Lung cancer or bronchogenic carcinoma is the most common organ malignancy accounting for 7% of all deaths in men and women. Patients usually present in their 50s-60s with preceeding symptoms of about 7 months. Major symptoms include cough, weight loss, chest pain, and dyspnea. The diagnosis can be made by CT directed fine needle aspiration or biopsy or frequently by malignant cells found in the sputum by cytological analysis. Unfortunately, this tumor is aggressive and the overall 5 year survival rate is 9%.
The cancer arises within the bronchi, usually around the hilus of the lung. It may grow to obstruct the lumen of the bronchus, invade through the wall of the bronchus to involve the underlying parenchyma, or it may extend along the peribronchial tissue to involve the mediastinum. It frequently spreads to regional lymph nodes such asthe tracheal, bronchial, and mediastinal nodes.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Bronchogenic carcinoma INCIDENCE Most common malignancy in both men and women
177,000 new cases diagnosed in 1996 in the United States
- Risk of lung cancer among white and black relatives of individuals with early-onset lung cancer.
Cote ML, Kardia SL, Wenzlaff AS, Ruckdeschel JC, Schwartz AG.
Population Studies and Prevention Program, Karmanos Cancer Institute at Wayne State University, Detroit, Mich, USA.
JAMA. 2005 Jun 22;293(24):3036-42. Abstract quote
CONTEXT: Evidence exists that lung cancer aggregates in families and recent findings of a chromosomal region linked to lung cancer susceptibility support a genetic component to risk. Family studies of early-onset lung cancer patients offer a unique opportunity to evaluate lifetime risk of lung cancer in relatives.
OBJECTIVE: To measure lung cancer aggregation and estimate lifetime risk among relatives of early-onset cases and population-based controls.
DESIGN AND SETTING: Familial aggregation and cumulative risk estimates from interview data of incident cases and concurrently ascertained controls between 1990 and 2003 in metropolitan Detroit, Mich.
PARTICIPANTS: The study included 7576 biological mothers, fathers, and siblings of 692 early-onset cases and 773 frequency-matched controls. One third of the population was black.
MAIN OUTCOME MEASURES: Cumulative lifetime risk of lung cancer, stratified by race and smoking behavior in relatives of early-onset cases and controls.
RESULTS: Smokers with a family history of early-onset lung cancer in a first-degree relative had a higher risk of developing lung cancer with increasing age than smokers without a family history. An increase in risk occurs after age 60 years in these individuals, with 17.1% (SE 2.4%) of white case relatives and 25.1% (SE 5.8%) of black case relatives diagnosed with lung cancer by age 70 years. Relatives of black cases were at statistically significant increased risk of lung cancer compared with relatives of white cases (odds ratio, 2.07, 95% confidence interval, 1.29-3.32) after adjusting for age, sex, pack-years, pneumonia, and chronic obstructive lung disease.
CONCLUSIONS: First-degree relatives of black individuals with early-onset lung cancer have greater risk of lung cancer than their white counterparts, and these risks are further amplified by cigarette smoking. These data provide estimates of lung cancer risk that can be used to offer counseling to family members of patients with early-onset lung cancer.
DISEASE ASSOCIATIONS CHARACTERIZATION ASBESTOS 50-90x increased risk
The Attribution of Lung Cancers to Asbestos Exposure A Pathologic Study of 924 Unselected Cases
Franco Mollo, MD
Corrado Magnani, MD
Patrizia Bo, MD
Paola Burlo, MD
and Maurizio Cravello, MD
Am J Clin Pathol 2002;117:90-95 Abstract quote
We studied a series of 924 nonselected surgical cases of lung carcinoma (without occupational history in clinical records) by histologic examination and light microscopic determination of asbestos body (AB) concentration to determine cancers attributable to asbestos exposure.
Lower lobes showed higher concentrations, but no significant associations were recorded between concentrations and histologic type of the lung carcinomas. Histologic asbestosis was demonstrated in 56 cases considered definitely asbestos-related. In 12 of them, the demonstration of asbestosis was attained only after repeated examination of additional sections, suggested by the finding of more than 1,000 ABs per gram of dry weight (gdw), an indicator of occupational asbestos exposure. In the 56 cases, the median AB concentration was 3,281/gdw. In 5 other cases without demonstration of ABs in histologic sections, concentrations higher than this median and interstitial fibrosis were observed. The AB count after digestion of pulmonary tissue may show greater sensitivity than the search in histologic sections as an indicator of substantial asbestos exposure.
Extrapolation of our estimate on a national scale suggests about 2,000 cases per year of asbestos-related cancers of the lung in Italy; 281 cases were reported (from all occupational causes) in the years 1990-1995.
INDUSTRIAL Nickel, chromates, coal, mustard gas, arsenic, beryllium, iron, haloether LITTORAL CELL ANGIOMATOSIS
Littoral cell angiomatosis with poorly differentiated adenocarcinoma of the lung.
Collins GL, Morgan MB, Taylor FM 3rd.
Department of Pathology, University of South Florida College of Medicine; the Department of Pathology, James A Haley VA Hospital; and St Joseph's Hospital, Tampa, FL
Ann Diagn Pathol 2003 Feb;7(1):54-9 Abstract quote
We report on a 64-year-old male United States Navy Veteran of World War II, one of two identical twins, diagnosed with littoral cell angiomatosis of the spleen, liver, and lymph nodes, later found to have a massive poorly differentiated adenocarcinoma involving the mediastinum, adjoining lung, and sternum with widespread metastases.
Herein we include our findings at autopsy, pertinent immunohistochemical studies, and a review of the literature pertaining to littoral cell angiomatosis with comment on its association with visceral malignancies.
RADON SCARRING Old scars secondary to infarcts, foreign bodies, wounds, or granulomas may provide a fertile field for scar carcinomas, the most common being adenocarcinoma TOBACCO SMOKING 80% of lung cancers occur in smokers
Cessation of 10 yrs reduces risk to baseline
Mucosal lining cells of the bronchi show atypical cells in nearly all cases
Over a thousand different carcinogenic compounds have been identified in the smoke
URANIUM 4x increased risk
PATHOGENESIS CHARACTERIZATION GENERAL
Aerogenous spread of primary lung adenocarcinoma induces ultrastructural remodeling of the alveolar capillary endothelium
Enjing Jin, MD
Masakazu Fujiwara, MS
Mikio Nagashima, MD
Hajime Shimizu, BS
Mohammad Ghazizadeh, MD, PhD
Xin Pan, MD
Satoru Arai, MD
Yoshiharu Ohaki, MD
Makoto Gomibuchi, MD, PhD
Tamiko Takemura, MD, PhD
Oichi Kawanami, MD, PhD
Hum Pathol 2001;32:1050-1058 Abstract quote
To determine whether pulmonary alveolar capillaries manifest ultrastructural remodeling at areas of neoplastic invasion of primary lung adenocarcinomas, we examined 17 well-differentiated adenocarcinomas of lung (2 bronchioloalveolar and 15 papillary adenocarcinomas) by electron microscopy.
The expression of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) was demonstrated by immunohistochemical stainings. VEGF messenger RNA (mRNA) isoforms were detected by reverse-transcription polymerase chain reaction (RT-PCR) in alveolar walls microdissected from normal and tumor-associated tissues. Cytoplasm of neoplastic cells expressed VEGF protein in all patients. Endothelial cell nuclei of alveolar capillaries showed positive reaction for PCNA. Alveolar capillary lumina were distended like venules, and some intercellular junctions remained open. The cytoplasm of the capillary endothelial cells was enlarged and developed numerous organelles such as Weibel-Palade bodies and vesiculovacuolar organelles, in contrast to marked attenuation in their normal counterpart. Capillary sprouting occurred from proper alveolar capillaries in 2 patients. Cytoplasmic segments became extremely attenuated and developed diaphragm-like fenestrae in 65% of the patients. A relatively higher expression of diffusable isoforms of VEGF mRNA was seen in the tumor-bearing alveolar walls than in normal walls. Expression of KDR (one of the VEGF receptors) mRNA in tumor exceeded that in normal tissues.
These results suggest that diffusable isoforms of VEGF mRNA released from the neoplastic cells are deeply involved in the induction of growth activity of alveolar capillary endothelial cells as much as in the characterization of tumor-associated microvessels in primary lung adenocarcinomas.
Detection of Early Invasion on the Basis of Basement Membrane Destruction in Small Adenocarcinomas of the Lung and Its Clinical Implications
Koichi Goto, M.D., Tomoyuki Yokose, M.D., Tetsuro Kodama, M.D., Kanji Nagai, M.D., Yutaka Nishiwaki, M.D., Masayuki Ando, M.D., Kiyoshi Mukai, M.D. and Atsushi Ochiai, M.D.
Pathology Division, National Cancer Center Research Institute East (KG, TY, KM, AO), Kashiwa, Chiba; Division of Thoracic Oncology, National Cancer Center Hospital East (KG, KN, YN), Kashiwa, Chiba; Division of Medical Oncology, National Cancer Center Hospital (TK), Tsukiji, Tokyo; and First Department of Internal Medicine, Kumamoto University School of Medicine (KG, MA), Kumamoto, Japan
Mod Pathol 2001;14:1237-1245 Abstract quote
To evaluate the correlation between the degree of basement membrane (BM) preservation and clinicopathological characteristics in the replacement-growth type (lepidic growth type) of small peripheral adenocarcinomas of the lung, the BM components of 72 surgically resected replacement-growth type adenocarcinomas of the lung, 2 cm or less in diameter, were evaluated immunohistochemically by using a monoclonal antibody to Type IV collagen and polyclonal antibodies to 7S collagen and laminin.
The tumors were classified into the following three distinctive histological types according to the condition of the elastic framework: Type I, bronchioloalveolar carcinoma without fibrotic foci; Type II, sclerosing bronchioloalveolar carcinoma without elastic framework destruction; and Type III, sclerosing bronchioloalveolar carcinoma with elastic framework destruction. The BM was well preserved in the area of bronchioloalveolar spread along fully expanded alveoli in all tumor types; however, BM preservation was significantly lost in the areas of collapsed alveoli in Type III tumors. There were no BM component staining reactions in the scarred regions of Type III tumors. In addition, lymph node metastasis was significantly greater in Type III tumors and BM-destroyed tumors.
We concluded that the BM was largely destroyed by tumor cell invasion in the scarred region of Type III adenocarcinomas. Type III tumors had discontinuous BMs in the area of collapsed alveoli, indicating that this BM-destructive pattern must be the first step in tumor invasion. Type I and II tumors were concluded to be noninvasive adenocarcinomas, because their BM components were well preserved and they had a good outcome.
Growth index is independent of microvessel density in non-small-cell lung carcinomas.
Tsoli E, Zacharatos P, Dasiou-Plakida D, Peros J, Evangelou K, Zavras AI, Yannoukakos D, Konstantopoulou I, Asimacopoulos PJ, Kittas C, Gorgoulis VG.
Department of Histology and Embryology, School of Medicine, University of Athens, Greece.
