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Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes. [ABSTRACT FROM AUTHOR]

Introduction: Carcinoma of the gallbladder is extremely rare, papillary adenocarcinoma comprises 90% of these cases. Although neuroendocrine neoplasms (NENs) comprise 0.5% of the cases of gallbladder cancer, the incidence is rising. NEN is classified into a well-differentiated neuroendocrine tumor and poorly differentiated neuroendocrine cancer (NEC). Histologically, NEC is small-cell or large-cell carcinoma. We present the extremely rare case, 15th in the literature to be precise, of large cell neuroendocrine carcinoma of the gallbladder. Case Presentation: A 72-year-old male presented to the emergency department with constipation and right upper quadrant pain for 3 months. Computed tomography scan of the abdomen demonstrated an ill-defined 7.2 × 4.9 cm hypodense lesion in the gallbladder fossa with extension into the liver. Histopathological and immunohistochemical analysis of the biopsy specimen confirmed the diagnosis of large cell neuroendocrine carcinoma of the gallbladder. He was started on palliative chemotherapy. Conclusion: The plethora of tumors present in the gallbladder necessitates a search for risk factors for gallbladder neoplasia, and underscores the need to more carefully examine the nature of “asymptomatic gallstones.” Further studies may reveal subclasses of cholelithiasis, gallbladder morphology, or imaging to define which patients should be followed more carefully, and may clarify additional risk factors for cancer of the gallbladder.

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland. [ABSTRACT FROM AUTHOR]

Abstract Background Neuroendocrine carcinomas are extremely rare in the esophagus as they represent less than 0.04% of all neuroendocrine tumors. To date, only 14 cases of poorly differentiated, high-grade esophageal NEC have been described in the literature. The majority of these patients presented with typical dysphagia symptoms. Due to its rarity, no standardized guidelines have been proposed to treat esophageal neuroendocrine carcinoma, although general recommendations suggest surgery with adjuvant chemoradiotherapy as the treatment of choice. Case presentation A 67-year-old previously healthy White male presented with a year-long intermittent nonspecific retrosternal discomfort, with the absence of any other symptoms. Esophagogastroduodenoscopy revealed an ulcerative mass in his lower esophagus, with concern of malignancy. Endoscopic ultrasound-guided biopsy revealed poorly differentiated neuroendocrine carcinoma of the esophagus with metastasis to a diaphragmatic lymph node. He was treated with neoadjuvant chemoradiation followed by surgery, and he has been in remission for over 5 years. Conclusion Here, we review the literature and report a unique case of a patient with a vague presentation of esophageal neuroendocrine carcinoma as he enters his sixth year of survival following neoadjuvant chemoradiotherapy.

Abstract Background Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Methods LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan–Meier analyses were applied to assess different therapy modalities. Results A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60–79 (OR 0.57; 95% CI 0.41–0.78; p

Introduction Prostatic large‐cell neuroendocrine carcinoma is poorly studied. Although several case reports are available, information on the clinicopathological characteristics of this disease is limited, particularly for the de novo (hormone‐naive) type. Herein, we report an extremely rare de novo case of this disease with a good prognosis despite a multi‐metastatic status. Case presentation An 83‐year‐old male patient presented with a high serum prostate‐specific antigen level and was found to have de novo prostatic large‐cell neuroendocrine carcinoma with an adenocarcinoma component upon pathological examination. Diagnosed with stage pT4cN1cM1c, he underwent chemo‐hormonal therapy using a luteinizing hormone‐releasing hormone antagonist and combined etoposide and cisplatin, which achieved a partial response. The patient has survived for 20 months without progression. Conclusion Although prostatic large‐cell neuroendocrine carcinoma is known for its aggressive clinical behavior, the de novo type with an adenocarcinoma component may be sensitive to hormonal therapy and achieve a good prognosis.

