Large Cell Neuroendocrine Carcinoma Research Articles

Neuroendocrine cervical cancer: Have we made any steps forward in its management?

IntroductionNeuroendocrine tumors (NEC) were first described by Albores-Saavedra in 1972 and these tumors account for only 0.9% to 1.5% of all invasive cervical cancers.1,2 The most common type is small cell neuroendocrine carcinoma (SCNEC) of the cervix, which accounts for 80% of cases.2 The poor prognosis despite advances in treatment remains still a huge problem, so the aim of our review is to cover all current therapeutic options. MethodWe searched for all available interventional studies, reviews, case reports and meta-analyses published from 1995 to 2023. ResultsIn 2017 Castle et al.9 published a systematic review and meta-analysis and concluded that SCNC and large cell neuroendocrine carcinoma (LCNC) are, in most cases, caused by HPV, primarily HPV18 and HPV16. Comparative genomics data suggest that cervical NEC may be genetically more similar to common cervical cancer subtypes than to extra-cervical SCNEC of the lung and bladder.13 Surgery is recommended as the primary treatment in early stages of disease, with radical hysterectomy and nodal assessment followed by adjuvant pelvic radiotherapy and/or chemotherapy. However, simple hysterectomy may be adequate when followed by adjuvant radiotherapy with concurrent cisplatin and etoposide as additional chemotherapy.15 Considering that pathologic and clinical behavior is similar to small cell lung cancer, patients usually receive platinum and etoposide as part of their primary therapy.16 The recurrent disease remains a major clinical problem, because there is no standard treatment modality for these patients, and individualized therapy is recommeded. ConclusionCurrent therapeutic modalities are mainly based on experience in the treatment of SCNEC of the lung. Certainly, a multidisciplinary approach is very important inorder to design a personalized management plan.

Mixed Large Cell Neuroendocrine Carcinoma and Endometrioid Adenocarcinoma: A Rare Case Report with Review of Literature

ABSTRACT We report the case of a 60-year-old female who presented with postmenopausal bleeding after she underwent investigations followed by a total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic lymphadenectomy. A diagnosis of low-grade endometrioid adenocarcinoma admixed with large cell neuroendocrine carcinoma (NEC) was made based on the histomorphology and immunohistochemical profile. NEC of the endometrium is a rare and highly aggressive neoplasm requiring a multidisciplinary approach for its treatment. As treatment strategies are changing over time, preoperating imaging evaluation and histopathological examination with molecular characterization whenever possible are essential to follow, to offer the appropriate information to surgeons and/or oncologists for optimal management in these patients.

Large cell neuroendocrine carcinoma of oral cavity: A rare case report with review of literature

Abstract Neuroendocrine tumours (NETs) primarily affect the lungs and larynx. Primary neuroendocrine carcinomas (NECs) rarely occur in the oral cavity. The classification of these tumours is ambiguous; however, the literature acknowledges their aggressiveness. Merkel cell carcinoma (MCC) is rare and more common in the skin but could occur intraorally. MCC and NECs are aggressive neoplasms and recommend intensive treatment. In this case report, a 22-year-old female presented with an ulceroinfiltrative lesion in the left buccal mucosa of the cheek, which was diagnosed as primary NEC in the oral cavity. This patient underwent wide local lesion excision of oral cavity mass, ipsilateral selective neck node dissection of levels 1–4 and postoperative chemotherapy. This aggressive tumour type requires large local excisions with margins like Merkel cell skin carcinomas. To our knowledge, this is the youngest oral cavity primary neuroendocrine cancer patient to date in the literature.

