A healthy, 78-year-old Korean woman was admitted to the hospital with an incidental mass in the left lung. The computed tomography (CT) scan of the left upper lung showed a sub-solid nodule measuring 23 mm in diameter, suggestive of AIS or minimally invasive adenocarcinoma. The patient had no surgical history, had never smoked, and was relatively healthy. A segmentectomy was performed to remove the pulmonary mass. Grossly, the resected lung measured 10.3×5.3×4.5 cm and weighed 30 g in total. The pleural surface of the mass was smooth. The tumor measured 2.2×1.8 cm, was fibrotic and whitish and grey colored without hemorrhage or necrosis, and did not involve the pleura. Hematoxylin and eosin–stained histology sections showed lepidic growth of atypical columnar cells with enlarged nuclei and irregular nuclear contours (Fig. 1A). There were multiple intraalveolar nodular proliferative foci composed of atypical spindle cells with eosinophilic cytoplasm (Fig. 1B). Cells in the nodular proliferative lesions were arranged in a whorled pattern, normally interpreted with a squamoid appearance, yet obvious squamous differentiation was not seen. The underlying pulmonary architecture was preserved, which suggested that stromal invasive foci were not present. Neither lymphovascular nor pleural invasion was evident; therefore, the final diagnosis was non-mucinous type AIS. Upon immunohistochemistry, the cells forming morule-like features were positive for thyroid transcription factor 1 (TTF-1) and cytokeratin (CK), but negative for p40, CDX-2, neuron-specific enolase, chromogranin, and synaptophysin (Fig. 1B, inset). There were no remarkable features in normal lung tissue. We also performed NGS analysis and revealed an insertion in epidermal growth factor receptor (EGFR) exon 20 (NM_001346897.1: c.2180_2185dup) with 35.5% mutation abundance. There was no evidence of recurrence or metastasis at 1-year follow-up.

A healthy, 46-year-old Korean woman was admitted to the hospital with an incidental mass in one lung. The CT scan of the right lower lung showed a sub-solid nodule measuring 29 mm in diameter with a 12-mm-sized solid portion. The mass was associated with apical pleural thickening, suggestive of a malignant tumor with pleural invasion. The patient had no surgical history, had never smoked, and was relatively healthy. A lobectomy was performed to remove the sub-solid nodule from the right lower lung. Grossly, the resected lung specimen was 16.9×14.5×4.3 cm. The pleural surface showed umbilicated foci, suggestive of pleural invasion. Upon sectioning, the cut surface showed an ill-demarcated, whitish-grey, fibrotic mass measuring 2.7×1.3 cm with pleural invasion. Upon microscopic examination, the tumor was identified as an acinar-predominant adenocarcinoma with a micropapillary component. In the region of the acinar-predominant adenocarcinoma, multiple morule-like foci were identified floating within the intra-alveolar space without clear evidence of squamous differentiation (Fig. 1C, D). In accordance with the gross findings, visceral pleural invasion was confirmed by microscopy. Lymphatic invasion was also evident, yet there was no lymph node metastasis. Additional studies were performed to determine molecular characteristics of the morule-like component. Fluorescent in situ hybridization for anaplastic lymphoma kinase (ALK) gene rearrangement was performed on a preoperative diagnostic needle biopsy specimen and showed split signals in four out of 100 analyzed cancer cells, indicating the absence of ALK rearrangement. We performed NGS analysis on a formalin-fixed paraffin-embedded section of a surgical specimen, and a L747S missense mutation was detected in EGFR exon 19 (NM_005228.3: c.2240T>C) with 24.8% mutation abundance. There was no recurrence or metastasis at 1-year follow-up.