Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.

Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms.

The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n = 301) correlated to patients' disease-free survival (DFS). The DiS-NEN-WHO 2019 stratified the 350 tumors into 91 (26%) neuroendocrine tumors (NET) G1, 52 (15%) NET G2, 15 (4%) NET G3, and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and retinoblastoma 1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p < 0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p < 0.01) and NET G2 patients (p = 0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO 2019 classification results in 3 prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of NETs.

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index > 20.

The clinicopathological features of lung neuroendocrine neoplasms (NEN) with a high proliferative index at the border area between atypical carcinoid and neuroendocrine carcinoma have not been investigated so far. The aim of this study was, therefore, to search for lung NENs which are well differentiated but show Ki67 values that overlap with those of poorly differentiated (PD)-NENs. Resected lung NENs from 244 Japanese patients were reviewed, and Ki67 indices were assessed in all tumors. The data were then correlated to clinicopathological parameters and patient outcome. Among 59 (24%) well-differentiated (WD)-NENs and 185 (76%) lung PD-NENs, 7 were defined as WD-NENs with Ki67 indices > 20%. The Ki67 indices of these tumors (mean 29%, range 24-36) were significantly lower than those of PD-NENs (mean 74%, range 34-99). All WD-NENs with Ki67 > 20% lacked abnormal p53 and loss of retinoblastoma 1 (Rb1) expression. In contrast, many PD-NENs expressed p53 (48%) and showed loss of Rb1 (86%). The 2- and 5-year disease-free survival rates in WD-NEN patients with Ki67 > 20% were lower than those of WD-NEN patients with Ki67 ≤20% (p < 0.01 for disease-free and overall survival). No statistical differences were detected between outcome of WD-NEN patients with Ki67 > 20% and those of PD-NEN. It is concluded that WD-NEN patients with Ki67 > 20% share the morphological and immunohistochemical features of WD-NEN patients with Ki67 ≤20%, but they have a worse prognosis, suggesting that this tumor group requires particular attention in future classifications and probably new therapeutic regimes.

Distribution and co-localization of diversified natriuretic peptides in the eel heart.

Atrial and B-type natriuretic peptides (ANP and BNP) are cardiac hormones important for cardiovascular and body fluid regulation. In some teleost species, an additional member of the natriuretic peptide family, ventricular NP (VNP), has been identified. In this study, we examine tissue distribution of these three NPs in the eel heart. Quantitative real-time PCR showed that anp is almost exclusively expressed in atria, bnp equally in atria and ventricles and vnp three-fold more in ventricles than in atria. The amount of bnp transcript overall in the heart was 1/10 those of anp and vnp. There was no difference in transcript levels between freshwater and seawater-acclimated fishes. Immunohistochemistry using specific antisera and in situ hybridization using gene-specific probes showed that NP signals were detected in most atrial and ventricular myocytes with some regional differences in density. Because of high sequence similarity of the three NPs, each of the three NP antisera individually was pre-incubated with 10-8 M of the other two non-targeted cardiac NPs to increase the specificity. A few atrial myocytes contained all three NPs in the same cell. Immuno-electron microscopy identified many dense-core vesicles containing ANP in atria and VNP in ventricles and some vesicles contained both ANP and VNP as demonstrated using pre-absorbed antisera. Based on these data and those of previous studies, we suggest that in eels ANP is secreted from atria in a regulatory pathway and VNP from ventricles in a constitutive pathway. In addition, VNP, not BNP, is the principal ventricular hormone in eels.

Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors.

In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration (P < 0.001), as well as with the severity of tumor-associated inflammation (P < 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator (P < 0.01, hazard ratio 0.4 for overall survival, P < 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.

A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases.