Hum Pathol 2002 Aug;33(8):812-8 Abstract quote
Induction of angiogenesis is essential for carcinogenesis and facilitates the processes of tumor development and metastasis. Vascular endothelial growth factor (VEGF) is an important angiogenic regulator under physiologic and pathologic conditions. To elucidate the role of angiogenesis in malignant growth, we evaluated angiogenesis and VEGF expression in a panel of 68 non-small-cell lung carcinomas (NSCLCs) and examined their relation with the kinetic parameters, ploidy, and p53 protein status, which have been analyzed previously.
Angiogenesis was estimated as microvascular density (MVD) of the tumor area by CD31 immunodetection. Expression of VEGF was also immunohistochemically evaluated. All possible associations were assessed through a series of statistical methods. The mean MVD value was 39 microvessels/mm(2), and high VEGF immunoreactivity was observed in all specimens, with a mean percentage of positive cells of 73%. The relation between MVD and VEGF expression was not statistically significant (P = 0.065). No association was observed between MVD or VEGF levels with the proliferation index, apoptotic index, tumor ploidy status, p53 expression, and overall survival.
We conclude that in a subset of NSCLCs, angiogenesis may be associated with VEGF, but other factors also participate in this process. Angiogenesis and growth (proliferation and apoptosis) are independent and probably differentially operated procedures, with only growth partially controlled by p53 protein expression.
Aberrant Nuclear Localization and Gene Mutation of beta-catenin in Low-Grade Adenocarcinoma of Fetal Lung Type: Up-Regulation of the Wnt Signaling Pathway May Be a Common Denominator for the Development of Tumors that Form Morules.
Nakatani Y, Masudo K, Miyagi Y, Inayama Y, Kawano N, Tanaka Y, Kato K, Ito T, Kitamura H, Nagashima Y, Yamanaka S, Nakamura N, Sano J, Ogawa N, Ishiwa N, Notohara K, Resl M, Mark EJ.
Division of Anatomic and Surgical Pathology (YN, KM, YI, NK), Hospital of Yokohama City University, and Department of Pathology (TI, HK, YNAG, SY), Yokohama City University School of Medicine, Yokohama, Japan.
Mod Pathol 2002 Jun;15(6):617-24 Abstract quote
The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA.
These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA.
The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.
Loss of cables protein expression in human non-small cell lung cancer: A tissue microarray study.
Tan D, Kirley S, Li Q, Ramnath N, Slocum HK, Brooks JS, Wu CL, Zukerberg LR.
Department of Pathology, Roswell Park Cancer Institute, State University of New York, Buffalo, NY; Department of Pathology, Massachusetts General Hospital, Boston, MA; and Department of Pathology, University of Pennsylvania, Philadelphia, PA.
Hum Pathol 2003 Feb;34(2):143-9 Abstract quote
Loss of heterozygosity (LOH) on chromosome 18q is common in lung cancer. The genes involved in LOH on 18q in lung cancer have not been well characterized. Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11-12.
Cables inhibits cell growth and suppresses tumor formation in nude mice, making it a candidate gene for 18q LOH in lung cancer. Little is known regarding Cables protein expression in human non-small cell lung cancer (NSCLC). In this study we examined Cables expression in 163 NSCLC and nonneoplastic lung specimens using tissue microarrays. Strong nuclear staining was present in normal lung and bronchial tissue. We also evaluated the Cables protein expression pattern and its correlation with histopathologic features and with clinical course of NSCLC.
The results of the present study demonstrate for the first time that numerous NSCLCs (45%) lose Cables expression. Furthermore, more adenocarcinomas show a loss of this novel protein than do squamous counterparts. The relationship between tumor histology type and Cables expression appears to be statistically significant (P = 0.028). Our results suggest that Cables may be involved in the pathogenesis of NSCLC.
- Comparative Mutational Analysis of Pulmonary Scar Epithelium, Bronchioloalveolar Carcinomas, and Invasive Well-Differentiated Pulmonary Adenocarcinomas: A Molecular Approach to Diagnostically Challenging Cases.
Sheikh HA, Sasatomi E, Finkelstein S, Yousem SA.
From the *Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA; and daggerRedPath Integrated Pathology, Pittsburgh, PA.
Am J Surg Pathol. 2005 Oct;29(10):1267-1273. Abstract quote
Discrimination of invasive well-differentiated adenocarcinoma (IAD) from reactive bronchioloalveolar epithelium entrapped in pulmonary scars (PSE) may be difficult on routine histology, especially on small biopsies. Ancillary studies to help in this regard are desirable. Whereas IADs have been shown to harbor cumulative mutational damage of tumor suppressor genes, little is known about molecular changes in PSEs.
In this study, we compared cumulative loss of heterozygosity (LOH) of tumor suppressor genes in PSEs (N = 12), bronchioloalveolar carcinomas (BACs, N = 15) and stage 1 IADs (N = 7). Unstained serial sections were microdissected to obtain lesional and normal tissue DNA. PCR was performed for up to 16 polymorphic markers. An allelic ratio of <0.5 or >2.0 was designated as LOH. Fractional allelic loss (FAL) was calculated for each case as the number of markers with LOH divided by the total number of informative markers. Mean percentage of informative markers was 76.8%. PSEs showed significantly lower mean FAL compared with BACs and IADs (3.0% vs. 20.4% and 28.5%, respectively; P < 0.003). Only 1 case of PSE showed LOH of one marker in two different areas, whereas the majority of allelic losses in the neoplasms were present in two or more microdissected foci.
Our study shows that PSEs harbor LOH of tumor suppressor genes at relatively low rates and in a random distribution compared with BACs and IADs, which show consistent allelic losses, and high FALs. These molecular differences may serve as an adjunct to histology in challenging glandular lesions of the lung.
Genetic Profile of Cumulative Mutational Damage Associated With Early Pulmonary Adenocarcinoma: Bronchioloalveolar Carcinoma vs. Stage I Invasive Adenocarcinoma.
Sasatomi E, Johnson LR, Aldeeb DN, Lomago DM, Thompson JW Jr, Swalsky PA, Luketich JD, Fernando HC, Finkelstein SD, Yousem SA.
*Departments of Pathology and daggerThoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA.
Am J Surg Pathol. 2004 Oct;28(10):1280-1288.Abstract quote
To detect the possible genetic alterations characteristic of bronchioloalveolar carcinoma (BAC) and to study molecular genetic factors responsible for determining the biologic aggressiveness of pulmonary adenocarcinoma, comparative analysis of loss of heterozygosity (LOH) on 9 chromosomal regions was performed in 14 BACs and in 20 stage I adenocarcinomas (AD).
The most frequently affected chromosome regions in BAC were 8q and 17p. In stage I AD, more than 60% of the cases showed LOH of 1p, 3p, 5q, 7q, 17p, and 18q loci, and LOH of 1p, 3p, 7q, and 18q was observed with greater frequency than in BAC (P < 0.05). Fractional allele loss (FAL) was significantly greater in stage I AD than in BAC (P < 0.001). In cases with microdissection of multiple sites, intratumoral heterogeneity of LOH status was observed in 73% of BAC and 94% of stage I AD, and homogeneous distribution of LOH of 9p was unique to BAC. The high FAL value was associated with a poor prognosis of BAC, but this trend did not reach statistical significance (P = 0.098).
In stage I AD, no correlation was found between LOH of particular chromosomal region or FAL and clinical outcome. LOH of 1p, 3p, 7q, and 18q was associated with invasive properties of pulmonary AD and may be useful in identifying invasive adenocarcinoma when conventional histomorphological tools are not helpful.
Clonality analysis of different histological components in combined small cell and non-small cell carcinoma of the lung.
Murase T, Takino H, Shimizu S, Inagaki H, Tateyama H, Takahashi E, Matsuda H, Eimoto T.
Department of Pathology, Nagoya City University Medical School, Japan.
Hum Pathol. 2003 Nov;34(11):1178-84 Abstract quote.
Combined small cell and non-small cell carcinoma is relatively rare in the lung. Examination of the clonal relationship of different components in this type of tumor may give a clue to the rarity.
We retrieved 6 such tumors; all 6 had small cell carcinoma and adenocarcinoma components, and 3 had an additional squamous cell carcinoma component. We examined the point mutations in the p53 gene and allelic loss (ie, the loss of heterozygosity [LOH] pattern) of chromosome 3p in each component. p53 mutations were detected in the small cell carcinoma component of 5 tumors and in the non-small cell carcinoma components of 2 tumors. In 1 case, the squamous cell carcinoma component had a p53 mutation locus identical to that in the small cell carcinoma component, but in the other case, the adenocarcinoma component had a different mutation than that in the small cell carcinoma component. Chromosome 3p LOH loci in the squamous cell carcinoma component were present in the small cell carcinoma component in all 3 cases, but some LOH loci were not identical in the small cell carcinoma and adenocarcinoma components in 3 cases.
These results suggest that the small cell and squamous cell carcinoma components of combined small cell lung carcinomas have an intimate clonal relationship. On the other hand, the adenocarcinoma component often may be derived from a separate clone or, more likely, undergo a progressive process separate from the squamous cell-small cell carcinoma beginning in a very early stage, that is, before the appearance of p53 and chromosome 3p abnormalities.
This tumorigenesis process may explain the relative rarity of combined small cell and non-small cell carcinoma, which occurs primarily in the peripheral lung, an infrequent site of squamous cell carcinoma.
DNA copy number changes in lung adenocarcinoma in younger patients.
Lindstrom I, Nordling S, Nissen AM, Tammilehto L, Mattson K, Knuutila S.
Department of Pathology, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Finland.
Mod Pathol 2002 Apr;15(4):372-8 Abstract quote
We performed a comparative genomic hybridization study on 25 lung adenocarcinoma samples from younger patients (<41 y of age) and compared the results with a previous comparative genomic hybridization analysis of lung adenocarcinoma samples from older patients (50-81 y of age).
Twenty of the 25 tumor samples from younger patients had DNA copy number changes. Gains, losses, and high-level amplifications were seen more frequently in the specimens from the younger group. The most striking difference between the two groups was the high frequency of gains and/or high-level amplifications in the long arm of chromosome 20 in the samples from the younger patients (14/25, 56%) compared with that in the samples from the older patients (2/24, 8%, P <.001). Gains in the long arm of chromosome 22 and of the chromosomal band 11q13 were also detected significantly more often in the younger group. No correlation was found between DNA copy number changes and clinical parameters.
Our results suggest that amplification of genes in the long arm of chromosome 20 may be important in the tumorigenesis of lung adenocarcinoma in young adults. Several candidate genes have already been described in the long arm of chromosome 20, particularly in breast cancer.
Protein Overexpression and Gene Amplification of c-erb B-2 in Pulmonary Carcinomas: A Comparative Immunohistochemical and Fluorescence In Situ Hybridization Study
Naoko Hirashima, M.D., Wataru Takahashi, M.D., Shinpei Yoshii, M.D., Tetsu Yamane, M.D. and Akishi Ooi, M.D.
