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OBJECTIVE To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant chemotherapy in dogs with pulmonary carcinoma. ANIMALS 340 dogs. PROCEDURES Medical records of dogs that underwent lung lobectomy for removal of a primary pulmonary mass were reviewed, and histopathologic type of lesions was determined. The canine lung carcinoma stage classification system was used to determine clinical stage for dogs with pulmonary carcinoma. RESULTS Pulmonary carcinoma was the most frequently encountered tumor type (296/340 [87.1%]), followed by sarcoma (26 [7.6%]), adenoma (11 [3.2%]), and pulmonary neuroendocrine tumor (5 [1.5%]); there was also 1 plasmacytoma and 1 carcinosarcoma. Twenty (5.9%) sarcomas were classified as primary pulmonary histiocytic sarcoma. There was a significant difference in median survival time between dogs with pulmonary carcinomas (399 days), dogs with histiocytic sarcomas (300 days), and dogs with neuroendocrine tumors (498 days). When dogs with pulmonary carcinomas were grouped on the basis of clinical stage, there were no significant differences in median survival time between dogs that did and did not receive adjuvant chemotherapy. CLINICAL RELEVANCE Results indicated that pulmonary carcinoma is the most common cause of primary pulmonary neoplasia in dogs; however, nonepithelial tumors can occur. Survival times were significantly different between dogs with pulmonary carcinoma, histiocytic sarcoma, and neuroendocrine tumor, emphasizing the importance of recognizing the relative incidence of these various histologic diagnoses. The therapeutic effect of adjuvant chemotherapy in dogs with pulmonary carcinoma remains unclear and warrants further investigation.

Background: Pulmonary neuroendocrine tumors (pNETs) include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with Bronchial Carcinoid (BC) and Large Cell Neuroendocrine Carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. Methods: We retrospectively analyzed patients undergoing anatomical lung resection for BC or LCNEC with lymph node involvement (N1/N2) at the final pathological examination (pN+). Characteristics of patients and differences in overall survival (OS) and Disease Free Survival (DFS) are presented according to tumor type. Overall survival (OS) of distinct histological groups was compared with survival in our institutional experience in stage I-patients, without nodal involvement (pN0). Results: 325 patients underwent surgical resection forneuroendocrine tumors ; 89 patients had nodal involvement. 5-year survival was 89% in pN+ BCs both for typical (TC) and atypical carcinoid (AC) but worse in pN+ LCNEC (47%). Cell type did not influence the prognosis in N0-disease, and no differences in survival were evident between N0 and N+ in BC group. In the group of LCNEC, 5-year OS was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). Conclusions: BCs have the best prognosis, and surgery remains the treatment of choice both for early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach Background: Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. Methods: We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0). Results: In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). Conclusions: Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.

Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) is a rare disease often associated with carcinoid tumors. We aimed at evaluating the impact of DIPNECH on characteristics and prognosis of patients who underwent radical treatment of pulmonary carcinoid tumors.We reviewed all patients operated on for curative-intent resection of carcinoid tumor in our department from 2001 to 2020. Cases exhibiting both pathological and radiological features of DIPNECH, as assessed by respective thoracic expert physicians, were analyzed separately.172 cases of resected carcinoid tumors were identified, including 25 (14.5 %) harboring pathological criteria of DIPNECH and radiologic features like mosaic attenuation (92.0 %), multiple nodules5 mm (76.0 %), and mucoid impactions (32 %). In DIPNECH patients, major pulmonary resections were usually performed (92.0 %) and resected tumors were mostly classified as pT1 (92 %). Mean Ki67 staining was 3.7 ± 5.2 %. The early postoperative period was mostly uneventful (96.0 %) and 5-year survival was 92.9 ± 6.9 %. Compared to non-DIPNECH cases, we found that patients were older (mean 65.6 ± 9.3 versus 54.1 ± 17.9, p = 0.002), more frequently female (84.0 % versus 56.5 %, p = 0.009), and exhibiting diabetes mellitus (45.8 % versus 18.5 %, p 0.001) or hypertension (45.8 % versus 24.1 %, p = 0.039). The rate of atypical carcinoid tumors was significantly higher in DIPNECH patients (40.0 % versus 19.9 %, p = 0.027), as well as rate of mediastinal lymph-nodes involvement (pN2+) (36.0 % versus 4.1 %, p 0.001). At multivariate analysis, only DIPNECH pattern and atypical histology were independent factors of pN2 invasion which was the only predictor of poorer prognosis on Log-Rank test.Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management.

