Long-term survival outcomes of female genital tract rhabdomyosarcoma in children, adolescents and young adults at a national rare disease diagnosis and treatment center in China

Abstract

Objective

Rhabdomyosarcoma (RMS) is a rare soft-tissue sarcoma mainly affecting children and adolescents. The genitourinary tract is the second common site involved by RMS. We report the therapeutic effects and long-term survival outcomes of female genital tract RMS.

Methods

Patients diagnosed with female genital RMS and younger than 25 years old from Peking Union Medical College Hospital between January 1996 and December 2023 were identified. Clinical features, treatment modalities, and survival outcomes were documented. Patient prognosis evaluation was re-evaluated according to the Children’s Oncology Group (COG) risk stratification system.

Results

A total of 26 patients were included, with a mean age of 8.1 years. The median follow-up duration was 59.3 months. Primary tumor sites were distributed as follows: vagina (n=12), cervix (n=8), vulva (n=2), pelvic region (n=2), uterus (n=1), and subcutaneous perineum (n=1). The COG Risk Stratification System classified 15 patients as low-risk subset 1, 8 as low-risk subset 2, 2 as intermediate-risk, and 1 as high-risk. Nine patients (34.62%) experienced disease recurrence with a median progression free survival of 15.3 months. The disease-specific mortality rate was 26.92% (7/26). Six patients (66.7% of recurrent cases) succumbed to the disease following recurrence, while one stage 4 patient died during initial treatment.

Conclusion

Patients diagnosed as RMS in female genital tract in early stage can have relatively good prognosis. Advanced stage and nonstandard primary treatment were related with increased risk of recurrence. Patients with disease recurrence tend to have poor prognoses and higher mortality rates.

Synopsis

Female genital tract rhabdomyosarcoma constitutes 10% in female patients. The overall survival rate varied among different risk groups. Advanced stage and omitting chemotherapy were related with increased risk of recurrence.

INTRODUCTION

Rhabdomyosarcoma (RMS) is a rare, high-grade malignant neoplasm, representing approximately half of pediatric soft tissue sarcomas and 4%–6% of all childhood malignancies [1]. RMS originates from primitive mesenchymal cells capable of myogenic differentiation [2]. The most common site of occurrence is the head and neck, accounting for nearly 40% of cases, followed by the genitourinary tract. Tumors arising from the female genital tract constitute 4% of all RMS and 10% in female patients [3]. The vagina is the most frequent site, followed by the cervix and uterine corpus. According to the World Health Organization 2020 classification, there are 4 pathological types: embryonal RMS (ERMS), alveolar RMS (ARMS), pleomorphic RMS, and spindle cell/sclerosing RMS. Generally, ERMS is the most common type and tends to have a better prognosis [4].

Over the decades, RMS treatment has evolved from radical surgeries to more conservative approaches to preserve organ function and minimize the side effects of surgery, chemotherapy, and radiotherapy. The overall survival (OS) rate for childhood female genital tract RMS is relatively high, exceeding 70%, though it varies among different risk sub-groups. In high-risk RMS, the reported 5-year failure-free survival (FFS) rate is less than 30% [5]. To date, substantial data have been collected from the former Intergroup Rhabdomyosarcoma Study (IRS) Group and the current Children’s Oncology Group (COG), which have enrolled approximately 80%–85% of all children with RMS in North America. However, due to the rarity of the disease, most of this data is pooled, with few studies specifically focusing on RMS of the female genital tract. Additionally, the long-term outcomes of female genital tract RMS are scarcely reported.

In this study, we aim to investigate the clinical features, therapeutic outcomes, and long-term survival of RMS of the female genital tract in girls treated at our center over 28 years.