Departments of Pathology (NH, TY, AO) and Surgery (WT, SY), Yamanashi Medical University, Yamanashi, Japan
Mod Pathol 2001;14:556-562 Abstract quote
Amplification of the c-er bB-2 gene (located on 17q11.2–12) is accompanied by overexpression of its cell surface receptor product, p185ERBB2. In pulmonary carcinomas, however, there has been disagreement between the reported frequencies of gene amplification and overexpression. To clarify their relationship, the correlation between the cellular expression of p185ERBB2 and the level of c-erb B-2 gene amplification was studied.
A total of 195 pulmonary carcinomas (182 primary and 13 metastatic) were examined immunohistochemically using a polyclonal antibody, which recognizes the internal domain of the human c-erb B-2 protein, and positive tumors were further examined for the gene amplification by dual-color fluorescence in situ hybridization using probes for centromere 17 and 17q11.2–12.
By immunohistochemistry, distinct membrane staining was found in an adenocarcinoma, a large cell carcinoma and a metastatic carcinoma from the breast, and cytoplasmic and/or faint membranous staining was observed in 23 non-small cell lung carcinomas. It was in the two primaries and the metastatic carcinoma that more than 8-fold amplification of c-erb B-2 was found by fluorescence in situ hybridization. Especially, in the two primary carcinomas, tumor cells had amplified genes with the signals forming one or two clusters, indicating that the amplified gene was present in homogeneously staining regions. Among the 23 tumors, three tumors showed low-level amplification (less than 3-fold), which was differentiated from polysomy 17 found in the other two. In the 30 non-small cell lung carcinomas selected at random from 151 with negative immunostaining, there were five trisomy 17, but no tumors with the gene amplification.
This suggests that although c-erb B-2 amplification in pulmonary carcinoma is rare, it occurs in the form of a homogeneously staining region and is thought to control the overexpression of the protein in the cell membrane. New adjuvant therapy using a humanized antibody to the oncoprotein may be beneficial to patients with these tumors.
c-myc Small cell carcinomas drs gene
Expression of drs mRNA in human lung adenocarcinomas.
Shimakage M, Takami K, Kodama K, Mano M, Yutsudo M, Inoue H.
Clinical Research Institute, Osaka National Hospital, Japan.
Hum Pathol 2002 Jun;33(6):615-9 Abstract quote
The drs gene was originally isolated from a rat primary embryo fibroblast cDNA library as a suppressor gene against v-src transformation. We have previously shown that expression of drs mRNA was markedly reduced in a variety of human cancer cell lines, including those of the colon, bladder, and ovary. Furthermore, introduction of drs cDNA by retrovirus vector into these cancer cell lines caused suppression of anchorage-independent growth without affecting cell proliferation. These findings suggest that down-regulation of drs mRNA is closely correlated with expression of malignant phenotypes in development of human cancers.
To clarify the correlation between down-regulation of drs mRNA and malignant tumor formation in human tumor tissues, we examined the expression of drs mRNA in well-differentiated, moderately differentiated, and poorly differentiated lung adenocarcinoma tissues by in situ mRNA hybridization.
The results clearly indicated that expression of drs mRNA was markedly reduced in 5 of 5 poorly differentiated lung adenocarcinomas examined but significantly expressed in normal lung tissues and 5 of 7 moderately-differentiated and 3 of 5 well-differentiated lung adenocarcinoma tissues. Neither gross deletion nor rearrangement of the drs genome was detected in these tissues. Down-regulation of drs mRNA was also observed in human lung adenocarcinoma cell lines derived from poorly differentiated adenocarcinomas.
Our results suggest that down-regulation of drs mRNA is correlated with a poor degree of differentiation and progression of lung adenocarcinoma.
EPIDERMAL GROWTH FACTOR RECEPTOR
- High epidermal growth factor receptor amplification rate but low mutation frequency in Middle East lung cancer population.
Al-Kuraya K, Siraj AK, Bavi P, Al-Jommah N, Ezzat A, Sheikh S, Amr S, Al-Dayel F, Simon R, Guido S.
King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia.
Hum Pathol. 2006 Apr;37(4):453-7. Epub 2006 Mar 6. Abstract quote
Epidermal growth factor receptor (EGFR) exon 18-21 mutations were shown to be highly predictive of response to gefitinib (Iressa) therapy in lung cancer. Studies on Western and Japanese lung cancers have indicated substantial differences in the EGFR mutation frequency between these populations.
To investigate the prevalence of EGFR in another distinct ethnic group, EGFR alterations were studied in 47 consecutive non small cell lung cancers from Saudi Arabia by immunohistochemistry, fluorescence in situ hybridization, and DNA sequencing. Detectable EGFR expression was seen in 69.8% of 43 interpretable cancers. Epidermal growth factor receptor amplification, present in 15.3% of 39 analyzable cancers, was strongly associated with high levels of EGFR expression (P = .0047). Only 1 exon 18-21 mutation was seen among 34 lung cancers that could be successfully sequenced. It is concluded that EGFR exon 18-21 mutations are rare in Middle East patients with lung cancer and occur in a similar range as in Western patients.
The remarkable high rate of EGFR gene amplifications could potentially facilitate studies on the predictive role of gene copy number changes for response to anti-EGFR therapies in Middle East patient sets.
Hum Pathol. 2005 Oct;36(10):1127-34. Abstract quote
The molecular mechanisms for frequent epidermal growth factor receptor (EGFR, a tyrosine kinase [TK]) and HER2 (the preferred coreceptor of EGFR) overexpression in lung cancer are poorly understood. Recent studies have shown the mutations of the TK domain in EGFR and HER2 to be present in lung cancer.
The purpose of this study was to investigate the relationship between mutation status and expression of EGFR and HER2 in lung cancer. Immunostaining took place for EGFR and HER2, and mutational analyses for EGFR, HER2, and KRAS (a signaling protein) were conducted using 130 resected lung cancer specimens. Thirty-seven EGFR mutations (28%) and 8 HER2 mutations (6%), both of the TK domains, and 5 KRAS (4%) mutations were found, whereas 73 (56%) EGFR and 47 (36%) HER2 overexpressions were found. EGFR overexpression was seen more frequently in tumors with EGFR mutation (28/37, 76%) than in tumors without EGFR mutations (45/93, 48%; P = .0059). No correlation was found between HER2 mutation and HER2 expression. Multivariate regression revealed that EGFR mutation, adenocarcinoma histology, and HER2 expression were associated with EGFR expression, whereas female sex, EGFR mutation, and EGFR expression were associated with HER2 expression.
In conclusion, EGFR and HER2 overexpression is frequent in lung cancer, and EGFR overexpression correlates with the EGFR TK domain mutations.
Epstein-Barr virus plays no role in the tumorigenesis of small-cell carcinoma of the lung.
Chu PG, Cerilli L, Chen YY, Mills SE, Weiss LM.
Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
Mod Pathol. 2004 Feb;17(2):158-64 Abstract quote.
Epstein-Barr virus infection has been associated with lymphoepithelioma-like carcinoma of the lung in Asian patients. Recently, Epstein-Barr virus proteins or genomic DNAs were detected in pulmonary squamous-cell carcinoma, adenocarcinoma, and undifferentiated small-cell carcinoma in American patients.
We studied 23 cases of small-cell carcinoma of the lung for evidence of Epstein-Barr virus infection by in situ hybridization, immunohistochemistry, and polymerase chain reaction methods. Of the 23 cases, 13 cases were primary small-cell carcinoma of the lung and 10 cases were metastatic small-cell carcinoma of the lung to the brain (one case), liver (two cases), and lymph nodes (seven cases). None of the 23 cases was positive for Epstein-Barr virus-encoded small nonpolyadenylated RNA (EBER)-1 by in situ hybridization. By immunohistochemistry, eight cases showed focal positivity for Epstein-Barr virus nuclear antigen-1. The positive immunostaining was focal and was observed in tumor cells, vascular endothelial cells, and lymphocytes, suggesting nonspecific staining. None of the 23 cases was positive for the transactivating immediate-early BZLF1 (ZEBRA) and latent membrane protein (LMP-1). Only one case was positive for the BamHI W region and LMP-1 gene by polymerase chain reaction assay. Some tumor cells in the BamHI W region positive case were also positive for Epstein-Barr virus nuclear antigen-1.
Our study indicates that rare cases of American small-cell carcinoma of the lung may contain Epstein-Barr virus-infected cells, but it is unlikely that Epstein-Barr virus plays a role in the tumorigenesis of small-cell carcinoma of the lung.
GLYCOSYLATION PATTERNS Differences in the O-Glycosylation Patterns Between Lung Squamous Cell Carcinoma and Adenocarcinoma
Anna López-Ferrer, MS, Carlos Barranco, MD, PhD, and Carme de Bolós, PhD
Am J Clin Pathol 2002;118:749-755 Abstract quote
Mucins are highly O-glycosylated proteins synthesized by epithelial cells, and their glycosylation patterns can be altered during neoplastic transformation. The 2 types of non–small cell lung cancer (NSCLC) display a similar pattern of mucin gene expression but different reactivity to periodic acid–Schiff diastase, suggesting that a higher number of carbohydrate chains are present in adenocarcinomas.
We compared the expression of core (Tn, sialyl-Tn, T) and terminal fucosylated and sialylated (Lewis antigens) carbohydrate structures in lung tumors. Specific antibodies were used for immunohistochemical and Western blot assays. Results indicated that core and terminal structures are detected more frequently in adenocarcinoma than in squamous cell carcinoma, except Lewis y, which is expressed strongly in both types of NSCLC.
These data suggest that in squamous cell carcinoma and adenocarcinoma, different sets of glycosyltransferases must be expressed and that different posttranslational modifications of the mucin genes can take place in these 2 tumor types.
JAAGSIEKTE SHEEP RETROVIRUS
Absence of jaagsiekte sheep retrovirus DNA and RNA in bronchioloalveolar and conventional human pulmonary adenocarcinoma by PCR and RT-PCR analysis
Samuel A. Yousem, MD
Sydney D. Finkelstein, MD
Patricia A. Swalsky, BS
Anke Bakker, BS
N. Paul Ohori, MD
Hum Pathol 2001;32:1039-1042. Abstract quote
Bronchioloalveolar adenocarcinoma (BAC) morphologically resembles sheep pulmonary adenomatosis (SPA), a contagious ovine pulmonary adenocarcinoma caused by the jaagsiekte sheep retrovirus (JSRV). Previously, positivity for JSRV by immunostaining, reverse-transcription polymerase chain reaction (RT-PCR), and Western blot was reported in most nonmucinous BACs.
Our objective in this study was to analyze additional BAC subtypes and conventional adenocarcinomas (CA) to further substantiate this association. Tumor tissue was microdissected from unstained paraffin sections of 26 cases of formalin-fixed, paraffin-embedded BAC (7 mucinous, 17 nonmucinous, 2 sclerosing) and 29 cases of CA. Positive controls consisted of 2 separate paraffin blocks of known SPA. Primer sequences were derived that were capable of hybridizing to all reported strain variants of both the DNA (endogeneous) and RNA (exogenous) forms of JSRV. Each sample was tested using both PCR (DNA) and RT-PCR (RNA).
