Current Management of Carcinoid Tumor: When Is a Wedge Enough?

Bronchopulmonary carcinoid tumors are rare, well-differentiated neuroendocrine neoplasms. They can be categorized as typical or atypical lesions and are low-to-intermediate-grade, respectively. The cornerstone of therapy for carcinoid tumors is surgical resection and current consensus guidelines recommend anatomic resection for stage I to IIIA disease. The renewed interest in sublobar resections for the treatment of lung malignancies has sparked debate over the degree of resection necessary for these indolent lesions. Segmentectomy provides an oncologic resection while preserving as much lung parenchyma as possible, and is a reasonable approach to apply to small, undifferentiated, or typical carcinoid lesions.

Incidence and prognostic nomogram for resected non-small cell neuroendocrine tumor: A population-based respective study in China and the SEER database.

Background: Pulmonary neuroendocrine tumors, including small cell lung cancer (SCLC) and non-small cell neuroendocrine tumor (NSCLC-NET), have obvious heterogeneity. The comparison between SCLC and NSCLC-NET, and prognostic nomogram of resected NSCLC-NET have not been performed. Methods: We retrieved data from SEER database. The incidence and prognostic factors were compared between SCLC and NSCLC-NET. By Cox regression, we constructed prognostic nomogram of resected NSCLC-NET. The nomogram was evaluated by ROC, calibration plot and decision curve analysis (DCA) and compared with 8th TNM staging system. A Chinese cohort was used for external validation. Results: The age-adjusted incidence of SCLC declined after 1991 but the incidence of NSCLC-NET continuously rose. Patients with typical carcinoid had the best prognosis in both overall survival and lung cancer specific survival, followed by atypical carcinoid, large cell neuroendocrine tumor and SCLC after operation. Patients receiving sleeve resection in NSCLC-NET had longer survival but segmental resection was more recommended in SCLC. High-smoking index was associated with worse overall survival in both SCLC and NSCLC-NET. Histological subtype, age, surgery type, N, M stage and chemotherapy were independent prognostic factors and used to construct prognostic nomogram of resected NSCLC-NET. The nomogram performed well with good discrimination, calibration and clinical usefulness, which was validated by a Chinese cohort (1, 3, 5-year AUC: SEER cohort 0.873, 0.901, 0.875; Chinese cohort 0.867, 0.892, 0.874). Compared to the 8th staging system, the nomogram had higher C-index (0.87 vs 0.728, P < 0.001), clinical usefulness, increasing AUC value over time and improved 68%. Conclusion: The prognostic nomogram of resected NSCLC-NET performed better than the 8th TNM staging system. It may have certain value in risk stratification and survival prediction of patients with resected NSCLC-NET and help clinicians to take measures for high-risk patients in advance.

Pulmonary neuroendocrine tumors: study of 266 cases focusing on clinicopathological characteristics, immunophenotype, and prognosis.

OBJECTIVE: Pulmonary neuroendocrine tumors (PNETs) consist of small-cell lung cancer (SCLC), large-cell neuroendocrine carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC). We aimed to analyze the immunophenotypic, metastatic, and prognostic risk factors for PNETs. MATERIALS AND METHODS: A total of 266 patients with PNETs were enrolled, including 219 patients with SCLC, 18 patients with LCNEC, 11 patients with TC, and 18 patients with AC. Clinicopathological characteristics and immunophenotypes were compared among the subtypes of PNETs. Risk factors for metastasis, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Thyroid transcription factor-1 (TTF-1) and the Ki-67 index were significantly different among subtypes of PNETs (all P < 0.05). Smoking (OR, 2.633; P = 0.031), high pretreatment carcinoembryonic antigen (CEA > 5 ng/ml: OR, 3.084; P = 0.014), and poorly differentiated pathotypes (P = 0.001) were independent risk factors for lymph-node metastasis. Smoking (OR, 2.071; P = 0.027) and high pretreatment CEA (OR, 2.260; P = 0.007) were independent risk factors for distant metastasis. Results of the multivariate Cox regression model showed pretreatment CEA (HR, 1.674; P = 0.008) and lymphocyte-monocyte ratio (LMR) (HR = 0.478, P = 0.007) were significantly associated with PFS; BMI (P = 0.031), lymph-node metastasis (HR = 4.534, P = 0.001), poorly differentiated pathotypes (P = 0.015), platelet-lymphocyte ratio (PLR) (HR = 2.305, P = 0.004), and LMR (HR = 0.524, P = 0.045) were significantly associated with OS. CONCLUSIONS: PNETs are a group of highly heterogeneous tumors with different clinical manifestations, pathological features, and prognoses. Knowing clinicopathological characteristics and immunophenotypes of PNETs is significant for diagnosis. Pretreatment PLR, LMR, and CEA have certain value in the prognosis of PNETs.

