Case Report: A case of uterine embryonal rhabdomyosarcoma in adult female—navigating the complexities of the diagnostic journey

Sijing Li¹Dongni Zhou²Qiao Zu²Ying Jia^2*

• ¹Chongqing Health Center for Women and Children Department of Obstetrics and Gynaecology, Chongqing, China
• ²The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Background Rhabdomyosarcoma (RMS) is a soft tissue sarcoma originating from primitive mesenchymal cells differentiated in varying degrees of skeletal muscle[1]. There are four major histologic subtypes of rhabdomyosarcoma: embryonal rhabdomyosarcoma (ERMS), alveolar rhabdomyosarcoma (ARMS), pleomorphic rhabdomyosarcoma (PRMS) and spindle cell/sclerosing rhabdomyosarcoma (SRMS)[2]. Botryoid rhabdomyosarcoma is a special type of embryonal rhabdomyosarcoma. RMS predominantly affects children and adolescents, representing one of the most common pediatric malignant solid tumors and accounting for 5% to 10% of all childhood tumors[3]. In adults, the incidence of RMS is approximately 0.1 to 0.3 cases per 1 million individuals annually[4]. Given its embryonic mesenchymal origin, RMS can arise in virtually any organ. The primary sites of adult rhabdomyosarcoma were the trunk (27%) and limbs (26%), followed by the reproductive tract (17%). Most RMS cases in the female reproductive tract are embryonal rhabdomyosarcoma (ERMS), with the botryoid subtype being particularly notable. ERMS constitutes 0.2% of malignant uterine tumors in adult females[5]. Almost all current information on adult ERMS comes from case reports. Due to the extreme rarity and variable clinical manifestations of cervical ERMS, patients are frequently overlooked or misdiagnosed during initial evaluation. Here, we present a case of embryonal rhabdomyosarcoma (ERMS) of the uterine cervix in an adult female. The patient went through many twists and turns in the diagnosis. The purpose of this study was to report this rare case and to highlight the diagnostic and therapeutic challenges associated with this condition.. Case Report The patient was a 41-year-old female with regular menstrual cycles and a history of one live birth out of seven pregnancies. She presented to our hospital with a 9-month history of abnormal vaginal bleeding. In June 2022, the patient experienced post-coital bleeding and sought treatment at a primary hospital, where colposcopy and hysteroscopy indicated a cervical polypoid mass. A cervical polypoid mass resection was performed, and the excised tissue was sent for pathological examination, which initially suggested cervical polyps. The patient still had recurrent vaginal bleeding after surgery, for which she repeatedly visited the primary hospital. During this period, the volume of the cervical mass progressively increased. In September 2022, a repeat biopsy of the cervical mass was conducted, and the pathological findings again indicated cervical polyps. The patient was initially evaluated at this center in February 2023. Gynecological examination found that the cervix of many grape-shaped blister tissue out of the external os of cervix, and contact bleeding was obvious. Colposcopy revealed obvious polypoid vegetation in the cervix, which protracted from the middle and upper part of the vaginal wall, with soft texture, accompanied by necrotic tissue and blood clots. A large number of blister-like tissues were seen around the mass (Figure 1). Biopsy of the cervical lesion showed that: the cervical vegetations and cervical blister-like tissues showed clusters of atypical cells, which were considered as neoplastic lesions. Immunohistochemistry: P16(-), p40(-), ki67 (+) about 20%. Special staining: reticular fibers (+). There were no significant abnormalities in tumor markers (e.g., CA125, HE4, CA199, SCC...). Enhanced MRI revealed an enlarged cervix with an irregularly shaped mass extending to the internal cervical os, without endometrial involvement. The cervical stromal ring was incomplete, and the lesion extended into the vagina. The parametrial tissue was unaffected, and the vaginal morphology and signal appeared normal. Both fallopian tubes and ovaries were unremarkable bilaterally, and no enlarged pelvic or abdominal lymph nodes were observed (Figure 2). PET-CT demonstrated cervical enlargement with lesion extension into the adjacent vagina and increased metabolic activity, consistent with malignant tumor characteristics (Figure 3). One month later (March 2023), the patient returned to our center for follow-up. On physical examination, a large amount of blister-like tissue was found to be prolapsing from the vagina. The prolapsed tissue was excised and sent for pathological examination, which confirmed rhabdomyosarcoma with anaplastic features, consistent with graphiform rhabdomyosarcoma. Immunohistochemistry: CK (-), CAM5.2 (-), CKL (-), CKH (-), EMA (-), SMA (-), Desmin (+), MyoD1 (+), Myogenin (+), Myoglobin (-), VIM (+), PAX5 (-), CD99 (-), NKX2.2 (-), WT1 (-), LCA (-), SS18 (-), Syn (-), CgA (-), Ki-67 90% (+). After five visits and four biopsies, the diagnosis of rhabdomyosarcoma was finally established (The four biopsies are shown in Table 1). Based on the pathological findings and imaging examinations, the patient was ultimately diagnosed with uterine embryonal rhabdomyosarcoma. The clinical stage was determined to be T1N0M0 (tumor size > 5 cm) and IRS IA. Elective surgery was scheduled following six weeks of chemotherapy. The