【摘要】 目的：评价肿瘤的位置、大小、组织学以及复发率。
方法： 前瞻性研究 Larkana的Chandka医学院附属医院眼科的53例组织学诊断为视网膜母细胞瘤患者，肿瘤侵及眼球、眼眶、颅内以及其他组织。 为研究肿瘤广泛性，检查包括：眼眶X线片，眼球B超，眼眶及头颅CT扫描/MRI，全骨扫描，胸部前后位X线片，腹部B超，腰椎穿刺，全血细胞计数，包括肝肾功能检查的血生化，根据肿瘤的位置、大小、复发及转移选择包括手术、局部放疗、系统化疗的治疗方案。有局部和系统转移的患者 ，由Larkana 的核医学和放疗机构的肿瘤专家进行局部放疗和系统化疗。术后1, 3 , 6，12mo复查随访，随后5a及5a以上，1a复查一次。评估肿瘤的位置、大小、组织类型和复发率。结果：患者53例，年龄8mo～8岁。男25例 (47%)，女28例 (53%)。肿瘤的眼别，左眼25例 (47%)，右眼19例(36%)，双眼 9例 (17%)。患者的首发症状，斜视3例(6%)，假性眼内炎4例 (8%)，眼眶炎性假瘤 6例 (11%)，转移性包块7例(13%)，蕈样生长的包块 8例 (15%)，白瞳征12例(23%)，眼眶浸润13例(25%)。行单纯眼球摘除术19例(36%)，行眼球摘除及改良型眶内容物剜除术并局部放疗和系统化疗 19例(36%)，行眼球摘除及完全型眶内容物剜除术并局部放疗和系统化疗15例 (28%)。肿瘤的组织类型，含大量染色质的高分化视网膜母细胞瘤25例(47%)，高度未分化视网膜母细胞瘤28例(53%)。首次手术后，由于手术切除点以上视神经受累，眼眶浸润和系统转移，发生复发和转移 37例 (70%)。结论：儿童红眼或白瞳征在确诊之前应怀疑视网膜母细胞瘤，应该及时经眼科专家检查，因为患者在肿瘤初期的早期表现提示会降低肿瘤的扩散、复发和死亡率。
【关键词】 晚期症状；视网膜母细胞瘤；挑战
INTRODUCTION
Retinoblastoma is the most common primary intraocular malignancy of childhood. The cell of origin is uncertain, but the malignant cell is probably derived from either primitive photoreceptor or other neuroectodermal cells. Retinoblastoma can develop as a result of a sporadic somatic mutation in retinal cells or as a germinal mutation, which can be inherited as an autosomal dominant with marked penetrance. Approximately 60% of cases are of nonheritable type, while 40% are of the heritable type[1]. The mean age at diagnosis for retinoblastoma is 18 months, with bilateral cases being found earlier (mean age of 12 months) than unilateral tumors (mean age of 24 months), incidence 1 in 20 000 live births with no sexual predilection[2]. Leukocoria, strabismus and inflammation are the initial signs in over 75% of cases. Parents most often note a "cats eye reflex", or leukocoria. Strabismus is another common presentation for retinoblastoma and esotropia is more common than exotropia. Both are due to either tumor or detachment diminishing central vision, usually from macular or optic nerve involvement. Orbital extension shows progressive proptosis, lid swelling and ecchymoses[1]. A major biologic characteristic of retinoblastoma, like all other malignancies, is the ability to invade and spread. Depending on the site of the primary lesion, retinoblastoma may spread by means of the choroids to the adjacent orbital structures, by the optic nerve (particularly when the origin is peripapillary) to the central nervous system; and by the vascular system to distant metastatic sites. CT scan and B scan reveals intraocular calcification and also extension of the lesion. Histopathology shows sheets of small dark cells with hyper chromatic nuclei and FlexnerWintersteiner rosettes bordered by areas of necrosis[3]. The lesions that most closely simulate leukocoria are cataract, coats disease, persistent hyperplastic primary vitreous (PHPV), retinal dysplasia, and retinopathy of prematurity. Approximately 95% of unilateral retinoblastomas are large enough to require the involved eyes to be enucleated. If the tumor is very small (4mm size), treat a posterior lesion with xenon arc photocoagulation, and an anterior lesion with cryotherapy. In slightly larger lesions (6mm) a radioactive plaque is used. Further management following enucleation for retinoblastoma is based on the presence or likelihood of extraocular spread as determined by biopsy of the globe especially beyond the line of transection of the optic nerve. The therapy consists of adjuvant combined chemotherapy with local orbital and central nervous system radiation if CNS spread is confirmed[4].