All BAC and CA cases were negative for JSRV. Positive controls yielded PCR products that were sequenced and precisely matched the published prototype stain of JSRV. To control for negative effects of tissue fixation, dilutions of positive control tissue were added to BAC and CA samples.
Detection of JSRV was evident at 1:50 dilution. Although the possibility of a viral association with BAC cannot be excluded, this study shows that the association with JSRV is probably very weak, if present at all.
- Expression and localization of mRNAs for matrix metalloproteinases and their inhibitors in mixed bronchioloalveolar carcinomas with invasive components.
Kanomata N, Nakahara R, Oda T, Aoyagi Y, Ishii G, Yokose T, Hasebe T, Nagai K, Yokozaki H, Ochiai A.
 1Pathology Division, National Cancer Center Research Institute East, Chiba, Japan  2Surgical Pathology Division, Kobe University Hospital, Kobe, Japan.
Mod Pathol. 2005 Jun;18(6):828-37. Abstract quote
Matrix metalloproteinases (MMPs) are believed to play an essential role in cancer invasion, although detailed differences between noninvasive and invasive lung carcinomas are still unclear.
To elucidate the expression and activity patterns of MMPs in noninvasive and invasive carcinoma of the lung, we performed in situ hybridization and real-time reverse transcription-polymerase chain reaction to detect messenger RNAs (mRNAs) of MMPs and their tissue inhibitors (TIMPs). The basement membrane was evaluated by immunohistochemistry for type IV collagen. Gelatinase activity was examined by zymography and in situ zymography. A total of 14 surgically resected primary pulmonary adenocarcinomas were used for this study.
All the tumors were adenocarcinoma mixed bronchioloalveolar carcinomas according to the 1999 WHO classification. MMP and TIMP2 mRNAs were detected by in situ hybridization in all samples, in both noninvasive and invasive carcinoma components. Signals for MMP mRNAs were significantly higher in both noninvasive and invasive carcinomas than in tumor-free lung tissue. However, the differences were small between noninvasive and invasive carcinomas, not only in the amount of mRNA but also in the activity of the MMPs. In most carcinomas, stromal fibroblast-type cells tended to express levels of MMP and TIMP2 mRNAs that were higher than or at least similar to those expressed in epithelial cells.
Our data on mixed adenocarcinoma suggest that noninvasive carcinoma areas already express a molecular mechanism involving MMPs similar to that expressed by invasive carcinoma areas. Stromal fibroblast-type cells seem to be the most important source of MMPs, from the earliest event of tumor invasion by pulmonary adenocarcinomas.
Mucinous bronchioloalveolar carcinomas display a specific pattern of mucin gene expression among primary lung adenocarcinomas
Marie-Christine Copin, etal.
Hum Pathol 2001;32:274-281. (Abstract quote)
Lung adenocarcinomas are heterogeneous clinically and histologically. Expression of the mucin genes was analyzed as a molecular marker of glandular cytodifferentiation in primary lung adenocarcinomas. Expression was correlated with histopathologic subtypes of World Health Organization classification with the aim of investigating the histogenesis of primary lung adenocarcinomas.
Thirty-four primary lung adenocarcinomas were examined by in situ hybridization for mucin gene expression (MUC1-4, MUC5AC, MUC5B, MUC6-7) and by immunohistochemistry for MUC5AC and MUC5B apomucin expression. Mucinous bronchioloalveolar carcinoma (BAC) had a homogeneous pattern of mucin gene expression different from those of other types of lung adenocarcinoma, involving secreted mucins (MUC5AC, MUC5B, and MUC6) and membrane-bound mucins (MUC1, MUC3, and MUC4). Non-BAC adenocarcinoma and mucinous BAC aberrantly expressed mucin genes MUC3, and MUC3 and MUC6, respectively, which are undetectable in normal fetal and adult lung. Our results show the particular phenotype of mucin gene expression in mucinous type of BACs and the heterogeneous expression of respiratory and nonrespiratory mucins in the other types.
This finding supports the theory of a common progenitor cell with the potential of multicellular differentiation. From a practical point of view, the aberrant expression of MUC3 and MUC6 could serve as a diagnostic marker in the management of the mucinous type of bronchioloalveolar carcinomas.
Commonly deleted, cigarette smoke carcinogen benzopyrene causes DNA damage to same sequences in p53 that are found in deletions in lung cancer
p53 Gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis
Hidenori Kawasaki, MD
Tsutomu Ogura, MD
Tomoyuki Yokose, MD
Kanji Nagai, MD
Yutaka Nishiwaki, MD
Hiroyasu Esumi, MD
Hum Pathol 32:1043-104 Abstract quote
Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. Several atypical epithelial lesions are frequently observed in the fibrotic area in IPF patients, and they have been suspected to be related to lung cargingenesis. Several studies have suggested that p53 protein accumulation and mutation occur in the early pathogenesis of squamous cell carcinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases.
To examine the cause of the high frequency of lung cancer in IPF, we examined the p53 changes in atypical epithelial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis.
We examined 19 lung cancer patients with IPF who underwent surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (RSP53) by the avidin–biotin–peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction mediated single-strand conformation polymorphism (polymerase chain reaction–single-strand conformation polymorphism) analysis and DNA sequencing. p53 protein was immunohistochemically detected in 13 (62%) of 21 squamous cell carcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squamous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squamous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions.
In conclusion, there are frequent p53 gene alterations in squamous metaplasia, which is distributed in the peripheral zone of the fibrotic area in patients with IPF. The present findings might provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in IPF patients, and suggest that p53 gene alterations play an important role in the early stages of lung carcinogenesis in patients with IPF. 9.
SUPEROXIDE DISMUTASE Differential Expression of Superoxide Dismutases in Lung Cancer
Anne-Mari Svensk, MD, etal.
Am J Clin Pathol 2004;122:395-404 Abstract quote
Oxidant-antioxidant balance is known to regulate growth factors and invasion of tumor cells.
Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), the first-line antioxidant defenses, were studied in lung carcinomas by immunohistochemical analysis (n = 139, 56, and 37, respectively) and in 8 lung tumor specimens by Western blot analysis and SOD activity measurement. Altogether, 49% of squamous cell carcinomas and 43% of the adenocarcinomas were positive for MnSOD by immunohistochemical analysis; corresponding values for CuZnSOD were 79% and 93%, respectively. MnSOD and CuZnSOD by Western blot analysis were 27% and 22% higher, and CuZnSOD activity was 93% higher (P = .06) in carcinomas than in nonmalignant lung tissue samples.
ECSOD, a mainly extracellular enzyme, showed weak positivity only in 4 of 37 carcinomas, and by Western blot analysis showed 70% lower immunoreactivity (P < .0001) than in nonmalignant lung tissue samples.
It is highly likely that low expression of ECSOD might have fundamental effects on the extracellular redox state of lung tumors with potential consequences on tumor behavior.
TELOMERASE REVERSE TRANSCRIPTASE
Expression of human telomerase RNA component and telomerase reverse transcriptase mRNA in atypical adenomatous hyperplasia of the lung.
Nakanishi K, Kawai T, Kumaki F, Hirot S, Mukai M, Ikeda E.
Division of Environmental Medicine, National Defense Medical College Research Institute and the Department of Pathology, National Defense Medical College, Tokorozawa, Japan.
Hum Pathol 2002 Jul;33(7):697-702 Abstract quote
It has been suggested that atypical adenomatous hyperplasia (AAH) may be a precursor of peripheral adenocarcinoma of the lung. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA onto chromosomal ends. Its activity is believed to be crucial for cellular immortality, and it is thought to participate in the development of most human cancers. However, little is known about the regulation of telomerase in AAH.
We investigated the expression of human telomerase RNA component (hTERC) and telomerase reverse transcriptase (hTERT) mRNA using in situ hybridization in surgically resected formalin-fixed, paraffin-embedded specimens: 29 AAHs (with 11 lesions interpreted as low-grade AAH and 18 as high-grade AAH) and 40 peripherally located nonmucinous bronchioloalveolar carcinomas (NMBACs) measuring < or = 20 mm in greatest diameter. Positive expressions of hTERC and hTERT mRNA were recognized in 27.3% and 27.3% of low-grade AAHs, 72.2% and 77.8% of high-grade AAHs, and 97.5% and 97.5% of NMBACs, respectively. Statistically, significant differences in both expressions could be shown between low-grade AAH and high-grade AAH and between high-grade AAH and NMBAC.
Thus, in terms of the incidence of these expressions, high-grade AAH was intermediate between low-grade AAH and NMBAC and tended to be closer to NMBAC. These results suggest that high-grade AAH may be a precursor lesion of peripherally located NMBAC.
The impact of fluorodeoxyglucose F 18 positron-emission tomography on the surgical staging of non-small cell lung cancer.
Vesselle H, Pugsley JM, Vallieres E, Wood DE.
Divisions of Nuclear Medicine and Thoracic Surgery, University of Washington, Seattle, Wash. 98195, USA.
J Thorac Cardiovasc Surg 2002 Sep;124(3):511-9 Abstract quote
OBJECTIVES: Staging data on patients with non-small cell lung cancer were prospectively collected to evaluate the accuracy and anatomic information provided by fluorodeoxyglucose F 18 positron-emission tomography and its impact on improving the accuracy of surgical staging.
METHODS: A total of 142 patients with potentially resectable non-small cell lung cancer were imaged with positron-emission tomography (neck to pelvis). Positron-emission tomographic scans were read prospectively with thoracic computed tomographic comparison. Patients without distant metastases at positron-emission tomography underwent staging with bronchoscopy and mediastinoscopy, with or without mediastinotomy or thoracoscopy. Patients with metastases, pleural implants, or N2 or N3 disease did not undergo primary resection.
RESULTS: Positron-emission tomography revealed unsuspected distant metastases in 24 of 142 patients (16.9%) and unsuspected pleural implants in 6 others. Nodal stage was surgically established in 118 cases. Positron-emission tomography showed that 5 patients had nodal disease not accessible by mediastinoscopy. In 35 (24.6%) of these 142 cases, positron-emission tomography directed the evaluation away from routine bronchoscopy and mediastinoscopy staging that would have resulted in inappropriate treatment selection. Positron-emission tomography correctly differentiated resectable stages IA through IIIA (N1) from stages IIIA (N2) through IV in 88.7% of cases. In identifying N2 or N3 disease, positron-emission tomography had an accuracy of 90.7%, a sensitivity of 80.9%, a specificity of 96%, and positive and negative predictive values of 91.9% and 90.1%, respectively. Of the 8 cases in which positron-emission tomography missed N2 disease, 7 had the disease discovered by mediastinoscopy and 1 had it discovered at thoracotomy.
CONCLUSIONS: The diagnostic accuracy of positron-emission tomography-enhanced clinical staging is high. Positron-emission tomography has previously been used primarily to screen for lymph node spread and distant metastases, but it also provides localizing information that allows directed and more sensitive surgical staging and refinement of patient selection for curative resection. Positron-emission tomography and surgical staging play complementary roles in the journey toward more accurate overall staging.
Randomized Controlled Trial with Low-Dose Spiral CT for Lung Cancer Screening: Feasibility Study and Preliminary Results.
