Toru Hachisuga

Expression of ras Oncogene Product and EGF Receptor in Cervical Squamous Cell Carcinomas and Its Relationship to Lymph Node Involvement

The expression of ras oncogene product p21 and epidermal growth factor (EGF) receptor was studied immunohistochemically in tissues obtained from 52 patients with squamous cell carcinoma of the uterine cervix. We examined the relationship between p21 and EGF receptor expression and lymph node metastasis in cervical cancer. The data demonstrate that the patients with positive staining for ras p21 in cervical carcinomas have a higher incidence of lymph node metastasis than the patients with negative staining for p21 (P = 0.027). Although the levels of p21 expression in the metastatic sites were reduced compared to those in the primary sites, tumor cells in metastatic lymph nodes also expressed p21. No relationship was found between EGF receptor expression and lymph node metastasis. These results suggest that expression of ras oncogene product may be associated with the biological aggressiveness of cervical carcinomas.

Detection of human papillomavirus genome and analysis of expression of c-myc and Ha-ras oncogenes in invasive cervical carcinomas

Invasive carcinomas of the uterine cervix of 38 patients were examined for the presence of human papillomavirus (HPV) genomes and for the state of the c-myc and Ha-ras oncogenes. A combination of Southern blot hybridization and polymerase chain reaction revealed the presence of the genome of HPV type 16 in 17 tumors (45%), that of HPV type 18 in 3 tumors (8%), and that of unknown types in 16 others (42%), while no viral DNA sequences were detected in 2 tumors. Of the 38 tumors, c-myc amplification was found in only 1 tumor, while there was no Ha-ras amplification. Overexpression of the c-myc gene was observed in 15 (44%) of the 34 tumors analyzed, while there was no overexpression of Ha-ras. Of the 23 squamous cell carcinomas analyzed, relapse-free rates at 24 months were 55% in tumors with c-myc overexpression and 100% in case of tumors with no c-myc overexpression, respectively. The results suggest the possibility that activation of the c-myc oncogene is involved in tumor progression.

Carcinoma of the lower uterine segment. Clinicopathologic analysis of 12 cases

Clinicopathologic features of 12 tumors of the lower uterine segment (isthmus) were studied and the findings compared with data on 196 tumors of the corpus endometrium proper. The mean age of these Japanese patients with tumors of the isthmus was 47 years and that of the patients with tumors of the corpus endometrium was 55 years. Seven of the isthmic tumors (58%) were graded as 3 (poorly differentiated) with histologic features of adenosquamous carcinoma, and all 12 tumors showed myometrial invasion. Endometrial hyperplasia or atypical endometrial glands were found in the endometrium adjacent to the tumor in 11 women. Normal mucosal structures of the lower uterine segment were uninvolved, in the area between the tumor and the endocervix, in only three patients. Four patients died of the disease within 36 months after surgery. In a comparison with the usual endometrial tumors of the corpus, tumors of the lower uterine segment tended to be high-grade adenosquamous carcinomas and myometrial invasion was more extensive. The short-term follow-up revealed that lower uterine segment tumors carried an unfavorable prognosis.

Detection of Epstein-Barr virus DNA from a lymphoma-like lesion of the uterine cervix

Abstract The case of a 60-year-old woman in whom a lymphoma-like lesion of the cervix was found during an episode of silent Epstein-Barr virus (EBV) infection is presented. Fractional curettage was performed because of abnormal endometrial smear. The endocervical curettage specimens were diagnosed as highly suggestive of malignant lymphoma, but microscopic examination of a subsequent hysterectomy specimen revealed a benign lymphoid hyperplasia. Those were retrospectively interpreted as a lymphomalike lesion of the cervix. In the absence of clinical symptoms of infectious mononucleosis, the results of serologic tests for EBV revealed an active EBV infection. EBV DNA was demonstrated in nuclei of large lymphoid cells in endocervical curettage specimens by in situ hybridization. She is alive and well 32 months postoperatively. When female patients with lymphoma-like lesions of the lower genital tract are encountered, examinations for EBV are recommended.

Interferon γ treatment for cervical intraepithelial neoplasia

Eight patients with cervical intraepithelial neoplasia (CIN) were administered perilesional injections of human recombinant interferon gamma (IFN-gamma), and the response was evaluated by colposcopy and exfoliative cytology and then by histopathology. In all patients, colposcopic and cytologic findings improved after two to four injections of IFN-gamma and the cytologic findings reverted to normal in five of these eight patients. All five were free of dysplastic lesions. The other three patients with positive cytology and positive colposcopy after completion of IFN-gamma treatment underwent hysterectomy or laser conization, and histopathologic examination revealed residual dysplastic lesions. On the other hand, a control study revealed that only one of eight patients showed spontaneous regression during the 3-month observation period. During the course of these treatments, keratinizing cells were often present in the cervical smears and isolated cell keratinization was often evident in the residual dysplastic lesions of the surgical specimens. These observations suggest that IFN-gamma treatment is an effective therapeutic method for CIN lesions and that IFN-gamma has the potential to differentiate nonkeratinizing squamous cells into keratinizing cells.

