Lepidic and alveolar subepithelial squamous cell carcinoma: expansion of the concept of peripheral squamous cell carcinoma with proposal for revised terminology based on morphologic, immunophenotypic, and clinical analysis of 22 cases

In recent years, peripheral type SCC with alveolar filling growth pattern was described with an increasing prevalence in up to 55% of patients. We describe a series of rare growth pattern of SCC with subtotal or partial growth of tumor cells under reactive type II pneumocytes, termed subepithelial growth. Retrospective case series of 19 resections specimens and 3 biopsies with subepithelial growth of SCC and clinical and radiological correlation is described. All 19 resected SCC showed in histology beside a central invasive component subtotal or partial growth of tumor cells under reactive type II pneumocytes (subepithelial component 10-100%). Immunohistochemistry (IHC) for TTF1/p40 double stain revealed p40 + /TTF1- in the tumor cells and p40-/TTF1 + in the pre-existing epithelial cells. IHC for p53 demonstrated in 91% cases mutation type labeling in the p40 + tumor cells and in 100% cases a wild-type pattern in TTF1 + cells. On CT-scan four cases with subtotal subepithelial component ≥50% presented as part solid nodule with a peripheral ground glass component. Most of tumors were peripheral (91%) and pTNM ranged from pT1bN0M0 to pT3N2M0. In 71% patients with available clinical information, progression free survival (PFS) was 100% after a median follow up of 20 months (range 4-56 months). In 19% of patients association with interstitial lung disease was observed. SCC may spread in a subepithelial manner along alveolar septa under pneumocytes type 2 and could have a corresponding peripheral ground glass radiological pattern. The prognosis of these patients seems favorable, although validation is larger patient cohorts is warranted.