Napsin A is useful to distinguish primary lung adenocarcinoma from adenocarcinomas of other organs

The aim of the present study was to compare the usefulness of the peripheral airway cell markers, naspin A and surfactant protein A (SP-A), for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs in various clinical conditions. Immunohistochemical expression of napsin A and SP-A was analyzed at primary sites of 120 lung carcinomas and 40 adenocarcinomas of other organs, at lung metastatic sites of 32 adenocarcinomas of other organs, and in metastatic lymph nodes of 21 lung adenocarcinomas and 45 adenocarcinomas of other organs. Napsin A and SP-A expressions were compared between primary and recurrent sites in 8 lung adenocarcinomas. Napsin A and SP-A expressions were noted in 84.3% and 53.0% of primary sites of 83 lung adenocarcinomas, respectively, but neither napsin A nor SP-A was expressed at primary sites of other histological types of lung carcinomas or at primary or metastatic sites of adenocarcinomas of other organs. In lung adenocarcinomas, napsin A and SP-A were expressed in metastatic lymph nodes in 81.0% and 19.0%, respectively, and at recurrent sites in 87.5% and 37.5%, respectively. Napsin A is superior to SP-A for distinguishing primary lung adenocarcinoma from adenocarcinomas of other organs at primary, metastatic, and recurrent sites.     

Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia

We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions. Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%). We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.     

A subset of lung adenocarcinomas and atypical adenomatous hyperplasia-associated foci are genotypically related: an EGFR, HER2, and K-ras mutational analysis

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors. We analyzed 18 cases of primary lung adenocarcinoma with concomitant AAH foci from 13 patients for mutations of EGFR (exons 18-21), HER2 (exons 19-20), and K-ras (exon 2) by direct sequencing polymerase chain reaction. Among mutated cases, concordant mutations of EGFR or K-ras in adenocarcinoma and related AAH were observed in 5 (63%) of 8 cases. In particular, 3 of 4 adenocarcinomas with EGFR mutations (all L858R point mutations in women, never or former smokers) had a concomitant and identical mutation in AAH, and 2 of 4 adenocarcinomas with K-ras mutations (both at codon 12 in women, a never and a current smoker) showed the same mutation in concomitant AAH. All cases were wild-type for HER2. Mutations of EGFR and K-ras genes represent an early event in lung adenocarcinomagenesis, and AAH convincingly seems to be a precursor lesion in a subset of cases of adenocarcinoma.     

The value of PE-10, a monoclonal antibody against pulmonary surfactant, in distinguishing primary and metastatic lung tumours

A new monoclonal antibody (PE-10) raised against components of pulmonary surfactant has been assessed for its ability to distinguish primary from secondary carcinomas in the lung. We applied this antibody to a series of 107 primary lung carcinomas, 40 adenocarcinomas of other sites, and 26 cases of adenocarcinoma metastatic to lung and pleura. Of the primary lung carcinomas, all the non-mucinous bronchiolo-alveolar carcinomas were positive whereas all the mucinous cases were negative; 60% of other types of adenocarcinoma were positive and 10% of large cell undifferentiated carcinomas, 20% of small cell carcinomas and 40% of atypical carcinoids also showed focal positivity. Squamous cell carcinomas were all negative. Adenocarcinomas of the breast, kidney, large bowel and ovaries were all negative, as were all 26 cases of adenocarcinoma metastatic to the lung and pleura. We conclude that this antibody is highly specific and moderately sensitive for primary tumours of the lung.     

Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas

In the resected lung, additional small lesions are occasionally found incidentally, and include the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer. In this study, we examined EGFR and KRAS gene mutations in 119 synchronous pulmonary lesions, including 40 precursor lesions (atypical adenomatous hyperplasia, AAH), 26 carcinomas in situ (non-mucinous bronchioloalveolar carcinoma, BAC), 14 minimally invasive adenocarcinomas, 34 overt invasive adenocarcinomas, and five of other subtypes of cancer. Although the mutually exclusive nature of KRAS and EGFR gene mutations was maintained even in preinvasive lesions, the incidences of the lesions along the putative progression schema were quite different. The KRAS gene was mutated in 33% of AAH, 12% of carcinomas in situ, 8% of minimally invasive adenocarcinomas and 0% of well-differentiated adenocarcinomas, whereas the frequencies of EGFR mutation did not fluctuate greatly, at 25%, 51%, 36%, 86% and 67%, respectively. These results are consistent with the findings of a published gene-targeted mouse model; the mice expressing oncogenic KRAS developed AAH but not invasive adenocarcinoma, whereas a spectrum of preinvasive to invasive adenocarcinomas was observed in the mice expressing mutant EGFR. Taking these factors together, it is suggested that AAH could develop by either KRAS or EGFR gene mutation, but AAH harbouring a KRAS gene mutation might not progress further to an invasive cancer.     

