According to the 2003 World Health Organization classification, malignant endometrial stromal sarcomas are categorized as low-grade endometrial stromal sarcomas (ESS) and undifferentiated endometrial sarcomas (UES) (Tavassoli, et al, 2003). In general, patients with ESS have a favourable prognosis, and behave in a relatively indolent manner. It has been shown that ESSs of the type associated with YWHAE-NUTM2 fusion have a more aggressive clinical behaviour, and poorer prognosis compared to conventional ESS. This is more adequately reflected by the revised WHO 2014 classification in which this subset of ESS is now classified as high-grade ESS (Kurman et al, 2014).

The tumour is derived from endometrial stromal cells.

Rare tumour whose true frequency is unknown, as tumours previously considered undifferentiated uterine sarcoma may belong to this category.

A total of 20 patients with YWHAE-NUTM2 ESS are identified thus far (Lee et al, 2012, Croce et al, 2013, Kruse et al, 2014). The median age of the patients was 50 years (range 28-67 years) which is in line with the median age in conventional ESS (Tavassoli et al, 2003).The most common symptoms of YWHAE-NUTM2 ESS were abnormal vaginal bleeding, and an enlarged uterus presenting as a pelvic mass, symptoms which occur also frequently in women with conventional ESS. Stage was known for 17 patients, including 6 patients with stage I, 6 with stage II, 4 with stage III, and 1 patient with stage IV disease.

The clinic-pathological features of YWHAE-NUTM2 ESS have been described by Lee et al (Lee et al, 2012, Lee et al, 2012). In the recently published 2014 WHO classification, ESS are subdivided into low-grade and high-grade ESS, in which the high-grade ESS typically harbours the YWHAE-NUTM2 genetic fusion (Kurman et al, 2014). Although it has been found that FISH analysis demonstrated absolute specificity of this genetic fusion for high-grade ESS, a considerable number of high-grade ESS is negative according to the literature (5 of 12 cases (42%)) (Lee et al, 2012). In the 2014 WHO classification, high-grade ESS has been defined as a malignant tumour of endometrial stromal derivation with high-grade, round cell morphology sometimes associated with a low-grade spindle cell (fibroblastic) component that is most commonly fibromyxoid.. Immunohistochemistry may be of help to differentiate between conventional ESS and YWHAE-NUTM2 ESS, reviewed recently (Chiang et al, 2013). The neoplastic cells of low-grade ESS are immunoreactive for CD10 and at least focally for actin. They are usually, but not always negative for desmin and h-caldesmon. Low-grade ESS is almost always positive for both estrogen and progesterone receptors. The spindle cell component of YWHAE-NUTM2 ESS is typically diffusely positive for CD10, ER, and PR, similar to the immunoprofile of conventional low-grade ESS, whereas the round cell component is consistently CD10-negative and shows absent to only focal, weak to moderate ER and PR staining. The cyclin D1 immunostain is quite discriminatory in this context (Lee et al, 2012), and recently Lee et al. found frequent expression of KIT in the high-grade round cell component, but lacking KIT hotspot mutations (Lee et al, 2014). The high-grade component shows strong membranous/cytoplasmic KIT staining and strong diffuse nuclear cyclin D1 positivity in more than 70% of tumour cells. The low-grade spindle cell component shows weak cytoplasmic KIT staining and weak to variable, heterogeneous cylin D1 expression. Conventional ESSs are typically negative for cyclin D1 expression.

Total abdominal hysterectomy with bilateral salpingo-oophorectomy, and debulking if applicable.

Follow-up information was available for 16 patients of the 20 abovementioned patients. Three patients died of their disease within 24 months, 1 patient had no evidence of disease, 4 patients developed recurrent disease, within 6, 12, and 18 months respectively. Four patients were alive with disease, no further information was available. Patients with high-grade ESS appear to have a prognosis that is intermediate between low-grade endometrial stromal sarcomas and undifferentiated sarcoma.

NOTE High-grade ESS typically harbours a rearrangement that consists of a fusion between the YWHAE and NUTM2A/B (previously known as FAM22A/B) genes subsequent to a t(10;17) (q22;p13). Although it has been found that FISH analysis demonstrated absolute specificity of this genetic fusion for high-grade ESS, a considerable number of high-grade ESS is negative according to the literature (5 of 12 cases (42%)) (Lee et al, 2012).

It has been shown that the use of FISH or RT-PCR studies may confirm the presence of YWHAE-NUTM2 genetic fusion in cases with a histo-pathological appearance as described above (Lee et al, 2012). Croce et al recommend to test for YWHAE rearrangements by FISH break-apart for ESS cases with high-grade morphology, and to complete the investigation by RT-PCR in borderline cases (Croce et al, 2013). It is important to note that it is not known whether discordance between FISH break-apart and RT-PCR results reflects a true biological reality (Croce et al). It is assumed that FISH break-apart is more sensitive than RT-PCR. This could be explained by the involvement of more partners (some unknown) in the translocation. It has been suggested that the threshold for FISH positivity of 30% of cells with rearrangements seems to be the reference cutoff. However, the authors state that the biological significance of some cells (up to 20%) with YWHAE rearrangements is still unexplained.

NUTM2A (NUT family member 2A)

10q23.2

or NUTM2B , located in 10q22.3

Further analysis of NUTM2A/B protein sequences revealed a bipartite nuclear localisation sequence (Arg-805 to Arg-822) encoded by exons 7 of NUTM2A and NUTM2B.

YWHAE (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon)

17p13.3

The gene product of YWHAE gene belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins, cytoskeletal configuration, metabolism, differentiation, survival, and transcription in eukaryotic cells (Mackintosh C, 2004).

It has been shown that the use of FISH or RT-PCR studies may confirm the presence of YWHAE-NUTM2 genetic fusion in cases with a histopathological appearance as described above (Lee et al, 2012). Croce et al recommend to test for YWHAE rearrengements by FISH break-apart for ESS cases with high-grade morphology, and to complete the investigation by RT-PCR in borderline cases (Croce et al, 2013). It is important to note that it is not known whether discordance between FISH break-apart and RT-PCR results reflects a true biological reality (Croce et al). It is assumed that FISH break-apart is more sensitive than RT-PCR. This could be explained by the involvement of more partners (some unknown) in the translocation. It has been suggested that the threshold for FISH positivity of 30% of cells with rearrangements seems to be the reference cutoff. However, the authors state that the biological significance of some cells (up to 20%) with YWHAE rearrangements is still unexplained.

The translocation produces an in-frame fusion gene that is comprised of exons 1-5 of YWHAE and exons 2-7 of NUTM2A/B.

YWHAE- NUTM2A/B oncogenic fusion results in nuclear accumulation of the functionally intact YWHAE protein-interaction domain. Known cytoplasmic YWHAE protein-protein interactions are thereby likely redirected to the nuclear compartment (Lee et al, 2012).