In February 2022, a patient in her early 50s, gravida 2, parity 2 (G2P2), was referred to her local physician in Colombia for post-menopausal bleeding. She had a significant medical history for hypertension. Her surgical history was significant for laparotomy for an ovarian cyst in 1995, two cesarean sections and abdominoplasty, as well as breast augmentation and repair of an anal fistula. Her family history was only notable for gastric cancer (maternal grandmother). Her physical and pelvic exams were normal.

A pelvic ultrasound was performed, revealing evidence of leiomyomatosis. Subsequently, the patient underwent dilation and curettage with hysteroscopic endometrial biopsy, revealing fusiform cells characterized by eosinophilic cytoplasm and elongated nuclei, along with sporadic mitosis (two per 10 high-power fields at 400×). CD10 expression was notably scarce, and Ki67 exhibited reactivity in 40% of neoplastic cells. These findings were indicative of a low-grade spindle cell tumor; however, the possibility of it being an endometrial stroma sarcoma could not be definitively ruled out. CT scans of the chest, abdomen, and pelvis were performed and metastatic disease was ruled out. Based on these results, in March 2022, the patient underwent a laparoscopic total abdominal hysterectomy and bilateral salpingo-oophorectomy. The frozen section evaluation reported a 1.6 cm endometrial stroma sarcoma, invading less than half of the myometrium.

Dr Pareja

Was there consideration of surgical staging?

Surgery is the primary treatment for uterine sarcoma and should include hysterectomy and bilateral salpingo-oophorectomy. However, surgical staging is not typically considered in sarcoma. The gold standard for treatment entails a comprehensive resection of all macroscopic disease with negative surgical margins.1 Some authors propose conducting a cytological study of peritoneal fluid.2 Controversy surrounds the role of pelvic and/or para-aortic lymphadenectomy. Lymph node involvement is infrequent when the disease is confined to the uterus. Consequently, lymphadenectomy does not provide benefit in early stages.1 3

The pathology reported a 1.6 cm low-grade endometrial stromal sarcoma localized to the uterine corpus.

Dr Mateo

What would be your approach to counseling the patient?

Uterine sarcomas are a heterogeneous and rare group of uterine mesenchymal malignancies that include different histological sub-types, representing approximately 4–7% of uterine tumors.4 5 They are aggressive and have a poor prognosis, even when diagnosed in early stages, with variations in prognosis and behavior among different histotypes.4

According to the SARCUT study, the International Federation of Gynecology and Obstetrics (FIGO) stage is the strongest prognostic factor for all sarcoma histotypes. Due to their low incidence and diverse etiology, information is scarce, and data on prognostic factors are limited. Low-grade endometrial stromal sarcoma is among the sarcomas associated with the best clinical outcomes, with a 5-year overall survival of 78.3%, 5-year disease-free survival of 68.1%, 10-year overall survival of 64.8%, and 10-year disease-free survival of 53.3%. The main factor impacting survival is residual disease after surgery.5

Dr Pareja

Based on the pathology, what would be the appropriate treatment?

According to the Europeans and the NCCN (National Comprehensive Cancer Network) guidelines, if the surgical resection has been complete, the optimal care for a low-grade endometrial stromal sarcoma confined to the uterus is surveillance.4 6 Exams should be performed every 3–4 months for 2–3 years, then every 6–12 months. For the first 3 years after the surgery, a CT of the chest/abdomen/pelvis should be performed every 3–6 months. Once the first 3 years have passed, the imaging should be performed every 6–12 months for the next 2 years. 6 Above all, patient education regarding symptoms of potential recurrence is paramount—up to 40–83% of patients report the new onset of symptoms before the clinical diagnosis of recurrence.4

Adjuvant treatment was not deemed necessary. The patient was under surveillance, and her last normal CT scan was in April 2023. In June 2023, she began experiencing lower abdominal pain and dyspareunia. Imaging in August 2023 revealed ascites and a 50×55 mm mass in the right iliac fossa on abdominopelvic CT scan. The MRI identified ascites and multiple confluent solid pelvic masses (116×112×106 mm), indicating an apparent origin from the right parametrium. The mass contacted the bladder, surrounded the rectum and sigmoid colon, with no evidence of disease beyond the pelvis.

Dr Mateo

How often does recurrence occur in a clinical early-stage low-grade endometrial stromal sarcoma?

Most sarcoma recurrences occur within the first 3 years post-initial treatment. In endometrial stromal sarcoma, recurrence rates range from 30–50%, primarily localized within the pelvic and abdominal cavity and occurring late, even in early stages, necessitating extended follow-up.4 7 The impact of early detection on prognosis and survival remains uncertain; however, there is a tendency toward early recurrence.