Intracavitary cardiac metastasis is a rare manifestation of primary lung cancer which can be associated with a very poor prognosis. In this condition, the right chambers of the heart are more commonly involved and the invasion of the left atrium (LA) through the venous routes is highly exceptional. Poorly differentiated large-cell neuroendocrine tumors also include only 3% of all primary lung carcinomas which can have adverse outcomes. Therefore, in this report, a rare case of a 72-year-old male patient with poorly differentiated large-cell neuroendocrine carcinoma of the right lung spreading to the LA through the right pulmonary veins was described.

SUMMARY Acromegaly caused by ectopic growth hormone-releasing hormone (GHRH)-secreting tumor is exceedingly rare. We report a case of acromegaly secondary to GHRH secretion by an incidentally diagnosed pulmonary neuroendocrine tumor (NET) and review 47 similar cases in literature. A 22-year-old male patient presented with symptoms of pituitary apoplexy. Magnetic resonance imaging (MRI) showed apoplexy of a pituitary adenoma. Routinely prior to surgery, a chest radiography was performed which revealed a mass in the left lung. During investigation, the patient was diagnosed with metastatic GHRH-secreting pulmonary NET. In retrospect, it was noted that the patient had pituitary hyperplasia 20 months prior to the MRI which showed the presence of a pituitary adenoma. The histological findings confirmed somatotroph hyperplasia adjacent to somatotropinoma. This case suggests that GHRH secretion can be associated with pituitary hyperplasia, which may be followed by pituitary adenoma formation.

Neuroendocrine tumors are a group of tumors that share morphological, immunohistochemical and ultrastructural pathology and molecular features...

Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1High SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1High SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors., Secreted proteins present a rich resource of potential cancer biomarkers. Here, the authors use mass spectrometry to analyze secretome remodeling in pulmonary neuroendocrine lung cancer cell lines and validate potential biomarkers and therapeutic targets in vitro and in mouse models.

Background: Classification of the pulmonary neuroendocrine tumor (pNET) categories is a step-wise process identified by the presence of necrosis and number of mitoses per 2 mm2. In neuroendocrine tumor pathology, Ki-67 was first described as a prognostic factor in the pancreas and incorporated into the grading system of digestive tract neuroendocrine neoplasms in the 2010 WHO classification. However, the significance of Ki-67 in pNETs was still a controversial issue. This study was to investigate the potentially diagnostic value of Ki-67 in pNETs. Methods: We retrieved 159 surgical specimens of pNETs, including 35 typical carcinoids (TCs), 2 atypical carcinoid (ACs), 28 large-cell neuroendocrine carcinomas (LCNECs), 94 small-cell lung cancers (SCLCs). Manual conventional method (MCM) and computer-assisted image analysis method (CIAM) were used to calculate the Ki-67 proliferative index. In CIAM, 6 equivalent fields (500 × 500 μm) at 10× magnification were manually annotated for digital image analysis. Results: The Ki-67 index among the 4 groups with ranges of 0.38% to 12.66% for TC, 4.34% to 29.48% for AC, 30.67% to 93.74% for LCNEC, and 40.71% to 96.87% for SCLC. The cutoff value of Ki-67 index to distinguish low grade with high grade was 30.07%. For the univariate survival analyses in pNETs, both the overall survival and progression-free survival correlated with Ki-67 index. In addition, the Ki-67 index performed by CIAM was proved to be of great positive correlation with MCM. Conclusions: Ki-67 index counted by CIAM is a reliable method and can be a useful adjunct to classify the low- and high-grade NETs. Key words: Antigen Ki-67; Computer-assisted numerical analysis; Neuroendocrine tumor; Prognostic factor

