[Malignant lymphoma and chronic inflammation].
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Chronic Disease↗
Biomedical subjects
K Aozasa
Publications and source records attributed to K Aozasa.
Frequent p53 mutations at dipyrimidine sites in patients with pyothorax-associated lymphoma.
A high incidence of non-Hodgkin's lymphoma of the pleural cavity has developed in Japanese patients with long-standing pyothorax (38 years on average) resulting from artificial pneumothorax for the treatment of pulmonary tuberculosis or tuberculous pleuritis. Patients with pyothorax-associated lymphoma (PAL) have long been exposed to antituberculous drugs, antibiotics, bacterial or viral products, and frequent diagnostic radiation for the confirmation of pneumothorax and pyothorax. We analyzed p53 mutations on paraffin-embedded specimens from 21 patients with PAL by PCR-single-strand conformational polymorphism followed by direct sequencing. An unusually high frequency of p53 mutations (14 of 21 cases, 67%) was detected in the PAL specimens, and mutations consisted of 13 nucleotide substitutions and 1 deletion. Furthermore, 10 of 13 substitutions (77%) occurred at dipyrimidine sites (CC:GG to CT:GA substitution). Such specificity has not been reported, except for solar light-related skin cancer and AIDS-related lymphoma in some parts. An UV light mimetic agent may be produced in the long history of chronic inflammation in tuberculosis or immunodeficient patients.
Aged↗
Natural killer cell-derived large granular lymphocyte lymphoma of lung developed in a patient with hypersensitivity to mosquito bites and reactivated Epstein-Barr virus infection.
A 17-year-old female developed natural killer (NK) cell-derived large granular lymphocyte (LGL) lymphoma of the lung. She had a past history of hypersensitivity to mosquito bites (HMB). After an eight-year chronic, active Epstein-Barr virus (EBV) infection, she developed multiple lung lesions and pleural effusion. In the effusion, 60% of the cells were LGL. They were CD2+, 3-, 16+, 56+, 57+, 45RO+/RA + weak, and possessed strong NK activity. No rearrangement of T-cell-receptor genes was detected. From all these results, a diagnosis of NK-LGL lymphoma of the lung was made. EB virus DNA was detected in cells infiltrating the pleural effusion. The clonality of the LGLs was determined by Southern blot hybridization with the terminal repeat sequence of EB virus as a probe, and by chromosomal abnormalities. The patient died from respiratory failure. Necropsy of the lung revealed diffuse lymphoma composed of polymorphic cells with typical angiocentric lesions. Reportedly, lymphomas of NK lineage show predominantly extranodal involvement, and primary lung lesions are rare. In the pleural effusion of the present case, abnormally high levels of soluble Fas ligand, interleukin-10 and interferon gamma were detected. This hypercytokinemia, reflecting the microenvironment of lymphoma cells, may play a role in the progression of the lymphoma and organ injury in the lung.
Adolescent↗
Prognostic factors of renal cell carcinoma: a multivariate analysis.
BACKGROUND AND OBJECTIVES: To establish appropriate therapeutic modalities for renal cell carcinoma (RCC), informations on the factors affecting prognosis of patients are essential. For this purpose, multivariate analysis including a large set of variables is necessary. METHODS: Prognostic significance of 14 clinical factors and 19 histologic factors including counting of silver-stained nucleolar organizer regions (AgNORs) were evaluated in 96 patients. Age of patients ranged from 41 to 85 (median 59) yr with a male to female ratio of 4:1. The tumors were staged based on the TNM classification as follows: 7 in stage I, 58 in stage II, 15 in stage III, and 11 in stage IV. RESULTS: The overall and metastasis-free survival rates in all patients were 80.1% and 72.7%, respectively. Multivariate analysis using Cox's proportional hazards model performed on the factors proved to be significant at the univariate analysis. Univariate analysis revealed four clinical factors including presence of macroscopic hematuria, symptoms such as pain and palpable abdominal mass, anemia, and adjuvant therapy, and nine histologic factors, including AgNOR count, to be significant for survival. Multivariate analysis showed that anemia, pathological stage, and AgNOR count were independent factors for overall survival of patients. The AgNOR count, in particular, is the only predictive factor for metastasis-free survival. CONCLUSIONS: Among various clinicopathological factors, anemia, pathological stage, and AgNOR count are significant prognosticators of RCC. The AgNOR count is also predictive factor for metastasis-free survival.
Adult↗
Large-vessel arteritis associated with chronic active Epstein-Barr virus infection.
