|Year : 2021 | Volume
| Issue : 2 | Page : 49-54
Conservative management of rhabdomyosarcoma of uterine cervix: A case series
Susan Mathews, PS Veena, Nithiyaanandan Natarajan
Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
|Date of Submission||25-Jan-2021|
|Date of Decision||17-Jun-2021|
|Date of Acceptance||31-Jul-2021|
|Date of Web Publication||21-Aug-2021|
Department of Radiation Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala
Source of Support: None, Conflict of Interest: None
Background: Rhabdomyosarcoma (RMS) of the uterine cervix is a rare disease, usually affects pediatric and adolescent girls. Excellent treatment outcomes have been reported with combined modality treatment employing surgery, chemotherapy, and radiation therapy. Fertility-sparing treatment options can be considered in young patients without compromising outcome. Aim: This study aimed to analyze the outcome of patients with cervical RMS who were managed conservatively. Materials and Methods: We retrospectively reviewed the clinical and pathologic data of all patients with cervical RMS who were registered at our institution during 1995–2010. Long-term outcome data of patients who had conservative surgery were analyzed. Results: During this period, six patients with cervical RMS were registered. Five patients, managed conservatively, were eligible for analysis. The median age was 20 years (range: 14–21 years). Excessive vaginal discharge was the most common presenting symptom (n = 3). All patients initially had either a polypectomy (n = 4) or gross tumor resection (n = 1) followed by received chemotherapy with VAC regimen (Vincristine, Actinomycin-D and Cyclophosphamide). One patient received local radiation (HDR brachytherapy) for microscopic residual disease. All patients were disease-free at the completion of primary therapy. At a median follow-up of 10 years, four patients remain relapse-free; three, having retained fertility, had successful pregnancies and healthy children. One patient developed ovarian failure consequent to radiation treatment but remains disease free. One patient developed local recurrence, 8 years after primary treatment, and underwent salvage hysterectomy followed by second-line chemotherapy. This patient too remains disease-free, 3 years after salvage treatment. Conclusion: RMS of the uterine cervix is highly curable in early stages. The focus now is on improving the quality of life by reducing treatment-related morbidity and late effects. Fertility preservation approaches should be considered in young females with RMS of cervix.
Keywords: Cervix, conservative management, rhabdomyosarcoma
|How to cite this article:|
Mathews S, Veena P S, Natarajan N. Conservative management of rhabdomyosarcoma of uterine cervix: A case series. Oncol J India 2021;5:49-54
|How to cite this URL:|
Mathews S, Veena P S, Natarajan N. Conservative management of rhabdomyosarcoma of uterine cervix: A case series. Oncol J India [serial online] 2021 [cited 2023 Jun 5];5:49-54. Available from: https://www.ojionline.org/text.asp?2021/5/2/49/324234
| Introduction|| |
Rhabdomyosarcoma (RMS) is derived from primitive mesenchymal cells of striated muscle lineage. RMS shows bimodal age distribution, with the first peak between 2 and 6 years and a second peak between 10 and 18 years; it is uncommon after 45 years. Intergroup Rhabdomyosarcoma Study Group (IRSG) classifies RMS into three histologic subtypes, namely embryonal, alveolar, and undifferentiated. The embryonal subtype is further divided into classic, botryoid, and spindle variants. Almost 20% of all RMS in children arise in the genitourinary tract; vagina being the most commonly involved site in girls. Primary RMS of the cervix is extremely rare accounting for only 0.5% of all RMS cases in girls and the diagnosis in adults is even rarer. Patients with cervical RMS generally present with abnormal vaginal bleeding or discharge and many also notice mass protruding from the vagina. Early appearance of symptoms could explain the early stage at presentation in majority of cases.,
Treatment of RMS is based on risk stratification, employing multimodality approaches such as utilizing surgery, chemotherapy, and radiotherapy. There have been significant improvements in patient outcome paralleling advancements in multi-modality treatment.,, Excellent results have been reported for female genital tract RMS but often at the cost of infertility consequent to hysterectomy and/or pelvic radiation therapy (RT). Polypectomy, cervical conization, and trachelectomy have been performed for fertility sparing in cases of localized RMS of the uterine cervix, as an alternative to radical hysterectomy.,
We conducted a retrospective review of our experience on conservative management of RMS of cervix and analyzed the long-term outcome of our patients.
| Materials and Methods|| |
A hospital database was searched for details of patients who presented with a diagnosis of cervical RMS from January 01, 1995–December 31, 2010. Clinical and pathology records of all patients were reviewed. Patients with tumors originating in the uterine cervix, where RMS was the primary histology and not just one component of any mixed histologies and in whom hysterectomy was not done, alone were considered. At our Center, children above the age of 13 years are registered in the adult patient clinic.
