Pathologic Classification of Lung Malignancies and Special Pathologic Procedures


  • The lung can be the site of origin of a variety of benign and malignant neoplasms of epithelial, mesenchymal, lymphoid, and other origins. These neoplasms are currently classified according to the very comprehensive classification scheme issued by the World Health Organization (WHO) in collaboration with the International Academy of Pathology and the International Association for the Study of Lung Cancer. However, for practical purposes, the majority of lung neoplasms are malignant epithelial neoplasms comprising only four carcinoma cell types: adenocarcinomas, squamous cell carcinomas, large cell carcinomas, and small cell carcinoma (SCLC). It remains controversial whether the subclassification of pulmonary carcinomas other than SCLC is of current clinical value in terms of their biologic behavior or prognosis. Indeed, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma are usually aggregated together in many clinicopathologic studies under the general category of non–small cell carcinomas (NSCLC).

  • The WHO classification scheme of neuroendocrine tumors of the lung is somewhat confusing. Although these neoplasms are generally considered as part of a spectrum of neoplasms ranging from low-grade malignancies such as typical carcinoid tumors, intermediate malignancies such as atypical carcinoid tumor, and high-grade neuroendocrine neoplasms such as SCLC and large cell neuroendocrine carcinoma, these neoplasms are categorized in three different subgroups: carcinoid tumor, SCLC, and large cell carcinoma. This problem is compounded by the overlap in the morphologic features of some of these neoplasms, resulting in considerable interobserver variation diagnostic problems.


  • Lung neoplasms are generally classified on the basis of their gross pathology and the histopathologic features observed with light microscopy on pathology slides stained with hematoxylin and eosin. The value of histochemistry, immunohistochemistry, and electron microscopy for the diagnosis and subclassification of lung neoplasms is limited in daily clinical practice. The pathologic evaluation of lung neoplasms includes a careful gross description that includes information about the tumor size and location and its relationship to adjacent structures such as the pleura and the airways.

  • Microscopic examination of neoplasms requires evaluation of the growth features of the tumor under relatively low-power microscopy (e.g., 4× to 20×) and observation of the cytologic characteristics of the neoplastic cells under higher power light microscopy (e.g., 400× to 1000×). The growth features of a neoplasm are most important for the tumor classification. For example, a squamous cell carcinoma, as it will be discussed below, is diagnosed in the presence of irregular nests of tumor cells that exhibit keratinization, intracellular bridges, and other growth features; adenocarcinomas are diagnosed in the presence of neoplastic cells that grow into acini or papillary structures; and neuroendocrine neoplasms are composed of cells arranged in nests, trabeculae, pseudorosettes, and other structures. The nuclear features of cells under high-power light microscopy are generally useful to distinguish them from non-neoplastic cells. Malignant cells usually exhibit increased cellular size, hyperchromasia, macronucleoli, irregular nuclear membranes, scanty cytoplasm and high nucleo/cytoplasmic ratio (N/C ratio). The cytoplasmic characteristics of tumor cells are generally useful, in addition to the tumor growth features under low-power microscopy for classification of cell type. For example, the cells of squamous cell carcinomas generally exhibit abnormal cytoplasmic keratinization, resulting in a densely eosinophilic cytoplasm, whereas the cytoplasm of the cells of adenocarcinomas can exhibit characteristic intracytoplasmic vacuoles.

  • Histochemical stains are of limited value for the diagnosis and classification of lung tumors. Mucicarmine and diastase-PAS stains can be helpful for the distinction between poorly differentiated adenocarcinomas, which exhibit intracytoplasmic red vacuoles with both stains, from large cell carcinomas and squamous cell carcinomas. Other histochemical stains such as Grimelius and other silver stains developed for the detection of intracytoplasmic neuroendocrine granules with light microscopy, are of limited value and have been mostly replaced by modern immunohistochemical techniques.

  • Immunohistochemical stains allow for the identification and localization of specific nuclear and cytoplasmic antigens in tissue sections, using detection methods such as peroxidase antiperoxidase, avidin biotin complex, and other chromogenic methods. Positive reactivity is interpreted in the presence of brown or red intracytoplasmic or intranuclear staining. These methods are currently used for the diagnosis and subclassification of selected lung neoplasms such as SCLC, and the differential diagnosis from metastatic lesions to the lung from primary lung carcinomas. For example, the cells of metastatic breast carcinomas can exhibit nuclear immunoreactivity for estrogen receptor and progesterone receptor, whereas primary adenocarcinomas of the lung generally exhibit nuclear immunoreactivity for thyroid transcription factor-I (TTF-I). Neuroendocrine lung neoplasms generally exhibit cytoplasmic immunoreactivity for synaptophysin, chromogranin, CD56 and other epitopes.


