Neuroendocrine Carcinoma Of Lung Research Articles

Complex Presentation of Lung Cancer with Obstructive Jaundice

Background: Lung cancer, particularly small-cell lung carcinoma (SCLC), often presents with respiratory symptoms. However, atypical manifestations including jaundice and abdominal pain can obscure the diagnosis, leading to challenges in early detection and treatment. Case Presentation: A 49-year-old male, with a history of smoking and diagnosed with Chronic Obstructive Pulmonary Disease (COPD), presented to the emergency department with a 3-day history of jaundice and a 3-week duration of mild abdominal pain. Initial investigations, including blood tests, showed hyperbilirubinemia and elevated lipase and amylase levels. An abdominal ultrasound was performed and revealed a hypoechoic, inhomogeneous mass in the head of the pancreas and multiple liver masses, suggesting a cephalo-pancreatic formation with liver metastasis. Further diagnostic procedures, including upper endoscopy and ERCP, followed by a TAP CT scan, identified a large mediastinal-pulmonary mass with invasion into major vessels and extensive metastasis. The immunohistochemical analysis of a duodenal ulcer biopsy confirmed a diagnosis of duodenal metastasis from a small-cell neuroendocrine lung carcinoma. Conclusion: Our case highlights that while rare, the possibility of metastatic spread should be included in the differential diagnosis when obstructive jaundice occurs in the context of high-risk factors for lung cancer.

Abstract 7566: Identification of cancer subtypes with a ctDNA-based targeted methylation assay

Abstract Introduction: Identifying cancer subtypes is necessary for cancer diagnosis, prognosis determination, and treatment selection. Furthermore, as transformation between subtypes is increasingly recognized as a key resistance mechanism to targeted therapies, serial subtype reassessment is likely to gain adoption. Cancer subtypes have traditionally been determined by pathologists based on histology; more recently, molecular subtyping has been performed using IHC, RNAseq, or assays that detect genetic alterations. However, these methods have significant limitations, including tissue biopsy requirement (IHC and RNAseq), low discriminative resolution for distinct transcriptional programs (IHC and mutation detection), and poor reproducibility and feasibility (RNAseq). The GRAIL plasma-only, ctDNA-based targeted methylation platform is a robust, biopsy-free, scalable assay that can distinguish cancer methylation patterns between different cancer signal origins through the use of a proprietary classifier. Here, we explore the GRAIL platform’s potential to detect finer-scale differences in cancer biology by developing classification algorithms for subtyping of three common cancer types. Methods: As part of the Circulating Cell-free Genome Atlas (NCT02889978) and STRIVE (NCT03085888) studies, clinical data were recorded and plasma samples were collected, accessioned, stored, and processed through GRAIL’s targeted methylation assay from 3,989 cancer and 6,013 non-cancer participants. We developed algorithms to predict cancer status and subtype for breast (triple negative breast cancer [TNBC] model; 531 cancer training participants), lung (lung histology model; 334 cancer training participants), and head and neck (HPV model; 3090 cancer training participants) cancers. Dimensionality reduction of methylation data was performed to illustrate subtype separation within these cancer types. Performance of these three algorithms was assessed on a held-out cohort of cancer samples (184 breast, 241 lung, 67 head and neck) with detectable ctDNA. Results: The lung histology model correctly classified 95% (105/111) of adenocarcinomas, 88% (68/77) of squamous cell carcinomas, and 94% (59/63) of lung neuroendocrine carcinomas and tumors. The TNBC model correctly classified 84% (58/69) of TNBCs and 82% (94/115) of non-TNBCs. The HPV model correctly identified 98% (48/49) of HPV-positive head and neck cancers, and 89% (16/18) of HPV-negative head and neck cancers. Conclusions: GRAIL’s proprietary ctDNA-based targeted methylation platform demonstrates the ability to accurately predict cancer subtypes in multiple cancers using only a plasma sample without the need for tumor biopsy. Future efforts will be directed towards generalizing the GRAIL subtyping method to additional cohorts and cancer types. Citation Format: Tracy Nance, Timothy Shaver, Yifan Zhou, Margaret Antonio, Yinjie Gao, Jonathan Heiss, Robert Calef, Joseph Hiatt, Oliver Venn, Joerg Bredno, John Beausang, Lisa Newman, Charles Swanton, Chun Zhang. Identification of cancer subtypes with a ctDNA-based targeted methylation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7566.

