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Background and objective Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry. Methods All patients enrolled in the registry undergo a diagnostic review whereby international IPF guidelines are applied via a registry MDD. We investigated the clinical applicability of these guidelines with regard to: (i) adherence to guidelines, (ii) Natural history of IPF diagnostic categories and (iii) Concordance for diagnostic features. Results A total of 417 participants (69% male, 70.6 ± 8.0 years) with a clinical diagnosis of IPF underwent MDD. The 23% of participants who did not meet IPF diagnostic criteria displayed identical disease behaviour to those with confirmed IPF. Honeycombing on radiology was associated with a worse prognosis and this translated into poorer prognosis in the ‘definite’ IPF group. While there was moderate agreement for IPF diagnostic categories, agreement for specific radiological features, other than honeycombing, was poor. Conclusion In clinical practice, physicians do not always follow IPF diagnostic guidelines. We demonstrate a cohort of IPF patients who do not meet IPF diagnostic guideline criteria, based largely on their radiology and lack of lung biopsy, but who have outcomes identical to those with IPF.

The aim of this study was to carry out a comparative analysis by transducin-like enhancer of split 1 (TLE1) immunohistochemistry and molecular analysis of SYT-SSX, for 16 pleural predominantly sarcomatoid mesotheliomas and six cases of pleuropulmonary synovial sarcoma (five pleural in distribution only, with one case of a predominantly subpleural upper lobe synovial sarcoma), all of which were solely or predominantly monophasic. Our comparison included survival and some clinical data. We consider that the following points emerged from this study.

This review updates the scientific literature concerning asbestos and lung cancer, emphasizing cumulative exposure and synergism between asbestos exposure and tobacco smoke, and proposes an evidence-based and equitable approach to compensation for asbestos-related lung cancer cases. This update is based on several earlier reviews written by the second and third authors on asbestos and lung cancer since 1995. We reevaluated the peer-reviewed epidemiologic studies. In addition, selected in vivo and in vitro animal studies and molecular and cellular studies in humans were included. We conclude that the mechanism of lung cancer causation induced by the interdependent coaction of asbestos fibers and tobacco smoke at a biological level is a multistage stochastic process with both agents acting conjointly at all times. The new knowledge gained through this review provides the evidence for synergism between asbestos exposure and tobacco smoke in lung cancer causation at a biological level. The evaluated statistical data conform best to a multiplicative model for the interaction effects of asbestos and smoking on the lung cancer risk, with no requirement for asbestosis. Any asbestos exposure, even in a heavy smoker, contributes to causation. Based on this information, we propose criteria for the attribution of lung cancer to asbestos in smokers and non-smokers.

Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.

Thyroid transcription factor 1 (TTF-1) is an immunohistochemical marker in the identification of lung and thyroid tumors. However, positive labelling for TTF-1 can occur in tumors from other sites, and this can result in misdiagnosis if only a limited panel of antibodies is used. We assessed the frequency of expression of 3 TTF-1 antibody clones, namely, 8G7G3/1, SPT24, and SP141 on a tissue microarray of 104 colorectal cancer (CRC), and whole-tumor sections of 165 CRC with known microsatellite instability (MSI) status. We also analyzed the expression of TTF-1 in a tissue microarray of 112 prostatic adenocarcinomas. The association of TTF-1 expression with clinicopathologic parameters and patient survival was analyzed. Six of 104 (5.7%) primary colorectal carcinomas expressed TTF-1 with SPT24 and SP141 clones, whereas only 2 (2%) of these tumors labeled positive for TTF-1 with clone 8G7G3/1. A significant association of TTF-1 expression with younger age at diagnosis (P=0.001) was found, but not with stage, or survival. The SP141 clone also labelled 24/165 (14.5%) of 165 CRC with known MSI status. There was an association with younger age (P

Background. Malignant mesothelioma (MM) is an aggressive tumor of the serosal membranes, mostly the pleura. It is related to asbestos exposure and has a poor prognosis. MM has a long latency period, and incidence is predicted to remain stable or increase until 2020. Currently, no biomarkers for a specific targeted therapy are available. Previously, we observed that expression of aquaporin 1 (AQP1) was an indicator of prognosis in two independent cohorts. Here we determine whether AQP1 inhibition has therapeutic potential in the treatment of MM.Methods. Functional studies were performed with H226 cells and primary MM cells harvested from pleural effusions. AQP1 expression and mesothelial phenotype was determined by immunohistochemistry. AQP1 function was inhibited by a pharmacological blocker (AqB050) or AQP1-specific siRNA. Cell proliferation, migration, and anchorage-independent cell growth were assessed. A nude mouse heterotopic xenograft model of MM was utilised for thein vivostudies.Results. Inhibition of AQP1 significantly decreases cell proliferation, metastatic potential, and motility without inducing nonspecific cytotoxicity or increasing apoptosis.In vivoblockade of AQP1 had no biologically significant effect on growth of established tumours.Conclusions. Targeted blockade of AQP1 restricts MM growth and migrationin vitro. Further work is warranted to fully evaluate treatment potentialin vivo.

The International Collaboration on Cancer Reporting (ICCR) is a quadripartite alliance formed by the Royal College of Pathologists of Australasia, the Royal College of Pathologists of the United Kingdom, the College of American Pathologists, and the Canadian Partnership Against Cancer. The ICCR was formed with a view to reducing the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish, and maintain standardized cancer-reporting data sets. The resultant standardization of cancer reporting would be expected to benefit not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets.To develop an evidence-based reporting data set for each cancer site.A project to develop data sets for prostate, endometrium, and lung cancers and malignant melanoma was piloted by the quadripartite group.A set of required and recommended data elements and appropriate responses for each element were agreed upon for the reporting of lung cancer.This review describes the process of development of the lung cancer data set.

