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Hypereosinophilia is a phenomenon which is associated with a broad variety of allergic, infectious, paraneoplastic and systemic diseases. Depending on the aetiology, these disorders differ in severity from self-limiting to life-threatening. Although it is well known that hypereosinophilia can occur in association with a solid tumour, exact numbers of incidence are lacking. We describe a patient with respiratory insufficiency and an elevated level of eosinophils in the peripheral blood. A diagnostic work-up revealed the presence of a disseminated non-small-cell carcinoma of the lung; an association not frequently described.

Objectives: Classification of non-small-cell lung cancer (NSCLC) into growth patterns is based on the following question: What does the tumour do with normal lung parenchyma? There are only three possible ways according to which a tumour can behave: (1) preservation of lung tissue and use of its microenvironment for further growth, (2) destruction of lung tissue and formation of new microenvironment for continued expansion and (3) preservation of lung tissue and formation of new microenvironment (modulation). The aim of the current study is to test the prognostic value of growth-pattern classification along with other clinical, pathological and immunohistochemical factors., Methods: Clinicopathological factors of 239 patients operated for NSCLC were retrospectively reviewed. Preoperative smoking status was determined based on two prospectively independent questionnaires. Co-morbidity was determined based on Charlson co-morbidity index (CCI). Haematoxylin-eosin tissue sections were analysed for the determination of tumour growth patterns, histological types, grading, necrosis and desmoplasia. Tumour cell proliferation, endothelial cell proliferation and microvessel density were determined based on double immunostaining with CD34 and Ki67 antibodies. Follow-up data were updated in 2008., Results: According to the growth-pattern classification, 161 patients (67.4%) had a destructive, 33 (13.8%) a papillary and 45 (18.8%) an alveolar growth pattern. Multiple Cox regression analysis showed that older age (p<0.001), lymph node metastasis (p<0.001), growth-pattern classification (p=0.036) and current smokers (p=0.027) were independent prognostic factors for overall survival. Similar results were obtained for disease-specific and disease-free survival. Papillary (hazard ratio=1.658 and confidence interval=1.001-2.748, p=0.050) and alveolar (hazard ratio=2.056 and confidence interval=1.305-3.237, p=0.002) growth patterns were independent predictors of early recurrence., Conclusions: Growth-pattern classification remains a significant prognostic factor in NSCLC providing a possible explanation for survival differences in the same disease stage., (Copyright © 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Background: We have recently shown the prognostic value of growth pattern classification in non-small cell lung cancer. The aim of this study is to validate the hypothesis that these growth patterns have a distinct angiogenic and proliferative profile., Methods: Hematoxylin-eosin stained tissue sections of 239 patients with non-small cell lung cancer were classified into growth patterns. One representative tissue section per patient was double immunostained with CD34 and Ki-67 antibodies. Endothelial cell proliferation fraction, tumor cell proliferation fraction, microvessel density, and Chalkley count were assessed at the invading front and the center of the selected tumor section., Results: According to the growth pattern classification, 161 patients (67.4%) had a destructive, 33 (13.8%) a papillary, and 45 (18.8%) an alveolar growth pattern. There were significant differences in endothelial cell proliferation fraction (p < 0.001), tumor cell proliferation fraction (p < 0.001), microvessel density (p < 0.001), and Chalkley count (p < 0.001) between the growth patterns. Multiple Cox regression analysis showed that a low endothelial cell proliferation fraction was consistently an independent prognostic factor for overall poor (hazard ratio = 0.93; confidence interval: 0.88 to 0.97, p = 0.002) and disease-free survival (hazard ratio = 0.94; confidence interval: 0.89 to 0.98, p = 0.007)., Conclusions: Growth patterns have a distinct angiogenic and proliferative profile. In non-small cell lung cancer, a low degree of angiogenesis (a low endothelial cell proliferation fraction) is associated with poor prognosis.

