High-grade endometrial stromal sarcoma presenting with multiple brain metastases: a case report

The patient was a 58-year-old Japanese woman with a history of eight pregnancies and three deliveries. Her menarche was at 12 years old, and she reached menopause at 52 years old. She had a history of Cesarean section, but no other significant medical, surgical, and family history. She experienced abnormal uterine bleeding 12 years prior to presentation, which led to the diagnosis of a degenerating uterine fibroid (6 cm) and adenomyosis (Fig.  1 a). Endometrial cytology performed at that time was negative for malignancy. The patient was then followed up for 5 years and discharged after menopause. She had annual gynecological checkups with no abnormal findings. Fig. 1 a T2-weighted magnetic resonance imaging scan of the pelvis (sagittal section, 12 years prior). A 6 cm × 6 cm degenerated uterine fibroid is observed within the myometrial to subserosal layers of the posterior uterine wall (yellow arrow). T2-weighted images show a mixture of high and low signal intensity, suggestive of myxoid degeneration. b Fluid-attenuated inversion recovery magnetic resonance imaging of the head (axial section). Well-circumscribed tumorous lesions are observed in the right parietal lobe and left insula (yellow arrows), with the surrounding high signal intensity being suggestive of edema. c Hematoxylin and eosin-stained section of a permanent brain tumor specimen. There is a proliferation of atypical cells, ranging from round to spindle-shaped, with accompanying necrosis. d Immunohistochemical staining for glial fibrillary acidic protein at the border zone between the brain parenchyma and the tumor. The brain parenchyma was strongly positive for glial fibrillary acidic protein, while the tumor showed negative staining a T2-weighted magnetic resonance imaging scan of the pelvis (sagittal section, 12 years prior). A 6 cm × 6 cm degenerated uterine fibroid is observed within the myometrial to subserosal layers of the posterior uterine wall (yellow arrow). T2-weighted images show a mixture of high and low signal intensity, suggestive of myxoid degeneration. b Fluid-attenuated inversion recovery magnetic resonance imaging of the head (axial section). Well-circumscribed tumorous lesions are observed in the right parietal lobe and left insula (yellow arrows), with the surrounding high signal intensity being suggestive of edema. c Hematoxylin and eosin-stained section of a permanent brain tumor specimen. There is a proliferation of atypical cells, ranging from round to spindle-shaped, with accompanying necrosis. d Immunohistochemical staining for glial fibrillary acidic protein at the border zone between the brain parenchyma and the tumor. The brain parenchyma was strongly positive for glial fibrillary acidic protein, while the tumor showed negative staining Her presenting complaints at a local orthopedic clinic were left hemiparesis and weight loss. Cranial computed tomography (CT) performed at the local clinic revealed multiple brain tumors. At the time of neurosurgical consultation, the patient was alert and oriented but exhibited a left upper extremity muscle strength of 3/5 and a left lower extremity muscle strength of 4/5. No sensory or higher-order cognitive deficits were observed. A subsequent pelvic CT demonstrated uterine enlargement and enlarged para-aortic, right common iliac, and bilateral obturator lymph nodes. She was referred to obstetrics and gynecology for evaluation of the primary site of her multiple brain metastases. On initial gynecological examination, her consciousness was clear. A pelvic exam revealed a mobile, enlarged uterus consistent with uterine fibroids. A speculum exam showed no cervical abnormalities or abnormal bleeding. Cervical and endometrial cytology results were negative for malignancy. Cranial magnetic resonance imaging (MRI) revealed well-demarcated masses in the left insula and right parietal lobe (Fig.  1 b). The homogeneous contrast enhancement and high signal intensity on diffusion-weighted imaging suggested lymphoma as a differential diagnosis. However, significant peritumoral edema was also observed, which is more characteristic of metastatic brain tumors. Given the patient’s significant neurological symptoms and the need for a definitive diagnosis to guide treatment, a craniotomy with tumor biopsy was performed, and the tumor was completely resected. In the pathological diagnosis of the tumor from the permanent specimen, hematoxylin and eosin (H&E) staining revealed the proliferation of atypical round-to-spindle-shaped cells with geographic necrosis (Fig.  1 c). The tumor cells were observed to be arranged in a palisading pattern around some necrotic areas. These findings were atypical for malignant lymphoma or metastatic carcinoma, raising the possibility of glioblastoma or sarcoma metastasis. Immunohistochemical staining for glial fibrillary acidic protein (GFAP) was negative in the tumor cells, suggesting the unlikelihood of a primary brain tumor (Fig.  1 d). The results of the immunohistochemical stains of the brain tumor specimen were as follows: S-100 protein (focal +), CAM5.2 (a few, weak +), AE1/AE3 (weak +), P53 (wild-type but overexpressed), Ki-67 (60%), alpha-smooth muscle actin (α-SMA) (−), desmin (−), CD34 (−), Pax-8 (−), calretinin (−), epithelial membrane antigen (EMA) (−), cytokeratin 7 (CK7) (−), cytokeratin 20 (CK20) (−), estrogen receptor (ER) (−), p16 (−), HMB-45 (−), melan-A (−), vimentin (+). These findings were consistent with a sarcoma, though a specific line of differentiation was difficult to determine. To identify the primary lesion, positron emission tomography-CT (PET-CT) was performed, revealing high uptake in the uterus (Fig.  2 a). In addition to the uterus, enlarged left external iliac, bilateral internal iliac, bilateral obturator, and para-aortic lymph nodes with high tracer uptake were observed. Multiple intraabdominal nodules suggestive of peritoneal dissemination were also identified. Furthermore, the osteolytic changes in the left femoral shaft raised the suspicion of bone metastasis. The patient was then referred to the gynecology department again. Fig. 2 a Post-craniotomy positron emission tomography-computed tomography scan for primary tumor evaluation. Diffuse high uptake (maximum standardized uptake value of 37.31) was observed in the uterine tumor (yellow arrow). Uptake was also noted in the left external iliac lymph nodes, bilateral internal iliac lymph nodes, bilateral obturator lymph nodes, and para-aortic lymph nodes. b Magnetic resonance imaging of the pelvis (top left: T2-weighted axial section; top right: contrast-enhanced T1-weighted sagittal section; bottom left: diffusion-weighted imaging axial section; bottom right: apparent diffusion coefficient map axial section). The uterine wall, including the anterior wall, is diffusely thickened. The degenerated myoma in the posterior wall of the uterus has not significantly changed in size or character since 2013. On contrast-enhanced T1-weighted images, the tumor appeared hypointense compared with the myometrium (yellow arrows), suggesting that the uterus was largely replaced by the tumor. High signal intensity on the diffusion-weighted imaging and low signal intensity on the apparent diffusion coefficient map are observed throughout the uterus (yellow arrows). Multiple foci of high signal intensity on diffusion-weighted imaging and low signal intensity on the apparent diffusion coefficient map are also seen in both adnexal regions, raising suspicion for ovarian metastases. c Hematoxylin and eosin-stained section of a computed tomography-guided biopsy of the uterine myometrium. Although the tumor is not clearly demarcated, necrosis and atypical spindle-shaped cells are prominent. The histological appearance is similar to that of the cerebral lesion, consistent with it being the primary source of brain metastasis. d mmunohistochemical staining of the computed tomography-guided uterine biopsy (top left: CD10; top right: desmin; bottom left: Ki67; bottom right: CD10 of brain tumor). Areas that were negative for desmin stained positive for CD10, indicating that CD10 expression is localized to the tumor cells rather than the uterine myometrium. The Ki-67 index was 20%. Immunohistochemical staining for CD10 in the brain tumor showed strong positivity a Post-craniotomy positron emission tomography-computed tomography scan for primary tumor evaluation. Diffuse high uptake (maximum standardized uptake value of 37.31) was observed in the uterine tumor (yellow arrow). Uptake was also noted in the left external iliac lymph nodes, bilateral internal iliac lymph nodes, bilateral obturator lymph nodes, and para-aortic lymph nodes. b Magnetic resonance imaging of the pelvis (top left: T2-weighted axial section; top right: contrast-enhanced T1-weighted sagittal section; bottom left: diffusion-weighted imaging axial section; bottom right: apparent diffusion coefficient map axial section). The uterine wall, including the