The incidence of adenocarcinoma as a percentage of the number of patients diagnosed with all types of lung cancer has increased recently. The cytology of sputum, brushing, or aspiration is the simplest and the most accurate method for the diagnosis of lung carcinoma along with histologic biopsy. The exfoliated cancer cells in sputum are large, usually round or polygonal, occasionally columnar, and are found in clusters or singly. The cell clusters have a three-dimensional papillary or spherical configuration. Cytoplasm of the cancer cells is pale or finely vacuolated. The large mucin vacuoles displace the nucleus to one side. The nuclei of adenocarcinoma are large with finely granular chromatin with prominent nucleoli. In bronchial brushing specimen, the tumor cells are more abundant than in sputum. Cancer cells appear in papillary clusters, or in sheets of large round or polygonal cells. The nuclei may be clear and vesicular and have visible and prominent nucleoli. Atypical type II pneumocytes are potentially important source of false-positive diagnosis of adenocarcinoma. The reactive pneumocytes are large cells with prominent nucleoli occurring singly and in small clusters. Differentiation of primary from metastatic adenocarcinoma of similar histologic type is clinically important but may prove impossible on cytologic criteria alone. There are cytologic patterns in which a preference for the primary site of origin of a metastatic carcinoma may be expressed.

View full abstract

Objective. To demonstrate the characteristic clinical features of acute exacerbation of interstitial pneumonia (IP) associated with lung cancer after anti-cancer treatment. Methods. Consecutive 776 cases with lung cancer between June 1999 and April 2007 were retrospectively evaluated to clarify the clinicopathological characteristics of acute exacerbation of IP associated with lung cancer after anti-cancer treatment. Results. Among 776 cases of lung cancer, 39 cases (5%) had concomitant IP. Acute exacerbation of IP after treatment was found in 6 of the 39 cases (15%), and 4 cases (10%) died of respiratory failure. There were no significant differences in LDH, KL-6, SP-D, PaO₂, %VC, or %DLco between the acute exacerbation group and the non-acute exacerbation group before anti-cancer treatment. Of the 6 cases with acute exacerbation of IP after treatment, exacerbation occurred after chemotherapy in 5 out of 24 cases (21%), and after surgical resection of the lung cancer in 1 out of 6 cases (17%). Among the 6 cases with acute exacerbation of IP, the subclassification of IP was IPF in 4 and collagen vascular disease-IP (CVD-IP) in 2. Among the 4 cases who died of respiratory failure after acute exacerbation of IP, the underlying systemic disease was IPF in 2 and CVD-IP in 2. Conclusion. Both IIPs and CVD-IP should go through the anti-cancer treatment, keeping the possibility of acute exacerbation of IP in mind.

View full abstract

Purpose. The aim of this study was to evaluate the efficacy and toxicity of weekly paclitaxel and carboplatin with concurrent radiation therapy for locally advanced non-small cell lung cancer (NSCLC). Patients and Methods. Between December 2001 and March 2005, 15 patients with locally advanced unresectable stage III NSCLC were treated with concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 40 mg/m² given on days 1, 8, 15, 22, 29, 36, 43 during 66 Gy of thoracic radiotherapy. Results. Enrolled patients were 12 men and 3 women, with the median age of 67 years. Thirteen patients received the scheduled radiotherapy. The cycles of chemotherapy administered ranged from 4 to 7, with a median of 6. Overall toxicities were mild. Grade 3 esophagitis was noted in 1 patient, but there were no cases of grade 3/4 pneumonitis. The overall response rate was 86.7%. The median survival time and 5-year survival rate were 37.7 months and 40.0%, respectively. Conclusion. Weekly paclitaxel and carboplatin with concurrent radiation therapy is feasible and promising for locally advanced non-small cell lung cancer.