Introduction Large cell neuroendocrine carcinoma (LCNEC) is a rare type of high-grade pulmonary neuroendocrine tumor. The study objective is to investigate its survival outcomes, incidence of brain metastases, and patterns of recurrence. Methods This is a single center study of patients with pathologic diagnosis of pulmonary LCNEC. Patient data were collected retrospectively and analyzed, including survival, incidence of brain metastases, and patterns of recurrence. Results Of 87 patients (stages I: 24, II: 14, III: 23, IV: 26), 52 were managed curatively and 35 palliatively. The median follow-up time was 17.3 months (range 0.6-89.5) for those treated with curative intent and 7.0 months (range 0.1-28.6) for those treated palliatively. The 2- and 5-year overall survival (OS) rates are 48.4% and 25.5% for the curative group, with a median OS of 13.5 months. In the palliative group, the OS are 30.8% at 1 year and 6.8% at 2 years, with a median OS of 7.0 months. Thirty-eight of 52 (73%) patients treated with curative intent had disease relapse, with the common sites being regional lymph nodes (20), brain (18), bones (11), and liver (9). The incidence of brain recurrence among those managed curatively are 21.4% and 41.3%, respectively at 1 and 2 years. Of 18 patients experiencing brain metastases, 14 developed them as part of a first relapse. Conclusions LCNEC's survival outcomes are poor. The incidence of brain metastases is higher than what is observed for other types of nonsmall cell lung cancers. Prophylactic cranial irradiation should be investigated as a means of improving outcomes.

BackgroundMalignant liver infiltration is an uncommon cause of acute liver failure (ALF) and has rarely been reported.Case PresentationWe present a patient with progressive jaundice and dissociation of bilirubin and aminotransferases, who had no history of relevant liver diseases or tumor except the use of Chinese traditional drugs for a cold. An abdominal computed tomography (CT) scan showed ascites without hepatic focal lesions. Laboratory studies revealed no evidence of hepatitis or underlying autoimmune disorders. Following 8 days of conservative management ALF rapidly worsened. Contrast-enhanced CT revealed diffuse regenerative nodules in the liver. The patient underwent liver biopsy, which demonstrated that the liver was infiltrated by pulmonary neuroendocrine tumor classified as small cell lung cancer. The patient died 13 days after diagnosis.Discussion and ConclusionsThis case represents a rare cause of ALF induced by pulmonary neuroendocrine tumor of small cell type and illustrates the importance of prompt biopsy in an unknown cause of ALF.

Objective Procalcitonin (PCT) has received much attention as a serum marker for bacterial infection. Elevated serum PCT is occasionally seen in severe trauma, heatstroke, and neoplastic diseases, including lung cancer with neuroendocrine component. Results In the present study, we evaluated PCT expression in the specimen of pulmonary neuroendocrine tumors, comparing large cell neuroendocrine carcinoma (LCNEC), carcinoid, and small cell lung carcinoma (SCLC). Pathological specimens of 10 LCNEC, 4 carcinoid, and 7 SCLC cases were evaluated with immunochemical staining of PCT. Clinical characteristics and serum levels of PCT and C-reactive protein were also evaluated. We observed positive PCT expression in 5 (50%) LCNEC and 2 (50%) carcinoid specimens that were surgically resected. Whereas serum PCT levels were not elevated in patients with PCT-positive carcinoid, two out of three LCNEC patients with high PCT expression in the tumor had elevated serum PCT levels that reflected disease progression. In patients with SCLC, PCT was not detected in the tumor or serum. This is the first immunohistochemical study of the PCT expression in the lung tumor specimens. We concluded that, in patients with LCNEC, high serum PCT levels may be indicative of disease activity and serve as a biomarker.

A 58-year-old man underwent DOTATATE PET/CT scan for follow-up of pulmonary neuroendocrine tumor after resection and adjuvant chemotherapy. On screening paperwork, the patient indicated having received the Johnson & Johnson/Janssen COVID-19 vaccine (Janssen Biotech, Inc) 1 day previously, administered in the right deltoid muscle. Reactive changes in regional lymph nodes is a known response for all 3 currently Food and Drug Administration-approved COVID-19 vaccines. Recent published data have demonstrated FDG PET-avid axillary lymphadenopathy subsequent to COVID-19 vaccination, and included here is a report of DOTATATE PET-avid axillary lymph node after injection of the Johnson & Johnson COVID-19 vaccine.

