Cytological screening for cervical cancer or its precursors using Papanicolaou's smear test (Pap test) has been highly efficient to reduce the morbidity and mortality of cervical cancer. However, evaluation of the Pap test relies on subjective diagnostic parameters and is affected by a high rate of false-positive and false-negative results. More objective diagnostic parameters to identify truly dysplastic or neoplastic cells in cervical smears as well as in cervical biopsy samples would therefore avoid insecurity for many patients and the high screening costs associated with repeated testing. Cervical dysplasia is induced by persistent infections through highrisk types of human papillomaviruses (HPVs). Outgrowth of dysplastic lesions is triggered by increasing expression of two viral oncogenes, E6 and E7, which both interact with various cell cycle-regulating proteins. Among these is the retinoblastoma gene product pRB, which is inactivated by E7. pRB inhibits transcription of the cyclin-dependent kinase inhibitor gene p16 INK4a . Increasing expression of the viral oncogenes in dysplastic cervical cells might thus be reflected by increased expression of p16 INK4a . In line with this hypothesis, we observed marked overexpression of p16 INK4a in all cervical intraepithelial neoplasm (CIN) I lesions (n ‫؍‬ 47) except those associated with low-risk HPV types (n ‫؍‬ 7), all CIN II lesions (n ‫؍‬ 32), all CIN III lesions (n ‫؍‬ 60) and 58 of 60 invasive cervical cancers. In contrast, no detectable expression of p16 INK4a was observed in normal cervical epithelium (n ‫؍‬ 42), inflammatory lesions (n ‫؍‬ 48) and low-grade cervical lesions (CIN I) associated with low-risk HPV types (n ‫؍‬ 7). Dysplastic cells could also be identified in cervical smears using a specific p16 INK4a monoclonal antibody. These data demonstrate that p16 INK4a is a specific biomarker to identify dysplastic cervical epithelia in sections of cervical biopsy samples or cervical smears.

In several studies, attempts were made to establish criteria for distinguishing malignant Brenner tumors from proliferating and low malignant potential ones. Although these criteria can be applied to the majority of cases, there still exist tumors that present problems in classification. In applying the World Health Organization (WHO) criteria for Brenner tumors, the most important feature for distinguishing the intermediate forms from the malignant ones is the presence of stromal invasion in the latter. This feature has generally been considered difficult to employ because of the fundamental fibroepithelial nature of Brenner tumors, the stroma being derived from the ovarian stroma. A logical and relatively easily applicable classification of Brenner tumors is presented in this report. Although more complex than the WHO classification, it includes newly recognized variants of the Brenner tumor and avoids using the same terminology to describe different types and degrees of epithelial abnormalities. Fourteen unusual Brenner tumors were studied, intermediate between typical benign and frankly malignant ones, and were classified into 3 categories representing progressive epithelial abnormalities. These include metaplastic, proliferating, and tumors of low malignant potential. In none of these does stromal invasion occur. Each of these categories corresponds to a particular urothelial abnormality or neoplasm. Through this classification, a better understanding of the morphology and biologic behavior of unusual types of Brenner tumors can be expected.

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The EPH/EFN family of receptor tyrosine kinases regulates cell adhesion and migration and has an important role in controlling cell positioning in the normal intestinal epithelium. Inactivation of EPHB2 has recently been shown to accelerate tumorigenesis in the colon and rectum, and we have previously demonstrated frequent frameshift mutations (41%) in an A9 coding microsatellite repeat in exon 17 of EPHB2 in colorectal tumors with microsatellite instability (MSI). In this study, we extended these analyses to extracolonic MSI cancers, and found frameshift EPHB2 mutations in 39% (25/64) of gastric tumors and 14% (8/56) of endometrial tumors. Regression analysis of these EPHB2 mutation data on the basis of our previously proposed statistical model identified EPHB2 as a selective target of frameshift mutations in MSI gastric cancers but not in MSI endometrial carcinomas. These results suggest a functional role for EPHB2 in gastric tumor progression, and emphasize the differences between the tumorigenic processes in MSI gastrointestinal and endometrial cancer.

Castrated or juvenile monkeys were given estrogen, progesterone and relaxin in various doses and combinations. Relaxin induced: (1) a dilatation of the superficial endometrial blood vessels and proliferation of their endothelial cells; this effect may be regarded as due to relaxin alone; (2) an intensified differentiation of the endometrial stroma cells into predecidual cells and granulocytes, dependent on estrogen priming and the simultaneous injection of progesterone; (3) a periarteriolar mantle-like accumulation of granulocytes in the basal endometrium dependent on the above pretreatment; ( 4 ) a degranulation of the granulocytes and hypersegmentation of their nuclei following prolonged administration of relaxin with estrogen and progesterone. Morphologically and histochemically the granulocytes of the monkey are almost identical with those of the human uterus and with the granular cells in the decidua and mesometrial gland of the pregnant rat. Immunohistologically relaxin has been demonstrated in the granulocytes of man and rat. The changes in the arterioles brought about by exogenous relaxin occur under physiological conditions only with the increased formation of endogenous relaxin during early pregnancy. They have been described in the immediate vicinity of ovum implantation in man, monkey, and rat. Their function possibly lies in the preparation of blood spaces for nutrition of the young embryo.Hisaw and Hisaw ('64) studied the effects of relaxin in the female monkey, stressing its influence on the thickness of the endometrium and myometrium and on the cervix and symphysis pubis. They concluded that relaxin tended to intensify the synergistic action between estrogen and progesterone on endometrial growth. Since granulocytic cells occur in the endometrium of the monkey (Cleveland, '41; Bartelmez et al., '51; Hellweg, '59), and resemble the endometrial granulocytes of the human female, and since relaxin has been demonstrated immunohistologically in the endometrial granulocytes of the human uterus (Dallenbach and Dallenbach-Hellweg, '64), a histological and histochemical study of the endometria of these monkeys treated with relaxin seemed to be of great interest. It appeared important, therefore, to determine if exogenously administered relaxin in certain dosages and in combination with estrogen and progesterone would have an effect on the number and distribution of the granulocytes and on the degree of granulation. Close attention was also given to the presence of other morphologically recog-AM. J. ANAT., 119: 61-78.nizable effects which might eventually be ascribed to relaxin, in addition to the increased endometrial growth recognized by Hisaw and Hisaw. MATERIAL AND METHODSThe endometria of 64 monkeys (Macaca m u l a t t a ) were examined histologically and histochemically, using essentially the same uteri which were studied by Hisaw and Hisaw ('64). Since the treatments of the castrated animals were presented in detail in their paper, they are not included here. Ten juvenile and non-castrated ani...

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