Garg K, Keith RL, Byers T, Kelly K, Kerzner AL, Lynch DA, Miller YE.
Department of Radiology (K.G., D.A.L.) and Division of Pulmonary Medicine and Critical Care (R.L.K., Y.E.M.), University of Colorado, Denver Veterans Affairs Medical Center.
Radiology 2002 Nov;225(2):506-10 Abstract quote
PURPOSE: To assess the feasibility of conducting a randomized controlled trial for lung cancer screening.
MATERIALS AND METHODS: Subjects are being recruited into a randomized controlled trial to undergo either low-dose spiral computed tomography (CT) or observation. Subjects are from a high-risk group with known chronic obstructive pulmonary disease and sputum atypia and a moderate-risk group randomly selected from the general population of a Veterans Affairs Medical Center. All subjects must be 50-80 years of age with 30 or more pack-years of cigarette smoking and must not have undergone chest CT during the previous 3 years. Baseline screening CT is performed with 50 mA, 120 kVp, 5-mm collimation, and a pitch of 2. CT scan interpretation and management of nodules is based on Society of Thoracic Radiology guidelines. The chi(2) test for categoric data was used for statistical analysis.
RESULTS: To date, 304 eligible subjects have been contacted, and 239 (79%) have agreed to participate in the trial. One hundred nineteen (88%) of the 136 subjects in the high-risk group and 120 (71%) of the 168 subjects in the moderate-risk group agreed to randomization (P <.001). To date, 190 subjects have been randomized. Of the first 92 subjects examined with CT, 22 (40%) of 55 in the high-risk group and eight (22%) of 37 in the moderate-risk group had one to six noncalcified nodules that required follow-up (P =.07). In all but three subjects, nodules were smaller than 5 mm. Two of the three larger nodules were malignancies.
CONCLUSION: Findings of this study indicate that a randomized controlled trial of CT to screen for lung cancer is feasible.
FISH (VYSIS) Multitarget FISH Analysis in the Diagnosis of Lung Cancer
Lukas Bubendorf, MD, Phaedra Müller, Ladina Joos, MD, Bruno Grilli, Sandrine Vogel, Michelle Herzog, Audrey Barascud, Georg Feichter, MD, Peter Dalquen, MD, and Michael Tamm, MD
Am J Clin Pathol 2005;123:516-523 Abstract quote
The aim of the present study was to explore the diagnostic usefulness of the multitarget fluorescence in situ hybridization (FISH) test, LAVysion (Vysis, Downers Grove, IL), for the detection of lung cancer cells in cytologic specimens. Specimens from bronchial washings, bronchial brushings, and transbronchial fine-needle aspirates (TBNAs) from 100 patients with suspected lung cancer and from a control group of 71 patients with nonneoplastic lung disorders were analyzed. FISH positivity was defined as more than 5 cells with gains of at least 2 chromosomes or gene loci. FISH significantly improved the sensitivity of bronchial brushings from 49% to 73%. The specificities of FISH and cytologic examination were 87% and 100%, respectively.
In contrast, FISH provided no additional diagnostic information in TBNAs and bronchial washings. There was no increased prevalence of genetic changes in contralateral bronchial washings from patients with lung cancer compared with the control group. The quantity of previous smoking had no effect on the prevalence of chromosomal changes.
TUMOR MARKERS GENERAL
Lung tumour markers in oncology practice: a study of TPA and CA125.
Buccheri G, Ferrigno D.
Divisione di Pneumologia, Ospedale 'S. Croce e Carle', Cuneo, I-12100, Italy.
Br J Cancer 2002 Nov 4;87(10):1112-8 Abstract quote
Several substances mark the course of lung cancer and may reliably help the clinician in decision-making. This is the first clinical study specifically designed to compare tissue polypeptide antigen and CA 125 tumour associated antigen.
Three hundred and eighty-four new lung cancer patients (309 males) were studied at their first clinical presentation and then strictly followed-up. Anthropometric, clinical and laboratory data - including tissue polypeptide antigen and CA 125 tumour associated antigen serum levels - were prospectively recorded. A total of 1000 tissue polypeptide antigen and CA 125 tumour associated antigen serum assays (384 pre-treatment and 616 posttreatment assays) were performed.
Both tissue polypeptide antigen and CA 125 tumour associated antigen correlated significantly with the T, N and M stage descriptors at diagnosis (Rho: 0.200, 0.203, 0.263 and 0.181, 0.240, 0.276, respectively), and then with the objective response to treatment (Rho: 0.388 and 0.207, respectively). A pleural neoplastic involvement was mainly associated to an increase of CA 125 tumour associated antigen (Rho: 0.397). Both tissue polypeptide antigen and CA 125 tumour associated antigen were strongly predictive of the patients' outcome, as assessed by the univariate analysis of survival (log-rank test: 37.24 and 29.01) and several Cox' proportional hazards regression models.
The two marker tests are similarly helpful and appear complementary, given the low inter-marker correlation and their independent prognostic capability.
Tumors growing within the bronchi may frequently cause obstructive symptoms
Emphysema or atelectasis Suppurative bronchitis or bronchiectasis Superior vena cava syndrome Pleuritis or pericarditis OTHER ENDOBRONCHIAL
Ann Diagn Pathol. 2005 Oct;9(5):284-8. Abstract quote
A case of papillary endobronchial squamous cell carcinoma incidentally discovered on routine imaging studies is described. The patient, a 75-year-old woman, underwent imaging studies as part of a standard evaluation for a fracture on the right side of the hip.
Chest radiographs were unremarkable other than for a nodular opacity overlying the left hemidiaphragm. Computed tomography of the chest, however, demonstrated an elongated, irregular mass in the right lower lobe that appeared to be associated with an adjacent segmental right lower lobe bronchus.
Endoscopy followed by surgical resection was undertaken, revealing a tan, soft mass measuring 1.5 x 1.3 x 0.8 cm that was confined to the bronchus and did not appear to extend into the surrounding lung parenchyma. Microscopically, the mass showed a papillary, superficial squamous cell carcinoma confined to the bronchial mucosa without invasion of adjacent structures. The pathological and imaging features of this unusual variant of bronchogenic carcinoma are reviewed as well as the radiological differential diagnosis of endobronchial lesions.
To our knowledge, this is the first report that describes the computed tomographic features of this rare lesion.
SYNCHRONOUS AND METACHRONOUS TUMORS
Am J Surg Pathol. 2005 Jul;29(7):897-902. Abstract quote
Distinction of multiple primary lung carcinomas from intrapulmonary metastases using empiric clinical and histopathologic criteria can be difficult. Recent advances have provided several molecular markers that can be used for clonal analysis of separate tumor nodules and enhance tumor staging and subsequent treatment and prognosis.
To address this issue, we performed a microdissection-based allelotyping of 20 cases of histologically similar, pathologic stage T4 adenocarcinomas (ADCs). Loss of heterozygosity (LOH) analysis included a panel of 15 polymorphic microsatellite markers located on 1p, 3p, 5q, 9p, 9q, 10q, 17p, and 22q. The tumor size, visceral pleural and angiolymphatic invasion, lymph node status, outcome, and survival were assessed.
Allelotypes of 60 cases of solitary primary non-small cell lung carcinomas (NSCLC) (stages I-II) were used to define the percentage of discordant LOH patterns within solitary primary lung carcinoma that would discriminate between survivors and nonsurvivors. These criteria were used in the analysis of pathologic stage T4 ADC. Two groups of stage T4 cases were created: molecularly homogenous (< or = 40% discordances) (14 cases, 70%), and molecularly heterogenous (>40% discordances) (6 cases, 30%). Molecularly homogenous tumors were more frequently associated with visceral pleural invasion (92% vs. 8%) (P = 0.018). Allelotype did not correlate with age, gender, tumor size, tumor differentiation, lymph node status, angiolymphatic invasion, survival, or outcome.
Our study showed that discordant and concordant genotypic profiles exist in morphologically similar synchronous ADC of the lung.
Molecular analysis of synchronous and metachronous tumors of the lung: Impact on management and prognosis
Jiaoti Huang, MD, PhD
Carmen Behrens, MD
Ignacio Wistuba, MD
Adi F. Gazdar, MD
Jaishree Jagirdar, MD
Ann Diagn Pathol 2001;5:321-329 Abstract quote
Patients with pulmonary neoplasms have an increased risk for developing a second tumor of the lung, either at the same time or different times. It is important to determine if the second tumor represents an independent primary tumor (ie, a synchronous or a metachronous tumor, depending on whether it is present at the same time or a later time) or recurrence/metastasis, because it will significantly change the management and prognosis. Because the two tumors from the same patient are often morphologically similar, histologic examination alone may not be sufficient to distinguish between the two possibilities.
We have attempted to approach this problem by microdissecting malignant cells and comparing patterns of loss of heterozygosity of multiple genes and chromosomal loci between paired tumors.
We found that primary tumors of the lung and their metastasis share nearly identical patterns of loss of heterozygosity. In contrast, most synchronous and metachronous tumors as defined by the current arbitrary criteria appeared to be genetically different; therefore, they likely represented independent primary tumors. Rare synchronous tumors had similar genetic profiles, raising the possibility of recurrence/metastasis.
Our data suggest that molecular analysis can help fingerprint tumors and has the potential to significantly impact management and prognosis of patients.
PROGNOSIS CHARACTERIZATION GENERAL
Prognostic value of immunohistochemical expressions of p53, HER-2/neu, and bcl-2 in stage I non–small-cell lung cancer
Helen Han, MD, MSc
Rodney J. Landreneau, MD
Tibetha S. Santucci, RN
Ming Y. Tung, MS
Robin S. Macherey, RN
Stanley E. Shackney, MD
Charles D. Sturgis, MD
Stephen S. Raab, MD
Jan F. Silverman, MD
Hum Pathol 2002;33:105-110. Abstract quote
The outcomes of patients with stage I non–small-cell lung cancer (NSCLC) vary greatly, with a 5-year survival rate of approximately 60%.
This study evaluated a number of molecular markers that may aid in predicting prognosis in stage I NSCLC after surgical resection. Immunohistochemical (IHC) staining of p53, HER-2/neu, bcl-2 proteins was performed on paraffin-embedded sections from 85 stage I NSCLC patients who underwent surgery and were followed up for 32 to 44 (median, 39.0; mean, 37.1) months postoperatively. Differences in survival rates were evaluated by log rank test. The prevalence of p53, HER-2/neu, and bcl-2 expression in stage I NSCLC is 59%, 29%, and 46%, respectively. HER-2/neu expression is seen more frequently in adenocarcinomas, and bcl-2 is seen more frequently in squamous carcinomas. p53 and HER-2/neu expression in stage I NSCLC is associated with significantly short survival. Patients whose tumors were both p53 and HER-2/neu positive had the worst outcome, with a survival rate of only 20%, compared with 80% in those whose tumors were both p53 and HER-2/neu negative (P = .0003). The survival rates were 54% in patients who were p53 positive but HER-2/neu negative and 50% in those who were in p53 negative, HER-2/neu positive.
