Mauro Papotti

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. Methods: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. Results: 39 patients (M:F = 26:13), with a median age of 64 years (44–83), were included. Lobectomy (69.2%), bilobectomy (5.1%), pneumonectomy (18%), and wedge resection (7.7%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9% of cases. After a median follow-up of 44 (4–169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0%, 54.6%, and 44.9%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95%CI = 1.46–12.07, p = 0.008 and HR = 13.56, 95%CI 2.45–74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95%CI 2.23–38.83, p = 0.002 and HR = 11.88, 95%CI 2.28–61.84, p = 0.003, respectively). Conclusion: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy.

Adrenal cortical carcinoma (ACC) is a rare and aggressive malignancy that poses challenging issues regarding the diagnostic workup. Indeed, no presurgical technique or clinical parameters can reliably distinguish between adrenal cortical adenomas, which are more frequent and have a favorable outcome, and ACC, and the final diagnosis largely relies on histopathologic analysis of the surgical specimen. However, even the pathologic assessment of malignancy in an adrenal cortical lesion is not straightforward and requires a combined evaluation of multiple histopathologic features. Starting from the Weiss score, which was developed in 1984, several histopathologic scoring systems have been designed to tackle the difficulties of ACC diagnosis. Dealing with specific histopathologic variants (eg, Liss-Weiss-Bisceglia scoring system for oncocytic ACC) or patient characteristics (eg, Wieneke index in the pediatric setting), these scores remarkably improved the diagnostic workup of ACC and its subtypes. Nevertheless, cases with misleading features or discordant correlations between pathologic findings and clinical behavior still occur. Owing to multicentric collaborative studies integrating morphologic features with ancillary immunohistochemical markers and molecular analysis, ACC has eventually emerged as a multifaceted, heterogenous malignancy, and, while innovative and promising approaches are currently being tested, the future clinical management of patients with ACC will mainly rely on personalized medicine and target-therapy protocols. At the dawn of the new Fifth World Health Organization classification of endocrine tumors, this review will tackle ACC from the pathologist’s perspective, thus focusing on the main available diagnostic, prognostic, and predictive tissue-tethered features and biomarkers and providing relevant clinical and molecular correlates.