The major tissue types of lung cancer are adenocarcinoma and squamous carcinoma, which account for about 80 percent of all primary lung cancers. Other rare types of primary lung cancer include adenosquamous carcinoma, large cell carcinoma, and carcinoma of salivary gland origin (adenoid cystic carcinoma, mucinous epidermoid carcinoma, etc.). Undifferentiated tumors with SMARCA4 deficiency in the chest have been added to the latest classification. Among the benign epithelial tumors, fine bronchial adenoma has been added.
1. Squamous carcinoma
The incidence of squamous carcinoma of the lung has been decreasing in recent years, accounting for about 30-40% of lung cancers, of which 2/3 are central and 1/3 are peripheral, which may be accompanied by cavity formation and, when located centrally, may protrude into the bronchial lumen in the form of polyps. This type of carcinoma is generally thought to originate from squamous metaplasia of bronchial epithelium stimulated by smoking, and is classified as highly, moderately, or poorly differentiated according to the degree of differentiation of keratinized cells in the nest. Squamous carcinomas are more likely to have lymphatic and hematogenous metastases, and may also directly invade mediastinal lymph nodes and parabronchial and mediastinal soft tissues. Local recurrence is more common after surgery than in other types of lung cancer. Extensive, multifocal molecular pathologic abnormalities are present in the bronchial and pulmonary respiratory epithelium of smokers and lung cancer patients, and regional oncogenic effects may result in multicentric tumors in the lung due to smoking.
2. Adenocarcinoma
Adenocarcinoma accounts for 40-55% of lung cancers and has surpassed squamous carcinoma as the most common type of lung cancer in many countries. Adenocarcinoma is clinically more common as a peripheral type, while cavity formation is rare. The most important changes in the pathology of adenocarcinoma of the lung in recent years have been the introduction of the concept of adenocarcinoma in situ, the recommendation to discontinue the term bronchoalveolar carcinoma, and the recommendation to discontinue the use of mixed adenocarcinoma as a type of invasive adenocarcinoma. Brief descriptions are as follows.
(1) Atypical adenomatous hyperplasia (AAH), which is at least a precancerous lesion of lung adenocarcinoma, is usually less than 0.5 cm in size and is often characterized by ground glass-like changes on CT scan. The microscopic histology shows intact alveolar structure, consistent alveolar epithelial hyperplasia in a rectangular or short columnar shape, mild atypia, and lack of or blurred nuclei.
(2) Adenocarcinoma in situ (AIS), a new concept introduced in 2011, is defined as a solitary adenocarcinoma ≤3 cm, consisting of type II alveolar epithelium and/or clara cells confined to normal alveolar structures (epithelial growth). The disease free survival rate of surgical resection of AIS is 100.
(3) Micro-invasive adenocarcinoma (MIA) is defined as a solitary adenocarcinoma of ≤3 cm, with clear boundaries and predominantly mural growth, and an infiltrative form other than mural, with a maximal diameter of infiltrating interstitium ≤5 mm, excluding risk factors such as vascular invasion, pleural invasion and intra-airway dissemination of tumor cells. The risk factors such as vascular invasion, pleural invasion and airway dissemination of tumor cells should be excluded. The overall 5-year survival rate is 100 if the MIA is completely resected.
(4) Infiltrative adenocarcinoma. Adenocarcinoma may be solitary, multiple, or diffuse in nature. The main forms of invasive adenocarcinoma are epithelial, alveolar, papillary, micropapillary, and solid. Among them, micropapillary and solid types are low differentiation subtypes and should be labeled with percentage content.