Esophageal Large-Cell Neuroendocrine Carcinoma Mimicking Benign Submucosal Tumor Treated with Endoscopic Submucosal Dissection

Esophageal Large-Cell Neuroendocrine Carcinoma Mimicking Benign Submucosal Tumor Treated with Endoscopic Submucosal Dissection

Predictors of lymph node metastasis and survival in radically resected rectal neuroendocrine tumors: A Surveillance, Epidemiology, and End Results (SEER) database analysis

BackgroundRectal neuroendocrine tumors are uncommon tumor types. Lymph node metastases may occur in up to 40%, potentially impacting decision-making. We aimed to assess risk factors for lymph node metastases of rectal neuroendocrine tumors and their association with overall and cancer-specific survival. MethodsThis retrospective case–control study involved patients with stage I to III rectal neuroendocrine tumors who underwent radical resection. Data were derived from the Surveillance, Epidemiology, and End Results database (2000–2020). Patients with pathologic evidence of lymph node metastases were compared to those without lymph node metastases for baseline patient and tumor characteristics. The main outcomes were lymph node metastases, overall survival, and cancer-specific survival. ResultsIn total, 580 patients (50.9% male; mean age: 58.9 years) were included. The lymph node metastases rate was 37.1%. Independent predictors of lymph node metastases were Grade 2 neuroendocrine tumors (odds ratio: 8.06; P = .001), neuroendocrine carcinoma (odds ratio: 2.59, P = .006), large-cell neuroendocrine carcinoma (odds ratio: 4.89; P = .017), T2 tumors (odds ratio: 6.44; P < .001), T3 tumors (odds ratio: 27.5; P < .001), and T4 tumors (odds ratio: 17.3; P < .001). Lymph node metastases were associated with shorter restricted mean overall survival (40.8 vs 52.7 months; P < .001) and cancer-specific survival (41.3 vs 54.8 months; P < .001). When adjusted for other confounders, the nodal status of rectal neuroendocrine tumors was not independently associated with overall (hazard ratio = 1.56; P = .165) or cancer-specific survival (hazard ratio = 1.69; P = .158). Significant factors associated with worse overall survival and cancer-specific survival were age, tumor size, neuroendocrine carcinomas, large-cell neuroendocrine carcinomas, and the number of positive lymph nodes. ConclusionsLymph node metastases of rectal neuroendocrine tumors were more likely associated with high-grade, large-sized, and T2 to T4 tumors. The number of involved lymph nodes was an independent predictor of overall and cancer-specific survival. Other independent survival predictors were tumor grade, size, and T stage.

Prognostic factors and nomogram for pulmonary resected high-grade neuroendocrine carcinomas: a 20-year single institutional real-world experience

BackgroundPulmonary high-grade neuroendocrine carcinomas(pHGNEC) encompassing small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are clinically aggressive tumors with poor prognosis. The role of surgery and prognostic factors guiding management remain unclear. We aimed to analyze prognosis following resection and identify predictive variables.MethodsThis retrospective study analyzed 259 patients undergoing pHGNEC resection from 2001–2023. Overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan–Meier curves. Prognostic factors were assessed with Cox regression and visualized using nomogram tools.ResultsMinimally invasive surgery was associated with better OS (p = 0.001) and DFS (p = 0.001). Higher T stage predicted worse OS (T2 p = 0.044, T4 p = 0.007) and DFS (T2 p = 0.020, T4 p = 0.004). Advanced TNM stage III (OS p = 0.018; DFS p = 0.015) and IV (OS p < 0.001; DFS p < 0.001) also correlated with poorer prognosis. In the SCLC subgroup, elevated preoperative CEA independently predicted worse OS (p = 0.012) and DFS (p = 0.004). T4 disease (OS p < 0.001; DFS p = 0.002) and advanced TNM staging (stage III OS p = 0.043; DFS p = 0.045; stage IV OS p < 0.001, DFS p < 0.001) were associated with worse outcomes. In LCNEC patients, VATS resection improved OS (p = 0.048) and DFS (p = 0.027) despite conversion. Prior malignancy predicted worse OS (p < 0.001). Advanced TNM disease (stage III OS p = 0.047; stage IV OS p = 0.003, DFS p = 0.005) were also negative prognostic factors. The prognostic nomogram incorporating above variables effectively stratified risk. Calibration plots revealed good correlation between predicted and actual survival.ConclusionsWe identified minimally invasive surgery, early TNM stage, younger age, and normal preoperative CEA as positive prognostic factors following pHGNEC resection. Our study provides an applicable prognostic nomogram to facilitate personalized pHGNEC management.

"Aberrant" expression of skeletal muscle markers in neuroendocrine carcinomas: a significant diagnostic pitfall.