Molecular alterations in atypical adenomatous hyperplasia occurring in benign and cancer-bearing lungs.

Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma.     

Loss of Heterozygosity on Chromosomes 9q and 16p in Atypical Adenomatous Hyperplasia Concomitant with Adenocarcinoma of the Lung

Atypical adenomatous hyperplasia (AAH) has recently been implicated as a precursor to lung adenocarcinoma. We previously reported loss of heterozygosity (LOH) in tuberous sclerosis (TSC) gene-associated regions to frequently be observed in lung adenocarcinoma with multiple AAHs. In this study, we analyzed LOH in four microsatellite loci on 9q, including the TSC1 gene-associated region, and four loci on 16p, including the TSC2 gene-associated region, in both 18 AAHs and 17 concomitant lung adenocarcinomas from 11 patients. Seven of 18 (39%) AAHs and 9 of 17 (53%) adenocarcinomas displayed LOH on 9q. Five (28%) AAHs and seven (41%) adenocarcinomas harbored LOH at loci adjacent to the TSC1 gene. Four of 18 (22%) AAHs and 6 of 17 (35%) adenocarcinomas displayed LOH on 16p. One (6%) AAH and five (29%) adenocarcinomas harbored LOH at loci adjacent to the TSC2 gene. These findings may indicate a causal relationship of LOH on 9q and 16p in a fraction of AAH lesions and adenocarcinomas of the lung. Especially, the frequencies of LOH on 9q and at the TSC1 gene-associated region were high. The TSC1 gene or another neighboring tumor suppressor gene on 9q might be involved in an early stage of the pathogenesis of lung adenocarcinoma.     

浆膜腔积液转移性肺腺癌细胞中TTF-1的表达

目的 探讨甲状腺转录因子-1(TTF-1)在浆膜腔积液肺腺癌细胞中的表达，为肺腺癌的诊断和鉴别诊断提供新的依据。方法 选用浆膜腔积液转移性腺癌共60例(胸水40例，腹水17例，心包积液3例)。经组织学或结合临床资料证实的肺腺癌36例，泌尿生殖道腺癌14例，胃肠道腺癌8例，乳腺癌2例。每例均制备HE染色的涂片和离心沉渣经琼脂和石蜡包埋而成的细胞块，并用细胞块切片作TTF-1免疫细胞化学染色。结果 36例肺腺癌中有26例表达TTF-1，24例肺外腺癌中只有2例表达TTF-1，其敏感性为72．2％，特异性为91．7％。结论 TTF-1在浆膜腔积液肺腺癌具有较高的敏感性和特异性，在排除甲状腺癌的可能性后，TTF-1阳性表达很大程度上提示腺癌原发于肺。     

Extremely high Langerhans cell infiltration contributes to the favourable prognosis of HPV-infected squamous cell carcinoma and adenocarcinoma of the lung

