Pathology of lung malignancies

INTRODUCTION — Lung cancer is the most common cancer worldwide and is still responsible for the most cancer deaths according to the World Health Organization, more than double the next two highest cancers of liver and lower gastrointestinal tract [1,2]. (See "Clinical manifestations of lung cancer".)

The pathologic features of the major lung malignancies will be reviewed here. Clinical features, diagnosis, and management of patients with the different lung malignancies are discussed in the appropriate topic reviews. (See "Clinical manifestations of lung cancer" and "Overview of the initial treatment and prognosis of lung cancer".)

CLASSIFICATION SCHEMES — Classification of lung carcinomas by histopathologic subtype provides important information about prognosis and is necessary for optimal treatment. (See "Overview of the initial treatment of advanced non-small cell lung cancer".)

2021 WHO classification of lung tumors — The 2021 World Health Organization (WHO) classification of lung tumors is very similar to the 2015 WHO classification of lung tumors and should be the foundation for lung cancer classification (table 1) [1,3]. The classification relies on the use of immunohistochemical characterization in addition to light microscopy for accurate diagnosis, allowing for subtyping that more judiciously guides treatment strategy and predicts clinical course. It provides standardized criteria and terminology for lung cancer diagnosis on small biopsies and cytology, which is critical, given that the majority of patients with lung cancer present with high-stage disease and are not surgical candidates. Finally, it provides guidance for doing molecular testing on many carcinoma types, particularly adenocarcinomas, recognizing the therapeutic importance of targetable genetic alterations. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

The 2021 WHO classification re-emphasizes several important concepts, building on the major changes made in the 2015 classification, particularly in the classification of adenocarcinoma, which utilized the expert panel recommendations of the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society [4,5]. The 2021 WHO classification reflects the following changes:

●The proposed grading scheme is based on the patterns and extent of high-grade patterns, which include solid, micropapillary, cribriform, and complex glandular patterns.

●The addition of the SMARCA4-deficient undifferentiated tumor to the classification.

●Renaming of lymphoepithelial-like carcinoma to lymphoepithelial carcinoma, a designation that includes both Epstein-Barr virus (EBV)-positive and EBV-negative tumors.

●Renaming enteric adenocarcinoma to enteric-type adenocarcinoma.

ADENOCARCINOMA — Adenocarcinoma is the most common type of lung cancer in contemporary series, accounting for approximately one-half of lung cancer cases. The increased incidence of adenocarcinoma is thought to be due to the introduction of low-tar filter cigarettes in the 1960s, although such causality is unproven [6]. The World Health Organization (WHO) classification emphasizes that tissue specimens should be managed not only for pathologic diagnosis, but also to preserve tissue for molecular studies, which have important treatment implications such as use of targeted therapies for certain subsets of patients. Patients with advanced lung adenocarcinoma and other non-small carcinomas not otherwise specified should have their tumors tested for the presence of a driver mutation (eg, mutated epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] translocation, and increasingly, other mutations) [3]. Increasingly, tumors are being tested for a wide variety of molecular alterations by next-generation sequencing. While these tests can be performed on small biopsies, there is a lower limit of sample size and so clinicians performing procedures, such as endoscopic ultrasound-guided biopsies, are encouraged to work with cytopathologists in order to assure that samples are sufficiently large to perform the desired testing. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

Histologic diagnosis of adenocarcinoma requires evidence of either neoplastic gland formation, pneumocyte marker expression (thyroid transcription factor 1 [TTF-1] +/- napsin), or intracytoplasmic mucin (picture 1 and picture 2). There is significant variation in the extent and architecture of neoplastic gland formation. The major nonmucinous subtypes are acinar, papillary, micropapillary, lepidic, and solid. These patterns and their proportions in resected specimens have prognostic significance [3,7,8]. The cribriform, solid, and micropapillary patterns have adverse prognostic significance [9], while solid and micropapillary patterns also may predict benefit for those patients having adjuvant chemotherapy after complete resection [10]. Mucinous lesions can also grow in a lepidic fashion and show papillary, micropapillary, solid, and cribriform architecture, but at this time the WHO does not make any specific recommendations about grading invasive mucinous carcinomas based on the growth patterns in a tumor. Less common forms of adenocarcinoma include colloid, enteric-like, lymphoepithelial, and fetal (picture 3).