chemotherapy regimen included Vincristine and Actinomycin (VA). After the first cycle of chemotherapy, the patient developed a large amount of vaginal bleeding without obvious causes, accompanied by prolapse of vaginal tissue. Physical exam showed a cervical polypoid mass measuring 6×5×5cm fell out of the vagina, and contact bleeding was obvious. The patient was extremely anxious, so she only completed one chemotherapy before surgery and underwent surgery in advance. In April 2023, she underwent a robot-assisted laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node dissection. The procedure was successful, and postoperative specimen examination indicated a uterine cavity depth of 9 cm with a flat endometrium. The cervical vegetations were string-like and the roots were located on the right posterior wall of the lower segment of the cervical canal. The vaginal wall was edematous and thickened without vegetation (Figure 4). Postoperative pathological biopsy showed that the cervical neoplasm was embryonal rhabdomyosarcoma, and locally degenerated rhabdomyosarcoma tissue was seen, located at the outer half of the cervical wall. Immunohistochemical analysis revealed focal positivity for Desmin, along with positive staining for MyoD1 and Myogenin, while CK, VIM, and S100 were negative. The Ki-67 proliferation index was approximately 70% (Figure 5). No metastatic lesions were identified in the bilateral fallopian tubes, ovaries, or pelvic lymph nodes. The uterine and vaginal walls were free of tumor involvement. Postoperatively, the patient received five cycles of intravenous chemotherapy using the VA regimen. At the 8-month postoperative follow-up in our center, MRI detected a 2.7 cm soft tissue nodule adjacent to the internal iliac vessels, with indistinct boundaries. Pelvic contrast-enhanced MRI findings suggested a suspected recurrence (Figure 6). Discussion Botryoid rhabdomyosarcoma is a special type of embryonal rhabdomyosarcoma. It often occurs in the genitourinary tract and respiratory tract, but rarely occurs in the cervix. Tumors located in the cervical region are highly malignant. ERMS of the cervix in adults is a rare disease. At present, most of the retrieved data are very limited case reports. This case report highlights a challenging diagnostic journey, involving two misdiagnoses and transitions between two medical institutions over a prolonged course of nine months. This case aims to enhance clinicians' awareness of cervical embryonal rhabdomyosarcoma (ERMS), particularly when evaluating patients presenting with abnormal vaginal bleeding, to ensure timely consideration of this rare condition. The clinical symptoms of ERMS are non-specific. In reported cases of cervical ERMS, the majority of patients presented with vaginal bleeding and a protruding polypoid mass. Typically, a friable polypoid mass or a mass covered by smooth mucosa is observed in the cervix. There are no effective auxiliary diagnostic methods for cervical ERMS, and even biopsy often fails to detect the tumor. Due to its polypoid appearance, the tumor frequently exhibits multiple lobules. Microscopically, typical embryonal rhabdomyosarcoma (ERMS) is characterized by normal mucosal epithelium covering the tumor surface, beneath which a dense "cambium layer" of tumor cells and rhabdomyoblasts at varying stages of differentiation are observed. Areas of hypercellularity around blood vessels alternate with hypocellular regions rich in myxoid matrix. Tumor cells are unevenly distributed, with large nuclei and variably eosinophilic cytoplasm. In some areas, tumor cells are loosely arranged within a myxoid stroma, and mitotic figures are frequently observed. Focal hyaline cartilage is present in 45% of cases[6], although it was not identified in this case. Tissue sections often yield negative results under microscopic examination due to insufficient pathological sampling, a low density of sarcoma cells at the sampling site, or incomplete eosin staining, leading to misdiagnosis as cervical polyps. Ferguson and Lee et al. reported that up to 25% of women initially received an incorrect diagnosis, with the correct diagnosis only established at the time of recurrence[7]. In this patient, the initial two pathological examinations indicated "cervical polyps." Upon review of these missed diagnoses, it was noted that immunohistochemistry was not performed during the first examination. Although immunohistochemistry was conducted during the second examination, Desmin and Myogenin staining were negative, and the tumor proliferation activity was not significantly elevated. This discrepancy may be attributed to the failure to sample the cell-rich area of the tumor, potentially due to hemorrhage in the lesion region. The application of immunohistochemistry plays an important role in the diagnosis of ERMS. In immunohistochemical staining, rhabdomyosarcoma (RMS) exhibits positive expression for Vimentin, Desmin, Myogenin, and MyoD1. Vimentin is primarily used to differentiate carcinoma from sarcoma, demonstrating high sensitivity but low specificity. In contrast, MyoD1 and Myogenin show high specificity and sensitivity for diagnosing RMS, with positive reactions localized to the nucleus, serving as diagnostic markers for rhabdomyosarcoma[8]. Li et al. analyzed the clinicopathological and immunohistochemical features of ERMS in 25 adult women over 20 years of age. Desmin and Myogenin were expressed in 