This report describes an autopsy case of large-vessel arteritis associated with chronic active Epstein-Barr virus (EBV) infection in a 10-year-old Japanese girl. All of the 3 main coronary arteries, bilateral common carotid and subclavian arteries, abdominal aorta and its major branches, and bilateral common iliac arteries were involved, and all showed aneurysmal dilation of the lumens. Histopathologic examination revealed mesoarteritis characterized by moth-eaten-appearing destruction of the medial elastic laminae, with T lymphocyte infiltration around the vasa vasorum and severe intimal thickening. The EBV DNA genome was detected in the diseased aortic tissue by polymerase chain reaction, and in the infiltrating lymphocytes by in situ hybridization. The clinical symptoms and histopathologic manifestations of the arterial lesions in this patient were obviously different from those of Kawasaki disease and Takayasu arteritis, and the arteritis was considered to be associated with the EBV infection.
Arteries↗
Hodgkin's disease of the chest wall: report of a case.
Hodgkin's disease primarily originating from the chest wall is very rare. A 48-year-old man was admitted to our hospital because of an abnormal shadow on a chest X-ray. Radiographic examinations suggested a neurogenic tumor located in the right second-intercostal space, and it was thus extirpated thoracoscopically. The tumor was thought to have arisen from the subpleural space, probably from a lymph node of the chest wall. The resected specimen measured 5.5 x 2.0 cm in size, and the pathological diagnosis was Hodgkin's disease of the diffuse lymphocyte predominant type. A clinical examination showed no other lesions in any other part of the body, including the bone marrow. Following surgery, adjuvant chemotherapy (COPP-ABVD) was given because of the possible scattering of malignant cells during surgery. To the best of our knowledge, this is the first report of Hodgkin's disease originating in the chest wall.
Chemotherapy, Adjuvant↗
Appearance of a different clone of Epstein-Barr virus genome in recurrent tumor of pyothorax-associated lymphoma (PAL) and a mini-review of PAL.
A case of pyothorax-associated lymphoma (PAL) is reported. A 76-year-old Japanese man developed a lymphoma in the pleural cavity after 46 years duration of pyothorax due to pulmonary tuberculosis. The histologic diagnosis of biopsy specimen was diffuse large cell lymphoma of B cell type. The lymphoma cells contained the monoclonal Epstein-Barr virus (EBV) determined by the analysis of terminal repeat of EBV genome and expressed EBV nuclear antigen 2 and latent membrane protein 1 (LMP1). He received antineoplastic chemotherapy and was induced to complete remission (CR). After 19 months of CR, the lymphoma developed again in the thoracic wall. Histopathology and immunohistochemical phenotypes of recurrent tumor were almost the same as those of the primary tumor with the exception of a little more frequent expression of LMP1. The EBV genome in lymphoma cells was monoclonal, however, the clone was different from that of the primary tumor. After antineoplastic chemotherapy, minor EBV-positive clones in primary lymphoma might survive and develop into recurrent tumor. These results suggest that the PAL starts as poly- or oligoclonal proliferation of B lineage cells. This poly- or oligoclonality of PAL at the initial stage may suggest underlying immunosuppressive conditions in the development of PAL.
Aged↗
Site-specific localization of Epstein-Barr virus in pharyngeal carcinomas.
In this study, the correlations of factors with Epstein-Barr virus (EBV)-association were investigated in 50 patients with nasopharyngeal carcinoma (NPC), 61 with oropharyngeal carcinoma (OPC), and 55 with hypopharyngeal carcinoma (HPC) in Okinawa and Osaka prefectures in Japan. The incidence of pharyngeal carcinoma in Okinawa was previously found to be higher than that in Osaka; the incidence of OPC was approximately 6 times higher and that of HPC was two times higher. The EBV genome was detected in the tumor cells of the present patients; 83% of the Okinawa and 92% of the Osaka NPC patients. The EBV genome was not detected in OPC or HPC. A univariate analysis showed that sex, the location of the tumor, histology, and the degree of lymphocytic infiltration correlated with the EBV-positive rate. A multivariate analysis revealed that only the location of the tumor was independently correlated with the EBV-positive rate. Histology and tumor size were factors affecting the prognosis of the patients with NPC. The NPC of poorly differentiated type frequently showed the EBV genome, and NPC with lymphocytic infiltration showed a more favorable prognosis compared to the other NPC types. These findings suggest that latent genes of EBV expressed in cancer cells might trigger a cytotoxic T cell reaction against the cancer.
DNA, Viral↗
Mechanism for the development of pyothorax-associated lymphoma.