2021 classification of adenocarcinoma — The 2021 WHO classification is similar to the 2015 classification (table 1) [3-5,11,12]. The table shows the characteristics of the preinvasive lesions and invasive tumors (table 2).

●The term "lepidic" is used to describe noninvasive growth of tumor cells along intact alveolar septae. This term is used to describe both this growth pattern, as well as a tumor type, when this pattern of growth predominates, even when other patterns are present:

•Atypical adenomatous hyperplasia (AAH), an entity that was previously and continues to be recognized in the WHO system as a preinvasive lesion for lung adenocarcinoma (picture 4). These lesions generally measure 5 mm or less.

•Adenocarcinoma in situ (AIS) is a localized (≤3 cm) adenocarcinoma in which growth is restricted to tumor cells growing along alveolar structures (lepidic growth pattern) and that lacks any invasion. Most AIS tumors are nonmucinous (picture 5). Mucinous lesions comprise a small subset of such tumors (picture 6). Observational studies indicate that AIS has a 100 percent cancer-specific survival if completely resected.

•Minimally invasive adenocarcinoma (MIA) describes a small, solitary adenocarcinoma (≤3 cm) with a predominantly lepidic growth pattern and ≤5 mm invasion. Most but not all of these lesions are nonmucinous (picture 7). The cancer-free survival in these patients should approach 100 percent with complete surgical resection, based upon observational studies.

•Lepidic-predominant adenocarcinoma is an invasive tumor with this pattern comprising the predominant pattern and with invasion >5 mm. This pattern can be combined with acinar, solid, papillary, and micropapillary (picture 8) patterns in various combinations.

●Invasive nonmucinous adenocarcinomas are classified by their predominant pattern. The percentage of each component should be listed, in 5 percent intervals. Any combination of patterns may occur (picture 9).

●The subtypes of clear cell, rhabdoid, and signet ring have been discontinued, recognizing these as cytologic features that can occur in any type of adenocarcinoma, to be included as descriptions when present in any amount.

●Invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma) often has a prominent lepidic component (picture 10). This term excludes tumors that meet criteria for AIS or MIA. Mucinous and nonmucinous tumors occur and should be classified as mixed when >10 percent of each component is present.

●Other uncommon variants of invasive adenocarcinoma include colloid, fetal, and enteric-type (picture 3). Fetal adenocarcinoma, once referred to as endodermal tumors resembling fetal lung, are considered by some to represent a "monophasic" subset of pulmonary blastoma [13,14]. Classical pulmonary blastoma is a biphasic tumor in which fetal adenocarcinoma is accompanied by a primitive mesenchymal component resembling the blastomatous component of renal Wilms tumors. Regardless of their true histogenesis, fetal adenocarcinomas have a distinctive histologic appearance and are associated with a better prognosis than typical pulmonary adenocarcinomas (picture 3).

●On small biopsies, lesions without identifiable adenocarcinoma patterns present, but in which immunohistochemical (IHC) stains support the diagnosis of adenocarcinoma (eg, TTF-1 positive) the terminology "non-small cell carcinoma, favor adenocarcinoma" is used (picture 11).

●At resection, in similar fashion to biopsies, a morphologically undifferentiated non-small cell carcinoma with TTF-1 positivity would now be classified as an adenocarcinoma with a wholly solid pattern based on IHC, as opposed to a large cell carcinoma.

●Tumor spread through air spaces [3] should be reported on resection specimens, as it appears to be associated with a higher recurrence rate in those who undergo limited resections, and is a predictor of worse clinical outcome.

Radiographic correlates of this classification have also been developed and include some of the following observations:

●AAH and nonmucinous AIS characteristically have a ground-glass radiographic appearance (image 1 and image 2). Minimally invasive, nonmucinous lesions may have a predominantly ground-glass appearance with a smaller solid component (image 3).

●By contrast, mucinous AIS has a solid appearance on imaging (image 4).

ADENOSQUAMOUS CARCINOMA — Adenosquamous carcinomas are defined as tumors composed of more than 10 percent malignant glandular and squamous components. The mixed histology probably represents the well-recognized heterogeneity of lung carcinomas rather than a prognostically distinct subset [15]. The reported incidence of adenosquamous carcinoma ranges from 0.4 to 4 percent of bronchogenic carcinomas. Adenosquamous carcinoma is an aggressive tumor and appears to have a poorer prognosis than either adenocarcinoma or squamous cell carcinoma [16,17]. As these tumors are comprised in part of a glandular component, molecular testing of the tumor is recommended. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer".)