AIMS: The infiltration of Langerhans cells in adenocarcinomas and squamous cell carcinomas of the lung was examined in relation to prognostic implications and human papillomavirus (HPV) infection. METHODS AND RESULTS: Samples from 62 adenocarcinoma and 59 squamous cell carcinoma patients in 1995-97, the prognosis of which had been followed up, were used. The Langerhans cells were demonstrated immunohistochemically using anti S100a and CD1 antibodies. Human papillomavirus (HPV) infection was examined by polymerase chain reaction (PCR) and nonisotopic in-situ hybridization (NISH) methods. Statistical analysis was carried out using the Kaplan-Meier method (Wilcoxon analysis) and multiple regression analysis. HPV infection was demonstrated in 12 cases (19.4%) of adenocarcinoma. The HPV-infected adenocarcinomas had abundant faintly eosinophilic cytoplasm, and were immunohistochemically positive for the surfactant apoprotein A. In the 59 cases of squamous cell carcinomas 19 were of the well differentiated form, and 29 and 11 were moderately and poorly differentiated cases, respectively. HPV was detected in 29 cases (49.2%) (13 well and 16 moderately differentiated cases). In all HPV-infected adenocarcinoma and squamous cell carcinoma cases, extremely large numbers of Langerhans cells (more than 100 per high-power field) were demonstrated in the tumour nests. In contrast, in the non-HPV-infected adenocarcinomas and squamous cell carcinomas, only a few (less than about 10 per high-power field) Langerhans cells were observed. The squamous cell carcinoma cases with high Langerhans cell infiltration, which were also infected with HPV, showed a significantly good prognosis (P = 0.007). The adenocarcinoma cases with high Langerhans cell infiltration tended to have a better prognosis than the cases with low Langerhans cell infiltration, but the difference was not statistically significant. The low number of highly infiltrated cases was insufficient for an adequate statistical analysis. Furthermore, there was no significant correlation between either Langerhans cell infiltration and smoking, or HPV infection and smoking, in either squamous cell carcinoma or adenocarcinoma cases. CONCLUSIONS: It was considered that the extremely high Langerhans cell infiltration in the tumours was caused by HPV infection. The extremely large number of Langerhans cells in the tumours contributes to the favourable prognosis for HPV-infected lung cancer.     

STAT3 activation and aberrant ligand-dependent sonic hedgehog signaling in human pulmonary adenocarcinoma

The Sonic hedgehog (SHH) signaling and STAT3 pathways play important roles during carcinogenesis with possible interaction. To determine the association of the activation of SHH signaling pathway and STAT3 pathway in carcinogenesis of human non-small cell lung carcinomas (NSCLC), firstly we examined the expression of SHH signaling molecules including SHH, Gli1(glioma-associated oncogene homolog 1) and HHIP (Hh interacting protein), as well as p-STAT3 (phosphorylation at Tyr705) by immunohistochemistry in 87 cases of NSCLC, 12 atypical adenomatous hyperplasia (AAH) and 20 adjacent normal lung tissues. The expression of SHH, Gli1, HHIP and p-STAT3 was detected respectively in 87/87(100%), 74/87(85.1%), 75/87(86.2%) and 54/87(62.1%) of the NSCLC cases, but not in the adjacent normal lung parenchyma. Ligand-dependent SHH pathway activation and STAT3 signaling activation were observed in most cases of NSCLC, and the high SHH pathway activation rate and STAT3 activation rate were significantly higher in adenocarcinoma compared with squamous cell carcinomas and large cell carcinomas (P<0.05). Both SHH and STAT3 pathway activation level correlated with histological grade in adenocarcinoma, being higher in well-differentiated types (P<0.05). Furthermore, high SHH pathway activation and p-STAT3 expression were also detected in 10/12(83.3%) of AAH cases as well as in most cases of early-stage adenocarcinoma - adenocarcinoma in situ (AIS) and minimally invasive adenocarcinomas (MIA). Correlation analysis showed that p-STAT3 protein expression level was correlated positively with ligand-dependent activation level of SHH signaling in adenocarcinoma (r(s)=0.585, P=0.000) and AAH (r(s)=0.996, P=0.000). We speculated that activation of STAT3 could up-regulate SHH gene expression directly or indirectly, and thereby activated SHH signaling resulting in lung tumor cell ontogeny. To explore the interactional mechanism, we then performed serial transient co-transfection assay in human pulmonary adenocarcinoma cell line H441 cells, and the results confirmed STAT3 activation can up-regulate SHH gene expression indirectly. In conclusion, aberrant ligand-dependent SHH signaling activation occurs frequently in NSCLC. The signaling plays a more active role in adenocarcinoma, and is an early event in carcinogenesis of lung adenocarcinoma. The involvement of STAT3 pathway activation might function in inducing the process.     

