Pleomorphic rhabdomyosarcoma (RMS) represents a rare sarcoma subtype of the adult population. Due to its clinical characteristics, treatment is currently based on the guidelines for adult soft tissue sarcoma therapy. Hence, in the metastatic setting, doxorubicin-containing regimens are used in the sarcoma community, with limited treatment benefit. Scanty published data are available on the efficacy of systemic treatment. Whether treatment response and outcome of these patients could be improved by using pediatric protocols used typically in other RMS subtypes, like embryonal and alveolar RMS, is unclear. We report on an impressive effect of multiagent pediatric chemotherapy in an adult patient with metastatic pleomorphic RMS.
We present the case of a 70-year-old man with metastatic pleomorphic RMS of his left thigh. Systemic chemotherapy according to the VAC regimen (vincristine, actinomycin, cyclophosphamide) was initiated. Follow-up clinical and radiologic assessment demonstrated an impressive treatment response.
Sixteen months after primary diagnosis, computed tomography scan shows no signs of tumor progression.
Our case report emphasizes that multiagent systemic therapy according to pediatric protocols should be considered in adult patients with pleomorphic RMS.
Tumori 2016; 102(Suppl. 2): e57 - e60
Article Type: CASE REPORT
AuthorsAttila Kollár, Rupert Langer, Codruta Ionescu, Jennifer L. Cullmann, Frank M. Klenke
- • Accepted on 22/01/2016
- • Available online on 15/02/2016
- • Published online on 11/11/2016
This article is available as full text PDF.
Rhabdomyosarcoma (RMS) accounts for approximately 3% of soft tissue sarcomas (STS) and is a common childhood malignancy. In contrast to the embryonal and alveolar variant, pleomorphic RMS occurs almost exclusively in the adult population (1). The prognosis of RMS in older patients appears to be worse. Reasons for these age-dependent differences seem to be multifactorial and include differences in the distribution of histopathologic subtypes and primary tumor sites, different chemosensitivity in older patients, and an increase in treatment toxicity with age (2).
Although the entity of pleomorphic RMS was questioned in the past due to confusing diagnostic criteria, the recent WHO classification has allocated it as a separate RMS subtype. The diagnosis is based on histomorphologic, immunohistochemical, and molecular characteristics, described by Fletcher and colleagues (3).
Pleomorphic RMS, which almost exclusively occurs in the adult population, is located most commonly at the extremities, the uterus, and in the paratesticular and head and neck regions. Further primary locations are of thoracic (thorax, heart, breast), intra-abdominal (kidney, adrenal gland, diaphragm, choledochus, liver), cutaneous, ocular, and cerebral origin. The age at diagnosis of adult pleomorphic RMS has been reported to range from 46 to 62 years and the tumors occurred predominately in males (4-5-6). In a retrospective case series by Furlong et al (6), the median age was 54 (21-81) years, 28 out of 38 patients (74%) were male, 55% of the tumors were located in the extremities, and the median tumor size at initial diagnosis was 6.8 cm (1.5-15 cm). The 5-year disease-free survival was 27%. Data on the usage of and response to chemotherapy were not reported.
The rarity of the disease and lack of clinical data makes it worthwhile to look into the clinical features, systemic treatment strategies, and disease outcomes in detail. We present a case of pleomorphic RMS of the left thigh treated according to a pediatric chemotherapy regimen. Due to multiple lung metastases, systemic therapy with vincristine, actinomycin D, and cyclophosphamide was initiated, resulting in a favorable response.
A 70-year-old man presented with a slowly growing mass of his left thigh in May 2014. Due to a minor trauma a few weeks earlier, a hematoma was suspected. His medical history included a malignant melanoma of the left calf in 1994 and an inguinal relapse 18 years later, both of which were resected, cholecystolithiasis, and dyslipidemia. Family history was negative for neoplastic diseases.
Magnetic resonance imaging (MRI) showed a large lesion of the left thigh (21 × 15 × 11 cm) with central necrosis (
Magnetic resonance imaging of left thigh (contrast-enhanced T1-weighted fatsat).
Hematoxylin & eosin and immunohistochemical staining for Ki-67 and desmin.
Due to the advanced stage of the disease and the high risk of skin perforation, systemic treatment according to the VAC regimen (vincristine, actinomycin, cyclophosphamide) was initiated immediately. Treatment consisted of 7 cycles, which were administered between June 2014 and November 2014. Overall, chemotherapy was tolerated well, clinically and hematologically; filgrastim was given as primary prophylaxis. Vincristine had to be stopped after the 4th cycle due to neurotoxicity. Due to progressing fatigue, systemic therapy was stopped after the 7th cycle. Clinical follow-up showed a rapid and marked decrease in tumor size at the primary tumor site within the first 10 weeks of treatment. The radiographic follow-up revealed a continuous response of the lung metastasis and delayed response of the primary tumor (
Radiologic follow-up according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
|Date of imaging||Target lesions, cm||Nontarget lesions (lung)||New lesions||Overall response|
|Primary tumor||Lung metastasis||Sum of target lesions|
|CR = complete remission; PD = progressive disease; PR = partial response; SD = stable disease.|
After 5 cycles of chemotherapy, the patient presented with symptoms of a grand mal epileptic seizure. Magnetic resonance imaging showed a small (1.5 cm), solitary right temporal lesion suggesting a solitary brain metastasis. Antiepileptic treatment with levetiracetam was initiated. Treatment consisted of stereotactic radiosurgery with 20 Gy applied in a single dose.