Aims: We have recently evaluated a classification of non-small-cell lung cancer based upon the presence of an angiogenic or a non-angiogenic growth pattern. The aim of the present study was to test the hypothesis that lung metastases of clear cell renal cell carcinoma (RCC) can grow without eliciting angiogenesis and give rise to the same set of growth patterns., Methods and Results: Tissue sections of 24 patients with lung metastases from clear cell RCC were analysed. Haematoxylin and eosin and reticulin staining were performed to evaluate growth pattern. Double-labelling with antibodies to CD34 and proliferating cell nuclear antigen (PCNA) was performed to determine the endothelial cell proliferation fraction (ECPF) and the microvessel density (MVD). Three growth patterns were observed. In the destructive growth pattern (54%), the architecture of the lung was not preserved. In the alveolar (33%) and interstitial growth patterns (13%), the normal lung parenchyma was preserved within the metastases. MVD was higher in the destructive than in the alveolar growth pattern (P = 0.009). ECPF was higher in the destructive (mean 31.1 +/- 22.7%, median 30.0) than in the alveolar growth pattern (mean 3.6 +/- 2.8%, median 3.2; P = 0.005)., Conclusions: The present study demonstrates that highly angiogenic primary tumours can give rise to non-angiogenic metastases. This type of metastasis may be resistant to antiangiogenic therapy.

Despite the indisputable link between smoking and the increased risk for lung cancer, the inclusion of this factor in prognostic survival analysis has been scarce. Important clinical questions regarding the smoking status are the basis of this study and are as follow: what is the prognostic benefit of having been a non-smoker or having stopped smoking prior to developing lung cancer and what is the prognostic benefit of smoking cessation at the time of diagnosis of lung cancer? Cigarette smoking status of 311 patients operated for non-small cell lung cancer (NSCLC) by a single surgeon was determined based on two independent questionnaires taken prospectively prior to lung operation. Of all patients analysed, 169 (54.3%) were current smokers, 25 (8.0%) were non-smokers, 82 (26.4%) were former smokers and 35 (11.3%) were recent quitters. A Cox multiple regression model was used to test the prognostic value of smoking status on survival together with other relevant clinicopathological factors. For overall survival, older age (P = 0.011), presence of lymph node metastases (P < 0.001) and current smoking (P = 0.001) were independent predictors of poor prognosis, while non-smokers (relative risk = 0.447, 95% confidence interval = 0.206-0.970, P = 0.042), former smokers (relative risk = 0.543, 95% confidence interval = 0.350-0.843, P = 0.006) and recent quitters (relative risk = 0.340, 95% confidence interval = 0.164-0.705, P = 0.004) had a significant better prognosis compared to current smokers (referent group). Similar results were obtained for disease-free survival. These results indicate that smoking cessation is beneficial for lung cancer patients at any time point prior to lung operation and current smoking at the time of operation is associated with poor prognosis.

The reductionistic approach to cancer research has led to an enormous amount of information and publications regarding the molecular biologic processes that take place in cancer tissue. However, the specific influence of this information on clinical practice has been limited. With the advent of new reductionistic tools like the transcriptomic and proteomic technologies, many would argue that further advances in the field of lung cancer research will be dominated by advances on the technical level. However, we anticipate that the most revolutionary advances will be those at a conceptual level. Medical science has always been reductionistic in essence, reducing and analyzing the composing elements of our complex biologic machinery, overlooking the fact that the interrelation among a set of simple determinants creates a new dimension of characteristics and functions. Problems emerging from a reductionistic approach are heterogeneity and variability. This review addresses the current conceptual problems in the field of lung cancer biology and provides a new conceptual model based on recent publications.

Background: Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose., Methods: From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5., Results: In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial., Conclusions: Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