Sodium/iodide symporter expression in primary lung cancer and comparison with glucose transporter 1 expression

The aim of the present study was to evaluate the expression of sodium/iodide symporter (NIS) and glucose transporter 1 (Glut1) in 139 primary lung cancers on immunohistochemistry, and to determine the diagnostic utility of NIS as an imaging reporter. Immunoreactivity for NIS and Glut1 was noted in 75 (54.0%) and 72 (51.8%) of the 139 cases, respectively. Analysis of NIS expression on Western blot confirmed the immunohistochemistry. NIS expression was significantly higher in the adenocarcinomas than in the other carcinomas, and Glut1 expression was significantly higher in the squamous cell carcinomas than in the other carcinomas (each P  < 0.0001). The frequency of NIS expression in those carcinomas lacking Glut1 expression was significantly higher than in those with Glut1 expression ( P  = 0.012). Among 64 adenocarcinomas, the frequency of the NIS(+)/Glut1(−) phenotype was 61.0%, which was the most frequent expression pattern. By studying the expression pattern of NIS in lung cancer, the present paper provides a helpful foundation for examining the potential utility of NIS-mediated radioiodide as an alternative diagnostic modality, especially for the management of patients with lung adenocarcinoma lacking Glut1 expression.     

Clonal growth of atypical adenomatous hyperplasia of the lung: cytofluorometric analysis of nuclear DNA content

The nuclear DNA content of 13 cases of atypical adenomatous hyperplasia (AAH) associated with adenocarcinoma, eight cases of small-sized well differentiated adenocarcinoma in which the tumors were less than 2.5 cm in size with no tumor recurrence within 5 yr after surgery, and eight cases of reactive type 2 pneumocyte hyperplasia of the lung was determined by cytofluorometry. Of the AAHs, four were solitary and composed entirely of cells of AAH (Group 1), and the remaining nine were in continuity with the focus of adenocarcinoma (Group 2). The average mean nuclear DNA content of the AAHs was significantly greater than that of reactive type 2 pneumocyte hyperplasia (p less than 0.005) and significantly smaller than that of adenocarcinoma associated with AAH (p less than 0.05). However, no significant difference was found in nuclear DNA content between AAH and small-sized well differentiated adenocarcinoma. Aneuploid stem lines were found in seven of the 13 (53.8%) AAHs, ten of the 13 (76.9%) adenocarcinomas associated with AAH, and five of the eight (62.5%) small-sized well differentiated adenocarcinomas but in none of the reactive type 2 pneumocyte hyperplasias. DNA histogram patterns I and II, in which aneuploid cells were less frequently present than in patterns III and IV, were more common in AAH than in adenocarcinoma associated with AAH and small-sized well differentiated adenocarcinoma. All of the reactive type 2 pneumocyte hyperplasia showed pattern I. As to the average mean nuclear DNA content, incidence of aneuploid stem lines, and DNA histogram pattern, there was no significant difference between groups 1 and 2 of the AAHs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Napsin A Expression in Subtypes of Thyroid Tumors: Comparison with Lung Adenocarcinomas

Napsin A is widely used in the diagnosis of lung adenocarcinoma and has also been reported to be positive in cases of thyroid carcinomas. We investigated napsin A levels through immunohistochemistry on whole sections of 210 primary thyroid tumors of various subtypes and another 41 metastatic thyroid carcinomas, and compared these with 125 primary and 25 metastatic lung adenocarcinomas. The results showed that napsin A was expressed in 23.8% thyroid tumors and 30.3% papillary thyroid carcinomas. Most cases showed a focal and weak to moderate expression. In comparison, 80.8% primary lung adenocarcinomas expressed napsin A, with mostly diffused and strong expression. For metastatic carcinomas of thyroid and lung origin, napsin A was detected in 39.0% of thyroid carcinomas in contrast to 88.0% in cases of lung adenocarcinomas. Comparisons of additional markers, TTF-1, CK7, thyroglobulin, and Pax-8 in metastatic carcinomas showed the overlapping expression of immunomarkers of TTF-1 and CK7. Thyroglobulin and Pax-8 were useful for distinguishing between metastatic carcinomas; however, Pax-8 may be a superior marker due to its higher sensitivity. The clinicopathological analysis of papillary thyroid carcinomas showed that the expression of napsin A was positively correlated with lymph node metastasis (p = 0.030). Here, we focused on the expression of napsin A in thyroid tumors and compared it with that in lung adenocarcinomas. The expression of napsin A is common in thyroid tumors and the combined expression of napsin A and TTF-1 in a metastatic thyroid carcinoma is a cause for concern due to chances of misdiagnosis as lung adenocarcinoma.

