Uterine sarcomas: a multidisciplinary challenge

Abstract

With an incidence lower than 1/100,000/year, uterine sarcomas are a rare subgroup within the rare family of sarcomas, giving rise to 1% of female malignancies. However, they are a variegated set of malignancies, encompassing leiomyosarcomas, endometrial stromal sarcomas, undifferentiated endometrial sarcomas and adenosarcomas [1]. Another group, malignant mixed mesodermal tumours, are currently regarded as metaplastic (aggressive) endometrial carcinomas, i.e. epithelial tumours in nature, not sarcomas [2]. Both the low incidence and the heterogeneity of uterine sarcomas pose their first multidisciplinary challenge, inasmuch as a correct pathological diagnosis is crucial to proper management. Even the differential diagnosis between benign and malignant tumours can be problematic. One may recall the existence of a distinct entity among smooth muscle tumours, i.e. smooth muscle tumours of uncertain malignant potential (STUMP), whose behaviour is by definition unpredictable pathologically, and of benign metastasising leiomyoma and disseminated peritoneal leiomyomatosis, i.e. benign smooth muscle tumours presenting with metastatic dissemination [3]. Improvements in the pathological classification, and grading systems, for all these tumours are highly necessary. Endometrial stromal sarcomas are low-grade malignancies, although the relapse rate after surgery of localised disease is relatively high, possibly amounting to one third of cases, although over a long period. Pathologically, these tumours are marked by their positivity for oestrogen and progesterone receptors. This underlies the efficacy in the advanced disease setting of progestins, aromatase inhibitors and gondadotropin-releasing hormone analogues [4]. Responses are frequent and long-lasting, also owing to the natural history of these tumours, even when metastatic. For this reason, surgery of lung metastases is an option to consider within a multidisciplinary approach. The usefulness of adjuvant hormonal therapies is still an open issue, given the relapse rate and the hormonal sensitivity of these tumours [5]. Bilateral oophorectomy, in addition to total abdominal hysterectomy for local treatment, also has an adjuvant intent. Currently, endometrial stromal sarcomas are conceptually separated from undifferentiated endometrial sarcomas, although a de-differentiation process of some endometrial stromal sarcomas into high-grade sarcomas may occasionally take place [6]. Undifferentiated endometrial sarcomas are inherently high-grade malignancies (pathologically marked by a high mitotic rate, cellular pleomorphism and necrosis), which are insensitive to hormonal therapy and clinically aggressive. This considered, an aggressive, multidisciplinary approach to this rare entity is logical. Medical therapy must resort to standard agents for high-grade softtissue sarcomas. On the contrary, adenosarcomas are low-grade malignancies encompassing a benign epithelial component and a low-malignant mesenchymal one. Their good prognosis is unfavourably affected when a truly sarcomatous overgrowth or myometrial invasion is present [7]. Uterine leiomyosarcomas are cured in less than one half of cases by total abdominal hysterectomy, with size and pelvic extent as the main prognostic factors. Improvements in grading systems would be required, in order to refine the prognostic value of pathological assessment. Radiation therapy did not add to surgery alone in a large randomised trial [8], in spite of positive evidence provided by uncontrolled and retrospective studies as far as the local regional relapse rate is concerned [9]. This may leave room for individualised decision-making on radiation therapy in some cases, depending on the surgical outcome and anatomical considerations. Of course, radiation therapy can be useful in local regional relapses. The efficacy of adjuvant chemotherapy is an open issue in soft-tissue sarcomas, and therefore in uterine leiomyosarcomas as well. These are essentially insensitive to hormonal therapies, although hormonal receptors are found in the tumour tissue in a proportion of cases and there is anecdotal evidence of hormonal sensitivity in occasional patients. Medical therapy in the advanced disease resorts to agents active in