MATERIALS AND METHODS

Patients under 25 years old who were diagnosed as female genital tract RMS in Peking Union Medical College Hospital from January 1996 to December 2023 were reviewed in this study. The definition of age under 25 in this study is derived from the European Society of Gynecological Oncology-European Society for Paediatric Oncology guidelines for the management of adolescents and young adults with non-epithelial ovarian cancers [6]. Medical information including demographic data, clinical symptoms, tumor site, pathological findings, staging, treatment modalities, and survival outcomes were collected. Pathological diagnoses were independently confirmed by 2 experienced pathologists. All patients were retrospectively stratified following the guidelines established by the COG [7]. Initially, patients were staged based on tumor site, invasiveness, tumor size, lymph node involvement, and presence of distant metastasis. Subsequently, they were categorized into 4 clinical groups according to surgical type, pathological features, and metastatic status. Finally, patients were classified into 4 risk groups (low-risk subset 1, low-risk subset 2, intermediate risk, high risk) based on stage, clinical group, and pathological assessment. Statistical analyses were performed with the SPSS v.25 (IBM Corp., Armonk, NY, USA). The alpha level of statistical significance was set at 0.05 and p-values were 2-sided. The Peking Union Medical College Hospital Institution Review Board approved this retrospective cohort study (approval ID: I-24PJ1608). Informed consent was obtained in writing from all patients or their legal guardians.

RESULTS

From January 1996 to December 2023, 230 patients were diagnosed with RMS at our hospital, including 105 males and 125 females. Of these, 49 patients had female genital tract RMS, accounting for 39.2% of all cases. The ages of female genital tract RMS patients ranged from 1 month to 62 years.

There were 26 patients who were younger than 25 years old and diagnosed as female genital tract RMS enrolled in this study, with a mean age of 8.6 years (range: 1 month to 24 years). The median follow-up duration was 59.3 months (range: 10 to 257 months). Primary tumor sites were distributed as follows: vagina (n=12, 46.15%), cervix (n=8, 30.77%), vulva (n=2, 7.69%), pelvic region (n=2, 7.69%), uterus (n=1, 3.85%), and subcutaneous perineum (n=1, 3.85%). The mean age of patients with vaginal RMS was 4.1 years, while those with cervical RMS had a mean age of 15.3 years. Histopathological analysis revealed 2 patients with ARMS involving the pelvis and subcutaneous perineum, 24 patients (88.46%) with ERMS affecting vagina, cervix, vulva, pelvic and uterus. Disease staging showed 24 patients at stage 1, 1 at stage 3, and 1 at stage 4. Clinical grouping categorized 13 patients in Group 1, 2 in Group 2, 10 in Group 3, and 1 in Group 4. The COG Risk Stratification System classified 15 patients as low-risk subset 1, 8 as low-risk subset 2, 2 as intermediate-risk, and 1 as high-risk. Table 1 presents the clinicopathologic features, grouping-related information for all patients.

Table 1. Clinicopathologic features and grouping-related information of patients with female genital tract RMS.

No.	Year of primary treatment	Age (yr)	Tumor site	Pathology	Stage	Clinical group	Risk group
1	1996	3	Vagina	ERMS	1	III	Low-risk subset 2
2	1997	5	Pelvis	ERMS	3	III	Intermediate risk
3	2008	1	Vagina	ERMS	1	I	Low-risk subset 1
4	2008	16	Vagina	ERMS	1	I	Low-risk subset 1
5	2009	2	Vagina	ERMS	1	I	Low-risk subset 1
6	2011	1	Vulva	ERMS	1	III	Low-risk subset 2
7	2012	14	Cervix	ERMS	1	I	Low-risk subset 1
8	2013	0.67	Vagina	ERMS	1	III	Low-risk subset 2
9	2013	23	Cervix	ERMS	1	I	Low-risk subset 1
10	2013	13	Cervix	ERMS	1	I	Low-risk subset 1
11	2014	2	Vagina	ERMS	1	I	Low-risk subset 1
12	2014	2	Vagina	ERMS	1	III	Low-risk subset 2
13	2015	11	Vagina	ERMS	1	III	Low-risk subset 2
14	2016	2	Vagina	ERMS	1	I	Low-risk subset 1
15	2016	14	Vulva	ERMS	1	I	Low-risk subset 1
16	2017	4	Vagina	ERMS	1	I	Low-risk subset 1
17	2017	10	Cervix	ERMS	1	II	Low-risk subset 1
18	2017	20	Cervix	ERMS	1	I	Low-risk subset 1
19	2018	1	Pelvis	ARMS	4	IV	High risk
20	2019	0.08	Vagina	ERMS	1	III	Low-risk subset 2
21	2019	16	Cervix	ERMS	1	III	Low-risk subset 2
22	2022	13	Cervix	ERMS	1	I	Low-risk subset 1
23	2022	13	Cervix	ERMS	1	I	Low-risk subset 1
24	2022	11	Uterus	ERMS	1	II	Low-risk subset 1
25	2022	6	Vagina	ERMS	1	III	Low-risk subset 2
26	2022	19	Subcutaneous perineum	ARMS	1	III	Intermediate risk

