Primary Ewing sarcoma of the uterine cervix: a case report and comprehensive review
Article information
Abstract
Primary Ewing sarcoma of the uterine cervix is an exceptionally rare and aggressive malignancy, with only 34 cases reported in the literature. Early recognition and prompt multimodal treatment are essential due to its poor prognosis. We report a case involving a 32-year-old multiparous woman who presented with foul-smelling vaginal discharge and irregular bleeding. Clinical examination revealed a 6×6 cm friable cervical mass extending into the upper vagina. Imaging demonstrated an FDG-avid cervical mass with regional lymphadenopathy. Histopathological analysis, supported by immunohistochemistry and fluorescence in situ hybridization, confirmed Ewing sarcoma with EWSR1 gene rearrangement. The patient received neoadjuvant chemotherapy with VDC (vincristine, doxorubicin, cyclophosphamide) and PIE (cisplatin, ifosfamide, etoposide) regimens, followed by surgical resection, adjuvant chemotherapy, and pelvic radiotherapy. Although initial disease control was achieved, the patient experienced disease recurrence with distant metastases after a 7-month disease-free interval and succumbed to the illness 9 months after diagnosis. This case underscores the importance of including Ewing sarcoma in the differential diagnosis of rapidly growing cervical tumors, particularly in young women. A multidisciplinary approach involving early molecular diagnostics and aggressive combined therapy is critical to improving clinical outcomes in such rare and aggressive cases.
INTRODUCTION
Ewing sarcoma (ES), also known as primitive neuroectodermal tumor (PNET), is a rare, aggressive malignancy originating from primitive neuroectodermal cells. Characterized histologically by sheets of small, round, blue cells, ES/PNET typically arises in bones or soft tissues of children and adolescents, with uterine cervical involvement being exceedingly rare—only 34 cases have been reported in English-language literature to date (Table 1) [1]. ES and PNET are now considered part of a tumor spectrum due to overlapping histological and genetic features, notably the t(11;22)(q24;q12) translocation resulting in the EWSR1–FLI1 fusion gene found in 85%–90% of cases, which drives oncogenesis [2]. Cervical sarcomas of neuroectodermal origin account for less than 1% of cervical cancers and are diagnostically challenging due to their heterogeneity. Given their rarity, management often mirrors skeletal ES treatment protocols [3]. Here, we present the 35th reported case of cervical ES and analyze prior cases to inform diagnosis, treatment, and prognosis.
Clinical characteristics, management, and outcomes of reported cases of peripheral neuroectodermal tumors of the cervix
CASE REPORT
A 32-year-old woman with three live births presented with a 6-month history of foul-smelling vaginal discharge and irregular uterine bleeding. Gynecological examination revealed a 6×6 cm friable, exophytic mass arising from the posterior cervical lip and extending into the upper two-thirds of the vagina, with no parametrium or rectal mucosal involvement. Contrast-enhanced magnetic resonance imaging (MRI) showed a lobulated, T2-hyperintense cervical mass measuring 6.6×5 cm. Whole-body positron emission tomography-computed tomography (PET-CT) revealed an FDG-avid lesion (maximum standardized uptake value) with regional lymph node involvement, but no distant metastases. Histopathological analysis revealed sheets of small, round blue cells (Fig. 1). Immunohistochemistry demonstrated strong positivity for CD99, vimentin, neuron-specific enolase (NSE), CD56, and CD117 (Fig. 2). Fluorescence in situ hybridization (FISH) confirmed EWSR1 gene rearrangement, consistent with ES. After multidisciplinary tumor board discussion, the patient received six cycles of neoadjuvant chemotherapy using alternating VDC (vincristine, doxorubicin, cyclophosphamide) and PIE (cisplatin, ifosfamide, etoposide), achieving partial clinical and radiological response. She subsequently underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and upper vaginectomy (Fig. 3). Histopathology confirmed residual tumor burden (64%) with clear margins. Immunohistochemistry remained positive for CD99 and NKX2.2. Postoperatively, she received six cycles of adjuvant VDC-IE chemotherapy. Contrast-enhanced CT revealed a nodular lesion at the vaginal vault, prompting pelvic external beam radiotherapy (EBRT; 50.4 Gy in 28 fractions over 5.5 weeks) followed by two sessions of intravaginal brachytherapy. Posttreatment contrast-enhanced MRI confirmed no residual disease. She remained disease-free for 7 months; however, follow-up PET-CT revealed widespread metastasis to the peritoneum, lungs, liver, and bones. Despite restarting VDC chemotherapy, she deteriorated rapidly and died after two further cycles.
