Endocervical Epithelium Research Articles

Clinicopathological study of the pattern and significance of cervical involvement in cases of endometrial adenocarcinoma.

The pattern of cervical involvement in 107 endometrial adenocarcinomas was assessed. The cervix was involved in 29%, higher than noted in previous studies. In 40.6%, the lesion was confined to surface endocervical epithelium only; the remainder had cervical stromal involvement. In the majority only small areas within the circumference of the cervix were affected, indicating a need for adequate tissue sampling. In some cases, malignant epithelium was found as a "migrant" within the endocervical canal, entrapped within cervical mucus or applied to surface epithelium, supporting the concept that endometrial cancer spreads by surface contiguity or implantation rather than by deep tissue planes or via lymphatic channels. Our findings reinforce the view that high-grade lesions and histological subtypes such as uterine serous papillary carcinoma are associated with a later presentation, higher stage and poorer prognosis. We have identified atypical changes in endocervical epithelium that may be misinterpreted as cervical involvement, particularly in the form of atypical reserve cell hyperplasia with a micropapillary pattern that may reflect a reaction to the presence of tumor. It is our assertion that the presence of tumor "migrants", and not endocervical surface atypia, is an indicator of increased probability of cervical involvement by endometrial adenocarcinoma (P = 0.015).

DNA image cytometry in the differential diagnosis of endocervical adenocarcinoma.

The value of DNA image cytometry in the differential diagnosis of endocervical adenocarcinoma was tested on a series of 65 cases of normal endocervical cells (n = 25), inflammatory changes (n = 18), and endocervical adenocarcinoma (n = 22). The investigation was performed on gynecologic routine smears by using a television image analysis system MIAMED-DNA (Leica, Wetzlar, Germany), combined with an automated Leica Medilux microscope. First, the Papanicolaou stained specimens were rescreened, and the x/y coordinates of at least 150 endocervical nuclei were stored per case by using a scanning program. After restaining according to Feulgen, the epithelial cells were relocalized and the DNA content, and the nuclear area were determined. The DNA content of 25-30 squamous epithelial cells of intermediate type served as an internal standard for the normal diploid value in each case. Various DNA cytometric parameters and the mean nuclear area were calculated. For statistical analysis, the cases of adenocarcinoma (n = 22) were defined as positive, and the cases with normal endocervical epithelium or inflammatory changes (n = 43) were defined as negative. The presence of nuclei with a DNA content greater than 9c was observed exclusively in adenocarcinoma (sensitivity, 95.9%; specificity, 100%), indicating that this parameter is suited best for the differentiation between malignant and nonmalignant endocervical epithelium. High sensitivity rates at a specificity level of 100% also were calculated for the 2.5cER (95.5%), the mean ploidy (90.9%), 5cER (90.9%), and the diploid deviation quotient (90.9%). For the 2cDI (86.4%), the entropy (81.8%) and the ploidy imbalance (77.3%) lower values were obtained. DNA single cell cytometry represents a highly relevant tool in the identification of malignant transformation in endocervical lesions that could be used as a complementary diagnostic method in cytologically difficult cases. Investigations on endocervical adenocarcinoma in situ should be performed in the near future.

Avaliação do Grau e da Extensão das Alterações Térmicas Produzidas pela Cirurgia de Alta Freqüência no Colo Uterino

Objetivo: estudar a ocorrência de dano térmico tissular nos espécimes excisados por cirurgia de alta freqüência e avaliar qualitativa e quantitativamente o dano térmico sobre o epitélio ectocervical e o endocervical e a provável influência do estado menstrual sobre sua gênese. Método: estudo prospectivo de 100 pacientes com lesão cervical intra-epitelial de alto grau. O dano térmico encontrado foi subdividido em três graus, leve, moderado e grave, de acordo com os critérios de Messing et al.¹ Resultado: a análise estatística permitiu avaliar que o dano térmico ocorreu em todos os casos, porém em 91% das vezes ele foi insignificante, permitindo a correta avaliação histopatológica. A extensão da alteração térmica tecidual sobre o epitélio endocervical foi de 271,6 mi, ao passo que a extensão no epitélio ectocervical foi de 254,8 mi, mostrando desta forma que a extensão do dano térmico é significantemente maior no epitélio endocervical. Das 100 pacientes avaliadas, 80 estavam no menacme e 20 na menopausa. O grau e a extensão do dano térmico tissular não variaram com o estado menstrual. Conclusão: não se observou qualquer diferença significativa na avaliação tanto do ponto de vista qualitativo quanto quantitativo. Por outro lado, evidenciou-se que na prática cotidiana não há necessidade de se fazer a mensuração do dano térmico.

