Immunohistochemical studies on epidermal growth factor receptor and the myc oncogene product in squamous cell carcinoma of the uterine cervix

Recent studies have demonstrated that the amount of epidermal growth factor receptor (EGF-R) is increased in squamous cell carcinoma cells and that the amino acid sequence of EGF-R shows great homology with the v-erb B transforming protein. In this study, we examined the tissue localization of EGF-R and myc oncogene product in normal squamous epithelium, dysplasia, carcinoma in situ, invasive squamous cell carcinoma of the uterine cervix and in metastatic lymph nodes by means of the avidin/biotin immunoperoxidase technique. Normal squamous epithelium was negative for EGF-R and myc product. The lesions of dysplasia and carcinoma in situ had a positive staining for EGF-R, but were still negative for myc product. There were differences in the staining intensity of EGF-R and myc product among the types of invasive carcinoma. Staining for EGF-R and myc product was negative in small cell non-keratinizing carcinoma, whereas strong staining for both EGF-R and myc product was observed in large cell non-keratinizing and keratinizing carcinoma. The intensity of positive staining for EGF-R and myc product declined in the lesions of cancer pearl. Metastatic lymph nodes were remarkably stained for EGF-R and myc product, while non-metastatic lymph nodes were negative for EGF-R and myc product. Our observations suggest that the amplified expression of EGF-R and myc product may accompany the malignant transformation of squamous epithelium of the uterine cervix, together with the metastasis.     

Immunohistochemical studies on epidermal growth factor receptor (EGF-R) in gynecological malignant tumor

The expression of Epidermal Growth Factor Receptor (EGF-R) in gynecological malignant tumors was investigated immunohistochemically. 1) With respect to the expression of EGF-R in the uterine cervix, it was seen in 20.0% with benign lesion. In cases of dysplasia, it was expressed in 62.5% of the cases with mild dysplasia, 81.8% with moderate dysplasia and 53.3% with severe dysplasia. In cases of CIS, it was seen in 46.7% and in cases of invasive cancer, it was seen in 22.2%. By hystological type, the expression rates were 27.3% for keratinized squamous cell carcinoma and 33.3% for large cell non-keratinized squamous cell carcinoma. No expression was seen in three cases of small cell non-keratinized squamous cell carcinoma or four cases of adenocarcinoma. In cases of benign lesions, EGF-R was localized in the cell walls of the basal layer, but in cases with dysplasia, it was found in the cell walls and also in the cytoplasm in all layers of the epithelium. 2) The expression rate in endometrial carcinoma was 14.3% and all of these cases were well-differentiated adenocarcinoma. There was no reverse correlation with estrogen receptors. 3) The expression rate for advanced malignant ovarian tumors was 31.4% and there was no clear correlation with the histological type. The prognosis tended to be better in cases expressing EGF-R than in those not. These results indicated that EGF-R appears to be related to the degree of advance of cervical dysplasia, but it was clear that the frequency of expression of EGF-R decreased when the cancer became invasive. In cases of malignant ovarian tumors, the expression of EGF-R tended to be related to the prognosis.     

Immunohistochemical studies on epidermal growth factor receptor in experimental squamous cell carcinoma of the uterine cervix of mice

The tissue localization of epidermal growth factor receptor (EGF-R) in experimental squamous cell carcinoma of the mouse uterine cervix was examined immunohistochemically. Carcinoma was induced by the insertion of a 20-methylcholanthrene (MC)-impregnated thread into the cervical canal of the mouse. Tissue sections (of normal columnar epithelium, proliferation, atypical proliferation, early invasive carcinoma, invasive carcinoma and metastatic carcinoma) were stained by the avidin/biotin immunoperoxidase technique using anti-EGF-R monoclonal antibody. Normal columnar epithelium was negative for EGF-R, whereas proliferation was partly positive. The lesions of atypical proliferation and early invasive carcinoma had a positive staining for EGF-R. The staining for EGF-R declined in the lesion of invasive carcinoma. Metastatic carcinoma was not stained for EGF-R. These results suggest that EGF-R may play an important role in the early stage of carcinogenesis of the mouse uterine cervix induced by 20-MC.     

