Significant high expression of cytokeratins 7, 8, 18, 19 in pulmonary large cell neuroendocrine carcinomas,compared to small cell lung carcinomas

The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2‐D gel electrophoresis (2‐DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2‐DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin‐fixed and paraffin‐embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC (P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers.     

Cytological cell blocks: Predictors of squamous cell carcinoma and adenocarcinoma subtypes

Fine needle aspirations biopsies, CT-guided and endobronchial ultrasound-guided, as a mode of diagnosing and/or staging lung carcinoma, are becoming more frequent. Also, there is greater necessity for classification of lung cancers into subcategories of squamous cell carcinoma and adenocarcinoma for appropriate management. Cytomorphology, based on smears alone, allows this classification in many instances. The aim of the current study was to explore the potential of cell blocks to increase the specificity of diagnosis. The morphological characteristics of sixty-two lung carcinomas were examined. Less well-differentiated squamous cell carcinomas were more readily classified as such on cell blocks. Likewise, cell block sections with architectural patterns including strips of cells, papillae and nests of cells correlated with bronchioalveolar, papillary and acinar/mixed subtypes of adenocarcinoma on follow-up histology. In conclusion, cell blocks provide additional morphological clues and material for ancillary studies for classification of lung carcinomas.     

Expression of epithelial and neural antigens in small cell and non small cell lung carcinoma

Seventy-one lung carcinomas from 66 different patients were stained with a panel of monoclonal antibodies. Twenty-nine were small cell lung carcinoma (SCLC), 15 adenocarcinomas, 17 squamous carcinomas and 10 large cell carcinomas. Three of the monoclonal antibodies recognize different cytokeratins, three recognize other epithelial antigens and one recognizes a neural antigen. Both formalin-fixed and cryopreserved tumours were studied using an indirect immunoperoxidase method. 23/29 SCLC reacted with all but one of the antibodies which recognize epithelial antigens. This staining was similar to that seen in non small cell lung carcinomas (NSCLC) and provides further evidence that SCLC are true epithelial tumours. All but one of the SCLC stained with the antibody recognizing a neural antigen. This antibody did not stain squamous or adenocarcinomas. However, four of the large cell carcinomas stained well with this antibody, suggesting that SCLC and some large cell carcinomas share a common pathway of differentiation. There were variations of staining seen both within and between tumours. This has obvious implications if immunotargetting with monoclonal antibodies is to be used diagnostically or therapeutically.     

Genetics of a combined lung small cell carcinoma and large cell neuroendocrine carcinoma with adenocarcinoma

Combined nonneuroendocrine-neuroendocrine lung tumors are relatively infrequent and little is known as for their genetic basis. Here, we report the case of a 69-year-old male with a solitary neoplasm in the upper lobe of the right lung. At histological examination, the tumor showed two components. The main part was an adenocarcinoma of the acinar type. The second part showed morphological and immunohistochemical phenotype of a neuroendocrine carcinoma composed of a small cell lung carcinoma and a large cell neuroendocrine carcinoma. The aim of our study was to investigate the genetic relationship between neuroendocrine and nonneuroendocrine tumor components. To this purpose, we performed a loss of heterozygosity (LOH) analysis with 40 chromosomal microsatellite markers. Microallelotyping revealed a common genetic profile in the different tumor areas. In 9 of 30 informative regions analyzed, LOH involved the same allele in all components, regardless of their histological type and grade. These findings support the true combined nature of this exocrine-neuroendocrine carcinoma of the lung and suggest a common monoclonal origin from a pluripotent epithelial (alveolar or bronchial) precursor cell for the two different tumor components.     