Background: To review the outcomes of surgically resected lung neuroendocrine neoplasms (LNEN) at a tertiary referral centre and to validate a previously published LNEN‐specific staging system (NETL). Methods: All patients who were identified on histopathology to have LNEN were included. Pre‐, intra‐ and post‐operative outcomes were collected, including long‐term survival. Patients were staged by both the TNM (seventh and eighth edition) and NETL staging (seventh and eighth edition definitions). Kaplan–Meier (KM) survival analysis was performed according to histopathology and stage, along with uni‐ and multivariate analyses. Result: A total of 132 patients were included in the study, with a median age of 65 years; 55% were female. Typical carcinoid (TC) was the most common pathology (53.4%) followed by large cell neuroendocrine carcinoma (LCNEC – 23.5%), atypical carcinoid (AC – 20.5%) and small cell carcinoma (3.0%). The most common operation performed was a lobectomy (55.3%). Overall survival at 5 years was 80% (100% TC, 78.2% AC, LCNEC 40.9%) and 5‐year disease free survival was 76.8% (TC 94.3%, AC 56.8%, LCNEC 56.4%). KM curves showed a trend towards NETL performing better than TNM, however, in multivariate analysis only the histological subtype was found to be significant in our study. Conclusion: This is the largest known Australian series of LNEN to date, showing survival comparable to international outcomes. We have demonstrated large variations in outcome, driven by histological grade. The TNM system does not correlate with survival and we have not been able to show that currently proposed NETL staging is superior. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the most commonly diagnosed cancer types. Studying the molecular changes that occur in lung cancer is important to understand tumor formation and identify new therapeutic targets and early markers of the disease to decrease mortality. Glycosaminoglycan chains play important roles in various signaling events in the tumor microenvironment. Therefore, we have determined the quantity and sulfation characteristics of chondroitin sulfate and heparan sulfate in formalin-fixed paraffin-embedded human lung tissue samples belonging to different lung cancer types as well as tumor adjacent normal areas. Glycosaminoglycan disaccharide analysis was performed using HPLC-MS following on-surface lyase digestion. Significant changes were identified predominantly in the case of chondroitin sulfate; for example, the total amount was higher in tumor tissue compared to the adjacent normal tissue. We also observed differences in the degree of sulfation and relative proportions of individual chondroitin sulfate disaccharides between lung cancer types and adjacent normal tissue. Furthermore, the differences in the 6-O-/4-O-sulfation ratio of chondroitin sulfate were different between the lung cancer types. Our pilot study revealed that further investigation of the role of chondroitin sulfate chains and enzymes involved in their biosynthesis is an important aspect of lung cancer research. [ABSTRACT FROM AUTHOR]

Background: Neuroendocrine carcinomas are extremely rare in the esophagus as they represent less than 0.04% of all neuroendocrine tumors. To date, only 14 cases of poorly differentiated, high-grade esophageal NEC have been described in the literature. The majority of these patients presented with typical dysphagia symptoms. Due to its rarity, no standardized guidelines have been proposed to treat esophageal neuroendocrine carcinoma, although general recommendations suggest surgery with adjuvant chemoradiotherapy as the treatment of choice. Case presentation: A 67-year-old previously healthy White male presented with a year-long intermittent nonspecific retrosternal discomfort, with the absence of any other symptoms. Esophagogastroduodenoscopy revealed an ulcerative mass in his lower esophagus, with concern of malignancy. Endoscopic ultrasound-guided biopsy revealed poorly differentiated neuroendocrine carcinoma of the esophagus with metastasis to a diaphragmatic lymph node. He was treated with neoadjuvant chemoradiation followed by surgery, and he has been in remission for over 5 years. Conclusion: Here, we review the literature and report a unique case of a patient with a vague presentation of esophageal neuroendocrine carcinoma as he enters his sixth year of survival following neoadjuvant chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is the most frequent form of lung cancer and represents a set of histological entities that have an ominous long-term prognosis, for example, adenocarcinoma, squamous carcinoma and large cell carcinoma. Both small cell and non-small cell lung cancer are the main causes of oncological death and the oncological diseases with the highest incidence worldwide. With regard to clinical approaches for NSCLC, several advances have been achieved in diagnosis and treatment; the analysis of different molecular markers has led to the development of new targeted therapies that have improved the prognosis for selected patients. Despite this, most patients are diagnosed in an advanced stage, presenting a limited life expectancy with an ominous short-term prognosis. Numerous molecular alterations have been described in recent years, allowing for the development of therapies directed against specific therapeutic targets. The correct identification of the expression of different molecular markers has allowed for the individualization of treatment throughout the disease course, expanding the available therapeutic arsenal. The purpose of this article is to summarize the main characteristics of NSCLC and the advances that have occurred in the use of targeted therapies, thus explaining the limitations that have been observed in the management of this disease. [ABSTRACT FROM AUTHOR]

Neuroendocrine (NE) tumors of the bladder are infrequent. Among them, large cell NE tumor has been outlined only in case reports and short case series, which describes them as aggressive malignancies with dismal prognosis requiring a multidisciplinary approach. The case of an 82-year-old patient with muscle-invasive large cell NE carcinoma of the bladder associated with urothelial carcinoma in situ is presented. Despite combined treatment modality, relapse with metastatic disease was detected 12.5 months after the initial diagnosis. Thereafter, we review several published cases, and results of the collected data are compared with the largest studies published on this topic.

