Shin-ya Ogata

Carcinosarcomas (malignant mullerian mixed tumors) of the uterus and ovary: a genetic study with special reference to histogenesis.

The histogenesis of carcinosarcomas (malignant mullerian mixed tumors) of the female genital tract is still not completely understood. In the present study, several different molecular pathologic techniques were applied to determine the histogenesis of 15 uterine and ovarian carcinosarcomas. The patterns of X-chromosome inactivation and the presence of p53 and K-ras mutations were analyzed in the carcinomatous and sarcomatous components. Microsatellite analysis was also performed. Ten tumors were monoclonal, one was biclonal (collision tumor), and another was probably biclonal; the other three were of indeterminate histogenesis. These data indicate that most uterine and ovarian carcinosarcomas are monoclonal.

New IASLC/ATS/ERS Classification and Invasive Tumor Size are Predictive of Disease Recurrence in Stage I Lung Adenocarcinoma

Introduction: The purpose of this study is to analyze and validate the prognostic impact of the new lung adenocarcinoma (ADC) classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society and invasive tumor size in stage I lung ADC of Japanese patients. Methods: We reclassified 191 stage I ADCs according to the new classification. The percentage of each histological subtype and the predominant type were determined. In addition, both total tumor size and invasive tumor size were examined. The relationship between these results and clinicopathological backgrounds was investigated statistically. Results: The 5-year disease-free survival (DFS) of adenocarcinoma in situ and minimally invasive adenocarcinoma was 100%; lepidic-predominant ADCs, 94.9%; papillary-predominant ADCs, 85.4%; acinar-predominant ADCs, 89.7%; and solid-predominant ADCs, 54%. The predominant growth pattern was significantly correlated with DFS (p < 0.001, overall). With regard to tumor size, total tumor size was not correlated with DFS (p = 0.475, overall), however, invasive tumor size was significantly correlated with DFS (⩽0.5 cm/ > 0.5cm, ⩽1cm/ >1 cm, ⩽2 cm/>2 cm, ⩽3 cm/ >3cm, 100%/91.5%/85.9%/80.8%/66.7%% in 5-year DFS) (p = 0.006, overall). A multivariate analysis showed solid-predominant and invasive tumor size were independent predictors of increased risk of recurrence (solid versus nonsolid: hazard ratio = 4.08, 95% confidence interval:1.59–10.5, p = 0.003; invasive tumor size: hazard ratio = 2.04, 95% confidence interval:1.14–3.63, p = 0.016). Conclusion: The new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society ADC classification and invasive tumor size are very useful predictors of recurrence of stage I ADCs in Japanese patients.

The Correlation of the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) Classification With Prognosis and EGFR Mutation in Lung Adenocarcinoma

BACKGROUND The purpose of this study was to validate the prognostic effect and the frequency of mutations in the gene expressing epidermal growth factor receptor (EGFR) in lung adenocarcinoma of Japanese patients, on the basis of the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. METHODS The new classification was used to reclassify 486 adenocarcinomas. The percentage of each histopathologic subtype and the predominant pattern were determined. EGFR mutation was also investigated. The relationship between these results and clinicopathologic backgrounds was investigated statistically. RESULTS No patients with adenocarcinoma in situ or minimally invasive adenocarcinoma died within the follow-up periods, followed by patients with lepidic predominant. Patients with papillary or acinar predominant, or invasive mucinous adenocarcinoma, showed almost similar overall survival (OS). The patients with solid predominant and micropapillary predominant showed the worst OS. Multivariate analysis showed that the new classification was an independent predictor of OS. The frequency of EGFR mutation was adenocarcinoma in situ (62%), minimally invasive adenocarcinoma (60%), lepidic (77%), acinar (49%), papillary (50%), solid (28%), micropapillary (43%), and invasive mucinous adenocarcinoma (0%). CONCLUSIONS This new adenocarcinoma classification is a very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma.