Pleural malignant mesothelioma (MM) includes several unusual and even rare but distinctive histological subtypes, in addition to the usual subdivision into epithelioid, biphasic and sarcomatoid MM. Criteria for discrimination between fibrous pleuritis versus desmoplastic mesothelioma include evidence of neoplastic invasion for diagnosis of desmoplastic MM, but this histological assessment is complicated by the recently-described 'fake fat phenomenon' in cases of fibrous pleuritis. The distinction between biphasic and monophasic synovial sarcoma of the pleura versus biphasic and sarcomatoid MM can be problematical and is most cogently based upon molecular detection of the t(X;18) translocation, whereas a clear diagnosis of MM for a pleural tumour histologically resembling synovial sarcoma is favoured by a negative result for this translocation and, probably, microRNA evidence supportive of a diagnosis of MM. Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yet is a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells). Recent reports have also focused upon germline mutations in the BRCA1-associated protein 1 (BAP1), not only in cases of familial mesothelioma, but also BAP1 deletion in sporadic MM. Prognostic factors for MM include not only the histological subtypes, but other independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis.

Background We hypothesized that in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), high expression of excision repair cross complementation group 1 (ERCC1) and low expression of thymidylate synthase (TS) are associated with prolonged survival. Patients and Methods Consecutive patients undergoing EPP at our institutions were reviewed. Tissue microarrays were constructed using five 1-mm cores per patient. TS and ERCC1 protein expression was evaluated by immunohistochemical techniques. The average percentage scores from evaluable cores were assessed and the median score was used to divide the group. Overall survival (OS) from the time of surgery was determined by the Kaplan-Meier method and results were compared by the log-rank test. Results Eighty patients were included: median age, 58 years; 79% men; 76% epithelial and 24% biphasic subtypes; 25% and pathologic stage I/II and 73% stage III/IV. The median OS was 18.2 months (80% deceased at the censor date). Nineteen patients received neoadjuvant chemotherapy; 2 patients received chemotherapy with adjuvant intent and 28 patients received palliative chemotherapy. The median score was 10.2% for TS and 35% for ERCC1. There was no correlation between TS expression and OS (13.7 vs. 21.6 months for low and high levels, respectively; P = .32). There was a trend between high ERCC1 expression and longer OS (27.6 vs. 10.3 months; P = .06). Conclusion In this series of patients with MPM undergoing EPP, TS expression was not associated with prolonged survival, but there was a trend for longer survival in patients with high ERCC1 expression.

A new lung adenocarcinoma classification has been published by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society. This new classification is needed to provide uniform terminology and diagnostic criteria, most especially for bronchioloalveolar carcinoma. It was developed by an international core panel of experts representing all 3 societies with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons.This summary focuses on the aspects of this classification that address resection specimens. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced, such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with either pure lepidic growth (adenocarcinoma in situ) and predominant lepidic growth with invasion of 5 mm or less (minimally invasive adenocarcinoma...

(1) Background: Malignant mesothelioma (MM) is an aggressive tumour of the serosal membranes, associated with exposure to asbestos. Survival is generally poor, but prognostication for individual patients is difficult. We recently described Aquaporin 1 (AQP1) as independent prognostic factor in two separate retrospective cohorts of MM patients. Here we assess the usefulness of AQP1 prospectively, and determine the inter-observer agreement in assessing AQP1 scores; (2) Methods: A total of 104 consecutive cases of MM were included. Sufficient tissue for immunohistochemistry was available for 100 cases, and these cases were labelled for AQP1. Labelling was assessed by two pathologists. Complete clinical information and follow up was available for 91 cases; (3) Results: Labelling of ≥50% of tumour cells for AQP indicated improved prognosis in a univariate model (median survival 13 versus 8 months, p = 0.008), but the significance was decreased in a multivariate analysis. Scoring for AQP1 was robust, with an inter-observer kappa value of 0.722, indicating substantial agreement between observers; (4) Conclusion: AQP1 is a useful prognostic marker that can be easily incorporated in existing diagnostic immunohistochemical panels and which can be reliably interpreted by different pathologists.

The new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification provides, for the first time, standardized terminology for lung cancer diagnosis in small biopsies and cytology; this was not primarily addressed by previous World Health Organization classifications. Until recently there have been no therapeutic implications to further classification of NSCLC, so little attention has been given to the distinction of adenocarcinoma and squamous cell carcinoma in small tissue samples. This situation has changed dramatically in recent years with the discovery of several therapeutic options that are available only to patients with adenocarcinoma or NSCLC, not otherwise specified, rather than squamous cell carcinoma. This includes recommendation for use of special stains as an aid to diagnosis, particularly in the setting of poorly differentiated tumors that do not show clear differentiation by routine light microscopy. A limited diagnostic workup is recommended to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (eg, thyroid transcription factor 1 or mucin) and a single squamous marker (eg, p40 or p63). Carcinomas lacking clear differentiation by morphology and special stains are classified as NSCLC, not otherwise specified. Not otherwise specified carcinomas that stain with adenocarcinoma markers are classified as NSCLC, favor adenocarcinoma, and tumors that stain only with squamous markers are classified as NSCLC, favor squamous cell carcinoma. The need for every institution to develop a multidisciplinary tissue management strategy to obtain these small specimens and process them, not only for diagnosis but also for molecular testing and evaluation of markers of resistance to therapy, is emphasized.

BACKGROUND: Malignant mesothelioma (MM) is an aggressive cancer of serosal membranes, mostly pleura. It is related to asbestos exposure and its incidence in most industrialized countries is projected to remain stable or to increase until 2020. Prognosis remains poor. Clinical prognostic scoring systems lack precision. No prognostic tissue markers are available. Aquaporin 1 (AQP1) is a cell membrane channel involved in water transport, cell motility, and proliferation. A blocker and an agonist are available. METHODS: Two independent cohorts of MM were studied. Cohort 1 consisted of 80 consecutive patients who underwent radical surgery (extrapleural pneumonectomy [EPP]). Cohort 2 included 56 conservatively managed patients from another institution. Clinical information was obtained from files. Diagnoses were histologically verified. Immunohistochemical labeling for AQP1 was performed on tumor tissue and the percentage of positive cells was scored. RESULTS: We demonstrated expression of AQP1 in normal and neoplastic mesothelium at the apical aspect of the cell, in keeping with a role in water transport. For both cohorts, expression of AQP1 by ≥50% of tumor cells was associated with significantly enhanced survival (9.4 months vs 30.4 months in EPP patients and 5 months vs 15 months in conservatively treated patients). This was independent of established prognostic factors, including histologic subtype, pathologic stage, sex, and age at time of diagnosis. CONCLUSION: Expression of AQP1 correlated significantly with prognosis in MM, irrespective of treatment or established prognostic factors. Immunohistochemical labeling for AQP1 should be included in the routine histopathologic workup. An agonist or blocker may become useful for treatment.