In this study, we investigate the expression of muscle markers, including the specific skeletal muscle markers myogenin and myoD1, in neuroendocrine carcinomas (NECs). The study included 23 NECs from various sites (14 small cell NECs and 9 large cell NECs). These were stained with desmin, myogenin and myoD1. Positive staining with at least one muscle marker was observed in 14 cases (61%). 8 (35%), 8 (35%) and 11 (48%) of the cases were positive with desmin, myogenin and myoD1 respectively. In most, but not all, cases positive staining was focal generally involving < 10% of tumour cells. Expression of muscle markers is not uncommon in NECs. This represents an important diagnostic pitfall of which pathologists should be aware. In reporting this phenomenon, we speculate on the pathogenesis of this "aberrant" expression of muscle markers.

Comparison of chemotherapy to chemo-immunotherapy as first-line treatment in patients with advanced large cell neuroendocrine carcinomas (LCNECs) of mixed histology: A multi-institutional international retrospective study.

8602 Background: LCNECs are a rare subtype of lung cancer, with limited clinical trial data and an unclear consensus on first-line treatment. Even less is known about the optimal treatment approach for pts with mixed LCNECs, a pathologic subtype where tumors contain both LCNEC histology as well as features of adenocarcinoma, squamous cell, or small cell lung cancer. Methods: We conducted an international multi-institutional retrospective analysis (n=13 institutions) of pts with advanced or metastatic mixed LCNECs who received 1st-line systemic therapy with either chemotherapy alone (chemo) or chemo-immunotherapy (chemoIO) between 2010-2023. Clinical outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events (trAEs). Survival comparisons were made via the log-rank test. Results: Seventy-three pts with mixed LCNECs received either chemo (n=42, 57.5%) or chemoIO (n=31, 42.5%). The most common chemo regimens were carboplatin/etoposide (n=27) and cisplatin/etoposide (n=8), while the most common chemoIO was carboplatin/etoposide/atezolizumab (n=19). Median age at 1st-line therapy initiation was 65 (IQR: 60-72). 64% of pts were male (n=47). The majority were former smokers (n=41, 56.2%), with 22 current smokers (30.1%), and 10 non-smokers (13.7%). Mixed histologies included LCNEC/NSCLC (n=45, 56.2%), LCNEC/SCLC (n=17), LCNEC/carcinoid (n=1), and unspecified mixed LCNEC (n=10). Median PFS for chemo was 5 months (95% CI 2.7-9.2) vs. 6 months (95% CI 4.4-8.3) for chemoIO ( p=0.86). Median OS for chemo was 14.2 months (95% CI 10.4-22.5) vs. 17.2 months (95% CI 9.4-27.2) for chemoIO ( p=0.66). The ORR did not differ between chemo (n=18, 45%) and chemoIO (n=15, 48.4%) ( p=0.81). In the chemo group, 60% (n=25) experienced trAEs of any grade, with 23.8% (n=10) experiencing grade 3+ events and four requiring hospitalizations. For chemoIO pts, 61% (n=19) experienced trAEs, with 25.8% (n=8) experiencing grade 3+ events and six requiring hospitalizations. Neutropenia was the most common grade 3+ trAE for both chemo (n=5) and chemoIO (n=4). Overall, there were no significant differences between chemo or chemoIO groups for ORR ( p=0.81), all-grade trAEs ( p=0.88), grade 3+ trAEs ( p=0.84), PFS ( p=0.86), or median OS ( p=0.66). There were no significant differences in median PFS ( p=0.46) or OS ( p=0.99) for pts with mixed LCNEC/NSCLC vs. LCNEC/SCLC. Conclusions: For mixed LCNECs, there was no significant difference in PFS or OS between first-line treatment with chemo vs. chemoIO, suggesting limited benefit from immunotherapy for these pts. Additionally, survival outcomes did not differ between mixed LCNEC/NSCLC and LCNEC/SCLC, suggesting a biology primarily driven by their neuroendocrine component.

Phase II study of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors.

