Junichi Tamaru

Role of p27Kip1 and Cyclin-Dependent Kinase 2 in the Proliferation of Non-Small Cell Lung Cancer

The cell cycle is governed by a family of cyclin-dependent kinases (Cdks). Cdk2 forms a functional complex with cyclin E and plays a pivotal role in the regulation of G1/S transition. Cdk2 activity is negatively regulated by interactions with inhibitors. p27Kip1, one of the most potent inhibitors of Cdk2, was recently identified as a powerful negative prognostic marker in non-small cell lung cancer as well as in colorectal and breast cancer. In the present study, the expression of p27 and Ki-67 antigen in nonneoplastic and cancerous lung tissues was determined by immunohistochemistry. After establishing that the antibody-measured p27 labeling index was a good reflection of the level of p27 expression measured by Western blotting, we show that p27 labeling index is decreased in cancerous lung tissues, compared with nonneoplastic lung tissues, and exhibits a significant inverse relation to the proliferation marker Ki-67 antigen, detected with monoclonal antibody MIB-1. Consistent with these data, all cancerous lung tissues showed enhanced degradation activity of p27 compared with nonneoplastic lung tissues and, in addition, increased levels of the phosphorylated form of Cdk2, as determined with Western blot analysis. The H1 histone kinase activity associated with Cdk2 was also increased in non-small cell lung cancers. Statistical analysis showed that proliferative activity as measured by MIB-1 labeling index was highly correlated with Cdk2 activity (r = 0.767, P < 0.0015). These results suggest that p27 and Cdk2 may play an important role in the proliferation of non-small cell cancer.

Non-Hodgkin's lymphoma confined to the nasal cavity: Its relationship to the polymorphic reticulosis and results of radiation therapy

From 1975 through 1988, nine patients with locally confined nasal non-Hodgkins lymphoma (NHL) were treated with radiation therapy in the Department of Radiology, Chiba University Hospital. Immunohistochemical study disclosed that all NHLs have T-lineage. Additionally, unique histological pictures of polymorphism, angiodestruction, and necrosis were seen in most of cases. These three findings are the histological features of polymorphic reticulosis (PMR), which is the main cause of lethal midline granuloma and has recently been shown to belong to T-cell malignancy. Therefore, it is concluded that the nasal T-cell NHL and PMR are really a single disease entity. The predominance of the T-cell lymphoma in the nasal cavity as well as its histological distinctness clearly indicate that the head and neck extranodal NHL cannot be discussed together. Although the disorder was considered to be locally limited at presentation, only 3 of the 9 patients with nasal NHL could be induced into long-term remission with involved field radiotherapy. The distant extranodal spread was the primary cause of failure. Multimodality treatment using intensive chemotherapy might improve the prognosis of nasal NHL.

CASE REPORT: A case of lymphoepithelioma-like carcinoma of the oesophagus and review of the literature

Abstract A 78‐year‐old Japanese female was admitted to our hospital with dysphagia and weight loss. An oesophageal tumour was demonstrated radiologically and endoscopically, and was diagnosed as oesophageal cancer by biopsy. Histologically, the resected tumour showed poorly differentiated squamous cell carcinoma with prominent lymphoid stroma and was diagnosed as the so‐called lymphoepithelioma‐like carcinoma (LELC). Epstein–Barr virus in the tumour was negative by polymerase chain reaction and in situ hybridization. Oesophageal LELC is extremely rare. The cases in the literature, as well as the one reported here, presented with gross features of a submucosal tumour‐like appearance. Although the differentiation of the tumour cells is often poor, prognosis seems to be better than for other types of oesophageal cancer. Oesophageal LELC has characteristic clinicopathological features and should be classified by criteria independent of other types of tumour.

MR imaging of primary adrenal lymphoma

We describe a patient with non-Hodgkins B-cell lymphoma of diffuse large cell type, which involved both adrenal glands without adrenocortical insufficiency. Magnetic resonance showed bilateral adrenal tumors with some enhancing septa.

Diffuse large B cell lymphoma expressing the natural killer cell marker CD56

The expression of the natural killer (NK) cell antigen, CD56, in hematological malignancies is rare. However, there are several reports that some hematological malignancies, such as T/NK cell lymphoma, multiple myeloma (MM) and acute myeloid leukemia (AML), express this molecule. In B cell non‐Hodgkin’s lymphomas (NHL), however, very limited number of cases have been reported to express CD56 molecule. Although one study has recently described that half of microvillous B cell lymphoma (MVL), an uncommon subset of large cell lymphoma, expressed CD56, there have been no reports about most common type of B‐NHL, diffuse large B cell lymphoma (DLBL) other than a mention of weak CD56 expression in one of 83 DLBL. We herein presented the first case of diffuse large B cell lymphoma expressing CD56 clearly. The immunophenotype determined by immunostaining and flow cytometric analysis was CD10+, CD19+, CD20+, CD45RO−, CD3− and CD56+. On immunohistochemical study, neither bcl‐2 nor TIA‐1 was positive for tumor cell. Monoclonal immunoglobulin heavy chain (IgH) gene rearrangement was detected, and the sequence analysis of the variable region of IgH (VH) suggested that this tumor was derived from antigen selected post germinal center B cell. Conventional combination chemotherapy (CHOP) was administered, and the patient has still been in complete remission for 10 months.