A follow-up scan in January 2015 showed a mixed response of the known lung lesions, but altogether a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (diagnosis of solitary brain lesion excluded in the RECIST evaluation) (
To date, the existing clinical knowledge on pleomorphic RMS is mainly based on case reports and retrospective case series. The latter generally report on adult patients with RMS including clinical information on the pleomorphic variant with limited data (
Retrospective series of adult/pleomorphic RMS
|Reference||RMS subtypes||number of patients||pleomorphic variant (n)||median age (years)||male gender (%)||localized stage (%)||Extremity location (%)||Chemotherapy (%)||Chemotherapy agent/regimen||Overall response rate (%)||5-y-OS (%)|
|ACT = actinomycin; CYC = cyclophosphamide; DOD = dead of disease; DOX = doxorubicin; IFO = ifosfamide; MAID = mesna, doxorubicin, ifosfamide, dacarbazine; NED = no evidence of disease; RMS = rhabdomyosarcoma; VCR = vincristine.|
|Ferrari et al. 2003 (1)||adult RMS||180||37||27 (all) 50 (pleo)||70 (pleo)||83||65 (pleo)||73 (all) 32 (pleo)||nr||85||40 (all) 53.4 (pleo)|
|Stock et al. 2009 (4)||adult RMS||57||16||62 (pleo)||56||93||65||61||DOX, VCR, CYC, IFO||nr||33|
|Esnaola et al. 2001 (5)||adult RMS||39||5||27 (all) 46 (pleo)||62||67||31||95||nr||82||31% (all) 26 (pleo)|
|Furlong et al. 2001 (6)||pleo RMS||38||38||54||74||nr||55||nr||nr||nr||5-y-DFS 27%|
|Hawkins et al. 2001 (7)||adult RMS||84||14||23||51||48||22||92||VCR, ACT, CYC, DOX, IFO||nr||35|
|Little et al. 2002 (8)||adult RMS||82||35||27||55||100||22||71||DOX or ACT with VCR, CYC||74||44|
|Simon et al. 2003 (9)||adult RMS||39||14||45||59||95||39||56||VCR, ACT, CYC||nr||35|
|Ogilvie et al. 2010 (10)||adult RMS||11||7||49||73||55||72||100||DOX, IFO, VCR||86||55|
|Gerber et al. 2013 (11)||adult RMS||138||16||28||57||68||22||91||VAC, DOX, VAdriCyclolfo, MAID||nr||34|
Accordingly, almost no data on chemotherapy sensitivity in pleomorphic RMS are available. In the pediatric population, collaborative clinical trials have shown a significant improvement in outcome when including chemotherapy in multimodality treatment concepts of localized RMS. In pediatric oncology group treatment protocols, 3-drug combination with vincristine, actinomycin, and cyclophosphamide (VAC) has been the backbone of RMS therapy. Although higher age at diagnosis seemed to be correlated with an adverse outcome in children, there is no evidence of limited treatment responsiveness to chemotherapy in adult RMS. Two studies reported an objective response rate to chemotherapy of up to 86% in adult RMS (5, 8). Ferrari and colleagues (1) reported on similar treatment response and outcome of adult RMS when treated according to pediatric regimens. However, differences in pharmacodynamics and pharmacokinetics between the adult and pediatric population often preclude adequate practicability, e.g., in terms of dosage of systemic therapy. So far, a single study has investigated the effect of chemotherapy on pleomorphic RMS in adults (10). Five patients out of 7 with pleomorphic RMS were treated with doxorubicin, ifosfamide, and vincristine in a neoadjuvant setting. Two patients had a complete response and 2 a partial response to this combined drug regimen. Nevertheless, due to limited data, no conclusions can be drawn about the ideal systemic therapy options in this sarcoma subtype. Considering the similarity of pleomorphic RMS to other STS in terms of biological characteristics and clinical behavior, chemotherapy regimens used for adult STS including doxorubicin and ifosfamide are used in the sarcoma community. This seems to be associated with a poor prognosis (5, 6). The present case report suggests that pediatric treatment protocols should be considered as a treatment option in pleomorphic RMS.
In conclusion, pleomorphic RMS represents an aggressive tumor entity of the adult population with a markedly dismal prognosis. Multidrug chemotherapy seems to be a possibility to improve treatment outcome. However, the optimal chemotherapy regimen remains to be defined.
- Kollár, Attila [PubMed] [Google Scholar] 1, * Corresponding Author (firstname.lastname@example.org)
- Langer, Rupert [PubMed] [Google Scholar] 2
- Ionescu, Codruta [PubMed] [Google Scholar] 3
- Cullmann, Jennifer L. [PubMed] [Google Scholar] 4
- Klenke, Frank M. [PubMed] [Google Scholar] 5
Department of Medical Oncology, Inselspital, Bern University Hospital, Sarcoma Center, Bern - Switzerland
Institute of Pathology, University of Bern, Bern - Switzerland
Department of Radiation Oncology, Inselspital, Bern University Hospital, Sarcoma Center, Bern - Switzerland
Institute for Diagnostic, Interventional, and Pediatric Radiology, Inselspital, University Hospital Bern, Bern - Switzerland
Department of Orthopedic Surgery, Inselspital, Bern University Hospital, Sarcoma Center, Bern - Switzerland