Summary Aims We previously established the use of a minimal panel of antibodies as sufficient to diagnose most epithelial malignant mesothelioma (MPM). We aimed to validate this approach and investigate the utility of a D2-40 antibody. Methods A series of 80 MPM patients selected for surgery and 21 consecutive patients with pleural metastatic carcinoma were included. A minimal panel of antibodies, consisting of calretinin, BG8 and CD15, and D2-40 was investigated. Results Therewere61 epithelial and 19 biphasic MPM as well as 12 metastatic lung, six breast (5 ductal adenocarcinomas, 1 mixed ductal/lobular adenocarcinoma), two serous papillary ovarian carcinomas and one moderately differentiated colorectal adenocarcinoma. The sensitivity of positive calretinin labelling to confirm the diagnosis of MPM was 97.5%, while the ‘diagnostic sensitivities’ of lack of labelling for BG8 and CD15 were 91.3% and 97.5%, respectively. The use of calretinin, BG8 and CD15 resulted in correct classification in 97.5% of all MPMs. All MPM cases investigated showed at least focal positive D2-40 labelling. Conclusions We have validated the usefulness of a minimal panel of antibodies with calretinin, BG8and CD15as the initial step to the diagnosis of MPM. D2-40 emerged as a helpful diagnostic tool for cases where our initial approach failed to conclusively diagnose MPM.

Asbestosis is defined as diffuse pulmonary fibrosis caused by the inhalation of excessive amounts of asbestos fibers. Pathologically, both pulmonary fibrosis of a particular pattern and evidence of excess asbestos in the lungs must be present. Clinically, the disease usually progresses slowly, with a typical latent period of more than 20 years from first exposure to onset of symptoms.Differential Diagnosis: Idiopathic Pulmonary FibrosisThe pulmonary fibrosis of asbestosis is interstitial and has a basal subpleural distribution, similar to that seen in idiopathic pulmonary fibrosis, which is the principal differential diagnosis. However, there are differences between the 2 diseases apart from the presence or absence of asbestos. First, the interstitial fibrosis of asbestosis is accompanied by very little inflammation, which, although not marked, is better developed in idiopathic pulmonary fibrosis. Second, in keeping with the slow tempo of the disease, the fibroblastic foci that characterize idiopathic pulmonary fibrosis are infrequent in asbestosis. Third, asbestosis is almost always accompanied by mild fibrosis of the visceral pleura, a feature that is rare in idiopathic pulmonary fibrosis.Differential Diagnosis: Respiratory BronchiolitisAsbestosis is believed to start in the region of the respiratory bronchiole and gradually extends outward to involve more and more of the lung acinus, until the separate foci of fibrosis link, resulting in the characteristically diffuse pattern of the disease. These early stages of the disease are diagnostically problematic because similar centriacinar fibrosis is often seen in cigarette smokers and is characteristic of mixed-dust pneumoconiosis. Fibrosis limited to the walls of the bronchioles does not represent asbestosis.Role of Asbestos BodiesHistologic evidence of asbestos inhalation is provided by the identification of asbestos bodies either lying freely in the air spaces or embedded in the interstitial fibrosis. Asbestos bodies are distinguished from other ferruginous bodies by their thin, transparent core. Two or more asbestos bodies per square centimeter of a 5-μm-thick lung section, in combination with interstitial fibrosis of the appropriate pattern, are indicative of asbestosis. Fewer asbestos bodies do not necessarily exclude a diagnosis of asbestosis, but evidence of excess asbestos would then require quantitative studies performed on lung digests.Role of Fiber AnalysisQuantification of asbestos load may be performed on lung digests or bronchoalveolar lavage material, employing either light microscopy, scanning electron microscopy, or transmission electron microscopy. Whichever technique is employed, the results are only dependable if the laboratory is well practiced in the method chosen, frequently performs such analyses, and the results are compared with those obtained by the same laboratory applying the same technique to a control population.

Immunohistochemical detection of thyroid transcription factor-1 (TTF-1) plays an important role in the diagnosis and subclassification of non-small cell carcinomas of the lung in biopsy and some cytology samples, specifically for identification of squamous cell carcinoma (classically negative) and non-mucinous adenocarcinoma (positive in most cases) and for discrimination between lung adenocarcinoma and pleural malignant mesothelioma (classically negative). Aims and methods We carried out a comparison of the widely used mouse monoclonal TTF-1 antibody based on the 8G7G3/1 clone versus the more recently introduced rabbit monoclonal antibody (MAb) based on the SP141 clone. Results Both antibodies labelled alveolar epithelium in normal lung parenchyma, but the SP141 antibody also labelled bronchial mucosal basal cells. All 13 cases of atypical squamous lesions (including one case of bronchial squamous dysplasia) were negative with the 8G7G3/1 antibody, but 6/13 cases of squamous carcinoma/dysplasia showed positive nuclear labelling with the SP141 antibody in the same tissue biopsy. All 35 cases of adenocarcinoma of the lung were positive with both antibodies. For 12 cases of sarcomatoid carcinoma of the lung, two cases were labelled with the 8G7G3/1 antibody, whereas positive labelling of 4/12 cases was observed with SP141. All 66 cases of epithelioid malignant mesothelioma were negative with both antibodies, but 8/19 cases of sarcomatoid mesothelioma showed positive nuclear labelling with the SP141 antibody (0/19 with 8G7G3/1). Conclusions Our findings indicate differences in the rates of positive and negative labelling with these two antibodies, and suggest the potential for misclassification of a proportion of squamous carcinomas of the lung as adenocarcinoma, and for misdiagnosis of some sarcomatoid mesotheliomas as sarcomatoid carcinoma of the lung. If the results of SP141 are assigned overriding significance, our findings further indicate that in isolation, neither negative labelling with either 8G7G3/1 or SP141 nor positive labelling with the SP141 MAb discriminates between sarcomatoid carcinoma and sarcomatoid mesothelioma, whereas positive labelling with the 8G7G3/1 MAb favours a diagnosis of sarcomatoid carcinoma. The literature suggests that these seemingly ‘aberrant’ results with the SP141 antibody are not ‘false’ positives, but rather real detection of low levels of TTF-1 protein in a broader range of tumours than is widely recognised.