OBJECTIVE: High-grade neuroendocrine carcinoma of uterine cervix (HGNCUC) has been recognized as a highly malignant tumor. Therapeutic strategy specific to neuroendocrine (NE) tumors needs to be considered, but some cases wouldn't allow simple final diagnoses. Insulinoma-associated protein 1 (INSM1), which is a zinc-finger transcription factor related to NE differentiation, is frequently expressed in NE tumors. We investigated the association between INSM1 and HGNCUC, and the possibility of INSM1 as a useful NE marker. METHODS: Thirty-seven cases of formalin-fixed and paraffin-embedded HGNCUCs were evaluated immunohistochemically for conventional NE markers and INSM1. We also surveyed polymerase chain reactions and examined the frequency and the genotype of human papillomavirus (HPV) infections. RESULTS: In HGNCUC, chromogranin A, synaptophysin and neural cell adhesion molecule (NCAM) were expressed in 86%, 86% and 68%, respectively. In addition, INSM1 was detected in 95%. Positivity for INSM1 was clearly evaluated histologically, because the intensity of nuclear staining on positive cells was high and nonspecific reactions were minimal. In uni- and multivariate analyses of prognostic factors on stage I and II surgical cases, the association between INSM1 expression and prognosis was insignificant. We confirmed 72% of 29 examined cases had high risk HPV infections (type 16, 14%; type 18, 86%). CONCLUSIONS: This study has clarified that INSM1 is closely related to the development of HGNCUC, and a useful new NE marker in conducting its correct and rapid diagnosis.

High-Grade Neuroendocrine Carcinoma with Bronchial Intraepithelial Tumor Spread: Possibly a New Histologic Feature of Large-Cell Neuroendocrine Carcinoma.

INTRODUCTION: During surgical resection of a peripherally located high-grade neuroendocrine carcinoma (HGNEC), we unexpectedly discovered prominent bronchial intraepithelial tumor spread up to the surgical end of the bronchus. Because bronchial intraepithelial tumor spread of peripherally located HGNEC has been rarely reported, we conducted a retrospective analysis at our hospital. METHODS: We histologically reviewed surgically resected HGNEC cases to assess bronchial intraepithelial spread of tumor cells. HGNECs with bronchial intraepithelial tumor spread were further studied by immunohistochemistry for neuroendocrine markers, and their clinicopathological characteristics were evaluated. RESULTS: Of 1778 cases of surgically resected lung cancer in our hospital, 47 cases of HGNEC were evaluated. Bronchial intraepithelial tumor spread was observed in nine cases (19.1%); eight of these cases were large-cell neuroendocrine carcinoma (LCNEC) or small-cell lung carcinoma with an LCNEC component. Moreover, bronchial intraepithelial tumor spread was continuous from the primary tumor to the resected end of the bronchus in four cases, and all these cases had an LCNEC component. Furthermore, HGNEC with bronchial intraepithelial tumor spread was associated with a higher recurrence rate than no bronchial intraepithelial tumor spread. CONCLUSION: The results of this study suggest that bronchial intraepithelial tumor spread is commonly observed in cases of peripherally located HGNEC and may be a unique form of tumor invasion, especially tumors with LCNEC morphology. Therefore, surgeons and pathologists should be cognizant of bronchial intraepithelial tumor spread in peripherally located HGNEC, as well as its potential role as an indicator of HGNEC aggressiveness.

ProGRP is a possible tumor marker for patients with Ewing sarcoma.

We analyzed serum ProGRP levels in patients with Ewing sarcoma, and found that 5 out of 9 patients had elevated levels; the values range equally with those of patients with limited disease of small-cell lung carcinoma. Serum ProGRP levels in patients with bone and soft tissue malignancies other than Ewing sarcoma are not elevated. Immunohistochemical studies demonstrated that ProGRP-like immunoreactivities were detected in Ewing sarcoma tissues obtained from 2 patients with elevated serum ProGRP levels, suggesting that ProGRP is a product of tumor cells of Ewing sarcoma. These results indicate that serum ProGRP could serve as a specific tumor marker for Ewing sarcoma. Since ProGRP is a major hormonal product of tumor cells of small-cell lung carcinoma, a typical neuroendocrine carcinoma, it is reasonable to postulate that the present study provides an evidence for Ewing sarcoma to possess neuroendocrine differentiation.

High-resolution computed tomography findings of early mucinous adenocarcinomas and their pathologic characteristics in 22 surgically resected cases.