Abstract Background Large cell neuroendocrine carcinoma (LCNEC) is a high-grade malignant pulmonary neuroendocrine tumour. The distinction of pulmonary large cell carcinoma (LCC) and LCNEC is based on the presence of neuroendocrine morphology and the expression of at least one neuroendocrine marker in at least 10% of tumour cells in the latter. According to the current classification, LCC with neuroendocrine morphology and without neuroendocrine marker expression is classified as LCC. This subgroup we have named LCNEC-null and aimed to analyze its characteristics. Methods 31 surgical samples resected in West China Hospital of Sichuan University between 2017 to 2021 were collected, including 7 traditional LCCs, 11 LCNEC-nulls and 13 LCNECs. Each case was conducted to immunohistochemistry and 425-panel-NGS. Results Compared to other LCCs, detailed analysis of LCNEC-nulls revealed biological features similar to those of LCNECs, especially for immunohistochemistry and molecular analysis: 1. diffusive, coarse granular and high expression of Pan-CK; 2. rare PD-L1 expression; 3. High rate of p53 expression and Rb deficiency 4. abundant genetic alterations are similar to LCNEC. All characteristics above deviated from traditional LCC, indicating they have the same origin as LCNEC. Furthermore, LCNEC could be genetically divided into two subtypes when we reclassified LCNEC-null as LCNEC, and the mutational type and prognosis differed significantly. Conclusions We consider that LCNEC-null should be reclassified as LCNEC based on analysis above. In addition, two genetic types of LCNEC with different prognosis also indicate two mechanism of tumour formation.