Generally, low-grade endometrial stromal sarcoma exhibits an indolent course and has a favorable prognosis; however, recurrence is still possible (approximately 30%). The most significant factor associated with recurrence and overall survival in sarcomas is the presence of residual disease after primary treatment.5 Physical examination, including a pelvic exam with a speculum and rectovaginal examination, detects 35–68% of recurrences.4

At that moment, the patient was referred to Clinica Las Americas where a physical examination was performed. A solid mass protruding into the cul-de-sac and firmly adhered to the anterior rectal wall was noted during rectovaginal examination.

Dr Mateo

What would your discussion with the patient be, considering concerns about disease recurrence?

According to GEIS group (Grupo Español de Investigación en Sarcomas), surgical resection of local recurrent disease should be considered by a multidisciplinary tumor board.8 When radiologically isolated vaginal or pelvic recurrence is identified, and no prior radiotherapy has been administered, two scenarios warrant consideration. The first scenario involves a surgical exploration, disease resection, and consideration of intra-operative radiation therapy. Pre-operative external beam radiation therapy, with or without systemic therapy, may also be considered. Post-surgery, if residual disease persists, external beam radiation therapy ± brachytherapy ± systemic therapy is advised. Alternatively, the second scenario recommends forgoing surgery and opting for external beam radiation therapy ± brachytherapy ± systemic therapy.6

In September 2023 the decision was made for tumor-reductive surgery, and the patient underwent an exploratory laparotomy. During the procedure, a 15×8×6 cm pelvic tumor was identified. An adhesiolysis was performed, leading to the resection of a portion of the sigmoid colon (11×7×4 cm), a segment of the ileum (3.5×1 cm with a 4×1.5 cm portion of adhered omentum), three serosal implants in the sigmoid (0.2×0.4 cm), and the appendix (6×5 cm with a 6×2.5 cm fragment of adipose tissue), which was extending into the tumor. Due to adhesions of the right parametrium, for greater safety, a double J stent was placed in the right ureter, and it was removed without complications 7 days later.

The pathology results showed the presence of fusocellular neoplasia with mild atypia, cells arranged in a storiform pattern, moderate mitosis, with foci of myxoid appearance. Inmunohistochemistry revealed negativity for CD10, cyclin D1, and anaplastic lymphoma kinase (ALK), consistent with undifferentiated uterine sarcoma in both the resected tumor and biopsied implants of the sigmoid serosa, ileum serosa, and appendix serosa.

Dr Pareja

Based on these findings, what would be the recommendations?

The patient underwent surgical exploration and resection without intra-operative radiation therapy. Both the resected tumor and biopsied implants of the sigmoid serosa and appendix serosa revealed evidence of undifferentiated uterine sarcoma. The only significant prognostic factor associated with overall survival and progression-free survival in undifferentiated sarcoma is incomplete cytoreductive surgery.5 As the presence of microscopic disease remains uncertain, the possibility of residual tumor cannot be excluded. Therefore, external beam radiation therapy ± brachytherapy ± systemic therapy may be deemed appropriate.6

The patient presented to Houston Methodist Hospital in October 2023 seeking treatment recommendations. On physical examination, the patient was noted to have a soft abdomen with no tenderness. The vaginal and pelvic examination did not reveal specific findings regarding recurrence or any evidence of palpable disease. The MRI and positron emission tomography-CT (PET-CT) performed on October 2023 showed status post hysterectomy, with the MRI revealing enhancing soft tissue at the right vaginal cuff encasing the right distal ureter, resulting in moderate hydroureter. The enhancing soft tissue in the MRI corresponded to a focal area of fluorodeoxyglucose uptake in the PET/CT. There was no suspicious pelvic lymphadenopathy and no evidence to suggest metastatic disease.

Dr Mateo

Could these findings be indicative of residual disease or a new recurrence?

The MRI and PET-CT were performed only 1 month after the tumor reductive surgery. As such, there is a possibility that the findings could represent post-operative changes or granulation tissue; however, a residual tumor could not be excluded.

Subsequently, the case was presented at the tumor board, involving pathology, oncology, radiation oncology, and urology. This was undertaken to formulate a strategic plan for further treatment. Based on the results from the MRI and PET-CT, the department of urology determined that the hydronephrosis was mild, and the kidney function was preserved. Therefore, the patient did not require urinary diversion.

The slides from the initial hysteroscopic endometrial biopsy (February 2022), the subsequent hysterectomy (March 2022), and the recurrent tumor (September 2023) were examined. The features present in the specimens were consistent with a diagnosis of uterine unclassified low-grade spindle cell sarcoma. In the hysterectomy slides, the tumor was observed to involve the endometrium and superficial myometrium (1.4 cm), with additional foci of metastatic sarcoma present on the fallopian tube serosa (0.7 cm) and ovarian surface (0.4 cm) (Figure 1).