Squamous Carcinoma In Situ

  • Squamous cell carcinoma of the lung develops through the sequence of squamous metaplasia and dysplasia of the bronchial epithelium ( Fig. 22-1 ).

    Figure 22-1

    Squamous metaplasia of the bronchial epithelium. The normal pseudostratified columnar epithelium has been replaced by squamous epithelium with keratinization. Squamous cell carcinoma of the lung is thought to develop through the sequence of squamous cell metaplasia, dysplasia, and squamous cell carcinoma in situ (hematoxylin and eosin, 200×).

  • Squamous dysplasia is characterized by the presence of disorganized growth within the epithelium. Dysplastic cells have altered nuclear polarity, variable nuclear size, and increased mitotic activity above the basal layer ( Fig. 22-2 ).

    Figure 22-2

    Bronchial epithelium with severe dysplasia. The left portion of the photomicrograph shows normal ciliated epithelium with abrupt transition to a dysplastic epithelium showing thickening of the bronchial wall and disorganized growth by atypical cells by enlarged hyperchromatic nuclei, loss of polarity and mitotic figures. This lesion is a precursor of squamous cell carcinoma (hematoxylin and eosin, 200×).

  • The grade of dysplasia is usually classified according to the extent of the dysplastic cells within the bronchial epithelium; mild dysplasia involves only the lower third of the epithelium, moderate dysplasia involves the middle two thirds of the epithelium, and high-grade dysplasia involves the entire thickness of the epithelium.

Atypical Adenomatous Hyperplasia

  • Atypical adenomatous hyperplasia (AAH) is considered a precursor of adenocarcinoma of the lung.

  • It is characterized by the presence of atypical pneumocytes with enlarged nuclei showing some hyperchromasia and focal nuclear pseudoinclusions, scanty cytoplasm with high N:C ratio and frequent hobnail features ( Fig. 22-3 ).

    Figure 22-3

    Atypical adenomatous hyperplasia. The lesion measured approximately 3 mm in size. It shows the presence of hyperplastic pneumocyte type II cells with hyperchromatic, enlarged nuclei with increased nuclear:cytoplasmic ratio. The degree of atypia is less severe than seen in cases with bronchioloalveolar carcinoma (hematoxylin and eosin, 200×).

  • Areas of AAH are frequently small in size, usually smaller than 5 mm in diameter.

  • The stroma exhibits no significant fibrosis or inflammation.

  • The cells of AAH can exhibit normal genotypic expression, such as immunoreactivity for p53 protein; these immunostains are not helpful for the distinction from bronchioloalveolar carcinoma.

Diffuse Pulmonary Neuroendocrine Cell Hyperplasia

  • Diffuse pulmonary neuroendocrine cell hyperplasia (DIPNECH) is an unusual syndrome characterized by the presence of multifocal areas of neuroendocrine cell hyperplasia within the lung. The neuroendocrine cells can present as isolated cells within the bronchiolar epithelium as neuroendocrine bodies or as small pulmonary tumorlets ( Fig. 22-4 ).

    Figure 22-4

    Carcinoid tumorlet in a patient with diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH). The lesion is composed of small nests of round cells with minimal nuclear atypia, admixed with a fibrotic stroma (hematoxylin and eosin, 40×).

  • These lesions are thought to be neoplastic precursors of carcinoid tumors and, less likely, high-grade neuroendocrine carcinomas of the lung.


Squamous Cell Carcinoma

Key Pathologic Features

  • Also known as epidermoid carcinoma

  • Malignant epithelial cells show cytoplasmic dyskeratosis, keratin pearl formation, and/or intracellular bridges

Summary of Epidemiology

  • Second most common form of carcinoma of the lung.

  • More than 90% of squamous cell carcinomas develop in cigarette smokers.


  • The majority of squamous cell carcinomas occur as central tumors arising from a major airway (so-called bronchogenic carcinoma).

  • Tumors can also develop in subsegmental bronchi or appear as peripheral lung nodules in a minority of patients.

Gross Features

  • Usually located in close proximity to a bronchus with involvement of the bronchial wall ( Fig. 22-5 )

    Figure 22-5

    Squamous cell carcinoma of the lung. The lesion has a small endobronchial component and extends into the adjacent lung parenchyma.

  • The bronchial wall can exhibit a nodular area, a plaque, a polyp, an area of ulceration, or less frequently, diffuse longitudinal involvement of the bronchial wall, resulting in extensive bronchial wall narrowing.

  • The lung parenchyma adjacent to the involved bronchus shows a well-circumscribed mass with bosselated borders.