Comprehensive Characterization of the Genomic Landscape in Chinese Pulmonary Neuroendocrine Tumors Reveals Prognostic and Therapeutic Markers (CSWOG-1901).

BACKGROUND: Pulmonary neuroendocrine tumors (pNETs) include typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). The optimal treatment strategy for each subtype remains elusive, partly due to the lack of comprehensive understanding of their molecular features. We aimed to explore differential genomic signatures in pNET subtypes and identify potential prognostic and therapeutic biomarkers. METHODS: We investigated genomic profiles of 57 LCNECs, 49 SCLCs, 18 TCs, and 24 ACs by sequencing tumor tissues with a 520-gene panel and explored the associations between genomic features and prognosis. RESULTS: Both LCNEC and SCLC displayed higher mutation rates for TP53, PRKDC, SPTA1, NOTCH1, NOTCH2, and PTPRD than TC and AC. Small cell lung carcinoma harbored more frequent co-alterations in TP53-RB1, alterations in PIK3CA and SOX2, and mutations in HIF-1, VEGF and Notch pathways. Large cell neuroendocrine carcinoma (12.7 mutations/Mb) and SCLC (11.9 mutations/Mb) showed higher tumor mutational burdens than TC (2.4 mutations/Mb) and AC (7.1 mutations/Mb). 26.3% of LCNECs and 20.8% of ACs harbored alterations in classical non-small cell lung cancer driver genes. The presence of alterations in the homologous recombination pathway predicted longer progression-free survival in advanced LCNEC patients with systemic therapy (P = .005) and longer overall survival (OS) in SCLC patients with resection (P = .011). The presence of alterations in VEGF (P = .048) and estrogen (P = .018) signaling pathways both correlated with better OS in patients with resected SCLC. CONCLUSION: We performed a comprehensive genomic investigation on 4 pNET subtypes in the Chinese population. Our data revealed distinctive genomic signatures in subtypes and provided new insights into the prognostic and therapeutic stratification of pNETs.

Lung carcinoid tumors with Diffuse Idiopathic Pulmonary NeuroEndocrine Cell Hyperplasia (DIPNECH) exhibit pejorative pathological features.

INTRODUCTION: 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. MATERIAL AND METHODS: 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. RESULTS: 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 nodules < 5 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. CONCLUSION: Carcinoid tumors with proven DIPNECH are associated with negative pathological features and may deserve a dedicated perioperative management.

A Rare Case of Acute Liver Failure Secondary to Diffuse Hepatic Infiltration of Small Cell Neuroendocrine Carcinoma.

BACKGROUND: Malignant liver infiltration is an uncommon cause of acute liver failure (ALF) and has rarely been reported. CASE PRESENTATION: We 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 CONCLUSIONS: This 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.

Procalcitonin expression in patients with large cell neuroendocrine carcinoma of the lung.

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.

Invasion of poorly differentiated large-cell neuroendocrine tumor of the lung through right pulmonary veins into the left atrium: A very rare case report.

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.

Revisiting glucose metabolism in cancer: lessons from a PKM knock-in model.

Isoform selection of pyruvate kinase M (PKM), a glycolytic enzyme, influences fates of glucose-derived carbons in cellular metabolic networks. We recently developed novel mouse lines to study PKM isoform function and identified PKM1 as a potential target in a subset of human lung cancers. This work provides new insight into cancer metabolism.

Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors.

