Squamous cell carcinoma (SCC) is a malignant epithelial neoplasm originating from the bronchial epithelium that may exhibit keratinization and/or intercellular bridging features. It includes spindle cell carcinoma, which is the most common type and accounts for approximately 40%-50% of primary lung cancers. Hypofractionated pulmonary squamous carcinoma is also known as the less differentiated portion of lung squamous carcinoma, as opposed to the more differentiated portion of lung squamous carcinoma. I. Cytology The cytologic presentation of squamous cell carcinoma varies according to the degree of tissue differentiation and the type of specimen. Large tumor cells can be seen in a background of necrosis and cellular debris, accompanied by irregular, deeply stained nuclei, centrally located, with one or more small nucleoli and abundant cytoplasm. The tumor cells are often scattered and may be peculiarly shaped such as spindle and tadpole, or they may show adherent aggregates, usually in flattened sheets with elongated or spindle-shaped nuclei. In well-differentiated squamous cell carcinomas, the keratinized cytoplasm appears egg blue with Robin’s stain, while it may appear orange or yellow with Papanicolaou stain. Superficial tumor cells predominate in exfoliated cell specimens, showing a single scattered distribution with a distinctly keratinized cytoplasm and dense, dark-stained nuclei. In contrast, the cells in the brushed specimens were mostly taken from deeper tissues, and more cells were seen to show adherent aggregation. The appearance of the tumor is often white or gray depending on the degree of fibrosis, with a hard texture, accompanied by local carbon pigmentation, and a stellate retrograde pattern in the center of the lesion to the surrounding area. The tumor may appear large with cavity formation. Central tumors may form intraluminal polypoid masses and/or infiltrate through the bronchial wall into the surrounding tissues, or they may obstruct the bronchial lumen leading to bronchial secretion retention, pulmonary atelectasis, bronchiectasis, obstructive lipoid pneumonia, and infectious bronchopneumonia. In a few cases, it can originate from the small peripheral airways. However, the findings have changed, as one study reported that 53% of squamous cell carcinomas can occur in the peripheral lungs. III. Pathology Squamous cell carcinoma may exhibit features such as keratinization, keratinized bead formation, and/or intercellular bridges. These features manifest differently depending on the degree of differentiation. These features are apparent in well-differentiated tumors and only locally seen in poorly differentiated tumors. Some tumors located in the proximal bronchi may show outward and intrabronchial growth. Sometimes only very limited intraepithelial spread without infiltration is seen, but infiltration formation is present in most cases. Clear cell type SCC is composed mainly or almost entirely of cells with clear cytoplasm. This type needs to be distinguished from large cell carcinoma, lung adenocarcinoma with extensive clear cell changes, and metastatic clear cell carcinoma of the kidney. Small cell type SCC is a poorly differentiated squamous cell carcinoma in which small tumor cells retain morphologic features of non-small cell carcinoma and exhibit localized squamous differentiation. This type must be distinguished from compound small cell carcinoma with a mixture of squamous cell carcinoma and true small cell carcinoma. Small cell type SCC lacks the nuclear features of small cell carcinoma, i.e., rough or vesicular chromatin, more pronounced nucleoli, richer cytoplasm, and clearer cell borders. Intercellular bridges or keratinization may be seen locally. The basal-like pattern may show distinct nuclei arranged in a peripheral fenestrated pattern. Poorly differentiated lung cancers with an extensive basal-like growth pattern but lacking squamous differentiation features may be considered basal-like large cell carcinomas. A peripheral type of SCC showing an alveolar cavity-filling pattern has been described: the tumor cells fill the alveolar cavity but are not accompanied by structural destruction of the alveoli, in contrast to the extended type of SCC that causes structural destruction of the alveoli and lung tissue. This type accounts for only about 5% of peripheral SCC. The rare non-keratinizing squamous cell carcinoma may resemble migratory cell carcinoma. Electron microscopy In squamous cell carcinoma, cytoplasmic keratin intermediate filaments can be observed, often clustered together to form tensegrity filaments. Poorly differentiated carcinomas have a small number of bridging grains and cytoplasmic filaments. Immunohistochemistry The vast majority of squamous cell carcinomas can show high expression of high molecular weight keratin (34βE12), cytokeratin 5/6 and carcinoembryonic antigen (CEA). Many cases can express low molecular weight keratin (35βH11) and very few express thyroid transcription factor-1 (TTF-1) or cytokeratin 7 (CK7). Differential diagnosis Differentiation from large cell carcinoma is based on the presence or absence of squamous differentiation. Intracellular mucin may be present locally. Even if invasive growth is not established, the diagnosis of papillary SCC can be established if there is significant cellular atypia. Diagnosis should be made with caution in small biopsy specimens demonstrating well-differentiated papillary squamous epithelium, as differentiation of papillary squamous carcinoma from papilloma can be difficult. Verrucous carcinoma of the lung is very rare and is included in papillary squamous carcinoma. Extensive invasion of anterior mediastinal tissue can make differential diagnosis with thymic squamous cell carcinoma difficult and needs to be combined with surgical and radiologic findings. In the interstitial lung, squamous cell carcinoma may be surrounded by alveolar cells and can sometimes be misdiagnosed as adenosquamous carcinoma. The presence of squamous metaplasia with cellular atypia in diffuse alveolar destruction (DAD) should be considered as a possible squamous cell carcinoma. the general characteristic manifestations of DAD such as hyaline membrane, diffuse alveolar septal connective tissue hyperplasia with alveolar cell hyperplasia and central squamification of fine bronchi are favorable to consider DAD as a saprophytic lesion process. VII. Pathological criteria Disease staging and behavioral manifestations at diagnosis remain the most useful prognostic indicators for primary squamous cell carcinoma. However, histologic staging may provide independent predictive information for prognosis. For example, well-differentiated squamous cell carcinoma tends to spread locally in the chest and directly invade adjacent mediastinal tissue, whereas poorly differentiated squamous cell carcinoma tends to metastasize early and distantly. The prognosis of alveolar cavity-filling peripheral squamous cell carcinoma is better.