BACKGROUND: The pathological criteria of early-stage mucinous adenocarcinoma of the lung have recently been defined; however, its characteristic radiologic imaging findings are still poorly understood. Thus, this study aimed to clarify the radiologic and pathological findings of early-stage mucinous adenocarcinoma. MATERIALS AND METHODS: In this study, we clinicopathologically reviewed 22 cases of surgically resected mucinous adenocarcinoma in situ (AIS) and minimal invasive adenocarcinoma (MIA), and attempted to elucidate the characteristic radiologic features of early mucinous adenocarcinomas using high-resolution computed tomography (HRCT). RESULTS: Radiologically, the mean value of the maximum diameter of 22 tumours was 2.1 cm (range, 1.0-2.9 cm). Based on the HRCT findings, the tumours were divided into part-solid ground glass nodules (n=11) and solid nodules (n=11). The mean CT attenuation value was 25.7 HU (range, 17-35 HU). All tumours, except 3 tumours pathologically diagnosed as AIS, showed air-containing features. According to the preoperative CT findings, 7 (35%) cases were diagnosed as inflammatory nodules. Of these, 4 cases had lobular-bounded margins, and 3 showed vaguely outlined ground glass shadows. CONCLUSION: The characteristic HRCT findings of mucinous AIS and MIA were solid or part-solid nodules with air-containing spaces. However, some AIS and MIA nodules showed lobular-bounded margins or marginally vaguely outlined ground glass shadows, and were difficult to differentiate from inflammatory nodules.

Comparison of chemotherapeutic efficacy between LCNEC diagnosed using large specimens and possible LCNEC diagnosed using small biopsy specimens.

BACKGROUND: It is often difficult to diagnose large cell neuroendocrine carcinomas (LCNEC) of the lung using small biopsy specimens. Some recent studies attempted to diagnose LCNEC using biopsy specimens; in 2011, the International Association for the Study of Lung Cancer pathological panels suggested possible LCNEC as a diagnosis for LCNEC by using biopsy specimens. Here, we compared the chemotherapeutic efficacy in possible LCNEC and LCNEC diagnosed using surgically resected specimens. METHODS: We retrospectively reviewed patients who received platinum-based chemotherapy as first-line chemotherapy at our institution during September 2002-September 2011. Further, we compared the clinical characteristics, chemotherapeutic responses, and survival outcomes of patients diagnosed as having "LCNEC definite" with those diagnosed as having "possible LCNEC." RESULTS: We selected 34 patients of whom 10 were diagnosed with LCNEC using surgically resected specimens and 24 patients with possible LCNEC were diagnosed using small biopsy specimens. In both groups, almost all patients were men and were smokers. Small-cell carcinoma-based chemotherapy, such as platinum plus irinotecan or platinum plus etoposide, was used for treating 60 % LCNEC patients (6/10) and 67 % possible LCNEC patients. In the LCNEC and possible LCNEC groups, respectively, the response rate was 70 and 54 % (p = 0.39), median progression-free survival was 2.9 and 4.4 months (p = 0.20), and median survival time was 12.8 and 9.1 months (p = 0.50). CONCLUSION: No statistically significant differences were found in chemotherapeutic responses and survival outcomes between the 2 groups, which suggests that chemotherapeutic efficacy is similar in both possible LCNEC and LCNEC.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia with a central and peripheral carcinoid and multiple tumorlets: a case report emphasizing the role of neuropeptide hormones and human gonadotropin-alpha.

We report a case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). We performed immunohistochemical analysis of 17 neuropeptides and human gonadotropin-alpha (hCGα), a trophoblastic peptide that promotes the proliferation of neuroendocrine cells. A 51-year-old woman with no history of smoking was found to have a nodule in the right middle lobe. Upon examination, the nodule was found to comprise diffuse linear and nodular neuroendocrine cell hyperplasia (NECH), numerous pulmonary tumorlets merging with one peripheral carcinoid, and an additional central carcinoid. Immunohistochemical analysis revealed diffuse but intense expression of the general neuroendocrine markers CD56, synaptophysin, and chromogranin A, together with gastrin-releasing peptide (GRP), calcitonin, and hCGα throughout the carcinoids, tumorlets, and NECH. Positive staining was also noted for adrenocorticotropic hormone, corticotropin-releasing hormone, met-enkephalin, vasoactive intestinal polypeptide, neurotensin, and growth hormone-releasing hormone in a few isolated cells of the carcinoids and the tumorlets, but staining for these proteins was entirely negative in the NECH lesions. The presence of these neuropeptides in neuroendocrine tumors might explain the presence of neuropeptide-producing tumors of the lungs, cases of which have been reported over the last 30 years. The preoperative serum proGRP level was high but returned to normal after surgical intervention, indicating that GRP was produced and secreted by carcinoids, tumorlets, and/or NECH lesions. It is also probable that neuroendocrine cells secreted GRP into the interstitium in a paracrine manner, leading to the development of dense fibrosis around the tumorlets. During the preoperative and postoperative periods, no evidence of bronchiolitis obliterans was noted, in contrast to some previously reported cases of DIPNECH.