Misleading wheeze in a case of atypical large cell neuroendocrine carcinoma of lung - A deadly variety

Neuroendocrine tumors are neoplasms arising from cells of endocrine and nervous system containing special secretory granules with biogenic amines and polypeptide hormones. One of the varieties that occurs commonly in the lung is large cell neuro endocrine carcinoma. The replicative potential of these neuroendocrine malignancies is so rapid that the patients usually present with metastatic disease. We describe a case of 29-year-old-male presented with nocturnal wheeze which led on to a misdiagnosis of bronchial asthma and finally found to be LCNEC with endobronchial obstruction. They are usually peripherally located lesions, mostly in the upper lung zones of an elderly male smoker. But he had a hilar mass with right lower lobe collapse due to endobronchial obstruction. Hence careful examination of wheeze whether unilateral or bilateral, monophonic or polyphonic, random or fixed, inspiratory or expiratory or biphasic may help in early identification of the endobronchial lesions.

Molecular features of gastroenteropancreatic neuroendocrine carcinoma: A comparative analysis with lung neuroendocrine carcinoma and digestive adenocarcinomas.

There is an ongoing debate about whether the management of gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) should follow the guidelines of small-cell lung cancer (SCLC). We aim to identify the genetic differences of GEPNEC and its counterpart. We recruited GEPNEC patients as the main cohort, with lung NEC and digestive adenocarcinomas as comparative cohorts. All patients undergone next-generation sequencing (NGS). Different gene alterations were compared and analyzed between GEPNEC and lung NEC (LNEC), GEPNEC and adenocarcinoma to yield the remarkable genes. We recruited 257 patients, including 99 GEPNEC, 57 LNEC, and 101 digestive adenocarcinomas. Among the mutations, KRAS, RB1, TERT, IL7R, and CTNNB1 were found to have different gene alterations between GEPNEC and LNEC samples. Specific genes for each site were revealed: gastric NEC ( TERT amplification), colorectal NEC ( KRAS mutation), and bile tract NEC ( ARID1A mutation). The gene disparities between small-cell NEC (SCNEC) and large-cell NEC (LCNEC) were KEAP1 and CDH1. Digestive adenocarcinoma was also compared with GEPNEC and suggested RB1, APC, and KRAS as significant genes. The TP53/ RB1 mutation pattern was associated with first-line effectiveness. Putative targetable genes and biomarkers in GEPNEC were identified in 22.2% of the patients, and they had longer progression-free survival (PFS) upon targetable treatment [12.5 months vs. 3.0 months, HR=0.40 (0.21-0.75), P=0.006]. This work demonstrated striking gene distinctions in GEPNEC compared with LNEC and adenocarcinoma and their clinical utility.

Musashi-1 Is a Novel Immunohistochemical Marker of Neuroendocrine Carcinoma of the Lung

Small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) have recently been grouped as lung neuroendocrine carcinomas (NECs). Because these lung NECs are clinically malignant and their treatment strategies differ from those of non-SCLC, the quality of diagnosis has a significant prognostic impact. The diagnosis of LCNEC requires positive immunohistochemical staining with chromogranin A, synaptophysin, and CD56, along with a morphological diagnosis, and insulinoma-associated protein 1 (INSM1) has been proposed as an additional marker but is still not an ideal or better marker. We investigated Musashi-1 as a novel immunohistochemical marker in 42 patients with SCLCs and 44 with LCNECs who underwent lung resection between 1998 and 2020 at our institution. We found Musashi-1 expression in 98% (41/42) SCLC and in 90% (40/44) LCNEC. These findings were similar to CD56 expression and superior to synaptophysin, chromogranin A, and INSM1. Musashi-1 also tended to show more diffuse and intense staining, especially in LCNEC, with more cases staining > 10% than any other existing markers (Musashi-1, 77%; INSM1, 45%; chromogranin A, 34%; synaptophysin, 41%; and CD56, 66%). In conclusion, we identified Musashi-1 as a novel immunohistochemical staining marker to aid in the diagnosis of lung NEC.