Malignant lymphomas frequently develop in the pleural cavity of patients with long-standing pyothorax. Thus, the term pyothorax-associated lymphoma (PAL) has been proposed for this type of tumor. Most PAL are of the type diffuse lymphoma of B cell and contain Epstein-Barr virus (EBV) DNA. This article reviews the mechanism for the development of PAL. The possible contribution of EBV infection, inflammatory cytokines and other genetic lesions, including the p53 gene, towards the growth advantage of neoplastic cells is described. Although the presence of EBV is focused in PAL cells, the contribution of EBV-mediated growth promotion in PAL is limited. Another important characteristic of PAL is that the virus antigen-positive lymphoma develops in patients with pyothorax, in whom the systemic immunodeficiency is unlikely to be present. Therefore, in the course of the development of PAL, the mechanism for the evading host immune surveillance must be obvious. In this context, the production of an immunosuppressive cytokine from PAL cells, human histocompatibility leukocyte antigen class I alleles of patients with PAL, and the mutations of cytotoxic T lymphocyte epitopes in an EBV-latent antigen are described. These mechanisms could be involved in the development of PAL, an EBV-positive lymphoma developing in an immunocompetent host, and also shed light on the tumorigenesis of other EBV-positive neoplasms and on the lymphomagenesis of other inflammatory lesions.
Cytokines↗
Utility of immunohistochemical detection of high molecular weight cytokeratin for differential diagnosis of proliferative conditions of the prostate.
BACKGROUND: Differential diagnosis of adenocarcinoma from other proliferative conditions in the prostate is often problematic. Immunohistochemistry using an antibody (34 beta E12) to high molecular weight cytokeratin, specifically present in basal cells of the prostate, could clearly demonstrate the presence or absence of these cells in the proliferating glands and thus provide an important clue in cancer diagnosis. METHODS: To examine the utility of immunostaining using 34 beta E12, we examined 88 equivocal lesions. Twenty lesions with apparently benign and malignant features were added as controls. We compared the morphologic features of these lesions with their immunoreactivities toward 34 beta E12 on a personal computer display following storage on the MICROPHOT-FXA system. RESULTS: Proliferating glands in all 20 benign lesions had 34 beta E12-reactive basal cells, but none of the malignant lesions did. The equivocal lesions were categorized on morphologic grounds into 2 groups: possibly benign and possibly malignant. Forty-five (51.1%) of the 88 equivocal lesions, were positive for 34 beta E12. These included 35 of the 45 (77.8%) possibly benign lesions and 10 of the 43 (23.3%) possibly malignant lesions. Among the equivocal lesions, 10 considered possibly benign on morphologic grounds showed negative reactivities, and 10 considered possibly malignant showed positive reactivities. Even through comparison on the computer display, no difference in morphology could be discovered between the negative and positive lesions in either group. CONCLUSION: Immunohistochemical procedures using 34 beta E12 are indispensable in the diagnosis of equivocal prostate lesions.
Adenocarcinoma↗
Epstein-Barr virus and gastrointestinal lymphomas in Korea.
To analyze the association of Epstein-Barr virus (EBV) with gastrointestinal non-Hodgkin's lymphomas arising in immunocompetent patients, 56 consecutive cases of gastrointestinal lymphomas (B-cell: 52-cases, T-cell: 3 cases, T/NK-cell: 1 case) occurring in the stomach (33 cases), intestine (22 cases) and esophagus (1 case) were investigated for the presence of EBV using polymerase chain reaction analysis as a screening method followed by EBER-1 RNA and DNA in situ hybridization (ISH) and immunohistochemistry for the expression of latent membrane protein 1 (LMP-1). Forty-seven cases demonstrated extractable DNA and EBV DNA was detected only in 4 cases. Among the, RNA (EBER-1) and DNA ISH analysis confirmed the presence of the EBV genome in tumor cells in 3 cases (T/NK-cell lymphoma of ileum, gastric high-grade B-cell lymphoma of mucosa-associated lymphoid tissue, gastric diffuse large B-cell lymphoma). Only the T/NK cell lymphoma showed diffuse positivity of tumor cells while 2 gastric B-cell lymphomas demonstrated a scattered positive reaction and no cases expressed LMP-1. Nine cases without extractable DNA by the PCR method showed no nuclear signal by EBER-1 ISH. These findings suggest that most sporadic primary gastrointestinal lymphomas in Korea are not associated with EBV.
