Endometrial stromal sarcomas are the second most common uterine sarcomas. Currently, they are classified into low-grade endometrial stromal sarcomas and undifferentiated endometrial sarcoma. Low-grade endometrial stromal sarcomas are biologically low-grade uterine sarcomas, and typically composed of uniform cells intimately associated with prominent arterioles, resembling the endometrial stroma in proliferative phase. There is usually little cytological atypia or pleomorphism, and mitoses are scanty. In contrast, undifferentiated endometrial sarcomas are frankly malignant, lack specific differentiation and any features of normal endometrial stroma. It is a highly aggressive neoplasm, often exhibiting myometrial invasion, haemorrhage and necrosis, as well as marked nuclear pleomorphism and high mitotic activity. The diagnosis of undifferentiated endometrial sarcoma is reached after excluding other uterine tumours with a sarcomatous component, such as adenosarcoma and malignant mixed Müllerian tumour. Histological variants of endometrial stromal sarcomas, including the so called ‘high-grade endometrial stroma sarcomas’ are addressed. The problems with histologic diagnosis and application of immunohistochemical studies and molecular pathology are highlighted.
Introduction
Endometrial stromal sarcomas (ESS) are the second most common pure mesenchymal tumours of the uterus, and account for about 10–15% of uterine malignancies with a mesenchymal component. According to the latest World Health Organization classification, ESS can be classified into low-grade ESS and undifferentiated endometrial sarcoma (UES). Low-grade ESS are low malignant tumours, typically composed of cells reminiscent of endometrial stromal cells in proliferative-phase, which invade the myometrium as well as intramyometrial or parametrial vessels, accounting for their old nomenclature, the endolymphatic stromal myosis or stromatosis. On the other hand, UES are highly malignant tumours that lack overt stromal differentiation and are referred to as ‘poorly differentiated’ or ‘high-grade undifferentiated’ endometrial sarcoma. Most ESS originate in the uterus, whereas rare extrauterine cases, presumably arising from endometriosis, are also encountered. In this review, we focus on the uterine ESS and summarise their clinicopathological, immunohistochemical and molecular features. Rare histological variants of ESS that may cause diagnostic problems are also discussed.
Low-grade endometrial stromal sarcoma
Most pure endometrial sarcomas are low-grade ESS that display overt endometrial stromal differentiation and bland nuclear features. They typically occur in women aged 40–55 years, and tend to be younger than those who present with other types of uterine malignancies, such as endometrial carcinoma, leiomyosarcoma or malignant mixed Müllerian tumour (MMMT). Cases involving adolescents or children have been reported. An association with prolonged oestrogenic stimulation, tamoxifen treatment, or previous pelvic irradiation has been observed in some patients.
Women with low-grade ESS commonly present with abnormal vaginal bleeding, pelvic or abdominal pain, although up to 25% of women are asymptomatic. Pelvic examination usually reveals an enlarged uterus with irregular contour. In addition, extrauterine spread is reported in up to one-third of women at the time of diagnosis, and the ovary is often involved in such cases. Thus, when ovarian tumours with histological features consistent with ESS are evaluated, it is important to exclude metastasis from uterine ESS because uterine ESS are far more common than primary ovarian ESS. Occasionally, women can present with lung metastases. Detection by cytology is extremely difficult because the cells lack sufficient atypia and mimic normal endometrial stromal cells. Such a possibility, however, should be kept in mind by the cytopathologist to avoid missing the diagnosis.
Gross features
The gross appearance of low-grade ESS can be variable. Typically, they present as irregular intracavity or intramural growth, accompanied by nodular or diffuse myometrial permeation, including worm-like plugs of tumour permeating into intramyometrial as well as parametrial veins and lymphatics. Some low-grade ESS may seem deceptively well circumscribed on gross examination. In this condition, careful inspection and thorough sampling of the tumour–myometrium interface is prudent to rule out the endometrial stromal nodule (ESN), a benign endometrial stromal neoplasm with non-infiltrative border. The cut surface of the low-grade ESS is typically soft, fleshy, bulging, and tan to yellow. Necrosis is not prominent.
Histologic features
Microscopically, the tumours are typically cellular and composed of uniform, oval to fusiform cells that resemble proliferative endometrial stromal cells ( Fig. 1 ). Nuclear atypia is mild. The tumours may contain a plexiform of small blood vessels, mimicking physiologic spiral arterioles. Large thick-walled muscular vessels and cleft-like spaces, often found in cellular leiomyomas, are uncommon.
