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A case of a purely eccrine nevus in an adolescent patient presenting with focal hyperhidrosis on an area comprising the left forearm and the dorsal aspect of the left hand is described. No clinically evident lesions were identifiable. Dermatopathologic findings were subtle, showing only a slight increase in the number of eccrine glands. Clinicopathological correlation was paramount to achieve the diagnosis.

Lung cancer has the second highest incidence and leads cancer mortality worldwide, being Non-Small Cell Lung Cancer (NSCLC) the most prevalent subtype. Immunotherapy with checkpoint blockers has shown outstanding benefits in a subset of NSCLC patients, which are not accurately identified due to the lack of robust biomarkers of response. We hypothesize that specific molecular alterations of NSCLC tumor cells impact the immune microenvironment. Defining this association could improve the prediction of response to immunotherapy. This work aims to identify a multiparametric biomarker signature. We studied 178 tumor samples from a cohort of early stage NSCLC with complete clinical annotation. We analyzed their molecular aberrations, calculated their Tumor Mutational Burden and described their immune landscape by immunohistochemistry and a dedicated RNAseq panel. We defined novel subgroups of NSCLC tumors with specific immune, molecular and clinical features, showing an association between their molecular genotype and immune phenotype. Based on these data, subgroups were proposed as pro-immunogenic, pro-tumorigenic or mixed. Adenocarcinomas clustered in 4 groups. The pro-tumorigenic group had a significant higher proportion of alterations in ARID1A, FGF10, ROS1, TP53. One pro-immunogenic group had a significant higher proportion of MET alterations and lower proportion of EGFR alterations. An immune mixed group significantly accrued never smokers and had no alterations in FGF10. Squamous cell carcinomas clustered in 4 groups. The pro-tumorigenic group had a significant higher proportion of alterations in CCND1, FGF3, FGF10, FGF19, NOTCH1, PIK3CA, PIK3CB, TFRC. A pro-immunogenic group had a significant higher infiltration of T CD4+, T CD8+ and B cells and a higher overall survival. Another pro-immunogenic group had a significant absence of MYCN and NF1 alterations. Taken together we identified a set of candidate predictive biomarkers of response to immunotherapy in NSCLC. Genes overexpressed in pro-immunogenic tumors are related to adaptive immune response stimulation (CD28, FCRLA, JCHAIN, LY9, MS4A1, SLAMF7, TNFRSF9, TNFRSF17), antigen presentation (CD1C, CD1D, HLA-A), apoptosis (FAS), immune chemotaxis (CCL20, CCR4, CCR6), and immune regulation (CD53, PDCD1, SH2D1A, ZAP70). On the other hand, genes upregulated in pro-tumorigenic tumors are involved in angiogenesis (VEGFA), cell cycle regulation (BUB1, CCNB2, FOXM1, MAD2L1, TOP2A), cell growth/survival (IGF1R), DNA replication/repair (KIAA0101) and iron metabolism (HMBS, TFRC). These findings are being validated by Digital Spatial Profiling in a cohort of patients with advanced stage NSCLC that were treated with checkpoint blockers. If confirmed, these results could remarkably improve patient selection and the benefit upon immunotherapy. Citation Format: Javier Ramos-Paradas, David Gomez-Sanchez, Aranzazu Rosado, Alvaro Conrado Ucero, Nuria Carrizo, Ana Belen Enguita, Maria Teresa Muñoz, Esther Conde, Luis Paz-Ares, Eva Maria Garrido-Martin. Comprehensive analysis of non-small cell lung cancer identifies molecular genotype-immunophenotype associations and candidate biomarkers predictive of response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1245.