SQUAMOUS CELL CARCINOMA — Squamous cell carcinoma was the most frequent histologic type of lung tumor in nearly all studies done prior to the mid-1980s. Now, adenocarcinoma is more common than squamous cell carcinoma, particularly in women.

The diagnosis of squamous cell carcinoma is predicated upon the presence of keratin production by tumor cells and/or intercellular desmosomes (referred to as "intercellular bridges") (picture 12 and picture 13 and picture 14 and picture 15), or by immunohistochemistry (IHC) consistent with squamous cell carcinoma (ie, expression of p40, p63, CK5, CK5/6, or desmoglein). Variants of squamous cell carcinoma include nonkeratinizing, keratinizing, and basaloid subtypes, with clear cell change now regarded as a cytologic feature rather than a separate tumor type [3,11]. Tumors are nonkeratinizing if there is no keratinization, keratinizing if any keratinization is present, and basaloid if basaloid features comprise more than 50 percent of the tumor. For tumors that are nonkeratinizing, IHC is required to distinguish between squamous carcinoma, solid type adenocarcinoma, and large cell carcinoma with a null phenotype. For such tumors, diffuse positive staining with a squamous marker should be present to confirm a squamous phenotype. The preferable marker is p40, as p63 is not specific for squamous differentiation, and may be seen in adenocarcinomas.

Most squamous cell carcinomas (60 to 80 percent) arise in the proximal portions of the tracheobronchial tree (picture 16) through a squamous metaplasia-dysplasia-carcinoma in situ sequence (squamous carcinoma in situ), although they are increasingly presenting as peripheral lesions [18]. Central and peripheral squamous cell carcinomas may show extensive central necrosis with resulting cavitation (picture 17). A small subset of central, well differentiated squamous cell carcinomas occur as exophytic, endobronchial, papillary lesions (picture 18). Patients with this unusual variant of squamous cell carcinoma typically present with persistent cough, recurrent hemoptysis, or relapsing pulmonary infections due to airway obstruction. Most patients with exophytic endobronchial squamous cell carcinoma have low-stage disease at diagnosis, with a correspondingly good prognosis; five-year survival rates are greater than 60 percent [19].

LARGE CELL CARCINOMA — Large cell carcinoma (LCC) is a malignant epithelial neoplasm lacking glandular, squamous, or neuroendocrine differentiation by light microscopy and immunohistochemistry (IHC; typically, p40 and thyroid transcription factor 1 [TTF-1]), and lacking cytologic features of small cell carcinoma. LCC usually presents as a large peripheral mass with prominent necrosis. Histologically, LCC is characterized by sheets of round to polygonal cells with prominent nucleoli and abundant pale staining cytoplasm without differentiating features (picture 19). IHC has allowed the reclassification of several entities formerly classified as LCCs; this approach has been supported by molecular studies [20]. Poorly differentiated carcinomas are reclassified as squamous cell carcinoma if they have p40 expression; solid adenocarcinoma if TTF-1 expression is observed, even if mucin is absent; and neuroendocrine carcinoma if staining with chromogranin and synaptophysin are present [3]. Poorly differentiated carcinomas are considered large cell only if they lack defining IHC markers and have the so-called "null" phenotype.

Because LCC represents a diagnosis of exclusion, it is inappropriate to apply the term to small biopsies or cytology specimens, both of which have inherent sampling problems [3]. The term non-small cell lung cancer, not otherwise specified is more appropriate for cases diagnosed in this way, when there is no evidence of squamous or glandular differentiation on IHC.

SARCOMATOID CARCINOMA — Sarcomatoid carcinoma is a broad term that represents a heterogeneous group of non-small cell lung carcinomas (NSCLCs). They are characterized by having a malignant epithelial component, but with features that suggest sarcomas. The main categories include pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma. In a large Surveillance, Epidemiology, and End Results database study, sarcomatoid carcinomas are rare, comprising less than 1 percent of all lung cancers [21]. A histologic diagnosis of sarcomatoid carcinoma was associated with overall worse survival (hazard ratio for death 1.60, 95% CI 1.35-2.06). Molecular testing for genetic alterations, in similar fashion to other NSCLCs, and in particular adenocarcinomas, is recommended for these tumors [3,5]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor" and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)

Pleomorphic carcinoma — This tumor is characterized by the presence of squamous, adenocarcinoma, or large cell carcinoma combined with greater than 10 percent of a component of pure spindle cells and/or neoplastic giant cells.