Large cell neuroendocrine carcinoma of the lung: is it possible to diagnose from biopsy specimens?

OBJECTIVE: We have recently proposed new diagnostic criteria for high-grade non-small cell neuroendocrine carcinoma, i.e. possible large cell neuroendocrine carcinoma, in biopsy specimens and have started a clinicopathological comparative study of high-grade neuroendocrine carcinomas in an advanced stage. This study aimed to elucidate the usefulness of our diagnostic criteria for inoperable advanced large cell neuroendocrine carcinoma and to know the true incidence of large cell neuroendocrine carcinoma among lung cancers. METHODS: We reviewed all cancer lesions (1040 specimens) obtained by transbronchial lung biopsies in our hospital from 2002 to 2009 and selected 38 biopsy specimens that satisfied our diagnostic criteria for high-grade non-small cell neuroendocrine carcinoma. All 38 cases were clinicopathologically investigated and all biopsy specimens were precisely studied for their morphological characteristics. RESULTS: Clinicopathological information about the selected 38 cases was very similar to the clinicopathological characteristics of large cell neuroendocrine carcinoma reported. Of 38 cases, six were at Stage I, II or IIIA, underwent surgery, and the diagnosis was confirmed to be large cell neuroendocrine carcinoma using surgical tumor specimens. In the 38 biopsy specimens, features of neuroendocrine morphology such as organoid nesting, peripheral palisading and rosette formation were not frequent histological features and the majority of tumor cells contained nuclei with a fine chromatin pattern. Mitoses were difficult to find; however, immunohistochemical Ki-67/MIB1 labeling indices were quite useful for evaluating proliferative activity, which ranged from 43.4 to 99.0%. CONCLUSIONS: Our study showed the diagnostic potential of using biopsy specimens for large cell neuroendocrine carcinoma, and we herein proposed more simplified diagnostic criteria for possible large cell neuroendocrine carcinoma in practical diagnostic use.

Immunohistochemistry of cytokeratins 7, 8, 17, 18, and 19, and GLUT-1 aids differentiation of desmoplastic malignant mesothelioma from fibrous pleuritis.

It is difficult to distinguish desmoplastic malignant mesothelioma (DMM) from fibrous pleuritis (FP). We investigated the utility of immunohistochemistry as a way of differentiating between DMM and FP. We examined 11 DMMs and 46 FPs with the aid of antibodies against 18 cytokeratin (CK) subtypes, calponin, caldesmon, desmin, and GLUT-1. The best sensitivity and specificity cut-off values in the receiver operating characteristic curves (ROC) for CKs 7, 8, 17, 18, and 19, and GLUT-1 were each above 60%. When cases with either DMM or FP were partitioned by the staining score associated with the best sensitivity and specificity cut-off values in ROC, the incidence of a positive expression for CKs 7, 8, 17, 18, and 19, and GLUT-1 was significantly higher in DMM than in FP. In conclusion, immunohistochemistry for CKs 7, 8, 17, 18, and 19, and GLUT-1 may be useful, alongside histological characteristics, for separating DMM from FP.

Correlations between serial pro-gastrin-releasing peptide and neuron-specific enolase levels, and the radiological response to treatment and survival of patients with small-cell lung cancer.

INTRODUCTION: To investigate whether decrease in the serum levels of pro-gastrin releasing peptide (ProGRP) and neuron-specific enolase (NSE) were correlated with the radiological response in patients with small-cell lung cancer (SCLC). METHODS: Of the 196 patients, we retrospectively reviewed 118 patients elevated baseline levels of ProGRP and NSE prior to the initial therapy (IT) who survived for more than 1 month. The radiological response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). RESULTS: Decrease in the serum ProGRP was strongly correlated with the decrease of the sum of the tumor diameters (SOD) before the third course (ρ=0.50) and after the fourth course (ρ=0.42) of IT. Decrease in the serum NSE was weakly correlated with the decrease of the SOD after the fourth course (ρ=0.27), but not before the third courses (ρ=0.22). In the receiver operating characteristic (ROC) curves predicting 1-year survivors, the area under the curve (AUC) for percent changes in serum ProGRP before the third course were significantly larger than those for NSE (0.714 vs. 0.527, p=0.004). CONCLUSIONS: Percent changes in serum ProGRP showed better correlation to SOD and prognostic impact than that of NSE.