Microsatellite alterations and target gene mutations in the early stages of multiple gastric cancer

Multiple gastric cancers may develop through the same genetic background: the mutator pathway due to defects in DNA mismatch repair genes, or the suppressor pathway due to defects in tumour suppressor genes. To clarify the critical genetic events in the early stages of multiple gastric cancer development, 29 early and four advanced gastric cancers were examined from 12 patients. Microsatellite alterations were studied involving microsatellite instability (MSI) and loss of heterozygosity (LOH) at tumour suppressor loci, representative of the mutator pathway and the suppressor pathway, respectively, as well as mutations of target genes (TGF‐β RII, BAX, hMSH3, and E2F‐4). MSI was determined in ten cancers (10/33; 30.3%) from seven patients (7/12; 58.3%). LOH was detected in six cancers (6/33; 18.2%) from five patients (5/12; 41.7%), most frequently at TP53, in four cancers (4/33; 12.1%) from four patients (4/12; 33.3%). In cases with multiple gastric cancers in the same stomach, the MSI status was generally the same, but in two patients (2/12; 16.8%) a tumour with MSI‐H and another with LOH were found to co‐exist in the same stomach. As for mutations of the target genes, it was found that E2F‐4 was mutated in six cancers (6/33; 18.2%) from four patients (4/12; 33.3%). Furthermore, identical E2F‐4 mutations were detected in four of the six intestinal metaplastic mucosae adjacent to each cancer carrying an E2F‐4 mutation. No mutations were detected in the other target genes. In conclusion, the present results indicate that the majority of multiple gastric cancers develop from the same genetic background, with the mutator pathway playing a more important role than the suppressor pathway. Mutations of E2F‐4 are early events in multiple gastric cancer development, occurring even in the intestinal metaplastic mucosa, with mutations of other target genes to follow during cancer progression. Copyright

Absence of BAT-26 instability in gastric intestinal metaplasia

BAT‐26 instability, a sensitive marker for the high‐frequency microsatellite instability (MSI‐H) phenotype, was analyzed in samples of gastric cancer and in adjacent intestinal metaplastic mucosae. Although all MSI‐H gastric cancer samples showed BAT‐26 instability, as assessed using 12 dinucleotide microsatellite markers, BAT‐26 instability was not found in the adjacent intestinal metaplastic mucosa in any of the samples.

The Clinical Impact of Solid and Micropapillary Patterns in Resected Lung Adenocarcinoma

Introduction Since the new adenocarcinoma (ADC) classification was presented in 2011, several authors have reported that patients with solid (S) and/or micropapillary (MP) predominant patterns showed a worse prognosis. On the other hand, there are several patients who have S and/or MP patterns even if their patterns are not predominant. However, the evaluation of these patients is uncertain. Methods A total of 531 ADCs were examined. We classified the patients into five subgroups according to the proportion of S and/or MP patterns: (1) both patterns absent (S–/MP–), (2) S predominant (S pre), (3) MP predominant (MP pre), (4) S pattern present although not predominant and MP pattern absent (S+ not pre/MP–), and (5) MP pattern present although not predominant (MP+ not pre). Results Of the 531 ADCs, 384 (72.3%) were classified as S–/MP–, 55 (10.4%) as S pre, 11 (2.1%) as MP pre, 42 (7.9%) as S+ not pre/MP–, and 39 (7.3%) as MP+ not pre. In a univariate analysis, the recurrence‐free survival (RFS) and overall survival differed significantly among the five subgroups (p < 0.01 and p < 0.01, respectively). In a multivariate analysis, patients with S–/MP– had significantly higher RFS rates than did those with other subgroups. On the other hand, patients with MP pre had lower RFS rates than did those with other subgroups. Conclusion Patients with S and/or MP patterns have a poorer prognosis even if their patterns are not predominant. The S and/or MP patterns must be treated at the time of diagnosis.

Prognostic impact and initial recurrence site of lymphovascular and visceral pleural invasion in surgically resected stage I non-small-cell lung carcinoma

OBJECTIVES This study aimed to analyse and validate the prognostic impact and effect of the initial recurrence site of lymphovascular and visceral pleural invasion (VPI) on survival outcomes for Stage I non-small-cell lung carcinoma (NSCLC). METHODS We retrospectively reviewed 433 patients undergoing resection of Stage I NSCLC. The relationship between the clinicopathological background and the pathological variables, lymphovascular invasion (LVI) and VPI, was evaluated by univariate and multivariate analyses. RESULTS Lymphovascular and VPI was observed in 41 and 45 patients, respectively. On univariate analysis, the presence of LVI was associated with a significant decrease in relapse-free survival (RFS) (P < 0.001) and overall survival (OS) (P < 0.001). The RFS of the patients of Stage IB with LVI was worse than the RFS of those of Stage IIA (T2aN1 and T2bN0)/IIB (T3N0), and similar to the RFS of those of Stage IIB (T2bN1). The presence of VPI was also associated with a significant decrease in RFS (P < 0.001) and OS (P = 0.01). On multivariate analysis, LVI was found to be an independent predictor of both decreased RFS and decreased OS. However, VPI was not an independent predictor of both. Recurrence was seen in 68 patients. As an initial recurrence site, distant recurrence was seen in 32 patients and local recurrence, in 36. The proportion of local recurrence was significantly higher in the patients with VPI than in those without VPI compared with between the patients with LVI and those without LVI. CONCLUSIONS We propose that LVI and/or VPI may be a candidate marker to determine adjuvant therapy or a more careful follow-up for these patients.

