FIGO staging for uterine sarcomas

Jaime Prat, MD

Hospital de la Santa Creu i Sant Pau Barcelona, Spain

Dr Jaime Prat received an MD from the University of Madrid and trained in anatomic pathology at The New York Hospital, Cornell Medical College, USA. After a postdoctoral fellowship in surgical pathology at Memorial Sloan-Kettering Cancer Center, he became a faculty member of the Harvard Medical School at the Massachusetts General Hospital. During this time, he was a Junior Faculty Clinical Fellow of the American Cancer Society. He is a diplomat of the American Board of Pathology in anatomic pathology, a fellow of the Royal College of Pathologists of Great Britain, and has been on faculty at the US and Canadian Academy of Pathology since 1977. Dr Prat has served as Chairman of the Department of Pathology at Hospital de la Santa Creu i Sant Pau and Professor of Pathology at Autonomous University of Barcelona since 1986. His research has focused on clincopathologic features and molecular genetics of gynecological malignancies; he is the author of over 250 publications and serves on several editorial boards. Dr Prat is a past President of the European Board of Pathology (1999–2004), and is President of the International Society of Gynecologic Pathologists (2007–2009). He is also a member of the World Health Organization Committee for Classification of Tumours of the Female Genital Tract (IARC, Lyon France).

Uterine sarcomas are rare tumors that account for approximately 1% of female genital tract malignancies and 3%–7% of uterine cancers [1]. Although the aggressive nature of most cases is well recognized, their rarity and histopathologic diversity have contributed to the lack of consensus on risk factors for poor outcome and optimal treatment [2]. Until now, the 1988 International Federation of Gynecology and Obstetrics (FIGO) criteria for endometrial carcinoma have been used to assign stages for uterine sarcomas despite the different nature of both tumor categories. A new FIGO classification and staging has been specifically designed for uterine sarcomas in an attempt to reflect their different biologic behavior.

Traditionally, uterine sarcomas have been classified histologically into carcinosarcomas (malignant mesodermal mixed tumors), accounting for 40% of cases; leiomyosarcomas (40%); endometrial stromal sarcomas (10%–15%); and undifferentiated sarcomas (5%–10%). Carcinosarcoma, also referred to as “malignant mixed mullerian tumor,” is a biphasic neoplasm composed of distinctive and separate, but admixed, malignant-appearing epithelial and mesenchymal elements. Recently, carcinosarcoma has been reclassified as a dedifferentiated or metaplastic form of endometrial carcinoma. Despite this, and probably because it behaves more aggressively than the ordinary endometrial carcinoma, carcinosarcoma is still included in most retrospective studies of uterine sarcomas, as well as the 2003 World Health Organization (WHO) classification [3].

According to the WHO classification [3], uterine tumors exhibiting smooth muscle differentiation are diagnosed as leiomyosarcomas based on the presence of at least two of the following three features: moderate to severe nuclear atypia; mitotic index ≥ 10 mitotic figures (MFs) per 10 high-power-fields (HPFs); and/or tumor cell necrosis [3], [4]. Occasionally, the histologic features are insufficient to allow classification into benign or malignant categories and, in such cases, the designation “smooth muscle tumors of uncertain malignant potential” (STUMP) is recommended [3], [4]. The term endometrial stromal tumor is applied to neoplasms typically composed of cells that resemble endometrial stromal cells of the proliferative endometrium [3]. They are classified into noninvasive (stromal nodules) and invasive (low-grade endometrial stromal sarcomas). Endometrial stromal sarcomas exhibit only mild nuclear atypia and characteristically invade the myometrium and lymphovascular spaces. Tumor cell necrosis is rarely seen. The diagnosis of undifferentiated endometrial sarcoma is applied to cases that lack smooth muscle or endometrial stromal differentiation and exhibit myometrial invasion, severe nuclear pleomorphism, high mitotic activity, and/or tumor cell necrosis. The histologic appearance of this tumor is more like the mesenchymal elements of a carcinosarcoma than a typical endometrial stromal tumor [3].