ARMS, alveolar rhabdomyosarcoma; ERMS, embryonal rhabdomyosarcoma; RMS, rhabdomyosarcoma.

Regarding primary surgical treatment, 13 patients underwent complete surgical resection, while 2 had gross total resection with microscopic residuals. The remaining 11 patients received biopsy or partial resection. After surgery, 22 patients were treated with full-dose, full-course chemotherapy as recommended by their physicians, with vincristine, actinomycin D, and cyclophosphamide (VAC) and vincristine, actinomycin D, and ifosfamide (VAI) being the predominant regimens. Four patients opted out of receiving any or full-course chemotherapy. One patient with a tumor originating from the subcutaneous perineum received radiotherapy following chemotherapy. Four patients received further treatment after initial chemotherapy, including 2 vaginal RMS patients reassessed as partial response, underwent vaginal mass resection with complete resection (CR), and subsequently received additional courses of chemotherapy. Another vaginal RMS patient reassessed as progressive disease (PD) after 4 rounds of chemotherapy, evidenced by pelvic metastasis, underwent radical surgery (laparoscopic radical trachelectomy and pelvic lymphadenectomy), followed by 6 additional courses of chemotherapy. One pelvic RMS patient, assessed as PD after initial chemotherapy, underwent thoracoscopic right lung metastasectomy and vaginal lesion excision, followed by radiotherapy, who died during palliative radiotherapy. Table 2 provides detailed information on the primary surgical, chemotherapy treatments and long-term outcomes of all patients.

Table 2. Treatment information and long-term outcomes of patients with female genital tract RMS.

No.	Primary surgical treatment	Surgical outcome	Adjuvant treatment	Outcome	Follow-up duration (mo)
1	Vaginal mass resection	Partial resection with gross residual	Chemotherapy, PVB×1+VP/VE×7+VACP×2		257
2	Exploratory laparotomy and pelvic tumor resection with omentectomy and ileocecal metastatic tumor resection	Partial resection with gross residual	Chemotherapy, VAC×39 wk	Recurrence, died	38
3	Vaginal mass resection	CR	Chemotherapy, VAI×4+VCE×2		75
4	Vaginal mass resection	CR	Chemotherapy, VAI×4		15
5	Vaginal mass resection	CR	Chemotherapy, VAC×39 wk		55
6	Biopsy of vulvar mass	Biopsy only	Chemotherapy, VAI×4+VCE×2		21
7	Cervical mass resection	CR	Chemotherapy, VAI×3		147
8	Biopsy of vaginal mass	Biopsy only	Chemotherapy, VAI×4	Recurrence, died	119
9	Hysteroscopic cervical mass resection	CR	Chemotherapy, VAC×46 wk	Recurrence, CR	65
10	Cervical mass resection	CR	Chemotherapy, VAI×2+VCE×2		61
11	Vaginal mass resection	CR	Chemotherapy, VAI×2		112
12	Biopsy of vaginal mass	Biopsy only	Chemotherapy, VACP/VIE×4; Hysteroscopic vaginal mass resection (CR); Chemotherapy, VAI×4		122
13	Hysteroscopic vaginal mass resection	Partial resection with gross residual	Chemotherapy, PEI×1+VAI×3; Laparoscopic radical trachelectomy and pelvic lymphadenectomy; Chemotherapy, VCE×6	Recurrence, died	17
14	Hysteroscopic vaginal mass resection	CR	Chemotherapy, VAI×4		88
15	Vulvar mass resection	CR	Chemotherapy, VAI×6	Recurrence, died	16
16	Hysteroscopic vaginal mass resection	CR	None	Recurrence, CR	23
17	Hysteroscopic cervical mass resection	Grossly resected tumor with microscopic residual	Chemotherapy, VAC×42 wk		48
18	Hysteroscopic cervical mass resection	CR	Chemotherapy, VAC×2		70
19	Laparotomy with pelvic lesion biopsy	Biopsy only	Chemotherapy, VAC/VI×3+VDC/IE×3+IE×2; Thoracoscopic right lung metastasectomy and vaginal lesion excision; Chemotherapy, VDC/IE×1; Palliative radiotherapy; Died	Died in initial treatment	15
20	Biopsy of vaginal mass	Biopsy only	Chemotherapy, PEB×1+VAI×3; Hysteroscopic vaginal mass resection (CR); Chemotherapy, PEB×2+TIP×2		55
21	Hysteroscopic cervical mass resection	Partial resection with gross residual	None	Recurrence, died	35
22	Hysteroscopic cervical mass resection	CR	Chemotherapy, VAI×4+VA×5		10
23	Vaginal cervicectomy with uterovaginal anastomosis	CR	None	Recurrence, CR	16
24	Laparoscopic hysterectomy and bilateral salpingectomy	Grossly resected tumor with microscopic residual	Chemotherapy, VA×2, suspended due to patient-related reasons	Recurrence, died	16
25	Partial resection of vaginal mass	Partial resection with gross residual	Chemotherapy, VAI×3		22
26	Percutaneous biopsy	Biopsy only	Chemotherapy, VAI×3; Radiotherapy		24

