Diagnosis: Endometrial stromal sarcoma

Discussion:
Endometrial stromal tumors may be benign (stromal nodule) or malignant (low grade and high grade endometrial stromal sarcomas). Endometrial stromal nodules and low grade endometrial stromal sarcomas have a haphazard (not fascicular) arrangement of uniform small cells resembling endometrial stroma (i.e., blunt, spindled to oval cells with scant cytoplasm and small, uniform nuclei). Each cell is individually enveloped by reticulin fibers. The stromal cells surround small / thin vessels that resemble spiral arterioles; thick vessels can be seen at the periphery of the tumor.

Low grade endometrial stromal sarcomas are defined by the presence of infiltration into the surrounding wall, which typically has a finger-like or tongue-like appearance (given the bulbous and convex size of the infiltrative nodularities); lymphovascular invasion is often seen and is a feature exclusive of low grade endometrial stromal sarcoma (endometrial stromal nodules should not have LVI). There is usually little cytological atypia or pleomorphism, and mitoses are scanty. Recurrent translocations are detected in > 80% of cases, most commonly the JAZF1::SUZ12 fusion (Am J Surg Pathol 2007;31:1277, Histopathology 2015;67:1).

High grade endometrial stromal sarcomas are a relatively recent diagnostic category, defined by the presence of recurrent aberrations such as YWHAE::NUTM2 fusion and BCOR alterations (Am J Surg Pathol 2012;36:641). YWHAE::NUTM2 rearranged sarcomas are characterized by a round cell component in which tumor nuclei are larger than in low grade sarcomas; a low grade spindle cell component is seen in 50% of cases. BCOR altered sarcomas tend to be predominantly fibromyxoid and feature monotonous to moderately atypical spindle cells (Mod Pathol 2018;31:674). Both forms of high grade endometrial stromal sarcoma are clinically aggressive.

In contrast, undifferentiated uterine sarcomas are frankly malignant and lack specific differentiation and any features of normal endometrial stroma. They often have destructive and irregular myometrial invasion, hemorrhage and necrosis, as well as marked nuclear pleomorphism and high mitotic activity.

The differential diagnosis of low grade endometrial stromal sarcoma includes:

• Endometrial stromal nodule: no / minimal infiltration, no angiolymphatic invasion
• Adenomyosis with sparse glands: this is usually an incidental finding in post menopausal women with typical areas of adenomyosis usually present; the foci of endometrial type stroma are small and do not have an expansile convex outline
• Cellular leiomyoma: no infiltration, no angiolymphatic invasion, fascicular growth with thick walled vessels throughout the tumor; strong expression of smooth muscle markers

In low grade endometrial stromal sarcoma, even after hysterectomy, there is often slow clinical progression with repeated local recurrences in up to 50%. Death due to disease occurs in 15%, often due to lung metastases, which may occur 30 years later.