Orbital Rhabdomyosarcoma: Current Perspectives
F Elomrani*, S L'annaz, H.Mrabti, H.Errihani
Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco.
Department of Medical Oncology,
National Institute of Oncology, Rabat,
Article Type : Review Article
Received: September 04, 2015; Accepted: October 16, 2015; Published: October 21, 2015
Citation: F Elomrani, S L'annaz, H.Mrabti, H.Errihani (2015) Orbital rhabdomyosarcoma: Current Perspectives. Int J Ophthalmol Eye Res 03(9), 150-153. doi: dx.doi.org/10.19070/2332-290X-1500032
Copyright:F Elomrani© 2015. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
Orbital rhabdomyosarcoma is mesenchymal tumor, presents 10-20% of all rhabdomyosarcoma are usually diagnosed in children. It presents clinically by rapidly progressive unilateral proptosis. Imaging is fundamental to assessing the extent of the tumor and the erosion of the bone, but only histology can confirm the diagnosis. The treatment involves a combination of chemotherapy, radiotherapy and surgery. The challenge is to choose a treatment with good cosmetic and functional results specially visual function and excellent survival.
Orbital; Rhabdomyosarcoma; Histology; Radiotherapy; Chemotherapy; Surgery.
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, orbital RMS presented 8% of all soft tissue sarcoma of the head and neck. Improved treatment has allowed a significant change in survival rates from 30% in 1960 to 90% currently [1, 2]. The treatment is multimodal it included surgery, radiotherapy and chemotherapy. Here we presented a general overview of orbital RMS.
Orbital RMS is the most common primary orbital malignancy in children with an annual incidence of 4.3 cases per million children, approximately 35 new cases per year in the United States [1, 3].
Most cases of orbital RMS were diagnosed before 16 years and the median age is between 5-7 years, however some cases were described in elderly patients . RMS is localized in the orbit, conjunctiva, eyelid and more rarely in the uveal tract, or by extension from the nasopharynx and paranasal sinus or orbital can be site of metastasis .
The hereditary transmission in orbital RMS is not well known, however some genetic mutations have been described in association with orbital RMS like: li –fraumeni syndrome, neurofibromatosis, Beckwith-Wiedemann Syndrome, Costello Syndrome, retinoblastoma, Nevoid Basal Cell Carcinoma Syndrome [5-7].
Orbital RMS manifested clinically by the appearance of a unilateral exophtalmos rapidly develop or slow growing mass, other signs may be associated like chemosis, swelling of the eyelids, painless, ophthalmoplegia, erythema and edema . Imaging is important for diagnosis and evaluation of residual disease, CT scan showed a well-defined orbital mass with irregular albeit enhances after contrast injection. Also, MRI showed a well-circumscribed homogeneous orbital mass enhances with gadolinium, usually hypointense to orbital fact and isointense to extraocular muscles on T1- weighted imaging, but on T2-weighted imaging the orbital mass is hyperintense to orbital fat and extraocular muscles [8, 9].
CT or MRI may help in diagnosing by showing the location, size of the tumor, the extracranial extension and bone erosion and may assist the surgical planning, but only the histology with immunohistochemical study can confirm the diagnosis and differentiates it from other tumors like vascular tumors, schwanomma , inflammatory disease, orbital cellulitis, leukemia, Burkitt lymphoma, metastasis, and orbital pseudotumor .
There are four histological types: alveolar, embryonal, pleomorphic and botryoid. The embryonal subtype is the most common orbital RMS is associated with a good prognosis than others. Histologically, the RMS is characterized by the presence of rhabdomyoblastic cells forming elongated, spindle cell types with cross striations representing cytoplasmic bundles in most cases by actin and myosin filaments. The diagnosis of RMS is made by immunohistochemistry, stains for myoglobin, myogenin, desmin and muscle specific actin [11, 12].
The use of cytogenetic is necessary to distinguish the alveolar RMS from the embryonal. The alveolar RMS is characterized by specific translocation, t(2;13)(q37;q14) or its variant t(1;13) (p36;q14) then to the embryonal subtype there is no specific chromosomal rearrangements or molecular markers .
Treatment of orbital RMS is multimodal, including surgical excision with or without radiotherapy and chemotherapy.