CR, complete resection; PEB, cis-platinum, etoposide and bleomycin; PEI, cis-platinum, etoposide and ifosfamide; PVB, cis-platinum, vincristine and bleomycin; RMS, rhabdomyosarcoma; TIP, paclitaxol, ifosfamide, and cis-platinum; VA: vincristine, actinomycin D; VAC, vincristine, acinomycin D, and cyclophosphamide; VACP, vincristine, acinomycin D, cyclophosphamide, and cis-platinum; VAI, vincristine, actinomycin D, and ifosfamide; VCE, vincristine, cyclophosphamide and etoposide; VDC/IE, vincristine, doxorubicin and cyclophosphamide/ifosfamide, etoposide; VI, vincristine, ifosfamide; VP/VE, vincristine, cis-platinum/vincristine, etoposide.

During follow-up, 9 patients (34.62%) experienced disease recurrence: 2 local, 2 regional, and 5 distant recurrences. Distant metastases were observed in the vertebrae, lungs, cervical lymph nodes, and brain. Recurrence rates were 33.33% (5/15) in low-risk subset 1, 37.5% (3/8) in low-risk subset 2, and 50.0% (1/2) in the intermediate-risk group. Among the relapsed patients, 4 underwent radical surgery and chemotherapy; 2 received radical surgery, chemotherapy, and radiotherapy; 1 underwent surgery and radiotherapy; 1 had chemotherapy and radiotherapy; and 1 received palliative therapy. Notably, all 4 patients who did not complete the full adjuvant chemotherapy experienced recurrence.

The disease-specific mortality rate was 26.92% (7/26). One patient with stage 4, high-risk disease died during initial treatment as a result of disease progression. Six patients (6/9, 66.7%) succumbed to the disease following recurrence (2 from low-risk subset 1, 3 from low-risk subset 2, and 1 from the intermediate-risk group). The 5-year OS rate was 76.92% (Fig. 1). Specifically, the 5-year OS rates for each risk group were 85.71% for low-risk subset 1, 71.43% for low-risk subset 2, 50% for the intermediate-risk group, and 0% for the high-risk group (Fig. 2, p=0.000 from log-rank test).

Fig. 1. The overall survival of patients with female genital tract rhabdomyosarcoma.

Fig. 2. The overall survival for each risk group by the Children’s Oncology Group risk stratification system.

DISCUSSION

This study reported a series of 26 childhood, adolescent and young adults patients diagnosed with RMS of the female genital tract. Long-term survival outcomes were closely related with COG risk stratification category and standardized chemotherapy.