TPS3183 Background: Advanced sinonasal malignancies are rare and heterogeneous cancers with limited therapeutic options. Tumor types include olfactory neuroblastoma (ONB), sinonasal undifferentiated carcinoma (SNUC) and large cell neuroendocrine carcinoma (LCNEC), chondrosarcoma, and sinonasal adenocarcinoma (SNAC). Pathogenic driver mutations in isocitrate dehydrogenases 1 and 2 ( IDH1 and IDH2) were identified first in glioma and myeloid malignancies. IDH1/2 enzymatic activity catalyzes conversion of isocitrate and NADP+ to α-ketoglutarate (α-KG) and NAPDH, which are critical for cellular metabolism and for α-KG-dependent dioxygenases; mutant IDH1/2 catalyze conversion of α-KG to the oncometabolite 2-hydroxyglutarate (2-HG), a competitive antagonist of α-KG in regulating dioxygenases activity, with subsequent impact on DNA histone methylation and cellular differentiation. R172S or R172T IDH2mut have been detected in up to 80% of SNUCs and in a minority of ONB, chondrosarcoma, LCNEC and SNAC. Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation block. It is currently approved for relapsed/refractory IDH2mut myeloid malignancies with proven clinical efficacy. Methods: This is a phase 2, single arm clinical trial conducted at the Center for Cancer Research (CCR) of the National Cancer Institute. The trial investigates the activity of enasidenib in adult patients with histologically or cytologically confirmed locally advanced or metastatic IDH2mut sinonasal cancers (SNUC, ONB, LCNEC, chondrosarcoma, SNAC). Participants must have RECIST 1.1 measurable disease and must have progressed following at least one prior systemic treatment line administered in the recurrent/metastatic setting; those with locally advanced disease must not be amenable to potentially curative approaches. Participants must also have ECOG performance status ≤ 2, be 18 years old or higher, and have adequate organ function. Participants with active, either new or progressive brain metastases or leptomeningeal disease are excluded. Enasidenib will be given continuously at a fixed dose of 100 mg orally daily in a 28-day cycle, until disease progression, unacceptable toxicity, or consent withdrawal. Imaging will be performed every 8 weeks. Baseline and on-treatment research biopsies will be mandatory, where clinically feasible. The trial aims to accrue a total of 25 participants. The primary end point is progression free survival. Secondary outcomes include safety, overall survival, and clinical benefit rate, defined as complete response, partial response and stable disease (per RECIST 1.1) lasting above 4 months. Correlative studies include evaluating changes in 2-HG plasma levels during treatment, and transcriptomic profiling. The study has just started enrolling in the CCR. Clinical trial registry: NCT06176989. Clinical trial information: NCT06176989 .

Cytopathology and clinicopathological correlation of renal neuroendocrine neoplasms

Cytopathology and clinicopathological correlation of renal neuroendocrine neoplasms

Lung cancer MDT quality assessment: A nationwide study.

8594 Background: This observational study evaluates concordance between lung cancer multi-disciplinary team (MDT) meetings, focusing on diagnosis, staging, and treatment recommendations, especially for curative options. Assessing MDT decisions aims to identify factors potentially affecting survival rates, promoting equal treatment access for patients nationwide. Methods: In Norway, patients with lung cancer are discussed at local MDT (without a thoracic surgeon present) and at university hospital MDT (with a thoracic surgeon present). All hospitals received 35 fictitious case reports of patients with inoperable non-small cell (NSCLC) and small cell lung cancer (SCLC) with anonymized CT and PET images for discussion at the ordinary MDT meetings. Of the 12 participating hospitals, 5 were university hospitals. Results: Of the 35 patient’s cases, 12 were assessed as having stage III NSCLC. For 10 of the 12 there were differences in stage assessment, from stage IIIA-B-C to IV, and in recommended treatment (Table). For each case, curative treatment was recommended by a varying number of MDTs, from zero to nine of 12. Treatment suggestions for the four SCLC patients were identical except for one patient with stage IV, performance status (PS) score 2-3 and stroke, for whom the recommended treatment ranged from best supportive care (BSC) to triple therapy. There was generally good consensus between recommending treatment with a tyrosine kinase inhibitor (TKI) in patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) translocation positivity. We found that factors leading to discrepancies in MDT decisions were patients age &gt;75-80 years, comorbidities, PS 2 or lack of a stated PS, PD-L1 more than 50-75% in stage IV and large cell neuroendocrine carcinoma (LNEC). Conclusions: MDT-recommendations regarding treatment varied between MDT sites, and this may have the greatest consequences for patients in stage III. MDT treatment recommendations varied between the sites, confirming that treatment choice can be challenging in certain type of cases like elderly, poor PS or LNEC. Shared decision-making (SDM) with patients was often recommended. As an important outcome of the study, we found no difference in treatment choice between local and university hospital MDTs. [Table: see text]