The Amount of MUC5B mucin in cervical mucus peaks at midcycle.

The physical character and amount of mucus secreted by the endocervix changes dramatically during the menstrual cycle to facilitate sperm migration at the time of midcycle ovulation. Mucins are highly glycosylated, high-molecular-weight proteins, which are the major structural components of the protective mucus gel covering all wet-surfaced epithelia, including that of the endocervix. We have previously demonstrated that the endocervical epithelium expresses messenger RNA (mRNA) of three of the large gel-forming mucins, designated MUC5AC, MUC5B, and MUC6, with mRNA of MUC5B predominating. Because mucin protein levels may be regulated posttranscriptionally, measurement of MUC5B protein levels with cycle are needed for correlation to mRNA levels. Measurement of specific mucin gene products within mucus secretions has been limited by availability of specific, well-characterized antibodies and by volume requirements of the isolation protocols for mucins, which include CsCl density centrifugation and fraction isolation. To measure MUC5B protein within the cervical mucus through the hormone cycle, we developed a polyclonal antibody specific to the mucin. The antibody, designated no. 799, is to a synthetic peptide mimicking a 19-amino-acid segment of an intercysteine-rich region within the D4 domain in the 3' region of the MUC5B protein. It recognizes native as well as denatured MUC5B on immunoblot, is preadsorbable with its peptide, and binds to apical secretory vesicles of epithelia expressing MUC5B. We used the MUC5B antibody along with a cervical mucin standard cervical mucin isolate in enzyme-linked immunosorbent assay to determine the relative amount of MUC5B mucin in samples of human cervical mucus taken through the menstrual cycle. We demonstrate a peak of MUC5B mucin in human cervical mucus collected at midcycle, compared with mucus from early or late in the cycle. This peak in MUC5B content coincides with the change in mucus character that occurs at midcycle, suggesting that this large mucin species may be important to sperm transit to the uterus.

COMPLETE TRANSURETHRAL RESECTION OF BLADDER ENDOCERVICOSIS

Endocervicosis of the bladder is a rare, benign lesion similar to endometriosis but characterized by mucinous endocervical epithelium. We report on a 37-year-old woman who presented with lower urinary tract symptoms due to a bladder mass. Biopsy of this mass was consistent with endocervicosis and the patient successfully underwent complete transurethral resection. CASE REPORT A 37-year old woman presented elsewhere with urinary frequency, nocturia 2 to 3 times a night, hesitancy, intermittent decrease in stream, incomplete voiding and abdominal pain exacerbated by voiding. Medical history was significant for severe endometriosis for which she had undergone total abdominal hysterectomy with bilateral salpingo-oophorectomy. She also had a history of asthma and irritable bowel syndrome. Medications included conjugated estrogen and ibuprofen. Physical examination revealed left lower quadrant tenderness but no other significant findings. Urinalysis was unremarkable and post-void residual was minimal on ultrasound. Flexible cystoscopy revealed a mass at the left superior bladder wall. The patient underwent cystoscopy with biopsy and partial resection of the mass, which revealed endocervicosis (fig. 1). Pelvic magnetic resonance imaging (MRI) was performed to assess the extent of the endocervicosis (fig. 2, A). There was no evidence of other abdominal or pelvic pathology. Therapeutic options discussed were partial cystectomy or complete transurethral resection. The patient elected the transurethral approach. Cystoscopy showed a 2.5 cm. bladder mass on the supraposterior left bladder wall. The mass was resected in its entirety down to bladder serosa, a Foley catheter was left in place for 2 days and there were no complications. Pathological examination confirmed endocervicosis. Microscopic examination revealed benign glands lined by mucin producing cells in the lamina propria (fig. 1). These lining cells resembled benign endocervical glands. Symptoms resolved and followup MRI at 3 months after resection showed no residual mass (fig. 2, B). DISCUSSION

Mucins of the human endocervix.