All information and clinical details, including age at diagnosis, presenting symptoms, past medical history, tumor characteristics, as well as treatment and follow-up details were obtained from the patient's medical records. Stage/Group was determined on the basis of extent of disease, resectability, and microscopic evaluation of surgical margins according to the IRSG clinical classification system [Table 1]. Patients included in the study had limited surgery – either polypectomy or resection of gross tumor followed by aggressive chemotherapy with vincristine, actinomycin D, and cyclophosphamide (VAC) regimen. The VAC regimen consists of vincristine 1.5 mg/m2 on day 1 (maximum dose up to 2 mg), actinomycin D 0.5 mg/m2 on day 1 and day 2, and cyclophosphamide 1–1.5 g/m2 on day 1. The cycle of chemotherapy was repeated at 3-weekly intervals up to 1 year. Patients were followed up once every 3 months for the first 2 years and once in 6 months for the next 3 years and once every year thereafter till May 2021.
|Table 1: Intergroup rhabdomyosarcoma Study Group clinical classification system for rhabdomyosarcoma|
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| Results|| |
Between 1995 and 2010, 6 cases of cervical RMS were registered at our centre. One patient was referred after hysterectomy and hence was excluded from the study. The remaining five patients, managed with a conservative approach without definitive surgery, were included in this analysis.
The patient characteristics and clinical details are summarized in [Table 2] and [Table 3], respectively. The median age at diagnosis was 20 years. Two patients were younger than 20 years, diagnosed at 14 and 17 years. The 14-year-old patient was on follow-up at our center having been diagnosed with papillary carcinoma of thyroid at the age of 5 years. She also gave a family history of malignancies. Two of her first-degree relatives (paternal grandmother and aunt) were diagnosed with breast and endometrial cancers, respectively, in the past. Excessive vaginal discharge with or without foul smell, abnormal vaginal bleeding, and mass coming down per vagina were the presenting symptoms. All 5 patients underwent pelvic examination under anesthesia and polypectomy or excision of the cervical mass lesion was performed at the same setting. There were no instances of a biopsy prior to excision of the mass. The median tumor size was 5.5 cm (range 4–11 cm). The lesions were described as fleshy, friable, and polypoidal and were easily removable in all cases. The mass was pedunculated in two patients. All patients had embryonal RMS histology: classical type in four cases and botryoid variant in one patient. All patients showed positivity for desmin on immunohistochemistry [Figure 1] and [Figure 2].
|Figure 1: H and E stain (a: ×100; b: ×200; and c: ×400) showing peri-endocervical gland cuffing resembling prominent cambium layer comprising neoplastic cells with oval/spindled hyper chromatic nuclei|
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|Figure 2: Immunohistochemical examination (×400) showing atypical cells positive for (a) desmin and (b) myogenin|
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Post excision examination and imaging did not reveal any residual disease in four patients and they were included under IRSG Group 1 [Table 1]. One patient who had endocervical tumor extension had bulky cervix but with no grossly visible residual disease and was assigned to Group 2 suspecting microscopic residual disease. All patients were free of metastatic disease on computed tomography (CT) scans.
Combination chemotherapy VAC regimen was administered to all the patients. An interim evaluation was done for patient with suspected microscopic residual disease, after 3 cycles of chemotherapy, to decide on additional local treatment. Three patients received 17 cycles of VAC, one patient received 12 cycles and the patient with residual disease received a total of 18 cycles of chemotherapy. Almost all patients required some dose modifications due to toxicities. Among patients receiving 17 cycles of VAC regimen chemotherapy, vincristine dose reduction was done in one patient who was diagnosed with RMS of cervix at the age of 14 years due to neurotoxicity.
The patient under IRSG Group 2 was found to have persistent endocervical disease after 3 cycles of chemotherapy with VAC regimen and was counseled for hysterectomy. However, she refused surgery and opted for radiotherapy. She received high dose rate (HDR) brachytherapy to the cervix; at a dose of 6 Gy to “Point A” was delivered three times, at weekly intervals. After brachytherapy, she continued on with the VAC chemotherapy for 1 year (15 cycles).