Introduction: Advances in the pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC) have demonstrated important new prognostic features that have led to changes in classification and diagnostic criteria. Methods: The literature and a set of cases were reviewed by a pathology/CT review panel of pathologists and radiologists who met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The group addressed the question of whether sufficient data exist to modify the 2004 World Health Organization (WHO) classification of adenocarcinoma and BAC to define a "minimally invasive" adenocarcinoma with BAC. The problems of diffuse and/or multicentric BAC and adenocarcinoma were evaluated. Results: The clinical concept of BAC needs to be reevaluated with careful attention to the new 2004 WHO criteria because of the major clinical implications. Existing data indicate that patients with solitary, small, peripheral BAC have a 100% 5-year survival rate. The favorable prognostic impact of the restrictive criteria for BAC is already being detected in major epidemiologic data sets such as the Surveillance Epidemiology and End-Results registry. Most lung adenocarcinomas, including those with a BAC component, are invasive and consist of a mixture of histologic patterns. Therefore, they are best classified as adenocarcinoma, mixed subtype. This applies not only to adenocarcinomas with a solitary nodule presentation but also to tumors with a diffuse/multinodular pattern. The percentage of BAC versus invasive components in lung adenocarcinomas seems to be prognostically important. However, at the present time, a consensus definition of "minimally invasive" BAC with a favorable prognosis was not recommended by the panel, so the 1999/2004 WHO criteria for BAC remain unchanged. In small biopsy specimens or cytology specimens, recognition of a BAC component is possible. However, it is not possible to exclude an invasive component. The diagnosis of BAC requires thorough histologic sampling of the tumor. Conclusion: Advances in understanding of the pathology and CT features of BAC and adenocarcinoma have led to important changes in diagnostic criteria and classification of BAC and adenocarcinoma. These criteria need to be uniformly applied by pathologists, radiologists, clinicians, and researchers. The 2004 WHO classification of adenocarcinoma is readily applicable to research studies, but attention needs to be placed on the relative proportion of the adenocarcinoma subtypes. Other recently recognized prognostic features such as size of scar, size of invasive component, or pattern of invasion also seem to be important. More work is needed to determine the most important prognostic pathologic features in lung adenocarcinoma.

Of putative specific markers for diffuse malignant mesothelioma, nuclear staining with Zymed polyclonal calretinin antibody has shown the best specificity to date for epithelial diffuse malignant mesothelioma versus adenocarcinoma. We compared specificity and sensitivity of this polyclonal antibody for diagnosis of diffuse malignant mesothelioma with a new monoclonal antibody from DAKO. One hundred eighteen adenocarcinomas and 111 diffuse malignant mesotheliomas-70 epithelial, 22 sarcomatous, and 19 biphasic-were immunostained with calretinin antibodies from Zymed (polyclonal rabbit, prediluted, PAD:DC8) and DAKO(monoclonal mouse, 1:100, clone DAK Calret 1) using manufacturer-recommended procedures. Cases were blinded and assessed for nuclear versus cytoplasmic staining, percent positive cells, and background. Both antibodies showed similar positive predictive values for diffuse malignant mesothelioma by nuclear staining (Zymed=95%; DAKO=97%). False positives in 4 (3.4%) and 2 (1.7%) adenocarcinomas, respectively, stained greater than 10% of cells. Sensitivity for epithelial malignant mesothelioma was slightly less for DAKO antibody (Zymed=80%; DAKO=73%). Neither antibody performed well on sarcomatous malignant mesothelioma (Zymed=2/22; DAKO=1/22). Both antibodies are useful in the diagnosis of epithelial malignant mesothelioma, although monoclonal antibody is slightly less sensitive.

Aim Thyroid transcription factor -1 (TTF1) is a useful immunohistochemical (IHC) marker for diagnosis of primary lung tumours including differential diagnosis between primary lung adenocarcinoma (AdCa) and mesothelioma (MM). Different TTF1 monoclonal antibodies (MoAbs) are available. The clone SP141 achieved the highest score in the 2014 RCPA QAP. Most published studies used the 8G7G3/1 MoAb and inconsistencies in labelling between different antibodies have been described. Our study compared the performance of 8G7G3/1 and SP141 TTF1 MoAbs in primary AdCa and squamous cell carcinoma (SCC) of lung, and MM. Methods We examined IHC labelling in 83 cases of MM (17 sarcomatoid, 66 epithelioid), 13 poorly differentiated SCCs and 35 AdCas. Results All AdCas labelled with both the SP141 and 8G7G3/1 MoAbs. All MMs and SCCs were negative with 8G7G3/1, but 7/17 sarcomatoid, 0/66 epithelioid MMs and 6/13 SCCs were positive with SP141. Discussion TTF1 expression is useful for diagnosis of primary lung AdCas, but different antibodies have different performance profiles, which may have clinical implications and must be taken into account.

In biopsy tissue, discrimination between reactive mesothelial hyperplasia and epithelial mesothelioma can pose a major problem for the surgical pathologist. Confidence in the diagnosis is often proportional to the amount of tissue available for study and depends largely on findings of invasion and the extent and cytologic atypia of the lesion, because there is no marker specific for the mesothelium and that discriminates consistently among normal, hyperplastic, and neoplastic mesothelial tissue. Therefore, mesothelioma in situ is diagnosable only when invasive epithelial mesothelioma is demonstrable in the same specimen, in a follow-up biopsy specimen, or at autopsy. Comparison of 22 cases of mesothelioma in situ that fulfill these requirements for diagnosis with 141 invasive mesotheliomas and 78 reactive mesothelioses indicates that strong linear membrane-related labeling for epithelial membrane antigen and silver-labeled nucleolar organizer region-positive material that occupies 0.6677 microm2 or more of the nucleus in an atypical in situ mesothelial lesion of the pleura are found consistently in neoplastic mesothelial cells. Although these findings may engender suspicion of mesothelioma in situ in high-risk persons, the criteria for diagnosis of pure mesothelial lesions of this type are still under study. Mesothelioma in situ should be considered proved only when unequivocal invasion is identified in a different area of the pleura or at a different time; a diagnosis of pure mesothelioma in situ should not be made in patients not exposed to asbestos.