Human papilloma virus and P53 overexpression in carcinomas of the uterine cervix, lower uterine segment and endometrium

&NA; Inactivation of the wild type p53 protein through complexing of protein synthesized by specific subtypes of human papilloma virus (HPV) or mutation in the p53 gene is considered to play an important role in cervical carcinogenesis. The association between p53 overexpression and the presence of HPV 16 and 18 DNA was assessed in 29 cervical carcinomas, 15 carcinomas of the lower uterine segment and 30 endometrial carcinomas. In 29 cervical carcinomas (21 adenocarcinomas and 8 adenosquamous carcinomas), 7 cases were positive for HPV 16 DNA while 5 were positive for HPV 18 DNA. Nine cases (31%) showed p53 overexpression. An inverse association was seen between the presence of HPV DNA and the p53 overexpression. In 15 carcinomas of the lower uterine segment, one case was positive for HPV 16 DNA while 2 were positive for HPV 18 DNA. Overexpression of p53 was seen in 8 (53%) carcinomas of the lower uterine segment. Two of 3 HPV DNA positive carcinomas of the lower uterine segment revealed p53 overexpression. HPV DNA was not detected in endometrial carcinomas and p53 overexpression was shown in 12 (40%) cases. The association between HPV DNA and p53 overexpression differs among the tumors arising in the cervix, lower uterine segment and endometrium.

Immunohistochemical study of p53 expression in endometrial carcinomas: correlation with markers of proliferating cells and clinicopathologic features

Using anti-p53 (PAb1801 and PAb240), anti-DNA polymerase α and Ki-67 monoclonal antibodies, the expression of p53 was studied in 11 normal endometria, 14 endometrial hyperplasias and 27 endometrial carcinomas and its relationship to the proliferative activity of the tumors was examined. Normal endometria and simple hyperplasias were completely negative for p53. The PAb1801 indices of complex hyperplasias and complex atypical hyperplasias were 2.5±1.8% and 5.0±3.2%, respectively. The PAb1801 indices of grade 1, grade 2 and grade 3 endometrial carcinomas were 10.2±14.2%, 44.4±29/0% and 45.0±32.5%, respectively. These results indicate a progressively enhanced p53 expression in the sequence from normal endometrium, through hyperplasia to carcinoma. A significant correlation between p53 expression and labeling indices of Ki-67 and DNA polymerase α was observed in endometrial carcinomas. The endo-metrial carcinomas with p53 overexpression developed mainly in post-menopausal patients and were frequently high-grade tumors with deep myometrial invasion. These findings may indicate that overexpression of p53 protein contributes to the proliferative activity of the tumor cells.

Glassy cell carcinoma of the endometrium

A case of glassy cell carcinoma of the endometrium in a 62-year-old woman is reported. Microscopically, a cytoplasm of ground-glass appearance was observed with a distinct cell wall and large nuclei containing prominent nucleoli. These histologic characteristics are consistent with those of glassy cell carcinoma of the cervix. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy with pelvic lymph node dissection followed by external irradiation to the whole pelvis. The patient was alive without evidence of disease at 5 1/2 years.

Local Immune Response in Infertile Patients with Minimal Endometriosis

OBJECTIVEnTo evaluate the role of local immunity in women with minimal endometriosis.nnnMETHODSnUterine endometrium and endometrial implants were obtained simultaneously from 30 infertile women with minimal endometriosis and examined immunohistochemically using antibodies of T cell, B cell, macrophage, Langerhans cell, immunoglobulin (Ig)G, and complement (C) 3d. Serum IgG, IgA, IgM, C3, C4, antinuclear antibody and anti-DNA antibody were also examined in 24 of the women. Data from uterine endometrium and serum were compared with 10 fertile women without endometriosis as a control.nnnRESULTSnMicroscopic examination revealed that the endometrial implants were divided into two groups: group 1 (n = 13) showed lymphocytic infiltration in the endometrial implants and group 2 (n = 17) showed no or slight lymphocytic infiltration. The endometrial implants of group 1 showed significantly more dense T-cell infiltration than those of group 2. Other types of infiltrating cells and deposits of IgG and C3d revealed no significant differences between groups 1 and 2. The immunohistochemical examination of the uterine endometrium and the serum data revealed no significant differences among all three groups. Cumulative pregnancy rates showed no significant difference between groups 1 and 2.nnnCONCLUSIONnThe difference of local immune response in endometrial implants did not affect systemic immunity.

Antitumor effects of human recombinant interferon-γ and tumor necrosis factor on five cervical adenocarcinoma cell lines, in vivo and in vitro

We examined the antitumor effects of recombinant interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) on cervical adenocarcinoma cell lines, in vitro and in vivo. Four of five cell lines showed a high sensitivity to IFN-gamma, in vitro. One of five cell lines showed a remarkable sensitivity to TNF, in vitro. Only one cell line resistant to both IFN and TNF was derived from a well-differentiated adenocarcinoma of endocervical type. Experiments using nude mice bearing transplanted tumors revealed that these cytokines were also effective against tumors in vivo. All these observations suggest that IFN-gamma or TNF can have positive effects in the treatment of patients with adenocarcinoma of the uterine cervix.