     

Molecular analysis of p53 and K-ras in lung carcinomas of coal miners

Thirty-three cases of non-small cell lung cancers (NSCLC) from the archives of National Coal Workers' Autopsy Study were studied for mutational alterations in p53 and K-ras using PCR-SSCP, DNA sequencing and PCR-oligonucleotide probe hybridization techniques. Mutations of the p53 were observed in 4 smokers (19%) and one in a never smoker (8%). Two polymorphisms in smokers were detected at codon 213, a common site for sequence variation. Among the smokers the p53 mutations were in the heavy smokers. In never smokers there was only a single p53 mutation and two K-ras mutations. In never smokers the frequency of K-ras mutations was similar (17%) in smokers, but one never smoker had two K-ras mutations. Mutations of p53 were more frequent in adenocarcinomas (27%) and they were AT-->GC transitions. Four of 11 (36%) adenocarcinomas were found to have K-ras codon 12 mutations, and one adenocarcinoma had two K-ras mutations. There were two large cell undifferentiated carcinomas with p53 mutation and one with a K-ras mutation. Two of the 16 squamous cell carcinomas were positive for p53 mutation, while no K-ras mutations were found in this group. The results of these preliminary studies indicate a moderately different mutational spectrum of p53 and K-ras in coal miners independent of cigarette smoking. The mutational spectrum observed in this study of coal miners with heavy cigarette smoking history suggest a protective effect of coal mine dust in preventing abnormal mutations induced by chemical carcinogens in cigarette smoke or reactive oxygen species. These limited preliminary studies provide insight into the possibility of accurately measuring changes in etiologic markers to unravel the uncertainties of cancer in coal miners.     

Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure

Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non-exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers' lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations.     

Primary mucinous adenocarcinoma of the lung with signet-ring cells: a histochemical comparison with signet-ring cell carcinomas of other sites

Five cases of primary mucinous adenocarcinomas of the lung with signet-ring cells were studied with regard to clinical, pathologic, and prognostic implications and compared with the signet-ring cell adenocarcinomas of extrapulmonary sites. The patients ranged in age from 55 to 74 years, with a mean age of 67.8 years. There were three men and two women. Histologically, three cases were usual adenocarcinomas and two were bronchioloalveolar carcinomas. The percentage of signet-ring cells ranged from 10% to 50%, with a mean of 22% and a median of 20%. Therapy included lobectomy, radiation, and chemotherapy. Three of five patients died of their disease within 9 months and two patients showed no evidence of disease 5 months after presentation. Routine histology showed no significant differences between the signet-ring cells of any of the tumors; however, by special histochemistry, tumors originating from lung, stomach, and colon showed a more intense reaction with alcian blue stain than tumors from nose, breast, or bladder. Contrary to a previous report, we found no increase in sulfated acid mucins in these five cases of lung tumor. We also were unable to demonstrate a qualitative or quantitative difference between mucopolysaccharides produced by lung, stomach, or colon tumors. Although rare, mucinous adenocarcinoma of the lung with signet-ring cells can exist as a primary tumor.     

Is sputum cytology reliable for detection of atypical lung epithelial proliferative changes triggered by cigarette smoking?