Background: Patients with pulmonary large cell carcinoma (LCC) have a high incidence of synchronous brain metastases (SBM) and a poor prognosis. Our study was to evaluate the predictive and prognostic value of the clinical characteristics of pulmonary LCC patients with SBM at initial diagnosis by utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Methods: LCC patients, diagnosed from 2010 to 2019, were identified from the latest SEER database which was released in April 2022. Logistic regression and Cox regression were used to identify the predictive and prognostic factors for LCC patients with SBM. Propensity score matching (PSM) and Kaplan–Meier analyses were applied to assess different therapy modalities. Results: A total of 1375 LCC patients were enrolled in this study and 216 (15.7%) of them had SBM at the initial diagnosis. The median overall survival (OS) of LCC patients with SBM was 4 months. Multivariate Cox regression identified age 60–79 (OR 0.57; 95% CI 0.41–0.78; p < 0.001), age ≥ 80 (OR 0.23; 95% CI 0.12–0.45; p < 0.001) and bone metastases (OR 1.75; 95% CI 1.22–2.51; p < 0.001) as significant independent predictors for developing SBM. Multivariable Cox regression revealed that age 60–79, T stage, bone metastases and chemotherapy were independent prognostic factor for OS. The surgery combined with chemotherapy and radiotherapy group, in which all patients were N0 stage and had no other site-specific metastases, exhibited the best median OS of 15 months. Conclusions: LCC patients with age < 60 or bone metastases were more likely to have SBM at initial diagnosis. Age, T stage, bone metastases and chemotherapy were independent prognostic factors for OS of LCC patients with SBM. Highly selected patients might achieve the best survival benefit from surgery combined with chemotherapy and radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulmonary large cell carcinoma (LCC) represents a kind of rare and highly malignant tumors with significantly worse survival outcomes compared to other types of NSCLC. Our study mainly demonstrated that for LCC patients ≥65 years old, radiation after surgery had the optimal therapeutic effect to improve survival outcomes compared to other sequences of radiation with surgery. Our research provided significant advice on the appropriate choice of radiation sequences with surgery for advanced LCC patients with age ≥65 years old. Background: Pulmonary large cell carcinoma, a type of non-small cell lung cancer (NSCLC), is a rare neoplasm with poor prognosis. In this study, our aim was to investigate the impact of radiation sequences with surgery for stage III/IV LCC patients between different age groups, especially in the elderly patients. Patients and Methods: The patients with LCC and other types of NSCLC in the Surveillance, Epidemiology and End Results (SEER) database from 2004 to 2015 were retrospectively analyzed. Then we divided the LCC patients into two age groups: <65 years old group and ≥65 years old group. Propensity score method (PSM) was used to control potential differences between different groups. The overall survival (OS) of LCC patients and other types of NSCLC patients were evaluated by Kaplan–Meier analysis. Univariate and multivariate Cox regression analysis were employed to explore the independent risk factors of OS. The forest plots of HRs for OS were generated to show the above outcomes more visually. Results: In total, 11,349 LCC patients and 129,118 other types of NSCLC patients were enrolled in this study. We divided LCC patients into <65 years old group (4300) and ≥65 years old group (7049). LCC patients was more common in whites (81.4%), males (58.3%), elderly (≥65 years old: 62.1%), east regions (52.7%), upper lobe (51.6%), right-origin of primary (55.4%), with advanced grade (54.2%) or stage (76.7%). After PSM, Kaplan–Meier analysis and multivariate Cox analysis showed significantly worse survival prognosis for LCC patients compared to other types of NSCLC, especially in the group ≥65 years old (HR: 1.230; 95% CI: 1.171–1.291; p < 0.001). For LCC patients, there were some risk survival factors including whites, males, not upper lobe, advanced stage, elder age at diagnosis, bone metastasis, liver metastasis, singled status, no lymphadenectomy, no surgery, and no chemotherapy (p < 0.05). In LCC patients ≥65 years old, radiation after surgery had significantly better impact on overall survival outcomes (HR: 0.863, 95% CI: 0.765–0.973, p = 0.016), whereas radiation prior to surgery (HR: 1.425, 95% CI: 1.059–1.916, p = 0.019) had significantly worse impact on prognosis of patients. In LCC patients <65 years old, radiation sequences with surgery had no significant impact on the OS of patients (p = 0.580), but ≥4 LNRs had significantly survival benefits to prognosis (HR:0.707, 95% CI: 0.584–0.855). Elderly LCC patients had worse malignant tumors than young patients, of which the majority were diagnosed as stage III/IV tumors. Conclusions: Postoperative radiotherapy may achieve a better prognosis for stage III/IV LCC patients older than 65 years old compared to other radiation sequences with surgery. [ABSTRACT FROM AUTHOR]

Large Cell Carcinoma (LCC) observed in low-dose computed tomography (LDCT) screening trials typically presented as a single solid peripheral nodule or mass, often with lobulated margins (panels A-D), and exhibited a fast growth (panels E-F and G-H). The 5-year survival (panel I) reflected the stage at diagnosis and was fair (15/20 alive) for stages I-II (dashed line) and poor (1/10 alive) (continuous line) for stages III-IV. [Display omitted] • LDCT screening enables the definition of early radiological features of LCC. • LCC was diagnosed in 30 (4%) of 750 subjects with LDCT screen-detected lung cancers. • LCC appeared as a peripheral solid nodule/mass often (43%) with lobulated margins. • 5 years after diagnosis, 5/20 stages I-II and 9/10 stages III-IV subjects had died of LCC. • Survival of screen-detected LCC depends on the stage at diagnosis. To investigate the early radiological features and survival of Large Cell Carcinoma (LCC) cases diagnosed in low-dose computed tomography (LDCT) screening trials. Two radiologists jointly reviewed the radiological features of screen-detected LCCs observed in NLST, ITALUNG, and LUSI trials between 2002 and 2016, comprising a total of 29,744 subjects who underwent 3–5 annual screening LDCT examinations. Survival or causes of death were established according to the mortality registries extending more than 12 years since randomization. LCC was diagnosed in 30 (4 %) of 750 subjects with screen-detected lung cancer (LC), including 15 prevalent and 15 incident cases. Three additional LCCs occurred as interval cancers during the screening period. LDCT images were available for 29 cases of screen-detected LCCs, and 28 showed a single, peripheral, and well-defined solid nodule or mass with regularly smooth (39 %), lobulated (43 %), or spiculated (18 %) margins. One case presented as hilar mass. In 9 incident LCCs, smaller solid nodules were identified in prior LDCT examinations, allowing us to calculate a mean Volume Doubling Time (VDT) of 98.7 ± 47.8 days. The overall five-year survival rate was 50 %, with a significant (p = 0.0001) difference between stages I-II (75 % alive) and stages III-IV (10 % alive). LCC is a fast-growing neoplasm that can escape detection by annual LDCT screening. LCC typically presents as a single solid peripheral nodule or mass, often with lobulated margins, and exhibits a short VDT. The 5-year survival reflects the stage at diagnosis. [ABSTRACT FROM AUTHOR]

