Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease.

BACKGROUND: A high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting. METHODS: We retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD. RESULTS: Among the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005). CONCLUSIONS: The results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD.

[Cardiopulmonary arrest due to massive hemoptysis from bronchiectasis].

A 61-year-old woman was admitted to our hospital because of hemosputum. When chest computed tomography (CT) was performed, sudden and massive hemoptysis occurred. She suffered cardiopulmonary arrest. After resuscitation, different lung ventilation was performed to control hemoptysis from the left lung. Bronchial artery embolization (BAE) was performed, however, hemoptysis recurred, and the left pneumonectomy was performed. She has been free from hemoptysis after operation, and has been discharged from the hospital 73 days after surgery.

[18F-fluorodeoxyglucose positron emission tomography (FDG-PET) negative poorly differentiated adenocarcinoma of lung with mediastinal lymph node metastases].

A 58-year-old woman was referred to our hospital for further medical examination of bilateral lung nodules on the chest computed tomography. Standardized uptake valve (SUV) max of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) were negative value at both lung nodules, but positive value (3.4) at a pretracheal lymph node. The size of the small lung nodule of the left lower lobe (S9) was unchanged, but the lung nodule of the right upper lobe (S1) was gradually enlarged. By the biopsy of the right lung nodule, the poorly differentiated adenocarcinoma was diagnosed pathologically. The right upper lobectomy with mediastinal lymph node dissection was performed. The metastasis was pathologically determined for FDG-PET positive lymph node. The most important reason for negative FDG-PET at primary lesion was considered that the expression of glucose transporter 1 (GLUT-1) was very few. FDG-PET has become a useful tool in the diagnosis of the pulmonary cancer, but we should understand its limitation and diagnose carefully.

Differential diagnosis of sarcomatoid mesothelioma from true sarcoma and sarcomatoid carcinoma using immunohistochemistry.

Differentiation of sarcomatoid mesothelioma from other sarcomatoid tumors involving the pleura and other structures by light microscopy remains an important diagnostic challenge for surgical pathologists. The purpose of the present study was to investigate the utility of diagnostic immunohistochemistry for differentiating sarcomatoid mesothelioma from its histological mimics: true sarcoma and pulmonary sarcomatoid carcinoma. A total of 39 specimens of mesotheliomas with sarcomatoid components, 43 specimens of true sarcomas, and nine specimens of pulmonary sarcomatoid carcinomas were obtained from Japanese patients and examined using a 10-antibody panel (calretinin, WT1, AE1/AE3, CAM5.2, epithelial membrane antigen, desmin, alpha-smooth muscle actin, S-100 protein, CD34, and CD68). CAM5.2 had the highest sensitivity and specificity for differentiating sarcomatoid mesothelioma from true sarcoma. The combination of CAM5.2, WT1, and AE1/AE3 is recommended for routine pathological diagnosis. Accurate clinical information is necessary for differentiating sarcomatoid mesothelioma from sarcomatoid carcinoma.

Immunohistochemical marker panels for distinguishing between epithelioid mesothelioma and lung adenocarcinoma.

The distinction between epithelioid mesothelioma and lung adenocarcinoma remains an important diagnostic challenge for surgical pathologists. The aim of the present study was to select a limited and appropriate panel of antibodies that can differentiate between epithelioid mesothelioma and lung adenocarcinoma. Specimens of 90 epithelioid mesotheliomas and 51 lung adenocarcinomas obtained from Japanese cases were examined using calretinin, WT1, AE1/AE3, CAM5.2, cytokeratin (CK) 5/6, vimentin, epithelial membrane antigen (EMA), thrombomodulin, CEA, CA19-9, and CA125. Ninety-six percent of epithelioid mesotheliomas were positive for calretinin; 99% for WT1; 100% for AE1/AE; 97% for CAM5.2; 70% for CK 5/6; 91% for vimentin; 96% for EMA; 71% for thrombomodulin; 77% for mesothelin; 7% for CEA; 17% for CA19-9; and 85% for CA125. In contrast, 33% of lung adenocarcinomas were positive for calretinin; 16% for WT1; 100% for AE1/AE3, CAM5.2, and EMA; 41% for CK 5/6; 47% for vimentin; 20% for thrombomodulin; 69% for mesothelin; 98% for CEA; 73% for CA19-9; and 80% for CA125. For distinguishing between epithelioid mesothelioma and lung adenocarcinoma, the combination of CEA, calretinin and each WT1 or thrombomodulin was suggested to be the best panel of immunohistochemical markers.

Aberrant methylation and loss of expression of O-methylguanine-DNA methyltransferase in pulmonary squamous cell carcinoma and adenocarcinoma.