View full abstract

Objective. We set out to detect primary lung cancer (PLC)-associated proteins using 2-dimensional polyacrylamide gel electrophoresis (2-DE) analysis and to identify the protein molecules for the exploration of biomarkers reflecting the biological characteristics of lung cancer. Study Design. We prepared samples for 2-DE from representative histological types of primary lung cancer; squamous cell carcinoma, adenocarcinoma and small cell carcinoma. We selected 8 cases of well or moderately differentiated squamous cell carcinoma confirmed postoperativly to possess typical histological features of primary lung squamous cell carcinoma. The mixture that contained equal amounts of these 8 samples was taken to be a standard sample of lung squamous cell carcinoma. Similary, we selected 8 cases of well or moderately differentiated adenocarcinoma to prepare a standard sample of primary lung adenocarcinoma. We also mixed specimens of 4 cases of small cell carcinoma, and prepared a standard sample of small cell carcinoma. We then labeled each standard sample with a fluorescent dye (either Cy2, Cy3 or Cy5) according to the manufacturer's protocol. Furthermore, using mass spectrometry we identified protein molecules that were detected in 2-DE analysis, followed by validation analysis by immunohistochemistry. Results. We detected 19 kinds of squamous cell carcinoma-associated spots (eSq), 16 kinds of adenocarcinoma-associated spots (eAd) and 17 kinds of neuroendocrine carcinoma-associated spots (eNE). From these spots, 6 kinds of eSq-protein molecules and 8 kinds of eAd-protein molecules were identified. Eight protein molecules out of these 14 identified molecules were cytokeratin (CK) molecules. CK5, CK6A, CK6C, CK6D and CK17 were identified as eSq-protein molecules, and furthermore CK8, CK18 and CK19 were identified as eAd-protein molecules. The results of a validation analysis using immunohistochemistry indicated a high possibility that CK5, CK5/6 and CK17 are biomarkers for squamous cell carcinoma, and that CK18 is a biomarker for adenocarcinoma. We succeeded in showing a significant relationship between the histopathological differentiation of PLC and the expression of CKs. Conclusion. There is a strong possibility that the biological characteristics of lung carcinoma may be clarified by classification based upon proteomic analysis, and the results of proteomic analysis may be applied to the selection of therapeutic strategies of PLC.

View full abstract

Background. Pleomorphic carcinoma is a rare primary pulmonary malignancy with an incidence rate of about 0.3% of all lung tumors. We report a case of pulmonary pleomorphic carcinoma with a cavity. Case. A 62-year-old man was referred to our hospital with persistent cough since about 2 months previously. Chest X-ray film showed a cavitating mass lesion in the left upper lung field. Chest CT showed a cavitating mass lesion 4 cm in diameter with irregular walls in the left upper lobe. Non-small-cell lung cancer was diagnosed by transbronchial lung biopsy, and we performed left upper lobectomy with hilar and mediastinal lymph node dissection. Histological findings showed that the squamous cell carcinoma consisted of spindle cell and giant cell components. Therefore, we diagnosed pulmonary pleomorphic carcinoma (pT2N0M0, stage IB). Eight months after the operation, the patient is alive without any sign of recurrence. Conclusion. Some reports show the prognosis of pleomorphic carcinoma to be very poor. Hence, strict follow-up is necessary for such patients.

View full abstract

Background. Pulmonary carcinosarcoma is a rare malignant tumor that contains both carcinoma and a true sarcomatous component. Case 1. The patient was a 67-year-old man who complained of nocturnal cough. Chest CT showed a 5.5×2.8×2.3 cm tumor. Bronchoscopy revealed a fungiform tumor at the inlet of right B¹. Right upper lobectomy and lymph node dissection (ND2a) were performed, and pathological examination revealed carcinosarcoma (pT2N0M0, stage IB). On postoperative day 200, head CT revealed a brain metastasis. Resection of the brain tumor was subsequently performed. Case 2. The patient was a 74-year-old man with abnormal chest CT findings. During follow-up after graft replacement of an aortic aneurysm, chest CT scans revealed a 6.2×4.4×3.7 cm tumor extending from the right postero-inferior mediastinum to the right thoracic space, mediastinal lymph node enlargement, and nodules in the bilateral lung fields. Bone scintigraphy showed multiple bone metastases. Pathological examination of a thoracoscopic biopsy specimen revealed pulmonary carcinosarcoma. Therefore, he was diagnosed as having stage IV carcinosarcoma, cT2N2M1 (PUL, OSS). Chemotherapy was given with cisplatin and vinorelbine, and the primary tumor decreased in size. However, he died of meningeal carcinomatosis about 6 months after the CT detected the tumor. Conclusion. Some resected cases of carcinosarcoma are reported to achieve long-term survival, but the overall prognosis of this malignancy is reported to be poor. We believe that surgery and chemotherapy for pulmonary carcinosarcoma need to be assessed by accumulation of more cases.