Variants include the following:

Spindle cell carcinoma — These are tumors composed only of malignant spindle cells. The diagnosis of "carcinoma" in this setting can usually be confirmed by the use of immunohistochemistry stains for keratin that will stain positively at least some tumor cells.

Giant cell carcinoma — Large, bizarre tumor cells are not specific to any one histologic category and can be seen in otherwise typical squamous cell and adenocarcinomas. The term giant cell carcinoma is restricted to those tumors in which bizarre pleomorphic giant cells (greater than 40 microns) comprise almost the entirety of the neoplastic population (picture 20). The tumor cells are frequently multinucleated and may contain polymorphonuclear leukocytes in their cytoplasm. Defined in this way, giant cell carcinoma has a very poor prognosis.

Carcinosarcoma — This lung malignancy is defined by the presence of a typical carcinoma (squamous or adenocarcinoma) combined with true sarcomatous elements such as rhabdomyosarcoma, osteosarcoma, and chondrosarcoma.

Pulmonary blastoma — These tumors are biphasic malignancies that have an adenocarcinoma component that has the appearance of fetal adenocarcinoma and a primitive mesenchymal stroma that resembles that seen in Wilms tumor. Other differentiated sarcomatous elements may also be present but they are not required for the diagnosis. They are usually large at the time of presentation and are highly malignant. (See "Presentation, diagnosis, and staging of Wilms tumor".)

NEUROENDOCRINE TUMORS — Several tumor types are grouped based upon shared neuroendocrine features (table 3) [3]. These tumors include small cell carcinoma, large cell neuroendocrine carcinoma, typical carcinoid, and atypical carcinoid. In addition, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, a possibly preinvasive epithelial lesion, is included in this category (table 3) [22].

Within the group of pulmonary neuroendocrine tumors, typical and atypical carcinoids share a number of features and are similar to carcinoid lesions arising at other sites. Small cell carcinomas and large cell neuroendocrine carcinomas are characterized clinically by a more aggressive course and pathologically by a much higher mitotic rate compared with pulmonary carcinoids (11 or more mitoses per 10 high-power fields) [3]. A high Ki-67 score (a marker of proliferation) may help distinguish small cell and large cell neuroendocrine carcinoma from pulmonary carcinoids, especially in small biopsies, but staining for Ki-67 is not part of the diagnostic criteria.

Small cell carcinoma — Small cell lung carcinoma (SCLC) accounts for approximately 15 percent of all bronchogenic carcinomas. SCLC shows a strong correlation with cigarette smoking and is extremely rare in persons who have never smoked. (See "Cigarette smoking and other possible risk factors for lung cancer".)

Small cell carcinomas also are being reported with increasing frequency in patients treated with tyrosine kinase inhibitors [23]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Mechanisms'.)

Molecular studies have identified a number of abnormalities in SCLCs, including in particular deletions in chromosome 3p. (See "Pathobiology and staging of small cell carcinoma of the lung", section on 'Genetic abnormalities'.)

The general pathologic features of SCLC have not changed.

●There is no prognostic importance to the historic "oat cell"/intermediate subtype distinction [24-26]; although on purely morphologic grounds, knowledge of the spectrum of SCLC is critical for the pathologist; the preferred term is simply small cell carcinoma.

●SCLCs are heterogeneous. Some are associated with isolated larger cells that have similar cytologic features and may even contain small nucleoli. These tumors tend to be as responsive to chemotherapy as are pure SCLCs and should be classified as such.

●Approximately 5 percent of cases of SCLC may also be combined with non-small cell elements, such as squamous carcinoma or adenocarcinoma, and still respond at least initially to therapy directed to small cell carcinoma. According to the World Health Organization (WHO), such tumors should be subsumed under the "combined" rubric, listing both components present (eg, combined small cell carcinoma and squamous cell carcinoma). For tumors to be considered combined small and large cell carcinoma (or large cell neuroendocrine carcinoma), at least 10 percent of the tumor should consist of large cells. There is no percentage requirement for adenocarcinoma, squamous cell carcinoma, or sarcomatoid carcinoma combined with small cell carcinoma.