8562 Background: Malignant Pleural Mesothelioma (MPM) has been characterized by an immune suppressive microenvironment. The immune checkpoint (IC) VISTA is notably expressed in MPM, in contrast to other IC proteins such us PD-L1. Recently, CD47 has been described as a possible diagnostic biomarker for MPM, although its impact in prognosis has not been established yet. Methods: This is a retrospective observational study of immunotherapy naïve MPM patients. Immunochemistry (IHC) assessment of PD-L1, VISTA and CD47 protein expression was performed on tissue microarray of 46 surgical samples. Means were compared using Mann-Whitney U test. Correlation was estimated using Pearson’s coefficients. Overall survival (OS) was assessed using Kaplan–Meier curves and Cox proportional hazard models. A two-sided alpha error of 0.05 was used to assess statistical significance. Statistical analysis was conducted with Stata/SE version 16.1. Results: A total of 46 patients, 71.7% (33/46) male, were included in our study. Among them, 77.8% (35/45) had stage IIIB-IV, 84.8% (39/46) had received systemic therapy and 16.7% (7/42) had undergone radical-intent surgery. Asbestos exposure was confirmed in 65,7% (23/35) patients. Regarding the histological subtype, 71.7% (33/46) were epithelioid (Ep) and 13.0% (6/46) non-epithelioid (NEp), including 5 sarcomatoid and 1 biphasic. In IHC analysis, VISTA and CD47 were expressed in 63.0% (29/46) and 58.7% (27/46), respectively, whereas only 28.3% (13/46) patients had positive PD-L1 expression (≥1%). Median expression of VISTA, CD47 and PD-L1 in tumor samples was 41.8 (95% IC 0.5 - 50.7), 26.3 (95% IC 0 - 45.8) and 0 (95% IC 0-0.5), respectively. VISTA and CD47 expression were significantly higher in the Ep subgroup vs. the NEp subgroup (VISTA 39.4% vs 7.2% p = 0.028; CD47 37.3 vs. 0.8 p = 0.01). Additionally, we found a significant positive correlation between VISTA and CD47 protein expression (Pearson's r = 0.55, p < 0.001), which was consistent with the results we found in an independent MPM patient series from TCGA PanCancer Atlas (N = 87) based on RNA expression (r = 0.46; p < 0.001). Median OS, available in 40/46 cases, was 16.6 months (95% CI 12.03-20.43). On multivariate analysis, CD47 ≥1% expression was significantly associated with longer OS (29.7 vs 10.53 months, HR 0.35, [IC 95% 0.14-0.86]; p = 0.02) after adjusting for histological subtype, PDL1 and VISTA expression. In contrast, PD-L1 ≥1% showed a trend towards worse prognosis (10.3 vs 19.3 months), without reaching statistical significance (HR 2.23 [95% IC 0.95-5.23]; p = 0.065). No OS differences were found regarding VISTA expression. Conclusions: To our knowledge, this is the first study to describe VISTA and CD47 correlation in MPM. Moreover, we demonstrate CD47 expression to be an independent prognostic marker in MPM, suggesting C47 may play a key role in tumor biology of MPM, for which further validation and functional studies are necessary.