A RARE PRESENTATION OF SMALL CELL LUNG CARCINOMA METASTASIZING TO PHEOCHROMOCYTOMA

Abstract Introduction/Objective Tumor-to-tumor metastasis is a rare phenomenon in which primary tumor cells metastasize hematogenously into another unrelated tumor. We report an interesting case of a tumor-to-tumor metastasis of small cell lung carcinoma to pheochromocytoma of the adrenal gland. Methods/Case Report A 75-year-old female former cigarette smoker with a past medical history of hypertension presented with a two-day history of dyspnea and epigastric pain. Physical examination demonstrated elevated blood pressure only. A computerized axial tomography scan of the chest and abdomen showed an incidental 3.1 cm right adrenal mass and right hilar lymphadenopathy. Detailed biochemical workup showed elevated serum epinephrine, norepinephrine, and 24-hour urine metanephrine. Adrenalectomy showed a 5.8 cm tumor mass with solid lobulated yellow to pink-tan and focally hemorrhagic cut surfaces. Microscopic examination showed a neoplasm composed of two distinct components. The predominant component consisted of nests ("zellballen") of large polygonal cells with variable nuclear pleomorphism, abundant amphophilic to basophilic cytoplasm, and a delicate intervening fibrovascular stroma, without significant mitotic activity. The minor component was characterized by sheets and nests of "small blue cells" with round to ovoid nuclei, stippled nuclear chromatin pattern, scanty cytoplasm, patchy necrosis, and high mitotic activity (>20 mitoses per 10 HPF). Foci of small cell carcinoma deposits were also present in the lymphatic channels of pheochromocytoma. Immunohistochemical stains demonstrated cytoplasmic staining of predominant component tumor cells for synaptophysin, chromogranin, and the absence of staining for TTF-1, CK CAM 5.2, and Ki-67. However, minor component tumor cells demonstrated cytoplasmic staining for synaptophysin, membranous staining for CK CAM 5.2, and nuclear staining for TTF-1 and Ki-67(60%). A final diagnosis of composite pheochromocytoma (predominant) and small cell neuroendocrine carcinoma (minor) was rendered. The possibility of a” collision” tumor comprising primary small cell carcinoma of pulmonary origin metastatic to an adrenal pheochromocytoma in light of the patient's cigarette smoking history and the presence of right hilar lymphadenopathy was favored. The subsequent biopsy of the right subcarinal adenopathy showed small cell carcinoma. Results (if a Case Study enter NA) NA Conclusion To the best of our knowledge, this is the only case of metastasis to a pheochromocytoma from a small cell neuroendocrine lung carcinoma.

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers.

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 μM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 μCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 μCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

P2.16-05 Durvalumab+EP in Advanced Large-Cell Neuroendocrine Carcinoma of Lung (aLCNEC): a Pilot Phase II study

P2.16-05 Durvalumab+EP in Advanced Large-Cell Neuroendocrine Carcinoma of Lung (aLCNEC): a Pilot Phase II study

Novel Mouse Cell Lines and In Vivo Models for Human High-Grade Neuroendocrine Lung Carcinoma, Small Cell Lung Carcinoma (SCLC), and Large Cell Neuroendocrine Carcinoma (LCNEC).

There is a clear need to expand the toolkit of adequate mouse models and cell lines available for preclinical studies of high-grade neuroendocrine lung carcinoma (small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC)). SCLC and LCNEC are two highly aggressive tumor types with dismal prognoses and few therapeutic options. Currently, there is an extreme paucity of material, particularly in the case of LCNEC. Given the lack of murine cell lines and transplant models of LCNEC, the need is imperative. In this study, we generated and examined new models of LCNEC and SCLC transplantable cell lines derived from our previously developed primary mouse LCNEC and SCLC tumors. RNA-seq analysis demonstrated that our cell lines and syngeneic tumors maintained the transcriptome program from the original transgenic primary tumor and displayed strong similarities to human SCLC or LCNEC. Importantly, the SCLC transplanted cell lines showed the ability to metastasize and mimic this characteristic of the human condition. In summary, we generated mouse cell line tools that allow further basic and translational research as well as preclinical testing of new treatment strategies for SCLC and LCNEC. These tools retain important features of their human counterparts and address the lack of LCNEC disease models.