The physical character and amount of mucus secreted by the endocervix changes dramatically at midcycle to facilitate the reproductive process. Mucins expressed by the endocervical epithelium contribute to this all-important physiologic event. This review summarizes work from our laboratory demonstrating the mucin gene expression profile of cervical epithelium and mucin levels in cervical mucus through the menstrual cycle. mRNA levels of the gel-forming mucin MUC5B, the major gel-forming mucin expressed by the endocervical epithelium, peak before midcycle and the amount of MUC5B protein per unit total protein in cervical mucus peaks at midcycle. Message levels for MUC4, a major membrane-spanning mucin of the endocervix, peak at midcycle, but protein levels of MUC4 in human cervical mucus have not been measured. Message for each mucin diminishes dramatically as progesterone levels increase in the blood. These data suggest hormonal regulation of the two mucin genes in the endocervix, but there is no information on their regulation at the biosynthetic level via genomic hormone response elements. Perhaps, through its hydrophilicity, the MUC5B mucin holds water in place at the endocervical canal surface at midcycle, keeping the canal patent for sperm motility. A second potential role of the increased mucins at midcycle is to protect the cervix and uterus at the time when increased water is secreted into the cervical canal to facilitate sperm penetrance. Pathogens and other seminal fluid components may be excluded from entering the uterus by mucin trapping. Studies to determine the mechanism of hormonal regulation of mucins as well as the function of individual mucins are needed.

Muellerianosis of the urinary bladder, endocervicosis type: a case report

This case reports muellerianosis of the urinary bladder, showing glandular lesions made up of endocervical type glands, in a 36-yr-old woman. The patient presented with lower abdominal discomfort and pain on voiding. The patient had undergone two Cesarean sections 5 yr and 3 yr earlier. On a pelvic ultrasonography, a well-circumscribed mass, 2.2x0.8 cm in dimension, was found with luminal polypoid projection in the posterior wall of the urinary bladder. The patient had a transurethral resection of the bladder mass. Histologically, the tumor was composed of irregularly shaped glands lined by endocervical mucous epithelium in the muscularis propria of the urinary bladder. Some glands exhibited cystic dilatation and contained mucinous secretions. The glands elicited no desmoplastic tissue reaction. The intraluminal mucin often contained polymorphonuclear leukocytes. The glands were mostly lined by tall columnar and bland looking mucous cells with mucin secretion. The ciliated cells were rarely observed. No endometrial component is noted. It would be appropriate to designate this lesion as "Muellerianosis of the urinary bladder, endocervicosis type". Awareness of the lesion and attention to its typical histologic features should facilitate its crucial distinction from adenocarcinoma.

Epidemiology and pathogenesis of cervical cancer

The majority of the estimated incidence of 471,000 new cases for invasive cervical cancer (CX) and 215,000 cancer deaths occurs in the developing countries. For Germany the CX accounts at 8th position of all cancers in women in 1997 with 5,800 newly diagnosed cases. But, every fourth woman between 25th- and 35th-year of life has been affected by CX. This counts at the upper third of the incidence in the European Union (EU). The estimated loss of live-years for women affected by CX is about nine years. The lethality for all stages of invasive cervical cancer is about 30%. For the last two decades stagnation of the reduction of mortality by CX has been reported for EU and the USA, especially affecting woman up to 35th-year of life. The percentage of this age group of all primary operative treated CX at the Leipzig University Hospital between 1979 and 1999 was 26.2%, with a mean age of 43.4 +/- 11.1 years. Improved screening for CX in the western countries and a change in environmental factors have been caused an increase of cervical precancerous (CIN-) lesions. The frequency of CIN-lesions has been estimated to be 100-times higher than the incidence of invasive cancer (21.1) in Germany. The pathogenesis of CX is multistage and CIN I and II represent highly regressive lesions, whereas CIN III requires therapeutic intervention, caused by high progression rate. The Bethesda-classification of low und high grade squamous intraepithelial lesions (SIL) cannot be recommended for biopsies or conisation specimens. Dsyplastic lesions of endocervical columnar epithelium should not be graded, the only general accepted lesion represents the adenocarcinoma in situ (ACIS). Both, CIN and ACIS represents proliferative active lesions, caused by infection with HPV. But the detection of morphologic alterations, associated with HPV, like koilocytes, are inverse correlated with the grade of the CIN-lesion.