  • The surface of the tumor is usually somewhat dry, friable or firm, white or gray with patchy deposition of environmental pigment deposition and variable amounts of necrosis.

  • Squamous cell carcinomas can develop extensive central necrosis with cavitation, simulating a lung abscess or other cavitary lesions.

Histopathological Features

  • The tumor cells appear as cohesive sheets with irregular, infiltrating borders associated with an inflamed and fibrotic stroma ( Fig. 22-6 ).

    Figure 22-6

    Squamous cell carcinoma composed of solid sheets of malignant epithelial cells with round nuclei, prominent nucleoli, slightly eosinophilic cytoplasm, and formation of a keratin pearl (hematoxylin and eosin, 100×).

  • The individual tumor cells tend to be polygonal in shape or spindle shaped.

  • They characteristically exhibit intracellular bridges that have been shown under electron microscopy to represent tight intracellular junctions (desmosomes) ( Fig. 22-7 ).

    Figure 22-7

    Squamous cell carcinoma showing the presence of intercellular bridges between the tumor cells (hematoxylin and eosin, 400×).

  • The cytoplasm of the tumor cells is frequently keratinized, appearing as a densely red cytoplasm ( Fig. 22-8 ).

    Figure 22-8

    Squamous cell carcinoma showing the presence of dense eosinophilic cytoplasm in some of the tumor cells, indicative of abnormal keratin formation or dyskeratosis. The presence of intercellular bridges can also be seen (hematoxylin and eosin, 400×).

  • Well-differentiated squamous cell carcinomas tend to develop keratin pearls indicative of abnormal keratinization (parakeratosis) and be composed of cells with sharp cytoplasmic membranes and intercellular bridges ( Fig. 22-9 ).

    Figure 22-9

    Squamous cell carcinoma showing keratin pearl formation and stromal invasion (hematoxylin and eosin, 200×).

  • Squamous cell carcinomas may exhibit lymphatic invasion or vascular invasion; the latter is less frequent than in adenocarcinomas.

Cytologic Features

  • Because squamous cell carcinomas usually present as central lung lesions, the yield of sputum cytology, bronchial brushings and bronchial lavage is higher than for peripheral adenocarcinomas of the lung.

  • The tumor cells appear in smears as dyscohesive sheets or as individual cells with round to spindled nuclei showing hyperchromasia, occasional prominent nucleoli, and irregular nuclear borders ( Fig. 22-10 ).

    Figure 22-10

    Sputum cytology showing malignant epithelial cells, consistent with squamous cell carcinoma. The tumor cells exhibit large hyperchromatic nuclei with irregular nuclear membranes and anisocytosis. The cytoplasm is densely red, consistent with dyskeratosis. The tumor cells exhibit increased nuclear:cytoplasmic ratio (Papanicolaou stain, 400×).

  • The cytoplasm of the tumor cells tends to have sharp cytoplasmic borders and intracytoplasmic keratinization.

  • Pyknotic cells, tadpole cells, and keratin pearls can be found in keratinizing squamous cell carcinoma cases.

Histochemistry and Immunohistochemistry

  • Histochemistry is of limited value for the diagnosis of squamous cell carcinoma.

  • The lesions stain negative with mucicarmine and d-PAS stains, a useful finding to exclude the possibility of adenocarcinoma in poorly differentiated lesions.

  • The tumor cells can exhibit cytoplasmic immunoreactivity for pan-cytokeratin, cytokeratin 5-6, and thrombomodulin and nuclear immunoreactivity for p63.

  • Squamous cell carcinomas usually exhibit negative immunoreactivity for TTF-1.

Variants of Squamous Cell Carcinoma

  • Squamous cell carcinomas can present as papillary, clear cell, small cell, or basaloid lesions.

  • Papillary squamous cell carcinomas usually present as exophytic papillary lesions that tend to grow mostly endobronchially with minimal extension into the peribronchial pulmonary parenchyma; these lesions usually present at a lower stage than other NSCLCs.

  • Clear cell squamous cell carcinomas are composed mostly of clear cells and exhibit only focal areas diagnostic for squamous cell differentiation. These lesions stain negatively with mucicarmine and d-PAS stain, in contrast to adenocarcinomas with clear cells.

  • The small cell variant of squamous cell carcinoma is difficult to distinguish from SCLC and /SCLC, combined variant with a squamous cell carcinoma component. The presence of focal nucleoli in some of the tumor cells is a feature that is unusual in small cell neuroendocrine carcinomas of the lung.

  • The cells of the small cell variant of squamous cell carcinoma stain negatively with immunostains indicative of neuroendocrine differentiation (e.g., chromogranin, synaptophysin).