Small round blue tumor cells with round nuclei, finely dispersed chromatin, visible nucleoli, and scant cytoplasm. A delicate vascular network and focal necrosis are seen. Hematoxylin and eosin staining (×200).
Tumor cells exhibit strong, diffuse membranous positivity. Immunohistochemistry for CD99 (×400).
Gross pathology. The specimen shows a cervical tumor with hemorrhagic and necrotic areas. Tumor is circumscribed and partially infiltrates the vaginal cuff.
DISCUSSION
Review of literature
Methodology and findings
We reviewed previously published case reports and series and identified 34 documented cases of primary cervical ES/PNET. Three bibliographic databases, PubMed, Embase, and Cochrane, were searched for published literature. The conducting and reporting of this review adhered to the PRISMA guidelines. Using keywords “Ewing sarcoma” OR “Ewing sarcoma uterine cervix” OR “EWSR1 rearrangement” OR “multimodal therapy Ewing sarcoma uterine cervix,” studies were identified. After removing duplicate studies, titles, and abstracts were screened by the first author and cross-checked by the second author. The relevance of each study was assessed based on the inclusion and exclusion criteria. Among these, Wei et al. (2022) [1] presented a case series comprising 26 cases of cervical ES. Our current case represents the 35th reported case. Data collected included patient age, presenting symptoms, diagnostic modalities, staging, treatment approaches, and clinical outcomes (Table 1).
Clinical features and diagnosis
The average age at diagnosis was 37 years (range, 19–76 years). Common symptoms were abnormal vaginal bleeding, pelvic pain, and discharge. Four cases were diagnosed incidentally during pregnancy (Table 1) [1]. On examination, tumors were typically large, friable, and hemorrhagic. Histologically, tumors comprised small, round cells with scant cytoplasm. Immunohistochemistry showed consistent CD99 positivity and frequent nuclear FLI-1 expression. NKX2.2 and CD56 also showed variable positivity. Differential diagnoses included small round cell tumors such as lymphoblastic lymphoma and rhabdomyosarcoma. EWSR1 gene rearrangement confirmed via FISH or RT-PCR was critical for diagnosis [2].
Treatment approaches and outcomes
Chemotherapy was used in 30 out of 34 cases, commonly VDC/IE-based regimens. Neoadjuvant chemotherapy followed by surgery and/or radiotherapy yielded the longest disease-free intervals. Radiotherapy was used in 14 cases, with improved disease-free survival (DFS; 28.7 months vs. 19.1 months). Pelvic lymph node dissection (PLND) was performed in 16 cases, though its survival benefit was unclear. DFS averaged 23.1 months with PLND versus 32.2 months without. Early-stage patients (IB–IIB) receiving multimodal therapy showed the best outcomes, with a 100% DFS during follow-up. However, prognosis remains guarded, especially in advanced disease, as reflected in the current case.
Discussion
Primary ES/PNET of the uterine cervix is an exceptionally rare and highly aggressive malignancy, comprising fewer than 1% of all cervical cancers. Before this report, only 34 cases had been described in the English-language literature [2,3]. The average age at diagnosis is 37 years (range, 19–76 years), and clinical presentations often include nonspecific symptoms such as abnormal vaginal bleeding, pelvic discomfort, and discharge (Table 1) [5,6]. These symptoms closely mimic more common cervical cancers, frequently delaying diagnosis [3,5]. Typically, these tumors present as large, friable, hemorrhagic growths, as seen in our case.
Histopathologically, ES/PNET is characterized by small, round blue cells with minimal cytoplasm. Immunohistochemical markers such as CD99 and FLI1 are commonly used for diagnosis, but they are not disease-specific. Several other small round cell tumors, including infantile spindle cell rhabdomyosarcoma, rhabdomyosarcoma, lymphoblastic lymphoma, endometrial stromal sarcoma, undifferentiated sarcoma, and small cell carcinoma, share similar histopathological features, which can complicate diagnosis [2].
Although CD99 is frequently expressed in ES/PNET, it is not exclusive to this tumor, as it is also expressed in lymphoblastic lymphoma. In cases where the tissue of origin is unclear, even after a thorough pathological evaluation by a sarcoma expert, identifying novel subtype-specific genetic alterations becomes crucial. Next-generation sequencing (NGS) panels have been increasingly recognized for their role in refining the diagnosis by detecting specific genetic changes that aid in the precise classification of sarcoma histotypes [15].