Parathyroid carcinoma with anaplastic feature: Association of a p53 gene mutation with anaplastic transformation

Parathyroid carcinoma is a rare neoplasm that accounts for only 1–3% of cases of primary hyperparathyroidism. Parathyroid carcinoma is a well‐differentiated tumor that is sometimes difficult to differentiate histopathologically from its benign counterpart, parathyroid adenoma. The molecular mechanism of parathyroid carcinogenesis remains unknown, and investigators have reported that abnormalities of the p53 gene do not play a significant role in parathyroid carcinogenesis, unlike in other human malignancies. The present report describes parathyroid carcinoma with anaplastic transformation of differentiated parathyroid carcinoma in a patient with primary hyperparathyroidism. Nuclear accumulation of p53 protein was found in anaplastic carcinoma cells but not in differentiated carcinoma cells. Polymerase chain reaction–single‐strand conformation polymorphism followed by direct sequencing showed that anaplastic carcinoma cells carried a missense mutation at codon 248 (CGG to CAG) of the p53 gene, while the remaining differentiated carcinoma cells had the wild‐type p53 gene. These findings suggest that the p53 gene mutation is associated with anaplastic transformation of parathyroid carcinoma.

Positive intraoperative pleural lavage cytology is a predictive marker of disease recurrence in stage I lung adenocarcinoma

OBJECTIVES This study aimed at analysing the relationship between the pleural lavage cytology (PLC) status and clinicopathological characteristics, including the outcome of examined patients and tumour recurrence sites in surgically resected stage I non-small-cell lung carcinoma. METHODS From April 2002 to August 2012, PLC was performed immediately after thoracotomy in 428 consecutive patients undergoing pulmonary resection for lung cancer. The relationship between clinicopathological characteristics and the PLC status was retrospectively analysed. RESULTS The frequency of PLC-positive results was 4.4%, and larger tumour size, stage IB and pleural invasion were found more frequently in PLC-positive patients. Patients with a PLC-positive status had significantly worse disease-free survival (DFS) than those with a PLC-negative status (PLC positive versus PLC negative: hazard ratio [HR] = 2.79, 95% confidence interval [CI]: 1.4-5.57, P < 0.004; 5-year DFS: 46.6 vs 76.5%). With regard to the PLC status and histological type, adenocarcinoma was associated with a worse DFS in PLC-positive patients when compared with PLC-negative patients (5-year DFS: 38.1 vs 81.1%, P < 0.001). In multivariate analysis, PLC status remained significantly associated with DFS in patients with a PLC-positive status having an increased risk of recurrence, compared with PLC-negative patients (HR = 2.494, 95% CI: 1.241-5.011, P = 0.01) only in the case of adenocarcinoma. CONCLUSIONS Our current study showed the clinicopathological characteristics associated with PLC status and demonstrated that PLC status was an independent predictor of increased recurrence in stage I lung adenocarcinoma.

Spherule-like acellular stroma in clear cell carcinoma of the ovary: its utility in frozen section diagnosis

cytotoxic drugs. We demonstrated that the selected case of c-KIT overexpression in squamous cell carcinoma of the uterine cervix from our previous preliminary report also showed significant PDGFRA protein overexpression, but no PDGFRA gene activating mutations. Although the tissue materials used in both the aforementioned studies (Taja-Chayeb and Longatto-Filho) were not restricted to the squamous cell type, our findings are in agreement with the described absence of activating mutations in cervical carcinogenesis. By correlating the immunophenotype with the molecular status of the genes expected to be involved, our findings suggest that c-KIT ⁄ PDGFRA immunophenotyping is not useful in predicting the presence of c-KIT and PDGFRA mutations in squamous cell carcinoma of the uterine cervix. Although the absence of c-KIT and PDGFRA mutations may support limiting the use of imatinib (Gleevec) and sunitinib (Sutent) targeting receptor tyrosine kinases (RTKs) to such clinical trials as therapeutic options for squamous cell carcinoma of the uterine cervix, current molecular profiling of the coexpression of KIT and PDGFRA with wild-type c-KIT and PDGFRA oncogenes will still be valuable in selecting other newly developed specific anti-RTK drugs.