  • The diagnosis of SCLC, combined variant, is only rendered in the presence of two distinct neoplastic components within a lesion. This diagnosis is particularly difficult to establish in small transbronchial biopsies.

  • Basaloid squamous cell carcinomas are poorly differentiated lesions that can be difficult to distinguish from basaloid carcinoma, a variant of large cell carcinoma. The presence of keratinization in at least some of the tumor cells and intracellular bridges is an important diagnostic feature for squamous cell carcinoma and are absent in large cell carcinoma.

Evaluation of Tumor Grade and Stage

  • Tumor grade

    • Squamous cell carcinomas are usually graded as well-differentiated, moderately differentiated, and poorly differentiated lesions (grades I to III). It is controversial whether undifferentiated lesions (grade IV) should be classified as poorly differentiated squamous cell carcinomas or simply as undifferentiated large cell carcinomas.

    • Grading criteria are not well specified in the WHO publication. Keratinized lesions can be classified on the basis of the percentage of cells that exhibit keratinization (e.g., 0-25%, 25%-50%, 50%-75%, 75%-100%) akin to skin neoplasms, or based on their overall degree of cytologic atypia.

    • In our practice, squamous cell carcinomas are graded based on the subjective evaluation of cytologic atypia and relative proportions of keratinized cells within the lesions.

  • Tumor stage

    • Important pathologic features that need to be evaluated for the stratification of patients with squamous cell carcinoma into a particular pT category include the tumor size, presence or absence of pleural invasion, and distance to the carina.

    • Measurements of tumor size need to be based on the microscopic edges of the tumor, because squamous cell carcinomas can result in bronchial obstruction with postobstructive endogenous lipoid pneumonia. The latter can inadvertently be included in the measurements of maximum tumor diameter.

    • The distance to the carina or the presence of the tumor in the lower bronchus is difficult to evaluate in a lobectomy specimen. This information should be provided by the surgeon at the time of specimen submission.

    • The criteria for pleural invasion are somewhat unclear, and some pathologists classify tumors smaller than 3 cm as pT2 in the presence of focal, partial invasion of the pleural elastic tissues as demonstrated by special stains (e.g., elastic von Gieson [EVG] stains). In contrast, other pathologists require the presence of complete involvement of the pleura by a neoplasm that reaches the visceral pleural surface. This issue needs to be clarified in the next edition of the American Joint Commission on Cancer Staging Manual .

    • The evaluation of intrapulmonary, peribronchial, and mediastinal lymph nodes for the presence of metastasis is important for the classification of the pN status of a patient with squamous cell carcinoma of the lung. According to current American Joint Commission on Cancer (AJCC) guidelines, the presence of a few tumor cells within a lymph node is a result of direct tumor extension or lymphatic invasion and qualifies as a positive node. According to the location of the node, it would be staged as pN1, pN2, or pN3, as discussed elsewhere in this volume. In contrast, lymph nodes from patients with breast cancer are staged as positive only in the presence of tumor deposits larger than 2 mm in size. In these patients, the presence of a few tumor cells is classified as “isolated tumor cells” and lymph node deposits measuring from 0.2 mm to 2 mm as “micrometastasis”

    • In a preliminary study, NSCLC patients with isolated tumor cells or micrometastases had similar prognosis to those with pN0 disease.

Pathologic Prognostic and Predictive Features

  • To my knowledge, there are no consensus prognostic and predictive features for patients with squamous cell carcinoma of the lung, other than tumor stage.

Key Pathologic Features for Differential Diagnoses

  • Squamous cell carcinomas need to be distinguished from large cell carcinoma of the lung, adenocarcinoma, and other tumors.

  • The presence of individual cell keratinization and/or intracellular bridges are diagnostic features to distinguish squamous cell carcinoma from large cell carcinoma

  • Squamous cell carcinomas frequently exhibit necrosis and artifactual spaces that simulate glandular formation. These spaces are usually not lined by epithelial cells, as malignant glandular lesions are, and lack reactivity with mucicarmine and d-PAS stains.


Key Pathologic Features

  • Peripheral, subpleural tumor.

  • Glandular formation, papillary formation, lepidic growth feature, mucin production in the tumor cells.

Summary of Epidemiology

  • Adenocarcinoma is currently the most common histologic subtype of lung cancer.

  • The majority of cases develop in smokers.

  • Adenocarcinoma, particularly the bronchioloalveolar variant, more frequently develops in nonsmokers, particularly women, than squamous cell carcinoma and small cell carcinoma.