O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein that protects cells against the carcinogenic effects of alkylating agents. The methylation status of the MGMT gene was investigated by methylation-specific polymerase chain reaction (PCR) and expression status was investigated by immunohistochemistry in 70 cases of pulmonary squamous cell carcinoma (pulmonary SqCC), including 23 cases of the central type and 47 cases of the peripheral type, and in 53 cases of the peripheral type of pulmonary adenocarcinoma (AC). The frequency of MGMT methylation was 36% in SqCC and 42% in AC. Cases with MGMT methylation correlated significantly with T factor in SqCC (P = 0.047) and AC (P = 0.03). In SqCC, the frequency of MGMT methylation was 26% in the central type and 40% in the peripheral type; a significant correlation was not found (P = 0.29). In AC with mixed subtypes showing MGMT methylation, the level of MGMT expression in the bronchioloalveolar carcinoma (BAC) area (non-invasive status) was significantly higher than that in the papillary or acinar AC area (invasive status; P = 0.0002). This trend was not found in AC with mixed subtypes showing no MGMT methylation (P = 0.10). These findings suggest that MGMT inactivation is an event that occurs in the late carcinogenic process in SqCC and AC, and that AC progress from non-invasive status to invasive status with MGMT inactivation induced by the promoter DNA methylation.

Aberrant methylation of p14(ARF), p15(INK4b) and p16(INK4a) genes and location of the primary site in pulmonary squamous cell carcinoma.

Aberrant methylation of cytosines in CpG islands of the promoter regions of tumor suppressor genes is found in human tumors as a common mechanism of gene silencing. We investigated the methylation status of the chromosome 9p21 gene cluster (p14(ARF), p15(INK4b) and p16(INK4a) genes) by methylation-specific polymerase chain reaction in 20 central and 40 peripheral types of pulmonary squamous cell carcinoma (SqCC) in order to determine the differences between the pathogeneses of the central and peripheral types of SqCC. The frequencies of methylation were 30% for the p14(ARF) gene, 20% for the p15(INK4b) gene and 40% for the p16(INK4a) gene in the central type and 25% for the p14(ARF) gene, 10% for the p15(INK4b) gene and 38% for the p16(INK4a) gene in the peripheral type. Cases in which there was methylation of the p16(INK4a) gene had a higher smoking index in the peripheral type (P = 0.007). This trend was not detected in the central type. Methylation of two or three genes was observed in 55% of methylation in at least one gene of the central type but in only 17% of the peripheral type. This overlap methylation of the chromosome 9p21 gene cluster was found more frequently in the central type (P = 0.02). These findings suggest one of the epigenetic differences between the central and peripheral types of SqCC.

Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung.

We investigated the aberrant promoter hypermethylation of p16, p15 and p14 genes and loss of heterozygosity (LOH) at 9p21-22 in 48 cases of adenocarcinoma of the lung. The frequencies of hypermethylation of genes were as follows: p16, 25.0%; p15, 22.9%; and p14, 18.8%. The frequency of LOH at chromosome 9p21-22 was 60.9%. The frequency of two-hit inactivation of the p16 gene by hypermethylation and LOH was 21.7%. Two-hit inactivation of the p16 gene showed loss of protein expression and was significantly correlated with tumor size, tumor grade and the Ki-67 labeling index. Hypermethylation of the p16 gene was not significantly correlated with hypermethylation of the p15 and p14 genes, both of which are close to the p16 gene locus, suggesting that hypermethylation of these genes occurs selectivity. In conclusion, biallelic inactivation of the p16 gene by hypermethylation and LOH might cause loss of p16 expression and play an important role in the development of adenocarcinoma of the lung. Therefore, controlling and monitoring for hypermethylation of the p16 gene may be partially useful for treatment and early diagnosis of adenocarcinoma of the lung.

Meningioma in mature cystic teratoma of the ovary.

A case of meningioma arising in a mature cystic teratoma of the ovary in a 60-year-old woman is described. The tumor was located in the right ovary, and salpingo-oophorectomy was performed. The right ovary was 10 x 10 x 8 cm in size and contained an unilocular cyst. In the wall, a solid nodule measuring 3 x 3 x 2 cm was noted. Histologically, the cyst wall was composed of typical mature cystic teratoma. In contrast, the mural nodule was composed of the proliferating spindle- and polygonal-shaped cells showing positive staining for epithelial membrane antigen and microcystic change was prominent. These findings were consistent with microcystic meningioma. The arachnoidal cells around mature brain tissue may be the origin of this unusual tumor. To the best of our knowledge, this is the first case of mature cystic teratoma with meningioma of the ovary reported in English medical literature. This case may further indicate the totipotential nature of mature cystic teratoma.

Sarcoidosis with multiple organ involvement emerging as Löfgren's syndrome.

A 52-year-old woman was admitted because of high-grade remittent fever, erythema nodosum, and arthritis which had been lasting two months. Antibiotics did not improve her condition. A chest CT scan examination revealed bilateral hilar and mediastinal adenopathy and multiple nodular opacities in the bilateral lungs. The wedge biopsy of the right lower lobe using video-assisted thoracoscopy presented the histological findings of sarcoidosis. Finally, this case fulfilled the criteria of Löfgren's syndrome. Due to the uncovered cardiac involvement, the systemic glucocorticoid therapy had to be initiated. This case suggests that atypical forms of sarcoidosis should be kept in mind as well, when facing cases with unknown fever.