Concise survey of endometrial pathologies detected at hysteroscopy
© Springer-Verlag Berlin / Heidelberg 2004
Published: 29 May 2004
The paper briefly reviews the main pathologies of the endometrium that can be detected by hysteroscopy. Emphasis is put on dysfunctional endometrial bleeding and the recently discovered molecular mechanisms that trigger its occurrence, on the difference between hyperplasia and intra-epithelial neoplasia of the endometrium and on the DNA alterations commonly found in endometrial adenocarcinomas. This review of uterine pathology is intended for gynecologic endoscopists and is accordingly focused on lesions of the endometrium and of the inner portion of the myometrium.
Hysteroscopy and endometrial sampling
Hysteroscopy is usually performed to investigate either infertility or abnormal uterine bleeding. In the former condition, the uterine cavity will most often appear normal and no lesion, irregular development and/or ripening of the endometrium or an endometritis will be disclosed at histology. In abnormal bleeding, the uterus may contain endometrial hyperplasia, atrophy, neoplasia, polyp, adenomyosis, submucosal leiomyoma, uterine sarcoma or no lesion, leading then to the diagnosis of dysfunctional uterine bleeding .
Hysteroscopy is superior to dilation and curettage for evaluating abnormal uterine bleeding . Indeed, the negative predictive value of hysteroscopy is >97% when no structural abnormality is disclosed in a completely visualized uterine cavity and when the endometrium appears uniformly thin and homogeneous [3, 4]. Theoretically, no further medical investigation should be necessary. However, because of the frequent lack of hysteroscopic diagnosis in case of endometritis, and considering the medico-legal climate that physicians currently face, systematic endometrial sampling may be recommended for pathological examination, even though the hysteroscopic view is negative.
Conversely, hysteroscopic detection of an abnormality is an indication for endometrial sampling. There is general agreement that a variety of endometrial sampling devices, including the Novak curette and pipelle biopsy, provide diagnostic accuracy equivalent to dilation and curettage . However, all these blind methods may not be of interest in cases of focal intra-epithelial neoplastic lesion, uterine fibroids or endometrial polyp. Hysteroscopy with selected endometrial sampling allows the targeting of a focal lesion and improves the efficiency of the histological analysis. Endometrial polyps or focal hyperplastic endometrium should be excised entirely, as the positive predictive value for the diagnosis of structural intra-luminal pathology on the sole hysteroscopic view is only 40% . This low value is probably due to gliding of the biopsy device on the surface of fibrotic lesions, and thus lack of adequate sampling of the lesion when a blind biopsy is performed after hysteroscopy. Hysteroscopic resection of the endometrium is generally not complete, but is at least equivalent to dilation and curettage regarding the extent of endometrial sampling. Histological analysis of shavings of the superficial myometrium and the overlying endometrium is adequate, although the tissue can be altered by the heating procedure at the edge of the shavings. Even adenomyosis may be suggested in the superficial myometrium despite the random orientation of the histological sections.
Dysfunctional uterine bleeding
Dysfunctional uterine bleeding is the main cause of metrorrhagia. It is defined as bleeding from the endometrium in the absence of pregnancy, of coagulation abnormality and of any pelvic lesion. Dysfunctional bleeding occurs either during hormonal treatment, in particular with progestins, or in its absence during spontaneous cycles as well as at menopause. It may occur upon prolonged estrogenic stimulation during anovulatory cycles and in hyperplasia, as well as in atrophic endometrium (see below). It is generally attributed to hormonal imbalance, but its relationship to sex steroids remains speculative at the present time .
Usually, the biopsy is performed during non-bleeding intervals, and the tissue then appears either normal or with the expected histology for the underlying condition, i.e., proliferative or hyperplastic upon prolonged estrogenic stimulation, or atrophic upon hormonal treatment.
Hysteroscopy is of limited value to assess the presence of endometrial mucosa with dilated glands (crypts) inside the myometrium. The hyperplastic pattern of the endometrium or its heterogeneous-appearing surface due to frequent concomitant interstitial myomas may be responsible for a high false-negative rate. In a regularly shaped uterus with endometrial atrophy, the crypts loaded with blood debris look like blue or brown spots, or small dips within the mucosa. The muscular hypertrophy appears as wild uterine inner sides, where the projection of bunches of muscular fibers are mixed with the endometrial crypts .
Histologically, adenomyosis is characterized by islands of endometrial glands and stroma inside the myometrium, together with hyperplasia of the surrounding myometrium in most cases. The intra-myometrial endometrial tissue is connected with the endometrium, its location resulting either from invagination of the mucosa inside the myometrium or from inclusion of the mucosa inside an “outgrowing” myometrium. The endometrial islands often look inactive like the basal layer of the endometrium, but may show secretory and menstrual features. The latter are responsible for prolonged and heavy menses. Because of its intra-myometrial location, adenomyosis cannot be sampled with a curette or a pipelle and can only be diagnosed on tissue shavings resected at hysteroscopy or on hysterectomy specimens.