Objectives To evaluate the prognostic significance of patterns of distant metastatic organs in metastatic pulmonary neuroendocrine tumors (PNETs). Methods 891 metastatic PNETs patients (G1-typical carcinoid, 200; G2-atypical carcinoid, 68; G3-large-cell neuroendocrine carcinoma, 623) diagnosed between 2010 and 2016 were identified. Multivariate analysis was performed using a Cox regression model to identify prognostic factors associated with cancer-specific survival (CSS). The novel M component was established based on the hazard ratio of different metastatic organs. A disease-specific staging system was then proposed by using k-means cluster analysis. Results For metastatic PNETs, involvement of bone, liver or brain and multiple metastatic organs were identified as independent prognostic factors in multivariate analysis. M categories was subdivided into three subcategories: M1a, lung involvement only or distant lymph node involvement only; M1b, bone involvement only or liver involvement only; M1c, brain involvement regardless of number of metastatic organs or multiple organs involvement except brain. Primary site surgery, chemotherapy and histologic subtypes were independently associated with CSS, but T component and N component were not. After regrouping histologic subtypes and novel M component, we proposed the following modified staging system: stage IVA (G1M1any, G2M1a-b), stage IVB (G2M1c, G3M1a-b) and stage IVC (G3M1c). The 2-year CSS were 77.9 %, 16.4 % and 5.3 %. Conclusions Subdivision of M component according to patterns of distant metastatic organs facilitates prognostic significance for PNETs. Brain metastases and multiple metastatic organs were associated with significantly inferior prognosis. Incorporating histologic subtypes and novel M categories create a disease-specific staging system showed good discriminatory capacity.

The presence of a symptomatic and recurrent unilateral pleural effusion should alert physicians to consider thoracentesis with mindful use of biomarkers not only for therapeutic purposes, but also for diagnosis of both benign and malignant etiologies.

Background: 68Ga DOTATATE PET/CT (68Ga-PET) has been proposed as a superior method in identifying ectopic ACTH syndrome (EAS). However, recent systematic review suggests its sensitivity is not as high as believed (1). We report a challenging case of EAS whose source was uncovered only after repeated 68Ga-PET. Clinical Case: A 15-year-old male presented with rapid onset of typical features of Cushing’s syndrome (CS) and metabolic impairment. Hormone evaluation confirmed severe ACTH-dependent CS. Pituitary transsphenoidal surgery was performed due to positive responses in desmopressin stimulation and high dose dexamethasone suppression test, in addition to a 4 mm nodule in pituitary MRI. No tumor was found in surgical specimen and no hormonal improvement was observed after surgery. Inferior petrosal sinus sampling demonstrated no central to peripheral ACTH gradient. Neck US, thorax/abdomen/pelvis CT were negative and PET-CT/FDG was inconclusive. OctreoScan® identified anomalous uptake on left mediastinum and led the patient to a thoracic surgery (TS) with nodule resection at left hilum. Pathology confirmed ACTH positive 10 mm neuroendocrine tumor (NET) infiltrating a lymph node. The patient had transient clinical and hormonal improvement, with recurrence 7 months later. Thoracic CT (T-CT) showed a 7 mm nodule on inferior segment of superior left lobe, PET-CT/FDG and OctreoScan® were negative but abnormal uptake was verified by 68Ga-PET in subcarinal area. A sub centimetric lymph node was resected and pathology confirmed ACTH positive NET, although the patient did not achieve remission. Octreotide LAR, cabergoline and ketoconazole did not control hypercortisolism and bilateral adrenalectomy was performed. Then, T-CT showed stable lung nodule and 2nd 68Ga-PET was negative. One year later, T-CT evidenced growth of lung nodule to 15 mm and 3rd 68Ga-PET demonstrated for the first time, abnormal uptake in this area. The patient underwent resection of left superior lung lobe along with ipsilateral hilar lymph nodes, and histopathology study revealed an ACTH-secreting atypical pulmonary carcinoid tumor with Ki67 of 10% and 5 out of 11 lymph nodes affected. ACTH fell from 288 to 64 pg/mL after surgery. Conclusion: Despite the high sensitivity attributed to 68Ga-PET, false negatives have been reported. In the present case, primary tumor was evidenced by 68Ga-PET seven years after the first resection of a metastatic lymph node, in the 3rd 68Ga-PET assessment and after tumor growth. This adds to the evidence that further studies are needed to better assess the accuracy of 68Ga-PET for EAS. Reference: [1] Varlamov et al. Diagnostic utility of Gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience. Pituitary 2019; 22:445–455