View full abstract

Background. Signet-ring cell carcinoma (SRCC) is common in the stomach, but it is rare in the lung. Case. A 74-year-old man was admitted to our hospital with continued high fever and massive pleural effusion. CT scan showed massive right pleural effusion and a nodular lesion in the right upper lobe. The CT-guided lung biopsy specimen yielded a diagnosis of adenocarcinoma. Right upper lobectomy with hilar and mediastinal lymph node dissection was performed. Histopathological examination demonstrated signet-ring cell carcinoma components in 80% of the specimen. The tumor cells were immunohistochemically positive for TTF-1 (thyroid transcription factor-1), SP-A (surfactant apoprotein A) and CK7 (cytokeratin-7), but not for CK20 (cytokeratin-20). The pathological stage was IIIA (T1N2M0). There was no evidence of any other primary or metastatic site. Conclusion. Signet-ring cell carcinoma is generally found in digestive organs and is very rare in the lung, but we should keep in mind that primary signet-ring cell carcinoma can originate in the lung.

View full abstract

Background. Malignant mesothelioma sometimes accompanies pneumothorax, but there have been few reports of malignant mesothelioma with continuous air leakage. We report a patient with malignant mesothelioma who was initially recognized as having massive pleural effusion and ipsilateral pneumothorax on chest roentgenogram on a medical examination. Case. A 43-year-old woman was found to have a right pneumothorax and massive pleural effusion on chest roentgenogram. As malignant pleural mesothelioma was suspected based on her chest computed tomogram findings after pleural drainage, thoracoscopic examination was performed. Multiple tumors were seen on the parietal pleura, and air leakage was detected from many sites of rupture of the visceral pleura when the lung was inflated. Pathological diagnosis of the tumor was malignant epithelial mesothelioma, and right extrapleural pneumonectomy was performed. Pathological examinations showed pleural injury due to tumor. Despite postoperative radiotherapy and chemotherapy, the patient died of tumor recurrence 25 months postoperatively. Conclusion. We encountered a case of malignant pleural mesothelioma demonstrating continuous air leakage. It seems necessary to carefully investigate the possibility of malignant disease when pneumothorax is detected in a patient over the age of 40.

View full abstract

Background. We report a rare case of mucosa-associated lymphoid tissue (MALT) lymphoma accompanied by pleural effusion. Case. A 78-year-old man, on human T-cell lymphotropic virus type-1 (HTLV-1) carrier, was found to have a nodular lesion in the right lower lung field on a screening chest radiography in 1998. Transbronchial biopsy did not yield a diagnosis. The lesion increased during follow-up, and he was readmitted due to dyspnea on exertion in November 2001. Chest radiography and CT scan showed an ill-defined mass in the right lower lobe with pleural effusion. Pleural puncture revealed bloody, exudative, lymphocytic pleural effusion. The diagnosis obtained after middle and lower bilobectomy was MALT lymphoma by immunohistochemical and gene analysis of tissue specimens. He received no adjuvant chemotherapy and is still alive without recurrence 65 months after the operation. Conclusion. Complete resection may improve the outcome of pulmonary MALT lymphoma even if it is accompanied by pleural effusion.