This paper presents a novel approach that merges a lightweight parallel depth-wise separable convolutional neural network (LPDCNN) with a ridge regression extreme learning machine (Ridge-ELM) for precise classification of three lung cancer types alongside normal lung tissue (adenocarcinoma, large cell carcinoma, normal, and squamous cell carcinoma) using CT images. The proposed methodology combines contrast-limited adaptive histogram equalization (CLAHE) and Gaussian blur to enhance image quality, reduce noise, and improve visual clarity. The LPDCNN extracts discriminant features while minimizing computational complexity (0.53 million parameters and 9 layers). The Ridge-ELM model was developed to enhance classification performance, replacing the traditional pseudoinverse in the ELM approach. Through comprehensive evaluation against state-of-the-art models, the framework achieves remarkable average recall and accuracy values of 98.25 ± 1.031 % and 98.40 ± 0.822 %, respectively, through rigorous five-fold cross-validation for four-class classifications. In binary classifications, outstanding results are obtained with recall and accuracy values of 99.70 ± 0.671 % and 99.70 ± 0.447 %%, respectively. Notably, the framework exhibits exceptional efficiency, with a testing time of only 0.003 s. Additionally, integrating the SHAP (Shapley Additive Explanations) in the proposed framework enhances Explain-ability, providing insights into decision-making and boosting confidence in real-world lung cancer diagnoses. [ABSTRACT FROM AUTHOR]

The aim of the present study was to integrate the available data published in the literature on oral and maxillofacial neuroendocrine carcinomas concerning the demographic, clinical and histopathological features of this condition. An electronic search with no publication date restriction was undertaken in April 2021 in four databases. Eligibility criteria included reports published in English having enough data to confirm a definite diagnosis, always showing a neuroendocrine marker. Cases originating in the oropharynx, including base of the tongue and tonsils, were excluded. Outcomes were evaluated by the Kaplan–Meier method along with Cox regression. Twenty-five articles (29 cases) from nine different countries were detected. Mean patient age was 56.3 (± 17.5) years, with a slight male predilection. Symptomatology was present in 72.2% of informed cases. Regarding clinical presentation, a non-ulcerated nodule located in the gingiva with a mean size of 3.4 (± 2.0) cm was most frequently reported. Concomitant metastasis was identified in seven individuals. Histopathologically, most neoplasms were of the small cell type, and immunohistochemistry for both epithelial and neuroendocrine differentiation was used in 65.5% cases. Radical surgery was the treatment of choice in almost all cases, with or without adjuvant therapy. Mean follow-up was 20.5 (± 21.2) months, and only four patients developed recurrences. Eleven (44.0%) individuals died due to the disease. Ulcerated lesions were a prognostic factor. This study provides knowledge that can assist surgeons, oncologists, and oral and maxillofacial pathologists with the diagnosis and management of neuroendocrine carcinomas. Our findings demonstrated that the long-term prognosis of this lesion continues to be poor. [ABSTRACT FROM AUTHOR]