95.6% (22/23) of the tumors, and the proliferative activity was significantly increased in all tumors[9]. Adult ERMS frequently invades the bladder, rectum, or other pelvic organs. Despite the prolonged disease course of nine months in this patient, the lesion remained confined to the cervix, without involvement of the parametrial tissue or adjacent organs. RMS is sensitive to chemotherapy and radiotherapy, but single-modality treatment is often ineffective. Therefore, a combination of surgery, radiotherapy, and chemotherapy, along with long-term follow-up, is essential. Effective RMS treatment relies on accurate disease assessment. The Intergroup Rhabdomyosarcoma Study Group (IRSG) grouping criteria are widely adopted both domestically and internationally, categorizing RMS into risk groups based on tumor location, size, resection status, presence of metastasis, and pathological type (Table 2)[10]. In the IRSG-V study, RMS risk is stratified into low-, intermediate-, and high-risk categories based on tumor pathology, grouping, and staging, guiding tailored treatment (Table 3). In this case, the patient achieved complete local resection with negative surgical margins, no regional lymph node involvement, and embryonal rhabdomyosarcoma (ERMS) pathology, indicating a low-risk classification. Current treatment strategies for ERMS in the cervix are based on the treatment of RMS at other sites and, according to the Intergroup Rhabdomyosarcoma Study Group (IRSG) trial, mainly target children. The worse prognosis of ERMS in adults compared to children and young women requires a more aggressive approach[11]. A combination regimen that includes vincristine, actinomycin, and cyclophosphamide is the standard chemotherapy for pediatric nonmetastatic rhabdomyosarcoma (intermediate or high risk). The Intergroup Rhabdomyosarcoma Study Group study showed that 5-year disease-free survival among patients with newly diagnosed, low-risk rhabdomyosarcoma was similar with VA versus VAC chemotherapy (89% VS. 85%)[12], suggesting that vincristine and actinomycin may be appropriate candidates for patients with newly diagnosed, low-risk rhabdomyosarcoma. Therefore, this patient was treated with a VA regimen of chemotherapy. Because the patient had no fertility requirements and was extremely anxious, extensive total hysterectomy, bilateral oophorectomy, and pelvic lymph node dissection were performed. A total of six cycles of VA regimen chemotherapy were administered both preoperatively and postoperatively. Unfortunately, the follow-up results of this patient at 8 months after surgery were not optimistic. Less than one year after surgery, contrast-enhanced pelvic MRI revealed enlarged pelvic lymph nodes, indicating a potential recurrence. RMS is also highly sensitive to radiotherapy. Concurrent chemoradiotherapy following chemotherapy is the standard treatment for unresectable tumors. Radiotherapy is considered for patients with low-risk ERMS who have residual disease after surgery or who have unfavorable primary sites where complete surgical resection is not feasible[13]. The addition of radiotherapy to VAC chemotherapy improved local control rates, particularly in patients with microscopic or gross residual disease after surgery. In this case, postoperative pathological examination revealed no residual tumor, negative surgical margins, or lymph node involvement; therefore, adjuvant radiotherapy was not administered. Literature reports indicate that the recurrence rate of cervical ERMS in adults can reach 20-40%, which may be associated with occult micrometastases or tumor biological behavior (e.g., fusion gene negativity, MYOD1 mutations, etc.). Most recurrences occur within 2 years postoperatively, though late recurrences (>5 years) have also been reported[14]. Among these cases, patients with tumors larger than 5 cm face an increased risk of adverse outcomes upon recurrence[15]. In this case, the primary lesion exceeded 5 cm in diameter, heightening the risk of recurrence. Although the surgical margins were negative, retrospective analysis suggests that adjuvant low-dose radiotherapy might have improved this patient's prognosis. In conclusion, cervical ERMS is a rare adult soft tissue malignancy with significant clinical and biological heterogeneity, and its clinical manifestations are non-specific. In this case, the patient underwent multiple evaluations before a definitive diagnosis was established. This challenging diagnostic process highlights the similarity between cervical RMS and benign conditions, such as cervical polyps. Clinicians should enhance their awareness of rare diseases like cervical RMS, particularly when encountering patients with "cervical vegetations" or "abnormal vaginal bleeding" to ensure timely consideration of malignant possibilities. Additionally, clinical biopsies may yield insufficient samples or negative immunohistochemical results; therefore, it is crucial to submit adequate tissue specimens for pathological examination. At present, the treatment of this disease emphasizes individualization. The main treatment options are surgery and chemotherapy. However, due to the rarity of the lesions, there is no experience in the treatment, and there is no expert consensus or guideline for reference. The treatment of this disease still needs to be further explored. We hope that this case report will help promote the diagnosis and treatment of this disease.