View full abstract

Background. Malignant pleural mesothelioma is classified into epithelioid type, sarcomatoid type and biphasic type histologically, and a case showing differentiation to bone is rare. Case. A 78-year-old woman presented with back pain and dyspnea. We diagnosed her condition as malignant pleural mesothelioma based on the findings of chest CT and cytology of pleural effusion. Bone scintigram on admission showed accumulation of RI as a site, corresponding to that of the tumor. We provided a symptomatic treatment in consideration of systemic state of the patient, but she died about 2 months later. At autopsy we established a diagnosis of malignant pleural mesothelioma of the sarcomatoid type accompanied by differentiation to osteosarcoma. Only 6 cases of malignant pleural mesothelioma with differentiation to bone tissue have been reported in Japan, but there are extremely few cases of differentiation to osteosarcoma. This case may suggest the multipotentiality of mesothelial cell as the mechanism of differentiation to osteosarcoma. The possibility of asbestos exposure was not clear in this case. Conclusion. We reported one autopsy case of malignant pleural mesothelioma with differentiated to osteosarcoma.

View full abstract

Objective and Methods. Lung cancer is one of the most lethal and increasing cancer world-wide. Lung cancer is composed of a wide range of distinct histological subtypes (small cell lung carcinoma, adenocarcinoma, squamous cell carcinoma and large cell neuroendocrine carcinoma), however, the overall genetic alterations of these tumors remain unclear. To analyze the genetic alterations of lung adenocarcinoma in a genome-wide way, we employed laser-capture microdissection of cancer cells and array CGH focusing on 800 chromosomal loci containing cancer related gene. Results. We analyzed 55 primary lung adenocarcinoma cases. We identified a large number of chromosomal numerical alterations including frequent amplifications on 7p12, 11q13, 12q14-15 and 17q12 and 2 homozygous deletions on 9p21 and 1 on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed 3 sub-groups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history, gender and the frequency of EGFR (Epidermal Growth Factor Receptor) mutation. The mutation status of EGFR was significantly associated with specific genetic alterations. Conclusion. Our results suggest that there exist multiple molecular-carcinogenesis pathways in lung adenocarcinoma which may associate with smoking habits and gender. Genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patients' prognosis and discovering novel cancer related genes including therapeutic targets.

View full abstract

Objective. Unsupervised hierarchical clustering in expression profiling analyses allows molecular classification of tumors, based on the similarity of the genome-wide expression patterns. This new molecular-based classification shares the current pathological classification in part, though it also provides additional clues to identify cancers by their biological groups. Here, we introduce a novel means of molecular classification of lung cancer. Study Design. We examined the gene expression profiling analyses of lung cancers published so far. Results. The molecular classification can differ from the current classification schema, dividing lung cancers into 2 distinct branches. One of the branches includes adenocarcinoma alone, which is associated with a normal expression profile, while the group in the other branch is composed of all 4 histological subtypes. The former subset of adenocarcinomas is characterized by frequent development in females and non-smokers, expression of thyroid transcription factor-1 and surfactant proteins, and specific involvement of EGFR gene mutation, suggesting a distinct subset of lung adenocarcinoma. Conclusion. The molecular classification based on expression profile revealed biological significance of the cellular lineage of the lung cancer.

View full abstract

Recent progress of molecular targeting medicine has been changing the concepts of cancer therapy. No one doubts about the importance of accumulating molecular expression data generated by high throughput analyses for upcoming personalized therapy. Tissue microarray, which can hold up to 1500 cores in a set, is an indispensable method among those high throughput techniques and is an excellent translational tool that connects the basic research to the clinical application. We discuss the usefulness of tissue microarrays, especially high density tissue microarrays, regarding future cancer therapy.

View full abstract

Adenocarcinomas developed in peripheral lung generally progress to invasive carcinoma through bronchioloalveolar carcinoma (BAC). When classifying small sized lung adenocarcinomas that include a BAC component pathologically, it is reasonable to divide them into two groups: replacement type and non-replacement type. Although the latter is invasive regardless of its size, the former group that includes a BAC component, particularly pure-BAC which is in situ carcinoma, shows an extremely favorable prognosis, although the prognosis becomes worse as fibroblast proliferation progresses. Many studies have examined the relationship between fibrosis or fibroblast proliferation and outcome, and morphologically, ratio between areas of fibrosis and fibroblast proliferation is known to affect outcome. Molecular biological studies have shown that BAC has a characteristically high rate of Bax inhibitor-1 expression and frequent mutation of epidermal growth factor receptor (EGFR) gene, but BAC does not show hypermethylation of p16 gene. These differences between BAC and non-BAC indicate that the character of BAC clearly differs from that of invasive adenocarcinoma (non-BAC).

