Perforation of Jejunal Metastasis from Primary Lung Carcinoma with Brain Metastasis: A Rare Case.

A case describes a 49-year-old male patient who underwent emergency exploratory laparotomy for small intestinal perforation. Peritonitis was present due to perforation of the jejunal tumor. Resection of the jejunal tumor with perforation was performed followed by end-to-end anastomosis of the jejunum. The resected jejunal tumor was identified in the histopathological examination as metastatic from a clear cell variant of squamous cell/large cell carcinoma of the lung. It was associated with metastatic lesions in the brain. Metastasis from the lung carcinoma in the jejunum is a very rare condition predisposing to small intestinal perforation which is also associated with brain metastasis.

Diagnostic criteria and evolving molecular characterisation of pulmonary neuroendocrine carcinomas.

Neuroendocrine carcinomas of the lung are currently classified into two categories: small-cell lung carcinoma and large-cell neuroendocrine carcinoma. Diagnostic criteria for small-cell and large-cell neuroendocrine carcinoma are based solely on tumour morphology; however, overlap in histologic and immunophenotypic features between the two types of carcinomas can potentially make their classification challenging. Accurate diagnosis of pulmonary neuroendocrine carcinomas is paramount for patient management, as clinical course and treatment differ between small-cell and large-cell neuroendocrine carcinoma. Molecular-genetic, transcriptomic, and proteomic data published over the past decade suggest that small-cell and large-cell neuroendocrine carcinomas are not homogeneous categories but rather comprise multiple groups of distinctive malignancies. Nuances in the susceptibility of small-cell lung carcinoma subtypes to different chemotherapeutic regimens and the discovery of targetable mutations in large-cell neuroendocrine carcinoma suggest that classification and treatment of neuroendocrine carcinomas may be informed by ancillary molecular and protein expression testing going forward. This review summarizes the current diagnostic criteria, prognostic and predictive correlates of classification, and evidence of previously unrecognised subtypes of small-cell and large-cell neuroendocrine carcinoma.

Challenges in Ki-67 assessments in pulmonary large-cell neuroendocrine carcinomas.

AIMS: To gather the best available evidence regarding Ki-67% values in large-cell neuroendocrine carcinoma (LCNEC) and determine whether certain cut-off values could serve as a prognostic feature in LCNEC. METHODS AND RESULTS: Aperio ScanScope AT Turbo, eSlide Manager and ImageScope software (Leica Biosystems) were used to measure Ki-67% in 77 resected LCNEC diagnosed by World Health Organisation (WHO) criteria. Cases were stratified into six classes by 10% Ki-67 increments. Using the Kaplan-Meier method, overall (OS) and disease-free survivals (DFS) were compared by AJCC stage, by six Ki-67% classes and with Ki-67% cut-points ≥20% and ≥40%. Tumours were from 0.9 to 11.5 cm and pathological stages 1-3. The system measured Ki-67% positivity using 4072-44 533 tumour nuclei per case (mean 16610 ± 8039). Ki-67% ranged from 1 to 64% (mean = 26%; median = 26%). Only 16 (21%) tumours had Ki-67% ≥40%. OS ranged from 1 to 298 months (median follow-up = 25 months). DFS ranged from 1 to 276 months (median follow-up = 9 months). OS and DFS differed across AJCC stage (overall log-rank P = 0.038 and P = 0.037). However, neither OS nor DFS significantly correlated with Ki-67% when six or two classes were used with either ≥20% Ki-67 or ≥40% Ki-67 as cut-point. A literature review identified 14 reports meeting our inclusion criteria with ≥10 LCNEC. Reported Ki-67% ranged from 2% to 100%. Problems contributing to variability in Ki-67% measurements are discussed. CONCLUSION: Our findings caution against a blanket use of 20%, 40% or other Ki-67% cut-points for LCNEC diagnosis or prognostication.

Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis.