Human papillomavirus DNA in glandular dysplasia and microglandular hyperplasia: presumed precursors of adenocarcinoma of the uterine cervix

Presumed precursors of adenocarcinoma of the uterine cervix were investigated with specific techniques to identify human papillomavirus (HPV) DNA. The presence of HPV DNA in 36 lesions of glandular dysplasia and 16 lesions of microglandular hyperplasia of the uterine cervix was studied by in situ hybridization using 3H-labeled HPV 16 and HPV 18 DNA probes. Only two of 36 lesions (6%) of glandular dysplasia contained HPV 18 DNA, although 64% of coexisting adenocarcinoma in situ, microinvasive adenocarcinoma, and cervical squamous intraepithelial neoplasia III lesions contained HPV 18 and/or HPV 16 DNA. Two lesions of HPV 18 DNA-positive glandular dysplasia coexisted with adenocarcinoma in situ that contained the same type of HPV DNA. None of the microglandular hyperplasia lesions contained HPV 16 DNA or HPV 18 DNA. These results suggest that, if HPV infection is an initial step toward carcinogenesis, it is unlikely that glandular dysplasia and microglandular hyperplasia are precursor lesions of adenocarcinoma of the uterine cervix. A large proportion of glandular dysplasia may represent reactive lesions of endocervical columnar epithelium. Two lesions of HPV 18 DNA-positive glandular dysplasia may represent well-differentiated components of adenocarcinoma in situ of the uterine cervix.     

宫颈鳞癌与腺癌生物学行为的回顾性对比分析

目的探讨宫颈鳞癌(SCC)和宫颈腺癌(AC)在生物学行为方面存在的差异,为宫颈癌的合理诊治提供更多的临床依据。方法回顾分析山东大学齐鲁医院妇产科1997年1月至2006年3月收治的273例宫颈癌初治患者的临床资料,对比分析SCC和AC在发病相关因素、临床病理特征、5年生存率等生物学行为方面的不同。结果SCC和AC两组病例中有吸烟史者分别占22%和10%、宫颈涂片阳性率分别为80%和46%,体重指数(body mass index,BMI)≥24kg/m2者分别占15%和34%,确诊时FIGOⅠ期、Ⅱ期、Ⅲ期、Ⅳ期患者分别占SCC患者的42%、46%、11%、1%和AC患者的31%、47%、12%、10%,卵巢转移率分别为0.5%和6.7%,5年生存率分别为69.9%和50.6%,以上差异均有统计学意义(P<0.05)。结论SCC和AC在发病相关因素、临床病理特征和预后等方面均有统计学差异,SCC组有吸烟史者的比例及宫颈涂片阳性率更高,AC患者中则体重超重或肥胖者占较高比例,AC患者确诊时晚期患者较多而且更容易发生卵巢转移,预后较SCC差。     

Clinico-pathologic study on the early diagnosis of cervical adenocarcinoma

We studied 94 cases of adenocarcinoma of the uterine cervix, with emphasis on early diagnosis of cervical adenocarcinoma, histopathologically. The results are as follows: The number of cases was 4 in Stage 0 (adenocarcinoma in situ, ACIS), 51 in Stage I, and 39 in Stage II. The proportion of ACIS to invasive adenocarcinoma was 4 of 94 (4.26%) and was significantly lower than that of cervical squamous cell carcinoma. Thirty-nine cervical biopsies of 29 cases, taken 1-3 years prior to the clinical presentation of cancer, were available for study. In 2 of 16 "negative specimens", areas of glandular dysplasia were found on review. Areas of ACIS and adenocarcinoma with early stromal invasion were also found on review in 5 and in 2 of 14 specimens diagnosed as atypical glands, respectively. This study strongly suggests that "atypical glands" such as glandular dysplasia and ACIS are precursor lesions of invasive adenocarcinoma of the uterine cervix and that the delay in diagnosing cervical adenocarcinoma may be due partly to "underdiagnosis" of cervical biopsy specimens.     