The neoplastic cells of low-grade ESS are morphologically indistinguishable from those of an ESN. Myometrial invasion and vascular invasion ( Figs. 2 and 3 ) are the two most important features used to distinguish between these two tumours. In contrast with ESN, which grows in a non-infiltrative pattern, low-grade ESS permeate the myometrium in the form of lobulated or finger-like projections, and often invade myometrial as well as extrauterine veins and lymphatics. The myometrial invasion of low-grade ESS, however, is occasionally limited and focal. Distinction between an ESN and a low-grade ESS on the curettage samples is difficult. For a women who desires to preserve her uterus, a combination of diagnostic imaging and hysteroscopy may be used to monitor the growth of the tumour. Occasionally, local excision has been found to be successful.
The mitotic rate of low-grade ESS is usually less than 3 MF/10 HPF, but there can be greater mitotic activity in neoplasms that are otherwise typical of low-grade ESS. In this condition, a diagnosis of low-grade ESS should be made regardless of the mitotic counts because mitotic counts do not influence prognosis in these tumours. Necrosis is rarely seen in low-grade ESS.
Low-grade endometrial stromal sarcoma
Most pure endometrial sarcomas are low-grade ESS that display overt endometrial stromal differentiation and bland nuclear features. They typically occur in women aged 40–55 years, and tend to be younger than those who present with other types of uterine malignancies, such as endometrial carcinoma, leiomyosarcoma or malignant mixed Müllerian tumour (MMMT). Cases involving adolescents or children have been reported. An association with prolonged oestrogenic stimulation, tamoxifen treatment, or previous pelvic irradiation has been observed in some patients.
Women with low-grade ESS commonly present with abnormal vaginal bleeding, pelvic or abdominal pain, although up to 25% of women are asymptomatic. Pelvic examination usually reveals an enlarged uterus with irregular contour. In addition, extrauterine spread is reported in up to one-third of women at the time of diagnosis, and the ovary is often involved in such cases. Thus, when ovarian tumours with histological features consistent with ESS are evaluated, it is important to exclude metastasis from uterine ESS because uterine ESS are far more common than primary ovarian ESS. Occasionally, women can present with lung metastases. Detection by cytology is extremely difficult because the cells lack sufficient atypia and mimic normal endometrial stromal cells. Such a possibility, however, should be kept in mind by the cytopathologist to avoid missing the diagnosis.
Gross features
The gross appearance of low-grade ESS can be variable. Typically, they present as irregular intracavity or intramural growth, accompanied by nodular or diffuse myometrial permeation, including worm-like plugs of tumour permeating into intramyometrial as well as parametrial veins and lymphatics. Some low-grade ESS may seem deceptively well circumscribed on gross examination. In this condition, careful inspection and thorough sampling of the tumour–myometrium interface is prudent to rule out the endometrial stromal nodule (ESN), a benign endometrial stromal neoplasm with non-infiltrative border. The cut surface of the low-grade ESS is typically soft, fleshy, bulging, and tan to yellow. Necrosis is not prominent.
Histologic features
Microscopically, the tumours are typically cellular and composed of uniform, oval to fusiform cells that resemble proliferative endometrial stromal cells ( Fig. 1 ). Nuclear atypia is mild. The tumours may contain a plexiform of small blood vessels, mimicking physiologic spiral arterioles. Large thick-walled muscular vessels and cleft-like spaces, often found in cellular leiomyomas, are uncommon.
The neoplastic cells of low-grade ESS are morphologically indistinguishable from those of an ESN. Myometrial invasion and vascular invasion ( Figs. 2 and 3 ) are the two most important features used to distinguish between these two tumours. In contrast with ESN, which grows in a non-infiltrative pattern, low-grade ESS permeate the myometrium in the form of lobulated or finger-like projections, and often invade myometrial as well as extrauterine veins and lymphatics. The myometrial invasion of low-grade ESS, however, is occasionally limited and focal. Distinction between an ESN and a low-grade ESS on the curettage samples is difficult. For a women who desires to preserve her uterus, a combination of diagnostic imaging and hysteroscopy may be used to monitor the growth of the tumour. Occasionally, local excision has been found to be successful.
The mitotic rate of low-grade ESS is usually less than 3 MF/10 HPF, but there can be greater mitotic activity in neoplasms that are otherwise typical of low-grade ESS. In this condition, a diagnosis of low-grade ESS should be made regardless of the mitotic counts because mitotic counts do not influence prognosis in these tumours. Necrosis is rarely seen in low-grade ESS.