Glycodelin-A Expression in the Uterine Cervix

Objective. Local immunosuppressive factors in the uterine cervix infected by human papillomavirus are felt to facilitate the malignant transformation process. Glycodelin-A is an immunosuppressive peptide found in several tissues of müllerian origin, most notably the pregnant and decidualized endometrium. Its expression in the uterine cervix has not been defined but could theoretically contribute to the immunopermissive environment of the cervix. To determine whether glycodelin-A is found in the cervix we examined the squamous and endocervical epithelia from both normal and neoplastic cervical specimens from 14 women.Methods. Immunohistochemisty identification of glycodelin-A was performed on archival paraffin-embedded sections from 10 hysterectomies and 4 cone biopsies. Sections were evaluated and staining was scored as negative, positive, or strongly positive with a separate score for the squamous and glandular components of the cervix.Results. Eleven of 14 cases, 79%, demonstrated positive staining of the squamous epithelium. Glycodelin-positive cases included hisologically normal (n = 4; 3 strongly positive, 1 positive) as well as dysplastic (n = 5; 1 strongly positive, 2 positive, and 2 negative) and malignant squamous cells (n = 5; 1 strongly positive, 3 positive, and 1 negative). Normal glandular epithelia were negative in all cases but 1, which demonstrated significant squamous and tubal metaplasia of the endocervical glands involved.Conclusion. Glycodelin-A is found in the squamous epithelium of both the histologically normal and the neoplastic cervix. Further characterization of these results will focus on the possible immunosuppressive effect glycodelin-A may have in the cervix.

Differential expression of MUC2 and MUC5AC in benign and malignant glandular lesions of the cervix uteri.

The expression of mucin genes in the normal glandular epithelium of the endocervix has been well characterized. However, mucin gene expression in neoplastic or particular non-neoplastic glandular cervical lesions has not been addressed. This immunohistochemical study was carried out to analyze the expression of MUC2 and MUC5AC in neoplastic and non-neoplastic glandular lesions of the cervix. Monoclonal antibodies were used on paraffin-embedded sections from 41 adenocarcinomas, 2 adenosquamous carcinomas, 13 adenocarcinomas in situ (ACIS), 3 glandular dysplasias, 8 endometrioses, 5 tubal metaplasias, 17 squamous metaplasias, 3 microglandular hyperplasias and normal tissue of the endocervix, endometrium and fallopian tube. The patterns of expression of MUC2 and MUC5AC were different and in principle contrary. Focal MUC2 expression was observed almost exclusively in neoplastic lesions (36%) and not in normal epithelia and non-neoplastic lesions, the one notable exception being immature metaplasia. In contrast, strong expression of MUC5AC was observed in both normal endocervical epithelium (100%) and neoplastic lesions (73%). The expression of MUC5AC, however, was diminished in most neoplastic glandular lesions. Co-expression of MUC2 and MUC5AC was consistently documented in the lesions with intestinal differentiation. In contrast, cases of tubal metaplasia and endometriosis were negative for MUC2 and MUC5AC. These results indicate that discrimination of mucin gene expression may be helpful in discriminating lesions of the cervix.

