Key points

Introduction

Lung cancer can be diagnosed pathologically based either on histologic biopsy or cytologic specimens. ^, In the 2015 World Health Organization (WHO) Classification of Lung Tumors ( Table 1 ), the diagnosis of lung cancer was addressed not only in resection specimens but a new approach to small biopsies and cytology specimens was introduced ( Table 2 ). ^, For these small specimens, diagnostic terms and criteria for all major histologic subtypes of lung cancer were recommended. ^, Due to the discovery of driver mutations in many lung cancers, such as EGFR mutation and ALK rearrangements that represent therapeutic targets, the importance of managing these small specimens for molecular testing is emphasized. Histologically there are 4 major types of lung cancer, including squamous cell carcinoma, adenocarcinoma, small cell carcinoma (SCLC), and large cell carcinoma (see Table 1 ). These major types can be subclassified into more specific subtypes, such as lepidic predominant subtype of adenocarcinoma or the basaloid variant of squamous cell carcinoma.

The 2015 WHO classification introduced multiple new concepts, including (1) widespread requirement of immunohistochemistry for accurate diagnosis for many lung tumors including resected lung cancers; (2) integration of molecular studies, to facilitate personalize treatment strategies for patients with advanced lung cancer; (3) recommendations for diagnosis and tissue management for small biopsies and cytology specimens ; (4) major changes in the approach to lung adenocarcinoma in resection specimens ; (5) restricting the diagnosis of large cell carcinoma to resected tumors that lack any clear morphologic or immunohistochemical differentiation or mucin; (6) a new subtyping of squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemical staining of squamous markers; and (7) grouping the neuroendocrine tumors together, although the diagnostic criteria remain the same. ^{, ,}

Lung cancer classification in small biopsies and cytology

The importance of precise histologic classification of lung cancer in small biopsies and cytology as well as the need for molecular testing in these small tissues has been driven by major progress in therapy for patients with advanced non–small-cell lung carcinoma (NSCLC). ^, The first major discovery was the efficacy of tyrosine kinase inhibitors as first-line therapy in patients with advanced lung adenocarcinoma with EGFR mutations. ^, Subsequently, multiple additional molecular targets have been identified mostly in lung adenocarcinomas, including ALK and ROS1 and RET rearrangements, BRAF and MET exon 14 splice site mutations. ^, Also, patients with adenocarcinoma or non–small-cell carcinoma (NSCC) not otherwise specified (NOS) have been shown to be more responsive to pemetrexed than those with squamous cell carcinoma. ^, In addition, bevacizumab it is contraindicated in patients with lung cancer with squamous cell carcinoma because these patients are at increased risk for life-threatening hemorrhage. Fifth, great promise has been shown with anti-programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) antibodies, although there is no consistent association with histologic type (adenocarcinoma vs squamous cell carcinoma) and clinical responses are not consistently associated with PD-L1 expression.

All of these therapeutic advances made it quite important to develop a new classification of lung cancer in small biopsies and cytology (see Table 2 ). Furthermore, 70% of patients with lung cancer present in advanced stages. A fundamental principle of this classification is to manage these small specimens for molecular testing in addition to diagnosis because molecular testing is now routine in lung cancers.

An unequivocal diagnosis of squamous cell carcinoma or adenocarcinoma can be made in small biopsies if the small biopsy or cytology shows tumor cells with keratinizing squamous cell carcinoma or shows a glandular pattern of adenocarcinoma (lepidic, acinar, papillary or micropapillary), respectively. In carcinomas that only show a solid pattern with no clear squamous or glandular features, immunohistochemical stains should be used with one adenocarcinoma marker (such as TTF-1) and one squamous marker (p40), which should allow for classification of most tumors. ^, Tumors are classified as NSCC, favor adenocarcinoma if they lack definite squamous or glandular morphology and show immunohistochemical staining that favors adenocarcinoma (ie, TTF-1 positive, p40 negative) ( Fig. 1 A, B ). Likewise, the tumor is classified as NSCC, favor squamous cell carcinoma for tumors lacking any clear morphology that shows a staining pattern that favors squamous cell carcinoma (p40 positive, TTF-1 negative) ( Fig. 1 C, D). In contrast, the term NSCC-NOS is used in tumors with no clear differentiation by morphology or special stains or if the stains are conflicting. This term should be used as infrequently as possible, ideally with a frequency of NSCC-NOS in small biopsies or cytology specimens of 5% or less. ^{, ,} Cytology is also very helpful in the diagnosis and classification of poorly differentiated NSCC. The use of the term “nonsquamous carcinoma” by pathologists is discouraged, although it is sometimes used for lumping tumors together in some clinical studies. The diagnosis of adenocarcinoma or squamous cell carcinomas as well as NSCC-NOS in small biopsies and cytology needs to be made keeping in mind that a variety of other lung cancers, metastatic melanoma, lymphomas, sarcomas, and metastatic tumors can present in the lung. ^,

Non–small cell carcinoma, favor adenocarcinoma. ( A ) This carcinoma shows no clear squamous or glandular differentiation. (hematoxylin-eosin, original magnification ×20). ( B ) The diffuse positive TTF-1 staining, allows for the diagnosis of non–small cell carcinoma, favor adenocarcinoma. Non–small cell carcinoma, favor squamous cell carcinoma. (TTF-1, original magnification ×20). ( C ) This carcinoma shows no clear squamous or glandular differentiation.(hematoxylin-eosin, original magnification ×20). ( D ) The diffuse positive p40 staining and negative TTF-1 staining (not shown) allows for the diagnosis of non–small cell carcinoma, favor squamous cell carcinoma. (TTF-1, original magnification ×20).