Histogenesis—Precursor Lesions

  • The histogenesis of pulmonary adenocarcinomas has been the subject of controversy. In the 1970s and 1980s, the lesions were thought to develop from pluripotential basal cells located in the bronchial epithelium. Electron microscopy findings suggested that the basal cells could differentiate into a glandular, squamous, or neuroendocrine phenotype, explaining the frequent heterogeneity seen in lung carcinomas.

  • The more recent literature supports the concept that adenocarcinomas probably develop from a preneoplastic lung lesion, AAH, that develops in small airways or peribronchiolar alveoli through the sequence of AAH, bronchioloalveolar carcinoma, and invasive adenocarcinoma.

  • AAH appears as ill-distinct nodules usually measuring less than 5 mm in diameter, although they can reach a size as large as 10 mm. The nodules of AAH exhibit pneumocyte type II with nuclear enlargement, hyperchromasia, nuclear pseudoinclusions resembling viral changes, focal nucleoli, increased N/C ratio, and nuclear stratification. The degree of cytologic atypia is less severe than that seen in bronchioloalveolar carcinoma.


  • The majority of pulmonary adenocarcinomas present as peripheral, subpleural lesions ( Fig. 22-11 ).

    Figure 22-11

    Peripheral adenocarcinoma of the lung showing focal central necrosis with cavity formation.

  • Up to 25% of primary adenocarcinomas can present as a peribronchial, more centrally located mass.

  • No consistent predilection for any particular lung lobe has been demonstrated.

Gross Features

  • Adenocarcinomas of the lung frequently present as peripheral, pigmented lesions with frequent retraction of the overlying pleura (so-called pleural puckering) ( Fig. 22-12 ). This “triad” can be remembered with the use of the triple “p” acronym (peripheral, pigmented, pleural puckering). Central areas of scarring are frequently present in adenocarcinomas ( Fig. 22-13 ).

    Figure 22-12

    Peripheral adenocarcinoma of the lung showing pigmentation of the tumor surface and indentation of the pleura (so-called pleural puckering).

    Figure 22-13

    Low-power photomicrograph of a well-differentiated adenocarcinoma of the lung showing central scarring (hematoxylin and eosin, 20×).

  • Adenocarcinomas usually have bosselated, irregular infiltrating margins.

Histopathologic Features

  • Adenocarcinomas are composed of large polygonal tumor cells with indistinct nuclear membranes and variable N/C ratio.

  • The tumor cells are arranged in acinar (glandular) spaces, papillary fronds, or solid cellular sheets ( Figs. 22-14 to 22-16 ).

    Figure 22-14

    Adenocarcinoma of the lung showing glandular space (acinar space) lined by malignant epithelial cells with large nuclei showing hypochromasia, prominent nucleoli, irregular nuclear membranes, amphophilic cytoplasm, marked variation in tumor size and shape (anisocytosis), and high nuclear:cytoplasmic ratio (hematoxylin and eosin, 200×).

    Figure 22-15

    Adenocarcinoma of the lung showing acinar spaces and finger-like projections (papillary feature) (hematoxylin and eosin, 200×).

    Figure 22-16

    Poorly differentiated adenocarcinoma of the lung, solid with mucin formation variant. Tumor cells form solid sheets without clear acinar or papillary features. Mucicarmine stain of this lesion showed positive reactivity in many of the tumor cells (hematoxylin and eosin, 400×).

  • The nuclei usually show prominent nucleoli and may exhibit nuclear pseudoinclusions that resemble “viral” changes.

  • The cytoplasm is typically vacuolated in well-differentiated adenocarcinoma, although a clear, amphophilic or even eosinophilic cytoplasm can be also noted in selected lesions ( Fig. 22-17 ).

    Figure 22-17

    Moderately differentiated adenocarcinoma of the lung with solid and focal glandular features. Please note the presence of numerous cells with clear cytoplasm (hematoxylin and eosin, 200×).

Cytologic Features

  • The cells of adenocarcinoma typically present in smears and other cytologic preparations as three-dimensional cellular clusters ( Fig. 22-18 ).

    Figure 22-18

    Fine-needle aspiration of a peripheral lung nodule showing malignant epithelial cells, which is consistent with adenocarcinoma. The tumor cells show nuclear overlap, round nuclei with hypochromasia, and prominent nucleoli, variation in tumor size and shape (anisocytosis), increased nuclear:cytoplasmic ratio, and indistinct cytoplasmic membranes (Papanicolaou stain, 400×).

  • The tumor cells tend to have large nucleoli and intracytoplasmic vacuoles, features that are useful for the distinction between adenocarcinoma and other forms of NSCLC.