Undifferentiated endometrial sarcoma
Undifferentiated endometrial sarcoma is less common than low-grade ESS. They usually occur in postmenopausal women who present with abnormal vaginal bleeding and uterine enlargement. The diagnosis of UES is applied to tumour that exhibits myometrial invasion, severe nuclear pleomorphism, high mitotic activity, tumour cell necrosis, or all, and lack specific differentiation ( Fig. 4 ). Thus, the diagnosis of UES should be made after excluding other high-grade tumours of the uterus with a sarcomatous component.
Gross features
Grossly, UES usually presents as one or more tan-yellow to grey, fleshy intracavity polypoid masses. Haemorrhage and necrosis are often conspicuous. Myometrial invasion is common, but the intravascular worm-like plugs characteristic of low-grade ESS are usually not seen.
Histologic features
Histopathologically, UES has a diffuse and destructive infiltrative pattern similar to high-grade leiomyosarcoma or MMMT rather than low-grade ESS. The obvious intravascular permeating pattern commonly found in low-grade ESS is typically absent. The neoplastic cells exhibit marked cellular atypia and brisk mitotic activity, almost always exceeding 10 MF/10 HPF. Coagulative tumour necrosis is common and sometimes extensive. Practically, the diagnosis of UES should only be considered after exclusion of a poorly differentiated carcinoma, leiomyosarcoma and MMMT, all of which may be morphologically similar. Extensive sampling and immunohistochemical studies for epithelial and smooth-muscle markers are helpful in the differential diagnosis.
High-grade endometrial stroma sarcoma: the ongoing debate
In surgical pathology practice, some low-grade ESS may contain an ‘undifferentiated’ or a high-grade component that retains some endometrial stromal differentiation, indicating that the high-grade component is presumably of endometrial stromal origin. The approach of classifying these tumours remains a controversy. The term ‘high-grade ESS’ is regarded as an alternative term for ‘UES’ to some authorities, whereas others regard it as a separate subtype of ESS. In our opinion, the term ‘high-grade ESS’ is still appropriate for rare high-grade endometrial sarcomas that exhibit endometrial stromal differentiation, particularly when such a tumour seems to have arisen from an associated low-grade ESS. Tumours in this group are composed of uterine sarcomas that have a greater degree of nuclear atypia but maintain a link to endometrial stromal origin either by morphology or growth pattern.
The most important feature for distinguishing low-grade ESS from high-grade sarcomas is the resemblance of the neoplastic cells to proliferative endometrial stroma. Some investigators have suggested that such monotonous cytologic uniformity should be viewed as an important feature of endometrial stromal differentiation. A recent study suggests that UES having uniform nuclei, which correspond with high-grade ESS, share some molecular genetic and immunohistochemical characteristics with that of low-grade ESS and they showed better outcome than UES with nuclear pleomorphism. Moreover, UES featuring uniform nuclei are characterised by frequent simultaneous expression of beta-catenin and cyclin D1. In contrast, UES, with highly pleomorphic nuclei, are all negative for cyclin D1. These findings suggest the UES with uniform nuclei may represent an intermediate subcategory of endometrial stromal tumours and can also be temporarily termed as ‘high-grade ESS’.
Endometrial stromal tumours with unusual pathologic features
Endometrial stromal tumours, including clinically benign ESN and low-grade ESS, may occasionally show unusual types of differentiation that can markedly alter the appearance of the tumour. These unusual features include fibrous and myxoid change, epithelioid, rhabdoid changes, smooth-muscle differentiation, sex cord-like differentiation, glandular differentiation, and fatty metaplasia. Some of these phenotypes are more likely to create problems in diagnosis.
The presence of fibrous and myxoid change in a endometrial stromal tumour can result in focal to diffuse hypocellularity within the tumour. The neoplastic cells in such cases may sometimes display a more spindle shape and fibroblastic or myofibroblastic phenotype. Features favour the diagnosis of ESS rest on the presence of foci of typical endometrial stromal tumour, the characteristic vasculature, the typical tongue-like pattern of myoinvasion, and the immunoprofile of typical endometrial stromal tumours.
