Takehisa Hashimoto

Surgical strategy for clinical stage I non-small cell lung cancer in octogenarians

OBJECTIVE The purpose of this study was to determine whether lobectomy without radical systematic mediastinal lymphadenectomy (LA) is a satisfactory alternative surgical treatment for octogenarians with clinical stage I non-small cell lung cancer (NSCLC). METHODS From April 1985 through December 2001, 49 patients aged 80 years and older who underwent surgical treatment for clinical stage I NSCLC were reviewed. Lobectomy without radical systematic mediastinal LA was performed for 27 patients (LA0 group) and lobectomy with radical systematic mediastinal LA was performed for 22 patients (LA group). RESULTS The mortality rate was 0% in the LA0 group and 4.5% in the LA group. Five-year survival rate according to the type of surgery was 44.8% in the LA0 group and 55.5% in the LA group, a difference that was not significant (P=0.88). Although there was no significant statistical difference, postoperative pulmonary complication was more frequent in the LA group than in the LA0 group (32% in the LA group versus 11% in the LA0 group P=0.07). Five-year survival rates according to serum carcinoembryonic antigen (CEA) levels were 0% for patients with elevated CEA levels (n=9) and 56.5% for patients with normal CEA levels (n=40) (P<0.01). CONCLUSION Lobectomy without radical systematic mediastinal LA appears to be a satisfactory surgical procedure for octogenarians with clinical stage I NSCLC. However, mediastinoscopy is necessary in such octogenarians if their serum CEA level is elevated so that the precise clinical stage can be determined and an accurate prognosis can be given.

Molecular markers for reinforcement of histological subclassification of neuroendocrine lung tumors

The degree of malignancy of neuroendocrine lung tumors (NEs) increases in this order: from typical carcinoids (TCs) through atypical carcinoids (ACs) to large cell neuroendocrine carcinomas (LCNECs) and small cell lung carcinomas (SCLCs). However, histological classification has sometimes proved difficult. We here investigated loss of heterozygosity (LOH) using eight microsatellite markers and expression of p53, Bcl‐2 and Bax proteins using immunohistochemical methods in 57 NEs (19 TCs, 5 ACs, 14 LCNECs and 19 SCLCs), looking for objective genetic markers to distinguish between subtypes. The frequencies of LOHs on D3S1300, RBi2 and TP53, the combinations of LOH status for RBi2 and TP53, and the immunohistochemically demonstrated Bcl‐2/Bax ratios and p53‐positive rates significantly differed among histopathologically diagnosed NEs. Differentiation between TC and AC was possible with reference to LOH on D3S1300, RBi2 and TP53, and the combined LOH status on RBi2 and TP53 (i.e., both LOH(‐) versus one LOH(+)). For comparison between AC and LCNEC+SCLC, LOH on TP53 or the combination of two markers—one LOH(+) versus both LOH(+)—was applied. Furthermore, in three discordant cases of diagnoses based on histology and LOH markers, diagnoses using the latter were considered to be more probable by survival analysis. The present study indicated that assessment of LOHs using microsatellite markers could provide objective markers that can distinguish subtypes of NEs, for which histological assessment may commonly result in disagreement.

Different Subtypes of Human Lung Adenocarcinoma Caused by Different Etiological Factors : Evidence from p53 Mutational Spectra

Human lung adenocarcinomas are only relatively weakly associated with tobacco smoke, and other etiological factors need to be clarified. These may also vary with the histopathology. Because the p53 mutation status (frequency and spectrum) of a carcinoma can provide clues to causative agents, we subclassified 113 adenocarcinomas into five cell types: hobnail, columnar/cuboidal, mixed, polygonal, and goblet (54, 23, 18, 13, and 5, respectively) and investigated relationships with p53 mutations and smoking history. In the hobnail cell type, a low mutational frequency (37%) and a high proportion of transitions (65%), especially G:C to A:T transitions at CpG dinucleotides (45%) associated with spontaneous mutations, were found with a weak relation to tobacco smoke. In contrast, a high mutation frequency (70%) with a higher proportion of transversions (50%), especially G:C to T:A (44%) on the nontranscribed DNA strand, caused by exogenous carcinogenic agents like tobacco smoke, were observed for the columnar cell type, as with squamous cell carcinomas. These results indicate that two major subtypes of lung adenocarcinoma exist, one probably caused by tobacco smoke, and the other possibly due to spontaneous mutations. For the prevention of lung adenocarcinomas, in addition to stopping tobacco smoking, the elucidation of endogenous mechanisms is important.