Abstract Pulmonary large cell carcinoma (LCC) is classified as a poorly defined entity among non‐small cell lung cancers (NSCLCs). At present, there are no effective anticancer drugs, such as molecular targeted drugs, for LCC, and it has been reported that patient prognosis is poor. Recently, the development of immune checkpoint inhibitors (ICIs) has changed the therapeutic strategies for patients with NSCLC. Here, we present a case of LCC successfully treated with pembrolizumab. A 58‐year‐old man who was a former smoker was diagnosed with LCC. The postoperative stage was T3N2M0. During postoperative adjuvant chemotherapy, swelling of the supraclavicular lymph node was observed and the patient was diagnosed with recurrence. The patient was treated with two regimens of conventional cytotoxic chemotherapy; however, he experienced some hoarseness. Imaging confirmed swelling of the hilar and mediastinal lymph nodes and the patient was subsequently diagnosed with disease progression. Previous surgical specimens when immunostained showed that a high proportion of the tumor cells were positive for expression of programmed death‐ligand 1 (PD‐L1), and it was decided to commence treatment with pembrolizumab. This treatment resulted in rapid regression of the hilar and mediastinal lymph nodes, and a progression‐free period maintained for at least 24 treatment cycles. The patient's hoarseness improved, and the lymph nodes decreased in size. Immunotherapy targeting PD‐1/PD‐L1 may be an option for patients with PD‐L1 positive LCC. This case report suggests that treatment with ICIs may be important in the selection of treatment for not only LCC but also relatively rare NSCLC with high PD‐L1 expression.

Background: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade malignant pulmonary neuroendocrine tumour. The distinction of pulmonary large cell carcinoma (LCC) and LCNEC is based on the presence of neuroendocrine morphology and the expression of at least one neuroendocrine marker in at least 10% of tumour cells in the latter. According to the current classification, LCC with neuroendocrine morphology and without neuroendocrine marker expression is classified as LCC. This subgroup we have named LCNEC-null and aimed to analyze its characteristics. Methods: 31 surgical samples resected in West China Hospital of Sichuan University between 2017 to 2021 were collected, including 7 traditional LCCs, 11 LCNEC-nulls and 13 LCNECs. Each case was conducted to immunohistochemistry and 425-panel-NGS. Results: Compared to other LCCs, detailed analysis of LCNEC-nulls revealed biological features similar to those of LCNECs, especially for immunohistochemistry and molecular analysis: 1. diffusive, coarse granular and high expression of Pan-CK; 2. rare PD-L1 expression; 3. High rate of p53 expression and Rb deficiency 4. abundant genetic alterations are similar to LCNEC. All characteristics above deviated from traditional LCC, indicating they have the same origin as LCNEC. Furthermore, LCNEC could be genetically divided into two subtypes when we reclassified LCNEC-null as LCNEC, and the mutational type and prognosis differed significantly. Conclusions: We consider that LCNEC-null should be reclassified as LCNEC based on analysis above. In addition, two genetic types of LCNEC with different prognosis also indicate two mechanism of tumour formation. [ABSTRACT FROM AUTHOR]

Here, we report a case of acute intestinal obstruction as the initial presentation of primary lung cancer in a male patient. Abdominal computed tomography (CT) showed multiple polypoid masses and regional lymphadenopathy with small bowel obstruction. The patient underwent emergency surgery for multiple luminal malignancy with mesenteric masses. According to the various clinicopathological features, the tumor was confirmed to be metastatic large cell carcinoma originating from the lung. Large masses in the left lower lobe of the lung were identified on the chest CT after emergency surgery, and non‐small cell lung cancer (NSCLC), not otherwise specified (NOS), was finally diagnosed on biopsy through bronchoscopy.

Herein, we summarize two rare cases of salivary neuroendocrine carcinoma arising in the parotid gland. The patients were a 54-year-old Japanese female and a 74-year-old Japanese male. In the first case, the tumor presented as a typical small cell carcinoma with extensive crush artifacts and nuclear molding, but metastatic foci of the lymph node revealed characteristic ribbon-like trabecular arrangements or sheet-like solid growths of tumor cells with moderate amounts of pale eosinophilic cytoplasm intermingled with bizarre giant or multinucleated cells. In the second case, the tumor was initially diagnosed as a small cell neuroendocrine carcinoma, but a retrospective review revealed that the large cell component was dominant and that it should be strictly considered a mixed large and small cell neuroendocrine carcinoma. The difference in prognoses between these two salivary subtypes remains unknown, and distinction between the small and large cell subtypes of neuroendocrine carcinomas seems merely simple and convenient in the salivary glands.

PurposeLarge cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored.Patients and MethodsPathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted.ResultsBoth LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort.ConclusionLCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.