Histochemistry and Immunohistochemistry

  • The presence of intracytoplasmic mucin detectable with mucicarmine and d-PAS stains can be helpful to confirm the diagnosis of adenocarcinoma, particularly in poorly differentiated neoplasms that are composed mostly of solid sheets of neoplastic cells and exhibit scanty glandular and/or papillary formation.

  • It remains controversial whether a poorly differentiated neoplasm that exhibits only rare cells with intracytoplasmic mucin should be classified as a large cell undifferentiated carcinoma or as a poorly differentiated carcinoma ( Fig. 22-19 ). These lesions are classified in our laboratory as large cell carcinomas unless approximately 10% of the tumor cells exhibit intracytoplasmic mucin.

    Figure 22-19

    Large cell carcinoma of the lung showing focal mucin secretion by the tumor cells. Unless this feature is present in a substantial number of the tumor cells, this type of lesion would not be classified as an adenocarcinoma, solid variant with mucin production in our laboratory (mucicarmine stain, 200×).

  • Pulmonary adenocarcinomas usually exhibit the following immunophenotype: cytokeratin 7 ( Fig. 22-20 ), cytoplasmic immunoreactivity, focal or negative cytoplasmic immunoreactivity for cytokeratin 20, and nuclear immunoreactivity for TTF-1 ( Fig. 22-21 ). This immunophenotype is seen in approximately 80% of the lesions and can be helpful to confirm the pulmonary origin of an adenocarcinoma and to distinguish it from metastatic lesions (e.g., breast, pancreas, other).

    Figure 22-20

    Adenocarcinoma of the lung showing keratin 7 immunoreactivity of the tumor cells (peroxidase antiperoxidase, 100×).

    Figure 22-21

    Adenocarcinoma of the lung showing nuclear immunoreactivity for thyroid transcription factor (TTF-1) (peroxidase antiperoxidase, 400×).

Variants of Adenocarcinoma

  • In addition to adenocarcinomas with acinar, papillary, and mixed features, the following variants of adenocarcinoma are recognized in the WHO classification: bronchioloalveolar carcinoma (BAC), mixed adenocarcinoma-BAC, solid adenocarcinoma with mucin production, fetal adenocarcinoma, mucinous (colloid) carcinoma, mucinous cystadenocarcinoma, signet-ring cell adenocarcinoma, and clear cell adenocarcinoma.

  • It is beyond the scope of this chapter to review the pathologic details of all these lesions. Mucinous (colloid) adenocarcinomas and signet-ring cell carcinomas of the lung are composed of cells with abundant intracytoplasmic mucin with or without a signet-ring cell configuration and the presence of abundant extracellular mucin secretion (so-called alveolar mucinosis). They can be difficult to distinguish from metastatic colloid adenocarcinomas of gastrointestinal, ovarian, or other origin; careful clinicopathologic correlation is required because mucinous adenocarcinomas of lung and other sites of origin frequently exhibit negative TTF-1 immunoreactivity and exhibit features seen in colonic adenocarcinomas, such as cytoplasmic immunoreactivity for cytokeratin 20 and nuclear immunoreactivity for CDX-2. The presence of cytoplasmic immunoreactivity for cytokeratin 7 is not seen in colonic adenocarcinomas but can be seen in carcinomas of lung, breast, ovary, pancreas, and other site of origin.

Evaluation of Tumor Grade and Stage

  • Adenocarcinomas are classified as well-differentiated, moderately differentiated, and poorly differentiated lesions (grades I to III). To my knowledge, there are no well-recognized criteria for this distinction, which is based on the degree of glandular and papillary formation and cytologic atypia.

  • Other details about the pathologic staging of NSCLC are discussed in the section on squamous cell carcinoma.

Pathologic Prognostic and Predictive Features

  • It is controversial whether tumor grade predicts the prognosis of patients with lung adenocarcinomas ( Figs. 22-22 to 22-24 ) .

    Figure 22-22

    Evaluation of the presence of pleural invasion is an important step in the pathologic staging of lung neoplasms. Photomicrograph of an adenocarcinoma showing partial pleural invasion without reaching the pleural surface. Partial invasion of the pleura, beyond the pleural elastic lamina, is considered in our laboratory as evidence of pleural invasion. A peripheral neoplasm, smaller than 3 cm in greatest dimension, would be staged as pT2 (hematoxylin and eosin, 100×).

    Figure 22-23

    Evaluation of nodal status is important for the pathologic staging of patients with lung neoplasms. Paratracheal lymph node showing metastatic poorly differentiated adenocarcinoma (pN2) (hematoxylin and eosin, 100×).

    Figure 22-24

    Bone biopsy showing metastatic adenocarcinoma (pM1) (hematoxylin and eosin, 40×).