Absence of gene mutations in KIT-positive thymic epithelial tumors

BACKGROUND Overexpression of KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is observed in human neoplasms such as gastrointestinal stromal tumors (GISTs), myeloproliferative disorders, melanoma and seminoma. In patients with GIST, overexpression of mutated KIT within the tumor is predictive of response to molecular targeted therapy using imatinib. However, the role of KIT expression in thymic carcinoma is not fully understood. METHODS Thymic epithelial tumors from 37 patients (17 thymic carcinomas and 20 thymomas) were examined. Immunohistochemical staining with anti-KIT polyclonal antibody and anti-CD5 was performed. Mutation analyses in the juxtamembrane domains, exons 9 and 11, and in the tyrosine kinase domains, exons 13 and 17, were undertaken using polymerase chain reaction (PCR) and direct DNA sequencing in KIT-positive samples. RESULTS KIT- and CD5-positive staining was observed only in thymic carcinoma. Percentage of positive staining was 100% in squamous cell carcinoma, with no positive staining in other histologies, including atypical carcinoid. Mutation analysis of the KIT gene was performed in 11 squamous cell carcinomas, 1 adenocarcinoma and 1 adenosquamous cell carcinoma. None of the tested samples showed mutations in any of the four exons. CONCLUSIONS Squamous cell carcinoma of the thymus frequently expressed KIT and CD5 proteins, whereas other tumors did not. Unlike GIST, overexpression of KIT does not necessarily indicate gene mutation in thymic carcinoma. KIT and CD5 appear useful for evaluating and subtyping thymic epithelial tumors.

Complications associated with pulmonary resection in lung cancer patients on dialysis

BACKGROUND There are few studies available investigating the perioperative problems experienced by lung cancer patients on dialysis undergoing pulmonary resection. METHODS A retrospective review of 7 patients on dialysis undergoing pulmonary resection for lung cancer was performed. RESULTS The patient population consisted of 7 men, with a mean age of 59.9 years. The underlying kidney disease was glomerulonephritis in 5 patients and nephrosclerosis in 2. The mean levels of blood urea nitrogen and serum creatinine were 70.7 mg/dL and 9.4 mg/dL, respectively. Histologic diagnoses were adenocarcinoma in 2 patients and squamous cell carcinoma in 5. Standard lobectomy with lymph node dissection was performed in all cases. There was one operation related death due to pulmonary edema and subsequent development of pneumonia. There were two cases of sputum retention and four of hyperkalemia. One patient died of cerebral bleeding that occurred during dialysis 2 months postoperatively. CONCLUSIONS In patients on dialysis who undergo pulmonary resection, there is a high incidence of pulmonary complications, in addition to hyperkalemia, hemodynamic instability, and a tendency for postoperative dialysis-associated bleeding.

Abnormal FHIT transcripts found in both lung cancer and normal lung tissue.

Occurrence of abnormal transcripts of the FHIT (fragile histidine triad) gene has been reported in various types of cancer. On the other hand, aberrant transcripts are sometimes found in non‐neoplastic tissues, so the relationship between the presence of abnormal transcripts of the FHIT gene and cancer pathogenesis is controversial. We investigated alterations in the FHIT locus, detected by nested reverse transcription‐polymerase chain reaction and/or allelic status, in 88 primary lung cancers and normal lung tissues, and 22 normal lung tissues with metastasitic lung cancer as a control. The frequencies of abnormal transcripts were 59% in lung cancer, 35% in paired normal lung, and 64% in normal control lung; the difference in frequencies between lung cancer and paired normal lung was significant, while that between lung cancer and normal control lung was not. Sequence analysis revealed that there were no cancer‐specific abnormal transcripts entirely missing two or more exons, nor were the abnormal transcripts of lung cancer identical with those of paired normal lung in the same individual. Furthermore, we found no correlation between loss of heterozygosity in the FHIT locus and occurrence of abnormal FHIT transcripts. These results suggest that the presence of abnormal FHIT transcripts, in terms of their frequency and variety, is not cancer‐specific in lung carcinogenesis, and the abnormality may be mainly due to abnormal splicing and processing of the transcripts. To estimate the precise function of the FHIT gene, further study of the FHIT protein in lung carcinogenesis is needed. Genes Chromosomes Cancer 24:105–111, 1999.