Purpose: Large cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored. Patients and Methods: Pathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted. Results: Both LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1 / TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR , BRAF , ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort. Conclusion: LCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care. [ABSTRACT FROM AUTHOR]

Neuroendocrine (NE) tumors of the bladder are infrequent. Among them, large cell NE tumor has been outlined only in case reports and short case series, which describes them as aggressive malignancies with dismal prognosis requiring a multidisciplinary approach. The case of an 82-year-old patient with muscle-invasive large cell NE carcinoma of the bladder associated with urothelial carcinoma in situ is presented. Despite combined treatment modality, relapse with metastatic disease was detected 12.5 months after the initial diagnosis. Thereafter, we review several published cases, and results of the collected data are compared with the largest studies published on this topic. [ABSTRACT FROM AUTHOR]

A previous retrospective study of a neuroendocrine carcinoma of the endometrium including 42 cases employed a central pathologic review to ensure the reliability of the findings. However, the pathological processes were not described in detail. In this study, we further analyzed these processes and the results of pretreatment endometrial cytology of neuroendocrine carcinoma. Of the 65 patients from 18 institutions registered in the study, 42 (64.6%) were diagnosed with neuroendocrine carcinoma of the endometrium based on the central pathological review. Thirteen of the 23 excluded cases conflicted from their original diagnoses: 5 (38.5%) were diagnosed with endometrioid adenocarcinoma, 5 (38.5%) with undifferentiated carcinoma, and 3 (23.1%) with carcinosarcoma. Immunohistochemical staining led to a change in diagnosis for 8 (61.5%) of the 13 cases. Pretreatment endometrial cytology was examined in 38 (90.5%) cases; 34 (89.5%) of these 38 cases were found, or suspected, to be positive. To ensure the selection of appropriate therapy and keeping patients correctly informed, it is important to distinguish neuroendocrine carcinoma from other similar histologic types. Endometrial cytology may help in the early detection of this disease. [ABSTRACT FROM AUTHOR]

Background The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. Methods We performed capture‐based ultra‐deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. Results Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. Conclusion Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events.

Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications. [ABSTRACT FROM AUTHOR]

Pulmonary large cell carcinoma (LCC) is classified as a poorly defined entity among non‐small cell lung cancers (NSCLCs). At present, there are no effective anticancer drugs, such as molecular targeted drugs, for LCC, and it has been reported that patient prognosis is poor. Recently, the development of immune checkpoint inhibitors (ICIs) has changed the therapeutic strategies for patients with NSCLC. Here, we present a case of LCC successfully treated with pembrolizumab. A 58‐year‐old man who was a former smoker was diagnosed with LCC. The postoperative stage was T3N2M0. During postoperative adjuvant chemotherapy, swelling of the supraclavicular lymph node was observed and the patient was diagnosed with recurrence. The patient was treated with two regimens of conventional cytotoxic chemotherapy; however, he experienced some hoarseness. Imaging confirmed swelling of the hilar and mediastinal lymph nodes and the patient was subsequently diagnosed with disease progression. Previous surgical specimens when immunostained showed that a high proportion of the tumor cells were positive for expression of programmed death‐ligand 1 (PD‐L1), and it was decided to commence treatment with pembrolizumab. This treatment resulted in rapid regression of the hilar and mediastinal lymph nodes, and a progression‐free period maintained for at least 24 treatment cycles. The patient's hoarseness improved, and the lymph nodes decreased in size. Immunotherapy targeting PD‐1/PD‐L1 may be an option for patients with PD‐L1 positive LCC. This case report suggests that treatment with ICIs may be important in the selection of treatment for not only LCC but also relatively rare NSCLC with high PD‐L1 expression. [ABSTRACT FROM AUTHOR]

Abstract Due to rapid advances in our understanding of the molecular pathogenesis of non‐small cell lung cancer (NSCLC), the 2015 World Health Organization (WHO) classification has defined large cell carcinoma (LCC) as a subtype that is lacking glandular or squamous cells, and any neuroendocrine differentiation. Accordingly, LCC is one of the rarest subtypes of NSCLC. LCC usually presents as a large peripheral tumour with prominent necrosis and its specific characteristics are not well known. Here, we report a case of LCC identified during differential diagnosis of diffuse alveolar haemorrhage in a patient with haemoptysis.

