A 59-year-old female presented with a 6 month history of post-menopausal bleeding. Transvaginal ultrasound revealed markedly thickened endometrium suspicious for malignancy. She underwent hysteroscopy with dilatation and curettage which yielded a diagnosis of “low-grade spindle cell neoplasm with myxoid stroma and endometrial glands”. Endometrial stromal sarcoma (ESS) (with glands) was favoured, although adenosarcoma could not be ruled out. She was then referred to gynecologic oncology for total hysterectomy and bilateral salpingo-oophorectomy. The surgery was complicated by dense bladder adhesions, and multiple suspicious pelvic lymph nodes were identified intraoperatively. Upon completion, there was no obvious disease remaining in the pelvis.
Post-operative computed tomography (CT) revealed bilateral pulmonary nodules suspicious for metastatic deposits. Follow up CT showed widespread metastatic disease affecting both lungs, the vertebral column, bilateral ilia, bilateral femoral diaphysis and retroperitoneal lymph nodes. Additionally, prior to gynecologic surgical intervention, the patient had identified a self-palpated right breast lump. Physical examination at the time revealed no concerning abnormalities, but subsequent mammogram showed heterogeneous features, with diffuse cortical thickening and micro-lobulated margins; risk assessment was determined to be BiRADS category 4C. Breast core biopsies were taken, revealing metastatic disease in the breast.
Gross Appearance
The uterine cavity was filled with multiple tan-grey, soft, fleshy endometrial masses ranging from 2.4–6.5 cm in greatest dimension. The largest mass had a myxoid appearance and was located in the left posterolateral wall. There was gross extension to the resection margin posteriorly.
Microscopic Description And Differential Diagnosis
An initial endometrial biopsy was composed predominantly of blood with strips of inactive endometrium. Associated cytology showed atypical glandular cells. This finding, along with the markedly thickened endometrium seen on transvaginal ultrasound, prompted recommendation for repeat sampling. Repeat biopsy showed a low-grade spindle cell neoplasm with myxoid stroma and admixed endometrial glands. Cellularity was variable and occasional mitoses could be identified. Endometrial glands showed no cytologic atypia. Immunohistochemical (IHC) studies were performed and revealed that the spindle cells stained positively for estrogen receptor (ER) and CD10. Desmin, actin, alpha-actin and p16 were all negative. Wild-type p53 expression was observed and alcian blue highlighted abundant stromal mucin. The principal differential diagnosis at this juncture included low-grade adenosarcoma, ESN, and low-grade endometrial stromal sarcoma (LG-ESS). Definitive surgical management was recommended.
Hysterectomy and bilateral salpingo-oophorectomy was performed. The neoplasm was both intracavitary and deeply myoinvasive with extension to the resection margin. The morphology again included atypical spindle cells, arranged in short fascicles and set within a myxoid stroma (Fig. 1). Mitotic activity was high (> 20 mitoses per 10 high power fields) and necrosis was identified within the intracavitary component. Ovarian and fallopian tube metastases were noted, as was lymphovascular invasion. Retroperitoneal lymph nodes were also involved. No atypical glands, phyllodes-like architecture or periglandular cuffing to suggest adenosarcoma could be identified, nor any morphology suggesting conventional LG-ESS. IHC was positive for CD10 (both strong/diffuse and negative zones were noted), cyclin D1, cKIT, beta catenin, vimentin and MDM2. Rare glands were ER positive, but progesterone receptor (PR), desmin, actin, alpha actin, WT1, CD34, DOG1, p16, S100, HMB45, AE1/AE3 and ALK-5A4 were negative. There was wild-type p53 expression and weak variable MART1 staining.
Although the differential diagnosis was broad and included myxoid leiomyosarcoma (LMS), inflammatory myofibroblastic tumour, gastrointestinal stromal tumour (GIST), melanoma, adenosarcoma and malignant mixed Mullerian tumour (MMMT), the histomorphologic and IHC features were most in keeping with a fibromyxoid variant of endometrial stromal sarcoma (ESS). The high mitotic activity, advanced stage disease and strong cyclin D1 expression suggested HG-ESS as the top differential. Because HG-ESS variants can be associated with specific translocations (e.g. YWHAE-NUTM2A/B and ZC3H7B-BCOR), this case was referred out for fluorescence in situ hybridization (FISH) testing to Ashion ATGen Clinical Laboratory in Phoenix, Arizona. Rearrangement of the BCOR (Xp11.4) locus was identified. The positive BCOR translocation supports the diagnosis of BCOR HG-ESS. Notably, BCOR HG-ESS has been proposed to have an association with MDM2 amplification.4 This was identified in this case with IHC MDM2 overexpression and was in keeping with patterns described in previous literature. FISH for MDM2 rearrangement was therefore performed, but no rearrangements were identified in the MDM2 (12q15) locus.
A few months postoperatively, the patient underwent breast core biopsy for a 10 mm mass at the 12 o’clock position of the right breast. Sections showed a moderately cellular, mitotically active, spindle-cell lesion arranged in short fascicles within a fibromyxoid stroma (Fig. 1). Normal mammary glandular parenchyma was not present. IHC showed positive expression of CD10, cyclin D1, CKIT, beta catenin, and MDM2. S100 and p63 were weakly and focally positive. Negative staining was observed with desmin, actin, AE1/AE3, CK5/6, CD34, HMB45 and ERG. Histomorphologic and IHC features were also compared to the hysterectomy specimen. Collectively, the features supported a diagnosis of metastatic HG-ESS.
Figure 1
BCOR HG-ESS from hysterectomy and breast needle core biopsy specimens.
A: H&E section of endomyometrium at 4X magnification showing benign endometrial glands and fascicular growth pattern of BCOR HG-ESS set within a myxoid stroma. B: H&E section of endomyometrium at 20X magnification showing atypical spindle cells arranged in short fascicles set within a fibromyxoid stroma. C: H&E section of a breast needle core biopsy of metastatic BCOR HG-ESS at 4X magnification showing a moderately cellular spindle cell lesion with no normal mammary glandular parenchyma. D: H&E section of a breast needle core biopsy of metastatic BCOR HG-ESS at 20X magnification showing a mitotically active, spindle-cell lesion arranged in short fascicles within a fibromyxoid stroma.
Treatment
Initial treatment in this case included docetaxel and gemcitabine chemotherapy. There was progression of disease following 3 cycles, after which therapy was changed to doxorubicin. Disease progression stabilized after initiation of doxorubicin chemotherapy. Palliative radiation therapy was undertaken for spinal and cranial metastases and the patient was transferred to hospice care.