In situ hybridization study on the localization of HPV DNA in the precancerous lesions of uterine cervix

Human papillomavirus (HPV) types 16 and 18 have been found closely associated with cervical cancer. In order to investigate the relationship between HPV DNA and cervical precancerous lesions, we examined the formalin fixed specimens obtained from 22 cases of mild dysplasia, 33 cases of moderate dysplasia and 31 cases of severe dysplasia of the uterine cervix for the presence of HPV 6/11, 16 and 18 DNAs by in situ hybridization using the biotinylated HPV DNA probes. We also followed some HPV DNA positive cases of cervical dysplasia for more than 6 months prospectively. The results of in situ hybridization analysis revealed that HPV DNA was detected in the nuclei of koilocytosis, dysplastic cells and metaplastic cells. HPV 6/11 was positive in 27.3% (6/22) of mild dysplasia and 21.2% (7/33) of moderate dysplasia. On the other hand, HPV 16 positive rate increased with the grade of dysplasia and 36.4% (12/33) of moderate dysplasia, 61.3% (19/31) of severe dysplasia were positive for HPV 16 DNA. Some of the follow-up cases which were positive for HPV 16 DNA were later found to have carcinoma in situ. Our results suggest that HPV type 16 might play an important role in cervical carcinogenesis.     

Detection of human papillomavirus DNA in human cervical lesions by tissue in situ nucleic acid hybridization

Cervical cancer is one of the most common female cancers in Taiwan. Certain types of human papillomavirus (HPV) are frequently detected in the epithelial precancerous and cancerous lesions of the cervix. By the use of tissue in situ hybridization, we investigated the relationship of various types of HPV (group I, HPV-6 & 11, group II, HPV-16 & 18, group III, HPV-31, 33 & 35) with cervical condyloma, carcinoma as well as precancerous lesions. Group I HPV DNAs were mainly found in cervical condylomatous lesions (2/2) of the cervix and cervical intraepithelial neoplasia I (CIN I) (2/4), but were only occasionally found in CIN II (1/4), CIN III (1/9) or non-keratinized squamous cell carcinoma (1/15). HPV DNAs of groups II and III were mainly detected in lesions of CIN III (5/9) and invasive squamous cell carcinoma (large cell, keratinized type: 4/7; large cell, non-keratinized type: 11/15). HPV DNA sequences were invariably detectable only in the cell nuclei of condyloma or dysplastic epithelium or invasive carcinoma. However, they could not only be detected in the upper layer dysplastic cells and koilocytes but also in the well and poorly differentiated cervical cancer cells. The distribution of HPV DNA positive cells in the carcinomas fell into four different patterns: (1) upper zone and non-invasive regions of the carcinoma (11/22, 50%), (2) basal zone and invasive regions (2/22, 9%), (3) randomly scattered (7/22, 32%), and (4) extensively distributed over the whole tumor lesions (2/22, 9%). Thus, our results are consistent with a strong correlation between the presence of HPV-16, 18, 31, 33 and 35 and malignant conversion of cervical epithelial cells.     

In situ adenocarcinoma and squamous carcinoma of uterine cervix. Pathological and immunohistochemical analysis with cytokeratin 13

OBJECTIVES: The aim of the study was the pathological and immunohistochemical analysis of cytokeratin 13 (CK13) in intraepithelial cervical tumors. STUDY DESIGN: We studied 415 in situ squamous carcinomas and 13 in situ mucinous cervical type adenocarcinomas of the uterine cervix. All patients underwent laser cervical conization and had a follow-up ranging 12-135 months. RESULTS: 3% of the squamous carcinoma patients recurred during the follow-up period, while the percentage of recurrence of in situ adenocarcinoma patients was 7.6%. We observed positive surgical edges in 46.1% of glandular tumors, and in 5% of squamous tumors. The percentage of recurrence was high among the cases with positive borders independently from their histopathologic type (14.3% in the squamous carcinomas versus 50% in the adenocarcinomas), compared to cases with negative edges (2.3% in the squamous carcinomas versus 0% in the adenocarcinomas). We observed CK13 positive staining in cervical squamous tumors and in mucinous cervical type adenocarcinomas, while there was no positive staining in non-neoplastic cervical glandular elements. CONCLUSION: CK13 positive immunostaining among in situ squamous and in situ mucinous cervical type adenocarcinoma cases adds additional evidence to data supporting a common origin of the two lesions.     

