Takashi Koshikawa

Clinicopathologic study of CD56 (NCAM)-positive angiocentric lymphoma occurring in sites other than the upper and lower respiratory tract.

The expression of the neural cell adhesion molecule (NCAM) (CD56, NKH-1) is a rare phenomenon in malignant lymphoma. Recently, several authors, including our group, described the clinicopathologic, phenotypic, and genotypic features of NCAM-positive tumors as a unique subgroup within a larger category of hematolymphoid malignancies. Ten cases of CD56+ angiocentric lymphoma occurring in sites other than the upper aerodigestive tract were studied for evaluating their characteristics. The disease occurred in six men and four women varying from 24 to 85 years (mean age, 53 years) who often exhibited a striking predilection for extranodal sites of involvement, such as the skin, gastrointestinal tract, and muscle, usually in the absence of peripheral lymphadenopathy. Although the cytologic appearances and immunophenotypic profile varied from case to case, these tumors often exhibited azurophilic granules, an angiocentric growth pattern, and surface CD3−, T-cell receptor (TCR) antigens−, and CD56+ phenotype without B-cell phenotype, except for a single case of CD3+, TCRα/β+, and CD56+ phenotype. Genotypic investigation exhibited germline configuration of the TCR β and γ chain genes and the immunoglobulin heavy chain gene in all five cases of surface CD3− phenotype examined, whereas the case of CD3+ phenotype showed rearrangement of TCRβ. They seem to constitute a distinct entity of the lineage spectrum spanning from natural killer (NK) cell to NK-like T cell.

Prognostic significance of abnormal p53 accumulation in primary, resected non-small-cell lung cancers.

PURPOSE This study was conducted to evaluate the prognostic significance of p53 abnormalities in primary, resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Methodologic validation of immunohistologic detection of p53 abnormalities in routine pathology sections was assessed using 31 lung cancer specimens for which p53 gene status was known from our previous molecular biologic studies. Applying the optimized cutoff value, we evaluated the prognostic significance of p53 abnormalities in an independent cohort of 208 NSCLC patients with complete follow-up data, whose resections were consecutively performed between January 1984 and December 1988. RESULTS Immunohistologic detection of p53 abnormalities appeared to be reliable and showed approximately 90% concordance with the p53 gene status. Using the selected cutoff value of 10%, 46% of 208 NSCLCs showed p53 abnormalities. There was no relationship between p53 abnormalities and clinical outcome in the entire cohort, which represented all histologic subtypes of NSCLC (P = .58). Based on the reasoning that the influence of p53 abnormalities may have been obscured by distinct biologic roles depending on histologic subtypes, we also separately analyzed subsets of patients with adenocarcinomas (n = 100) and with squamous cell carcinomas (n = 88) and found that it may be a useful prognosticator only in adenocarcinoma patients (P = .04). CONCLUSION p53 abnormalities are not a significant prognostic factor in primary, resected NSCLC when all histologic subtypes are combined, but may be a useful prognosticator for adenocarcinomas. Additional studies are warranted for further evaluation, specifically of adenocarcinomas.

Diagnostic utility of EUS-guided FNA in patients with gastric submucosal tumors

BACKGROUND Submucosal tumors (SMTs) comprise both benign and malignant lesions, and most of the gastric lesions tend to be malignant. The addition of EUS-guided FNA (EUS-FNA) has the potential to improve this distinction, but published series are limited. OBJECTIVE To evaluate the yield of EUS-FNA in gastric SMTs with referral to a criterion standard final diagnosis. DESIGN Retrospective study. SETTING Tertiary-care referral center. PATIENTS This study involved 141 consecutive patients with gastric SMTs, who underwent EUS-FNA from January 2000 to December 2008. Immunohistochemical staining with c-kit, CD34, actin, and S-100 antibodies was done if a spindle cell tumor was found. Based on FNA sample adequacy, and whether a specific diagnosis could be established, EUS-FNA results were categorized as diagnostic, suggestive, or nondiagnostic. The criterion standards for final diagnosis were the surgical histopathological results or the follow-up course for malignant, inoperable cases. INTERVENTION EUS-FNA. MAIN OUTCOME MEASUREMENTS Diagnostic yield of EUS-FNA and factors related to sampling adequacy for cytological and immunohistochemical evaluation. RESULTS A total of 141 patients (52% female, mean age 56.7 years) underwent EUS-FNA (range 1-5 passes). The overall results of EUS-FNA were diagnostic, suggestive, and nondiagnostic in 43.3%, 39%, and 17.7% of cases, respectively. Adequate specimens were obtained in 83% of cases, and 69 cases (48.9%) had a definitive final diagnosis. The most common gastric SMT was GI stromal tumor (59.5%). EUS-FNA results were 95.6% accurate (95% confidence interval [CI], 87.5%-99%) for the final diagnosis and 94.2% (95% CI, 85.6%-98.1%) accurate for differentiating potentially malignant lesions. A heterogeneous echo pattern was the only independent predictor for sampling adequacy (adjusted odds ratio 6.15; P = .002). There were no procedure-related complications. LIMITATIONS Possibility of selection bias. CONCLUSION EUS-FNA is an accurate method for diagnosis of gastric SMTs and for differentiating malignant lesions.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach.