Focal smooth-muscle differentiation have been found in about half of cases of endometrial stromal tumours. If more than 30% of the tumour comprises smooth muscle, then these tumours are designated mixed endometrial stromal tumours with smooth muscle tumours or mixed endometrial stromal tumour with smooth-muscle differentiation. The term ‘stromomyoma’ should no longer be used because it implies that the tumour is absolutely benign. Molecular studies have shown that these tumours are of endometrial stromal derivation, as t(7;17), a specific translocation of EST, can be detected in both the endometrial stromal and smooth-muscle component. Therefore, the determination of malignancy in such cases should follow the criteria for endometrial stromal tumours.
Grossly, mixed endometrial stromal tumour with smooth-muscle differentiation is characterised by an admixture of soft tan to yellow nodules and firm white whorled nodules. Alternatively, paler and firmer tissue may be found surrounding the softer nodules, a picture that is not characteristic of smooth-muscle tumours in general. Histologically, the endometrial stromal component resembles that of pure endometrial stomal tumours. The smooth-muscle component is composed of spindle cells in disorganised short and long fascicles or nodules composed of epithelioid cells separated by collagen. The irregular nests with epithelioid pattern often have prominent central hyalinisation, sometimes with a radiating ‘starburst’ pattern, a feature less commonly encountered in conventional smooth-muscle tumours. Mixed endometrial stromal tumours with smooth-muscle differentiation often have circumscribed margins instead of infiltrating margins.
Distinction between endometrial stromal tumours and cellular leiomyoma is important because endometrial stromal tumours along with myometrial, vascular invasion, or both, permits the diagnosis of sarcoma. Cytologically bland but infiltrative smooth-muscle tumours, however, are not necessarily considered sarcomas. Immunohistochemical study is helpful but should be interpreted in correlation with the morphological features. Adequate sampling is important. Conventional areas of endometrial stromal tumours should be positive for CD10, whereas the smooth-muscle component should be positive for smooth-muscle markers.
About one-quarter of otherwise typical endometrial stromal tumours may exhibit minor foci of sex cord-like elements, most often in the form of anastomosing trabeculae, cords, and less commonly tubules. They may be the predominant pattern, whereas the stromal element is less conspicuous or absent. In the latter case, the term uterine tumour resembling ovarian sex cord stromal tumour (UTROSCT) has been used. In addition to the morphologic resemblance, these elements also may be positive for markers of sex-cord differentiation, such as inhibin, CD99 and calretinin, suggesting that these foci represent true sex-cord differentiation akin to that seen in the ovary.
It is important to differentiate UTROSCT from low-grade ESS, as UTROSCT typically behaves in a benign fashion, whereas women with low-grade ESS may develop recurrences. UTROSCT is strictly defined as a tumour with prominent sex cord-like differentiation with inconspicuous endometrial stromal background. It is necessary to sample the tumour extensively to rule out an endometrial stromal component, and thus be able to classify the tumour as a UTROSCT. The distinction of an endometrial stromal tumours with sex-cord differentiation from a UTROSCT can be made only in a hysterectomy specimen.
True glandular differentiation may also be occasionally seen in endometrial stromal tumours, most commonly as well-formed endometrioid glands. They are usually focally distributed and can vary in appearance from benign to those resembling a well-differentiated adenocarcinoma. Although divergent differentiation is the most likely explanation for their presence, some examples may represent entrapped non-neoplastic endometrial glands. The differential diagnoses in these cases include adenosarcoma and adenomyosis. Cases of adenomyosis with sparse glands may particularly create problems in diagnosis. Adenomyosis with sparse glands is an incidental finding in postmenopausal women and can be distinguished from low-grade ESS primarily based on the atrophic appearance of the stroma, the lack of grossly identifiable mass, and the lack of vascular involvement. Another striking entity, atypical polypoid adenomyoma (APA) may also cause diagnostic challenge. APA often exists as a polypoid lesion in the lower segment of uterine corpus or the upper endocervix. In addition to the presence of fibromyomatous component like the usual adenomyoma, the endometrial glands display variable degree of architectural complexity with or without cytological atypia. Extensive squamoid or morule metaplasia exists at the glandular epithelium ( Fig. 5 ). Myometrial invasion may be found in some cases of APA. Coexisting atypical hyperplasia may also be found in the adjacent endometrium. In fact, the major diagnostic challenge involves the distinction between APA and endometrioid adenocarcinoma with myometrial invasion. The differential diagnosis is particularly difficult in curetting specimens, where the samples are received in fragments. APA may develop recurrences if incomplete removal occurs after polypectomy.
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