The clinical presentation of cervical RMS is mostly a cervical mass and/or vaginal bleeding. Typical tumors are nodular, papillary, polypoid or grape-like masses, but they may grow infiltratively, involve surrounding tissues or metastasize distantly. An MRI scan of the abdominopelvic region is preferred as an adjunctive test. Cystoscopy, vaginoscopy, and bimanual examination (or rectoscopy if necessary) are also recommended [2]. Before 1972, the majority of children with uterine RMS were treated with radical surgery. Starting in 1976, the IRSG used initial surgery followed by chemotherapy for cervical polyp-like lesions. In 2002, the WHO classified soft tissue tumors into ERMS, ARMS and pleomorphic rhabdomyosarcoma. ERMS was further classified into the botryoid subtype and spindle cell subtype, which is slightly different from the classification in 2020. This patient had cervical ERMS of the botryoid subtype, which was called cervical sarcoma botryoides at that time. The particular features of this case were as follows: (1) the patient did not undergo curative surgery, whether polypectomy, hysterectomy or others, and only the biopsy was performed without destruction of the hymen; (2) the patient's chemotherapy regimen was not classical vincristine, actinomycin-D, cyclophosphamide (VAC) or vincristine, ifosfamide, actinomycin (VIA), and the chemotherapy cycles were inadequate. However, there were no recurrence signs; and (3) the patient conceived spontaneously and had a good pregnancy outcome.
The etiology of ERMS is unclear. It has been reported that two sisters developed cervical RMS successively, suggesting that there may be a genetic component to the disease [4]. Recent studies have found that these patients often have multiple primary cancers, especially Sertoli-Leydig tumors, and there may be a correlation between pathogenic variants of DICER1 and ERMS, especially cervical EMRS [5, 6]. However, the possible role of genetic factors in the development of EMRS needs to be further investigated. Unfortunately, genetic testing was not performed on this patient.
The previous view of the primary surgical approach was extensive hysterectomy with adequate vaginal excision and simultaneous pelvic and para-aortic lymph node dissection. However, patients with cervical ERMS are usually very young. The inability to have children or even normal development of female sexual characteristics after radical surgery causes significant physical and psychological harm. The scope of surgery has now evolved from extensive to limited. Extensive surgery does not have a survival benefit. Conservative tumor resection has provided adequate local control [7]. The IRSG recommends that less vigorous operative resection may be possible in combination with primary chemotherapy when treating uterine RMS [8]. INSTRuCT suggests more conservative approaches with chemotherapy alone in patients with complete response or organ-sparing surgery in combination with intracavitary brachytherapy or external beam radiotherapy. All children with uterine ERMS should be considered for fertility preservation, but hysterectomy is recommended for children with persistent corpus uteri tumors [2]. Recent international data showed that only 12% of patients with cervical tumors were treated with radical surgery, while the rate of local control at this site was 88% [2]. Surgery should be performed to remove the primary tumor and some normal tissues around its periphery to achieve lesion-free margins, followed by chemotherapy. Surgical options include simple mass excision, cervical conization, radical hysterectomy, etc. If complete removal of the tumor cannot be performed during the initial surgery, reassessment by cystoscopy, vaginoscopy, bimanual digital rectal examination and an abdominopelvic MRI are recommended after three cycles of induction chemotherapy. In patients with signs of tumor, local control with resection or radiation therapy should be attempted. Reassessment should be performed after six cycles of chemotherapy [2]. The exact procedure and scope of surgery should be determined by the patient's age, size of the lesion, tissue type, and whether it infiltrates the surrounding organs. However, recurrence after conservative treatment is not uncommon, especially in patients who have not received postoperative chemotherapy or have received insufficient cycles of chemotherapy [9]. In this case, the patient underwent an outpatient biopsy of the vaginal orifice tissue without disruption of the hymen and then underwent only fractional curettage and multipoint cervical biopsy without any curative surgery during her hospitalization. She then received an inadequate course of chemotherapy. To date, it has been 16 years without recurrence. This case provides further clinical thoughts on the scope of surgery for local cervical ERMS. For early lesions, is mass excision alone sufficient as long as the margins are negative? Is cervical conization or a more extensive hysterectomy necessary?