SCLC is composed of cells with a size no larger than the size of three resting lymphocyte nuclei (picture 21). These may be round, oval, angulated, and with usually small amounts of cytoplasm. The nuclei are typically hyperchromatic and either have a dispersed "salt and pepper" chromatin or a homogeneous dispersed chromatin. The cells are fragile and the tumors are generally extensively necrotic, both of which may contribute to the difficulty in establishing a histologic diagnosis on small samples. Tumor cells are usually positive for one or more of chromogranin or synaptophysin, although around 10 percent may be unreactive for classic neuroendocrine markers. Cytokeratin staining is often dot-like in morphology. Subtypes of small cell carcinoma are just beginning to be described, that may carry diagnostic, prognostic, and therapeutic implications [27].

Large cell neuroendocrine carcinoma — Large cell neuroendocrine carcinoma has an architecture that suggests neuroendocrine differentiation: the cells are arranged in organoid, trabecular, or palisading patterns (picture 22A-B). Necrosis is usually prominent and may be extensive and infarct-like. Evidence of neuroendocrine differentiation is usually demonstrated by immunoreactivity for chromogranin and synaptophysin (picture 23A-B). These tumors are generally high grade, most commonly located in the peripheral lung, and associated with an aggressive clinical course (table 3) [3].

Large cell neuroendocrine carcinoma comprises cells generally much larger than three resting lymphocytes with abundant cytoplasm that is often eosinophilic (table 3) [28]. The nuclear chromatin tends to be coarse and granular. The mitotic rate is significantly higher than that seen in atypical carcinoids, and should be above >10/2 mm² [3].

Well-differentiated NETs — Well-differentiated neuroendocrine (carcinoid) tumors (NETs) are neuroendocrine epithelial malignancies with a lower grade than large cell neuroendocrine or small cell carcinoma; they can be further divided into typical (low-grade) or atypical (intermediate-grade) NETs. In contrast to digestive tract NETs, the terms "typical" and "atypical" carcinoid are still used to describe low- versus intermediate-grade NETs arising in the lung. Another difference between digestive tract and lung NETs is that mitotic rate (rather than Ki-67 index) and necrosis are the primary determinants of grade in lung primaries. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system", section on 'Classification and terminology'.)

Typical carcinoid (low-grade NET) — These neuroendocrine tumors (NETs) are composed of cytologically bland cells containing regular round to oval nuclei with finely dispersed chromatin and inconspicuous or small nucleoli (picture 24) [3]. The cells are usually polygonal in shape and are arranged in distinct organoid, trabecular, or insular growth patterns with a delicate vascular stroma (picture 25). Mitotic figures are scarce (<2/10/2 mm²), and necrosis is not seen. Peripherally located tumors differ in that they are often composed of closely packed, spindle-shaped cells. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging".)

A variant of carcinoid tumors has been described that has carcinoid morphology, but an elevated mitotic count or Ki-67 proliferation index in the range of what is expected for large cell neuroendocrine carcinoma. These tumors were not well-defined enough so that the 2021 WHO classification does list them as a separate entity.

Atypical carcinoid (intermediate-grade NET) — Pathologic criteria for recognition of atypical carcinoid/intermediate-grade NETs as delineated by the WHO include the presence of well-differentiated neuroendocrine morphology and at least one of the following:

●Necrosis (picture 26)

●Mitoses (2 to 10 per 10/2 mm²)

Cytologic atypia is also a characteristic but is not a criterion for a diagnosis of an intermediate-grade NET. There is an inconsistent correlation between "atypical" histology in lung NETs and DNA aneuploidy [29].

The neuroendocrine lung tumors described above usually can be diagnosed on the basis of light microscopy alone. Immunohistochemical staining for neuropeptides (eg, CD56, chromogranin, synaptophysin) can be helpful in difficult cases but is not required for diagnosis. The classification, histology, staging, clinical features, and treatment of well-differentiated NETs arising in the lung are discussed separately. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging" and "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis".)

DIPNECH — Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a generalized proliferation of pulmonary neuroendocrine cells that may be confined to the mucosa of the airways, invade locally to form "tumorlets," or form invasive NETs. Histologically, the cells are round to oval or spindle shaped and have a moderate amount of eosinophilic cytoplasm with round to oval nuclei that have a salt-and-pepper chromatin pattern. The tumorlets are poorly defined with irregular infiltrative margins and a conspicuously fibrotic stroma; they are intimately related to an airway and are ≤5 mm in diameter (figure 1) [30]. The full range of neuroendocrine markers is almost always expressed in DIPNECH. Some patients with DIPNECH have associated obliterative bronchiolar fibrosis (obliterative or constrictive bronchiolitis). (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Immunohistochemistry' and "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia'.)