BACKGROUND The accurate diagnosis of pleural lesions obtained from small closed biopsy is difficult. As yet there is no single reliable test to distinguish between malignant and benign mesothelial tissue. METHODS Immunostaining of epithelial membrane antigen (EMA) and the quantitation of silver stained nucleolar organizer regions (AgNORs) each were applied to benign and malignant histologic sections of pleural and peritoneal biopsies. The usefulness of these stains was tested both individually and in combination in the diagnosis of epithelial malignant mesothelioma. RESULTS One hundred and three of the 141 malignant lesions (73%) were immunoreactive for EMA but only 3 of the 73 benign lesions (4%) reacted equivocally, and none positively. The average count of AgNORs/cell in malignant lesions (n = 80) was elevated compared with benign cases (n = 26), but a significant overlap was exhibited in the AgNOR count and this form of analysis was considered to be of little value in distinguishing benign from malignant mesothelial processes. Much less overlap was observed when the average AgNOR area was measured. By using the maximum benign AgNOR area of 0.6677 μm2 as the upper threshold, 51 cases (63.8%) were identified as malignant; the test demonstrated 100% specificity and 63.8% sensitivity. By combining the EMA and AgNOR results, 76 of 80 of the malignant mesothelioma cases (95%) tested positive for at least 1 of the tests with no false-positive results identified. CONCLUSIONS This study confirms the usefulness of EMA in diagnosing malignant and benign mesothelial lesions, and demonstrates the enhanced diagnostic value of combining EMA immunoreaction with the average area of AgNOR per cell, thereby increasing sensitivity in the diagnosis of epithelial malignant mesothelioma. Cancer 1998;82:583-90. © 1998 American Cancer Society.

The fine structure and immunoprotein content of the crystalloids are described in two cases of paraproteinemic crystalloidal keretopathy, both of which had clinical features thought by the referring ophthalmologists to be those of atypical lattice-type corneal dystrophy (presumably because of lattice-like lines). Most keratocytes in one case were surrounded by a mantle of densely packed tubular crystalloids. Individual tubules were annular in cross section with mean dimensions as follows: overall diameter, 29.32 nm (SD 1.26); internal diameter (core), 8.53 nm (SD 1.12); wall thickness, 10.39 nm (SD 0.85) (n = 10). Crystalloids were extracellular and found only in the corneal stroma, with none in Bowman's layer or Descemet's membrane. In the second case, the tubules had a similar distribution but formed geometric arrays with no clear relationship to, or envelopment of the keratocytes. The tubules were thin-walled, with mean dimensions as follows: overall diameter, 26.12 nm (SD 1.12); internal diameter (core), 15.46 nm (SD 1.12); wall thickness, 5.33 nm (SD 0) (n = 10). In both cases the tubules were kappa-light chain- and gamma-chain-positive. Laboratory investigations revealed the presence of two IgM-kappa paraproteins and an IgG-kappa paraprotein in the serum of the first patient. The second patient had an IgG-kappa paraproteinemia and bone marrow changes consistent with low-grade non-Hodgkin's lymphoma. These cases emphasize and extend the morphological range of corneal IgG crystalloids; the second case also demonstrates that corneal IgG crystalloids may be an early indicator of un underlying immunoproliferative disease.

The detection of neoplastic invasion remains the linchpin for a clear diagnosis of malignant mesothelioma. Cytology-only diagnosis of epithelioid mesothelioma on aspirated effusion fluid remains controversial. A major problem is poor sensitivity, although cytodiagnosis is achievable in many cases at a high order of specificity, especially when a large volume of effusion fluid is submitted for cytological evaluation, enabling the preparation of cell-block sections for immunohistochemical investigation and when the cytological findings can be correlated with imaging studies to assess the anatomical distribution of the lesion and evidence of nodularity of the pleural disorder and, in some cases, to demonstrate evidence of invasion. Although 'positive' and 'negative' immunohistochemical markers have proved remarkably effective in distinguishing between epithelioid mesothelioma and secondary carcinoma and other malignant tumours metastatic to serosal membranes, no mesothelial marker has 100% sensitivity and specificity for mesothelioma diagnosis, so that panels of 'positive' antibodies and markers with negative predictive value are required. At present, no tissue or serum marker (including the molecular detection of p16/CDKN2A) has been proved to have sufficient specificity, consistency and reproducibility that it can replace evidence of invasion as the decisive marker for diagnosis when there is any uncertainty concerning a diagnosis of epithelioid mesothelioma and in the case of atypical fibrous lesions of the pleura (especially collagen-rich lesions, namely fibrous pleuritis vs desmoplastic mesothelioma), in which even the assessment of invasion can be problematical as illustrated in part 2 of this review.

Lung cancer is now the leading cause of death from cancer in Australia. Most patients are diagnosed with late-stage disease. Although diagnosis at pre-invasive stages could theoretically improve outcomes, mooted precursor lesions are often asymptomatic and often undetectable by non-invasive investigations. Nonetheless, they merit study to identify early and essential molecular steps involved in lung carcinoma pathogenesis, with the aim of developing therapies targeted against one or more such steps. Some lung cancers appear to develop via a series of progressive morphological changes with correlating molecular alterations, but others seem to arise in histologically normal epithelium, and these differences may reflect anatomically and functionally distinct epithelial compartments of the respiratory tract. Pre-invasive precursor lesions recognised by the World Health Organization (WHO) include squamous metaplasia with dysplasia and carcinoma in situ, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Other lesions that likely represent pre-invasive lesions, but which are not currently WHO-listed, include human papillomavirus (HPV)-related respiratory papillomatosis and mesothelioma in situ. No single cancer stem cell marker has been identified. Field cancerisation plays an important role in lung cancer development, and includes the spread of pre-invasive clones along the respiratory epithelium or the occurrence of multiple separate foci of pre-invasive abnormalities such as squamous dysplasia and carcinoma in situ.In addition to well-characterised step-wise progression in squamous cell carcinomas and some adenocarcinomas, alternative pathways exist, and are currently being investigated. In addition, molecular techniques, including miRNA screening on blood samples or cytology samples--such as sputum samples--may become clinically relevant and more accurate in predicting lung cancer progression.