Background: Lung cancer is the most common cancer worldwide and the leading cancer killer. Lung cancer is classified histologically into two types; small-cell lung cancer and nonsmall-cell lung cancer (NSCLC) (squamous cell carcinoma, adenocarcinoma (AC), large cell carcinoma [LCC]). Malignant pleural mesothelioma is a rare thoracic tumor. We aimed to provide comprehensive epidemiological data about lung cancer in the eastern part of Libya. Patients and Methods: A retrospective medical records review of lung cancer patients attending the oncology department of Benghazi Medical Center from January 1, 2006 to December 31, 2015. Results: There were 684 lung cancer cases out of 7725 total registered cancer cases (8.85%), 627 were male (91.7%, median age 63.5), and 57 females (8.3%, median age 64). NSCLC was the dominant histology 78.5%, SCLC 11%, and malignant mesothelioma 2.5%. NSCLC subtypes were AC (35.1%), squamous carcinoma (25.7%), LCC (4.6%), and not otherwise specified (12.6%). Only 30.6% of cases were diagnosed in Libya, the most commonly used diagnostic modalities were bronchoscopic biopsy 46.6%, and computed tomography guided biopsy 17.4%. Only 18 cases were tested for epidermal growth factor receptor sensitizing mutations and anaplastic lymphoma kinase rearrangement fusion. Stage IV was the most common initial stage for NSCLC 60%, malignant mesothelioma 47.1%, and 74.7% of SCLC presented with extensive disease. Only 42.9% of males and 5.3% of female lung cancer patients were smokers. Conclusions: Lung cancer is a major health burden in Libya, and it is increasing in incidence; this epidemiological study tries to put this problem into public health and clinical perspective. [ABSTRACT FROM AUTHOR]

Here, we report a case of acute intestinal obstruction as the initial presentation of primary lung cancer in a male patient. Abdominal computed tomography (CT) showed multiple polypoid masses and regional lymphadenopathy with small bowel obstruction. The patient underwent emergency surgery for multiple luminal malignancy with mesenteric masses. According to the various clinicopathological features, the tumor was confirmed to be metastatic large cell carcinoma originating from the lung. Large masses in the left lower lobe of the lung were identified on the chest CT after emergency surgery, and non‐small cell lung cancer (NSCLC), not otherwise specified (NOS), was finally diagnosed on biopsy through bronchoscopy. [ABSTRACT FROM AUTHOR]

Large-cell carcinoma (LCC) of the lung is defined as an undifferentiated non-small cell lung cancer (NSCLC) and accounts for approximately 7.5% of lung cancers. Immune checkpoint inhibitors (ICIs) may be effective for LCC, but there has been no firm evidence due to its low frequency. We herein report an 80-year-old woman with LCC of the lung who was successfully treated with pembrolizumab but developed sclerosing cholangitis as an immune-related adverse event. This case highlights the efficacy of ICIs for LCC as well as the importance of the immediate and detailed management of ICI-related sclerosing cholangitis.

Objective: We conducted a retrospective, multi-institutional, collaborative study to accumulate cases of neuroendocrine carcinoma of the endometrium, to clarify its clinicopathologic features, treatment, prognosis and prognostic factors to collate findings to establish future individualized treatment regimens. To our knowledge, this is the largest case study and the first study to statistically analyze the prognosis of this disease. Methods: At medical institutions participating in the Kansai Clinical Oncology Group/ Intergroup, cases diagnosed at a central pathologic review as neuroendocrine carcinoma of the endometrium between 1995 and 2014 were enrolled. We retrospectively analyzed the clinicopathologic features, treatment, prognosis and prognostic factors of this disease. Results: A total of 65 cases were registered from 18 medical institutions in Japan. Of these, 42 (64.6%) cases were diagnosed as neuroendocrine carcinoma of the endometrium based on the central pathological review and thus included in the study. Advanced International Federation of Gynecology and Obstetrics stages (stage III and IV) and pure type small cell neuroendocrine carcinoma cases had a significantly worse prognosis. Upon multivariate analysis, only histologic subtypes and surgery were significant prognostic factors. Pure type cases had a significantly worse prognosis compared to mixed type cases and complete surgery cases had a significantly better prognosis compared to cases with no or incomplete surgery. Conclusion: Our findings suggest that complete surgery improves the prognosis of neuroendocrine carcinoma of the endometrium. Even among cases with advanced disease stages, if complete surgery is expected to be achieved, clinicians should consider curative surgery to improve the prognosis of neuroendocrine carcinoma of the endometrium. [ABSTRACT FROM AUTHOR]

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Background: The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. Methods: We performed capture‐based ultra‐deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. Results: Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. Conclusion: Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events. [ABSTRACT FROM AUTHOR]