The rare mullerian adenosarcoma is a mixed tumor of low malignant potential that shows an intimate admixture of benign glandular epithelium and low-grade sarcoma, usually of endometrial stromal type [5]. Typically, the stroma concentrates around the glands forming periglandular cuffs. The histologic picture is reminiscent of a phyllodes tumor of the breast. Well-differentiated tumors may exhibit only mild nuclear atypia and very few or no MFs in the stromal component. In such cases, the presence of hypercellular periglandular cuffs helps to distinguish adenosarcoma from its rarer benign counterpart, the adenofibroma [6]. Heterologous mesenchymal elements, usually rhabdomyosarcoma, are found in 10%–15% of cases.

The prognosis of patients with uterine sarcomas has not changed in recent decades: the overall 5-year survival has been between 17.5% and 54.7% in various studies [7]. In a recently reported series of 100 cases, the 2-, 5-, and 10-year overall survival rates were 62%, 51%, and 38%, respectively. In multivariate analysis, stage, age, tumor size, and parity have been shown to independently influence overall survival [2], [7].

Currently, it is believed that most uterine sarcomas are leiomyosarcomas. After excluding several histologic variants of leiomyoma frequently misdiagnosed as sarcomas (such as cellular, mitotically active, epithelioid, myxoid, and atypical leiomyomas), it has also become apparent that leiomyosarcomas are associated with poor prognosis even when confined to the uterus. Conversely, most tumors classified as STUMP have been associated with favorable prognosis and, in these cases, only follow-up of the patients is recommended. Also, there is universal agreement that low-grade endometrial stromal sarcomas are indolent tumors associated with long-term survival despite recurrences and metastases [8]. However, classification and terminology of high-grade endometrial sarcomas have been controversial. Tumors exhibiting ≥ 10 MF/10 HPF and/or grade 2 or 3 nuclear atypia have been variously classified as high-grade endometrial stromal sarcomas, undifferentiated endometrial sarcomas, or undifferentiated sarcomas [3]. A recent study [9] has pointed out that undifferentiated endometrial sarcoma showing nuclear uniformity may represent an intermediate subcategory of endometrial stromal tumors (former “high-grade endometrial stromal sarcoma”) that shares some molecular genetic and immunohistochemical features with endometrial stromal sarcomas and is associated with better outcome than undifferentiated sarcomas exhibiting nuclear pleomorphism.

In patients with mullerian adenosarcomas, vaginal or pelvic recurrence occurs in approximately 25%–30% of cases at 5 years and is associated almost exclusively with myometrial invasion and sarcomatous overgrowth [5]. Myometrial invasion is found in approximately 15% of cases, but deep invasion in only 5% [5]. Sarcomatous overgrowth, defined as the presence of pure sarcoma, usually of high-grade and without a glandular component, occupying at least 25% of the tumor, has been reported in 8%–54% of uterine adenosarcomas [5].

Lymph node metastases have been identified in 6.6% and 11% of two series of patients with leiomyosarcoma who underwent lymphadenectomy [2], [10]. In the first series, the 5-year disease-specific survival rate was 26% in patients who had positive lymph nodes compared with 64.2% in patients who had negative lymph nodes (P < 0.001) [10].

Morphologic evaluation of hematoxylin and eosin stained sections has been equivocal in the prediction of behavior of uterine sarcomas and various ancillary techniques are increasingly used to improve prognostic accuracy. Immunohistochemical studies of selected oncoproteins as well as molecular analysis of non-random translocations, i.e., t(7;17) JAZF1/JJAZ1 (juxtaposed with another zinc finger 1/joined to JAZF1) which occurs frequently in low-grade endometrial stromal sarcoma, will undoubtedly lead to a more accurate classification of uterine sarcomas, with improved prognostic relevance.