Clinicopathological evaluation of the Revised European-American Classification of Lymphoid Neoplasms (REAL) in Japan.

After the publication of a Revised European-American Classification of Lymphoid Neoplasms (REAL classification) in 1994, there have been reports from Europe and America regarding its practical utility and clinical significance. However, no studies have been published from Eastern countries including Japan. It has been well recognized that the distribution of malignant lymphoma in Japan is quite different from that seen in Western countries. In addition, some new entities have also been described in the REAL classification. Therefore, it seems important to examine its practical utility and clinical significance in Japan. Of the 579 cases reviewed, approximately 68% were B-cell non-Hodgkins lymphoma (NHL) followed by 27% T-cell lymphomas. Hodgkins disease (HD) comprised only 5% of all cases, making the ratio of NHL to HD 20.6. The most common type was diffuse large B-cell lymphoma which represented about 37% of all cases. Peripheral T-cell lymphomas, unspecified (PTCL), occurred in 15% whereas marginal zone B-cell lymphoma followed (14.9%). However, follicle center lymphoma (FCL) was less common (4.4%) as has been previously reported. We evaluated the clinical significance of the new REAL classification in 244 cases. International Prognostic Index (IPI) was a powerful predictor of survival (p<0.0001), and the immunophenotype was significant (p<0.05). Furthermore, here, we also attempt to establish a prognostic scheme based on the histologic type. In conclusion, the REAL classification appears to be useful and clinically significant in Japan.

A cystic adenomatoid tumor of the uterus simulating lymphangioma grossly.

We are reporting a rare case of an adenomatoid tumor of the uterus having multicystic gross appearance. A 32‐year‐old woman complaining of dysmenorrhea had multicystic mass lesions on the posterior wall of the right cornual region of the uterus. The specimen showed a honeycomb appearance with mucoid content. Microscopically, numerous gland‐like spaces lined with low cuboidal cells were observed beneath the serosa, and mucopolysaccharide material accumulated in the cystic spaces forming honeycomb‐like lesions surrounded by myometrial tissue.

Involvement of the Appendix in a Relapsed Case of Primary Nasal NK/T-Cell Lymphoma

We report here a 20-year-old man presenting with primary nasal NWT-cell lymphoma which showed an aggressive clinical course spreading to the spleen and skin despite various treatments. Eight months after high dose chemotherapy followed by autologous peripheral blood stem cell transplantation, acute appendicitis with perforation occurred and the patient underwent appendectomy. The histopathological diagnosis was NKR-cell lymphoma of the appendix. Lymphoma of the appendix is extremely rare and the majority of appendiceal lymphomas are of B-cell origin. This is the first report of involvement of appendix by nasal NKR-cell lymphoma.

Reappraisal of the Relationship Between Immunoglobulin Heavy Chain Gene Rearrangement and Epstein-Barr Virus Infection in Reed-Sternberg Cells of Hodgkin's Disease

We investigated 44 cases of Hodgkins disease for Epstein-Barr virus genome with EBER-1 in situ hybridization. Twenty of 44 (45.5%) were positive for EBV. Simultaneously, immunoglobulin gene rearrangements were assessed in 32 of these 44 cases with PCR on DNA extracted from Reed-Sternberg cell (RS-cell) -rich areas microdissected from paraffin sections. Clonally rearranged immunoglobulin (IgH) gene was observed in 15 cases (46.9%). EBV-negative cases showed more frequent IgH rearrangement than EBV-positive cases (10 and 5 cases, respectively). In 9 cases, the RS cells were CD20-positive immunohistochemically and these were all EBV negative and the IgH gene was rearranged in all except one. These findings may suggest that EBV infection has occurred before the immunoglobulin gene rearrangement or that EBV infection has influenced the rearrangement of the immunoglobulin gene. The results may also hint towards the obscure B-cell nature of the RS cells.

Reciprocal/dichotomic expression of vimentin and B cell differentiation antigens in Reed-Sternberg's cells

An immunohistochemical study of 63 cases of Hodgkins disease was undertaken using formalin-fixed paraffin embedded tissue sections. The antibodies used were against L26, LN-1, LN-2, EMA (epithelial membrane antigen), Leu-M1, Vimentin, UCHL-1, S-100, and lysozyme. Hodgkins disease could be divided into three groups: the first group was LN-1+/L26+/vimentin-, the second LN-1-/L26+/vimentin+, and the third LN-1-/L26-/vimentin+). Sixteen cases of follicular lymphomas were also examined and were all positive for LN-1 and L26 and negative for vimentin. Thus the vimentin negativity of the first group, including 7 nodular lymphocyte-predominant cases, gives further evidence of their germinal center B-cell origin. Since vimentin is expressed mainly in the immature stage of B-lymphocytes, the second group of Hodgkins disease may represent immature B-cell Hodgkins disease. In the third group, vimentin was present in Reed-Sternbergs (RS) and Hodgkins (H) cells in 45 of the 48 cases (92.5%). In none of 48 cases were these cells positive for S-100 or lysozyme, but strong vimentin-positivity still suggested monocytic or histiocytic origin. The results of our study suggest, at least, divergent origin of RSs and Hs cells.