  • The prognostic significance of lymphatic invasion is controversial ( Fig. 22-25 ).

    Figure 22-25

    Lymphatic invasion in a patient with adenocarcinoma of the lung (hematoxylin and eosin, 100×).

  • Vascular invasion has been associated with a poor prognosis in these lesions.

  • Immunostains for epithelial growth factor receptor (EGFR) may be a predictor of response to anti-EGFR drugs ( Fig. 22-26 ).

    Figure 22-26

    Adenocarcinoma of the lung showing membrane immunoreactivity of the tumor cells for epidermal growth factor receptor (EGFR) (peroxidase antiperoxidase, 100×).

Key Pathologic Features for Differential Diagnoses

  • The presence of glandular, papillary formation, or mucin secretion in the cytoplasm of neoplastic cells helps to distinguish pulmonary adenocarcinomas from squamous cell carcinomas, large cell carcinomas, and other NSCLC.

  • Immunostains and careful clinicopathologic correlation help to distinguish pulmonary adenocarcinomas from metastases.

Bronchioloalveolar Carcinoma of the Lung

Key Pathologic Features

  • BAC is currently classified as a variant of lung adenocarcinoma.

  • The diagnosis of BAC is established in the presence of lepidic growth of the tumor cells along alveolar septa with no significant alveolar fibrosis and lack of stromal invasion.

Summary of Epidemiology

  • BAC is not significantly associated with cigarette smoking.

  • BAC in Asian women appeared to exhibit particular genotypic changes discussed in other chapters of this book.

Histogenesis—Precursor Lesions

  • BAC develops from areas of AAH.

  • The differential diagnosis between AAH and small BAC, nonmucinous type can be difficult. Areas of AAH tend to exhibit smaller size (up to 10 mm in size and frequently less than 5 mm in size) and less cytologic atypia than is seen in small BAC. The interpretation of the degree of cytologic atypia is somewhat subjective and may result in diagnostic problems amongst different pathologists.


  • Similar to other adenocarcinomas of the lung.

Gross Features

  • BAC, nonmucinous type appears as ill-defined gray, nodular, soft areas that blend imperceptively with the adjacent pulmonary parenchyma ( Fig. 22-27 ).

    Figure 22-27

    Small peripheral bronchioloalveolar carcinoma of the lung, nonmucinous type, presenting as an ill-defined, soft subpleural nodule.

  • BAC, mucinous type, present as more distinct gray-yellow, glistening, soft nodules that exude mucinous materials. Large BAC mucinous type can simulate pneumonia due to the presence of large areas of gray-yellow consolidation, with indistinct borders ( Fig. 22-28 ).

    Figure 22-28

    Bronchioloalveolar carcinoma of the lung, mucinous type presenting as an ill-defined area of gray-yellow consolidation. Please note the presence of interstitial fibrosis in the remainder of the lung. The tumor presents in a patient with usual interstitial pneumonia.

Histopathologic Features

  • Nonmucinous BAC is characterized by the presence of polygonal cells with round nuclei showing prominent nucleoli and frequent nuclear pseudoinclusions. The cells have increased N/C ratios with frequent hobnail changes. The latter are characterized by the presence of cells with nuclei that protrude into the alveolar lumen and a basally located cytoplasm ( Fig. 22-29 ).

    Figure 22-29

    Bronchioloalveolar carcinoma, non-mucinous type showing the presence of polygonal tumor cells with round nuclei, hobnail features, growing along the inner surface of alveolar spaces (so-called lepidic growth feature) (hematoxylin and eosin, 100×).

  • The cells of BAC tend to show focal nuclear pseudostratification ( Fig. 22-30 ).

    Figure 22-30

    Bronchioloalveolar carcinoma, nonmucinous type, showing pseudostratification of the tumor cells. The tumor cells exhibit round nuclei with prominent nucleoli and mild anisocytosis (hematoxylin and eosin, 200×).

  • By definition, no significant interstitial fibrosis or stromal invasion is present in BAC, nonmucinous type.

  • Mucinous BAC is characterized by the presence of columnar epithelial cells with basal nuclei and tall columnar cytoplasm growing along alveolar septa in a lepidic growth pattern ( Fig. 22-31 ). The nuclei have frequent nucleoli and occasional nuclear pseudoinclusions. The cytoplasm is abundant, clear, with intracytoplasmic vacuoles, and low N/C ratio ( Fig. 22-32 ). The alveolar spaces adjacent to the tumor are frequently filled with abundant mucin. Mucinous BAC can be particularly difficult to distinguish from metastasis (e.g., gastrointestinal malignancies, pancreatic neoplasms, others).