View full abstract

Objective. To elucidate the histogenesis of pulmonary squamous cell carcinoma in terms of the location (central or peripheral) by analyzing the various genetic alterations and protein expressions. Methods. As a model of multistep carcinogenesis of central type squamous cell carcinoma, the various preinvasive lesions including hyperplasia, dysplasia and squamous cell carcinoma in situ were collected, and analyzed the abnormalities of tumor suppressor genes, especially p53 gene. Moreover, concerning the peripheral type squamous cell carcinoma, the abnormal methylation of p14, p15 and p16 genes and p16 expression were analyzed, and moreover, the expression of differentiation markers including Maspin, p63 and TTF-1 were also immunohistochemically analyzed. Results. The accumulation of genetic alterations was observed according to the atypia in dysplasias and squamous cell carcinoma in situ. The higher frequency of abnormal methylation of various genes in central type squamous cell carcinomas was observed comparing with peripheral type. In the peripheral type squamous cell carcinomas, the methylation of p16 gene and smoking index were well correlated. Some peripheral type squamous cell carcinomas showed positivity for TTF-1, usually not detected in squamous cell carcinomas. Conclusion. The analyses of profiles of genetic and epigenetic alterations and the expressions of various genes among dysplasia and squamous cell carcinomas would be useful to speculate on the histogenesis.

View full abstract

Classification of lung neuroendocrine (NE) tumors has changed greatly since the introduction of large cell neuroendocrine carcinoma (LCNEC) and the abolition of small cell carcinoma (SCLC) intermediate cell type. Carcinoid is now divided into typical and atypical types (TC and AC) and it has been proved that there is a prognostic difference between the two. However, presentation of the 4 types of NE tumors like TC-AC-LCNEC-SCLC is misleading. Carcinoid differs from carcinoma in terms of epidemiology, pathology, genomics and therapeutics. It is proposed that lung NE tumors should be divided into two: carcinoid and high-grade NE carcinoma and subsequently each should be subclassified. Expression profiling couldn't distinguish LCNEC from SCLC, rather it detected 2 prognostically different groups. It seems that different signal pathways are activated in the 2 groups. Interestingly, evidence shows that SCLC has a nature of lung precursor cells, possibly explaining its good responsiveness to chemotherapy. In future, there will be growing interests on the chemo-responsiveness of LCNEC.

View full abstract

Objective. Small sized peripheral lung lesions are often resected without obtaining cytopathological diagnosis based on the result of advanced imaging technique. We have improved the preoperative diagnostic accuracy and provided information on prognosis by using the technique of a rapid cytological diagnosis. Method and Result. We used modified rapid Shorr stain as a rapid cytology test, by which we could immediately report cytological diagnosis in about one minute. In bronchoscopy, when rapid cytology test yielded no diagnosis, additional bronchoscopic examinations were performed. The integration of rapid cytology test into bronchoscopic examination improved diagnostic sensitivity of lung cancer of 2 cm or less from 64% to 92%. Moreover, the tumor stamp cytology of resected adenocarcinoma of 2 cm or less was classified into 5 types, and relationship with the prognosis was clarified. The prospective study to verify whether this classification adds to the decision for limited operation is ongoing. Conclusion. The cytopathlogy of respiratory organ can promptly offer various information as long as an appropriate specimen is obtained.

View full abstract

Recently in Japan, the incidence of mesothelioma has increased extremely, as a reflection of amounts of the use of asbestos in 1960's through 1990's. By the establishment of a new law for non-occupational asbestos-exposure in addition to the present system for occupational asbestos-exposure, the relief and compensation has be widely provided, and in these condition, the diagnosis of mesothelioma is an important point, and in particular the accuracy of pathological diagnosis as mesothelioma is required. As mesothelioma is a rare tumor in the past and the histological type shows a wide variety, diagnostic accuracy needs to be improved. As immunohistochemical staining is very useful using various antibodies as positive or negative markers of mesothelial cells, it is recommended that the diagnosis should be made by selecting adequate antibodies according to the histological types of mesothelioma.

View full abstract