Histopathologic features and subtypes of invasive cutaneous squamous cell carcinoma: A comprehensive review

Invasive cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous malignancy after basal cell carcinoma and displays a remarkably heterogeneous spectrum of histopathologic variants, several of which pose significant diagnostic challenges and carry distinct clinical, immunohisto-chemical, and molecular implications. In this review, we discuss the principal histopathologic subtypes of invasive cSCC, including acantholytic, sarcomatoid (carcinosarcoma/metaplastic), spindle cell, clear cell, verrucous, papillary, pigmented, adenosquamous, signet ring cell, rhabdoid, lymphoepithelial, and squamo-melanocytic variants, as well as cSCC associated with Merkel cell carcinoma and tumors showing single-cell infiltration. For each entity, we summarize the characteristic clinical presentation, key histopathological features, differential diagnosis, immunohistochemical profile, and, where available, molecular alterations, with particular attention to UV-induced mutations in TP53, NOTCH1/2, and CDKN2A shared across most subtypes. Treatment and prognostic data are also reviewed, highlighting that while most variants follow conventional surgical principles for cSCC, with margin-controlled excision and Mohs micrographic surgery playing a central role, certain subtypes-namely spindle cell/sarcomatoid, rhabdoid, and tumors with single-cell infiltration-are associated with markedly more aggressive behavior and require intensified management. Conversely, entities such as acantholytic, clear cell, verrucous, papillary, and pigmented SCC generally behave indolently despite sometimes alarming histological appearances. Overall, prognosis in cSCC remains primarily driven by established risk factors-tumor size, depth, differentiation, location, and perineural invasion-rather than histologic subtype alone. A refined understanding of these variants, supported by targeted immunohistochemistry and molecular evaluation when indicated, is essential for accurate diagnosis, appropriate risk stratification, and optimal treatment planning.