MATERIALS AND METHODS
Subjects We evaluated 53 patients with histological diagnosis of retinoblastoma involving the eye, orbit, intra cranial cavity and systemic tissues, at Department of Ophthalmology, Chandka Medical College Hospital, Larkana. To assess the extent of the tumor, various investigations, including, Xrayorbits, BScan, CTscan/MRI orbitsbrain, whole body bone scanning, Xray chest PA view, ultrasound abdomen, lumbar puncture, complete blood cell count, blood chemistry assessment, including renal and hepatic function parameters were performed. The selection of mode of treatment like surgical procedures, local radiotherapy and systemic chemotherapy used depend on the site, size, recurrence and metastasis of the tumor. The patients with local and systemic metastases were referred to the oncologist at larkana Institute of the nuclear medicine and radiotherapy for local radiation and systemic chemotherapy. Follow up examinations were carried out at 1, 3, 6 and 12 months after the operation, and then annually for evaluation of recurrence.
Treatment The surgical procedures performed were enucleation alone in 19 (36%) cases, enucleation with modified exentration followed by local radiotherapy and systemic Chemotherapy in 19 (36%) cases and enucleation with total exentration followed by local radiotherapy and Systemic Chemotherapy in 15 (28%) cases. The dose of local radiotherapy: 4000 Gr cycles in divided doses. The dose of systemic chemotherapy (cycles given intravenously combined on the 0,3,6,9,12,15,18 and 21 weeks respectively): cyclophosphamide 40mg/kg,doxorubicin 0.67mg/kg, vincristine 0.05mg/kg.
RESULTS
Total 53 patients were included in this study. The age range was from 8 months to 8 years. 25 (47%) cases were male and 28 (53%) were female. Twenty five (47%) cases were suffering from tumor in the left eye, 19 (36%) were suffering from the tumor in the right eye and 9(17%) were suffering from the tumor in both eyes. 19 patients (36%) presented earlier, with 12 had leukocoria, 4 pseudohypopyon, 3 had strabismus on presentation. Thirtyfour (64%) patients had late presentation (Table 1). Nineteen (36%) patients were operated for enucleation, another 19 (36%) were operated for enucleation with modified exentration, and remaining 15 (28%) were enucleated with total exentration. The histological types of the tumor were welldifferentiated retinoblastoma with abundant FlexenerWintersteiner rosettes in 25 (47%) cases and highly undifferentiated retinoblastoma 28 (53%) cases. After primary surgery, the recurrences and metastases of the tumors were noticed in 37 (70%) cases due to optic nerve involvement beyond the point of surgical transaction, orbital invasion and metastasis.Table 1 Presentation of the patients with retinoblastoma（略）
DISCUSSION
Orbital tumors are the major cause of displacement of the eyeball (proptosis). Among the orbital tumors, the incidence of retinoblastoma is very high. Retinoblastoma is the most common primary intraocular tumor of children[5] and is responsible for approximately 5% of blindness in children and 1% of death in infancy[6]. It is also the most common ocular and orbital tumor in Pakistan[7]. In our study, out of 125 primary malignant orbital tumors, 53 (42%) cases were retinoblastomas. Also in our study, there was no evidence of direct hereditary transmission of the disease from the patient to the offspring may be due to early death of most of patients in our setup. In our study most of the patients were presented too late, 34 (64%) cases with eye and orbital fungating mass (Figure 1), the secondaries to the regional lymph nodes (Figure 2), orbital bones cranial cavity(Figure 3), proptosis (Figure 4), pseudo orbital inflammation (Figure 5), leukocoria(Figure 6), pseudohypopyon (Figure 7). In 6 cases the lesion was seen in other eye during examination under general anesthesia.