BACKGROUND: Recent research supports a significant role of immune checkpoint inhibitors in the treatment of solid tumors. However, relevant reports for programmed death-ligand 1 (PD-L1) and CD8+ tumor-infiltrating lymphocytes (TILs) in pulmonary neuroendocrine tumors (PNETs) have not been fully studied. Therefore, we investigated PNETs for the expression of PD-L1 and infiltration by CD8+ TILs as well as the prognostic value of both factors. METHODS: In total, 159 specimens of PNETs (35 TC, 2 AC, 28 LCNEC, 94 SCLC) were included in this study. Immunohistochemistry (IHC) was used to detect the expression of PD-L1 in these cases. Cases demonstrating ≥5% tumor cell expression or any expression (> 1%) of PD-L1 on immune cells were considered positive. CD8+ TILs both within stroma and tumor areas of invasive carcinoma were analyzed using whole-slide digital imaging. Manual regional annotation and machine cell counts were performed for each case. RESULTS: Positive expression of PD-L1 was observed in 72 cases (45.3%), including 9 cases (5.7%) with expression exclusively on tumor cells, 46 cases (28.9%) with expression exclusively on immune cells, and 17 cases (10.7%) with the expression on tumor cells and immune cells. PD-L1 expression was associated with necrosis (p < 0.001), high pathologic grade (p < 0.001) and histologic type (p < 0.001). No correlation was observed with overall survival (OS) (p = 0.158) or progression-free survival (PFS) (p = 0.315). In contrast, higher CD8+ T cell density was associated with the absence of vascular invasion (p = 0.004), histologic type (p = 0.005), negative lymph node metastasis (p = 0.005) and lower clinical staging (p = 0.007). Moreover, multivariate analysis revealed that CD8+ stromal TIL was an independent prognostic factor for improved OS (p = 0.009) and PFS (p = 0.002). CONCLUSION: PD-L1 was expressed in approximately half of the PNETs. The majority of the expression was observed in immune cells. Positive expression of PD-L1 showed no correlation with OS or PFS, while higher CD8+ TILs within stroma was proved to be an independent prognostic factor for favorable OS and PFS of PNETs.

A major procalcitonin elevation without sepsis in a metastatic small cell lung carcinoma.

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.

Acromegaly in a patient with a pulmonary neuroendocrine tumor: case report and review of current literature.

BACKGROUND: Pulmonary neuroendocrine tumors (NET) form a heterogeneous group of rare diseases. In these tumors, paraneoplastic syndromes have been described to drive the course of the disease, among them acromegaly induced by paraneoplastic secretion of growth hormone-releasing hormone (GHRH). CASE PRESENTATION: We report the case of a 43 years old patient initially diagnosed with acromegaly accompanied by weight gain and acral enlargement. Subsequently, further diagnostic work-up identified a solitary pulmonary neuroendocrine tumor (NET). Laboratory tests revealed markedly increased growth hormone (GH) and insulin-like growth factor 1 (IGF-1) without GHRH elevation in the absence of pituitary pathologies confirming the paraneoplastic origin of clinical presentation with acromegaly. Curative surgery was performed leading to normalization of the elevated hormone levels and improvement of the clinical symptoms. Immunohistochemically, a typical carcinoid (TC) was seen with low proliferation index and abundant IGF-1 expression. CONCLUSIONS: The association of acromegaly and pulmonary NET has only rarely been reported. We present an individual case of paraneoplastic GH- and IGF-1 secretion in a patient with pulmonary NET. Based on their rarity, the knowledge of paraneoplastic syndromes occurring in patients with pulmonary NET such as acromegaly due to paraneoplastic GH- and IGF-1 secretion is mandatory to adequately diagnose and treat these patients.

Evaluation of napsin A, TTF-1, p63, p40, and CK5/6 immunohistochemical stains in pulmonary neuroendocrine tumors.

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.

Biological correlation of ¹8F-FDG uptake on PET in pulmonary neuroendocrine tumors.

BACKGROUND: It is widely recognized that pulmonary neuroendocrine tumors (PNET) include a spectrum that ranges from low-grade typical carcinoid (TC) and atypical carcinoid (AC) to high-grade large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). However, little is known about the usefulness of 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron-emission tomography (PET) in such tumors. We therefore, conducted a study including the analysis of the underlying biology of (18)F-FDG uptake. MATERIALS AND METHODS: Thirty-four patients with early-stage PNETs who underwent (18)F-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter-1 (Glut1 and Glut3), hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase-I, vascular endothelial growth factor (VEGF), microvessel density (MVD) determined by CD34 and (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. RESULTS: (18)F-FDG uptake correlated significantly with Glut1, HIF-1α, VEGF and CD34 expression. Uptake of (18)F-FDG tended to increase from low-grade to high-grade PNETs. Tumor metabolic activity was a useful marker for predicting postoperative prognosis in patients with early-stage PNETs. CONCLUSION: The amount of (18)F-FDG uptake is determined by the presence of glucose metabolism, hypoxia and angiogenesis.

Pulmonary neuroendocrine tumors with nuclear inclusion.

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 ß-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.

Morphologic analysis of pulmonary neuroendocrine tumors.