    Figure 22-31

    Bronchioloalveolar carcinoma of the lung, mucinous type, showing tumor cells growing in a lepidic pattern. Please note the presence of abundant intra-alveolar mucin (hematoxylin and eosin, 20×).

    Figure 22-32

    Bronchioloalveolar carcinoma, mucinous type, showing columnar tumor cells with intracytoplasmic mucin–containing vacuoles. Please note the presence of minimal nuclear anisocytosis (hematoxylin and eosin, 400×).

Cytological Features

  • BAC, nonmucinous type, can be particularly difficult to diagnose in cytologic samples, because the tumor cells frequently exhibit minimal atypia ( Fig. 22-33 ). The presence in fine-needle aspiration biopsies, bronchoalveolar lavage, or other cytologic samples of many monotonous pneumocytes with mild atypia can be useful to render the correct diagnosis.

    Figure 22-33

    Fine-needle aspirate biopsy of bronchioloalveolar carcinoma of the lung, nonmucinous type. The tumor cells appear as a flat sheet of epithelial cells with slightly enlarged nuclei, prominent nucleoli, and minimal anisocytosis. These lesions can be difficult to distinguish from reactive pneumocyte hyperplasia (Papanicolaou stain, 400×).

  • Mucinous BAC can be diagnosed in cytologic samples in the presence of large atypical epithelial cells with large nucleoli and abundant mucin secretion. These lesions cannot be distinguished on cytologic preparations from invasive adenocarcinomas.

Histochemistry and Immunohistochemistry

  • The cells of mucinous BAC exhibit abundant intracytoplasmic mucin detectable with mucicarmine stain and d-PAS stain.

  • The cells of nonmucinous BAC stain negative with mucicarmine stain and d-PAS stain, and exhibit the same immunophenotype as other pulmonary adenocarcinomas.

  • The tumor cells of BAC, mucinous type tend to lack TTF-1 immunoreactivity. The tumor cells can exhibit cytoplasmic immunoreactivity for cytokeratin 20 and villin, features usually seen in gastrointestinal adenocarcinomas. However, the tumor cells of primary mucinous BAC usually exhibit cytoplasmic immunoreactivity for cytokeratin 7, a feature not seen in colonic adenocarcinomas.

Evaluation of Tumor Grade and Stage

  • BAC usually exhibit low-nuclear grade (grade I) with minimal pleomorphism of the tumor cells.

  • They are staged according to the AJCC guidelines for NSCLC; details about pathologic staging are discussed in the section about squamous cell carcinoma.

Pathologic Prognostic and Predictive Features

  • BAC, nonmucinous type, is considered as an early lung neoplasm that seldom metastasizes to regional lymph nodes or to extra-pulmonary locations.

  • In contrast, the prognosis of patients with BAC, mucinous type, is usually more guarded because these lesions are frequently multiple and can metastasize.

Key Pathologic Features for Differential Diagnoses

  • BAC is distinguished from invasive adenocarcinomas by the presence of stromal invasion, characterized by the presence of tumor extension into the alveolar septa as individual cells or tumor cords, with reactive fibrosis and local remodeling of the lung architecture. BAC can become secondarily inflamed, for example as a result of infection or other etiologies; in these cases the presence of tumor invasion can be particularly difficult to detect with certainty.

  • Lesions with mixed features of BAC and invasive adenocarcinoma are, in our experience, more frequent than pure BAC.

Adenosquamous Carcinoma

Key Pathologic Features

  • The tumor exhibits the presence of squamous and glandular differentiation. A second cell type needs to be present in at least 10% of the neoplasm for the lesion to be classified as adenosquamous carcinoma.

Summary of Epidemiology

  • Similar to other forms of NSCLC

Histogenesis—Precursor Lesions

  • Dysplasia of the bronchial epithelium is a precursor lesion of squamous cell carcinoma. AAH is a precursor lesion of adenocarcinoma. It is unclear which of these preneoplastic lesions precede an adenosquamous carcinoma of the lung.

  • An origin of NSCLC from undifferentiated basal cells or from mucinous cells present in the bronchial epithelium has been proposed. These cells could differentiate into squamous and glandular phenotypes.


  • Adenosquamous carcinomas do not have a predominant location within the lung.

Gross Features

  • In my experience, the majority of adenosquamous carcinomas appear as peripheral lung lesions with identical gross pathologic features to those of adenocarcinoma.

  • Less often, adenosquamous carcinomas present as bronchogenic, central lung masses that are grossly indistinguishable from a squamous cell carcinoma.

Histopathologic Features

Jun 24, 2019 | Posted by in CARDIAC SURGERY | Comments Off on Pathologic Classification of Lung Malignancies and Special Pathologic Procedures

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