Primary low-grade endometrial stromal sarcoma of the ovary with mesenteric metastasis: An unusual case report

Introduction

Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that occurs in less than 1% of all patients. ¹ Among gynecological malignancies, low-grade endometrial stromal sarcoma (LGESS) accounts for only 0.2%. ² LGESS is the second most common mesenchymal malignancy of the uterus, after uterine leiomyosarcoma (uLMS). ³ It is composed of cells similar to endometrial stromal cells in the proliferative stage. The tumor cells are diffuse and infiltrative, and sometimes can be observed growing in a swirl shape around small blood vessels. The tongue-shaped invasion of tumor into the muscular layer or lymphatic vessel invasion serves as the pathologic basis for the diagnosis of LGESS. Immunohistochemical staining showed estrogen receptor (ER) and progesterone receptor (PR) positivity, along with diffuse strong CD10 positive expression in tumor cells. The results of molecular pathology indicated that about two-thirds of the tumors had multiple gene fusions, among which the JAZF1-SUZ12 gene fusion was the most common.^3–5 Due to the absence of specific clinical manifestations, preoperative imaging diagnosis is challenging and ultimately relies on postoperative pathological diagnosis, which often leads to misdiagnosis.

Low-grade endometrial stromal sarcomas (LGESS) are easily diagnosed when they occur in the uterus. However, the diagnosis becomes challenging when they have extrauterine sites, particularly if they exhibit unusual locations and variant morphologies. ⁶ Low-grade extrauterine endometrioid stromal sarcomas (LGEESS) frequently originate from endometriosis. However, in the absence of endometriosis, pathologists often misdiagnose or miss the diagnosis of LGEESS. ⁷ The correct diagnosis of extra-reproductive LGESS (primary or metastatic) in women is clinically important and can provide benefits for patient’s treatment. Here, we report a case of primary ovarian ESS with mesenteric metastasis, in which there is no endometriosis, initially undetected in frozen sections. We provide a comprehensive report on the clinical features, pathological characteristics, and immunohistochemical and molecular findings of the patient, offering valuable insights for clinical pathologists.

Case report

A 46-year-old married woman was admitted to our hospital with a pelvic mass, increased menstrual volume, and a prolonged menstrual period lasting 3 months. She had undergone laparoscopic ovarian cystectomy and myomectomy in 2013. After 6 months, vaginal ultrasonography detected a well-circumscribed 13 × 12 mm hypoechoic lesion in the muscular layer of the anterior wall of the lower uterine segment. Surgical treatment was recommended, but the patient declined. On February 6, 2023, vaginal ultrasonography re-detected multiple uterine fibroids and bilateral ovarian cysts, and she was subsequently admitted for surgery. The ultrasonography showed that the mass on the left anterior wall of the cervix had grown to 26 × 33 × 15 mm. An 83 × 88 × 63 mm anechoic structure was observed on the left side of the uterus. After evaluation by gynecologists, a total hysterectomy and bilateral salpingo-oophorectomy (BSO) were performed as necessary. Intraoperative exploration uncovered bilateral ovarian and mesenteric tumors. During the operation, a hard nodule measuring 2.5 × 2.5 × 2 cm was found in the sigmoid colon. After consulting with intestinal surgery experts, it was suggested to take a portion of the nodule for a frozen section. The family requested that no treatment be administered temporarily.

Resected samples of ovarian and mesenteric tumors were sent to the pathology department for frozen section biopsy. Macroscopically, the specimen of the left ovarian cyst was broken, with a maximum diameter of 9 cm and a thickness of 0.2 cm. The inner and outer walls were light, the contents had been lost, and dark red, blood clot-like materials were attached to the inner wall. The myometrium was cut in a lobar shape without obvious space-occupying lesions. There were no apparent abnormalities in the cervix. The mesenteric lesion consisted of a small amount of gray-red and light-yellow soft tissue with a medium texture.

Microscopically, the cystic walls of the bilateral ovaries were partially covered by small blue round cells exhibiting mild dysplasia, and the boundary with the surrounding stroma was unclear (Figure 1(a)). The thickness of tumor cell proliferation varied, with the thickest areas tending to form nodules (Figure 1(b)). On high-power examination, the tumor cells were small, spindle-shaped, with round or oval nuclei, less cytoplasm, and inconspicuous nucleoli, similar to the proliferative endometrial stroma. The tumor’s stroma had rare mitotic figures but was abundant in thin-walled spiral blood vessels (Figure 1(c)). Tumor cells in the mesenteric lesions were histomorphologically identical to those of the ovarian cyst wall (Figure 1(d)), which contained a definite intravascular tumor thrombus (Figure 1(e)). On immunohistochemistry, the tumor cells were diffusely positive for CD10 (Figure 2(a)), estrogen receptors (ER) (Figure 2(b)), progesterone receptors (PR), and vimentin, but negative for pan-cytokeratin (Pan-CK), smooth muscle antibody (SMA), desmin, CD34, S-100, inhibin-α, epithelial membrane antigen (EMA), CD99, LCA, calretinin, cyclin D1, and BCOR. The Ki-67 proliferation index of the tumor cells was approximately 8%. Additionally, the tumor cells in the mesenteric lesions were also diffusely positive for CD10 (Figure 2(c)), while the peripheral vascular endothelial cells were positive for F-8 (Figure 2(d)). Fluorescent in situ hybridization (FISH) analysis revealed the presence of JAZF1 (7p15) disruption (Figure 3). Based on the above characteristics, the final diagnosis is primary low-grade ESS of the ovary with mesenteric metastasis. After surgery, progesterone hormone therapy was chosen instead of chemotherapy or radiotherapy. No recurrence or metastasis was observed during the 6-month follow-up after surgery. However, due to the short follow-up period, the final prognosis remains unclear.