BACKGROUND: Little information is available concerning prognostic factors for bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical, and molecular approach could be used for their prognostic evaluation. METHODS: Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, and MDM2), and genomic (TP53, RB1, ATM, JAK2, KRAS, and STK11) findings were analyzed in BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). The Ki-67 index was expressed as the percentage of positive cells in hot spots as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNECs, the Ki-67 index was evaluated only in the LCNEC component. RESULTS: A total of 111 LCNECs were distinguished into 70 pure LCNECs, 35 Co-LCNECs (27 with adenocarcinoma [ADC] and 8 with squamous cell carcinoma [SqCC]), and 6 LCNECs with only napsin A immunoreactivity. The Ki-67 index cutoff at 55% evaluated in the neuroendocrine component was the most powerful predictor of OS (log-rank p = 0.0001) in all LCNECs; 34 cases had a Ki-67 index <55% (LCNEC-A) and 77 had a Ki-67 index ≥55% (LCNEC-B). Statistically significant differences in OS (log-rank p = 0.0001) were also observed between pure and Co-LCNECs. A significant difference in OS was found between pure LCNECs-A and Co-LCNECs-A (p < 0.05) but not between pure LCNECs-B and Co-LCNECs-B. Co-LCNEC-ADC and LCNEC napsin A+ cases had longer OS than pure LCNEC and Co-LCNEC-SqCC cases (log-rank p = 0.0001). On multivariable analysis, tumor location, pure versus combined features, and napsin A, but no single gene mutation, were significantly associated with OS after adjustment for Ki-67 index and study center (p < 0.05). CONCLUSIONS: The Ki-67 proliferation index and the morphological characterization of combined features in LCNECs seem to be important tools for predicting clinical outcome in BP-LCNECs.

Clinicopathological significance of the expression of PD-L1 in non-small cell lung cancer.

INTRODUCTION: PD1/PD-L1 pathway targeting therapies are nowadays an established treatment option for patients with NSCLC. We assessed whether PD-L1 expression in NSCLC tumor cells was associated with specific clinical features or overall survival using four different clones. METHODS AND RESULTS: A retrospective study included formalin-fixed paraffin embedded (FFPE) surgical tumors from 482 patients. PD-L1 status was assessed with immunohistochemistry in tumor cells on tissue microarrays using clones 28-8, 22C3, SP263 and SP142. Associations with OS were assessed by Kaplan-Meier and multivariate Cox's regression analysis. Patients' median age: 68 years (39-86); histology: adenocarcinoma (AdCa) 61%, squamous-cell carcinoma (SqCC) 33%, and large cell carcinoma (LCC) 6%; p-stage: IA (46%), IB (30%), IIA (10%), IIB (11,4%), IIIA (1,2%), IIIB - IV (0,4%). PD-L1 positivity (≥1%) in NSCLC for clones 28-8, 22C3, SP263, SP142 was 41.5%, 34.2%, 42.7%, 10.4%, respectively (Pearson Chi-square p < 0.0001). PD-L1 expression was correlated with histology, tumor size and grading. Statistically significant association between PD-L1 expression and OS in NSCLC and Non-AdCa was observed with clone SP142 (log-rank p = 0.045 and p = 0.05, respectively). Statistically significant association between PD-L1 expression and OS in LCC was observed with clones 22C3 (log-rank p = 0.009) and SP263 (log-rank p = 0.050). CONCLUSIONS: Overexpression of the PD-L1 clone SP142 was associated with poor overall survival in NSCLC and Non-AdCa. Clones 22C3 and SP263 were associated with poor prognosis in LCC. PD-L1 status might serve as a prognostic marker in NSCLC.

Circulating markers of cellular immune activation in prediagnostic blood sample and lung cancer risk in the Lung Cancer Cohort Consortium (LC3).

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

Immunohistological expression of oestrogen receptor, progesterone receptor, mammaglobin, human epidermal growth factor receptor 2 and GATA-binding protein 3 in non-small-cell lung cancer.