An essential prerequisite of nonangiogenic growth appears to be the ability of the tumour to preserve the parenchymal structures of the host tissue. This morphological feature is visible on a routine tissue section. Based on this feature, we classified haematoxylin and eosin-stained tissue sections from 279 patients with non-small-cell lung cancer into three growth patterns: destructive (angiogenic; n=196), papillary (intermediate; n=38) and alveolar (nonangiogenic; n=45). A Cox multiple regression model was used to test the prognostic value of growth patterns together with other relevant clinicopathological factors. For overall survival, growth pattern (P=0.007), N-status (P=0.001), age (P=0.020) and type of operation (P=0.056) were independent prognostic factors. For disease-free survival, only growth pattern (P=0.007) and N-status (P<0.001) had an independent prognostic value. Alveolar (hazard ratio=1.825, 95% confidence interval=1.117-2.980, P=0.016) and papillary (hazard ratio=1.977, 95% confidence interval=1.169-3.345, P=0.011) growth patterns were independent predictors of poor prognosis. The proposed classification has an independent prognostic value for overall survival as well as for disease-free survival, providing a possible explanation for survival differences of patients in the same disease stage.

Between 1990 and 2000, 56 consecutive patients underwent lung resection for removal of metastatic disease. Mortality, disease-free interval, and overall survival were studied. Only patients with a complete follow-up were included and data were collected conform the protocol of the International Registry of Lung Metastases. The primary tumour in our series was an epithelial tumour in 25 patients (45%), sarcoma in 15 (27%), germ cell tumours in 11 (19%) and melanoma in 5. Operative mortality was 1.4% (1 out of 73 procedures). Germ cell tumours had the best survival (76% at 5 years), and melanoma the worst (0% at 5 years). Multivariate analysis showed that survival for patients who underwent 2 or more metastasectomies was surprisingly good with a 5-year survival rate of 46%. Survival was not related to disease-free interval, multiple lung metastases, or pneumonectomy. It is in accordance with some reports that a short disease-free interval, numerous lung metastases, or recurrence after the first metastasectomy should not preclude patients from operation.

A 38-year-old patient presented with an anterior mediastinal mass after chemotherapeutic and surgical treatment for lung metastases from a malignant histiocytoma. Because of the risk for tumour recurrence the thymic mass was resected. Thymic hyperplasia was found on pathological examination. In this case thymic hyperplasia is a rebound phenomenon aflcer chemotherapy. It appears to atrophy during the administration of chemotherapy and regrow afterwards. Surgical resection provides the definitive diagnosis and treatment.

Introduction: Survival after isolated lung perfusion (ILuP) with melphalan was tested in a model of unilateral pulmonary adenocarcinoma., Methods: On day 0, rats were randomized into four groups: Group 1 (n = 9) received tumor cells intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n = 21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell injection for induction of unilateral left lung metastases. On day 7, groups 1 and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0 mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point of the study was death from metastatic disease., Results: Median survival of ILuP-treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18 +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/- 6; p = 0.0004)., Conclusions: ILuP with melphalan prolongs survival in the treatment of experimental metastatic pulmonary carcinoma.

Background: Malignant mesothelioma, a mesoderm-derived tumor, is related to asbestos exposure and remains a diagnostic challenge because none of the genetic or immunohistochemical markers have yet been proven to be specific. To assist in the identification of mesothelioma and to differentiate it from other common lesions at the same location, we have tested the performance of syntactic structure analysis (SSA) in an automated classification procedure., Materials and Methods: Light-microscopic images of tissue sections of malignant mesothelioma, hyperplastic mesothelium, and adenocarcinoma were analyzed using parameters selected from the Voronoi diagram, Gabriel's graph, and the minimum spanning tree which were classified with a K-nearest-neighbor algorithm., Results: Results showed that mesotheliomas were diagnosed correctly in 74% of the cases; 76% of the adenocarcinomas were correctly graded, and 88% of the mesotheliomas were correctly typed. The performance of the parameters was dependent on the obtained classification (i.e., tumor-tumor versus tumor-benign)., Conclusions: Our results suggest that SSA is valuable in the differential classification of mesothelioma and that it supplements a visually appraised diagnosis. The recognition scores may be increased by a combination of SSA with, for example, cellular or nuclear parameters, measured at higher magnifications to form a solid base for fully automated expert systems.