BackgroundFor the diagnosis of gastric submucosal tumors (SMTs), endoscopic ultrasound (EUS) alone does not reveal the complete pathology, such as the degree of malignancy, and EUS-guided fine-needle aspiration biopsy (EUS-FNAB) has been reported to be more useful. Recently, most cases initially diagnosed as leiomyosarcomas have received further study with immunohistochemical staining and have been given the new diagnosis of gastrointestinal stromal tumors (GISTs). The degree of malignancy of GISTs differs widely in clinical aspects. In this study, we examined whether EUS-FNAB was useful in diagnosing GISTs and differentiating their degrees of malignancy.MethodsFrom January 1997 to March 2002, 21 cases of gastric GISTs were diagnosed from the immunohistochemical staining of specimens resected at Aichi Cancer Center Hospital. Of these 21 patients, 14 (5 with high-grade malignancy and 9 with low-grade malignancy) underwent EUS-FNAB preoperatively, and were examined further: their EUS-FNAB specimens were submitted for additional immunohistochemical testing.ResultsThe EUS-FNAB specimens from all patients were positive for c-kit and CD34 immunohistochemical testing, coinciding with the staining results of the resected specimens. The MIB-1 labeling indices in specimens of high-grade malignancy were significantly higher than those of low-grade malignancy. If we assumed that a tumor with an MIB-1 labeling index of more than 5% was a high-grade malignancy, the diagnostic accuracy was 85.7%.ConclusionsThe EUS-FNAB procedure is a useful tool for diagnosing GISTs of the stomach with immunohistochemical staining. When used with MIB-1 staining, the procedure may indicate GIST prognosis and influence decisions regarding therapeutic strategies.

Growth Fractions of Transitional Cell Carcinomas of the Bladder Defined by the Monoclonal Antibody KI-67

We used an immunohistochemical technique with the monoclonal antibody Ki-67, which recognizes nuclear antigen expressed in proliferating cells to determine the growth fractions of 5 normal mucosa specimens and 55 transitional cell carcinomas of the bladder. Normal mucosa had a mean value of 0.37 +/- 0.35% cells positive for Ki-67, whereas 9 histological grade 1 tumors showed 2.2 +/- 1.5%, 31 grade 2 tumors averaged 10.1 +/- 7.5% and 15 grade 3 tumors yielded 19.5 +/- 9.0%. These values were significantly different from each other (p less than 0.01), with Ki-67 indexes for grade 2 varying from 0.3 to 24.6%. Nonpapillary tumors had significantly higher indexes than papillary tumors (20.1 +/- 8.0 versus 6.7 +/- 5.9, p less than 0.01). The Ki-67 indexes were 4.6 +/- 4.5% for stage Ta (20 cases), 7.8 +/- 4.7% for stage T1 (14) and 20.2 +/- 7.8% for stages equal to or higher than T2 (21). Significant differences were noted between stages Ta and T1 (p less than 0.05) and between stages T1 and T2 or greater (p less than 0.01). Tumors with muscle layer invasion often showed more than 15% Ki-67 positive cells. Our results imply that Ki-67 indexes not only provide objective information to determine a malignant potential but also help to select the treatment.

Clinicopathologic study of PRAD1/cyclin D1 overexpressing lymphoma with special reference to mantle cell lymphoma : A distinct molecular pathologic entity

Mantle cell lymphomas (MCLs) are frequently associated with the overexpression of PRAD1/cyclin D1, activated by 11q13 translocation and its molecular counterpart BCL-1 gene rearrangement. We recently described the correlation of positive nuclear staining using monoclonal antibody against a PRAD1/cyclin D1 product with mRNA overexpression in MCLs. In the present study, we immunohistochemically investigated the PRAD1/cyclin D1 protein in a large series of 334 lymphoproliferative disorders, including 39 cases of MCLs on paraffin sections. Based on the cyclin D1 positivity, CD5 expression, and the morphologic features of the tumor tissue, four groups of MCL-related lesions were identified among the B-cell lymphomas examined: 36 cases with cyclin D1 overexpression, 35 (95%) of which exhibited CD5-positivity and MCL-morphology (Group 1); four cases of lymphomas with MCL morphology and CD5 expression but lacking cyclin D1 overexpression (Group II); four cases of lymphomas without cyclin D1 overexpression and surface CD5 but that fall within the morphologic boundaries of MCLs (Group III); and 11 cases of CD5-positive diffuse large cell lymphomas without cyclin D1 overexpression (Group IV). The Group I cases demonstrated quite homogeneous clinicopathologic features identical to those of MCLs. This group showed a poor prognosis (11% had 5-year survival), which is highly contrasted with that of Group II (100%). Although the four groups of MCL-related lesions sometimes overlapped in their histologic or phenotypic spectrums, each appeared to show distinct clinicopathologic and prognostic profiles. Our study provides a basis for further clarification of the nature of the neoplasms of Groups II, III, and IV. Moreover, this comprehensive study may indicate that the overexpression of PRAD1/cyclin D1 is biologically essential to defining MCLs.