AIMS: Non-small-cell lung cancer (NSCLC) and breast cancer are common entities. Staining for oestrogen receptor (ER), progesterone receptor (PgR), mammaglobin (MAMG) and GATA-binding protein 3 (GATA3) is frequently performed to confirm a mammary origin in the appropriate diagnostic setting. However, comprehensive data on the immunohistological expression of these markers in NSCLC are limited. Therefore, the aim of this study was to analyse a large cohort of NSCLCs and correlate the staining results with clinicopathological variables. METHODS AND RESULTS: A tissue microarray was stained for ER, PgR, MAMG, human epidermal growth factor receptor 2 (HER2), and GATA3, and included 636 adenocarcinomas (ADCs), 536 squamous cell carcinomas (SqCCs), 65 large-cell-carcinomas, 34 pleomorphic carcinomas, and 20 large-cell neuroendocrine carcinomas. HER2 status was determined for immunohistochemically positive cases with chromogenic in-situ hybridisation. Markers with a proportion of ≥5% positive cases in ADC and SqCC were considered for survival analysis. Among ADCs, 62 (10%), 17 (3%), one (<1%), seven (1%), and 49 (8%) cases were positive for ER, PgR, MAMG, HER2, and GATA3, respectively. Among SqCCs, 10 (2%), 14 (3%), two (<1%) and 109 (20%) cases were positive for ER, PgR, HER2, and GATA3, but none of the samples showed positivity for MAMG. ER positivity was associated with ADC, female sex, smaller tumour size, and lower clinical stage. None of the markers had an impact on survival. CONCLUSION: We report on ER, PgR, MAMG, HER2 and GATA3 expression in a large cohort of NSCLCs. Interpretation of these markers in the differential diagnostic setting should be based on a multimarker panel.

Feasibility of a deep learning algorithm to distinguish large cell neuroendocrine from small cell lung carcinoma in cytology specimens.

INTRODUCTION: Distinguishing small cell lung carcinoma (SCLC) from large cell neuroendocrine carcinoma (LCNEC) in cytology is challenging. Our aim was to design a deep learning algorithm for classifying high-grade neuroendocrine carcinomas in fine needle aspirations. METHODS: Archival cytology cases of high-grade neuroendocrine carcinoma (17 small cell, 13 large cell, 10 mixed/unclassifiable) were retrieved. Each case included smears (Diff-Quik® and Papanicolaou stains) and cell block or concomitant core biopsies (haematoxylin and eosin [H&E] stain). All slides (n = 114) were scanned at 40× magnification, randomised and split into training (11 large, nine small) and test (two large, eight small, 10 mixed) groups. Tumour was annotated using QuPath and exported as JPEG image tiles. Three distinct deep learning convolutional neural networks, one for each preparation/stain, were designed to classify each tile and provide an overall diagnosis for each slide. RESULTS: The H&E-trained algorithm correctly classified 7/8 (87.5%) SCLC cases and 2/2 (100%) LCNEC cases. The Papanicolaou stain algorithm correctly classified 6/7 (85.7%) SCLC. and 1/1 (100%) LCNEC cases. The algorithm trained on Diff-Quik® stained images correctly classified 7/8 (87.5%) SCLC and 1/1 (100%) LCNEC cases. CONCLUSION: Using open source software, it was feasible to design a deep learning algorithm to distinguish between SCLC and LCNEC. The algorithm showed high precision in distinguishing between these two categories on H&E sectioned material and direct smears. Although the dataset was limited, our deep learning models show promising results in the classification of LCNEC and SCLC. Additional work using a larger dataset is necessary to improve the algorithm's performance.

Atypical and incomplete pulmonary hypertrophic osteoarthropathy in the left distal femur: a case report.

BACKGROUND: Pulmonary hypertrophic osteoarthropathy (PHO) is a rare paraneoplastic syndrome that mainly occurs in patients with lung cancer. Most symptoms occur symmetrically, and unilateral symptoms without clubbing are infrequent. This report presents the case of a rare atypical symptom that was highly suspected of being PHO. CASE PRESENTATION: A 77-year-old woman with swelling and severe pain in the left femur for 2 months was referred to our hospital. Radiography revealed a remarkably osteogenic thickening and sclerotic lesion in her distal femur. Preliminary diagnoses of malignant bone tumor and hematological tumor were made based on laboratory test results, radiological examination, and clinical manifestation. A needle biopsy was performed, which ruled out the diagnosis of malignant bone tumors. A low-grade bone tumor was still suspected. After that, en bloc resection was performed, followed by replacement of the femur with a mega-prosthesis. Pathological analysis revealed no malignant tumor cells, and immunohistochemical staining for CDK4 and MDM2 yielded negative results. Meanwhile, pulmonary large cell carcinoma was identified on biopsy. Based on published studies, a diagnosis of atypical PHO was made according to clinical and imaging manifestations. CONCLUSIONS: This is an infrequent case of PHO with unilateral symptoms in the left femur. When clinical manifestations and radiological findings are inconsistent with the pathological results, the possibility of benign lesions with malignant clinical manifestations or imaging features should be carefully considered.

Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens?

AIMS: Pulmonary large cell neuroendocrine carcinoma (LCNEC) is underdiagnosed on biopsy specimens. We evaluated if routine neuroendocrine immunohistochemical (IHC) stains are helpful in the diagnosis of LCNEC on biopsy specimens. METHODS AND RESULTS: Using the Dutch pathology registry (PALGA), surgically resected LCNEC with matching pre-operative biopsy specimens were identified and haematoxylin and IHC slides (CD56, chromogranin-A, synaptophysin) requested. Subsequently, three pathologists assigned (1) the presence or absence of the WHO 2015 criteria and (2) cumulative size of all (biopsy) specimens. For validation, a tissue microarray (TMA) of non-small-cell lung cancer (NSCLC) (n = 77) and LCNEC (n = 19) was used. LCNEC was confirmed on the resection specimens in 32 of 48 re-reviewed cases. In 47% (n = 15 of 32) LCNEC was also confirmed in the paired biopsy specimens. Neuroendocrine morphology was absent in 53% (n = 17 of 32) of paired biopsy specimens, more often when smaller amounts of tissue were available for evaluation [29% < 5 mm (n = 14) versus 67% ≥5 mm (n = 18) P = 0.04]. Combined with current WHO criteria, positive staining for greater than or equal to two of three neuroendocrine IHC markers increased the sensitivity for LCNEC from 47% to 93% on paired biopsy specimens, and further validated using an independent TMA of LCNEC and NSCLC with sensitivity and specificity of 80% and 99%, respectively. CONCLUSIONS: LCNEC is difficult to diagnose because neuroendocrine morphology is frequently absent in biopsy specimens. In NSCLC devoid of obvious morphological squamous or adenocarcinoma features, positive staining in greater than or equal to two of three neuroendocrine IHC stains supports the diagnosis of LCNEC.

Pure large cell neuroendocrine carcinoma of ovary: A rare clinical entity.

OBJECTIVE: Large cell neuroendocrine carcinoma (LCNEC) of the ovary is a rare tumour. Its pure form without any associated surface epithelial stromal or germ cell component is more rarely seen. Its prognosis is generally very poor even when the diagnosis is made at an early stage. We report a case of pure large cell neuroendocrine tumour of ovary. The patient was a 73-year-old woman with symptom of pelvic pain. Ultrasonography detected an abdominal tumour larger than 10 cm. She underwent an exploratory laparotomy with resection of the pelvic mass. After the surgery six cycles of chemotherapy (Etoposide and Cisplatin) were administered to the woman. She is still healthy after the last chemotherapy. Due to the rarity of the disease, few number of reported cases and the lack of systematic population based studies or registry data, we reported this case.

Large Cell Neuroendocrine Carcinoma of the Prostate: A Systematic Review and Pooled Analysis.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) of the prostate is an extremely rare entity, and the clinicopathological course, potential effective treatment, and prognosis are yet to be elucidated. MATERIALS AND METHODS: A systematic search in Pubmed, Embase, and Ovid from inception to January 2019 was conducted. We reviewed each individual case of prostatic LCNEC and summarized specific features and outcomes for this rare pathologic entity. RESULTS: Thirteen studies with a total of 20 patients (mean age: 70.3, range 43-87) were included in our review. Seventeen patients harbored primary LCNEC of the prostate, of which 9 patients were diagnosed with de novo carcinoma, and 8 patients were with a history of prostatic adenocarcinoma treated with hormonal therapy (mean duration: 2.9 years, range 2-5). The other 3 patients were diagnosed with metastatic LCNEC originating from lung (2 cases) and bladder (1 case). All patients met the diagnostic criteria of the typical morphological features as well as immunohistochemical staining results. Nearly all primary de novo LCNEC of the prostate were at a late stage at initial diagnosis. The pattern of distant metastasis resembled that of prostatic adenocarcinoma with the most common sites as bone spread (8/16, 50%). Most patients received systematic chemotherapy after diagnosis; however, the prognosis remained poor and patients deteriorated rapidly but with exception. Three reported cases in the context of de novo LCNEC admixed with prostatic adenocarcinoma kept sustained response to androgen deprivation therapy (ADT) and achieved obviously better survival outcomes compared with other patients. CONCLUSIONS: LCNEC of the prostate is a rare entity that mostly occurs after long-standing hormonal therapy of prostatic adenocarcinoma. The prognosis was universally poor irrespective of the systematic chemotherapy. However, patients of de novo tumor mixed with prostatic adenocarcinoma may respond to ADT and harbor a better outcome than those of pure de novo or post-ADT LCNEC of the prostate.

