Abstract
“…cervical sarcomas are still not characterized well and standardized concepts for their management are lacking due to their rarity and histopathological diversity.”
The most common histological subtype of cervical cancer is squamous cell carcinoma, which is followed by adenocarcinoma, adenosquamous and small-cell/neuroendocrine carcinoma. The mesenchymal tumors or the uterine cervix are distinctly uncommon and heterogenous diseases. Cervical sarcomas are rare tumors that constitute less than 1% of all cervical malignancies. Although substantial progress has been achieved in the diagnosis and treatment of uterine sarcomas, cervical sarcomas are still not characterized well and standardized concepts for their management are lacking due to their rarity and histopathological diversity. Apart from case reports, only a few retrospective studies of sarcomas of the uterine cervix have been published to date [1–5] and these are difficult to compare because some of them also include carcinosarcoma, which is considered to be a type of metaplastic carcinoma rather than a sarcoma. However, a large-scale prospective investigation of cervical sarcomas is difficult due to its low incidence and complicated histological subtypes.
Cervical sarcomas consist of several entities that display distinct clinicopathological profiles. Histopathology may exhibit skeletal or smooth muscle, fatty, fibrohistiocytic, fibroblastic, nerve sheath, neuroectodermal component and tumors with uncertain differentiation. The seven most common types of cervical sarcomas, listed in descending order, and discussed below, are: embryonal rhabdomyosarcoma (ERMS); leiomyosarcoma (LMS); undifferentiated endocervical sarcoma (UES); alveolar soft part sarcoma (ASPS); Ewing's sarcoma/primitive neuroectodermal tumor (PNET); and liposarcoma [6]. The most common presentation is abnormal vaginal bleeding. No imaging modality can offer a reliable preoperative diagnosis and computed tomography is unable to differentiate between different types of cervical pathology.
The most common sarcomas are the rhabdomyosarcomas, of the embryonal subtype. Cervical ERMS most commonly occurs in the reproductive age group, during the second and third decades of life. Most of our information is based on individual case reports and small case series. There are no definite guidelines available for treatment of patients with rhabdomyosarcoma of the cervix, although the majority are treated with a combination of surgery and chemotherapy. Three large series of ERMS of the cervix have been reported in the literature [7–9]. In a clinicopathological study consisting of 13 cases by Daya and Scully, 12 patients were alive and in good health 1–8 years (average: 3.5 years) after surgery and only one had died of the tumor after 1 year [7]. Three of the 13 patients treated with fertility-sparing surgery followed by chemotherapy had comparable results to those treated with more radical surgery, with or without chemotherapy. In a study of 14 patients with ERMS of the uterine cervix by Dehner et al., 12 patients remained disease-free after conservative surgery and chemotherapy [8]. In a recently published series by Li et al., it was emphasized that ERMS should be part of differential diagnosis for cervical spindle cell tumors, regardless of patient age [9]. Taken together, these studies suggest that cervical ERMS has a relatively favorable prognosis. As ERMS tends to occur in young females, who often desire future fertility, treatment has evolved from radical fertility-compromising surgery to less radical and conservative surgical procedures and chemotherapy in order to preserve fertility without compromising disease-free and overall survival.
LMS most commonly occurs in perimeno-pausal and postmenopausal women in their fourth to sixth decades of life [6]. The largest series to date reported 67 cases of cervical LMS, accounting for 21% of 323 patients of cervical sarcoma [4]. Primary therapy for localized disease entails complete surgical resection in the form of total abdominal hysterectomy with bilateral salpingo-oophorectomy. The role of lymphadenectomy in the management of LMS remains debatable due to low incidence of lymph nodal involvement [5]. Postoperative adjuvant pelvic radiotherapy may reduce the risk of local recurrence in patients with early-stage disease; however, it cannot prevent the development of recurrent disease in distant sites. Several retrospective studies suggested improved local control, without any improvement in overall survival, in patients with uterine LMS who were treated with postoperative adjuvant pelvic irradiation [10,11]. In a prospective, randomized, multicenter Phase III study of uterine sarcomas, comprising 103 patients of uterine LMS, postoperative pelvic radiotherapy did not improve disease-free or overall survival [12]. The role of adjuvant chemotherapy is still being investigated. As with other high-grade sarcomas, LMSs metastasize early due to hematogenous spread, primarily to the lungs. The chemotherapeutic regimens with evidence of efficacy in advanced, metastatic uterine LMS are gemcitabine plus docetaxel, and doxorubicin with or without ifosfamide. Multimodality treatment including surgery, radiotherapy and chemotherapy should be used in these patients for a better outcome [5].
“The diversity of histological subtypes and variable biological behavior, along with the small number of patients and different stages at presentation, result in unclear protocol for the treatment of cervical sarcomas.”