Endocervical Curettage in Evaluating Abnormal Cervical Cytology

Between 1980 and 1995, 2126 patients were referred to the Colposcopy Clinic of Baylor College of Medicine (Houston, TX) for evaluation of an abnormal cervical smear. All patients were studied with a repeated cervical smear, colposcopy, and endocervical curettage (ECC). They were treated for cervical abnormality with cryosurgery (N = 1279), laser vaporization (N = 358), or the loop electrosurgical excision procedure (LEEP) (N = 489). The medical charts of these patients were reviewed to evaluate the role of ECC in the management of abnormal cervical cytology. The mean age of patients was 27 years (range = 13–77 years). The likelihood of atypia being found on ECC increased with the age of the patient, especially for high-grade lesions. Less than 5 percent of the women under 20 years of age (17 of 345) had human papillomavirus (HPV)/cervical intraepithelial neoplasia 1 (CIN-1), compared with 14 percent of women aged 41 years or more (P = .0001 for trend). Only 2 percent of the younger women (8 of 345) had CIN-2 or CIN-3, compared with 22 percent of the older women (27 of 125) (P = .0000 for trend). When the colposcopic examination was satisfactory (1854 patients), ECC results were abnormal 10 percent of the time (186 of 1854); but when the colposcopic examination was not satisfactory (272 patients), atypical epithelium was seen in 34 percent of the ECC specimens (91 of 2720) (P < .001). Biopsy samples of suspicious lesions seen on colposcopy were obtained. Of 128 women whose biopsy was read as normal, 27 women (21 percent) had abnormal ECC results. Of the 54 women in whom no abnormality was seen on colposcopy and who had no biopsy performed, ECC results were abnormal in 23 patients (43 percent) (P = .001). Ten percent of the 1045 women with biopsy results showing HPV or CIN-1 had abnormal ECC results (2.5 percent were high-grade lesions); 14 percent of the 898 women whose biopsy showed CIN-2 or CIN-3 had an abnormal ECC specimen (4 percent were low-grade lesions). One patient had cervical carcinoma, which was identified by both biopsy and ECC. Of the patients treated with LEEP, 202 had an abnormal ECC specimen. Ectocervical disease was found in 175 of the 202 women (86 percent), and endocervical disease was also seen in 24 of these 175 women (12 percent). In the 120 women who had CIN-2 or CIN-3 on ECC specimens, CIN-2 or CIN-3 was also present in the ectocervical epithelium (LEEP specimens) in 83 cases (69 percent), and invasive cancer was found in 6 other women. In addition, invasive cancer was found in one woman whose ECC specimen was read as HPV/CIN and in one woman with a normal ECC specimen. There were three invasive cancers found in the endocervical epithelium, all in women with an abnormal ECC specimen. Endocervical disease was found in 27 of the 287 LEEP specimens (9 percent) from women with a normal ECC. None of these women had invasive cancer. A cervical smear was obtained and ECC was performed in 1054 patients at the 1-year follow-up examination. Of the 40 women with low-grade disease on ECC, the Pap smear was read as normal in 34, as low-grade disease in 4, and as high-grade disease in 2. Of the 48 women with high-grade lesions on ECC, Pap smear results were read as normal in 31, as low-grade disease in 4, and as high-grade disease in 13. Invasive carcinoma was found in the ECC specimens of two patients; cervical smears indicated one low-grade and one high-grade squamous intraepithelial lesion. In all, 65 of the 986 women with normal Pap smears (6.6 percent) had abnormal ECC specimens; 31 (3.2 percent) were subsequently found to have CIN-2, CIN-3, or carcinoma in situ. J Reprod Med 2000;45:285–292

Expression of a homeobox gene (SIX5) in borderline ovarian tumours

Aims—To assess the expression of SIX5 (a homeobox gene) mRNA in surface coelomic epithelium, endocervical epithelium, Fallopian tube epithelium, and benign, borderline, and malignant epithelial ovarian tumours. Methods—10 normal premenopausal...

Study of the glandular endocervical epithelium cells from post menopaused women receiving hormonal replacement therapy comparing a morphologic analyzes with pcna immunoexpression

International Journal of Gynecology & ObstetricsVolume 70, Issue S3 p. C82-C82 Panel cervixs Study of the glandular endocervical epithelium cells from post menopaused women receiving hormonal replacement therapy comparing a morphologic analyzes with pcna immunoexpression Marcos Ymayo, Marcos YmayoSearch for more papers by this authorJ. Robalta, J. RobaltaSearch for more papers by this authorJ. Focchi, J. FocchiSearch for more papers by this authorJ. de Lima, J. de LimaSearch for more papers by this author Marcos Ymayo, Marcos YmayoSearch for more papers by this authorJ. Robalta, J. RobaltaSearch for more papers by this authorJ. Focchi, J. FocchiSearch for more papers by this authorJ. de Lima, J. de LimaSearch for more papers by this author First published: 10 December 2003 https://doi.org/10.1016/S0020-7292(00)80579-2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume70, IssueS32000Pages C82-C82 RelatedInformation