The predominant expression of hepatocyte nuclear factor 4α (HNF4α) in thyroid transcription factor-1 (TTF-1)-negative pulmonary adenocarcinoma.

Kunii R, Jiang S, Hasegawa G, Yamamoto T, Umezu H, Watanabe T, Tsuchida M, Hashimoto T, Hamakubo T, Kodama T, Sasai K & Naito M
(2011) Histopathology58, 467–476
The predominant expression of hepatocyte nuclear factor 4α (HNF4α) in thyroid transcription factor‐1 (TTF‐1)‐negative pulmonary adenocarcinoma

Three New Regions on Chromosome 17p13.3 Distal to p53 with Possible Tumor Suppressor Gene Involvement in Lung Cancer

We investigated loss of heterozygosity (LOH) at the distal portion of the p53 gene on the short arm of chromosome 17 in lung cancers in order to search for new tumor suppressor genes. The roles of the putative genes were also studied in terms of pathological features. One hundred and forty‐five resected non‐small cell lung cancers were examined for LOH using 11 markers mapped on, and distal to the p53 locus, and deletion maps were constructed. Four commonly deleted regions were found: one from TP53 to ENO3, where the p53 gene resides, and three others from ENO3 to D17S1566, D17S379 to D17S1574 and distal to ABR, with LOH frequencies almost the same as, or higher than, at the TP53 locus. Examination of the relationship between LOH of the latter three regions and histopathological parameters of adenocarcinomas (genetically negative for p53 mutation) revealed allelic losses on D17S379 to be associated with advanced lesions, while D17S513 was more frequently deleted in poorly differentiated tumors. These results indicate that new tumor suppressor gene(s) may reside on these three distinctly deleted regions on chromosome 17p13.3 distal to the p53 gene in lung cancer, with possible roles in progression and differentiation of adenocarcinomas.

Successful removal of massive cardiac neurilemoma with cardiopulmonary bypass

A 46-year-old woman was referred to our hospital because of cardiac enlargement seen on a chest radiograph. Imaging studies showed a massive intrapericardial tumor with a size of 12x8x7 cm. Tumor dissection included inspection of the inner aspect of the superior vena cava with use of cardiopulmonary bypass, because the mass was tightly adherent to both superior vena cava and right atrium. The pathologic diagnosis was neurilemoma.

Lobectomy Versus Segmentectomy in Radiologically Pure Solid Small-Sized Non-Small Cell Lung Cancer.

BACKGROUND The indication for limited resection of radiologically pure solid non-small cell lung cancer (NSCLC) is controversial owing to its invasive pathologic characteristics. This study was performed to compare the outcomes after lobectomy and segmentectomy in these NSCLC patients. METHODS We retrospectively reviewed 251 patients with radiologically pure solid cT1a N0 M0 NSCLC who underwent lobectomy or segmentectomy, and the preoperative characteristics of the patients treated with the two operative techniques were matched using propensity score methods. Overall survival (OS) and disease-free survival (DFS) curves were compared using the log rank test, and differences in survival were also evaluated by the McNemar test. The preoperative factors and surgical procedure were analyzed with the multivariate Cox proportional hazards regression model to identify independent predictors of poor OS and DFS. RESULTS In the propensity score matched lobectomy and segmentectomy groups (87 patients per group), the 5-year and 10-year OS rates were 85% versus 84% and 66% versus 63%, respectively; and the 5-year and 10-year DFS rates were 80% versus 77% and 64% versus 58%, respectively. There were no significant differences between the two groups in OS or DFS by the log rank test, and also no significant differences in 3-year, 5-year, or 7-year OS or DFS by the McNemar test. Although age, smoking status, pulmonary function, and carcinoembryonic antigen were identified as significant predictors of both OS and DFS, the surgical procedure was not identified. CONCLUSIONS Similar oncologic outcomes after lobectomy and segmentectomy were indicated among patients with radiologically pure solid small-sized NSCLC.