Endobronchial carcinoid tumors (ECT) are the most common pulmonary neuroendocrine tumor in the pediatric population. We report two cases of ECT in children who presented with recurrent pneumonia and bronchial asthma-like symptoms. Rigid bronchoscopy revealed an endobronchial mass with biopsy confirming the diagnosis. Both children underwent surgical resection with an uneventful post-operative course. Neither of children required adjuvant chemotherapy nor radiotherapy and with a mean of follow-up of 8 years with no recurrence. Physicians should be aware that children with recurrent pneumonia and asthma-like symptoms may have ECT. Appropriate investigations including CT scan, bronchoscopy, and biopsy would ensure early diagnosis and surgery.

A 69-year-old man with recurrent multiple myeloma underwent FDG PET/CT evaluation. A pulmonary nodule without higher-than-background FDG avidity was later biopsied as a low-grade neuroendocrine tumor. On further Ga-DOTATATE PET/CT evaluation of patient's neuroendocrine tumor, the lytic myeloma lesions revealed only mild DOTATATE avidity while the primary pulmonary neuroendocrine tumor showed intense DOTATATE uptake. The distinct imaging characteristics of different primary malignancies correlated with their underlying different pathology.

Background/aim: It is not always easy to diagnose pulmonary neuroendocrine tumors (PNETs). The aim of the present study is to make a differential diagnosis by studying the same markers in patients with non-small-cell lung carcinoma (NSCLC), patients with benign lung disease (chronic obstructive pulmonary disease and pneumonia), and healthy volunteers to determine the roles of these markers in pulmonary neuroendocrine tumor diagnosis and to identify their power. Materials and methods: A total of 100 participants including 23 PNET patients and 28 NSCLC patients who were pathologically di-agnosed but not yet treated, 25 participants with benign disease, and 24 healthy volunteers were included in this cross-sectional study.Results: No significant difference was found between the chromogranin A (CgA) and squamous cell carcinoma antigen 1 (SCCA1) values among the groups (PNET, NSCLC, benign, healthy volunteers), but the difference in progesterone-releasing peptide (ProGRP), neuron-specific enolase (NSE), and adjusted NSE was statistically significant (P values were respectively ProGRP, P = 0.006; NSE, P = 0.015; NSE adjusted, P = 0.09). In a comparison of the PNET and NSCLC groups, having a ProGRP value higher than 84.6 pg/mL re-vealed PNET with 60.9% sensitivity and 89.3% specificity (P = 0.001). Conclusion: The ProGRP value is the only indicator that distinguishes the PNET group from the other 3 groups.

Background: Pulmonary neuroendocrine tumor (NET) occurs with 20% of all lung cancers, and there are a limited number of literatures about the molecular aberrations, treatment and prognosis; especially in resected cases, as the operation indication for large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) is rare due to their aggressive behaviors. We investigated the relationship between postoperative survival and molecular expression patterns of pulmonary NET to establish a more effective treatment strategy. Methods: In the present study, the curative surgical resection of pulmonary NET was reviewed retrospectively. A total of 105 patients with pulmonary NET, who underwent complete resection between 1978 and 2016, were subjected to analysis with respect to histological characterization and clinical behaviors of pulmonary NET using immunohistochemistry (IHC) of neuroendocrine markers and programmed cell death-ligand 1 (PD-L1). Results: The pathological types included 67 SCLC, 18 LCNEC, 14 typical carcinoids (TCs) and 6 atypical carcinoids (ACs). The ACs had significantly worse prognosis than TCs. PD-L1 expression ratio in SCLC/LCNEC/TC/AC was 26.1%/50%/15.4%/20%, respectively. However, it was not significantly correlated with each prognosis. Therefore, the SCLC patients were analyzed, the overall 5-year survival of SCLC patients was found to be 47.3%. In the univariate analysis of the molecular expression of SCLC, neuroendocrine markers such as chromogranin-A (CGA) and synaptophysin (SYN) showed poor prognosis, albeit without significant differences. Conclusions: The neuroendocrine markers such as CGA and SYN might assist the prediction of prognosis and probably influence the decision for adjuvant chemotherapy or follow-up intervals after surgery in SCLC patients; however additional studies are essential.

