, most notably, amelanotic melanoma.

Figure 16-41 A,

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