The differences among these 4 groups were statistically significant (P = .001). Bcl-2 does not seem to be a prognostic factor for survival. Multivariate analysis showed that overexpression of p53 and HER-2/neu, presence of angiolymphatic invasion, and tumor size > 3.0 cm were independent factors predicting poor survival. p53 and HER-2/neu by IHC staining appear to be valuable prognostic markers in stage I NSCLC patients after surgery. The worst outcome was seen in patients who expressed both p53 and HER-2/neu, suggesting that these patients might benefit from additional adjuvant therapy.
- Prognostic significance of HER2/neu, p53, and vascular endothelial growth factor expression in early stage conventional adenocarcinoma and bronchioloalveolar carcinoma of the lung.
Saad RS, Liu Y, Han H, Landreneau RJ, Silverman JF.
1Department of Pathology, Allegheny General Hospital, Pittsburgh, PA, USA.
Mod Pathol. 2004 Oct;17(10):1235-42. Abstract quote
In this study, we investigated the prognostic value of HER2/neu, p53, and vascular endothelial growth factor in early stage conventional adenocarcinoma and bronchioloalveolar carcinoma of the lung.
We studied 100 patients and consisted of 50 cases with conventional adenocarcinoma and 50 cases with bronchioloalveolar carcinoma (32 nonmucinous and 18 mucinous subtypes). Representative sections were immunostained for HER2/neu, p53, and vascular endothelial growth factor. Positivity was scored quantitatively by three observers and correlated with multiple prognostic parameters including survival. In the conventional adenocarcinoma, HER2/neu, p53, and vascular endothelial growth factor were expressed in 19/50 (38%), 32/50 (64%), 33/50 (66%), respectively. In this group, p53 showed a significant correlation with recurrence while vascular endothelial growth factor correlated with angiolymphatic invasion (P<0.05). HER2/neu, p53, and vascular endothelial growth factor expression was associated with significantly shorter survival (log rank, P<0.05). Patient whose tumors coexpressed both p53 and HER2/neu had the worst outcome.
In the bronchioloalveolar carcinoma, HER2/neu, p53, and vascular endothelial growth factor were expressed in 9/50 (18%), 3/50 (6%) and 12/50 (24%), respectively which was significantly less than in conventional adenocarcinoma (P<0.05). HER2/neu positivity showed a significant correlation with shorter survival (log rank, P<0.05) in nonmucinous type.
In conclusion, vascular endothelial growth factor was associated with angiolymphatic invasion and poor prognosis in conventional adenocarcinoma. Also, in conventional adenocarcinoma, p53, and HER2/neu expression appeared to be poor prognostic markers, while in bronchioloalveolar carcinoma, only HER2/neu was associated with a poorer prognosis. This immunostaining pattern suggests that conventional adenocarcinoma has different molecular abnormalities than bronchioloalveolar carcinoma.
Prognostic factors in T1 NO MO adenocarcinomas and bronchioloalveolar carcinomas of the lung.
Goldstein NS, Mani A, Chmielewski G, Welsh R, Pursel S.
Dept of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Am J Clin Pathol 1999 Sep;112(3):391-402 Abstract quote
There are few prognostic factors for patients with T1 N0 M0 pulmonary conventional and bronchioloalveolar adenocarcinomas (BACs), despite a 25% to 35% failure rate.
To identify prognostic factors related to disease-free survival, we retrospectively studied the histologic features of 218 cases of T1 NO MO adenocarcinomas.
The mean overall follow-up was 5.9 years, and the 5-year disease-free survival was 72%; 148 patients (67.9%) were disease-free, and in 57 (26.1%), nonpulmonary metastases developed.
Features significantly associated with decreased 5-year disease-free survival were larger tumor size, increasing central fibrosis, most common and highest nuclear grade, lymphatic vascular space invasion, and more than 50% tumor necrosis. Patients with lymphatic vascular space invasion had a 35% 5-year metastases-free survival. A tumor size of 2 to 3 cm, lymphatic vascular space invasion, highest nuclear grade 3, and increased central fibrosis were associated with metastases. Lymphatic vascular space invasion had the strongest odds ratio of 5.4. These histologic features can stratify patients with T1 N0 M0 neoplasms who have an increased risk of metastases.
Future studies are needed to address the usefulness of adjuvant therapy for patients with neoplasms that display these negative factors.
Immunohistochemically detected micrometastases in peribronchial and mediastinal lymph nodes from patients with T1, N0, M0 pulmonary adenocarcinomas.
Goldstein NS, Mani A, Chmielewski G, Welsh R, Pursel S.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Am J Surg Pathol 2000 Feb;24(2):274-9 Abstract quote
The T1, N0, M0 subset of stage I lung adenocarcinoma is a tumor that has a 5-year disease-free survival rate of 66% to 85%. To date, there has not been a rigorous immunohistochemically detected lymph node micrometastasis study composed of patients with identical stage and type of tumors, and in which standard histologic features were incorporated into multivariate analyses.
We immunohistochemically examined the peribronchial and mediastinal lymph nodes from 80 consecutively accrued patients with T1, N0, M0 adenocarcinomas and bronchioloalveolar carcinomas unselected for distant metastasis, and an additional 39 patients with similar stage and type neoplasms who were selected for their development of metastases to evaluate the prevalence of micrometastases, their association with distant metastases, and their relationship with other pathologic prognostic features.
All slides were stained with keratin AE1/3. Micrometastases were confirmed with Ber-Ep4. Three immunohistochemically detected lymph node micrometastases were identified in three of 80 consecutively accrued patients (4%). These three positive stains constituted 0.5% of the 573 stains required to immunohistochemically screen all of the lymph node blocks from these patients. Among the 39 patients who were selected because they developed distant metastases, three immunohistochemically detected lymph node micrometastases from three patients were identified, which constituted 8% of patients in this group and 1% of the 280 stains required to screen all of these patients' lymph nodes. Small vessel invasion, maximum tumor dimension, and immunohistochemically detected lymph node micrometastases were independently associated with metastases on multivariate analysis. Among patients who developed metastases, there was no significant difference in the disease-free survival rate between those with and those without immunohistochemically detected lymph node micrometastases.
Given the low sensitivity in terms of the number of immunohistochemical stains performed, and the prognostic significance of standard histologic features, the use of immunohistochemical screening lymph nodes from all patients with T1, N0, M0 adenocarcinomas is questionable.
Bronchioloalveolar carcinoma of the lung: recurrences and survival in patients with stage I disease.
Breathnach OS, Kwiatkowski DJ, Finkelstein DM, Godleski J, Sugarbaker DJ, Johnson BE,
Mentzer S. Lowe Center for Thoracic Oncology, Division of Experimental Medicine, Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
J Thorac Cardiovasc Surg 2001 Jan;121(1):42-7 Abstract quote
OBJECTIVES: The aim of our study was to retrospectively compare the patient characteristics, the frequency and pattern of recurrent disease, and survival in patients with stage I bronchioloalveolar carcinoma and adenocarcinoma of the lung.
METHODS: Patients with stage I bronchioloalveolar carcinoma or adenocarcinoma other than bronchioloalveolar carcinoma resected between 1984 and 1992 with adequate clinical follow-up were studied. The clinical characteristics of the patients, extent of initial surgical resection, sites of recurrent disease, and overall survival were examined and compared between the 2 groups. The median follow-up for patients with bronchioloalveolar carcinoma and adenocarcinoma was 6.2 years and 5.9 years, respectively.
RESULTS: A total of 138 patients were identified. Thirty-three patients had bronchioloalveolar carcinoma and 105 patients had adenocarcinoma. Eleven (33%) of the patients with bronchioloalveolar carcinoma had never smoked cigarettes versus 9 (9%) of the patients with adenocarcinoma (P =.0036). There were no significant differences between patients with bronchioloalveolar carcinoma and adenocarcinoma in sex distribution and overall recurrence rate. Of the 12 patients with recurrent bronchioloalveolar carcinoma, 1 patient (8%) had extrathoracic disease develop at the site of first recurrence compared with 49% of patients with recurrent adenocarcinoma (P <.001). The 5-year survival in patients with bronchioloalveolar carcinoma and in those with adenocarcinoma was 83% and 63%, respectively (P =.04).
CONCLUSIONS: Stage I bronchioloalveolar carcinoma is more likely to occur in nonsmokers. Survival is longer in patients with bronchioloalveolar carcinoma. Further research is warranted to define the etiology, clinical course, and molecular abnormalities in patients with bronchioloalveolar carcinoma to generate more effective therapeutic approaches.
CD117 CD117 immunoreactivity in stage I adenocarcinoma and squamous cell carcinoma of the lung: relevance to prognosis in a subset of adenocarcinoma patients.
Pelosi G, Barisella M, Pasini F, Leon ME, Veronesi G, Spaggiari L, Fraggetta F, Iannucci A, Masullo M, Sonzogni A, Maffini F, Viale G.
1Department of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy.
Mod Pathol. 2004 Jun;17(6):711-21. Abstract quote
CD117, a trans-membrane tyrosine kinase receptor, has been immunolocalized in a large variety of human neoplasms. Little, however, is known about the prevalence and clinical implications of CD117 in stage I adenocarcinoma and squamous cell carcinoma of the lung.
We evaluated 201 consecutive stage I adenocarcinoma and squamous cell carcinoma of the lung for CD117 immunoreactivity (dichotomized as negative or positive if containing less than 5% or >/=5% immunoreactive neoplastic cells, respectively), also taking into account the pattern (either membranous or cytoplasmic), and the intensity of immunostaining in comparison with intratumoral mast cells. The immunostaining results were then correlated with tumor biopathological characteristics and patients' survival. Membranous CD117 immunoreactivity was documented in 19 (22%) of 88 adenocarcinomas and 15 (13%) of 113 squamous cell carcinomas, whereas cytoplasmic labelling was seen in 28 (32%) adenocarcinomas and eight (7%) squamous cell carcinomas. In both tumor types, membranous or cytoplasmic CD117 immunoreactivity was associated with higher proliferative fraction and with features of more aggressive tumor behavior, including higher stage, size and grade, occurrence of clinical symptoms, high microvessel density and neuroendocrine differentiation. Furthermore, immunoreactive tumors exhibited increased levels of bcl-2, cyclin-E, Her-2, p27(Kip1) and fascin, the latter being a marker of tumor cell metastatization in lung cancer.
Membranous but not cytoplasmic labelling emerged as an independent risk factor for death and reduced time to progression in adenocarcinoma but not in squamous cell carcinoma patients, when singly adjusted for confounding factors. CD117 immunoreactivity identifies a peculiar subset of stage I adenocarcinoma and squamous cell carcinoma of the lung with highly proliferative tumors and may have prognostic relevance in adenocarcinoma patients.
Targeting the CD117 pathway could be a novel therapeutic strategy in a subset of pulmonary carcinomas.
CYCLOOXYGENASE 2 EXPRESSION
Arch Pathol Lab Med. 2005 Sep;129(9):1113-7. Abstract quote
CONTEXT: Previous studies report that increased expression of cyclooxygenase 2 (COX-2) correlates with poor clinical outcome in several malignancies, including non- small cell lung carcinoma (NSCLC). Cyclooxygenase 2 inhibitors have been reported to effectively inhibit carcinogenesis in colon cancer experimental models.