Submucosal leiomyomas may cause bleeding by compressing and eroding the overlying endometrium. Hysteroscopy allows specification of the localization and the sessile (type 2) or pedunculated (types 0 and 1) implantation of the submucosal leiomyomas . A biopsy with a curette or a pipelle will usually sample only the eroded and inflamed atrophic endometrium, but not the underlying smooth muscle neoplasm. The leiomyoma itself can be excised at hysteroscopy, or torn out when polypoid and protruding through the cervix. The leiomyoma is usually fibrosed, hence its common clinical designation as “fibroid.” Areas of necrosis may occur, but they merge into fibrotic hyaline tissue and no atypia is found in the surrounding smooth muscle cells. In contrast, leiomyosarcoma shows a prominent mitotic activity, severe nuclear atypias, hemorrhages and clear-cut necrotic foci surrounded by non-fibrosed tumoral tissue.
Endometrial atrophy appears as a thin pallid or glossy mucosa. The vascular network of the superficial muscular layer may be visible through the thin endometrium. Endometrial sampling using the pipelle is often inefficient, but the sole hysteroscopic view is usually sufficient to establish the diagnosis. Bleeding episodes are associated with the occurrence of small superficial foci showing features of dysfunctional bleeding as explained above.
A hypertrophic mucosa with large hairy shreds is the prototypical hysteroscopic pattern of endometrial hyperplasia. Distinction between neoplastic transformation and benign hyperplasia requires endometrial sampling using a curette or selected endometrial resection in case of focal hyperplasia . Actually, two different diseases were previously called endometrial hyperplasia: the non-atypical hyperplasia, which corresponds to a true hyperplasia and is the only lesion that can still be called hyperplasia, and the atypical hyperplasia, which is a precancerous lesion and should rather be referred to as intraepithelial neoplasia (see below).
During bleeding episodes, the tissue usually shows the histological pattern of dysfunctional uterine bleeding, with focal menstrual-like degradation of the stroma. Bleeding can also be secondary to ischaemic necrosis of a largely thickened mucosa, in particular when massive decidualization is induced by a progestogenic treatment. Endometrial hyperplasia will regress heterogeneously when the estrogenic stimulation fades with time. Thus, some areas of the endometrium will remain thicker than other places, and cysts will still be randomly present in a rather atrophic mucosa. The histological picture will gradually change into a senile cystic atrophy of the endometrium. One can easily understand the semantic dilemma generated by all the intermediate states between florid hyperplasia and complete cystic atrophy of the mucosa. Although not precancerous by itself, hyperplasia is associated with continuous cellular proliferation that increases the likelihood of DNA alterations, which can then lead to the transformation of the epithelial cells into a true neoplastic lesion and accounts for the increased rate of adenocarcinoma occurring in a hyperplastic endometrium.
Functional endometrial polyps are usually small, with a wide and short pedicle, an irregular shape and a similar color to the adjacent endometrium during the follicular phase . They may become transparent during the secretory phase. Non-functional polyps are classically larger, with a sharp pedicle, a rounded shape and a greyish color contrasting with the adjacent endometrium.
The classical hysteroscopic pattern of endometrial neoplasia is a heterogeneous hypertrophic endometrium with various foci of hypervascularization, vegetations or dips. Since the neoplastic process starts focally, diagnosis of endometrial intra-epithelial neoplasia (EIN) or adenocarcinoma obviously requires adequate endometrial sampling selected at hysteroscopy. The neoplastic focus may indeed be missed by a too limited or a blind sampling.
Carcinosarcoma (or malignant mixed Müllerian tumor) is an aggressive variant of poorly differentiated endometrial adenocarcinoma, showing partial transdifferentiation of the cancerous cells into homologous or heterologous sarcomatous components. These tumors usually present as bulging hemorrhagic and necrotic masses protruding inside the uterine cavity. Adenosarcoma also forms an exophytic mass, but usually lacks necrotic features. This rare neoplasm is a variant of the low-grade stromal sarcoma, developing inside the endometrium.
Since neoplasia is monoclonal, it starts from one cell and is thus focal in the endometrium. Obviously, the transforming mutations that lead to neoplasia will occur more frequently in a proliferating than in a resting tissue, and EIN thus develops more often from a hyperplastic endometrium than from an atrophic one. However, we all know cases of adenocarcinoma arising focally from an atrophic endometrium. The most frequent DNA alterations observed in EIN are: (1) methylation of the promoter of hMLH-1, silencing the gene that codes for a protein of DNA mismatch repair , (2) microsatellite instability, which results from deficient DNA mismatch repair, and (3) mutations or deletion of PTEN (Phosphatase and TENsin homologue), a tumor suppressor gene located on the chromosome region 10q23 that codes for a lipid phosphatase involved in a signal transduction pathway affecting cell survival . Loss of chromosome 17p and mutation of p53 gene, often associated with an increased immunohistochemical labeling of the p53 protein, are observed in the aggressive serous variant of endometrial carcinoma .
In conclusion, although highly valuable and reliable as a method for the examination of the endometrium, hysteroscopy still needs to be completed by histological examination to obtain a definitive diagnosis when any abnormality is disclosed. It is to be hoped that visual targeting of the site of biopsy will further ameliorate the correlation between the macroscopic and the microscopic appearances of the various endometrial lesions enhancing the accuracy of the diagnosis and finally improving the care of the patient.
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