RMS primarily affects pediatric and adolescent populations, but the specific age of onset varies by tumor site. In our study, patients with vaginal RMS were significantly younger than those with cervical RMS, with mean ages of 4.1 and 15.3 years, respectively. This is consistent with previous studies, Nasioudis et al. [8] reported that vulvo-vaginal RMS is more common in prepubertal girls and postmenopausal women compared to adolescents and premenopausal women, showing a statistically significant difference.

According to the IRS-III and IRS-IV studies, the 5-year FFS rate in children with RMS varied across risk groups, with a 5-year FFS rate of 90% in the low-risk subset 1, compared to less than 30% in the high-risk group [9]. Our findings in this study were slightly lower than the published data and our previous report [10]. This discrepancy may be attributed to the extended follow-up duration, underscoring the importance of long-term follow-up to monitor for disease recurrence in children and adolescents with RMS. Additionally, the patients enrolled in the IRS included those with tumors originating from the head, neck, and extremities, which are more amenable to surgical resection and suitable for radiation therapy, potentially leading to a better prognosis.

Over the past decades, treatments of female genital tract RMS have shifted from radical surgeries combined with chemotherapy and or radiation therapy to more conservative approaches, including conservative surgeries, reduced doses and regimens of chemotherapy and omitted radiation therapy when feasible. This change aims to minimize surgical side effects, preserve organs, protect genitourinary and digestive functions, maintain sexual health and fertility, and enhance psychological well-being and quality of life [3]. The International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumors (MMT) 84 and 89 protocols indicated that girls with non-metastatic female genital tract RMS who achieved a complete response to initial chemotherapy did not require further local treatment. For those needing local treatment, brachytherapy was deemed more appropriate than radical surgeries or external beam therapy [11]. This led to the development of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) conservative treatment protocol. The International Soft-Tissue Sarcoma Consortium suggests that RMS responds excellently to chemotherapy, and the primary goal of initial surgery is to establish a diagnosis rather than achieve CR, particularly for uterine and vaginal RMS. For patients who do not achieve a complete response to induction therapy, re-excision is performed only if complete gross resection is possible while preserving organs. Otherwise, local therapy with radiation, preferably brachytherapy, is recommended [12]. In 2016, our study group reported a series of 8 children and adolescents’ patients with RMS. At that time, we found that organ-preserving surgery combined with chemotherapy were sufficient for local disease control, radiotherapy was not performed in any of patient. We did not observe a higher recurrence rate compared to radical surgery [10]. In this study, only 2 patients required radical surgeries due to disease progression during induction chemotherapy. When comparing stage 1 patients who received standard chemotherapy following primary surgical treatment, we found that those who underwent CR had a relatively better prognosis than those who received partial resection or biopsy only. The recurrence rate was 18.2% (2 out of 11) in the CR group compared to 22.2% (2 out of 9) in the latter group. Overall, in our case series, CR with organ preservation combined with chemotherapy proved effective, allowing most patients to forgo radiation therapy, consistent with published data [13].

As for chemotherapy, our study demonstrated that standard full-course chemotherapy following primary surgical treatment was strongly associated with a reduced risk of recurrence. Meanwhile, efforts have been made to reduce the chemotherapy burden without jeopardizing survival in recent decades. In accordance with the SIOP MMT-89 study recommendations, after 2005, the chemotherapy regimen for some of our patients was modified to the VAI protocol, with fewer courses than previous treatments. The EpSSG currently recommends a regimen of 4 cycles of vincristine, actinomycin D (VA) for patients in the low-risk group, and a 25-week treatment protocol consisting of 4 cycles of VAI followed by 5 cycles of VA for patients in the standard-risk group. In our study, when focused on the subset of low-risk patients who completed the full course of chemotherapy as advised by their physicians, we categorized 19 patients into 2 groups based on the number of chemotherapy cycles received: a short-term chemotherapy group and a long-term chemotherapy group. Specifically, 8 patients received no more than 4 cycles, while 11 patients received more than 4 cycles. The recurrence rates were 12.5% in the short-term group and 27.27% in the long-term group, while the mortality rates were 12.5% and 18.18%, respectively. Chi-square tests were conducted to compare the recurrence and mortality rates between the 2 groups, revealing no significant differences (p=0.435 for recurrence, p=0.737 for mortality). These findings suggest that efforts to reduce the duration of chemotherapy were relatively safe within the context of this study. However, according to a report by Yan et al. [14] in 2023, the OS and EFS rates in the MMT-84 and MMT-89 studies were lower than those in the RMS 2005 study, with only a 73% 5-year OS for infants in MMT-84 and MMT-89, compared to 88% in RMS 2005, where patients with completely resected ERMS at diagnosis received 8 to 9 courses of VA or VAI therapy over 22 to 25 weeks. The overall relapse rate was significantly higher among patients treated with the MMT chemotherapy protocol compared to those who received the RMS 2005 protocol (34% vs. 12%). One possible explanation is that the proportion of ERMS and genitourinary RMS cases in the MMT-84 and MMT-89 studies was lower than in RMS 2005, which may have contributed to the different survival outcomes [14]. Although cross-trial comparisons present challenges and potential biases, and the heterogeneity of our data complicates direct comparisons within our study, these findings underscore the importance of remaining vigilant. While focusing on reducing the potential side effects of chemotherapy, we must also be attentive to the potentially increasing recurrence rates and poor prognosis.

