This study aims to define the clinicopathological characteristics and prognosis of non-predominant lepidic invasive adenocarcinoma presenting as Ground Glass Opacity (GGO) nodules. The goal is to assess statistical relationships between histology, tumor size, location, and the incidence of relapse and lymph node dissemination. A retrospective multicenter study was conducted, including patients with GGO observed on CT scans between 2003 and 2021. Anamnestic, radiological, and histological data, as well as SUV values, lymphatic and vascular invasion, pathological stage, resection type, and adjuvant treatment, were analyzed. The primary endpoints were to evaluate prognostic factors for death and recurrence using Cox regression analysis. All 388 patients, including 277 with non-predominant lepidic invasive adenocarcinoma and 161 with lepidic adenocarcinoma, underwent curative anatomical resection. Non-predominant lepidic invasive adenocarcinoma demonstrated a worse prognosis than lepidic adenocarcinoma (p = 0.001). Independent prognostic factors for death and recurrence included lymph node involvement (p = 0.002) and vascular and lymphatic invasion (p < 0.001). In conclusion, non-predominant lepidic invasive adenocarcinoma and lymphatic and vascular invasion are prognostic factors for death and recurrence in GGO patients. Results suggest adjuvant treatment in the case of pN1-N2 disease, emphasizing the necessity of lymphadenectomy (sampling or systematic) for accurate staging and subsequent therapeutic procedures.

Background/Objectives: Acute Fibrinous and Organizing Pneumonia (AFOP) is a rare pulmonary condition histologically characterized by intra-alveolar fibrin deposition and organizing pneumonia without hyaline membranes. This study aims to describe the clinicopathologic and radiologic features of isolated AFOP nodules presenting as solitary pulmonary nodules (SPNs) mimicking malignancy in patients with recent COVID-19 infection. Methods: We retrospectively analyzed consecutive cases of histologically confirmed AFOP (n = 20) and organizing pneumonia (OP; n = 119) presenting radiologically as SPNs suspicious for malignancy from January 2021 to December 2023. Clinical data, COVID-19 status, radiologic features (including nodular characteristics, ground-glass opacity [GGO], and consolidation), and histopathological findings were collected and analyzed. Digital image analysis quantified the intra-alveolar fibrin content. Results: AFOP nodules showed a significant association with previous COVID-19 infection compared to OP (55% vs. 0.8%, p < 0.001). Radiologically, AFOP lesions were predominantly located in the upper lobes, frequently exhibiting a mixed pattern of GGO and consolidation within solitary nodules (8–28 mm diameter), distinctly differing from the predominantly lower-lobe homogeneous consolidations in OP. Histologically, AFOP was defined by prominent intra-alveolar fibrin “balls,” correlating significantly with radiological consolidation patterns (r = 0.991, p < 0.05). Regions of consolidation demonstrated higher fibrin contents compared to areas of predominant GGO. Conclusions: Isolated AFOP nodules presenting as SPNs post-COVID-19 infection strongly mimic malignancy radiologically, highlighting the necessity for multidisciplinary diagnostic approaches integrating radiological and histopathological data to avoid unnecessary interventions. Recognition of this rare but distinctive clinical entity is essential for appropriate patient management.