anterior wall, is diffusely thickened. The degenerated myoma in the posterior wall of the uterus has not significantly changed in size or character since 2013. On contrast-enhanced T1-weighted images, the tumor appeared hypointense compared with the myometrium (yellow arrows), suggesting that the uterus was largely replaced by the tumor. High signal intensity on the diffusion-weighted imaging and low signal intensity on the apparent diffusion coefficient map are observed throughout the uterus (yellow arrows). Multiple foci of high signal intensity on diffusion-weighted imaging and low signal intensity on the apparent diffusion coefficient map are also seen in both adnexal regions, raising suspicion for ovarian metastases. c Hematoxylin and eosin-stained section of a computed tomography-guided biopsy of the uterine myometrium. Although the tumor is not clearly demarcated, necrosis and atypical spindle-shaped cells are prominent. The histological appearance is similar to that of the cerebral lesion, consistent with it being the primary source of brain metastasis. d mmunohistochemical staining of the computed tomography-guided uterine biopsy (top left: CD10; top right: desmin; bottom left: Ki67; bottom right: CD10 of brain tumor). Areas that were negative for desmin stained positive for CD10, indicating that CD10 expression is localized to the tumor cells rather than the uterine myometrium. The Ki-67 index was 20%. Immunohistochemical staining for CD10 in the brain tumor showed strong positivity Abdominal and bimanual examinations were unremarkable, except for the previously known uterine fibroid. She did not have abnormal vaginal bleeding. Her blood tests revealed normal levels of CA-125, CA19-9, and lactate dehydrogenase; however, there was a slight elevation of the interleukin-2 receptor level (1172 U/ml, reference range: 122–496 U/ml). After referral to the gynecology department, the patient underwent endometrial cytology and biopsy, both of which were negative for malignancy. However, a contrast-enhanced MRI of the pelvis suggested uterine primary tumor (Fig.  2 b). The thickened areas showed high signal intensity on diffusion-weighted imaging (DWI) and low signal intensity on apparent diffusion coefficient (ADC) mapping. Enlarged left internal iliac and bilateral obturator lymph nodes and findings suggestive of ovarian metastasis were also noted. The imaging diagnosis was diffuse myometrial invasion of endometrial cancer. Multiple degenerating fibroids were also observed in the posterior uterine wall, with some showing signs of red degeneration. Thus, a transabdominal CT-guided biopsy was performed. H&E staining revealed prominent necrosis and atypical spindle cells, similar to the brain tumor (Fig.  2 c). Immunohistochemical staining for desmin showed positive staining in bundles with minimal atypia, consistent with the staining of existing smooth muscle. CD10 staining, which highlights the endometrial stroma, was positive in areas that tested negative for desmin, confirming that the tumor cells were positive for CD10 (Fig.  2 d). Further immunohistochemical staining showed a Ki-67 labeling index of 20% (Fig.  2 d), positive staining for cyclin D1 and vimentin, and negative staining for p16 and p53, confirming the diagnosis of HG-ESS [ 9 ]. Subsequently, the brain tumor specimen was stained for CD10 and showed strong positivity, confirming that the former was indeed an HG-ESS metastasis, leading to the diagnosis of HG-ESS (Fig.  2 c, d). The final diagnosis was stage IVB ESS (International Federation of Gynecology and Obstetrics (FIGO) 2008), cT2bN1M1. Following the diagnosis of stage IVB high-grade endometrial stromal sarcoma, the patient was treated with single-agent Adriamycin chemotherapy. During the diagnostic period (approximately 2 months), the brain metastases progressed, leading to the worsening of her hemiparesis. Owing to the presence of multiple brain metastases, whole-brain radiation therapy was initially proposed, but the patient and family did not consent to this treatment owing to concerns about side effects. Therefore, as an alternative, Gamma Knife radiosurgery was performed with the consent of the patient and family. Despite Gamma Knife radiosurgery, the patient’s condition deteriorated rapidly and the second cycle of chemotherapy was withheld; the best supportive care was initiated. The patient was subsequently transferred to a palliative care hospital where she died approximately 2 weeks later (4 months after her initial presentation).