A clinicopathological and immunohistological re-evaluation of adenosquamous carcinoma of the lung.

Since the World Health Organization histological criteria were published in 1999, several studies have focused on adenosquamous carcinoma of the lung. Therefore, we aimed to clinicopathologically re-evaluate this tumor using immunohistochemical methods. In our hospital, there have been 21 surgically resected adenosquamous carcinomas. The frequency of adenosquamous carcinoma was 1.9% and the clinical data including the patient prognosis data obtained in this study were similar to those reported previously. A fluorodeoxyglucose positron emission tomography study first revealed that the median maximum standardized uptake value of adenosquamous carcinoma was 9.3 and ranged from 2.0 to 24.5. According to the results of immunohistochemical staining for thyroid transcription factor-1 (TTF-1) and p63, adenosquamous carcinomas were divided into four subgroups: group 1, TTF-1+ and p63+ (10 cases); group 2, TTF-1- and p63+ (six cases); group 3, TTF-1+ and p63- (three cases); and group 4, TTF-1- and p63- (two cases). Of the six group 2 tumors, three were composed of unique solid nests with mucin-filled cysts and showed characteristic p63 expression, which might suggest a special type of adenosquamous carcinoma. Immunohistochemical analysis of TTF-1 and p63 expression shows that adenosquamous carcinoma is composed of diverse tumor groups, for which the biological and histogenetic nature further needs to be clarified.

Comparison of chemotherapy for unresectable pulmonary high-grade non-small cell neuroendocrine carcinoma and small-cell lung cancer.

BACKGROUND: Pulmonary large cell neuroendocrine carcinoma (LCNEC) shares several features with small cell lung carcinoma (SCLC). Most histologic diagnoses of LCNEC are currently obtained by surgical specimens. While the diagnosis of LCNEC by biopsy specimens is challenging, a definitive diagnosis of this highly malignant tumor is critical in unresectable cases to determine the optimal therapeutic strategy. The objective of this study was to assess the efficacy of chemotherapy for unresectable high-grade non-small cell neuroendocrine carcinoma (HNSCNEC) called by us, which likely includes most LCNECs except for combined types, and to compare the efficacy of chemotherapy for HNSCNEC, with that for extended disease SCLC (ED-SCLC). METHODS: Between September 2002 and October 2007, we reviewed 14 patients with HNSCNEC, which was defined using biopsy specimens according to histological and immunohistological criteria proposed by us. We simultaneously evaluated the clinical response to the chemotherapy and survival time of the 14 HNSCNEC and 77 ED-SCLC patients. RESULTS: The chemotherapy regimens in the 14 patients with unresectable HNSCNEC were platinum-based combination regimens or irinotecan or vinorelbine or docetaxel alone. The chemotherapy regimens in the 77 patients with ED-SCLC were platinum-based combination regimens. We assessed an objective response rate, a one-year survival rate, and median survival time as 50% (7/14), 34% and 10 months, respectively, in the 14 HNSCNEC patients, and as 53% (41/77), 48% and 12.3 months, respectively, in the 77 ED-SCLC patients. CONCLUSION: The clinical efficacy of chemotherapy for unresectable HNSCNECs, including most LCNECs, is comparable to that for ED-SCLC.

Malignant pleural mesothelioma: clinicopathology of 16 extrapleural pneumonectomy patients with special reference to early stage features.