Figure 1

The tumor metastasized to the ovarian surface (left side of photo) (hematoxylin and eosin, 40 x).

Dr Deavers

In this case, what would be the relevant differential diagnosis to consider?

The tumor’s location within the endometrium and superficial myometrium, coupled with staining for WT1, is indicative of a uterine sarcoma. Gynecologic smooth muscle and endometrial stroma normally exhibit positivity for WT1 ( Figure 2 ). However, additional inmunohistochemical and molecular studies do not demonstrate specific differentiation indicative of any typical uterine sarcoma. There were no glands present within the tumor, as in an adenosarcoma.

Figure 2

There is diffuse nuclear staining for WT1 (immunohistochemistry, 100 x).

Markers for leiomyosarcoma (smooth muscle markers: SMA, desmin, H-caldesmon), low-grade endometrial stromal sarcoma (CD10, ER, PR), PEComa (muscle markers, HMB-45, MelanA), and inflammatory myofibroblastic tumor (smooth muscle markers, ALK) all tested negative. Other mesenchymal tumors/sarcomas were also ruled out: histiocytic sarcoma (CD163), peripheral nerve sheath tumor (S100), and GIST (CD117).

To rule out a sarcomatoid carcinoma, keratin cocktail and epithelial membrane antigen (EMA) staining was performed. Keratin was negative, although there was staining for EMA. This finding is of uncertain significance as sarcomas on occasion may express EMA. P53 had a wild-type pattern. A comprehensive sarcoma panel was performed by next-generation sequencing. A variant of uncertain significance was found in the PTPRD gene. No rearrangement of JAZF1, PHF1, MBTD, YWHAE, or BCOR was found.

Dr Deavers

What findings lead us to classify it as a low-grade unclassified spindle cell uterine sarcoma?

The tumor exhibits similar morphologic features in all three specimens. It is characterized by a proliferation of uniform, bland spindle cells arranged in short fascicles with thin-walled vessels between them. There is only mild atypia, up to four mitoses per 10 high-power fields, and no necrosis is observed. No glands were present in the tumor ( Figure 3 ). Keratin cocktail immunohistochemistry was negative (helping to exclude sarcomatoid carcinoma), while there was nuclear staining for WT1 (identified in uterine smooth muscle and endometrial stroma). These features are consistent with a spindle cell sarcoma that is low grade.

Figure 3

The tumor is composed of uniform, bland spindle cells arranged in short fascicles (hematoxylin and eosin, 100 x).

With immunohistochemical and molecular studies, the tumor does not have results typical of any usual uterine sarcoma (leiomyosarcoma, low-grade endometrial stroma sarcoma, adenosarcoma, PEComa, inflammatory myofibroblast tumor). As there is no clear evidence of specific differentiation, it is an unclassified spindle cell sarcoma.

The pathology results indicated a low-grade tumor. Therefore, chemotherapy was not recommended. External beam radiation of the pelvis and brachytherapy were considered the best options to reduce the risk of local recurrence.

Dr Farach

What was the rationale for the recommendation?

In the context of sarcomas, radiotherapy is typically not considered for low-grade cases. However, in this patient, since the tumor is low-grade and locally recurrent, with concerns along the right ureteric margin, it has been decided to administer radiation therapy to the pelvis and vaginal cuff. This approach is aimed at reducing the risk of local recurrence and addressing concerns related to positive margins or residual disease near the right ureter.

Dr Farach

What was the dosing and the side effects discussed with the patient?

External beam radiation therapy targeting the pelvis at a dose of 45 Gy in 25 fractions was administered to the vaginal cuff, followed by interstitial high-dose brachytherapy delivering 30 Gy over five fractions. This treatment protocol is typically applied for significant gross disease in gynecological therapy. The entire course lasts for 8 weeks, a standard timeframe for pelvic cancers. The most common side effects of this treatment are vaginal stenosis, synechiae, cystitis, proctitis, diarrhea, and fatigue.

The patient tolerated external beam radiation well, reporting occasional symptoms like dyspareunia, right-sided pelvic pain, and bilateral leg weakness, which alleviated spontaneously. After three fractions of external radiotherapy, in November 2023 a follow-up PET-CT showed no evidence of recurrence, and prior activity in the right vaginal cuff/lateral fornix was not identified. As of the last visit in January 2024, the patient had completed external radiotherapy and brachytherapy, with no evidence of disease.

Dr Mateo

What would be your recommended surveillance?

A pelvic PET-CT and MRI are usually recommended 8 weeks after finishing the radiation treatment. In our case, involving a recurring low-grade sarcoma, intensive follow-up should be conducted every 4 months for the first 3 to 5 years, followed by assessments every 6 months for the subsequent 5 years. Limited information is available on this topic, but the standard minimum follow-up duration for most types of sarcoma is 10 years.