Although low-risk RMS has a relatively good prognosis, recurrence or refractory disease are detrimental. Published data suggested that about one third of pediatric and young RMS patients experienced recurrence or refractory disease, which are associated with poorer outcomes and increased morbidity [15]. In our study, the overall recurrence rate was 34.62% among all patients, with rates of 33.33% in low-risk subset 1, 37.5% in low-risk subset 2, and 50.0% in the intermediate-risk group. These rates are slightly higher than those reported in previous studies. Given the unique tumor location in the female genital tract, treatment strategies prioritized preserving organ function, resulting in the majority of patients being classified into clinical group III. Previous research [15] has indicated that the clinical group at initial diagnosis affects post-relapse survival, as demonstrated in the IRS III–IV studies, which may contribute to the higher recurrence rate observed in our study. Additionally, alveolar histology and unfavorable tumor sites, such as perineal, gastrointestinal, pelvic, or extremity, have been identified as risk factors for relapse. This may explain the highest recurrence rate in the intermediate-risk group, where 2 patients had ARMS originating from the subcutaneous perineum and ERMS arising from the pelvis. Besides, 4 patients did not receive the full dose and duration of initial chemotherapy, which was also a high-risk factor for recurrence. For patients with relapsed disease, surgeries and re-irradiation with external beam are not always appreciated due to fear of mutilation or excessive damage. Treatment modalities are always limited, and evidence-based data are rare, especially in female genital tract RMS. Ballantyne et al. [16] conducted a systematic review included 13 studies with 55 patients who had recurrence or refractory RMS. The results of the systematic review suggest that surgery and brachytherapy may be an effective treatment for a highly selected subset of relapse and refractory RMS patients, but only one patient had pelvic RMS was included and the quality of evidence is relative low. In our study, treatment modalities were selected by physicians based on the recurrence site, tumor burden, and the feasibility of complete surgical resection. Overall, 7 patients underwent radical surgeries, 7 received chemotherapy with or without surgery, 4 underwent radiotherapy, and 1 received palliative care. However, the outcomes of relapsed patients were poor, with a mortality rate of 66.7%. This is consistent with previously reported data, as in the CWS studies reported a 5-year OS of 21% for patients who relapsed after treatment for primary localized disease [17], and 3-year OS of 37% in the SIOP-MMT studies [18]. Further evaluation through prospective research is needed to gain a better understanding of treatments for relapsed RMS.

The strength of our research is the extended follow-up period, with the longest duration exceeding 21 years. However, our study has several limitations. Due to the data being sourced from a single center and the rarity of the disease, the sample size is relatively small. Besides, being retrospective, it includes varied treatment modalities due to the 28-year span of patient diagnoses, during which multiple guidelines were published and several advancements in medication occurred. This makes it challenging to compare the prognoses of different treatments.

In conclusion, we found that for early-stage low risk RMS patients, conservative surgery with CR of tumor followed by chemotherapy is sufficient, resulting in a relatively good prognosis. Advanced stage and nonstandard initial treatment significantly increased the risk of recurrence. Patients experiencing disease recurrence demonstrate poor prognostic outcomes and elevated mortality rates.