At treatment completion, a cervical biopsy was repeated in three of the five patients and they were kept on follow-up with a negative report. Two patients were followed up after negative positron-emission tomography (PET) and magnetic resonance imaging. The median follow up period for all patients was 10 years with a minimum follow up of 8 years and maximum of 14 years. At a median follow-up of 10 years, one patient experienced local recurrence. All other patients remain disease-free; three of them had successful pregnancies and healthy children. The median time to resume menstrual cycles after completion of treatment was 10 months (range 9–12 months). The patient who received brachytherapy for persistent local disease developed ovarian failure and is on hormone replacement. She remains disease-free 14 years after primary treatment [Table 3].
The patient who developed local recurrence 8 years after primary treatment had recurrent symptoms of excessive discharge per vaginum and clinical examination revealed a 3 cm pedunculated polypoid mass with narrow stalk arising from the endocervical region. Polypectomy was performed and histopathology confirmed recurrence of embryonal RMS. PET-CT showed residual uptake in the endocervical canal with no evidence of extracervical disease. She underwent salvage hysterectomy followed by second-line chemotherapy with cisplatin- and etoposide-based combination regimen for 6 cycles. Her further evaluation revealed no residual or recurrent disease and she was kept on regular follow-up. Three years after completion of second-line treatment, she remains disease-free. This patient was previously treated for papillary carcinoma thyroid and was then diagnosed with cervical RMS (botryoid variant) at the age of 14 years.
| Discussion|| |
RMS of cervix is extremely rare and most of our information pertaining to treatment and outcomes are based on individual case reports. In the present case series, we evaluated the long-term outcomes of fertility-sparing conservative treatments for the patients with RMS of cervix.
Cervical RMS appears to have more favorable outcomes compared to RMS of other genital areas. In general, the treatment of RMS comprises surgical excision and treatment with chemotherapy with or without addition of RT to the local site based on the treatment response.,,,, With excellent outcomes being reported for multimodality approach, morbidity reduction and fertility preservation have assumed major focus in these young patients.
Treatment for RMS of gynecologic sites has evolved from pelvic exenteration in the 1960s to multidrug chemotherapy and/or radiotherapy with less radical surgery in 1970s and toward more organ-sparing procedures such as local excision, polypectomy, and cervical conization with chemotherapy in the 1990s.,, The conclusions drawn from the results of Intergroup Rhabdomyosarcoma Studies (IRS), IRS-I to IRS-IV, justify conservative surgical approach in patients with localized, completely resected disease (Group 1). A wide range of surgical interventions have been reported for RMS of cervix in the various published case series: polypectomy, conization, cervicectomy, trachelectomy, and even radical hysterectomy depending on the extent of the tumor and necessity for fertility preservation.,,, It is still unclear as to what would constitute adequate surgical management for fertility preservation in these young patients. Several groups advocate simple trachelectomy quoting greater chance for positive margins with conization and polypectomy. However, simple trachelectomy is associated with higher risk of second trimester miscarriage and preterm deliveries. In the present series, conservative surgical procedures in the form of either polypectomy or resection were performed in all five cases of embryonal RMS of cervix which was then followed up with VAC chemotherapy. One of these five cases developed local recurrence 8 years after completion of primary treatment but was salvaged with hysterectomy and second-line chemotherapy.
The IRSG trials I–IV included 4272 eligible patients between 1972 and 1997, out of which 151 had primary gynecologic site RMS (vulva, vagina, uterus, or cervix). In these studies, treatment evolved from aggressive initial surgery with or without RT and multiagent chemotherapy in IRS-I to initial intensive chemotherapy (VAC) after biopsy confirmation and delayed local treatment, tailored to chemotherapy response. These IRS studies report an estimated 5-year overall survival of 87% for local and or regional RMS of the female genital tract. With survival figures indicative of almost cure, the emphasis now is on improving the quality of life by reducing treatment related morbidity and late effects of therapy. De-escalation of chemotherapy has also been suggested with the use of VA chemotherapy instead of VAC for embryonal RMS of the female genital tract after complete or near-complete excision of primary tumor (Group I or II).