Background: In recent years, Saudi Arabia has witnessed major tobacco smoking-related disease, such as cardiovascular disease and cancer, particularly among the younger population. Methodology: The present study aimed at evaluating the effect of cigarette smoke on lung epithelial cells. Results: This was a cross-sectional case-control study involving 300 apparently healthy volunteers living in Ha’il, Northern Saudi Arabia. Cigarette smokers (N = 100) were used as cases, and non-smokers (N = 200) were used as controls. A sputum specimen was obtained from each participant, employing all necessary safety precautions and sample adequacy measures. Results: Among 300 study subjects, cytologic atypia was identified in 14/300 (4.7%). Among the 14 cases with atypical cytologic changes, 13/14 (92.9%) were in smokers and 1/14 (7.1%) was in a non-smoker. The risk of lung cytologic atypia associated with cigarette smoking, was OR (95% CI) = 29.73 (3.82-230.87), P = 0.0001. Out of 300 study subjects, metaplasia was identified in 45/300 (15%). Among 45 cases with metaplastic changes, 26/45 (57.8%) were in the smokers and 19/45 (42.2%) were in non-smokers. The risk of lung epithelial metaplasia associated with cigarette smoking was OR (95% CI) = 3.34 (1.74-6.41), P = 0.0003. Conclusion: Cigarette smoking is a significant risk for developing lung epithelial atypia, lung metaplasia, and inflammatory cell infiltrate (especially chronic inflammation). Sputum cytology is a simple, non-invasive method that can be used in screening at-risk populations for early detection of lung proliferative changes associated with tobacco smoking.     

Limitations of the Usefulness of Microvillous Ultrastructure in Distinguishing between Carcinoma Primary in and Metastatic to the Lung

We performed ultrastructural analysis on 70 consecutive patients with solitary cancers in lung with the following histologic classifications: adenocarcinoma (42 cases), bronchioloalveolar carcinoma (13), large cell carcinoma (4), and adenosquamous carcinoma (11). Of these 70 cases, nineteen (13 adenocarcinomas, 4 bronchioloalveolar carcinomas, and 2 adenosquamous carcinomas) contained cell surface microvilli with microvillous core rootlets and/or glycocalyceal bodies. Subsequent clinical followup revealed that three of these 19 cases were actually metastatic colon carcinoma. The remaining 16 patients are currently free of extrathoracic primary disease and are therefore, presumably, primary carcinoma of the lung. Since both primary and metastatic tumors showed cell surfaces with microvilli having core rootlets and glycocalyceal bodies, we conclude that the presence of these ultrastructural features does not always permit the distinction between primary and metastatic adenocarcinoma in lung.     

Differentiation of ovarian mucinous carcinoma and metastatic colorectal adenocarcinoma by immunostaining with beta-catenin

AIMS: To investigate whether localization of beta-catenin is helpful in differentiating primary ovarian mucinous carcinoma and colorectal adenocarcinoma metastatic to the ovary. Extra-ovarian cancers which metastasize to the ovaries, especially from colorectal adenocarcinoma, frequently mimic primary ovarian carcinomas, particularly endometrioid and mucinous types. Distinguishing primary ovarian carcinoma from metastatic colorectal carcinoma is important for both therapeutic and prognostic reasons. Even after thorough histological examination, metastatic colorectal adenocarcinomas are still often mistaken for primary ovarian adenocarcinomas. Although some tumour makers have been advocated and are helpful in most cases, sometimes the distinction between primary mucinous carcinoma and metastatic colorectal carcinoma remains a problem. Activation of Wnt signalling through mutations of APC or beta-catenin is a key event in the development of colorectal cancer. These mutations lead to nuclear localization of beta-catenin, which can be demonstrated immunohistochemically. METHODS AND RESULTS: Formalin-fixed paraffin-embedded specimens from 43 primary ovarian mucinous carcinomas and 23 metastatic colorectal adenocarcinomas were included in this study. Sections were immunostained with antibodies to beta-catenin, cytokeratin (CK)7, CK20 and carcinoembryonic antigen (CEA). Nuclear localization of beta-catenin was found in 83% (19/23) of metastatic colorectal cancers and 9% (4/43) of ovarian mucinous carcinomas. Ovarian mucinous carcinomas were usually positive for CK7 (34/43, 79%). For comparison, 40 non-mucinous carcinomas of the ovary and 42 metastatic adenocarcinomas from other organs were also immunostained with antibodies against beta-catenin. Although nuclear localization of beta-catenin was occasionally seen in non-mucinous carcinoma of the ovary and metastatic adenocarcinoma from other organs, such tumours were usually distinguishable by their clinicopathological picture and rarely raised diagnostic problems. CONCLUSIONS: Immunostaining of beta-catenin is a useful marker for differentiating between ovarian mucinous carcinoma and metastatic colorectal adenocarcinoma.