Due to the need not only for diagnosis, but also for molecular testing, pathologists should minimize the amount of tissue used for making the diagnosis by performing as few special stains as possible. A useful strategy is to cut the block once after review of initial sections to cut as many unstained slides as possible at the time of initial immunohistochemical workup to have enough material to send for molecular testing or to perform additional stains if needed. Also, if multiple small pieces of tumor are obtained, it is best to put them in separate blocks. If the tumor shows only a solid pattern by morphology, it may be best to perform one adenocarcinoma (ie, TTF-1) and one squamous (ie, p40) marker to determine if the tumor is adenocarcinoma or squamous cell carcinoma. Other more detailed recommendations are found elsewhere. ^,

Preinvasive lesions

Classification of the preinvasive lesions for lung cancer has undergone major changes since the 1967 WHO classification of lung tumors when there were no preinvasive lesions. ^{, ,} Currently it is recognized that there are 3 categories of preinvasive lesions, including bronchial squamous dysplasia and carcinoma in situ, for squamous cell carcinoma, atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) for adenocarcinoma and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) for carcinoid tumors.

Atypical Adenomatous Hyperplasia

AAH is usually an incidental finding in the lung parenchyma adjacent to resected lung cancers and it consists of a small nodular atypical pneumocyte proliferation that resembles but falls short of criteria for AIS ( Fig. 2 ). ^, It occurs in 5.7% to 21.4% of lung adenocarcinoma resection specimens, depending on the extent of lung tissue sampled. ^,

AAH. ( A ) This millimeter-sized atypical pneumocyte proliferation is ill-defined with mild thickening of the alveolar walls. (hematoxylin-eosin, original magnification ×4). ( B ) The alveolar walls show mild fibrous thickening and the hyperplastic pneumocytes show minimal atypia and there are some gaps between the cells. (hematoxylin-eosin, original magnification ×20).

Most AAHs are small nodular pneumocyte proliferations usually measuring smaller than 5 mm in diameter. Although there is no absolute size cutoff to separate AAH from AIS, frequently they are multicentric. ^, AAHs are composed of type II pneumocytes and/or Club (formerly Clara) cells that are cuboidal to low columnar in shape lining alveolar walls and respiratory bronchioles (see Fig. 2 B).

Adenocarcinoma in Situ

AIS is defined as a small (≤3 cm) proliferation of atypical pneumocytes with pure lepidic pattern without invasion ( Fig. 3 ). The vast majority are nonmucinous, but rarely they can be mucinous. Nonmucinous tumors consist of a proliferation of type II pneumocytes or Club (formerly Clara) cells. The mucinous AIS cases consist of tall columnar goblet cells having abundant apical mucin. Patients have been reported to have 100% 5-year disease-free survival if these lesions are completely resected. ^, By computed tomography (CT), AIS will most often show a pure ground glass nodule if nonmucinous and a solid nodule if mucinous AIS.

AIS, nonmucinous. ( A ) This circumscribed nonmucinous tumor grows purely with a lepidic pattern. No foci of invasion or scarring are seen. (hematoxylin-eosin, original magnification ×4). ( B ) High power shows a crowded proliferation of atypical pneumocytes lining the alveolar walls. (hematoxylin-eosin, original magnification ×20).

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (Preinvasive Lesion for Carcinoids)

Carcinoid tumors are rarely found to be associated with the preinvasive lesion called diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). This is a rare condition characterized by a diffuse proliferation of neuroendocrine cells with multiple tumorlets and neuroendocrine cell hyperplasia in peripheral airways ( Fig. 4 ). Clinical presentation can appear as interstitial lung disease or as multiple pulmonary nodules that are frequently incidental findings. The interstitial lung disease presentation is usually associated with small airway obstruction due to bronchiolar fibrosis. Patients who present with clinical manifestations of interstitial lung disease can show a chest CT that is normal or the CT can show mosaic attenuation from air trapping, bronchial wall thickening, and bronchiectasis. The use of the term DIPNECH has recently been proposed to be restricted to patients who present with interstitial lung disease like features including respiratory symptoms, mosaic attenuation on chest CT scans, pulmonary function abnormalities, and constrictive bronchiolitis pathologically.

DIPNECH. ( A ) This carcinoid tumorlet is present in the lung parenchyma adjacent to a carcinoid tumor. (hematoxylin-eosin, original magnification ×4). ( B ) Neuroendocrine cell hyperplasia is seen here as small clusters of neuroendocrine cells at the base of the bronchiolar mucosa. (hematoxylin-eosin, original magnification ×40).

Adenocarcinoma

Adenocarcinoma Classification in Resected Specimens

Invasive adenocarcinoma

Adenocarcinomas account for 50% of all lung cancers in the United States ( Table 3 ). They are most often situated in the lung periphery and are often small and subpleural, but they can be large and central ( Fig. 5 ). Histologic classification is according to the predominant subtype. This is achieved by performing comprehensive histologic subtyping in which each histologic pattern is estimated in a semiquantitative fashion in 5% increments. The term lepidic predominant adenocarcinoma (LPA) is used for tumors that have a predominant lepidic growth pattern consisting of type II pneumocytes and/or Club (formerly Clara) cells where the invasive component is greater than 5 mm ( Fig. 6 A). The other 4 major subtypes consist of acinar ( Fig. 6 B), including the cribriform pattern ( Fig. 6 C), papillary ( Fig. 6 D), and micropapillary patterns ( Fig. 6 E), including the recently described filigree pattern ( Fig. 6 F) ^{, ,} and solid with mucin or TTF-1 expression ( Fig. 6 G, H). ^,

Table 3

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