In the present case, immunohistochemical analysis showed positivity for vimentin, NSE, CD56, and CD117, which helped exclude the possibility of small cell carcinoma. Additionally, NKX2.2 was used as an adjunct to improve diagnostic specificity. The definitive diagnosis of ES/PNET relies on the detection of EWSR1 gene rearrangements, which can be confirmed through techniques such as FISH or reverse transcription polymerase chain reaction. EWSR1 gene rearrangements are present in over 85% of ES/PNET cases and are essential for confirming the diagnosis [2].
Given the complexity of diagnosing ES/PNET and the potential for misdiagnosis due to overlapping features with other small round cell tumors, the application of NGS is becoming indispensable. NGS can detect specific gene fusion events, such as the EWS-FLI1 fusion gene, which is the hallmark of ES. The chromosomal translocation t(11;22)(q24;q12), involving the EWS gene at 22q12.2 and the FLI1 gene at 11q24.1–q24.3, leads to the formation of the EWS-FLI1 fusion protein. This translocation is present in approximately 85% to 90% of cases and serves as a key diagnostic marker [2,15].
In this study, a combination of histopathology, immunohistochemistry, and EWSR1 gene rearrangement detection via FISH was employed, leading to the confirmation of ES of the cervix. This underscores the importance of integrating genetic testing, particularly NGS, into the diagnostic process for more accurate and specific identification of ES, especially in challenging cases where histopathology alone may not provide conclusive results.
Multimodal therapy is the cornerstone of treatment, typically involving neoadjuvant chemotherapy (VDC/IE), surgical resection, and adjuvant chemotherapy or radiotherapy [4]. Data suggest improved DFS, averaging 27 months with this approach [3–6,12]. Conversely, patients treated without systemic therapy often relapse early [5]. In our case, recurrence occurred within 7 months despite comprehensive treatment.
Radiotherapy was administered in 14 cases and correlated with longer DFS (28.7 months vs. 19.1 months) [7]. EBRT and brachytherapy were used in our patient. The role of PLND remains uncertain, with mixed DFS outcomes (23.1 months vs. 32.2 months) [3,7].
In the present case, the patient already presented at stage III, which is likely to result in a poor prognosis due to the advanced stage at diagnosis, leading to an early relapse. Most of the studies reviewed involved cases diagnosed at stage II, which is why their disease-specific survival and overall survival are likely higher than in the present case. The survival reported in the reviewed literature ranged from 12 days to 4.2 years, depending on the stage at presentation [3].
Novel aspects of the present case: ES of the cervix
The novel aspect of this case lies in the rare and unexpected presentation of ES in the cervix at a young age with an advanced stage of disease. ES is typically associated with bone and soft tissue, and its occurrence in the cervix is extremely rare. Diagnosing this condition in the cervix, particularly with its presentation as a small cell carcinoma-like tumor, poses a significant challenge due to its overlap in histological features with other cervical tumors.
In this case, the diagnosis was established through a combination of histopathology, immunohistochemistry, and molecular studies, which allowed us to differentiate it from other small cell malignancies of the cervix, such as small cell carcinoma and neuroendocrine tumors. The use of these advanced diagnostic techniques is crucial in distinguishing ES from other potential misdiagnoses, making this aspect of the case novel in its diagnostic approach.
Furthermore, despite aggressive treatment with chemotherapy, surgery, and chemoradiation, the disease’s advanced stage at diagnosis significantly impacted the patient’s long-term outcome, as evidenced by poor DFS. This case highlights that, in advanced-stage ES of the cervix, even intensive treatment regimens fail to provide substantial long-term benefits, contrasting sharply with the more favorable prognosis typically seen in early-stage disease. This underscores the need for early detection and the challenges posed by diagnosing rare sarcomas in uncommon locations, as well as the critical importance of personalized treatment strategies for such rare malignancies.
Conclusion
Accurate diagnosis of primary ES/PNET of the uterine cervix requires a combination of histology, immunohistochemistry (CD99, FLI-1, NKX2.2), and molecular confirmation. Multidisciplinary, individualized treatment remains essential, and international collaboration is key to improving future outcomes.
Notes
Conflict of Interest
No potential conflict of interest relevant to this article was reported.
Funding
None.
Author Contributions
Conceptualization: all authors. Data collection: all authors. Writing–original draft: all authors. Writing–review and editing: all authors. All authors contributed to the manuscript and approved the final version for publication.
Institutional Review Board Statement
Written informed consent obtained from the patient for publication.
Data Availability Statement
Data sharing is not applicable as no new data were created or analyzed in this study.