First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC).

8502 Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .

Generation of an induced pluripotent stem cell line SDPHi002-A from a patient with lung cancer

Here, an induced pluripotent stem cell (iPSC) line from a patient with lung neuroendocrine carcinoma was generated. The iPSCs were developed using nonintegrating episomal vectors carrying OCT4, SOX2, KLF4, BCL-XL and c-MYC. The established iPSCs (SDPHi002-A) had normal karyotype, excellent differentiation potential in vitro, showing pluripotent stem cell morphology and high expression of pluripotent markers.

Abstract 5034: Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas

Abstract Introduction/Background: Atypical lung carcinoids and lung neuroendocrine carcinomas (NECs) are currently incurable. Most of these cancers express the C-X-C chemokine receptor 4 (CXCR4), making CXCR4 an attractive target for cancer diagnosis and treatment using radioligand therapy (RLT) with nuclides such as alpha emitter Pb212 conjugated to Pentixather (Pent). Alpha particles produce dense ionization tracks and damage cytosolic structures such as mitochondria, leading to the generation of reactive oxygen species such as superoxide (O2 ●−) and hydroperoxides (H2O2 and ROOH) in targeted cancer cells. The FDA approved thioredoxin reductase inhibitor, auranofin (Aur), inhibits peroxiredoxin-mediated hydroperoxide metabolism increasing cell killing in targeted cancer cells. Hypothesis: Inhibition of hydroperoxide metabolism using Aur can enhance therapeutic efficacy of alpha particle emitting 212Pb-Pent in preclinical models of lung carcinoids and NECs. Results: Clinically, IHC revealed greater than 75% of atypical carcinoids and NECs tested had moderate to high CXCR4. qRT-PCR, flow cytometry and immunohistochemistry performed on different lung carcinoid and NEC lung cell lines, determined that the majority moderately or highly express CXCR4. The minimal non-toxic dose of Aur that inhibits 50-70% of thioredoxin reductase activity was 4 mg/kg (intraperitoneal once a day) in DMS273 (small cell lung cancer) xenografts 212Pb-Pent given IV (1 and 3 µCu/g) was effective at increasing the survival of mice with DMS273 xenografts. Mice were then treated with 1.5, 3 or 6 µCu/g 212Pb-Pent w/wo Aur 4 mg/kg/day. A trend test showed that both increasing dose of 212Pb-Pent and the addition of Aur, caused a significant (p&amp;lt;0.01) delay in tumor growth. There were no significant changes in body weights, complete blood counts, and serum alanine aminotransferase indicating the combination treatments were well tolerated. Radiation dosimetry estimates using quantitative SPECT/CT imaging with Pb203-Pent demonstrated average absorbed doses of 0.133 Gy/µCi (liver), 0.098 Gy/µCi (kidneys), 0.013 Gy/µCi (H292 xenografts), 0.028 Gy/µCi (DMS53 xenografts), 0.057 Gy/µCi (DMS273 xenografts), and 0.096 Gy/µCi (H69AR xenografts). Xenograft absorbed dose levels were positively correlated with CXCR4 expression. Conclusion: The use of 212Pb-Pent therapy to target CXCR4 on NECs showed pre-clinical efficacy in a dose dependent manner that was enhanced by Aur without significant normal tissue toxicity supporting the hypothesis that CXCR4 can be successfully targeted with the radionuclide theragnostic pair, Pb212/Pb203-pentixather. Citation Format: Melissa A. Fath, Dijie Liu, Claudia Robles-Planells, Jordan T. Ewald, Keegan A. Christensen, Spenser S. Johnson, Stephen A. Graves, Douglas R. Spitz, Yusuf Menda, M. Sue O’Dorisio. Targeting CXCR4 and thioredoxin reductase in high grade neuroendocrine tumors and neuroendocrine carcinomas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5034.