Cytological features of signet‐ring cell carcinoma of the lung: Comparison with the goblet‐cell‐type adenocarcinoma of the lung

Signet‐ring cell carcinoma (SRCC) and goblet‐cell‐type adenocarcinoma (GCA) are mucin‐producing lung adenocarcinomas. Primary SRCC shows an aggressive clinical course, whereas GCA shows infrequent distant metastasis, but more frequent intrapulmonary metastases resembling lobar pneumonia. To distinguish SRCC from GCA, this study investigated the respective cytological features of these lesions. We selected 10 cases each of SRCC and GCA from the archival imprint smears. We assessed them for the following 10 cytological features. Necrosis/debris was observed in 60% of the SRCC and 90% of the GCA. A mucinous background was observed in 10% of the SRCC and 90% of the GCA. Significant inflammation was observed in none of the SRCC and 80% of the GCA. Stromal cluster was observed in 30% of the SRCC and 70% of the GCA. Nuclear overlapping was observed in 50% of the SRCC and in all of the GCA. Single tumor cells were observed in 80% of the SRCC and 10% of the GCA. Honeycomb‐like cluster was observed in none of the SRCC and 80% of the GCA. Prominent nucleolus was observed in 50% of the SRCC and 40% of the GCA. Nuclear membrane irregularity was observed in 70% of SRCC and 60% of the GCA. Nuclear pleomorphism was observed in all of the SRCC and none of the GCA. The cytological features of SRCC were the presence of single tumor cells and nuclear pleomorphism, whereas that of GCA were the presence of abundant mucin and significant inflammation in the background, and a honeycomb‐like cluster. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Fine-needle aspiration cytology of bronchial acinic cell carcinoma: a case report

Salivary gland-type carcinomas of the lung are rare but well-known tumors. Among them, acinic cell carcinoma (ACC) is extremely rare and its cytological features have not been reported. We present a case of bronchial ACC and describe its cytological characteristics. The tumor occurred in a 58-yr-old man as a 15-mm polypoid lesion at the right middle lobar bronchus and filled its lumen. Transbronchial brush cytology and a biopsy failed to collect tumor cells but transbronchial fine-needle aspiration (FNA) cytology was successful. The smear obtained was richly cellular and a large number of thick-layered or monolayered sheet-like tumor cell clusters and dissociated tumor cells were observed. Cribriform globular spaces were common and a lobulated acinar structure was found focally. The tumor cells had a fine granular large polygonal cytoplasm and rather uniform round or ovoid nuclei. The nuclei were situated eccentrically or centrally and the nuclear/cytoplasmic ratio was consistently low. These cytological features were essentially similar to those of ACC of the head and neck region. The patient underwent a lobectomy and the tumor was resected completely. Transbronchial FNA cytology was useful for diagnosing bronchial ACC and differentiating it from other conventional and salivary gland type carcinomas.     

周围型肺腺癌和周围型肺鳞癌的能谱CT表现

目的:观察周围型肺腺癌和周围型肺鳞癌的能谱CT表现。方法:回顾性分析经病理证实并行能谱CT扫描的周围 型肺腺癌122 例和周围型肺鳞癌89 例。测量病灶在动脉期及静脉期下的CT40 keV值、CT70 keV值、CT100 keV值、碘（水）浓度 （IC）、水（碘）浓度（WC）和有效原子序数（Zeff）,并计算能谱曲线斜率（K70 keV）。比较两组之间各能谱参数之间的差异。结 果:两组之间性别差异有统计学意义（P<0.05）,而其他临床特征和临床症状在两组之间差异无统计学意义（P>0.05）。动 脉期和静脉期,周围型肺腺癌的CT40 keV、CT70 keV、K70 keV、IC及Zeff均大于周围型肺鳞癌,差异具有统计学意义（P<0.05）;而 两组之间的WC和CT100 keV无统计学意义（P>0.05）。ROC曲线分析显示,动脉期各定量参数联合较静脉期各定量参数联 合的诊断效能好,曲线下面积、敏感性和特异性分别为86%、77%、83%。结论:周围型腺癌和周围型鳞癌的能谱CT表现 存在一定差异,可为二者的鉴别提供参考。     

LRIG1 regulates cadherin‐dependent contact inhibition directing epithelial homeostasis and pre‐invasive squamous cell carcinoma development

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine‐rich immunoglobulin repeats‐1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re‐expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E‐cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition. © 2012 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Circulating tumour tissue fragments in patients with pulmonary metastasis of clear cell renal cell carcinoma