High-grade endometrial stromal sarcoma (HG-ESS) is a subtype of uterine sarcoma, a group of gynecological malignancies with a poor prognosis [ 1 ]. The classification of endometrial stromal sarcoma has undergone several revisions. In the 2003 World Health Organization (WHO) classification (3rd edition), HG-ESS was termed “undifferentiated endometrial sarcoma” owing to its lack of consistent resemblance to endometrial stroma [ 2 ]. However, subsequent research identified distinct cytomorphological features resembling endometrial stroma with prominent atypia and specific genetic alterations, including cyclin D1 expression, in some of these tumors. This led to the reclassification of HG-ESS as a distinct entity in the 2014 WHO classification (4th edition) [ 3 ]. Consequently, manuscripts published before 2003 should be interpreted cautiously, making it challenging to accurately identify cases that would currently be classified as HG-ESS. Endometrial stromal sarcomas are rare, accounting for less than 1% of all uterine tumors, with HG-ESS being even less common [ 4 ]. Owing to its rarity, definitive diagnostic imaging features, tumor markers, and characteristic histopathological findings remain poorly established. HG-ESS, despite typically affecting women around 50 years of age, can also occur in younger individuals [ 5 ]. Its common clinical manifestations include abnormal vaginal bleeding, abdominal pain, and abdominal distension [ 5 ]. HG-ESS is an aggressive malignancy that is often diagnosed at an advanced stage. Although lung metastasis is frequently reported, lymph node, bone, intestinal, and cutaneous metastases have also been observed [ 6 ]. Brain metastasis is rare, and its incidence remains unclear [ 7 , 8 ]. Treatment for HG-ESS typically involves surgery, followed by adjuvant chemotherapy or radiation therapy, although a standardized protocol is lacking owing to its rarity [ 9 ]. Prognosis remains poor, especially in advanced stages [ 10 ]. Herein, we describe the case of a woman in her 50s who presented with multiple brain metastases as the initial manifestation of HG-ESS in the absence of typical gynecological symptoms.

This compelling case highlights the significant diagnostic challenges posed by HG-ESS, a rare and aggressive uterine malignancy with a poor prognosis. The atypical initial presentation with multiple brain metastases, in the absence of common gynecological symptoms, led to a considerable delay in definitive diagnosis. Furthermore, the potential origin of HG-ESS from adenomyosis, as suggested here, warrants further investigation. Despite aggressive disease progression, the importance of molecular analysis, including fusion gene identification, for prognostication and potential therapeutic implications cannot be overstated, though it was a limitation in this rapidly deteriorating case. This report contributes valuable insights to the limited literature on HG-ESS, emphasizing the variability in its presentation and the complexities of its management.

Brain metastases from gynecologic malignancies are rare, and their prognosis is generally poor, even with multidisciplinary treatment. While most reported cases of brain metastasis from gynecologic origins pertain to primary sites in the ovary, and those from the uterus are often associated with choriocarcinoma, HG-ESS presenting with brain metastasis is exceptionally uncommon, with its exact incidence remaining unclear [ 11 ]. Given the rarity of HG-ESS itself, accounting for less than 1% of all uterine tumors [ 4 ], cases with brain metastasis are even less common. Prognosis for HG-ESS is generally poor, especially in advanced stages, and the presence of brain metastases further complicates the clinical course. Owing to the scarcity of reported cases, data on progression-free survival and overall survival specifically for HG-ESS with brain metastases are extremely limited. This case highlights a highly atypical initial presentation of HG-ESS, as the patient presented with multiple brain metastases in the absence of typical gynecological symptoms such as abnormal vaginal bleeding, abdominal pain, or abdominal distension, which are common initial manifestations of HG-ESS. It is noteworthy that it took approximately 2 months to reach a definitive diagnosis in this case. Three main factors contributed to this delay. First, HG-ESS is an extremely rare disease, and owing to the limited number of cases reported, definitive diagnostic imaging features, histopathological findings, and immunohistochemical markers have not been fully established in literature. Second, the initial presentation with multiple brain metastases, while appropriately demanding immediate investigation, contributed to a delay in adequately