The relationship between occupational or environmental exposure to asbestos and the development of mesothelioma, typically after prolonged latency, has been accepted as one of cause and effect. Most studies have concluded that asbestos is not mutagenic to mammalian cells in vitro. We have studied the potential of crocidolite asbestos to induce mutations in a stable mesothelioma cell line, using a mutation assay that measures mutation at the autosomal HLA-A locus and permits clonal growth of mutant cells. The mesothelioma cell line chosen is more akin to the in vivo target cells of asbestos than human peripheral blood lymphocytes used in previous studies. Exposure of mesothelioma cells in culture to both 200 micrograms/ml and 50 micrograms/ml crocidolite for 72 hr did not result in a statistically significant difference in the mutation frequency (MF) in the HLA-A assay when compared to the spontaneous MF in these cells. Mutations in the mesothelioma cells were classified according to their molecular basis. Notwithstanding the lack of statistically significant change in overall MF, molecular analysis of mutants obtained following exposure of mesothelioma cells to crocidolite demonstrated a statistically significant increase in the class of mutations arising from loss of heterozygosity (LOH) events involving the selection locus (HLA-A) and more distal loci. Mutations following exposure to 200 micrograms/ml and 50 micrograms/ml crocidolite showed a greater frequency of LOH than did spontaneous mutants (P < 0.01 and P < 0.001, respectively). These results correlate with those obtained in an earlier study using lymphocytes. The mesothelioma cell-based assay may be useful in detecting the mutagenicity of other asbestiform fibers and man-made fibers.

Although asbestos and erionite are proven human carcinogens, most studies have concluded that these fibres are not mutagenic to mammalian cells in vitro. We have studied the potential of these fibres and chrysotile fibres to induce mutations in human peripheral lymphocytes, using a mutation assay that measures mutation at the autosomal HLA-A locus. Exposure of lymphocytes in culture to 400 micrograms/ml of crocidolite or erionite for 72 hr did not result in a statistically significant increase in the mutation frequency (MF) in the HLA-A assay, although a trend towards increased MF was observed. Exposure to 400 micrograms/ml chrysotile resulted in no increase in MF; however a significant increase was observed at 50 micrograms/ml. Mutations in somatic cells can be classified according to their molecular basis. Molecular analysis of mutants obtained following exposure of lymphocytes to crocidolite and erionite demonstrated a statistically significant increase in the class of mutations arising from loss-of-heterozygosity (LOH) events involving the selection locus (HLA-A) and more distal loci. Mutations following exposure to crocidolite and erionite showed a greater frequency of LOH than did spontaneous mutants (p < 0.02 and p < 0.005 respectively). Mutants following exposure to chrysotile did not display a significant difference in LOH when compared with spontaneous mutants. Thus, although an increase in overall mutation frequency following fibre exposure did not achieve statistical significance, the modest increase seen following exposure to erionite and crocidolite is translated into a highly significant change in those components of the spectrum of mutations which result in LOH.

The early diagnosis of mesothelioma is notoriously difficult, both from a clinical and pathological perspective. Patients often undergo several medical investigations without definitive diagnosis. The discovery of biomarkers that can be assessed in pleural effusions, histological samples, and serum may assist with the difficult early diagnosis of mesothelioma. In this chapter we focus on those markers that have been examined in the setting of either early diagnosis of mesothelioma in symptomatic individuals or that have been proposed as suitable for screening of asbestos-exposed individuals, with an emphasis on cytology and histology.

Malignant mesothelioma (MM) is an aggressive tumour affecting the mesothelial surfaces of the pleural and peritoneal cavities and, rarely, the pericardium and the tunica vaginalis testis. Despite a ban of asbestos in many industrialised nations, the present high incidence of MM is expected to continue, due to the long latency period between first asbestos exposure and occurrence of disease, making it an important health issue for the future. The diagnosis of MM can be difficult, both from a clinical and pathological perspective. It is not unusual for patients to undergo several medical investigations without definitive diagnosis early in their course of illness. Understandably, there is intense interest in the discovery of markers that can be assessed in pleural effusions, histological specimens, and serum to assist with the difficult early diagnosis of MM. Considering the primary aetiological role of asbestos, there is theoretically an easily identifiable target population for screening with a biomarker with adequate sensitivity and specificity or with a combination of biomarkers. In this review we focus on biomarkers that have been examined in the setting of either early diagnosis of MM in symptomatic patients or screening of asbestos-exposed individuals.

Introduction: Histological subtype is an established prognostic factor in malignant pleural mesothelioma (MPM). We retrospectively investigated the accuracy of classifying histological subtype on diagnostic biopsies and examined the impact of different diagnostic procedures on the outcome. Methods: Consecutive patients with histologically confirmed MPM who underwent extrapleural pneumonectomy (EPP) from 1994 to 2009 were included. Patient records were reviewed, and the initial diagnoses of histological subtype were obtained. The archival EPP specimens were reviewed by a panel of pathologists. The histological subtype obtained at review was compared with the initial diagnosis. Results: Eighty-five patients underwent EPP. Two patients achieved a pathological complete response after neoadjuvant chemotherapy, leaving 83 patients to be included in this review. Different diagnostic methods were used before EPP: 81% thoracoscopy; 7% thoracotomy; 11% computed tomography-guided procedure; and 1% other. Patients determined to have an epithelial subtype ( n = 64) at EPP were diagnosed correctly at initial diagnostic biopsy in 84% of cases, whereas patients considered to have a biphasic subtype ( n = 19) at EPP were diagnosed correctly at diagnostic biopsy in 26% of cases. The sensitivity and specificity of diagnostic biopsy for epithelial MPM was 93% and 31%, respectively. The overall subtype misclassification rate was 20%. Biopsy by thoracotomy was most accurate in subtype classification (83%) compared with thoracoscopy (74%) and computed tomography-guided procedure (44%). Conclusions: The determination of histological subtype from a diagnostic biopsy is difficult due to sampling error, but an adequate specimen obtained from surgical biopsy increases the accuracy of subtype classification compared with radiological-guided biopsies.