Gastrointestinal Neoplasms↗
Hepatitis C viral genome in a subset of primary hepatic lymphomas.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are not only hepatotropic but possibly hematotropic. Recent studies showed the presence of HBV in lymphoma cells of extrahepatic origin. In the current study, we examined the presence of HBV DNA and HCV RNA in the tumor tissues of nine patients with primary hepatic lymphoma (PHL). Immunohistochemical study using polyclonal anti-HCV antibody was possible in four cases. The age of the patients ranged from 45 to 78 years (median, 58 yr), with a male-to-female ratio of 2:1. A history of chronic hepatitis was found in three patients and of cirrhosis in one. Histologically, all of the cases were non-Hodgkin's lymphoma of B-cell phenotype, with a diffuse large cell type being the most common. Polymerase chain reaction using both the S and X region primers failed to detect HBV DNA in the lymphoma tissues. The HCV genome was detected by in situ hybridization in the tumor cells but not in the surrounding hepatocytes in the one case of cirrhosis, which probably resulted from a blood transfusion more than 20 years previous; immunohistochemical analysis revealed positive staining for anti-HCV antibody in the cytoplasm of lymphoma cells in this case. In two cases, positive signals were found only in the hepatocytes surrounding the lymphoma. This is the first report showing the presence of the HCV genome in the lymphoma cells of PHL. HCV could be involved in development of PHL directly or via exogenic antigenic stimulus from HCV-infected hepatocytes.
Aged↗
Mutation of the p53 gene in postradiation sarcoma.
Radiotherapy is known to cause secondary malignancies in the radiation field; postradiation sarcomas (PRS) are one example of such malignancies. Little is known about the genetic changes, including p53 gene alterations, that are thought to play a role in the tumorigenesis of human PRS. In the present study, p53 gene mutations were analyzed on paraffin-embedded specimens from 24 patients with PRS (4 men and 20 women) by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by direct sequencing. The primary tumors of these patients were uterine cervical cancers in 14, breast cancers in 3, malignant lymphomas in 2, and others in 5. Total radiation doses ranged from 36 to 300 Gy (median, 60 Gy). The latent period between completion of radiation therapy and development of PRS ranged from 3 to 34 years (median, 10 years). Malignant fibrous histiocytoma was the most common PRS, accounting for 12 cases. PCR-SSCP revealed the aberrant mobility shifts of bands in 24 cases: 21 shifts in exon 5, 18 in exon 7, and 12 in exon 8. Direct sequencing of the SSCP product revealed a total of 58 mutations in 21 (88%) of 24 cases: 4 cases had a single mutation, 5 had 2 mutations, 5 had 3 mutations, 6 had 4 mutations, and 1 had 5 mutations. Although 31% of the mutations did not change an amino acid, every tumor had at least one mutation that did, which may have provided the selection pressure for expansion. The frequency of p53 gene mutation in sporadic soft tissue sarcomas was 20%. These findings highlighted the extraordinarily high frequency of p53 gene mutations in PRS. G:C to A:T transition at dipyrimidine sites was found in 14 (58%) of 24 cases. Collectively, these findings indicate that radiation is causative for soft tissue sarcomas via p53 gene mutations.
Adolescent↗
Different patterns of p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of microdissected specimens.
Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and can be divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic carcinoma (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 29 cases of PCA and 1 benign prostatic hypertrophy were analyzed for p53 mutation by single-strand conformation polymorphism (SSCP) of polymerase chain reaction (PCR)-amplified DNA fragments followed by direct sequencing. These patients had received total prostatectomy (27 cases) or transurethral resection (3 cases). Under direct microscopic observation, DNA was microdissected from 108 lesions: 67 lesions from 22 cases of PIN (55 HGPIN and 12 LGPIN), 29 from 22 cases of PCA, and 12 from 11 cases of adjoining benign glands. Analysis revealed 13 mutations in 10 lesions from six cases. All 13 were point mutations: 7 missense, 5 silent, and 1 nonsense. Mutations were detected in 3 cases (14%) of PIN and 5 cases (25%) of PCA. PIN lesions with p53 mutations were all categorized as HGPIN. Neither LGPIN nor benign glands adjoining PIN and/or PCA had mutations. Two PIN and one PCA lesion in each of two cases had mutations that were different from each other. G-to-A transition was the commonest mutation pattern. The current findings showed that HGPIN, but not LGPIN, and PCA are similar with regard to p53 mutation. The diverse patterns of p53 mutation among HGPIN and PCA lesions suggested multiclonal development of prostatic precancerous lesions.
Amino Acid Substitution↗
Incidence of prostatic intra-epithelial neoplasia in Osaka, Japan.