Due to the occasional presence of neuroendocrine tumorlets and hyperplasia in the background of resected peripheral typical carcinoids (well-differentiated lung NETs), DIPNECH is considered by the WHO to be a preinvasive lesion, and a likely precursor to pulmonary NETs [30]. At diagnosis, approximately one-half of patients with DIPNECH have a synchronous carcinoid (well-differentiated NET). It is unknown what proportion of patients with DIPNECH will eventually develop a carcinoid/NET.

Most patients with DIPNECH are middle-aged women who have longstanding respiratory symptoms, evidence of airflow obstruction, air trapping on chest imaging, and histologic evidence of obliterative bronchiolitis. However, patients may be asymptomatic, with DIPNECH identified during surveillance for metastatic disease from another cancer (eg, breast) [31]. Radiographic findings include nodular bronchial wall thickening, bilateral pulmonary nodules, ground-glass attenuation, and bronchiectasis. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia'.)

SALIVARY GLAND TUMORS — The full range of tumors that occur in the major and minor salivary glands of the head and neck can occur in the lung, trachea, and bronchi (see "Pathology of head and neck neoplasms", section on 'Salivary gland tumors'). Most occur centrally, but they can occur in the periphery of the lungs. However, these tumors, even some of the benign ones, eg, pleomorphic adenoma, can metastasize to the lung. So, prior to concluding that a tumor represents a primary pulmonary salivary gland tumor, a careful review of the patient's history is warranted. Sometimes the tumors can metastasize years after the primary has been removed.

OTHER CARCINOMAS

NUT carcinoma — This tumor is genetically defined by the presence of nuclear protein in testis (NUT) rearrangements. It can involve the lung, mediastinum, and pleura. They usually present as large, bulky tumors and can affect patients of all ages, although the median age at presentation is approximately 24 years of age. Histologically they are comprised of undifferentiated tumors cells, which can show abrupt keratinization. Diagnosis requires confirmation of the characteristic chromosomal translocation or demonstration of this by immunohistochemistry (IHC) (picture 27).

Thoracic SMARCA4-deficient undifferentiated tumor — This is a high-grade malignancy that has an undifferentiated or rhabdoid morphology genetically defined by a deficiency of SMARCA4 (BRG1), a member of the BRAF chromatin-remodeling complex. It tends to occur in adults, and is associated with a history of smoking. The genetic alterations can be identified by sequencing, but demonstration of deficiency of SMARCA4 can also usually be accomplished by IHC, which shows loss of expression of BRG1 in tumor cells (picture 28).

DIFFERENTIAL DIAGNOSIS — The diagnosis of a primary lung cancer is clinicopathologic. Many metastatic tumors can have a similar morphologic appearance to primary lung cancers. While comparison to the primary tumor from another site is always recommended when a patient with a known malignancy, eg, colon, develops a lung malignancy, immunohistochemistry has become extremely important in helping the pathologist arrive at the correct diagnosis (table 4). A panel of antibodies is typically used in this context. Stains such as CK7 (favors lung primary) and CK20 (favors colon primary) along with CDX2 (favors gastrointestinal primary) may be useful in establishing the diagnosis. Newly described entities such as nuclear protein in testis (NUT) carcinoma and thoracic SMARCA4-deficient undifferentiated tumor should be added to the differential and require the use of additional stains to properly diagnose.

SUMMARY

●Classification – Lung malignancies should be classified according to the World Health Organization system (table 1). (See 'Classification schemes' above.)

●Histologic categories – The most common histologic category is adenocarcinoma. Most of the remaining cases are squamous cell carcinomas, or neuroendocrine tumors, the most common being small cell carcinoma. Large cell carcinoma is becoming increasingly rare due to more biologically based classification schemes. Newly described tumors need to be considered and cases worked up accordingly. (See 'Adenocarcinoma' above and 'Large cell carcinoma' above and 'Other carcinomas' above.)

●Impact on treatment – Classification of lung cancers is necessary for appropriate treatment. (See "Overview of the initial treatment and prognosis of lung cancer" and "Overview of the initial treatment of advanced non-small cell lung cancer".)