BACKGROUND: Few studies on how to diagnose pulmonary neuroendocrine tumors through morphometric analysis have been reported. In this study, we measured and analyzed the characteristic parameters of pulmonary neuroendocrine tumors using an image analyzer to aid in diagnosis. METHODS: Sixteen cases of typical carcinoid tumor, 5 cases of atypical carcinoid tumor, 15 cases of small cell carcinoma, and 51 cases of large cell neuroendocrine carcinoma were analyzed. Using an image analyzer, we measured the nuclear area, perimeter, and the major and minor axes. RESULTS: The mean nuclear area was 0.318±0.101 µm(2) in typical carcinoid tumors, 0.326±0.119 µm(2) in atypical carcinoid tumors, 0.314±0.107 µm(2) in small cell carcinomas, and 0.446±0.145 µm(2) in large cell neuroendocrine carcinomas. The mean nuclear circumference was 2.268±0.600 µm in typical carcinoid tumors, 2.408±0.680 µm in atypical carcinoid tumors, 2.158±0.438 µm in small cell carcinomas, and 3.247±1.276 µm in large cell neuroendocrine carcinomas. All parameters were useful in distinguishing large cell neuroendocrine carcinoma from other tumors (p=0.001) and in particular, nuclear circumference was the most effective (p=0.001). CONCLUSIONS: Pulmonary neuroendocrine tumors showed nuclear morphology differences by subtype. Therefore, evaluation of quantitative nuclear parameters improves the accuracy and reliability of diagnosis.

Pulmonary neuroendocrine tumors: an entity in search of cytologic criteria.

Pulmonary neuroendocrine tumors (PNET) are histologically subclassified into typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCLC). The criteria for subclassification in cytological specimens are not well defined. In this study, we reviewed histologically confirmed 18 TC, 8 AC, 10 LCNEC, and 10 SCLC cytologic specimens from 45 patients. The following features were reviewed: small clusters, geographic sheets, trabecular structures, pseudo-rosettes, single cells, doublets, triplets or short cords, papillary-like structures, capillary vasculatures, necrosis, smear background, cell size, cell pleomorphism, amount of cytoplasm, plasmacytoid cells, spindle cells, nuclear atypia, molding, palisading and smearing, chromatin textures, nucleoli, and mitotic figure count. Based on our results, geographic clusters and necrosis were often seen in LCNEC and SCLC; while AC only showed scattered single cell necrosis. TC and AC commonly exhibited trabecular structures. Papillary-like structures and capillary vasculature were only present in TC, AC, and LCNEC. Cells forming doublets, triplets, and short cords were more commonly seen in SCLC and rarely seen in other entities. Plasmacytoid and spindle cells were only seen in TC and AC. Nuclear smearing was not identified in TC, rare in AC, focally present in LCNEC and obvious in SCLC. Mitotic figures were nearly absent in TC, ≤5/10 HPF in AT, and ≥10/10 HPF in SCLC. LCNEC showed a wide span of mitotic count ranging between 2 and 16/10 HPF. In this study, we propose a set of cytological features that are essential for subclassification of PNETs in cytologic specimens.

Morphologic Analysis of Pulmonary Neuroendocrine Tumors

BACKGROUND: Few studies on how to diagnose pulmonary neuroendocrine tumors through morphometric analysis have been reported. In this study, we measured and analyzed the characteristic parameters of pulmonary neuroendocrine tumors using an image analyzer to aid in diagnosis. METHODS: Sixteen cases of typical carcinoid tumor, 5 cases of atypical carcinoid tumor, 15 cases of small cell carcinoma, and 51 cases of large cell neuroendocrine carcinoma were analyzed. Using an image analyzer, we measured the nuclear area, perimeter, and the major and minor axes. RESULTS: The mean nuclear area was 0.318+/-0.101 microm2 in typical carcinoid tumors, 0.326+/-0.119 microm2 in atypical carcinoid tumors, 0.314+/-0.107 microm2 in small cell carcinomas, and 0.446+/-0.145 microm2 in large cell neuroendocrine carcinomas. The mean nuclear circumference was 2.268+/-0.600 microm in typical carcinoid tumors, 2.408+/-0.680 microm in atypical carcinoid tumors, 2.158+/-0.438 microm in small cell carcinomas, and 3.247+/-1.276 microm in large cell neuroendocrine carcinomas. All parameters were useful in distinguishing large cell neuroendocrine carcinoma from other tumors (p=0.001) and in particular, nuclear circumference was the most effective (p=0.001). CONCLUSIONS: Pulmonary neuroendocrine tumors showed nuclear morphology differences by subtype. Therefore, evaluation of quantitative nuclear parameters improves the accuracy and reliability of diagnosis.