[Diagnosis and treatment of the neuroendocrine tumors of the lung]. / A tüdõ neuroendokrin daganatainak diagnózisa és kezelése.

Lung neuroendocrine tumors comprise 20% of all pulmonary tumors. Their appearance and behavior are very heterogeneous. Histologically they are divided into four groups, well-differentiated and low-malignant typical carcinoid, poorly differentiated and worse prognosis atypical carcinoid, and highly malignant small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. Of these, the most common is small cell lung cancer with an incidence of 15%, while those of large cell neuroendocrine tumors and lung carcinoids are 3% and 2%, respectively. The treatment and prognosis of carcinoids are very different from those of highly malignant small cell and large cell neuroendocrine carcinomas. The paper summarizes the characteristics of lung neuroendocrine tumors.

Large-cell neuroendocrine carcinoma of the skin: ultrastructural and immunohistochemical findings.

Large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive neuroendocrine tumor, found mainly in the lung. Although LCNEC has been reported in various organs, LCNEC of the skin is extremely rare, poorly recognized and probably underestimated. Here we report a case of LCNEC of the skin, focusing on the histopathological and ultrastructural findings in detail. The patient was an 85-year-old Japanese woman presented with a mass on her right upper eyelid. Biopsy specimen showed an infiltrative mass with extension into the subcutis. Tumor cells were arranged in organoid and trabecular patterns with sheets, nests and trabecular cords. Extensive necrotic areas were observed. Most of the tumor cells were characterized by large cell size, polygonal shape, low nuclear-cytoplasmic ratio, coarse nuclear chromatin and frequent nucleoli. They were positive for CD56, NSE, AE1/AE3, CK7, and negative for CK20, TTF-1, synaptophysin and chromogranin A. A systematic radiographic examination revealed no additional neoplastic lesions other than the right upper eyelid mass. These findings suggest that the present case is a LCNEC of the skin. The existence of LCNEC in the skin should be recognized, as it is a rare variant of carcinoma that can potentially be misconstrued as a metastasis or as Merkel cell carcinoma.

Endobronchial ultrasound-guided transbronchial needle aspiration of hilar and mediastinal lymph nodes detected on 18F-fluorodeoxyglucose positron emission tomography/computed tomography.

OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration is of diagnostic value in hilar/mediastinal (N1/N2) lymph node staging. We assessed the utility of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer patients with N1/N2 lymph nodes detected on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography. METHODS: Fifty lung cancer patients with N1/N2 disease on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography underwent endobronchial ultrasound-guided transbronchial needle aspiration for pathological lymph nodes between November 2012 and April 2015. The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration, lymph node site and size, number of needle passes and complications were evaluated retrospectively from patients' medical records. Malignancy was defined as a maximum standardized uptake value (SUVmax) >2.5. RESULTS: The median longest diameter of the 61 lymph nodes (29 subcarinal, 21 right lower paratracheal, 6 left lower paratracheal, 4 right hilar and 1 upper paratracheal) was 23.4 mm (range: 10.4-45.7); the median number of needle passes was 2 (range: 1-5). There were no severe complications. A definitive diagnosis was made by endobronchial ultrasound-guided transbronchial needle aspiration in 39 patients (31 adenocarcinomas, 3 small-cell carcinomas, 2 squamous-cell carcinomas, 3 large-cell neuroendocrine carcinomas). In the remaining 11 patients, the diagnosis was indefinite: insufficient endobronchial ultrasound-guided transbronchial needle aspiration material was collected in two patients and non-specific lymphadenopathy was confirmed by endobronchial ultrasound-guided transbronchial needle aspiration or thoracotomy in the other nine patients. The mean lymph node SUVmax was 7.09 (range: 2.90-26.9) and was significantly higher in true-positive than in false-positive nodes (P < 0.05, t-test). Non-specific lymphadenopathy was diagnosed by expert visual interpretation of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography images in five of the nine patients. CONCLUSION: Endobronchial ultrasound-guided transbronchial needle aspiration accurately diagnoses N1/N2 disease detected on (18)F-fluorodeoxyglucose positron emission tomography/computed tomography.