A morphologic and morphometric analysis of the glandular endocervical epithelium cells from post menopaused women receiving hormonal replacement therapy

A morphologic and morphometric analysis of the glandular endocervical epithelium cells from post menopaused women receiving hormonal replacement therapy

MÜLLERIANOSIS OF THE URETER: A METAPLASTIC LESION

A 39-year-old nulliparous woman with no history of pelvic surgery or endometriosis was admitted to the hospital in 1988 with acute right ureteral colic without expulsion of calculi, which she had intermittently experienced in the previous 2 years. Excretory urography (IVP) demonstrated a moderately dilated right ureter due to stenosis in the pelvic region (fig. 1, A). Ureteroscopy revealed a stricture, which was dilated with a balloon catheter, followed by clinical improvement. The patient declined surgery. For 10 years she had similar isolated episodes of pain every 2 to 3 months, which were seemingly unrelated to menses. In December 1998 the patient was rehospitalized with incapacitating colic. IVP revealed grade III ureteral hydronephrosis due to a 5 cm. stenotic ureteral segment (fig. 1, B). Ureteroscopy revealed a luminal polypoid bosselated lesion suggestive of endometriosis. However, CA 125 levels were only 7.5 units per ml. A segmental ureteral resection followed by ureterovesical implantation on a “psoic” bladder with an antireflux submucous path was performed. Macroscopically, the 5.3 3 1.5 cm. segment revealed a diffuse thickening of the ureteral wall punctuated by microcysts. Histologically, masses of fibroblastic tissue suboccluded the ureteral lumen involving the lamina propria and inner fibers of the muscularis, and were lined by urothelium which was continuous with a columnar mucinous epithelium. This proliferation was populated by numerous, often cystic, foci of endometrioid, tubal and endocervical epithelia, which had characteristic mullerian immunohistochemical profiles positive for estrogen and progesterone receptors as well as OC125 monoclonal antibody, carbohydrate antigen 19.9, coexpression of vimentin and low molecular weight CAM 5.2 cytokeratins (fig. 2).

Ovariectomy increases squamous metaplasia of the uterine horns and survival of SENCAR mice fed a vitamin A–deficient diet

Retinoic acid is necessary for the growth and differentiation of organisms and exerts its molecular actions by binding to specific nuclear receptors that belong to the thyroid-steroid hormone receptor superfamily. Steroids and retinoids control the differentiation of the female reproductive epithelia: estrogen maintains the squamous differentiation of vaginal and ectocervical epithelia, whereas retinoic acid maintains the simple columnar endocervical and uterine epithelia. These lining epithelia transform into a squamous metaplastic phenotype in vitamin A-deficient animals. Furthermore, mortality due to vitamin A deficiency is usually attributed to infection resulting in part from dysfunction of the protective epithelia. Our objective was to test the hypothesis that estrogen depletion might change the squamous metaplastic response to vitamin A deficiency and affect animal survival. We used female SENCAR mice maintained on a purified vitamin A-deficient diet containing either 0 or 3 microg retinoic acid/g diet. Mice were either ovariectomized or intact. Squamous cells arising in the normally simple columnar epithelium of the endocervix and uterine cavity were monitored by keratin 5 expression with immunohistochemistry. Ovariectomy did not change the time to onset of vitamin A deficiency. It increased the number of squamous metaplastic cells and prolonged survival in mice consuming a vitamin A-deficient diet by as much as 40%. Factors other than epithelial differentiation per se control survival outcome of vitamin A-deficient mice. The results also show a significant increase in longevity of vitamin A- deficient mice when ovariectomized.