Lung cancer in females from nonsmoker families in India: Observations and inferences in 5 years.

e20610 Background: Incidence in lung cancer in last two decades has been changing drastically in terms of gender, age, smoking behaviour of patients, stage at presentation, histopathology, genetic abnormalities, operability at presentation and survival. More perplexing is the increase in its occurrence in females from non smoker families, mitigating the sole importance of the traditional risk factors of tobacco and smoking in the recent times. This highlights the need to investigate other risk factors like radon exposure from indoor pollution where females stay most of the time, exposure to arsenic and other chemicals in daily life, particle pollution, physical inactivity and inflammatory diseases of airways. Methods: It was an observational study of patients who were diagnosed and treated at a high volume cancer centre in Karnataka state of India. 89 never smoker female patients under 50 years of age from non smoker families with no obvious exposure to second hand or third hand smoke were enrolled from October, 2018 to June, 2023. It was a longitudinal prospective cohort study where the demographic data, symptoms with duration, histopathology including genetic abnormalities, treatment details and survival were noted. Results: 89 never smoker females from non smoker families with ages ranging from 36 to 50 years had a median age of 46 years. About 70% of the ladies were from houses closely associated with farm in past or present. 55% of them had overweight and obese body habitus. Most common presenting symptom was dry cough with median duration of about 3 months in about 89%. Other symptoms were pleuritic chest pain(39%), breathlessness (19%), generalized body ache(9%) and jaundice(2%). Stage of disease was IV(69%), IIIC(12.3%), IIIB(11.2%), IIIA(5.6%) and II in just one patient. Most common sites of metastasis were contralateral lung(45%), bone(20%), liver(20%), adrenal glands(10%) and brain (15%). Most common histopathology was adenocarcinoma(87.6%), adenosquamous carcinoma(7.8%), squamous cell carcinoma(3.3%), large cell neuroendocrine carcinoma in just one patient. EGFR was mutated in 56(62.9%) with deletion 19( 33%) and L858R(21%) being the most common abnormalities. ALK rearrangements and ROS1 fusion were seen in about 9(3.3%) and 3(3.3%) patients respectively. Surgery was done in only 3 patients and chemoradiation after neoadjuvant chemotherapy was given in 8(8.9%) patients. Median overall survival was about 42 months in stage IV patients. Conclusions: Changing demographic profile of lung cancer warrants more research into the other causes of lung cancer. More stage IV disease highlights the emphasis on prevention and screening for the disease.

Prognostic nomogram, demographics and comparative analysis of prostate small cell and large cell neuroendocrine carcinoma.

e17010 Background: This retrospective study aims to examine the patient demographics, survival rates, and treatment methods for small-cell neuroendocrine carcinoma (SCNEC) and large-cell neuroendocrine carcinoma (LCNEC) of prostate origin while also identifying the main differences from common types of prostate cancer. Methods: Our analysis utilized the Surveillance, Epidemiology, and End Results database (SEER), and data was collected from 2000-2020. Results: A total of 718 cases of prostate small and large neuroendocrine carcinoma were identified. The median age was found to be 71.5 years and the median follow-up was 11.0 years (95% confidence interval (95% CI) = 9.2-12.8). Most patients were over the age of 80 years (33.8%) and Caucasians (74.4%). The overall 5-year survival was 8.0% (95% CI = 6.8-9.2). The 5-year cause-specific survival (CSS) was 16.2% (95% CI = 14.3-18.1). For treatment modality, the five-year survival for each were as follows: chemotherapy, 3.5% (95% CI = 2.1-4.9); surgery, 18.2% (95% CI = 13.6-22.8); multimodality therapy (surgery and chemotherapy), 4.8% (95% CI = 1.7-7.9); and combination (chemoradiation with surgery), 5.0% (95% CI = 1.0-9.0). The prognostic nomogram created to predict patient survivability matched the findings from the statistical analysis with a statistical difference found in race, income, housing, stage, and nodal status. This analysis showed a slight increase in mortality for patients of Asian race. In addition, there was a significant increase in death for patients of stage 3 tumors, as well as patients who underwent surgery and radiation. The nomogram also indicated a slight increase in mortality with tumors of greater size. Conclusions: Small-cell and large-cell neuroendocrine carcinomas of the prostate are rare; their aggressive nature calls for a deeper understanding and improved prognostic tools. By leveraging insights from registry-based studies, clinicians can better strategize treatment options, improving patient outcomes in this challenging arena of oncology.