Clinical evaluation of follow-up methods and results of atypical glandular cells of undetermined significance (AGUS) detected on cervicovaginal Pap smears.

OBJECTIVES: The aim of this study was to evaluate the efficacy of the follow-up methods and results of atypical glandular cells of undetermined significance (AGUS) detected on cervicovaginal Pap smears. METHODS: From May 1991 to December 1996, we have performed 407, 451 cervicovaginal Pap smears, of which 326 patients were identified as AGUS. Of the 326 patients, 268 patients were followed by repeat Pap smears, colposcopy, cone biopsy, or endometrial curettage. RESULTS: The incidence of AGUS on Pap smears is approximately 0.08%. The mean age of the patients was 43 years (range 22-79 years). The most common complaint was abnormal vaginal bleeding. The gross findings of the cervix were normal to mild erosion. The following past histories of patients could affect the AGUS results on Pap smear: 30 had cone biopsy, 21 had Pap smears on pregnancy and within 8 weeks after delivery or evacuation, 3 were on hormonal replacement therapy, 2 had intrauterine devices for contraception, and 5 were undergoing follow-up after treatment of cervical cancer. The benign lesions detected during follow-up periods were 6 microglandular hyperplasia of the cervix, 5 atypical squamous metaplasia of the cervix, 2 cervical endometriosis, 2 tubal metaplasia, 10 cervical myoma, 11 cervical polyps, 9 endometrial polyps, 3 uterine myoma, 1 pelvic endometriosis, 1 ovarian endometriosis, and 4 uterine adenomyosis. The premalignant or malignant lesions of the cervix were 4 low-grade squamous intraepithelial lesions, 24 high-grade squamous intraepithelial lesions, 8 glandular atypia/dysplasia, 5 adenocarcinoma in situ, 3 microinvasive adenocarcinoma, and 4 invasive adenocarcinoma. The neoplastic lesions of the uterus were 6 endometrial hyperplasia, 11 endometrial adenocarcinoma, 1 malignant mixed Müllerian tumor, and 1 metastatic endometrial adenocarcinoma. Sixty-seven (25%) of 268 patients followed up were identified as having clinically significant lesions of the cervix or uterus. The detection rates of abnormal lesions were 3.1% with repeated Pap smears (3/98), 28.4% with colposcopic-directed biopsy (31/109), 63.6% with cone biopsy (35/55), and 29.7% with endometrial curettage (19/64). CONCLUSION: AGUS on Pap smears showed various benign and malignant lesions of the cervix or uterus. The clinicians must communicate with the pathologists regarding the patient's clinical information as well as the origin of the atypical glandular cells in Pap smears. We recommend that patients with AGUS on Pap smear should undergo immediate intensive diagnostic studies, including colposcopic-directed biopsy with endocervical curettage or cone biopsy, to detect cervical lesions and endometrial curettage to detect endometrial lesions.     

宫颈鳞癌和腺癌中微血管密度和基质金属蛋白酶-2 、9及其抑制剂-1、2表达的研究

目的通过观察肿瘤微血管密度(MVD)及MMP-2、MMP-9和TIMP-1、TIMP-2在宫颈鳞癌与腺癌组织中的表达情况,在蛋白水平探讨宫颈腺癌较鳞癌恶性程度高的可能原因.方法采用免疫组织化学方法(SP) 检测40例宫颈鳞癌和20例宫颈腺癌组织的MVD和MMP-2、MMP-9、TIMP-1、TIMP-2蛋白的表达情况.结果MVD在宫颈腺癌中较鳞癌高.MMP-2在宫颈鳞癌的阳性表达强度较腺癌高(P=0.006);MMP-9、TIMP-1在腺癌的阳性表达较鳞癌高(P=0.078,P=0.000);TIMP-2在两组间比差异无显著性(P＞0.05).在宫颈癌的临床病理特征中,MMP-2和MMP-9在鳞癌和腺癌中的表达不一,而TIMP-1始终是在腺癌中的表达较鳞癌高.结论宫颈腺癌较鳞癌恶性程度高的原因,可能与较高的MVD和TIMP-1的高表达有关.     