The standard of care for orbital RMS in the past was complete resection enucleation or exenteration of the tumor but due to the poor overall survival (OS) about 25-30% observed by sugery alone and in attempt to improve this outcome, the North American Intergroup Rhabdomyosarcoma Study Group (IRSG) and European cooperative groups add adjuvant chemotherapy and radiotherapy in cooperative group trials, the OS was improved to around 90% [14-17].
The diagnosis of orbital RMS is histopathologic following wide excision, incisional or excisional biopsy. It is preferable to perform incisional biopsy to avoid the risk of spread tumor cells. Thanks to its good prognosis after treatment by radiotherapy and chemotherapy, regardless of amount of tissue excised, some authors suggests that an incisional biopsy is sufficient. But some surgeons believe that complete excision with negative margins decreases tumor size which facilitates post-operative treatment [18, 19].
After biopsy of the tumor, orbital RMS can be staged according to the IRS post-surgical staging system [20-23].
Group I: localized disease completely resected.
Group II: microscopic disease remaining after biopsy.
Group III: macroscopic residual disease remaining after biopsy.
Group IV: distant metastasis.
This classification allows to adapt the treatment depending on stage of the tumor and its prognosis [20, 21].
RMS is a chemosensitive tumor, the goal of chemotherapy is to obtain tumor response and to reduce the use of local treatments. Many drugs was tested to treat rhabdomyosarcoma such as vincristine, dactinomycin, cyclophosphamide, doxorubicin, ifosfamide, etoposide and irinotecan. Various combination of this drugs was used. The most protocol used is association between vincristine, doxorubicin and cycophosphamde (VAC), this protocol improve complete response by 67% when used after surgery versus 25% in surgery alone . Others combinations with other molecules were used to treat tumors with resistant to VAC combination.
In three American studies for patients with complete resection the postoperative radiotherapy does not provide any benefit over VAC or VA protocols [25, 26]. To avoid the toxicity of cyclophosphamide SIOP developed MMT-84 protocol, they replace cyclophosphamide by high dose of Ifosfamide (VAI or VAC), the response rate was higher with ifosfamide just in few study [28, 29]. The high dose of ifosfamide (9g/m²/course) is more effective in stage III this dose was tested in MMT-89 protocol. For the SIOP, ICG and CWS the standard regimen is IVA (Ifosfamide 6g/m²/ course+VA) .
Doxorubicin has an antitumor activity in rhabdomysarcoma, it was tested in association to VAI in German study CWS-86 showed an improvement in objective response rate . In metastatic disease the combination of doxorubicin and ifosfamide showed an improvement in objective response rate (63%) but no significant improvement in overall survival .
The use of cisplatin and etoposide in second line after failure of IVA showed an efficacy in MMT-84 protocol  . But in a randomized study comparing VAC versus VAC + cisplatin + doxorubicin versus VAC + cisplatin + etoposide in patient with macroscopic residual disease or metastatic disease, the combination does not improve overall survival comparing with VAC alone .
Topotecan seems to be effective in first line therapy; it showed a good response rate about 45% .
In aim to improve the results of chemotherapy in metastatic rhabdomyosarcoma, the high dose intensive chemotherapy followed by peripheral stem cell rescue did not showed any efficacy [35, 36].
RMS is radiosensitive tumor, its benefit was showed in 1960’s with improvement in recurrence free survival with doses between 55 and 65 Gy  . In a pooled analysis of 306 orbital RMS patients showed 10 year EFS to be significantly better for patients receiving RT as part of their initial treatment compared to those who did not (82 vs 53%) however no statistical difference in OS . The North American groups IRSG protocols used adjuvant radiotherapy systematically after surgical resection  but in the SIOP protocol they performed radiotherapy if high risk RMS like alveolar subtype or if persistent a residual disease after chemotherapy [33, 37].
Recently new technologies in radiation oncology are used including proton beam radiotherapy, intensity modulated radiotherapy (IMRT), 3-D conformational radiotherapy and implant brachytherapy, this therapies tend to offer an excellent survival, to reduce dose to normal tissue adjacent and to decrease the long termside effects of treatment .
IMRT for head-and-neck RMS was studied by Wolden et al ,they showed that IMRT with image fusion gave a good results in local control by using a minimal dose to the normal adjacent tissue .