Association of human leukocyte antigen (HLA) status with immune checkpoint inhibitor (ICI) pneumonitis in patients with non-small cell lung cancer (NSCLC).

8620 Background: Pneumonitis is a potentially serious complication occurring in 5-20% of lung cancer patients receiving ICI. The genetic risk factors for ICI pneumonitis are unclear. Given the association between HLA genetic variants and autoimmune diseases, we hypothesized that certain HLA genetic variants are associated with risk of ICI pneumonitis. Methods: Patients with advanced EGFR/ ALK wild type, PD-L1 tumor proportion score ≥50% NSCLC who received ICI were enrolled from year 2019 to 2022. Germline HLA typing was performed on buccal swab specimens using the Alltype Fastplex assay. Clinicopathological characteristics, treatment courses and survival outcomes were retrospectively collated. The primary endpoint was the correlation of common HLA variants (present in &gt;30% of subjects) to the risk of ICI pneumonitis. Results: 42 patients (all Chinese, 36 male, 33 current/former smokers) were enrolled. Median age was 71 years old (range 51-91). 34, 6, 1 and 1 patients had adenocarcinoma, NSCLC not otherwise specified, squamous cell carcinoma and large cell neuroendocrine carcinoma respectively. Majority (33/42, 79%) received pembrolizumab monotherapy while 9 (21%) patients received pembrolizumab plus chemotherapy. Median follow up time was 27.8 months. At data cutoff, 28 (67%) patients received ICI for more than 1 year and 10 (24%) patients stopped ICI after completion of 2-year course of treatment. Seven (17%) patients developed pneumonitis, of which 3 were grade 2 and 4 were grade 3 in severity. Median time to development of pneumonitis was 6.9 months (range 0.3-25.2). Demographic characteristics were similar between patients who did or did not experience pneumonitis. In the entire cohort, twenty-two (52%) patients harbored the class II DPB1*02 allele. This allele was significantly associated with development of ICI pneumonitis. All 7 patients who had ICI pneumonitis harbored the DPB1*02 allele. The incidence of pneumonitis in patients harboring the DPB1*02 allele was 32% compared to 0% in those without this allele (p=0.009). Patients who experienced pneumonitis had worse survival rates than those without (p=0.03), but expression of DPB1*02 allele was not associated with inferior survival outcomes. Conclusions: Our results suggested that expression of DPB1*02 allele may be associated with development of ICI pneumonitis. A larger case-control study is ongoing to validate this association. [Table: see text]

Exploring systemic treatment approaches for advanced pure large cell neuroendocrine carcinoma (LCNEC): A multicenter retrospective analysis.

Exploring systemic treatment approaches for advanced pure large cell neuroendocrine carcinoma (LCNEC): A multicenter retrospective analysis.

Descriptive analysis of brain metastases (BM) of solid neoplasms in an academic hospital from a low- and middle-income country (LMIC) with a Hispanic population.