Tumour metastasis is the result of a complex sequence of events, including migration of tumour cells through stroma, proteolytic degradation of stromal and vessel wall elements, intravasation, transport through the circulation, extravasation and outgrowth at compatible sites in the body (the ‘seed and soil’ hypothesis). However, the high incidence of metastasis from various tumour types in liver and lung may be explained by a stochastic process as well, based on the anatomical relationship of the primary tumour with the circulation and mechanical entrapment of metastatic tumour cells in capillary beds. We previously reported that constitutive VEGF‐A expression in tumour xenografts facilitates this type of metastatic seeding by promoting shedding of multicellular tumour tissue fragments, surrounded by vessel wall elements, into the circulation. After transport through the vena cava, such fragments may be trapped in pulmonary arteries, allowing them to expand to symptomatic lesions. Here we tested whether this process has clinical relevance for clear cell renal cell carcinoma (ccRCC), a prototype tumour in the sense of high constitutive VEGF‐A expression. To this end we collected and analysed outflow samples from the renal vein, directly after tumour nephrectomy, in 42 patients diagnosed with ccRCC. Tumour fragments in venous outflow were observed in 33% of ccRCC patients and correlated with the synchronous presence or metachronous development of pulmonary metastases (p < 0.001, Fisher's exact test). In patients with tumours that, in retrospect, were not of the VEGF‐A‐expressing clear cell type, tumour fragments were never observed in the renal outflow. These data suggest that, in ccRCC, a VEGF‐A‐induced phenotype promotes a release of tumour cell clusters into the circulation that may contribute to pulmonary metastasis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Metastatic metaplastic breast carcinoma mimicking pulmonary squamous cell carcinoma on fine‐needle aspiration

Metaplastic squamous cell carcinoma (SCC) of the breast is a rare type of breast cancer. Metastases to the lung, which can be a major site of second primary tumor development among breast cancer patients, are difficult to distinguish from primary SCC of the lung and present a unique challenge for pathologists. There are few available discriminating immunohistochemical markers as squamous differentiation typically leads to loss of expression of characteristic primary epithelial cell markers of both breast and lung origin. GATA protein binding 3 (GATA‐3) is a useful marker of breast origin in metastatic ductal and lobular carcinomas including poorly differentiated triple‐negative carcinomas and some metaplastic carcinomas. Here, we present a case of metastatic SCC presenting as a solitary lung mass with regional lymph node metastases and a single satellite lesion in a patient with a history of metaplastic SCC of the breast. In addition to the routine markers of squamous differentiation, the metastases were also positive for estrogen receptor (ER) and GATA‐3 on cytologic material obtained by transbronchial FNA. This suggests that immunoreactivity for ER and GATA‐3 may support a diagnosis of metastatic SCC in the context of a prior metaplastic SCC of the breast. Diagn. Cytopathol. 2015;43:844–849. © 2015 Wiley Periodicals, Inc.     

Immunohistochemical and Ultra structural Study of Mixed Small cell/Large cell Carcinoma of the Lung

The authors examined the immunohistochemical and ultra-structural characteristics of mixed small cell/large cell carcinoma (mixed subtype) of the lung which has been newly categorized as anaplastic small cell lung carcinoma. The 34 cases of small cell lung carcinoma examined consisted of 18 cases of pure small cell carcinoma (pure subtype), 12 cases of the mixed subtype and 4 cases of combined small cell carcinoma. Immunohistochemically, the number of immunoreactive tumor cells for chromo-granin A was smaller (P<0.05) and that for creatine kinase BB was relatively larger in the mixed subtype. Sialyl Les i antigen (SLX), one of the SSEA 1 related carbohydrate antigens, was expressed specifically in the mixed subtype. Ultrastructurally, tumor cells in the mixed subtype had smaller amounts of neurosecretory granules and larger amounts of desmosomes than those in the pure subtype (P<0.05, P<0.005, respectively). These results suggest that the mixed subtype may show more epithelial than neuroendocrine differentiation and that SLX may be a specific marker for the mixed subtype to be used in pretherapeutic diagnosis. Acta Pathol Jpn 41: 540 551, 1991.