High-grade prostatic intra-epithelial neoplasia (HGPIN) is the most likely precancerous lesion for prostatic carcinoma. A high incidence of its association with cancer has been reported in Western countries. On the other hand, information regarding its incidence is limited in Japan, where the mortality due to prostate cancer is much lower. We reviewed 53 clinical stage T2 or T3 prostatic cancers of Japanese patients living in Osaka, Japan (mean age, 67.2 years). These cases were subdivided into a pre-operatively non-castrated group (34 cases) and a medically or surgically castrated group (19 cases). HGPIN was found in 27 cases. The incidence of HGPIN was significantly lower in the castrated group (21.0%) compared with the non-castrated group (67.6%). In the non-castrated group, patient age, pathological stage, Gleason score, tumor size and serum prostate-specific antigen showed no significant correlation with HGPIN. Advanced pathological stage and tumor size tended to decrease the incidence of HGPIN, although this was not statistically significant. When the study group was limited to stage T2 tumors of the non-castrated group, the incidence of HGPIN was 81.0%. HGPIN in Japan may also be clinically and etiologically significant as a precursor of clinical cancer.
Aged↗
Reassessment of gastric lymphoma in light of the concept of mucosa-associated lymphoid tissue lymphoma: analysis of 53 patients.
BACKGROUND: The concept of mucosa-associated lymphoid tissue (MALT) lymphoma is now widely accepted. However, precise characterization of the features of MALT lesions in the stomach is needed. For this, extensive analysis of resected gastrectomy specimens from a large number of patients with MALT lymphoma is essential. METHODS: Fifty-three patients who underwent gastrectomy for the treatment of primary gastric lymphoma were studied. In the histologic examination, a mean of 46 specimens per case were analyzed; the distribution of lymphomatous lesions was plotted on maps of gastrectomy specimens, input into a computer, and used to measure the size of lesions. RESULTS: The median age of the patients was 56 years, and the male-to-female ratio was 27:26. Stage of disease was I(E) for 35 patients, II(E) for 15, and III for 3. Histologically, 25 patients had low grade lesions, 18 had combined high and low grade lesions, and had 10 high grade lesions. Macroscopically, low grade MALT usually had multiple instances of superficial spreading of lesions without ulceration, whereas high grade MALT exhibited a solitary tumor-forming lesion. All of the superficial spreading type without ulceration were low grade MALT. The higher the grade of tumor, the larger the tumor size. Twenty-four patients received chemotherapy. The 5-year survival rate was 67.2%. Multivariate analysis revealed that only the clinical stage was a significant factor in prognosis. CONCLUSIONS: Low grade MALT can be differentiated from other types of MALT by macroscopic findings. When the MALT concept is adopted, stage of disease is important in relation to survival.
Adult↗
Mutations of p53 tumor-suppressor gene in angiosarcoma.
Transgenic mice deficient for the p53 gene were reported to frequently develop angiosarcoma (AS), suggesting that alterations in the gene are associated with tumorigenesis of AS. However, little is known about genetic changes, including p53 gene alterations, in human AS because of its rarity. We analyzed p53 mutations on paraffin-embedded specimens from 33 patients with AS by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) followed by direct sequencing. Age of patients ranged from 18 to 91 (median 70) years, with a male to female ratio of 1.5:1. Sites of tumor were the head in 13 patients, the trunk in 4, the extremities in 4, the heart in 4, bones in 2 and others in 6. PCR-SSCP revealed aberrant mobility shifts of bands in 17 cases: 11 in exon 5, 5 in exon 7 and 4 in exon 8. Direct sequencing on these 17 cases revealed a total of 20 mutations. The frequency of p53 mutations was different by site of tumors: 7 of 13 in head, all 4 in extremities, 2 of 4 in heart and none of 4 in trunk. Our findings suggest that occurrence of p53 mutation is a major pathway for development of human AS.
Adolescent↗
Cancer risk after renal transplantation in Japan.
Excess of cancer in patients receiving renal transplantation is well-known in Western countries, but information in Japan remains limited. Our study examined whether excess risk is found in patients receiving renal transplantation in Japan. Between 1970 and 1995, 1155 males and 589 females underwent renal transplantation in 6 hospitals, and a total of 12,982 person-years of observation was accumulated. Malignancies developed in 2.6% of patients; O/E ratio was 2.78. Median interval from renal transplantation to tumor development was 58 months. The interval in the patients receiving medication with cyclosporine-A (CyA) (median, 42.5 months) was significantly shorter than that with non-CyA (median, 95.5 months). Median age at the diagnosis of malignancy was 40 years, which is much younger than that in the general population. Relative risk was highest in renal cancer, followed by thyroid cancer, malignant lymphoma and uterine cancer. A distribution of malignancies was different from that reported from Western countries. These findings showed the excess risk of malignancies in Japan with renal transplants, especially in male patients, similar to that observed in Western countries, though the types of malignancy were different.
Adolescent↗