e14015 Background: Multidisciplinary management of BM of solid cancers integrates different combinations of treatment modalities. The scarcity of SRS centers has prevented widespread adoption of this therapy for appropriately selected patients. Methods: One-hundred eighteen (51.7% female, 48.3% male, median age 59 years) BM patients from a National Health Institute from Mexico (INCMNSZ) were included and analyzed. Results: The most common primary tumors were lung and breast cancers (25 cases each, representing 21% of the whole cohort), kidney cancer (14%), male germ cell tumors (10%), metastatic carcinoma of unknown primary (CUP) (5%), upper- and lower- gastrointestinal cancers (5%), thyroid differentiated cancers (5%), followed by melanoma, prostate, ovarian, hepatobiliary cancers and sarcoma (3% each of them) and urothelial carcinoma (2%) being the least common. No biopsy was reported for only one case. The most common histomolecular tumors were adenocarcinoma of the lung (17 cases), renal cell carcinoma (17), triple negative (TN) breast cancer (BC) (9), HER-2+ BC (7), Nonseminomatous germ cell tumor (7), CUP (6), ER+/HER-2+ BC (5), Germ cell tumor with choriocarcinoma (5), small-cell lung cancer (SCLC) (5), melanoma (5), prostate adenocarcinoma (5), thyroid differentiated cancer not otherwise specified (NOS) (5). Rectal adenocarcinoma, high-grade serous ovarian cancer, ER+/PR+ BC, sarcomas and NSCLC (3 cases, each) and urothelial carcinoma (2). Rare tumor subtypes, with one case, each included hepatocellular carcinoma, PR+/HER2+ BC, follicular thyroid cancer, esophageal, gastric and colonic adenocarcinomas, neuroendocrine prostate, neuroendocrine gallbladder, endometrial, large cell neuroendocrine lung carcinomas and cholangiocarcinoma. A solitary BM was present in 44 patients (37.3%), 2-3 BM in 30 (25.4%) and &gt;3 BM in 44 patients (37.3%). 18 patients (15.2%) were not symptomatic at the time of diagnosis. 79 patients were treated with Whole-Brain Radiotherapy (WBRT), ten with a combination of surgery and adjuvant WBRT, seven with surgical resection without radiotherapy, only five included SRS as part of their treatment and seventeen received only supportive care. There was no difference in overall survival (OS) between treatment modalities excluding supportive care (p=0.05). Conclusions: Our experience from a LMIC with Hispanic population highlights that more than 50% of BM metastasize from solid tumors different from lung and breast cancers. Even though SRS has been included in recent guidelines from ASCO and ESMO, WBRT is the option most commonly included in multimodality treatments.

Integrated genomic and transcriptomic characterization of neuroendocrine carcinomas for improved treatment decision-making.

e15138 Background: Neuroendocrine carcinomas (NECs) are poorly characterized due to their innate heterogeneity, thus limiting treatment and clinical trial options for patients. Here, we used whole exome sequencing (WES) and RNA sequencing (RNA-seq) to explore the genetic and microenvironmental landscape of NECs in order to understand the unique features of different NEC types, with the aim of improving treatment modalities. Methods: We analyzed 51 NEC clinical samples morphologically verified by a pathologist: lung NEC (20 small cell NEC and 1 large cell NEC cases), gastroenteropancreatic NEC (GEP, 12 cases), cancer of unknown primary (7 cases), Merkel cell carcinoma (MCC, 5 cases), genitourinary tract NEC (3 cases), and breast NEC (3 cases). Findings on tumor mutational burden (TMB, mut/Mb), microsatellite instability (MSI), gene expression signatures, and tumor microenvironment (TME) profiling were reported. Small cell lung cancer (SCLC) subtyping was performed as reported by Gay et al. on the entire NEC cohort. Results: Half of the patients with lung NEC and 84% of those with extrapulmonary NEC satisfied the molecular inclusion criteria for clinical trials, with the most frequent criterion being KRAS G12X or G13X mutations. Among the extrapulmonary NEC samples, 13.7% were deemed eligible for targeted therapy, specifically for cases with BRAF V600E mutation and/or high TMB (&gt; 10 mut/Mb). We detected varying TMB and distinct gene expression features across the entire cohort. Specifically, we found 2 MCC cases to be Merkel cell polyomavirus-positive with low TMB and devoid of UV-associated mutations. One GEP-NEC case exhibited a high MSI (MSI-high) status. We detected 6 SCLC cases (3 non-smokers, 3 former smokers) with surprisingly low levels of tobacco-associated mutations (&lt;10% of all mutations). Two GEP-NEC cases had high levels of mutations associated with tobacco smoking. While TME profiling showed no significant difference in cell population makeup across all samples, transcriptional SCLC subtyping revealed significant differences among the cases. Inflammatory SCLC (SCLC-I) samples showed statistically significant enrichment of all subpopulations of the immune microenvironment (i.e., B cells, T cells, NK cells), supporting the use of immune checkpoint blockade for treatment. The POU2F3+ SCLC (SCLC-P) samples showed low expression of all neuroendocrine diagnostic markers (i.e., INSM1, NCAM1, SYP, CHGA). Conclusions: Given the heterogeneous molecular features across diverse NEC tumors, a uniform treatment strategy is unlikely to benefit all NEC patients. Hence, our ability to detect these unique molecular features is crucial for matching individual NEC patients with specific clinical trials and targeted therapies that may improve their outcomes. Thus, a concerted effort using in-depth genomic, transcriptomic, and TME profiling for NEC tumors is warranted.