OBJECTIVE: We examined COX-2 expression in 259 cases of NSCLC to evaluate its prognostic significance.
DESIGN: Sections of NSCLC from patients with a median 5-year follow-up were immunostained with COX-2 monoclonal antibody (1:150) using the Dako mouse EnVision;pl system. Extent of COX-2 expression in neoplastic cells was recorded as follows: 0, 0% to 10% of cells positive; 1, 11% to 33% positive; 2, 34% to 66% positive; and 3, more than 66% positive. Intensity was scored as either increased (+) or not increased (-), compared to internal control smooth muscle and endothelial cells. Kaplan-Meier analysis was used to assess the relationship between survival and COX-2 expression, using the log-rank test for statistical significance.
RESULTS: No relationship was found between the extent and/or the intensity of COX-2 expression and patient survival when the entire cohort was considered. However, when separately analyzed according to disease stage and intensity of COX-2 expression, a significant relationship (P = .03) between increased COX-2 expression and shortened patient survival was found only in patients with stage I and II NSCLC.
CONCLUSIONS: To our knowledge, this is the largest series of NSCLCs in which COX-2 has been investigated as a prognostic marker. The findings in this large series support previous studies of smaller cohorts that reported that increased COX-2 expression predicts poor outcome in patients with early-stage NSCLC.
- EGFR expression as an ancillary tool for diagnosing lung cancer in cytology specimens.
1Department of Hematopathology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
- Mod Pathol. 2007 Sep;20(9):905-13. Epub 2007 Jul 20. Abstract quote
Lung cancer evolves in a multistep process, and its early detection portends a better prognosis. Bronchial washings/brushings and fine-needle aspirations are often used as early screening and cytological diagnosis of lung cancer. In some cases, it is difficult to differentiate morphologically malignant from reactive cells. Epidermal growth factor receptor (EGFR) is a transmembrane receptor overexpressed in high percentage lung cancers, and contributes to tumor growth. Assessing EGFR expression levels by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) may provide critical information of tumor marker abnormalities, assist in the cytological diagnosis, and stratify patients for EGFR inhibitor therapy.
Fifty patients with bronchial washings/brushings or fine-needle aspiration specimens, and corresponding histologically confirmed lung biopsies, were studied for EGFR expression with FISH and IHC. Copy numbers of the EGFR gene locus were analyzed with those of chromosome 7 by FISH. EGFR and FISH results were compared to our FISH data with combined EGFR, c-myc, 5p15.2, and chromosome 6 probes in selected cases. Cell blocks, if available, and tissue biopsy sections were used for EGFR IHC. The intensity of IHC was scored, and quantified. Only balanced aneuploidy of EGFR was identified by FISH. Gene amplification was not detected. The chromosomal abnormalities of EGFR were often accompanied by other chromosomal aneuploidies demonstrated in c-myc (8q24), 5p15.2 or 6p, indicating a general genomic instability. About half of the specimens with confirmed malignancy showed EGFR balanced aneuploidy by FISH, and gene copy number was not coupled with protein expression in many cases.
The benign or reactive cytology specimens confirmed by biopsies had high specificity by FISH (96%) and IHC (88%). FISH and IHC analysis of EGFR, possibly along with other tumor markers, may be a useful ancillary tool to classify difficult cytology cases and inform clinicians arranging targeted chemotherapy.
- Epidermal Growth Factor Receptor Mutation in Lung Cancer are Linked to Bronchioloalveolar Differentiation.
Departments of *Biochemistry double daggerPathology section signThoracic Surgery paragraph signOncology, AP-HP, Hopital Europeen Georges Pompidou, Universite Paris V, 75015 Paris daggerINSERM UMR-S775, 75006 Paris, France.
- Am J Surg Pathol. 2006 Oct;30(10):1309-1315 Abstract quote
In lung cancer, an association was made between drastic clinical response to epidermal growth factor receptor (EGFR) inhibitors and the presence of somatic mutations within the tyrosine kinase domain of the EGFR. In some cases, patients with partial response or disease stabilization do not always have EGFR-mutated tumors.
To go further in the characterization of the EGF pathway, we screened EGFR, ERBB2, ERBB3, KRAS, BRAF, and PIK3CA for mutations in 2 groups of White patients with nonsmall cell lung cancer (45 cancers from women and 46 cancers from men). Associations between TP53 mutations, clinicopathologic parameters, and EGF pathway molecular alterations were analyzed. All mutations were exclusive and essentially found in EGFR and KRAS. We demonstrated that EGFR mutations were linked to female sex, absence of smoking, late age at diagnosis, and adenocarcinoma (ADC) with bronchioloalveolar (BAC) features. Moreover, in invasive ADC with BAC component, microdissection assays showed that mutations were retrieved in both tumor subtypes suggesting that EGFR mutations appear early in lung carcinogenesis. On the contrary, KRAS mutations correlated with smoking, younger age at diagnosis, and ADC subtype regardless of BAC differentiation.
These results suggest the existence of distinct carcinogenesis pathways both leading to disruption of EGF regulation and targeted either by tobacco carcinogens or by unidentified toxic. The identification of BAC features in ADC helps clustering patients that are more likely to fit the EGFR-mutated group.
Altered E-cadherin and epidermal growth factor receptor expressions are associated with patient survival in lung cancer: a study utilizing high-density tissue microarray and immunohistochemistry.
Deeb G, Wang J, Ramnath N, Slocum HK, Wiseman S, Beck A, Tan D.
Department of Pathology, Roswell Park Cancer Institute, State University of New York, Buffalo, NY 14263, USA.
Mod Pathol. 2004 Apr;17(4):430-9. Abstract quote
E-cadherin (E-cad) and epidermal growth factor receptor (EGFR) are important cell adhesion and signaling pathway mediators.
This study aimed to assess their expression in lung adenocarcinoma (AdC) and squamous cell carcinoma (SCC) and their association with clinicopathologic variables. In all, 130 resectable lung cancers (stages I-IIIA) were studied using a high-density tissue microarray. Two to three cores from each case were arrayed into three blocks using a Beecher system.
- Immunohistochemistry was performed using an avidin-biotin complex method and monoclonal antibodies against E-cad and EGFR. Unequivocal membrane staining in >10% of tumor cells was considered as a positive expression of E-cad and EGFR. Markers expression and coexpression were analyzed against clinicopathologic variables (age, gender, smoking status, performance status, weight loss, histology, grade, stage, and lymph node involvement) and patient survival. There were 118, 126, and 115 cases that were fully assessable for E-cad, EGFR, and both markers, respectively. For E-cad, 65 cases (55%) were positive (+), 53 (45%) were negative (-); 23 cases of the negative group had only cytoplasmic staining. For EGRF, 43 cases (34%) were (+), and 83 (66%) were (-). There was no significant association between E-cad or EGFR, and any of the clinicopathologic variables except for an association between EGFR(+) and SCC histologic type. Both negative and cytoplasmic staining of E-cad correlated with shorter patient survival with P=0.008 and 0.002, respectively. EGFR expression did not correlate with patient survival; however, patients with E-cad(-)/EGFR(+) phenotype had poorer survival than those with E-cad(+)/EGFR(-) (P=0.026).
Our study suggests that lung AdC and SCC may be stratified based on expression of E-cad and EGFR with the E-cad(-)/EGFR(+) expression having a worse disease outcome. Moreover, the cytoplasmic expression of E-cad may represent an altered localization of this protein in association with tumorigenicity.
Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer.
Toledo G, Sola JJ, Lozano MD, Soria E, Pardo J.
Department of Pathology, University of Navarra, Pamplona, Spain.
Mod Pathol. 2004 Apr;17(4):440-8. Abstract quote
The fragile histidine triad (FHIT) gene, located at chromosome 3p14.2, is deleted in many solid tumors, including lung cancer. Its protein product is presumed to have tumor suppressor function.
We investigated the incidence of loss of heterozygosity and loss of FHIT expression in a series of non-small-cell lung carcinomas and its correlation to apoptosis, proliferation index and prognosis. FHIT expression was determined by immunohistochemistry in formalin-fixed paraffin-embedded tissues from 54 squamous cell carcinomas (SCC) and 44 adenocarcinomas (AC) of the lung. DNA from frozen tumor and corresponding normal tissues were analyzed for allelic losses at two loci located internal (D3S1300, D3S1234) and three loci in flanking regions centromeric and telomeric (D3S1210, D3S1312, D3S1313) to the FHIT gene.
Apoptosis was detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL). Proliferation index was determined with ki-67 and flow cytometric analysis.
We correlated the results with tumor histology, prognosis and some immunohistochemical markers (p53, bcl-2, bax, c-myc, p21(waf1), cyclin-D1). FHIT expression was related to tumor histology: 52 of 54 (96.3%) SCC and 20 of 44 (45.5%) AC were negative for FHIT (P<0.0001). We found LOH at 3p14.2 in 67.8% of the 98 cases: 72.3% of SCC and 61.4% of AC. Loss of FHIT expression was associated with a higher proliferation index (ki-67, P=0.007; flow cytometry, P<0.004) and lower apoptotic index (P=0.018). LOH at FHIT gene were associated to a high proliferation (flow cytometry, P<0.001) and lower apoptotic level (P=0.043). The log-rank test demonstrated a significant inverse correlation (P=0.039) between loss of FHIT expression and patient survival. FHIT plays an important role in the development of non-small-cell lung cancer, particularly in SCC.
Loss of FHIT protein is correlated with a high proliferation and low apoptotic index in tumor cells, and is an independent prognostic indicator for the clinical outcome in patients with these tumors.
HISTOLOGICAL PATTERNS COX-2, MMP-9, and Noguchi Classification Provide Additional Prognostic Information About Adenocarcinoma of the Lung A Study of 117 Patients From Brazil
Nise H. Yamaguchi, MD, PhD, Ana J. de F.C. Lichtenfels, etal.
Am J Clin Pathol 2004;121:78-86 Abstract quote
We report immunohistochemical staining results for cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 in primary tumors of 117 patients with resected adenocarcinoma of the lung (median follow-up, 20 months).
For COX-2, we graded the degree of tumor staining according to the sum of staining intensity and the proportion of cells staining. For MMP-9, we used morphometry to quantify cytoplasmic staining. We used the Cox proportional hazards model to analyze overall survival. With only 29 patients censored at last follow-up, after controlling for the effect of pathologic stage, staining for COX-2 and MMP-9 and subtype of tumor were related significantly to survival ( P < 6 × 10 –5 ).
The effects of COX-2 and MMP-9 were opposite. Whereas any staining for COX-2 decreased the hazard and increased survival time, increased staining for MMP-9 increased the hazard and decreased survival time. The results also suggested that staining for COX-2 decreases with dedifferentiation.
Our results suggest that staining for the combination of COX-2 and MMP-9 and categorizing tumors into papillary and nonpapillary types may provide important prognostic information for patients with resected adenocarcinoma of the lung; it is possible that these 3 variables could aid decisions about postoperative adjuvant treatment.