considering the possibility of an underlying gynecological malignancy. The absence of typical HG-ESS symptoms, such as abnormal vaginal bleeding, further contributed to this diagnostic delay. Finally, while the PET-CT findings indicated that the previously known uterine fibroid was unlikely to be the primary tumor, its presence initially contributed to the delay in diagnosis by masking the underlying HG-ESS. Given that the patient had a negative endometrial cytology at the time of initial presentation with abnormal uterine bleeding, the absence of further gynecological investigation might be considered a missed opportunity. While cytology has limitations in detecting some endometrial malignancies, further investigations such as endometrial biopsy, especially in the presence of persistent or recurrent abnormal bleeding, could have potentially led to an earlier diagnosis. However, it is also important to acknowledge that the initial focus on the neurological symptoms was clinically warranted. Typical presenting symptoms of HG-ESS include menorrhagia and irregular menstruation in premenopausal women and abnormal vaginal bleeding in postmenopausal women [ 5 ]. Other common manifestations include abdominal distension and abdominal pain [ 12 ]. The most common metastatic sites for HG-ESS are the lungs and lymph nodes [ 6 ]. Brain metastases are rare, and the exact incidence remains unknown. While our case presented with multiple brain metastases, Gulsen et al . reported a case of HG-ESS with a single hemorrhagic brain metastasis [ 8 ]. A limited number of cases of ESS presenting with brain metastasis have been documented [ 13 , 14 ]. It is important to acknowledge that literature on brain metastases in ESS is limited. However, on the basis of the few reported cases, including the one presented here, there appears to be some variability in the presentation of brain metastases, such as the number of lesions (single versus multiple) and their characteristics (for example, hemorrhagic versus non-hemorrhagic). This highlights the variability in the presentation of brain metastases in HG-ESS and the need for clinicians to be aware of this rare but potentially fatal complication. Further research and reporting of cases are needed to better understand the patterns of brain metastasis in this rare malignancy. Although a standard treatment protocol for HG-ESS has not yet been established, Adriamycin is a commonly used chemotherapeutic agent for soft tissue sarcomas, and it has shown activity against uterine sarcomas in previous studies [ 9 , 15 ]. Similarly, while a standard treatment protocol for brain metastasis has not yet been established, treatment generally follows the principles of managing brain metastases from other primary tumors [ 16 ]. However, the prognosis for gynecological malignancies with brain metastasis remains poor, even with multidisciplinary treatment [ 17 ]. The patient had a history of uterine fibroids predominantly located in the posterior uterine wall and adenomyosis mainly affecting the anterior wall. PET-CT revealed no uptake in posterior wall fibroids, suggesting that they were unlikely to be related to HG-ESS development. Furthermore, the CT-guided biopsy was performed in the anterior uterine wall, the site of the previously diagnosed adenomyosis. The biopsy specimen showed a mixture of myometrial and tumor cells, making it difficult to determine on the basis of needle biopsy alone whether normal endometrial stromal components had undergone sarcomatous transformation and invaded the myometrium or whether the endometrial stroma within the adenomyosis had become malignant. The possible origin of HG-ESS from adenomyosis, as suggested in this case, warrants further investigation. This case report contributes to the limited existing literature on HG-ESS and underscores the importance of continued research and data collection to improve our understanding and management of this rare condition. Recent studies have indicated the involvement of fusion genes, such as ZC3H7B-BCOR and YWHAE-NUTM2A/B, in HG-ESS [ 18 , 19 ]. HG-ESS harboring these fusion genes is associated with rapid clinical progression and a poor prognosis. Unfortunately, in the present case, owing to the rapid progression of the disease after the pathological diagnosis of HG-ESS, genetic testing of the tumor tissue could not be performed. Molecular analysis, including the identification of fusion genes, can provide valuable prognostic information and may have therapeutic implications. Therefore, even in cases of aggressive disease progression, attempts to perform genetic testing should be strongly considered. We recognize that the inability to perform this analysis represents a limitation of the present case.