A unique case of combined papillary renal cell carcinoma (PRCC) and mucinous tubular and spindle cell carcinoma (MTSCC) presenting in a man aged 67 years is reported. The two separate components were distinct on morphological, immunohistochemical (IHC), and genetic grounds, while type 2 PRCC predominated. Three years after the initial diagnosis, the PRCC component metastasized to the lungs where it morphologically mimicked a pulmonary neuroendocrine tumor. Retrospectively focal neuroendocrine differentiation was demonstrated by IHC in the PRCC component of the primary neoplasm.

SummarySmall cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.

Pulmonary neuroendocrine tumor is a subtype of lung cancer, which does not have favorable outcome. The small-cell and large-cell variants of this cancer comprise 20% of all lung cancers. However, large-cell neuroendocrine tumor (LCNET) is not frequent and seen in about less than 3% of cases of lung cancer. Here, we describe a young nonsmoker male with the unholy triad of LCNET, newly diagnosed diabetes mellitus, and skin metastasis.

We report the case of a 54-year-old man with metastatic pulmonary neuroendocrine tumor associated with major procalcitonin (PCT) elevation without sepsis. Three lines of antibiotic therapies were successively introduced but had no positive effect on PCT kinetic and disease progression. Under palliative care, increasing of PCT level was constant during the hospitalization, along with major asthenia and pain and metastatic progression. PCT is an excellent biological marker of bacterial infection, both sensitive and specific. Nevertheless, we highlight here the existence of a frequent association between neuroendocrine tumors and elevation of PCT in the absence of sepsis.

Rationale: Typical pulmonary carcinoid is a kind of low-grade malignancy neuroendocrine tumor. Cushing's syndrome is a very rare clinical feature of typical pulmonary carcinoid caused by hypercorticism. Complete tumor resection is the standard curative treatment for primary typical pulmonary carcinoid. However, our knowledge on the gene level of typical pulmonary carcinoid is limited. Patient concerns: A 42-year-old man was admitted to our hospital for progressive weight gain within one year. No other obvious symptoms were obsessed in this patient. He was clinical diagnosed with ectopic adrenocorticotropic hormone syndrome through hormonal tests and imaging exams. Positron emission tomography-computed tomography detected a pulmonary nodule localized in the middle lobe of the lung and it is thought to be the ectopic source. Intervention: This patient received a pulmonary wedge resection. After the surgery, a genetic sequencing was performed and it reported a mutation (S1240Cfs∗21) in the BCOR gene. Diagnosis: Postoperative pathology confirmed the diagnosis of ACTH-producing typical pulmonary carcinoid. Outcomes: The patient had a smooth postoperative course and no recurrence of the tumor was found for 3 years. Lessons: Mutation in BCOR gene is quite common in pulmonary neuroendocrine tumor and it has been proven to play a role in the development of some tumor. We herein first report BCOR gene mutation in Cushing's syndrome secondary to TPC and it may become a promising therapeutic target in the future.