To test the possibility of organ-sparing particularly lens-sparing, a study conducted by Hein et al ,comparing IMRT versus 3D conformational photon radiotherapy, they observed that although IMRT resulted in a reduced dose to the ipsilateral lacrimal gland and the lens, but against no significant difference was found for optic nerve and ipsilateral retina, with low dose radiation to the brain compared to 3D conformal radiotherapy .
Brachytherapy has advantages over external beam radiotherapy EBRT by delivering a locally high dose while avoiding surrounding tissue, reducing time treatment and toxicity and improving functional prognosis especially visual prognosis. Blank et al, reported the use of brachytherapy it limited in case of complete tumor resection without intracranial extension and when the use of EBRT will be very toxic .
The treatment of orbital RMS is multimodal including surgery chemotherapy and radiotherapy based on risk as classified by IRS staging system. The European pediatric Soft tissue sarcoma Study Group (EpSSG) protocol (EpSSG-RMS-2005) proposes for each group [42, 43].
- Group I are treated with chemotherapy only VA (vincristine and actinomycin).
- Group II are treated with a combination of chemotherapy using VAC protocol and radiotherapy at 36 Gy.
- Group III are treated with a combination of chemotherapy (VAC) and radiotherapy (45 Gy),for group II and III the use of ifosfamide added to VA in the first four courses if complete response after three courses of chemotherapy but if not obtained complete response use radiotherapy at 45 Gy.
- Group IV are treated with a combination of intensive chemotherapy (IVA and doxorubicin) and radiotherapy, followed by one year of maintenance chemotherapy and radiotherapy to all involved sites.
The survival of patients with orbital RMS was improved over the years grace to advances in chemotherapy and radiotherapy .The overall 3-year survival was 95% for RMS localized to the orbit and 73% for RMS with parameningeal extension . The prognosis depends on several factors age and anatomical site and histological type. Embryonal RMS has good prognosis versus alveolar RMS with a 5 year-survival of 94% versus 74%  . The prognosis was good for localized groups (I,II,III) 92% at 5 Year-survival and 87% at 10 years [8, 45, 46]. At recurrence, the prognosis also depends on histology, age, IRS group, and previous treatment [47, 48].
The perspective for the future is to identify patients who can be safely treated by only chemotherapy and to reserve local treatment (surgery and or radiotherapy) for patients at high risk of recurrence in goal to reduce side effects of treatment and to improve cosmetics and functional results.
Orbital RMS is a rare tumor, its diagnosis and management requires a multidisciplinary team. The treatment of orbital RMS should be based on international recommendations. The challenge in future it 'is the selection of patients according to risk of recurrence, to choose the less mutilating and most effective treatment.
- Ries LAG, Smith MA, Gurney JG, Linet M, Tamra T, et al (1999) Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995. NIH Pub. No. 99-4649.Bethesda, MD: National Cancer Institute, SEER Program.
- Notis CM, Abramson DH, Sagerman RH, Ellsworth RM (1995) Orbital rhabdomyosarcoma: treatment or overtreatment. Ophtalmic Genet 16(4):159-162.
- Gandhi P, Fleming J, Haik B, Wilson M (2011) Ophthalmic complications following treatment of paranasal sinus rhabdomyosarcoma in comparison to orbital disease. Ophthal Plast Reconstr Surg 27(4): 241-246.
- Wharam M, Beltangady M, Hays D, Heyn R, Ragab A, et al. (1987) Localized orbital rhabdomyosarcoma. An interim report of the Intergroup Rhabdomyosarcoma Study Committee. Ophthalmology 94(3): 251-254.
- Shields CL, Shields JA, Honavar SG, Demirci H (2001) Clinical Spectrum of Primary Ophthalmic Rhabdomyosarcoma. Ophthalmology108(12): 2284-2292.
- Li FP, Fraumenti JF (1969) Rhabdomyosarcoma in Children: Epidemiologic Study and Identification of a Familial Cancer Syndrome. J Nat Cancer Inst 43(6): 1365-1373.
- Sobel R, Woerner S (1981) Rubinstein-Taybi Syndrome and nasopharyngeal rhabdomyosarcoma. J Pediatr 99(6): 1000-1001.
- Sohaib S, Moseley I, Wright J (1998) Orbital rhabdomyosarcoma-the radiological characteristics. Clin Radiol 53(5): 357-362.
- Cooper S, Munk P, Downey D, Nicolle DA, Lee DH, et al. (1994) Findings of magnetic resonance and colour-flow Doppler imaging of orbital embryonal rhabdomyosarcoma. Can Assoc Radiol J 45(3): 217-220.