Therapeutic efficacy of platinum/etoposide regimens in the treatment of advanced poorly differentiated neuroendocrine carcinomas of the lung: A retrospective analysis.

Lung neuroendocrine neoplasms (NENs) are rare malignancies developed from bronchial mucosa. Because of its rarity and complex histopathology, there is limited data on the role of chemotherapy in this subset of tumors. Few studies regarding the treatment of poorly differentiated lung NENs, known as neuroendocrine carcinomas (NECs), are available and many limits are detectable as heterogeneity of tumor samples including different origins and different clinical behaviors, moreover, no evidence of therapeutic advances have been achieved along the last thirty years. We performed a retrospective analysis of 70 patients affected by poorly differentiated lung NECs: half of patients underwent a first line therapy with a combination of cisplatin plus etoposide; the remaining patients receiving carboplatin instead of cisplatin, plus etoposide. Results: In our analysis, the outcomes of patients treated with either cisplatin or carboplatin schedule are similar in terms of ORR (44% versus 33%), DCR (75% versus 70%), PFS (6.0 versus 5.0 months) and OS (13.0 versus 10 months). Median number of chemotherapy cycles was 4 (range 1-8). The 18% of patients required a dose reduction. Main toxicities reported were hematological (70.5%), gastrointestinal (26.5%) and fatigue (18%). Survival rate in our study suggests that high grade lung NENs are characterized by an aggressive behavior and a poor prognosis, despite the treatment with platinum/etoposide according to available data. Clinical results of present study contribute to strengthen available data on the usefulness of platinum/etoposide regimen in the treatment of poorly differentiated lung NENs.

Uncommon etiology of Cullen´s sign and Grey Turner sign.

Cullen´s sign and Grey Turner sign are, respectively, the cutaneous ecchymoses located in periumbilical region and tissues flanks along the lower portion of the abdomen. Both have been observed in <1% of individuals with acute pancreatitis, suggesting poor prognosis in terms of gravity and mortality. However, these signs are not exclusive for acute pancreatitis, as they can appear in other identities such as: ruptured ectopic pregnancy, aortic aneurysm, rectus abdominis muscle hematoma, perforated duodenal ulcer, common bile duct rupture and biliary peritonitis, idiopathic perirenal hemorrhage, infectious mononucleosis with splenic rupture, metastatic esophageal and thyroid cancer, non-Hodgkin lymphoma, amoebic liver abscess, portal hypertension, and liver tumor disease. Based on the review of the literature, it is patent that Cullen´s sign and Grey Turner sign are neither sensitive nor specific for acute pancreatitis, therefore it may be best to relate these findings in the physical examination to conditions associated with abdominal pathology and retroperitoneal hemorrhage. We report the case of a 60-year-old Spanish female, with previous history of squamous small cell neuroendocrine lung carcinoma with hepatic extension in follow-up by palliative care services. Due to disease progression after two palliative chemotherapy sessions, the patient came to the emergency room with jaundice and abdominal pain in superior regions. On physical examination, notable findings included ecchymoses in the right flank and periumbilical region. Laboratory findings showed elevated bilirubin and transaminase levels, as well as a small increase in the serum amylase and lipase levels. Cholangioresonance was performed to discard acute biliary pancreatitis. The imaging revealed no enlargement of the pancreas, dilatation of the common bile duct without visible stone, and a liver full of new cancerous liver implants. These findings were consistent with diffuse distribution metastases lesions, concluding the progression of liver disease.