Achaete-scute homolog 1 is a lineage oncogene of high-grade pulmonary neuroendocrine tumors. Due to the relatively few studies investigating the epigenetic regulation of achaete-scute homolog 1 expression, we wanted to address whether DNA methylation of the achaete-scute homolog 1 CpG island is associated with clinicopathological features in pulmonary neuroendocrine tumors and to investigate its effect on the expression of this gene. Here, We performed multiplex immunohistochemistry (PerkinElmer, Waltham, MA, USA) to check for achaete-scute homolog 1 and Notch homolog 1 expression in 139 pulmonary neuroendocrine tumor samples. Quantitative measurements of achaete-scute homolog 1 CpG island methylation were conducted using the MassARRAY EpiTYPER (Sequenom, San Diego, CA, USA). The correlation between immunohistochemistry data, methylation data, and clinicopathological information was analyzed. Achaete-scute homolog 1 methylation levels were increased in pulmonary neuroendocrine tumors compared to those in normal controls (0.107 vs 0.061, p < 0.001), and among the achaete-scute homolog 1 CpG island, only CpG_6 and CpG_7.8 showed higher methylation levels in pulmonary neuroendocrine tumors (0.208 and 0.135, respectively) compared to those in normal lung tissues (0.072 and 0.087, respectively; p < 0.001). Moreover, the methylation level of CpG_6.7.8 was higher in patients with stage I pulmonary neuroendocrine tumors than in patients with stage II/III pulmonary neuroendocrine tumors (0.19 ± 0.16 vs 0.14 ± 0.07, p = 0.012). The hypermethylation of CpG_6.7.8 showed an inverse correlation with achaete-scute homolog 1 protein expression (r = -0.408, p = 0.007, Spearman test). Finally, we found that CpG_6.7.8 of the achaete-scute homolog 1 CpG island is frequently hypermethylated in early-stage pulmonary neuroendocrine tumors, and this aberrant hypermethylation is negatively correlated with achaete-scute homolog 1 expression in this tumor spectrum.

Objective: A panel of immunohistochemical (IHC) stains frequently used to subclassify non–small cell lung cancers (NSCLCs) includes napsin A, TTF-1, CK5/6, p40, and p63. The expression profiles of these stains in neuroendocrine tumors have not been systematically evaluated. Method: Sixty-eight resected pulmonary neuroendocrine tumors, including 52 typical carcinoids (TCs), eight atypical carcinoids (ACs), seven small cell carcinomas (SCLCs) and one large cell neuroendocrine carcinoma (LCNEC), were stained for napsin A, TTF-1, p63, p40, and CK5/6. Tumors were scored as positive (>1% tumor cells reactive) or negative, and percentage of reactive tumor cells was recorded. Results: Napsin A, p63, p40, and CK5/6 were consistently negative in neuroendocrine tumors. TTF-1 was positive in 17 of 52 TCs, 4 of 8 ACs, 5 of 7 SCLCs, and 0 of 1 LCNECs. Conclusion: Pulmonary neuroendocrine tumors have a distinct but nonspecific profile on IHC panel commonly applied to subclassify NSCLCs. They are napsin A−/p40−/p63−/CK5/6−/TTF-1±. Recognizing this profile may have value in separating neuroendocrine tumors from NSCLCs.

Nuclear inclusion or pseudoinclusion is a peculiar cytological feature, and its recognition in appropriate clinicopathological settings can aid in the diagnosis of several disease entities. To the best of our knowledge, only 1 case of pulmonary neuroendocrine tumor (NET) with nuclear pseudoinclusion has been reported. A review of 227 patients who had undergone surgical resection for pulmonary NETs revealed 2 tumors with different mechanisms of nuclear inclusion. To explore the cause of nuclear inclusion, NET with nuclear inclusion was characterized immunohistochemically and ultrastructurally. Nuclear inclusions were observed in 2 of the 227 (0.9%) patients with pulmonary NETs. The first patient was a 46-year-old woman with small cell carcinoma. Tumor cells with nuclear inclusions were distributed focally. Ultrastructural analysis showed that these inclusions were pseudoinclusions. The second patient was a 62-year-old man with large-cell neuroendocrine carcinoma. Nuclear inclusions were observed in the focal area of the tumor. Immunohistochemical analysis revealed that the intra-nuclear materials consisted of biotin and aberrant cytoplasmic and nuclear accumulation of β-catenin. Mutational analysis revealed a CTNNB1 gene mutation. Although very rare, diagnostic errors may be observed in cases of pulmonary NETs with nuclear inclusions. The mechanisms of nuclear inclusion differed, with one due to herniation of the cytoplasm into the nucleus (pseudoinclusion) and the other due to accumulation of biotin resulting from a CTNNB1 gene mutation.