e18015 Background: PD-L1 is a biomarker of response to anti-PD1 in HNSCC. CA209-7HE trial (NCT04282109) is a randomized, open-label, multicenter, phase II trial including first line R/M HNSCC pts non-eligible for cisplatin-based chemotherapy. Pts were stratified according to Karnofsky performance status, HPV and tissue PD-L1 by Combined Positive Score (CPS). Subjects were randomized to either paclitaxel + nivolumab or paclitaxel + cetuximab. Primary objective was 2-year overall survival. We present the data on centrally determined PD-L1 patterns and its correlation with pt clinical characteristics. Methods: From 176 preliminary samples, only 141 were analyzed. 10 were excluded for not fulfilling quality requirements and 25 belonged to non-eligible pts. 74% (104) were paraffin blocks and 26% (37) tissue slides. 72.3% (102) were primary tumor biopsies, 12.7% (18) local soft tissue relapses, 9.2% (13) lymph node metastases and 5.6% (8) distant metastases. 46.6% (66) were collected from irradiated areas. Hematoxylin-eosin stain confirmed sample representativeness. At least 100 tumor cells/sample was required. Immunohistochemistry for PD-L1 was performed using DAKO PD-L1 IHC 22C3. Means and proportions were dropped for descriptive analyses. Multivariate logistic regresion was used to identify variables associated with higher CPS. Results: Clinical characteristics included 73% (103) males; 77% (108) were either former [56% (78)] or current smokers [21.2% (30)] and clinical stage was recurrent in 48.9% (69), metastatic alone in 29.8% (42) and both recurrent and metastatic in 21.3% (30). Diagnoses included 35.4% (51) oral cavity, 32.3% (45) oropharynx (only 2 pts HPV positive), 16.3% (23) larynx and 15.6% (22) hypopharynx. Mean time to CPS assessment was 5.25 days (CI 95% 4.95 – 5.55). CPS distribution was as follows: 21.7% (31) were CPS < 1, 42.8% (60) were CPS 1-20 and 35.4% (50) were CPS > 20. Multivariate model revealed that oral cavity tumors showed an increased likelihood of CPS > 20 (OR 2.35, 95%CI 1.46 - 3.78; p < 0.001) which was also seen among non-smokers (OR 3.37, 95% CI 1.16 - 9.73; p = 0.02) and pts with recurrent and metastatic disease (OR 2.75, 95% CI 1.03- 7.32; p = 0.04). Oropharyngeal tumors showed lower probability for CPS > 20 (OR 0.35, 95% CI 0.14 - 0.89; p = 0.03). Neither prior irradiation nor origin of the biopsy were associated with any significant variation in CPS. Conclusions: Central assessment of CPS is feasible with no significant treatment delay. HPV negative oropharyngeal tumors were not associated with higher CPS. We also found that oral cavity tumors, non-smokers and pts with recurrent and metastatic disease were independently associated with an increased probability of higher CPS. Future results will elucidate the promising role of combinatorial regimens with immunotherapy in these subpopulations. Clinical trial information: NCT04282109.

e21128Background: Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors ...

The new the International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) pathologic classification of lung cancer has markedly changed the pathologic diagnosis of lung adenocarcinoma. This classification deals with many aspects that directly affect clinical practice, and opens new gateways for future research. By means of a multidisciplinary approach, it differs significantly from the former 2004 the World Health Organization (WHO) classification, which was mainly written by pathologist. The present review, in line with the consensus article, is divided in two components: the diagnosis and classification of lung adenocarcinoma in resection specimens and the diagnosis of lung cancer in small biopsies and cytology. Resection specimens are currently classified according to the predominant histologic pattern after comprehensive subtyping in 5% increments. This approach has led to the addition of new pathologic subtypes [adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and micropapillary predominant adenocarcinoma)] and to the discontinuation of some heterogeneous entities included in the former 2004 WHO classification (mixed subtype adenocarcinoma and bronchioloalveolar carcinoma). Overall, these changes have resulted in a better stratification of lung adenocarcinoma tumors in more homogeneous morphologic, clinical and biological subgroups. Pathologic subtyping has demonstrated prognostic utility in resected stage I-III patients, and recent data support their predictive role for the benefit of adjuvant chemotherapy. Moreover, comprehensive pathologic subtyping may potentially affect TNM staging and surgical management or early-stage tumors. On the other hand, for the first time, the novel pathologic classification provides standardized terminology and diagnostic criteria of small biopsies and cytology. Criteria are proposed not only for adenocarcinoma but also for other histologies, but special emphasis was put on the distinction between adenocarcinoma and squamous-cell carcinoma due to its major clinical implications. This review outlines the main issues of the new lung adenocarcinoma classification from a clinical perspective. We describe the different pathologic subtypes in resection specimens, with their most relevant clinical implications. Further on, we address the new terminology and diagnostic criteria for lung adenocarcinomas in small specimens, oriented to their importance for the management and treatment of metastatic lung cancer patients. Finally, we discuss some unanswered questions and relevant issues for the near future.

e22112 Background: Detection of EGFR m in p with NSCLC is done in a routine way. Given the data published on ALK positive p detection is crucial for therapeutic decision making. ALK t should be per...