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BACKGROUND The actions of the extracellular‐matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP‐2, MMP‐9, membrane type 1 (MT1)‐MMP, tissue inhibitors of metalloproteinases (TIMPs) 1‐3, and the presence of active gelatinases were investigated in endometrial carcinoma. METHODS Endometrial carcinomas were grouped according to histologic grade (Grades 1‐3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty‐nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP‐2 (gelatinase A), MMP‐9 (gelatinase B), MT1‐MMP, and TIMPs 1‐3. In situ hybridization was performed to localize MMP‐2 and MMP‐9 mRNA. The presence of active gelatinases was assessed using in situ zymography. RESULTS Epithelial tumor cells were the main site of MMP‐2, MMP‐9, and MT1‐MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP‐9 and MMP‐2 but not MT1‐MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase‐9 and MT1‐MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP‐2 did not correlate with these factors. In addition, MT1‐MMP was co‐localized with MMP‐2, supporting its role in the activation of proMMP‐2. Tumor cells from all histologic grades stained intensely for TIMP‐2 and TIMP‐3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP‐1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase‐9 and MMP‐2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues. CONCLUSIONS These data suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis. Cancer 2002;94:1466–75. © 2002 American Cancer Society. DOI 10.1002/cncr.10355

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The clinico-pathologic details of 200 patients with micro-invasive squamous-cell carcinoma of the cervix have been analyzed. All tumors invaded 5 mm or less below the basement membrane. One hundred and nine were categorized as FIGO stage 1a1 (early stromal invasion) and 91 as FIGO stage 1a2 (micro-carcinoma). The horizontal spread (length) of 12 micro-carcinomas exceeded 7 mm. Twenty-three had stromal invasion 3 mm or more, and 22 had capillary-like space involvement. Fifty-eight patients underwent pelvic lymphadenectomy in addition to hysterectomy and none had positive nodes. Univariate and multivariate analyses of possible prognostic factors including depth, horizontal spread, width, area, volume, grade, growth pattern, capillary-like space involvement, and stromal reaction failed to show any to be significantly associated with recurrence. The median duration of follow-up is now 8 years (0-22 years). Despite complete resection, seven (3.5%) patients developed recurrence of in situ or invasive carcinoma (three after early stromal invasion and four after micro-carcinoma), all of which were located at the vaginal vault. There were two deaths, one due to pulmonary squamous-cell carcinomatosis 21 years after early stromal invasion, the connection being tenuous, and the other due to local recurrence. There have been no recurrences to date in 23 patients treated by conization alone. The uniformly good prognosis of patients in this study is attributed to meticulous sampling of operative specimens resulting in accurate diagnosis and appropriate treatment, which may be conization alone provided the margins are free, there is no capillary-like space involvement, and the depth of penetration is less than 3 mm.

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