Clinical and Pathologic Differences between Small-Cell Carcinoma and Large-Cell Neuroendocrine Carcinoma of the Lung.

Both small-cell carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) of the lung are often clinically dealt with as being in the same category as neuroendocrine carcinoma, and their clinical differences have not been adequately assessed. The postoperative prognosis was retrospectively analyzed using the data of 196 patients who underwent resection for SCLC or LCNEC. Of the patients included, 99 (50.5%) had SCLC and 97 (49.5%) had LCNEC. The median duration of follow-up was 39 months (interquartile range [IQR] 21-76) and 56 months (IQR 21-87) for SCLC and LCNEC, respectively. The estimated 5-year overall survival (OS) probabilities were 53.7% and 62.7% (p = 0.133) for patients with SCLC and LCNEC, respectively. In the SCLC group, a multivariate analysis showed that adjuvant chemotherapy (hazard ratio 0.54, 95% confidence interval 0.30-0.99, p = 0.04) was the only factor that was significantly associated with OS. In the LCNEC group, univariate analyses demonstrated that pathologic stage I (p = 0.01) was the only factor that was associated with better OS after surgery. We found different clinical features in SCLC and LCNEC; in patients with SCLC, because OS could be expected to significantly improve with postoperative adjuvant chemotherapy, patients with resected SCLC of any pathologic stage should receive adjuvant chemotherapy. For patients with LCNEC, because pathologic stage I LCNEC is related to better prognosis than any other stages, a thorough clinical staging, including invasive staging, according to present guidelines should be performed to identify clinical stage I LCNEC with the highest certainty.

The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study.

Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.

Mutational analysis of pulmonary large cell neuroendocrine carcinoma: APC gene mutations identify a good prognostic factor

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm with biological heterogeneity. Mutations in multiple genes have been identified in LCNEC. However, associations between gene alterations, histopathological characteristics, and prognosis remain ambiguous. Here, we investigated the clinicopathologic, immunohistochemical, and genomic characteristics of 19 patients with LCNEC and 9 patients with atypical carcinoid (AC). We revealed high mutation frequencies of TP53 (89.5 %), RB1 (42.1 %), APC (31.6 %), and MCL1 (31.6 %) in LCNEC, while genetic alterations were rarely found in AC. APC alterations mainly occurred to the exon 16 and were only identified in LCNEC with wild-type RB1. The 19 LCNEC were further subgrouped into APC wild-type (LCNEC-APCMT, 6/19) and APC-mutated (LCNEC-APCWT, 13/19) subgroups. In comparison with LCNEC-APCWT, LCNEC-APCMT displayed lower TMB (median: 12.64 vs 4.20, P = 0.045), and relatively mild cytologic atypia. In addition, LCNEC-APCMT distinguished itself from AC and LCNEC-APCWT by obviously downregulated expression of neuroendocrine markers (CD56 and Syn, P < 0.01) and significantly altered expression of genes downstream of APC (β-catenin migrating into the cytoplasm and nucleus, P < 0.001; c-Myc upregulating, P = 0.005). The OS of LCNEC-APCMT was numerically intermediate between AC and LCNEC-APCWT. We first proposed that APC alterations were common in LCNEC with wild-type RB1 and that LCNEC-APCMT was associated with lower TMB and better OS in comparison with LCNEC-APCWT.