Expression of cytokeratins in early neoplastic epithelial lesions of the uterine cervix

Polyclonal and monoclonal antibodies to cytokeratin polypeptides were used to study the expression of these intermediate filament proteins in normal, squamous metaplastic, and neoplastic epithelium of the uterine cervix, in order to investigate the morphogenesis of early epithelial changes preceding cervical squamous cell carcinoma. A polyclonal keratin antiserum showed a positive reaction in all different epithelial cell types of the uterine cervix. A positive reaction was also found in subcolumnar reserve cell hyperplasia, in squamous metaplastic and dysplastic cells, and in (squamous) carcinoma in situ. A monoclonal antibody specific for columnar epithelium (RGE 53) gave a positive reaction in endocervical columnar cells and in some immature metaplastic cells but was negative in subcolumnar reserve cells, squamous (metaplastic) cells, dysplastic cells, and most cases of carcinoma in situ. Another monoclonal cytokeratin antibody (RKSE 60) pointed to early keratinization in light microscopically nonkeratinizing squamous (metaplastic) and dysplastic epithelium. A possible overlap in staining patterns of RGE 53 and RKSE 60 was seen in some cases of immature metaplasia. Morphologic changes occurring in the transformation zone upon dedifferentiation are accompanied by alterations in cytokeratin expression. Similarities in cytokeratin expression were found between dysplasia and carcinoma in situ on one hand and subcolumnar reserve cell hyperplasia and squamous metaplasia on the other. This study favors an epithelial origin and a squamoid nature of subcolumnar reserve cells.     

Primary signet ring cell carcinoma of the uterine cervix: A clinicopathologic study of two cases with review of the literature

Haswani P, Arseneau J, Ferenczy A. Primary signet ring cell carcinoma of the uterine cervix: A clinicopathologic study of two cases with review of the literature. Int J Gynecol Cancer 1998; 8 : 374–379.
Signet ring cell carcinoma of the endocervix is most commonly considered to be metastatic in origin. We describe two cases of apparently primary cervical signet ring cell adenocarcinoma occurring in patients aged 33 and 38 years, respectively. Both patients had been treated previously for cervical "condylomas". The lesions, occupying the posterior lip of the cervix, were formed predominantly of malignant neoplastic signet ring cells. One case was positive for HPV type 18 and coexisted with adenocarcinoma in situ and a high grade squamous intraepithelial lesion (HSIL). One patient died 18 months after the diagnosis of carcinoma with massive intra-abdominal metastasis; autopsy was not performed. The second patient is alive and well nine months postsurgery and undergoing pelvic radiotherapy for FIGO stage IB1 adenocarcinoma with one of the pelvic nodes containing a metastasis. Although in neither of the two cases was absolute proof obtained of the absence of a gastrointestinal tract tumor, the clinical presentation of the tumors, the history of previous HPV infection of the cervix, the coexistent in situ adenocarcinoma and HSIL and the detection of HPV type 18 in one case lent support for a primary cervical origin of this rare form of adenocarcinoma.     

Human papillomavirus DNA in adenocarcinoma in situ, microinvasive adenocarcinoma of the uterine cervix, and coexisting cervical squamous intraepithelial neoplasia