Clinicopathologic study of nasal T/NK‐cell lymphoma among the Japanese

A high prevalence of nasal lymphoma expressing a T‐ or natural killer (NK)‐cell phenotype (NTCL) with frequent association of Epsteln‐Barr virus (EBV) has been indicated in Asians. To Characterize NTCL among the Japanese, the clinlcopathdogic features of 32 cases were evaluated and the casses worn also analyzed for EBV‐RNA using an ISH method. Morphologically, 31 cases were Identified by atypical pleomorphic lymphoid infiltrates with polymorphous, anglcentric, and necrotic features. Their lymphoma cells ranged in size from small to large and were mixed in varying proportion from case to case. The other one case showed a monomorphic ‘blastic’ appearance. EBV‐encoded small RNA (EBER) was detected in the neoplastic cells of 27 of the 32 cases examined. In the five EBV‐negative cases, one was the ‘blastic’ type. Clonal T‐cell receptor gene rearrangement was detected in none of seven cases examined. The patients had a median follow‐up of 9 months (range, 1 month to 14 years and 11 months). The Kaplan‐Meler estimate of overall survival was 49% at 5 years, correlating with clinical stage. These data support the concept that most cases of NTCL are identified as tumors with T/NK‐cell characteristics and EBV association, distincity different from other peripheral T‐cell lymphomas. Furthermore, the one case of an EBV‐negative ‘blastic’ variant appears not to fit well Into the pleomorphic category but more closely resembles the pathologic features of extranasal angiocentric lymphoma with lymphoblastold appearance. This study also showed no clear difference in clinical aspects other than the original site or in prognosis, between NTCL and extranasal angiocentric lymphomas despite the higher incidence of EBV association and the tendency for that peculiar anatomical site to be restricted to the former group.

Tobacco, Alcohol and Dietary Factors Associated with the Risk of Oral Cancer among Japanese

The mortality rate among Japanese men due to oral cancer is increasing, but risk factors among Japanese other than smoking and drinking have not been examined. To investigate the dietary factors involved in oral cancer, we conducted a hospital‐based case‐referent study in Aichi, Japan. Cases comprised 189 men and 77 women aged 20–79 years with one of the following cancers: tongue, mouth, oropharynx and hypopharynx. The reference group comprised 9,858 male and 26,669 female outpatients without cancer. Smoking and drinking were highly associated with an increased risk of oral cancer. Japanese sake showed a lower odds ratio (OR) than beer or hard liquor (OR=3.6, 4.5 and 4.8, respectively). In the cross analysis between smoking and drinking, smoking combined with drinking increased the risk of oral cancer to three times that of smoking only (OR=6.2 vs. 2.2). Frequent intake of raw vegetables (OR=0.5) and fruit (OR=0.5) were inversely associated with the risk of oral cancer after adjustment for age, sex, smoking, drinking and year of visit. Western‐style breakfast and salty food preference decreased the risk of oral cancer, and salty food preference was still statistically significant by multivariate analysis (OR=0.7). In conclusion, smoking cessation, drinking control and frequent intake of raw vegetables and fruit among Japanese are likely to be effective preventive measures against oral cancer.

Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients.

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkins disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennerts) lymphoma. The fourth group consisted of cytotoxic Hodgkins-like ALCL/HD (n = 10), included seven cases of Hodgkins-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).

Inconsistent association of Epstein-Barr virus with CD56 (NCAM)-positive angiocentric lymphoma occuring in sites other than the upper and lower respiratory tract

We previously described nine cases of angiocentric lymphoma of a possible natural killer (NK)‐cell lineage with a surface CD3− CD56+ phenotype occurring in sites other than the upper and lower respiratory tract. This study was performed to investigate the association of Epstein‐Barr virus (EBV) with these lymphomas, using the polymerase chain reaction (PCR) for the presence of EBV‐DNA, in situ hybridization (ISH) for EBV‐encoded small RNAs (EBERs) and immunohistology for EBV‐determined nuclear antigen‐2 (EBNA‐2) and latent membrane protein‐1 (LMP‐1) in paraffin sections. PCR and ISH produced almost identical results, and EBERs were identified in the nuclei of the lymphoma cells of three cases, two of which exhibited LMP‐1 in the cytoplasm of tumour cells without EBNA‐2 expression. Molecular genetic analysis revealed EBV to be incorporated into these three EBER‐positive cases either clonally or biclonally. It was revealed by re‐evaluation of their morphology with the established EBV status on each case that, in contrast to the rather variable and irregular cellular composition of the EBV‐ positive tumours, the EBV‐negative tumours stood out because of their remarkably uniform ‘blastoid’ appearance, and could be grouped as blastic NK‐cell lymphoma. The relationship of the EBV‐positive cases with nasal NK‐cell tumours has yet to be clarified.