In view of its chemo sensitivity, low-risk patients with embryonal RMS of cervix are treated with chemotherapy after limited surgery. Chemotherapy possibly targets lymphatic micrometastasis. Elsebaie MA and Elsayed Z in their analysis of 137 patients with primary nonmetastatic gynecologic RMS observed that lymphadenectomy could be reserved for high-risk clinical presentations. Polypectomy/gross total resection of tumor followed by chemotherapy appears to be a reasonable option in young patients with cervical RMS especially those belonging to Group 1. We proceeded with VAC regimen chemotherapy in all our patients, after a gross total excision of tumor by either polypectomy or resection. More aggressive local treatment tailored to chemotherapy response could be considered in those with residual disease after initial surgery. Additional local treatment in the form of HDR brachytherapy had to be given in one of our patients who had evidence of persistent local disease after 3 cycles of chemotherapy. In our series of five patients, preservation of fertility was possible in three patients with this approach.
Although specific information on prognostic factors for primary cervical RMS cannot be drawn from series with limited patient numbers, it appears that patients with cervical RMS tend to present early and with tumors having favorable prognostic features. Data from other sites document factors such as polypoidal/exophytic growth pattern, embryonal histology, early disease stage at presentation, and absence of nodal and distant metastasis to be favorable prognostic features., All patients in our series had prognostic features associated with favorable outcomes. Esnaola et al. in their study of 39 RMS patients (no cervical RMS) reported that metastatic disease at presentation and poor response to chemotherapy to be strongly associated with poor prognosis.
The Kiel Pediatric Tumor Registry and German CWS study reported 92% 10-years survival in cases presenting as polypoidal growth, whereas 10-year survival for diffuse intramural growth was 68%. Kriseman et al. in a series of 11 cases of cervical RMS reported that only one patient who declined treatment at diagnosis of recurrence died of the disease. Buruiana et al. reported on three cases of RMS of cervix with no residual disease after surgery (2 trachelectomies and 1 hysterectomy), all three patients were without any recurrence during long-term follow-up. Daya and Scully in a series of 13 cases of sarcoma botryoides of the uterine cervix reported that all patients were alive without any evidence of disease 1–8 years postoperatively except one patient who died of the disease. In our series, all the patients were alive at a median follow-up of 10 years. One patient who developed local recurrence 8 years after primary treatment underwent salvage hysterectomy followed by second-line chemotherapy and was disease-free at her last follow-up, 3 years after salvage treatment.
RMSs have been associated with certain inherited conditions including Li-Fraumeni syndrome, Beckwith–Wiedemann syndrome, neurofibromatosis Type 1, Costello syndrome, Noonan syndrome, and MEN2A. Several authors report the occurrence of multiple primary cancers in patients with cervical RMS. Kriseman et al. from MD Anderson Cancer Center, in their report on 11 patients with primary cervical RMS, found three patients with other primary malignancies. The other primary malignancies they encountered were Sertoli–Leydig tumor, pinealoblastoma, thyroid cancer, and a parotid adenocarcinoma. They cite other series with similar associations and points to a possible genetic link between cervical RMS and other primary tumors, most notably Sertoli–Leydig tumor. In our patient with papillary carcinoma thyroid and cervical RMS, there is a history of malignancies in several close members of her family suggesting a possible genetic association. Interestingly, she was also the only one to relapse locally after primary treatment. Palazzo et al. demonstrated deletion of the short arm of chromosome 1 and trisomies 13 and 18 on chromosomal analysis of a patient with sarcoma botryoides of the endocervix. Dehner et al. revealed a presence of DICER1 germline mutation in a 9-year girl of cervical RMS in addition to pleuropulmonary blastoma suggesting a possible genetic association of these malignancies. Our patient did not consent to any further evaluation and genetic counseling.
| Conclusion|| |
From the findings of our small series on cervical RMS, it is observed that embryonal RMS is the most common subtype of cervical RMS and that majority of patients present with early-stage disease.
The long-term outcome data from our series correspond to the high cure rates reported for RMS of the uterine cervix by several other authors. Fertility-sparing treatment options should be considered in all young patients with early-stage disease. Multimodality treatment with surgery limited to polypectomy/gross tumor resection followed by aggressive chemotherapy and additional local treatment tailored to chemotherapy response appears to be a reasonable approach for fertility sparing in all patients with early-stage cervical RMS. The possible genetic link of RMS needs further evaluation.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]