Altered Expression of CD44 and Variant Isoforms in Human Adenocarcinoma of the Endocervix during Progression

Objective. Altered expression of the CD44 family of cell adhesion molecules has been associated with tumor progression and metastasis. The aim of this study was to investigate the expression of the gene products of CD44 standard (CD44s) and several alternatively spliced variants (CD44v4, v6, v7, and v9) in adenocarcinoma of the endocervix and to correlate the degree of their expression with disease progression.Methods. Immunohistochemical staining for CD44s and CD44v4, v6, v7, and v9 was performed on formalin-fixed, paraffin-embedded endocervical specimens. Seventeen cases of adenocarcinoma in situ (AIS) and 22 cases of invasive adenocarcinoma of the endocervix were included in this study, and the immunoreactivity was compared with that of normal endocervical epithelium.Results. (1) In the normal endocervical mucosa, immunoreactivity for CD44s and the splice variants was lacking or was confined to only the basal portion of the glandular epithelium along the basement membrane; (2) CD44s was diffusely expressed along the entire cytoplasmic membrane, including the luminal surface of the tumorous glands in 94% of AIS and 95% of invasive adenocarcinomas; (3) a significantly stronger expression of CD44s was observed in invasive adenocarcinomas than in AIS; (4) in contrast to all other splice variants, CD44v9 demonstrated an increased expression in nearly all in situ and invasive lesions compared to the normal tissue; (5) CD44v4 and v6 were expressed only in a small proportion of invasive adenocarcinomas and were near totally absent in the in situ lesions; and (6) CD44 v7 was totally absent in all normal, in situ, and invasive lesions studied.Conclusions. It appears that neoplastic transformation of endocervical epithelium is associated with qualitative and quantitative changes in the expression of CD44 standard molecule and some CD44 splice variants.

Comparison of c-met Expression in Ovarian Epithelial Tumors and Normal Epithelia of the Female Reproductive Tract by Quantitative Laser Scan Microscopy

The transmembrane tyrosine kinase receptor c-met with its ligand, hepatocyte growth factor/scatter factor (HGF/SF), acts as a mitogen, motogen, and morphogen in many normal epithelia. HGF/SF-met signaling has also been implicated in neoplastic progression and metastasis. In this study, immunofluorescence staining and quantitative laser scanning confocal microscopy were used to measure c-met expression in ovarian surface epithelial tumors from 17 oophorectomy specimens. These specimens were from patients aged 25 to 81 (mean age, 52) and included 10 malignant tumors, 4 borderline tumors, and five benign tumors including a Brenner tumor. For comparison, c-met expression was measured in normal tissues from the same patients, including 4 ovarian surface epithelia, 4 fallopian tube epithelia, 2 endometria, and 3 endocervical epithelia, as well as 3 cases of endometriosis. Relative pixel intensity values of c-met expression ranged from 0.4 in a normal ovarian surface epithelium to 22.3 in a borderline serous tumor. Malignant tumors (mean, 9.6) and borderline tumors (mean, 12.9) had higher average c-met expression levels than normal tissues (mean, 3.6) and endometriosis (mean, 1.8). The expression levels of benign tumors were intermediate (mean, 7.9). Among the normal tissues, c-met expression in fallopian tubes (mean, 8.2; range, 3.4-12.9) was higher than that of the other normal epithelia (mean, 1.6; range, 0.4-4.3). In eight cases where both normal and malignant tissues were sampled, c-met expression was significantly greater in malignant than in normal epithelia (P = 0.01). These findings indicate that c-met plays a role in the biology of the normal tissues examined. They confirm that its expression increases in the malignant progression of ovarian surface epithelial tumors, and suggest that increases comparable to those in frankly malignant carcinomas have already been reached in borderline lesions, ie, early in the neoplastic process.

Epithelioid trophoblastic tumor: a neoplasm distinct from choriocarcinoma and placental site trophoblastic tumor simulating carcinoma.