3. Neuroendocrine carcinoma
Pulmonary neuroendocrine tumors are divided into carcinoid/neuroendocrine tumors (typical carcinoid tumors and atypical carcinoid tumors), small cell lung cancer, and some large cell neuroendocrine cancers. Small cell lung cancer accounts for 15 of all lung cancers and is a poorly differentiated neuroendocrine carcinoma with common necrosis and a high nuclear fission index. Small cell lung cancer has neuroendocrine granules on electron microscopy in at least 2/3 of cases. Complex small cell carcinoma refers to small cell carcinoma combined with other non-small cell lung cancer types and is seen in less than 10 cases of small cell carcinoma. Based on clinical behavior and pathologic features, carcinoid/neuroendocrine tumors are divided into typical carcinoid tumors, which are less malignant, and atypical carcinoid tumors, which are slightly more malignant. The distinction between the two is made by the presence or absence of small focal necrosis, which is also distinguished by the presence or absence of two nuclear fractions in a 2-mm2 field of view. Compared with typical carcinoid tumors, atypical carcinoid tumors often occur in the periphery, have an increased metastatic rate, and have a relatively poor prognosis. Large cell neuroendocrine carcinoma is a large cell carcinoma with immunohistochemical and morphologic features of neuroendocrine differentiation. It is usually a peripheral nodule with necrosis, and the prognosis is similar to that of small cell carcinoma. Compound large cell carcinoma refers to the combination of other well-differentiated non-small cell carcinoma components, and most of the compound components are adenocarcinoma.
4. Other types of lung cancer
(1) Adenosquamous carcinoma: only occupies 0.6-2.3 of all lung cancers. According to the new WHO classification, a tumor must contain at least 10 adenocarcinomas or squamous carcinomas to be diagnosed as adenosquamous carcinoma, often located in the periphery and accompanied by central scar formation. Metastatic features and molecular biology are not different from other non-small cell carcinomas. (2) Sarcomatoid carcinoma: A poorly differentiated type of non-small cell carcinoma containing sarcoma or sarcomatoid component [spindle and/or giant cell-like], with 3 subtypes: pleomorphic carcinoma, carcinosarcoma, and pulmonary blastoma. (3) Carcinoma of salivary gland origin: including adenoid cystic carcinoma, mucinous epidermoid carcinoma, and epithelial-myoepithelial carcinoma. The key to differentiation is that the latter is a poorly differentiated adenocarcinoma with obvious heterogeneity. (4) Large cell carcinoma is a poorly differentiated adenocarcinoma without the differentiation characteristics of adenocarcinoma, squamous carcinoma or small cell carcinoma, which is an exclusionary diagnosis. (5) In addition to NUT carcinoma, undifferentiated tumor with SMARCA4 deficiency in the chest is added to the new classification. It is a highly malignant undifferentiated tumor with unique immunohistochemical phenotype and biological behavior, accompanied by SMARCA4 gene mutation and protein expression deficiency.
5. Immunohistochemistry and special staining
Proper selection of immunohistochemistry programs can effectively preserve sufficient tissue specimens for molecular diagnosis. When the tumor is poorly differentiated and lacks clear morphologic features of adenocarcinoma or squamous carcinoma, immunohistochemistry or mucin staining is necessary to make a definitive diagnosis. Immunohistochemical markers for differentiation of adenocarcinoma from squamous carcinoma are TTF-1, Napsin-A, p63, p40 and CK5/6, of which p40 and TTF-1 can solve most of the problems in differentiating adenocarcinoma from squamous carcinoma. For patients with further disease progression, in order to preserve tissue for molecular pathology as much as possible, histologic classification using restricted immunohistochemical index tests, such as detection of protein p63/p40, which is expressed singly on squamous carcinoma cells, and TTF-A/Napsin-1, which is expressed singly on adenocarcinoma cells, is recommended to classify most non-small cell lung cancers. The identification of solid-type adenocarcinoma with intracellular mucus material should be confirmed by mucus carmine staining and AB-PAS special staining; special staining of elastic fibers should be performed when pleura is suspected to be involved. Neuroendocrine tumor markers are CD56, Syn, CgA, Ki-67, and TTF-1, and at least one neuroendocrine marker should be positive based on the morphological features of neuroendocrine tumor, and the number of positive cells should be more than 10% of the tumor cells to diagnose neuroendocrine tumor.