The earliest pathological events in the development of malignant pleural mesothelioma (MPM) are not understood. The aim of the present study was to elucidate the early histopathological features of MPM. A total of 16 extrapleural MPM pneumonectomy patients were investigated. Early stage mesothelioma was arbitrarily defined as a tumor < or =5 mm in thickness regardless of the nodal status or other organ involvement. Eight of these patients (six with epithelioid, two with biphasic) had early stage mesothelioma by this definition. Macroscopically there was no visible tumor, but the parietal and visceral pleura were thickened and there was focal adhesion between them. Microscopically, the mesothelioma lesions were multifocal and discontinuous on the pleura. In extremely early cases of epithelioid mesothelioma, tumor cells were generally arrayed in a single layer, but papillary proliferation was observed elsewhere. In sarcomatoid mesothelioma, mesothelioma cells proliferated, forming multiple small polypoid nodules on the pleura. Epithelial membrane antigen was helpful to distinguish reactive from neoplastic mesothelium, but glucose transporter-1 was not. Mesothelioma cells disseminate diffusely throughout the parietal and visceral pleura and mediastinal fat tissue before becoming visible. Stage Ia mesothelioma (neoplasm limited to the parietal pleura) would not be observed in daily practice.

A new possible lung cancer marker: VGF detection from the conditioned medium of pulmonary large cell neuroendocrine carcinoma-derived cells using secretome analysis.

The prognosis of malignant neuroendocrine tumors of the lung is known to be very poor. Aiming to identify new markers of pulmonary neuroendocrine tumors in early stages and also differential diagnostic markers between large cell neuroendocrine carcinoma and small cell lung cancer, we comprehensively analyzed peptides which were secreted into conditioned medium by LCN1, a large cell neuroendocrine carcinoma cell line. Specific peaks in conditioned medium but not in used medium alone were detected using matrix-associated laser desorption/ionization time of flight mass spectrometry. Two peptide fragments of 40 and 19 amino acid residues were identified by matrix-associated laser desorption/ionization time of flight mass spectrometry. These two fragments were demonstrated to be parts of VGF nerve growth factor inducible (VGF), which is usually expressed in nerve cells or neuroendocrine cells. RT-PCR analysis of lung cancer cell lines showed that VGF mRNA was expressed only in neuroendocrine carcinoma-derived cells. Our data suggest that VGF can be used as a novel serological diagnostic marker of pulmonary neuroendocrine tumors.

Optimal extent of lymph node dissection for T1 gastric cancer, with special reference to the distribution of micrometastasis, and accuracy of preoperative diagnosis for wall invasion.

BACKGROUND/AIMS: Preoperative diagnosis for wall invasion and lymph node metastasis is sometimes difficult in T1 gastric cancer. Optimum dissection extent of lymph nodes for T1 gastric cancer was studied from the aspect of subclassification of wall invasion and lymph node metastasis including micrometastasis. METHODOLOGY: 184 patients with cT1 or pT1 gastric cancer were studied. The grade of clinical wall invasion (cT) and clinical lymph node status (cN) were diagnosed by endoscopy and computed tomography or intraoperative findings. Lymph node metastasis (pN) was studied by hematoxylin and eosin staining and immunohistochemistry (IHC). RESULTS: In 79 cM tumors, 60 (75.9%) were diagnosed as pM. In 88 cSM tumors, 42 (47.7%) were diagnosed as pSM. In 94 pM gastric cancers, micrometastases were found in two patients (2.1%) and in N1 stations. Two (1.9%) of 70 pSM cancers had micrometastasis in No. 7, 8a and 12a stations. Lymph node metastasis (pN) correlated significantly with the depth of tumor invasion, lymphatic invasion and venous invasion. Regarding the pN2 stations, one (1.1%) of 94 pM tumors had lymph node metastasis in No.7 station, and 9 (12.9%) of 70 pSM tumors had nodal involvement in No.7, 8a, 11p, 12a and 14v stations. All eight pN+/cM tumors were diagnosed as nN0 and four (1.4%) of 23 pN+/cSM tumors were correctly diagnosed as pN+. In contrast, 8 (9.9%) of 81 cN0/cM tumors and 19 (24.1%) of 79 cN0/cSM tumors had histological lymph node metastasis (pN+). CONCLUSIONS: Accuracy of the clinical diagnosis of lymph node metastasis is very low. Accordingly, prophylactic lymph node dissection is recommended even for cT1 and cN0 tumors. For cN0/cM cancer, D1+No.7 is recommended. D1+No.7, 8a, 9, 11p is recommended for cSM cancer, located in U or M region and additional dissection of No. 14v is recommended for cSM cancer located in L region.