Background: Isolated left lung perfusion with melphalan and human tumor necrosis factor-alpha for pulmonary metastatic adenocarcinoma in the WAG/Rij rat was studied., Methods: Survival was determined for melphalan, human tumor necrosis-alpha. Lung, pulmonary effluent, and serum melphalan were analyzed by chromatography after isolated lung perfusion or intravenous injection. On day 0, rats were injected with 2.0 x 10(6) CC531S cells intravenously. On day 7, rats underwent sham thoracotomy, received melphalan intravenously, or underwent isolated left lung perfusion with saline, melphalan, tumor necrosis factor, and a combination of the latter two. On day 14, tumor nodules were counted., Results: For the doses of 400 microg tumor necrosis factor, 1,000 microg tumor necrosis factor, or both melphalan and tumor necrosis factor (2 mg + 200 microg), survival rates after contralateral pneumonectomy were 33%, 17%, and 80%, respectively. Survival in all other groups was 100%. Left lung melphalan level was significantly higher after isolated lung perfusion compared to intravenous administration. Significantly fewer left lung nodules were found for 0.5 mg isolated lung perfusion with melphalan (28+/-17) compared to isolated administration (200+/-0) (p = 0.001), and for 1.0 mg intravenous lung perfusion with melphalan (16+/-10) compared to controls (171+/-65) (p = 0.00047). Tumor necrosis factor showed no significant effect., Conclusions: Isolated lung perfusion with melphalan is an effective treatment for pulmonary metastases from adenocarcinoma in the rat.

A patient with a late relapse of non-seminomatous germ cell tumour in a localisation of residual mature teratoma in the lung is reported. The mechanisms for late relapse and the therapeutic options, as reported in the literature, are discussed.

Objective: Precise tumor (T) and nodal (N) staging is imperative in non-small cell lung cancer (NSCLC) as it determines subsequent treatment, certainly when considering neoadjuvant treatment for stage IIIA or IIIB disease. To determine the accuracy of present-day computed tomographic (CT) scanning a prospective study was performed comparing imaging TNM [(i)TNM] and pathological TNM [pTNM]., Methods: In 74 patients with NSCLC without distant metastases (i)TNM was determined on CT findings. The TNM system advocated by the American Joint Committee on Cancer was used. All patients underwent cervical mediastinoscopy. When superior mediastinal nodes were negative this was followed by thoracotomy and pathological examination of the resected specimen and lymph nodes to determine pTNM., Results: The agreement between (i)TNM and pTNM was only 35.1%. The primary tumor (T) was correctly staged in 54.1%, overstaged in 27.0% and understaged in 18.9% of the patients. Invasion of chest wall, pericardium and of major mediastinal structures (T3, T4) was not reliably detected by CT scan. Sensitivity and specificity of CT regarding hilar and mediastinal lymph node staging were 48.3 and 53.3%, positive and negative predictive value 40 and 61.1% and its overall accuracy 51.4%. The nodal (N) factor was correctly determined by CT scan in 35.1%, overstaged in 44.6%, and understaged in 20.3% of the patients., Conclusions: Even with present-day CT scanners (i)TNM provides no accurate staging and routine mediastinoscopy is necessary for precise mediastinal lymph node staging. Likewise, (i)T3 and (i)T4 determinations are unreliable and should not contraindicate thoracotomy.

Precise mediastinal lymph node (LN) staging is imperative in otherwise operable non-small cell lung cancer (NSCLC), as it determines subsequent treatment and possible inclusion in a neoadjuvant trial. The roles of mediastinoscopy and computed tomography (CT) remain controversial. To determine the accuracy of current CT scanners, a prospective study was performed. From April 1993 until September 1995, 100 consecutive patients with NSCLC without distant metastases underwent staging by CT and cervical mediastinoscopy. Naruke's map was used for classification, and LNs larger than 1 cm were considered CT positive. There were 91 males and 9 females, with a mean age of 64 (range 45-82) yrs. Fifty nine tumours were central and 41 peripheral, 64 right-sided and 36 left-sided. Thoracotomy with mediastinal LN sampling was performed in 74 patients, nonoperated patients having multilevel stage IIIA or stage IIIB disease. Twenty five (25%) mediastinoscopies were positive and three were false-negative (3%). There were 29 false-positive CT scans and 12 false-negative. Overall sensitivity and specificity of CT were 63 and 57%, respectively, and of mediastinoscopy 89 and 100%, respectively. Positive and negative predictive values of CT were 41 and 77%, respectively, and of mediastinoscopy 100 and 96%, respectively. Accuracy of CT was 59% and of mediastinoscopy 97%. Accuracy of CT was lowest for left-sided and centrally located tumours, and for LN station 7. Even with current computed tomography scanners, sensitivity and specificity remain low. Although overall cost may increase, routine cervical mediastinoscopy is necessary for precise staging of non-small cell lung cancer, and subcarinal lymph nodes should be routinely sampled.

