Key Points

A new classification of lung cancer in small biopsy and cytology specimens is reviewed

• These small tissues need to be managed not only for diagnosis but also molecular testing
• Personalized therapies for patients are based on histologic diagnosis and special studies
• Immunohistochemistry is now essential to make a pathologic diagnosis of most lung cancers.
• Resected lung adenocarcinomas are classified according to predominant subtype
• Squamous cell carcinoma subtypes are keratinizing, nonkeratinizing and basaloid
• Large cell carcinoma is limited to undifferentiated tumors by morphology and special stains
• Neuroendocrine tumors are grouped together but typical and atypical carcinoids are very different from the high grade small cell carcinoma and large cell neuroendocrine carcinoma
• Spread through air spaces is a new important feature of invasion in lung cancers
• Synoptic templates should be used in reporting of lung cancers.

Globally, lung cancer is the most common cause of nonmelanoma cancer incidence and mortality in men and women combined accounting for 11.6% of total cancer cases and 18.4% of cancer deaths.[1] Worldwide in males it is the most common cancer and cause of cancer death while in females it is the third most commonly diagnosed cancer and the second leading cause of cancer death.[1] It is estimated by the American Cancer Society that there will be 228,150 new cases of lung cancer in the United States during 2018 and 142,670 cancer deaths.[2] The incidence of lung cancer incidence in males in the US began to decline in the early 1980s,[3] however, it appears to have plateaued in women.[3] In young women there is a higher incidence of lung cancer than in young men and this is not completely explained by differences in smoking behaviors between the sexes.[4]

The pathologic diagnosis of lung cancer can be made based either on histologic biopsy or cytologic specimens.[5],[6] Over the past decade, major advances have revolutionized the approach to diagnosis and classification of lung cancers largely summarized in the 2011 IASLC/ATS/ERS Lung Adenocarcinoma Classification which was adopted with minor changes in the 2015 WHO Classification of Lung Tumors (Table 1) has made major changes in how lung adenocarcinoma is diagnosed.[5],[6] This WHO classification addressed both resection specimens and small biopsies and cytology specimens with recommendations for diagnostic terms and criteria for other major histologic subtypes in addition to adenocarcinoma. The four major histologic types of lung cancer are squamous cell carcinoma, adenocarcinoma, small cell carcinoma (SCLC) and large cell carcinoma.[6] These major types can be subclassified into more specific subtypes such as lepidic predominant subtype of adenocarcinoma or the basaloid variant of large cell carcinoma.[6] More detailed reviews of the pathology, cytology and molecular biology of lung cancer can be found elsewhere.

Historically due to major clinical differences in presentation, metastatic spread and response to therapy the most important lung cancer classification issue was the separation of small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC).[6] However, over the past decade, the importance of more precise classification has become much more important due to the dependence on histologic subtyping which impacts decisions about treatment and molecular testing strategies.[6],[9],[10],[11],[12],[13],[14],[15] Since 70 percent of lung cancer patients present with advanced stage disease, a new approach to classification is now established for small biopsy and cytology specimens.[5],[6],[16],[17]

Patients with adenocarcinoma or nonsmall cell carcinoma, not otherwise specified are also eligible for either pemetrexed,[18],[19],[20] or bevacizumab based regimens.[21] However, if the histology is squamous cell carcinoma, these patients are not candidates for these therapies. In addition, immunotherapy has revolutionized lung cancer treatment introducing an entirely new requirement for PD-L1 immunohistochemical testing for some of the candidate medications.[22],[23],[24],[25] The implications of these new therapeutic paradigms for lung cancer classification are profound and will be outlined in this review.

Major advances and changes in the 2015 WHO classification include 1) use of immunohistochemistry for accurate diagnosis for many lung tumors including resected lung cancers, 2) a focus on incorporating molecular studies, especially to aid in in particular integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, 3) a new approach to diagnosis and tissue management for small biopsies and cytology specimens according to the 2011 IASLC/ATS/ERS Classification,[5],[6],[14],[26] 4) a completely different approach to lung adenocarcinoma in resection specimens, [5],[6],[14] 5) limiting the diagnosis of large cell carcinoma to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, 6) modifying subtyping of squamous cell carcinomas into keratinizing, nonkeratinizing and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, 7) putting the neuroendocrine tumors into a single group, although the diagnostic criteria remain the same, 8) introduction of NUT carcinoma to a category of other and unclassified tumors, [6],[14],[27]