- Cota N, Chandna A, Abernethy LJ (2000) Orbital abscess masquerading as a rhabdomyosarcoma. J AAPOS 4(5): 318-320.
- Wexler L, Helman L (1997) Rhabdomyosarcoma and the undifferentiated sarcomas. In Principles and Practice of Pediatric Oncology. Lippincott Raven Publishers, Philadelphia. 799-829.
- Weiss S, Goldblum J (2001) Rhabdomyosarcoma. In Enzinger and Weiss’s Soft Tissue Tumors. (4th edtn), CV Mosby Company, St Louis. 785-835.
- Whang-Peng J, Knustsen T, Theil K, Horowitz ME, Triche T (1992) Cytogenetic studies in subgroups of rhabdomyosarcoma .Genes chromosomes Cancer 5(4): 299-310.
- Olivier Pascual N, Calvo JM, Abelairas Gómez JM (2005) Orbital rhabdomyosarcoma: difficulties with European treatment protocol. Arch Soc Esp Oftalmol 80: 331-338.
- Shields CL, Shields JA, Honavar SG, Demirci H (2001) Primary ophthalmic rhabdomyosarcoma in 33 patients. Trans Am Ophthalmol Soc 99: 133-143.
- Raney RB, Maurer HM, Anderson JR, Andrassy RJ, Donaldson SS, et al. (2001) The Intergroup Rhabdomyosarcoma Study Group (IRSG): major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma 5(1): 9-15.
- Wharam MD, Hanfelt JJ, Tefft MC, Johnston J, Ensign LG, et al. (1997) Radiation therapy for rhabdomyosarcoma: local failure risk for clinical group III patients on intergroup rhabdomyosarcoma study II. Int J Radiat Oncol Biol Phys 38(4): 797-804.
- Shields JA, Shields CL (2003) Rhabdomyosarcoma: review for the ophthalmologist. Surv Ophthalmol 48(1): 39-57.
- Raney RB, Walterhouse DO, Meza JL, Andrassy RJ, Breneman JC, et al. (2011) Results of the intergroup rhabdomyosarcoma study group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children’s oncology group. J Clin Oncol 29(10): 1312-1318.
- Andrade CR, Takahama Junior A, Nishimoto IN, Kowalski LP, Lopes MA (2010) Rhabdomyosarcoma of the head and neck: a clinicopathological and immunohistochemical analysis of 29 cases. Braz Dent J 21(1): 68-73.
- Arndt C, Tefft M, Gehan E, Anderson J, Jenson M, et al. (1997) A feasibility, toxicity, and early response study of etoposide, ifosfamide, and vincristine for the treatment of children with rhabdomyosarcoma: a report from the intergroup rhabdomyosarcoma study (IRS) IV pilot study. J Pediatr Hematol Oncol 19(2): 124-129.
- Ruymann FB, Vietti T, Gehan E, Wiener E, Wharam M, et al. (1995) Cyclophosphamide dose escalation in combination with vincristine and actinomycin D (VAC) in gross residual sarcoma: a pilot study without hematopoietic growth factor support evaluating toxicity and response. J Pediatr Hematol Oncol 17(4): 331-337.
- Blank LE, Koedooder K, van der Grient HN, Wolffs NA, van de Kar M, et al. (2010) Brachytherapy as part of the multidisciplinary treatment of childhood rhabdomyosarcomas of the orbit. Int J Radiat Oncol Biol Phys 77(5):1463-1469.
- Sutow WW (1968) Vincristine (NSC-67574) therapy for malignant solid tumors in children (expect Wilm’s tumor). Cancer Chemother Rep 52: 485-487.
- Crist WM, Anderson Jr, Meza Jl, Fryer C, Raney RB, et al (2001) Intergroup rhabdomyosarcoma study IV: results for patient with non metastatic disease.J Clin Oncol 19(12): 3091-3102.
- Oberlin O, Rey A, Anderson J, Carli M, Raney RB, et al (2001) Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment –results of international workshop. J Clin Oncol 19(1): 197-204.
- Flamant F, Rodary C, Rey A, Praquin MT, Sommelet D, et al (1998) Treatment of non metastatic rhabdomyosracoma in chilidhood and adolescence. Result of the second study of the International Society of Pedriatric Oncology:MMT-84. Eur J Cancer 34(7): 1050-1062.