This report describes the clinicopathologic and immunohistochemical features of 14 cases of epithelioid trophoblastic tumor (ETT), a distinctive but rare gestational trophoblastic tumor. The patients with this neoplasm were in the reproductive age group and presented with abnormal vaginal bleeding. Although diagnosis was usually associated with a gestational event, the latter was sometimes remote. Two of the 14 patients presented with extrauterine ETT without evidence of prior gestational trophoblastic disease in the uterus. Serum human chorionic gonadotropin levels were elevated in eight of nine patients in whom this information was available. In the uterus, ETT presented as a discrete, hemorrhagic, solid and cystic lesion that was located either in the fundus, lower uterine segment, or endocervix. Microscopically, the tumor was composed of a relatively uniform population of mononucleate intermediate trophoblastic cells forming nests and solid masses. The cells resemble the trophoblastic cells in the chorion laeve, and we have therefore designated them "chorionic-type intermediate trophoblast." Typically, islands of trophoblastic cells were surrounded by extensive necrosis and were associated with a hyaline-like matrix creating a "geographic" pattern that is quite characteristic of this lesion. The mean mitotic count was two mitoses per 10 high-power fields, and the average Ki-67 nuclear labeling index was 18%. Immunohistochemically, all cases were diffusely positive for inhibin-alpha, cytokeratin (AE1/AE3), epithelial membrane antigen, E-cadherin, prolyl 4-hydroxylase, and epidermal growth factor receptor but were only focally immunoreactive for human placental lactogen, human chorionic gonadotropin, PlAP, and Mel-CAM. The monomorphic growth pattern of ETT resembles placental site trophoblastic tumor to a much greater degree than choriocarcinoma which is characterized by a dimorphic population of trophoblast. In contrast to placental site trophoblastic tumor, the cells of ETT are smaller and display less nuclear pleomorphism. In addition, ETT grows in a nodular fashion compared with the infiltrative pattern of placental site trophoblastic tumor. In some of the cases, the trophoblastic cells in ETT replaced the endocervical surface epithelium, giving the appearance that the tumor was derived from the cervix. Moreover, because the associated hyaline-like material in ETT resembles keratin, the tumor can be misinterpreted as a keratinizing squamous cell carcinoma of the cervix. Ten patients underwent total hysterectomy and two had an endometrial curettage only. The two patients who presented with extrauterine ETT underwent small bowel resection and lung resection. Two of 12 patients with ETT in the uterus developed metastasis in the lungs and bone. One of these patients is alive with disease at 43 months and one patient was lost to follow-up after 2 months. One of the two patients who had extrauterine disease died of widespread tumor 36 months after diagnosis. The remainder of the patients are alive and well from 1 to 120 months. In summary, ETT is a rare trophoblastic tumor that simulates carcinoma and can behave in a malignant fashion. It appears to be less aggressive than choriocarcinoma, more closely resembling the behavior of placental site trophoblastic tumor. Based on the morphologic and immunohistochemical features, it appears that ETT develops from neoplastic transformation of chorionic-type intermediate trophoblast.

Expression of metalloproteinases and their inhibitors in adenocarcinoma of the uterine cervix.

Metalloproteinases (MMPs), a family of enzymes that participate in extracellular matrix degradation and remodeling, may play a role in tumor invasion and metastasis and have been correlated with tumor behavior and survival. The action of MMPs is regulated by tissue inhibitors of MMPs (TIMPs). Adenocarcinomas of the uterine cervix are neoplasms that primarily affect young women and are associated with human papillomavirus (HPV). Eighteen cervical adenocarcinomas and 5 controls were immunohistochemically analyzed for the expression of MMP-2, MMP-3, MMP-9, and their inhibitors, TIMP-1 and TIMP-2, in tumor cells and peritumoral stromal cells. These cells were also studied for the presence of MMP-2, MMP-9, and TIMP-2 mRNA by in situ hybridization (ISH). HPV status was studied using ISH for HPV 16 and 18. MMP-2 and -9 were expressed immunohistochemically in tumor cells in 17 of 18 tumors, MMP-3 in 5, TIMP-1 in 3, and TIMP-2 in 1. Stromal cells of most tumors expressed all the above proteins. The normal endocervical epithelium was uniformly negative for MMP-2, MMP-3, MMP-9, and TIMP-2, and variably expressed TIMP-1. Intense signals for MMP-2, MMP-9, and TIMP-2 mRNA were less frequently detected by ISH in tumor cells and peritumoral stromal cells and were absent in normal endocervical epithelium. All tumors contained HPV DNA 16, 18, or both. MMP and TIMP expression did not correlate with tumor type, grade, or HPV type. MMPs and their inhibitors are present in most cervical adenocarcinomas, independent of tumor grade or subtype, but with the exception of TIMP-1, they are not expressed in nonneoplastic endocervical epithelium. This finding might be helpful in the diagnosis of endocervical adenocarcinomas. HPV is prevalent in cervical adenocarcinomas, but its role in determining tumor behavior remains unclear.