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

The ultrastructural appearances of corneal crystalloidal deposits are described in two patients with an IgG-kappa paraproteinemia of uncertain pathogenesis. The crystalloids in one patient were overwhelmingly intracellular and were found mainly in stromal keratocytes, but also in basal corneal epithelial cells and the limbal vascular endothelium. Four types of crystalloid or immunoprotein-containing granules were recognizable in this case: 1) fibrillary crystalloids with a curvilinear filamentous substructure; 2) angulated geometric crystalloids that often had a linear filamentous substructure and transverse or oblique periodicity; 3) cordlike crystalloids; and 4) lysosomelike granules with amorphous contents. Immunoelectron microscopy demonstrated that all of these structures labeled for kappa-light chains, and rectangular type 2 crystalloids showed approximately a twofold greater concentration of the colloidal gold probe than the type 1 fibrillary crystalloids. The evidence suggested development of the crystalloids within lysosomes, with a progression from the granules containing amorphous material, through fibrillary crystalloids, to the geometric structures. The circumferential distribution of the corneal deposits, as well as the presence of vascular endothelial crystalloids and reduplication of external laminae around limbal blood vessels, suggests that the crystalloids originated predominantly or entirely from the blood, with transport of immunoprotein across damaged limbal microvasculature. The abnormal vasculature may also have contributed to corneal edema, which in turn may have exacerbated corneal opacification. The crystalloidal deposits in the other case were exclusively extracellular; they were located beneath and between corneal basal epithelial cells, and predominantly as a mantle around individual keratocytes. The crystalloids in this case consisted overwhelmingly of thick-walled tubules about 40 nm in diameter that labeled for both kappa-light chains and gamma chains with the colloidal gold immunoprobe. In addition, lucent vesicles within keratocytes were found only in sections labeled for kappa-light chains and were positive. The factors that might contribute to the formation of corneal crystalloidal deposits in immunoproliferative disorders are discussed, and include: 1) an inherent propensity for crystallization of some immunoglobulins or kappa-light chains, perhaps because of abnormal molecular structure; and 2) local factors in the cornea that might promote deposition and crystallization of immunoprotein, such as temperature, pH, the water content, and extracellular matrix components.

We recently encountered unusual organelles in a tumor from a 75-year-old white British female presenting with a scalp lesion which histologically was a poorly differentiated malignant neoplasm (Fig. 1). On the basis of histology and immunohistochemistry [positive staining for factor Vlll-related antigen (Fig. 2), JC70A (CD31),1 and Ulex europaeus agglutinin 1] the tumor was diagnosed as an epithelioid angiosarcoma. An unexpected finding was that some unambiguous tumor cells were positive for S100 protein. Occasional S100 protein-positive dendritic cells, interpreted as reactive Langerhans cells, were also present. To confirm a confidently held diagnosis, but one which was nevertheless uncertain because of the S100 protein staining, electron microscopy was conducted. Not unexpectedly, Weibel-Palade bodies were not identified,2 but the rough endoplasmic reticulum, polyribosomes, aggregates of haphazardly arranged intermediate filaments, and a well developed lamina were seen as being consistent with epitheli...

This report summarizes the proceedings of a workshop organized with the purpose of bringing together many of those with substantial experience in this troublesome area of pathology for an active interchange of ideas, opinions, problems, and solutions. Recognition was given the fact that current knowledge and technical capabilities are woefully inadequate for dealing with the diagnostic questions now being asked. Until such time as these inadequacies can be remedied, a very conservative approach to the interpretation of ultrastructural studies is advocated.

Immunohistochemistry with panels of antibodies is a standard procedure to distinguish between malignant mesothelioma and metastatic adenocarcinoma. Most studies assess only the sensitivity and specificity for single antibodies, even when the paper concludes by recommending an antibody panel. It was the aim of this study to use a novel statistical approach to identify a minimal panel of antibodies, which would make this distinction in the majority of cases.Two hundred consecutive cases of pleural malignancy (173 pleural mesotheliomas of epithelial type and 27 cases of secondary adenocarcinoma) were investigated using a standard panel of 12 antibodies (CAM5.2, CK5/6, calretinin, HBME-1, thrombomodulin, WT-1, EMA, CEA, CD15, B72.3, BG8, and TTF-1). Regression and classification tree-based methods were applied to select the best combination of markers. The modelling procedures used employ successive, hierarchical predictions computed for individual cases to sort them into homogeneous classes.Labelling for calretinin and lack of labelling for BG8 were sufficient for definite correlation with a diagnosis of malignant mesothelioma. CD15 provided further differentiating information in some cases.A panel of three antibodies was sufficient in most cases to diagnose, or to exclude, epithelial mesothelioma. Calretinin exhibits the strongest correlative power of the antibodies tested.

Only a small number of malignant mesotheliomas with heterologous elements have been described. There are currently no criteria for diagnosis and little data regarding prognosis. We suggest that the term heterologous mesothelioma should be reserved for tumours that show malignant heterologous elements, notably osteosarcomatous, chondrosarcomatous, or rhabdomyoblastic elements but have immunohistochemical and clinical characteristics of mesothelioma. We identified 27 such cases and characterized the clinical and pathological characteristics of these tumours. In our series, 89% originated in the pleura, and 11% from the peritoneal cavity. The median age at diagnosis was 68 years, ranging from 27 to 85 years. Of these cases, 93% occurred in males and 7% in women. Of the 27 mesothelioma cases 16 (59%) were sarcomatoid, 10 (37%) were biphasic, and one was reported as epithelioid; 40% (11 cases) showed osteosarcomatous elements only, 19% showed areas of rhabdomyosarcoma only, 19% contained areas of chondrosarcoma only, and 22% exhibited osteochondromatous elements. Immunohistochemical labelling for cytokeratins was present in the majority of cases. Exposure to asbestos was identified in all the 17 cases for which an exposure history was available (63%). Median survival was 6 months after diagnosis, similar to the survival seen in sarcomatoid mesotheliomas. The differential diagnosis includes primary and secondary pleural sarcomas, including osteosarcomas and chondrosarcomas. Immunohistochemical labelling for cytokeratins is helpful in the distinction, but lack of labelling for cytokeratins in a spindle cell/sarcomatoid tumour does not exclude the diagnosis of mesothelioma, irrespective of the presence of heterologous elements. We suggest that if the anatomical distribution conforms to that of mesothelioma, a diagnosis of heterologous mesothelioma should be made in preference to a diagnosis of primary pleural osteosarcoma or chondrosarcoma, regardless of cytokeratin positivity, as for conventional non-heterologous sarcomatoid mesothelioma.