- De Kraker J, Voute PA (1989) Experience with ifosfamide in pediatric tumors. Cancer Chemother Pharmacol 24(1): S28-S29.
- Treuner J, KoscielniakE, Keim M (1989) Comparison of the rates of response to ifosfamide and cyclophosphamide in primary unresectable rhabdomyosarcoma.Cancer Chemother Pharmacol 24(Suppl 1): S48-S50.
- Miser JS, Kinsella TJ, Triche TJ, Tsokos M, Jarosinski P, et al (1987) Ifosfamide with mesna uroprotection and etoposide :an effective regimen in the treatment of recurrent sarcomas and others tumors of children an young adults. J Clin Oncol 5(8): 1194-1198.
- Bonadonna G, Monfardini S, De len AM, Fossati-Bellani F, Beretta G (1970) Phase I and preliminary phase II evaluation of adriamycin. Cancer Res 30(10): 2572-2582.
- Sandler E, Lyden E, Ruymann F, Maurer H, Wharam M, et al (2001) Efficacy of ifosfamide and doxorubicin given as pahse II window in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37(5):442-448.
- Dobbs JBA BP, Hawkins D, Crist WM, Baker KS (1997) Practical radiotherapy planning. In Pediatric tumors. Arnold E(Ed), London. 272-283.
- Pappo AS, Lyden E, Breneman J, Wiener E, Teot L, et al (2001) Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19(1): 213-219.
- Khoscielniak E, Rodary C, Flamant F, Carli M, Treuner J, et al (1992) Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis. Med Pediatric Oncol 20(3):209-214.
- Weigel BJ, Breitfeld PP, Hawkins D, Crist WM, Bakers KS (2001) Role of high-dose chemotherapy with hematopotetic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23(5): 272-276.
- Sommelet D, Pinkerton R, Brunat-Mentigny M, Farsi F, Martel I, et al (1998) Standards, options and recommandations (SOR) for clinical care of rhabdomyosarcoma (RMS) and other soft tissue sarcoma in children. Federation of the French cancer centers. French Society of Pediatric Oncology.Bull cancer 85(12): 1015-1042.
- Warrier AR, Syriac S, Rathnam KK (2010) Late recurrence in orbital rhabdomyosarcoma: complete remission after multimodality management. J Cancer Res Ther 6(3): 307-309.
- Sultan I, Qaddoumi I, Yaser S, Rodriguez-Galindo C, Ferrari A (2009) Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27(20): 3391-3397.
- Oberlin O, Rey A, Lyden E, Bisogno G, Stevens MC, et al. (2008) Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26(14): 2384-2389.
- Yock T, Schneider R, Friedmann A, Adams J, Fullerton B, et al. (2005) Proton radiotherapy for orbital rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons. Int J Radiat Oncol Biol Phys 63(4): 1161-1168.
- Orbach D, Brisse H, Helfre S, Freneaux P, Husseini K, et al. (2003) Effectiveness of chemotherapy in rhabdomyosarcoma: example of orbital primary. Expert Opin Pharmacother 4(12): 2165-2174.
- Abramson DH, Fass D, McCormick B, Servodidio CA, Piro JD, et al. (1997) Implant brachytherapy: a novel treatment for recurrent orbital rhabdomyosarcoma. J AAPOS 1(3): 154-157.
- Chan WM, Liu DT, Pang CP, Lam DS, To KF, Choi PC, et al. (2005) Pediatric malignancies. Case 1: hypermethylation in orbital alveolar rhabdomyosarcoma. J Clin Oncol 23(21): 4790-4791.
- Rootman J (2003) Diseases of the orbit: a multidisciplinary approach. Lippincott Williams and Wilkins, Philadelphia. 54: 262-268.
- Sun XL, Zheng BH, Li B, Li LQ, Soejima K, et al. (1990) Orbital rhabdomyosarcoma. Immunohistochemical studies of seven cases. Chin Med J(Engl) 103(6): 485-488.
- Mazzoleni S, Bisogno G, Garaventa A, Cecchetto G, Ferrari A, et al. (2005) Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 104(1): 183-190.
- Chisholm JC, Marandet J, Rey A, Scopinaro M, de Toledo JS, et al. (2011) Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29(10): 1319-1325.