Prognostic significance of percentage of bronchioloalveolar pattern in adenocarcinomas of the lung
Claudia Y. Castro, MD
Dona M. Coffey, MD
L. Jeffrey Medeiros, MD
Philip T. Cagle, MD
Ann Diagn Pathol 2001;5:274-284 Abstract quote
Bronchioloalveolar (BA) carcinoma of the lung is considered to have a better prognosis than that of common adenocarcinomas of the lung. However, a minor component of the BA pattern is common in many lung adenocarcinomas and the criteria for designating an adenocarcinoma as BA are not well defined.
We assessed the clinicopathologic features of 238 cases of lung adenocarcinoma with a partial or predominant BA pattern. Tumors were classified as BA if more than 75% of the tumor had a BA growth pattern. In other words, the tumor grew along pre-existing lung structures without invasion or destruction of parenchyma. Tumors with 50% to 75% BA pattern were considered mixed and tumors with less than 50% BA pattern were designated as solid/acinar (S/A). Fixed, paraffin-embedded tissue sections of each neoplasm were also assessed using immunohistochemical methods with a panel of antibodies specific for p53, retinoblastoma protein, p16, cyclin D1, and cyclin E, and the results were correlated with clinical and pathologic parameters. Our results show that the 5-year survival rate of patients with BA and mixed tumors, 63% and 60%, respectively, was significantly better than that of patients with S/A tumors (P = .026). Patients with BA tumors were more frequently women (55.9%) compared with patients with mixed (48.3%) and S/A (43.8%) tumors. Bronchioloalveolar and mixed tumors were similarly associated with tobacco use, 88.2% and 85%, respectively; slightly less than S/A tumors (93.8%). Clinical and pathologic parameters did not correlate with immunohistochemical results.
In conclusion, patients with BA or mixed tumors have similar 5-year survival, better than that of patients with S/A tumors, suggesting that adenocarcinomas can be designated as BA when at least 50% of the tumor has a BA pattern.
- PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration.
Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, Kelsey KT.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Hum Pathol. 2005 Jul;36(7):768-76. Abstract quote
The tumor suppressor PTEN encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase/AKT cell survival pathway. Mutations of this gene are common in brain, prostate, endometrial, and gastric cancers but occur rarely in non-small-cell lung cancer (NSCLC), although the PTEN protein is often lost in lung tumors.
We have studied hypermethylation of the PTEN promoter, loss of heterozygosity (LOH) at microsatellites in chromosome 10q23 (surrounding and intragenic to the PTEN locus), and hypermethylation of PTEN's highly homologous pseudogene, PTENP1, and their association with PTEN protein loss in a surgical case series study of primary NSCLC. PTEN protein expression was reduced or lost in 74% (86/117) of tumors, with loss occurring more often in well to moderately differentiated tumors. In squamous cell carcinomas, PTEN loss occurred significantly more often in early-stage (stage I or II) disease. PTEN protein loss also occurred more frequently in tumors with low to no aberrant TP53 staining. Methylation of PTEN occurred in 26% (39/151) of tumors, and LOH at 10q23 was rare, occurring in only 19% (17/90) of informative tumors. Neither methylation nor LOH was a significant predictor of PTEN protein expression, although LOH occurred exclusively in early-stage disease.
In NSCLC, loss of PTEN protein expression occurs frequently, although the mechanism responsible for loss is not clearly attributable to deletion or epigenetic silencing. PTEN loss may also be a favorable prognostic marker, although further studies are needed to confirm this finding.
Widespread molecular alterations present in stage I non-small cell lung carcinoma fail to predict tumor recurrence.
Baksh FK, Dacic S, Finkelstein SD, Swalsky PA, Raja S, Sasatomi E, Luketich JD, Fernando HC, Yousem SA.
Departments of Pathology (FKB, SD, SDF, PAS, ES, SAY) and Surgery (SR, JDL, HCF), University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania.
Mod Pathol 2003 Jan;16(1):28-34 Abstract quote
Stage I non-small cell carcinoma (NSCLC) of the lung is typically treated with surgery alone, but with a 30 to 40% recurrence rate. Prognostic factors to stratify these patients into high- and low-risk groups would be of significant clinical value, but published data are conflicting.
We studied 39 Stage I NSCLC treated with resection alone, followed for a minimum of 5 years, and divided into recurrent (RC) and non-recurrent (NRC) groups (n = 12 and 27, respectively). Allelic imbalance (loss of heterozygosity, LOH) involving genomic regions containing L-myc (1p32), hOGG1 (3p26), APC/MCC (5q21), c-fms (5q33.3), p53 (17p13), and DCC (18q21), and point mutational change in K-ras-2 (12p12) were studied by PCR-based microsatellite analysis and DNA sequencing. Mutations in k-ras-2 were seen in 25% and 19% of RC and NRC tumors, respectively, most frequently in adenocarcinomas. LOH in the RC and NRC respectively were 50% and 37% for L-myc, 60% and 33% for hOGG1, 60% and 50% for APC, 38% and 35% for c-fms, 78% and 75% for p53, and 17% and 45% for DCC.
No statistical significance was seen comparing any of the allelic alterations with recurrence. LOH for hOGG1 and L-myc were more commonly seen in squamous cell carcinomas. Stage I NSCLC are genetically heterogeneous with respect to mutation acquisition.
The approach of investigating a panel of genes for alterations can be applied to any given tumor type, and provides information on patterns of mutations/LOH that can help us better understand the molecular biology of tumorigenesis.
THYROID TRANSCRIPTION FACTOR
Prognostic significance of thyroid transcription factor-1 expression in both early-stage conventional adenocarcinoma and bronchioloalveolar carcinoma of the lung.
Saad RS, Liu YL, Han H, Landreneau RJ, Silverman JF.
Hum Pathol. 2004 Jan;35(1):3-7 Abstract quote.
Thyroid transcription factor 1 (TTF-1) is a diagnostic immunohistochemical marker for primary pulmonary neoplasms, but its utility as a prognostic marker is not well established. Surgical specimens from 100 cases of pulmonary adenocarcinoma were retrieved from the hospital computer system, including 50 cases of conventional adenocarcinoma (CA) and 50 cases of bronchioloalveolar adenocarcinoma (BAC) (32 nonmucinous type and 18 mucinous type). Representative sections were immunostained for TTF-1.
Positive immunohistochemical study was correlated with other prognostic parameters. In the CA group, strong or moderate TTF-1 expression was seen in 30 of 50 (60%) patients and was associated with significantly better survival compared with those patients having weak staining (7 cases; 14%) or negative staining (13 cases; 26%) (P <0.01; log-rank test). Spearman and Pearson's correlation showed no significant correlation between TTF-1 expression and tumor grade, size, recurrence, or vascular invasion; therefore, TTF-1 was considered an independent predictor of survival. In the BAC group, TTF-1 was strongly expressed in 34 of 50 cases (68%) and was negative in 16 of 50 cases (32%), including 14 mucinous BACs. Although TTF-1 immunoreactivity was not statistically associated with good survival in BAC patients, those patients with strong immunohistochemical expression showed a trend toward longer survival.
Our results indicate that TTF-1 positivity is an independent predictor of better survival, especially in patients with CA. Mucinous and nonmucinous BACs exhibit disparate staining patterns with TTF-1, with nonmucinous BAC demonstrating greater positivity. Although nonmucinous BAC patients showing strong positive staining had longer survival, the difference was not statistically significant, which is probably related to the overall good survival of patients with early-stage BAC.
Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: A high-throughput tissue microarray and immunohistochemistry study.
Tan D, Li Q, Deeb G, Ramnath N, Slocum HK, Brooks J, Cheney R, Wiseman S, Anderson T, Loewen G.
Hum Pathol. 2003 Jun;34(6):597-604 Abstract quote
Thyroid transcription factor 1 (TTF-1), a homeodomain-containing transcription factor, plays a pivotal role in lung development, cell growth, and differentiation processes. The current literature reports considerable variation in frequency of TTF-1 protein expression in human non-small cell lung cancer (NSCLC). TTF-1 expression has not been extensively investigated as a prognostic marker in NSCLC.
To assess the prevalence of TTF-1 expression, and to evaluate its potential role in disease prognosis, 140 stage I-IIIA NSCLCs with long-term follow-up were studied under uniform conditions using high-density tissue microarray (TMA) combined with immunohistochemistry. Patient survival and association of TTF-1 expression with clinicopathologic parameters were analyzed.
One hundred twenty-six tumor samples were fully assessable after tissue processing. Sixty-four samples (50.8%) expressed TTF-1 and 62 (49.2%) displayed no expression. TTF-1 expression was significantly (P < 0.001) correlated with histological subtype: 51 adenocarcinomas (AdCs) (51 of 75; 68%) versus 9 squamous cell carcinomas (SCCs) (9 of 43; 21%) were TTF-1 positive. TTF-1 expression, performance status, nodal status, and tumor stage were significantly related to patient survival. In multivariate analysis, positive TTF-1 expression tended to favor a better patient outcome (P = 0.05). Overall, NSCLC patients with positive TTF-1 expression had a median survival of greater than 57.3 months, whereas those with negative expression had a median survival of 39.4 +/- 5.2 months (log-rank test, P = 0.0067).
In this study we found that TTF-1 is predominately expressed in adenocarcinoma. The loss of TTF-1 expression was associated with aggressive behavior of NSCLCs. The results from this study strongly indicate that further investigation is warranted to better define the role of TTF-1 as a prognostic factor in this malignancy.
Immunoreactivity for Thyroid Transcription Factor-1 in Stage I Non–Small Cell Carcinomas of the Lung
Am J Surg Pathol 2001;25:363-372 Abstract quote
We evaluated retrospectively the prevalence and clinical significance of TTF-1 immunoreactivity in 222 patients with stage I non–small cell lung carcinoma (NSCLC) with a follow-up time of at least 5 years, and we investigated its relationship with other markers of tumor growth, namely cell proliferation and angiogenesis.
TTF-1 immunoreactivity was documented by using the commercially available monoclonal antibody 8G7G3/1 in 72% of 97 adenocarcinomas, 5% of 119 squamous cell carcinomas, and in the glandular component of two adenosquamous carcinomas. Four large cell carcinomas were completely unreactive.
In adenocarcinomas, but not squamous cell carcinomas, TTF-1 immunoreactivity correlated significantly with microvessel density (p = 0.04) and inversely with the tumor proliferation fraction assessed by Ki-67 immunostaining (p = 0.03). Also, TTF-1-immunoreactive adenocarcinomas showed a trend for a size less than 3 cm (p = 0.08). TTF-1 expression was not related to specific growth patterns, tumor grade, or tumor cell typing. TTF-1 immunoreactivity did not significantly affect patient survival, although patients with more than 75% immunoreactive neoplastic cells showed a trend for longer overall and disease-free survival.
Our findings suggest that TTF-1 could be involved in the development of small pulmonary adenocarcinomas, but it has not prognostic implications in patients with stage I NSCLC.
5 Year Survival
Overall 5 year survival rate is 9%.
Metastasis Site of Metastasis Frequency Adrenal glands >50% Liver 30-50% Brain 20% Bone 20%
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