CLINICAL CASE OF NON-TYPICAL METASTASIS OF NEUROENDOCRINE LUNG CARCINOMA TO THE VASCULAR MEMBRANE OF THE EYE

Metastases in eye structures are rare (1-5% cases at systemic spread of different malignancies, mainly breast and lung cancers). The prognosis is poor. The overall survival usually does not exceed 12or even 6months. If metastases are found in the choroid membrane, the probability that the patient has multiple metastatic lesions of other organs increases significantly. Lung neuroendocrine neoplasms are rare (1-2% of all malignancies in adults), but mainly aggressive tumors. They are cha-racterized by "blurred", nonspecific clinical symptoms, the correct diagnosis is delayed seriously, and distant metastases are seen in more than 40% of patients (usually in chest structures, liver, bones, brain, and adrenal glands; metastasis to vascular membrane of the eye ranks the 6th place). Own clinical observation of a male patient with rare metastasis of lung neuroendocrine carcinoma to the choroid of the left eye is presented. The disease is manifested by an ocular metastasis, which was initially considered an embryonic tumor. Other metastatic lesions (hilar lymph nodes, liver, soft tissues) were detected on computed tomography a little bit later. The diagnostic algorithm using routine histological examination and immunohistochemistry, including detection of neuroendocrine markers (chromogranin A, synaptophysin), cytokeratin 7 and Ki-67expression in primary and metastatic tumors is described.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis

Introduction: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. Methods: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). Results: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III–IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. Conclusion: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.

Value of immunohistochemistry in crushed areas of pulmonary neuroendocrine carcinoma

Immunohistochemical demonstration of neuroendocrine differentiation is often performed in routine diagnostic practice for lung neuroendocrine carcinoma. However, these carcinomas are often crushed, especially on small specimens. The value of immunohistochemistry on crushed areas is not known. We aimed to assess the value of immunohistochemical markers in crushed areas. We performed a retrospective study of 299 patients with a diagnosis of pulmonary neuroendocrine carcinoma. We showed that the markers TTF-1, synaptophysin, chromogranin A, CD56, and INSM1 were more often negative in crushed areas compared with well-preserved areas. The proliferation index with anti-Ki67 was decreased but remained on average around 90%. For all markers, the percentage of labeled cells was lower than in the preserved areas. Finally, we show that cases without labeling in the crushed areas and maintained labeling in the non-crushed areas have a lower percentage of labeling than cases without this labeling mismatch. Finally, there were no false positives of these stains.Neuroendocrine markers are valid in crushed areas when positive. However, the percentage of labeled cells may be lower than on preserved areas and lead to false negatives. Finally, the proliferation index, although decreased, remains close to that on preserved areas.

Large cell neuroendocrine lung carcinoma – A challenging rare tumour

Large cell neuroendocrine lung carcinoma – A challenging rare tumour

Prognostic nomograms for lung neuroendocrine carcinomas based on lymph node ratio: a SEER database analysis.

ObjectiveThe current study aimed to explore the prognostic value of the lymph node ratio (LNR) in patients with lung neuroendocrine carcinomas (LNECs).MethodsData for 1564 elderly patients with LNECs between 1998 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database. The cases were assigned randomly to training (n = 1086) and internal validation (n = 478) sets. The association between LNR and survival was investigated by Cox regression.ResultsMultivariate analyses identified age, tumor grade, summary stage, M stage, surgery, and LNR as independent prognostic factors for both overall survival (OS) and lung cancer-specific survival (LCSS). Tumor size was also a prognostic determinant for LCSS. Prognostic nomograms combining LNR with other informative variables showed good discrimination and calibration abilities in both the training and validation sets. In addition, the C-index of the nomograms was statistically superior to the American Joint Committee on Cancer (AJCC) staging system in both the training and validation cohorts.ConclusionsThese nomograms, based on LNR, showed superior prognostic predictive accuracy compared with the AJCC staging system for predicting OS and LCSS in patients with LNECs.

MA01.09 Characterising Aggressive Pulmonary Carcinoids Through Integrative Omics Analysis Within the lungNENomics Project

Typical and atypical carcinoids are well differentiated lung neuroendocrine tumours (LNETs) that belong to the group of lung neuroendocrine neoplasms, which also include highly aggressive lung neuroendocrine carcinomas (LNECs). Although carcinoids show relatively good prognosis in comparison to carcinomas, metastatic disease and relapse do occur. In a previous study we introduced the concept of molecular groups of carcinoids: A (further separated into A1 and A2) and B, which did not clearly correspond to individual histological types.