RMS is a chemosensitive tumor. Even for IRSG Group I (localized disease, completely excised, no microscopic residual tumor) patients, postoperative chemotherapy is recommended. In Europe, the standard chemotherapy regimen for ERMS is VIA, while IRSG recommends VAC [10]. IRS-Ⅳ found no difference in the effectiveness of VAC, vincristine, ifosfamide and etoposide (VIE), and VIA in patients with localized or regional rhabdomyosarcoma [11]. The intensity of chemotherapy was increased in four consecutive trials conducted by the IRSG. Detailed protocols can be found in Arndt CA's report [1]. The most common toxic side effect is bone marrow suppression, followed by sepsis [11]. If patients with tumors localized at the cervix demonstrate an incomplete response after induction chemotherapy, brachytherapy should be carried out [2]. Our patient received the IEP regimen, not the commonly used chemotherapy regimen in the previous guidelines, which has been reported in some other sites of rhabdomyosarcoma, but the patient also achieved a good curative effect.
The prognosis of uterine RMS reported in the literature varies widely. The results of IRS III and IV reported by Corpron CA included 14 patients, including 3 with metastatic disease. Four of them died from multidrug chemotherapy toxicity or sepsis, 1 died from tumor progression, and 8 of 9 patients survived without evidence of disease, 2 of whom underwent hysterectomy and vagotomy [8]. The recently reported 10-year overall survival rate was 92% for vaginal and uterine RMS in children and adolescents, and approximately half of these patients did not undergo radical surgery [12]. The presence of residual lesions after the initial surgery is the most important prognostic factor. Factors associated with prognosis include disease stage, age, tissue subtype, regional lymph node involvement, distant metastasis, and treatment modality [7]. It is currently considered that well-defined (polypoid) presentations, embryonal histology, and superficial tumors are suitable for preserving reproductive function, while alveolar/pleomorphic histology and deeply invasive disease increase the risk of tumor recurrence [10]. This case is further support for this conclusion.
As mentioned earlier, the current treatment philosophy for ERMS of the genital tract is to protect the patient's reproductive function as much as possible. However, pregnancy outcomes after treatment were less frequently reported. Two patients with cervical mass excision who were found to have ERMS during pregnancy were reported. They both underwent radical surgery during or after cesarean delivery in late pregnancy, and one of them had chemotherapy with a VAC regimen during pregnancy [13, 14]. Another case reported a patient with an 8 × 7 cm cervical ERMS lesion who had an unplanned pregnancy after 3 cycles of doxorubicin and ifosfamid. She was untreated during pregnancy and successfully delivered a normal baby. After 6 months, a local polypoid area less than 1 cm in diameter was found, and conization and pelvic lymphadenectomy were performed [15]. Even without radiotherapy, high doses of alkylating agents, such as cyclophosphamide and ifosfamide, are considered to be associated with decreased germ cell function and fertility [2]. The latest consensus indicated that 37% of women could get pregnant after cervical cancer surgery, and the live birth rate was 67% [2]. The patient in this case had a successful spontaneous pregnancy 16 years after her diagnosis of cervical ERMS without recurrence. It also makes us look forward to reports on the subsequent growth and pregnancy outcome of other children with genital tract RMS.
In recent years, the treatment concept has changed from extensive surgical resection to limited surgery combined with chemotherapy and radiotherapy, but the prognosis has improved dramatically. This case suggests that preservation of reproductive function is often feasible in immature women with cervical EMS, and the prognosis is usually good as long as the primary tumor can be surgically removed and the lesion is free of residual disease. In particular, it is essential to emphasize that chemotherapy is significant in reducing recurrence. For pediatric patients with genital tract tumors, protection of reproductive function and psychological health is of particular importance. How to accurately assess the patient's condition, grasp the surgical protocols and develop the chemoradiotherapy plan deserve further exploration.