UES (initially referred to as endocervical stromal sarcoma) comprises sheets or fascicles of stellate or spindle cells that lack any specific line of differentiation when viewed under a light microscope. The microscopic appearance of undifferentiated endocervical sarcoma resemble that of a moderate-to-high grade, undifferentiated sarcoma [13]. Owing to the lack of immunohistochemical investigation of these tumors and their variable behavior, it is likely that UES represents a morphologically heterogeneous group of neoplasms. However, the outcomes of these patients have generally been unfavorable. Follow-up is available in 17 of the 26 reported cases [1,3–6,14]. A total of seven patients succumbed to their disease within 2 years of the diagnosis.
ASPS that originates from the uterine cervix is quite rare. Less than 20 cases have been reported in the literature and the age at diagnosis ranged from 8 to 57 years, with a mean of 30.4 years. Complete surgical resection with adequate margins is the treatment of choice for ASPS of the cervix. The role of lymph node dissection on the clinical outcome of cervical ASPS, however, is not yet clear [15]. The role of chemotherapy or radiotherapy has not yet been defined for ASPS of the cervix or soft tissues. In a review of the literature by Fadare, it was found that 82% of patients with cervical ASPS were treated with surgical intervention, which included at least a hysterectomy [13]. With follow-up ranging from 9 months to 16 years, none of the cases developed metastasis or recurrence. This signifies that the prognosis is good once the lesion has been completely resected; however, more cases and longer follow-up are required to establish this possibility. Unfortunately, the rarity of this tumor has precluded the development of precise guidelines for adjuvant treatment protocols.
“…patients with cervical sarcomas require a united and multidisciplinary treatment approach and the expertise of an oncology team for optimal management.”
Ewing's sarcoma/PNET are small, round-cell tumors differing in their degrees of neuroectodermal differentiation. These are extremely rare in the uterine cervix. In a review of the literature, Arora et al. and Farzaneh et al. identified nine previously reported cases, however, a total of 11 cases have been reported in the English literature so far [16,17]. There is considerable variation in the treatment of reported cases; the majority of the patients had surgery, chemotherapy and/or radiation therapy. More recently, neoadjuvant chemotherapy followed by local treatment has been favored in accordance with the protocol for bony Ewing's sarcoma [17,18]. The duration of follow-up varied from 5 to 50 months. Ten of the 11 patients were alive without evidence of disease. Multimodality treatment comprising surgery, radiotherapy and chemotherapy should be the standard of care in this rare entity. The prognosis of cervical PNET is currently difficult to determine, owing to few cases being reported.
Malignant peripheral nerve sheath tumors (MPNSTs) are characterized by proliferation of spindle cells with conspicuous atypia, high mitotic activity, nuclear pleomorphism and invasiveness. Approximately ten cases of MPNST have been reported in the literature. Management of patients with MPNST involves a combined modality approach. The treatment of choice is surgery (complete resection with negative margins). In a recent study by Jebsen et al., it was found that MPNST was associated with a 35% 5-year risk of local recurrence [19]. A total dose of 50 Gy seems adequate following wide margin surgery. After inadequate surgery, there is a rationale for increasing the dose [19]. High grade, large tumor size, deep tumor location and positive surgical margins are well-established poor prognostic factors. The efficacy of chemotherapy in the specific setting of MPNSTs is difficult to illustrate. In a recent meta-analysis by Pervaiz et al., it was concluded that there is marginal efficacy of chemotherapy in localized resectable soft tissue sarcoma compared with local recurrence, distant recurrence and overall survival [20]. It was noted that these benefits were further improved with the addition of ifosfamide to doxorubicin-based regimens; however, associated toxicities must also be considered. Follow-up information is available in five of the ten reported cases: three patients were alive without any evidence of disease at the last follow-up, whereas the fourth patient developed abdominal and pelvic metastasis at 20 months, and the fifth developed lung and peritoneal metastasis at 6 months after primary treatment and was lost at follow-up at 33 months. Further close observation of patients during a long-term period is necessary.
In a review of the literature, Karateke et al. identified five cases of pure liposarcoma originating from the cervix including their own case [21]. Two were pleomorphic, one was round cell, one was well differentiated, and one was round and myxoid. Both of the cases of pleomorphic liposarcoma recurred within 1 year after surgery. Two patients were disease-free at the last follow-up, while follow-up information was not available for one patient.
The diversity of histological subtypes and variable biological behavior, along with the small number of patients and different stages at presentation, result in unclear protocol for the treatment of cervical sarcomas. The reported cases have been treated by a wide variety of treatment strategies, which makes assessment of their natural history and intrinsic biological behavior difficult to understand. Assumptions about the poor prognosis and aggressive behavior associated with cervical sarcomas are no longer appropriate and, consequently, each case must be evaluated within the context of the reported cases of that specific histological subtype. Thus, patients with cervical sarcomas require a united and multidisciplinary treatment approach and the expertise of an oncology team for optimal management. The combined work between gynecologists and oncologists will produce a multidisciplinary approach that will provide patients with the best outcome and quality of life, through the timely use of surgery, radiotherapy and chemotherapy.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.