Context.—Metastatic renal cell carcinoma (MRCC) involving the thorax can be difficult to distinguish from diffuse malignant mesothelioma (DMM) using traditional morphologic approaches. Standard panels of immunohistochemical markers are of limited benefit. Objective.—To investigate several antibodies to renal cell carcinoma–associated proteins for differentiating MRCC from DMM. Design.—One hundred DMMs and 20 MRCCs were evaluated for immunoexpression of erythropoietin. The same cases and an additional 45 DMMs were evaluated for CD10 and renal cell carcinoma marker (RCCMa) immunoreactivity. Results.—Erythropoietin was expressed in 100% of DMMs and MRCCs. Staining for CD10 was observed in 54% of DMMs and 100% of MRCCs. RCCMa stained 26% of DMMs and 55% of MRCCs. Although erythropoietin staining was similarly strong and diffuse in both DMM and MRC, patterns of staining for RCCMa and CD10 differed between MRCC and DMM. Immunoreactivity was strong and diffuse for both RCCMa and CD10 in most MRCCs. Of CD10-positive DMMs, nearly half showed staining in less than 50% of tumor cells and about one fourth of positive cases exhibited only weak to moderately intense staining. Only half of RCCMa-positive DMMs showed staining in more than 49% of tumor cells and staining was only weak to moderately intense in most cases. Conclusions.—Given the overlap in the expression of renal cell carcinoma markers in MRCC and DMM, results with these markers must be interpreted cautiously and should be used in conjunction with mesothelium-associated markers. Differences in expression may potentially help distinguish MRCC from DMM inasmuch as strong and diffuse expression of RCCMa and CD10 supports a diagnosis of MRCC over DMM.

Purpose To review recent advances in pathology and computed tomography (CT) of lung adenocarcinoma and bronchioloalveolar carcinoma (BAC). Methods A pathology/CT review panel of pathologists and radiologists met during a November 2004 International Association for the Study of Lung Cancer/American Society of Clinical Oncology consensus workshop in New York. The purpose was to determine if existing data was sufficient to propose modification of criteria for adenocarcinoma and BAC as newly published in the 2004 WHO Classification of Lung Tumors, and to address the pathologic/radiologic concept of diffuse/multicentric BAC. Results Solitary small, peripheral BACs have an excellent prognosis. Most lung adenocarcinomas with a BAC pattern are not pure BAC, but rather adenocarcinoma, mixed subtype with invasive patterns. This applies to tumors presenting with a diffuse/multinodular as well as solitary nodule pattern. The percent of BAC versus invasive components in lung adenocarcinomas appears to be prognostically important. However, a consensus definition of “minimally invasive” BAC with a favorable prognosis could not be achieved. While recognition of a BAC component is possible, the diagnosis of BAC with exclusion of invasive adenocarcinoma cannot be made by small biopsy or cytology specimens. Conclusion There is a need to work toward a mutual understanding and consensus between pathologists, clinicians, and researchers with the use of the term BAC versus adenocarcinoma. Future studies should make some attempt to quantitate these components and/or other features such as size of scar, size of invasive component, or pattern of invasion. Hopefully, this work will allow definition of a category of adenocarcinoma, mixed subtype with predominant BAC/minimal invasion and a favorable prognosis.

Despite an extensive literature, the relationship between asbestos exposure and lung cancer remains the subject of controversy, related to the fact that most asbestos-associated lung cancers occur in those who are also cigarette smokers: because smoking represents the strongest identifiable lung cancer risk factor among many others, and lung cancer is not uncommon across industrialised societies, analysis of the combined (synergistic) effects of smoking and asbestos on lung cancer risk is a more complex exercise than the relationship between asbestos inhalation and mesothelioma. As a follow-on from previous reviews of prevailing evidence, this review critically evaluates more recent studies on this relationship--concentrating on those published between 1997 and 2004--including lung cancer to mesothelioma ratios, the interactive effects of cigarette smoke and asbestos in combination, and the cumulative exposure model for lung cancer induction as set forth in The Helsinki Criteria and The AWARD Criteria (as opposed to the asbestosis-->cancer model), together with discussion of differential genetic susceptibility/resistance factors for lung carcinogenesis by both cigarette smoke and asbestos. The authors conclude that: (i) the prevailing evidence strongly supports the cumulative exposure model; (ii) the criteria for probabilistic attribution of lung cancer to mixed asbestos exposures as a consequence of the production and end-use of asbestos-containing products such as insulation and asbestos-cement building materials--as embodied in The Helsinki and AWARD Criteria--conform to, and are further consolidated by, the new evidence discussed in this review; (iii) different attribution criteria (e.g., greater cumulative exposures) are appropriate for chrysotile mining/milling and perhaps for other chrysotile-only exposures, such as friction products manufacture, than for amphibole-only exposures or mixed asbestos exposures; and (iv) emerging evidence on genetic susceptibility/resistance factors for lung cancer risk as a consequence of cigarette smoking, and potentially also asbestos exposure, suggests that genotypic variation may represent an additional confounding factor potentially affecting the strength of association and hence the probability of causal contribution in the individual subject, but at present there is insufficient evidence to draw any meaningful conclusions concerning variation in asbestos-mediated lung cancer risk relative to such resistance/susceptibility factors.

Predictions of future cases of mesothelioma in Australia to the year 2020 are in the order of a total of 10,000 new cases. Compensation claims are testing the attribution in a particular case between occupational asbestos exposure and lung cancer. The cost of the problem necessitates clarifying and standardizing the criteria for a confident diagnosis of asbestos-related disease. The possibility of differences in criteria that determine attribution of asbestos to a disease prompted a consensus meeting of pathologists, epidemiologists, physicians, oncologists, radiologists, and others to define current thinking and to agree on an Australian document based on the scientific evidence for establishing diagnoses and attribution data of asbestos-related diseases in Australia. The participants' findings are reported.