Previously, human papillomavirus (HPV) DNA, mainly HPV-18 DNA, was detected in more than 40% (17/40 cases) of invasive adenocarcinoma of the uterine cervix in our laboratory. In order to identify HPV DNA in the precursor lesions of adenocarcinoma of the cervix, 11 cases of adenocarcinoma in situ containing microinvasive adenocarcinoma and 10 cases of adenocarcinoma in situ were studied for the presence of HPV DNA by in situ hybridization using highly sensitive 3H-labeled HPV-16 and HPV-18 DNA probes. HPV types present in cervical squamous intraepithelial neoplasia (CIN) coexisting with adenocarcinoma in situ and microinvasive adenocarcinoma were also studied. Apart from the coexisting CIN II-III with glandular neoplasms, 48 cases of CIN III (severe dysplasia and squamous carcinoma in situ) removed by conization or hysterectomy and known to be free of adenocarcinoma were used for comparison. HPV DNA was detected in 64% of microinvasive adenocarcinoma, 70% of adenocarcinoma in situ, and 63% of the control CIN III. HPV-18 DNA was the preponderant type of HPV DNA found in adenocarcinoma in situ and microinvasive adenocarcinoma. All cases of HPV DNA-positive microinvasive adenocarcinoma contained the same type of HPV DNA as the lesions of coexisting adenocarcinoma in situ. CIN coexisting with microinvasive adenocarcinoma or adenocarcinoma in situ contained the same type of HPV as identified in the glandular lesions, whereas all of the HPV DNA-positive control CIN III cases contained HPV-16 DNA. These results suggest that adenocarcinoma in situ is a precursor lesion of adenocarcinoma of the cervix that contains HPV DNA, and that CIN coexisting with adenocarcinoma may be a result of a metaplastic process of adenocarcinoma or of bidirectional differentiation of the affected reserve cells.     

子宫颈组织中一氧化氮合酶的表达及其临床意义的研究

目的：研究正常宫颈组织、子宫颈糜烂组织及子宫颈癌组织中iNOS、eNOS表达,分析它们与病理、临床表现之间的关系,探讨NO在正常子宫颈、宫颈炎症和肿瘤中的作用。方法：对31例行病理及iNOS、eNOS检测,病理检查采用HE染色法;iNOS、eNOS检测采用免疫组化法,NOS阳性表现为黄褐色染色。结果：①宫颈糜烂在切片中表现为上皮细胞水肿,上皮下免疫细胞浸润,上皮缺损,柱状上皮化生等,宫颈腺体间质及腺腔内可见白细胞及淋巴细胞浸润、渗出,子宫颈癌表现为癌细胞失去极性,核异型、大小不一,癌巢间质有免疫细胞浸润;②iNOS与eNOS均呈颗粒状,黄褐色杂色。在宫颈分布较广泛,主要分布于宫颈鳞状上皮、腺体上皮、柱状上皮、血管内皮等处。在宫颈鳞状上皮中,iNOS、eNOS并非均匀分布于上皮中,中间层细胞染色较强。eNOS染色弱于iNOS;宫颈糜烂者巨噬细胞及肥大细胞、中性粒细胞等免疫细胞iNOS呈阳性染色,均为胞浆着色;宫颈癌者癌细胞iNOS胞浆着色,部分核呈弱阳性杂色,癌巢间质免疫细胞iNOS阳性染色,而eNOS仅可见于血管内皮。结论：NOS在宫颈分布较为广泛,在细胞分泌、炎症反应、抗肿瘤免疫过程中发挥着重要作用。     

子宫颈癌组织中水通道蛋白8和bcl-2蛋白的表达及其相关性

目的 探讨水通道蛋白(AQP)8、bcl-2蛋白在宫颈癌组织中的表达及其相关性.方法 采用免疫组化Envision二步法检测AQP8和bcl-2蛋白在74例宫颈癌(其中鳞癌46例、腺癌28例)、34例宫颈上皮内瘤变(CIN)和15例正常宫颈组织中的表达情况,并分析两者的相关性.结果 AQP8和bcl-2蛋白主要在CIN异型细胞和宫颈癌细胞的细胞质内表达,AQP8蛋白在宫颈鳞癌、腺癌、CIN和正常宫颈组织中的阳性表达率分别为98%、61%、71%和53%,鳞癌高于腺癌、CIN和正常宫颈组织,差异有统计学意义(P＜0.01);腺癌与CIN、正常宫颈组织比较,CIN与正常宫颈组织比较,差异均无统计学意义(P＞0.05).bcl-2蛋白在宫颈鳞癌、腺癌、CIN和正常宫颈组织中的阳性表达率分别为74%、71%、53%和20%,鳞癌与腺癌组织比较,差异无统计学意义(P＞0.05);鳞癌、腺癌高于CIN、正常宫颈组织,CIN也高于正常宫颈组织,差异均有统计学意义(P＜0.01).AQP8和bcl-2蛋白在宫颈癌组织中的表达呈明显正相关(rs=0.463,P=0.000).结论 AQP8和bcl-2蛋白在宫颈癌组织中的表达呈明显正相关,AQP8蛋白表达上调可能与宫颈癌的发生、发展有一定的关系.     