Ovarian large cell neuroendocrine carcinoma in the youngest woman.

Large cell neuroendocrine carcinoma (LCNC) of the ovary is a rare tumor in gynecologic oncologic field. An 18-year-old woman presented with abdominal distention and a pelvic mass measuring ten cm in diameter, who previously underwent laparoscopic ovarian cystectomy due to large borderline mucinous ovarian neoplasm 18 months prior. A debulking operation was optimally performed, which included total abdominal hysterectomy with bilateral salpingo-oophorectomy, bilateral pelvic lymph node dissection, bilateral paraaortic lymph node dissection, omentectomy, optimal debulking of gastrohepatic mass and subdiaphragmatic mass, and pelvic peritonectomy. Despite adjuvant chemotherapy with paclitaxel and carboplatin, the patient died of progressive disease seven months after surgery. The authors report the youngest case of LCNC of the ovary, that failed chemotherapy and had the previous history of the conservative surgical treatment due to mucinous borderline tumor.

[Large cell carcinoma, lymphoepithelioma-like carcinoma, NUT carcinoma]. / Carcinome à grandes cellules, carcinome lymphoepithelioma-like, carcinome NUT.

The diagnosis of large cell carcinoma can only be made on a sampled resected tumor and should not be applied to biopsies or cytology. In the 2015 WHO classification, the definition of large cell carcinoma is restricted to carcinomas both lacking morphological signs of glandular, squamous or neuroendocrine differentiation and exhibiting a null or unclear phenotype (TTF1-/p40 ou p63 ou CK5/6+ focally). These carcinomas have an adenocarcinoma molecular profile because they harbor a significant number of KRAS and BRAF mutations, a profile that is more similar to adenocarcinoma than squamous cell carcinoma. They also have a worse prognosis than the other types of non-small cell lung carcinoma. Many large cell carcinomas previously classified on morphological data alone are now reclassified in the adenocarcinoma and squamous cell carcinoma types, including immunohistochemical features. The other large cell carcinoma subtypes from the 2004 WHO classification, i.e. large cell neuroendocrine carcinoma and basaloid carcinoma, are grouped respectively with the other neuroendocrine tumors and squamous cell carcinomas. Clear cell and rhabdoid features are now considered as cytological variants that can occur in any histopathological subtype and not as distinct subtypes. Lymphoepithelioma-like carcinoma is moved to the group of other and unclassified carcinomas as NUT carcinoma.

Factors associated with timeliness of post-primary care referral, diagnosis and treatment for lung cancer: population-based, data-linkage study.

BACKGROUND: The NHS Cancer Plan for England set waiting time targets for cancer referral (14 days from GP referral to first hospital appointment) and treatment (31 days from diagnosis, 62 days from urgent GP referral). Interim diagnostic intervals can also be calculated. The factors that influence timely post-primary care referral, diagnosis and treatment for lung cancer are not known. METHODS: Northern and Yorkshire Cancer Registry, Hospital Episode Statistics and lung cancer audit data sets were linked. Logistic regression was used to investigate the factors (socioeconomic position, age, sex, histology, co-morbidity, year of diagnosis, stage and performance status (PS)) that may influence the likelihood of referral, diagnosis and treatment within target, for 28 733 lung cancer patients diagnosed in 2006-2010. RESULTS: Late-stage, poor PS and small-cell histology were associated with a higher likelihood of post-primary care referral, diagnosis and treatment within target. Older patients were significantly less likely to receive treatment within the 31-day (odds ratio (OR)=0.79, 95% confidence interval (CI) 0.69-0.91) and 62-day target (OR=0.80, 95% CI 0.67-0.95) compared with younger patients. CONCLUSIONS: Older patients waited longer for treatment and this may be unjustified. Patients who appeared ill were referred, diagnosed and treated more quickly and this 'sicker quicker' effect may cancel out system socioeconomic inequalities that might result in longer time intervals for more deprived patients.