OPEN IN VIEWER

Figure 1.

Hematoxylin eosin stain. (a) The ovarian cyst wall was covered with small round cells (×10). (b) The tumor cells were arranged in solid and sheet-like patterns (×200). (c) Displayed mild atypical features (×400). (d) Mesentery lesions showed atypical tumor cells (×40). (e) and intravascular tumor embolus (×100).

OPEN IN VIEWER

Figure 2.

Immunohistochemistry stain. Tumor cells of ovarian staining positive for (a) CD10 (×10). (b) positive for ER (×20). (c) Tumor cells staining positive for CD10 in mesenteric lesions (×40). (d) The expression of F-8 was positive in mesenteric vessels and tumor emboli (×100).

OPEN IN VIEWER

Figure 3.

Fluorescence in situ hybridization. The presence of disrupted JAZF1 (7p15) genes.

Discussion

Low-grade ESS is a low-grade malignancy with a good prognosis but a high risk of recurrence. It is more common in perimenopausal women, with an average age of 44.5 years, and there are no clear risk factors identified for the disease. Common symptoms include abnormal vaginal bleeding and pelvic pain. ⁷ A limited number of cases have been reported, and the underlying mechanisms remain poorly understood. Consequently, this presents a significant challenge for accurate pathological diagnosis. Most LGESSs originate from endometriosis, clinical signs and symptoms are associated with the specific tumor location. ⁸ The common sites of involvement reported are typically those where endometriosis occurs. Our current case presented with bilateral ovarian cystic lesions. The lesions were characterized by scattered, multifocal attachments of dark-black and crispy materials on the gray, smooth cyst wall, which was easy to detach. Our patient also presented with mesenteric metastasis and obvious intravascular tumor thrombus at the time of diagnosis, aligning with the findings reported in the literature. ⁹

Microscopically, the tumor cells of LGESS exhibited morphological similarities to endometrial stromal cells during the proliferative phase, characterized by mild cellular atypia, rare or no mitotic figures, thin-walled spiral arteries, an expansive growth pattern, and an unclear boundary with the surrounding stroma. These features were significantly different from the high-grade ESS (HGESS). On immunohistochemistry, the immunohistochemical markers CD10, ER, and PR were strongly positive in LGESS, while Cyclin D1 and BCOR were negative, which was contrary to HGESS and consistent with previous literature on LGESS. Some studies have shown that interferon-induced transmembrane protein-1 (IFITM1), as a new immune marker of LGESS, is superior to CD10 in the auxiliary diagnosis of LGESS and can distinguish uterine smooth muscle tumors from endometrial stromal tumors. ¹⁰ Cytogenetically, LGESSs have been reported to harbor fusions of the JAZF1-SUZ12 genes and PHF1 genetic abnormalities.^11,12 Here, our molecular testing revealed a disruption of the JAZF1 gene.

It’s worth noting that when diagnosing primary extrauterine low-grade ESS, adequate sampling and observation of the uterus are necessary. A page-shaped incision is recommended to rule out primary uterine tumor metastasis. Once the tumor undergoes high-grade transformation, there is obvious nuclear atypia, frequent mitoses, characteristic immunohistochemical markers, and molecular gene changes, which alter its differential diagnosis. For LGEESS primarily involving the ovary, the differential diagnosis mainly includes the following four aspects: first, adult granulosa cell tumors of the ovary. Most of the tumor cells are arranged in trabecular, ribbon, and follicular patterns, with nuclear grooves and Call-Exner bodies (CEB). An immunohistochemical panel of Inhibin-α combined with CD10 may be useful for distinguishing ESS from adult granulosa cell tumors. Additionally, 90% of adult-onset granulosa cell tumors exhibit FOXL-2 gene mutations. Second, the metastatic ESS can be difficult to differentiate from other similar tumors in terms of morphology, immunohistochemistry, and molecular pathology. Careful sampling and evaluation should be undertaken to exclude the presence of a primary tumor in the uterus. Hence, when the primary foci are extrauterine, it is necessary to remove the uterus and conduct detailed sampling and pathological examination of the endometrium and myometrium. Third, ovarian endometriosis cysts can occur. Due to the lack of well-defined endometrioid epithelial cells, repeated exfoliation and degeneration of the epithelium cannot be excluded during cyst formation. The nodular tendency of stromal proliferation and the mild cytologic atypia of stromal cells are helpful for differential diagnosis In addition, ovarian endometriotic cysts typically exhibit remote hemorrhage and proliferative fibrous stroma, features that are rarely seen in ESS and may help distinguish between the two. Furthermore, primary ovarian lymphocytic tumors are mostly solid masses with rare cystic changes and exhibit spiral arteriolar hyperplasia. The tumor cells show greater atypia and more mitoses compared to the cells of ESS. Additionally, distinguishing these tumors through immunohistochemistry is relatively straightforward.

Conclusion

The small round stromal cells may often be mistaken for inflammatory cells or granulosa cells in the ovary, which are easily misdiagnosed when reported on frozen sections, thus presenting a great challenge to clinical pathologists. Low-grade extrauterine endometrioid stromal sarcomas (LGEESS) is rare. A case of uterine stromal sarcoma of primary ovarian is reported, which was missed on the frozen section, but we corrected the diagnosis on the paraffin section. Hopefully, this will attract the attention of more pathologists.