Expression of matrix metalloproteinase-2 in preinvasive and invasive carcinoma of the uterine cervix

PURPOSE: To study the immunohistochemical expression of matrix metalloproteinase-2 (MMP-2) in preinvasive and invasive carcinoma of the uterine cervix so as to demonstrate whether the expression of MMP-2 is an early or late event in the process of dedifferentiation and cancer progression. METHODS: A total number of 50 samples of cervical tissue were studied for MMP-2 immunoreactivity. The cases were selected to include ten normal cases used as a control group, 20 CIN cases and 20 cervical carcinoma cases. The CIN group was subdivided into CIN1 (n = 7), CIN2 (n = 6) and CIN3 (n = 7), while the carcinoma group was represented by squamous cell carcinoma (n = 16) and adenocarcinoma (n = 4). RESULTS: MMP-2 expression was totally absent in control cervices and low-grade squamous intraepithelial lesions, while high-grade squamous intraepithelial neoplasia and invasive carcinoma showed up-regulation of MMP-2 expression with no significant difference concerning the type of carcinoma. This overexpression of MMP-2 points to the possibility that it is an early marker of tumor progression in cervical carcinoma. CONCLUSIONS: MMP-2 has a key role in extracellular matrix degradation and invasion in carcinoma of the uterine cervix. Its expression in high-grade squamous intraepithelial lesions may denote a potential risk for invasion and metastasis.     

Nucleolar organizer regions in malignant transformation of uterine cervix

Nucleolar organizer regions (NORs) in 70 cases of precancerous and cancerous lesions of the uterine cervix were investigated. The greater the degree of dysplasia, the higher the mean number of silver-stained NOR (Ag-NOR) dots (mild dysplasia, 2.2; moderate dysplasia, 2.5; severe dysplasia, 3.1). The mean number of dots in moderate or severe dysplasia was significantly higher than that in normal squamous epithelial cells. The mean numbers of dots in carcinoma in situ (CIS) and invasive carcinoma were 3.8 and 3.7, respectively, and were significantly higher than those in normal squamous epithelial cells, mild dysplasia, moderate dysplasia, and severe dysplasia. The mean number of Ag-NOR dots in the cases of mild dysplasia that progressed to CIS was 2.7, which was significantly higher than that in the cases that regressed. In precancerous lesions, the correlation coefficient between the mean number of Ag-NOR dots and the mitotic index was 0.552 (p less than 0.01), whereas no correlation was noted between these measurements in CIS and invasive carcinoma. In conclusion, the number of Ag-NOR dots is a good marker to detect cell proliferation in precancerous lesions and their malignant tendency.     

In situ hybridization study on the detection of HPV DNA in adenocarcinoma and adenosquamous carcinoma of the uterine cervix]

Human papillomavirus (HPV) types 16 and 18 have been found closely associated with squamous cell carcinoma and related lesions of the uterine cervix. In order to investigate the relationship between HPV and adenocarcinoma and adenosquamous carcinoma of the uterine cervix, formalin-fixed, paraffinembedded tissues prepared from 38 cases consisting of 30 cases of adenocarcinoma and 8 cases of adenosquamous carcinoma were examined for the presence of HPV DNA by in situ hybridization with digoxigenin labeled HPV 6/11, 16, 18 DNA probes. HPV DNA was localized on the nuclei of the cancer cells in adenocarcinoma and adenosquamous carcinoma. HPV DNA was detected in 13 cases (43.3%) of adenocarcinoma and 4 cases (50.0%) of adenosquamous carcinoma, and HPV type 18 DNA was detected in 13 cases (34.2%) of adenocarcinoma and adenosquamous carcinoma. These findings suggest an association between HPV, especially HPV type 18, and adenocarcinoma and adenosquamous carcinoma of the uterine cervix.