From January 27, 1992 to December 12, 1994, 100 consecutive patients (86 men and 14 women) with a mean age of 62.5 years underwent lung resection for a non-small cell lung cancer. Squamous cell carcinoma was predominantly found (52%), followed by adenocarcinoma (23%) and large cell carcinoma (18%). Postoperative staging was Stage 0, 1 patient; Stage I, 57; Stage II, 17; Stage IIIa, 20 and Stage IIIb, 5. Thirty-day mortality was 4% (4 patients) with 10.7% for pneumonectomy and 0% for lobectomy or lesser resection. For the whole group 1-, 2- and 3-year survival rates were 83%, 68% and 65% respectively. Survival rates for N0, N1 and N2 after 3 years were 70%, 59% and 54% respectively. In the univariate analysis, a trend to statistical significance was noted between N0 and N1 (p = 0.08). There was no difference in short-term survival between N0 and N2 which represents a highly selected group of patients with N2 disease. In the multivariate analysis the only two independent variables with impact on survival were number of pack-years and diameter of the tumour (p < 0.05). Ninety-two quality of life questionnaires (EORTC QLQ-C30) were sent to home physicians. We collected 31 questionnaires (34%) after 2.5 months. A clear relationship was not seen between complaints of pain or dyspnea and extent of resection or lung function postoperatively. Instead, the global quality of life seemed to be influenced by the extent of resection to the advantage of a lobectomy and disadvantage of a pneumonectomy. Difficulties related to quality of life analysis are discussed and future directions are given.

Between 1988 and 1994, 24 patients underwent 32 procedures for pulmonary metastases. Primary tumours were gastrointestinal, malignant melanoma, osteogenic sarcoma, renal cell carcinoma, head and neck cancer and finally testicular carcinoma. Age ranged from 16 to 78 years, with a female/male ratio of 7/17. Pulmonary metastasectomy was performed in 9 cases through median sternotomy, in 21 cases through thoracotomy and in 2 cases by thoracoscopy. In 9 cases repeated resection was necessary. Overall mortality was 0% (95% confidence limits are 0.00 +/- 14.25). Computed tomography of the chest in combination with tumour markers, were most important during follow-up to detect recurrent disease. The overall 5-year actuarial survival and disease-free survival were 0.56 +/- 0.17 and 0.30 +/- 0.14 respectively. With regard to testicular carcinoma 5-year actuarial survival was 100%. Pulmonary metastasectomy is a recommended procedure in the treatment of selected patients with metastatic pulmonary disease. Resections should be as conservative as possible and if necessary, repeated. In our study this procedure proved especially effective in case of testicular carcinoma.

A case is presented of a 72-year old male patient presenting with a massive intestinal blood loss due to a solitary jejunal metastasis of a poorly differentiated adenocarcinoma of the right lung resected two years earlier. After diagnostic workup and stabilization a small bowel resection with end to end anastomosis was performed. Patient is alive and well 5 months after operation. Solitary bleeding intestinal metastasis of a primary bronchogenic tumour are extremely rare but should be included in the differential diagnosis of gastrointestinal blood loss in a patient with a known bronchogenic tumour. Resection with end to end anastomosis is the treatment of choice.

Two patients are reported in whom an initial diagnosis of disseminated non small cell bronchogenic carcinoma was subsequently changed into a final diagnosis of extragonadal germ cell tumour. The clinical importance of the differential diagnosis between these two malignancies is highlighted and the management of extragonadal germ cell tumours is discussed.