Although surgical intervention remains the definitive therapy for unilateral retinoblastoma[8] and has close to a 90% cure rate in the absence of metastasis[9], there is clearly a need to develop therapies for bilateral retinoblastoma that spare the eye and any visual function it may retain. Local control using cryotherapy or laser photocoagulation may meet this need but can only be used when the tumor is small or when vitreous tumor seeds are absent[10,11]. Externalbeam radiation therapy is useful occasionally in the treatment of vitreous tumor seeds but is accompanied by high morbidity including radiation retinitis, closed angle glaucoma, and second malignancies in the field of radiation in patients with constitutional mutations of the retinoblastoma gene[12].
In line with the treatment recommended by Sheild et al[13]we performed enucleation alone where retinoblastoma fills most of the eye, especially when there is a concern for tumor invasion in to the optic nerve or choroids. While enucleation with exentration followed by radiotherapy and or chemotherapy in patients who has very late presentation such as eye and orbital invasion, eye and orbital fungating mass and associated with metastasis to orbital bones, central nervous system, regional lymph nodes, liver or haemopoetic system.
External beam radiotherapy and enucleation can now be avoided in most cases of ReeseEllsworth groups I (minimal disease) through IV (moderate disease) retinoblastoma[13]. The most advanced stage of retinoblastoma, ReeseEllsworth group V, continues to provide the greatest difficulty for management, and external beam radiotherapy and enucleation are often employed in addition to chemoreduction to save the childs life.
In our study patients with CNS involvement from retinoblastoma are virtually incurable with any treatment strategy. Even though the chemotherapy regimens prescribed in our study included drugs with proven penetration to the CNS such as cyclophosphamide with a dose of 40mg/kg. Other drugs such as doxorubicin with a dose of 0.67mg/kg and vincristine with a dose of 0.05mg/kg. Systemic chemotherapy given intravenously combinedly on the 0,3,6,9,12,15,18 and 21 weeks respectively. We used local radiotherapy with a dose of 4000 Gr cycles in divided doses. Any child with red eye or white pupillary reflex should be suspected of having retinoblastoma, until proved otherwise, and should be promptly referred to an ophthalmologist because early presentation of patient in the initial stage of the tumor will result in decreased risk of tumor extension, recurrence and mortality.
【参考文献】
1 Char DH. Retinoblastoma diagnosis, in clinical ocular oncology .1st edition, Churchill Livingstone company, New York. 1989:189203
2 Kanski JJ. Tumors of the eye, In Kanski clinical ophthalmology, 3rd edition, 1994, ButterworthHeinemmann company, London 202232
3 Handerson JW. Miscellaneous tumors of presumed neuroepithelial origin, orbital tumors . Raven press, New York, 3rd edition 1994:239268
4 Rootman J. Metastatic and secondary tumors of the oribit.Diseases of the orbit . JB Lippincott company, London 1988:405460
5Asif M.Orbital masses incidence and clinical presentation. Pak J Ophthalmol 1998;14(4):149152
6 Cross HE, Hansen RC, Morow G, Davis JR. Retinoblastoma in a patient with a 13qxp translocations. Am J Ophthalmol 1977;84:548554
7 Islam ZU. Prevalence and clinical presentation of retinoblastoma in the NorthWest Frontier Province of Pakistan. Pak J Ophthalmol 1985;1:111122
8 Shields CL, Shields JA. Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus 1999;36(1):818
9 Tamboli A. Podgor MJ, Horm JW. The incidence of retinoblastoma in the United States: 1974 through 1985. Arch Ophthalmol 1990;108(1): 128132
10 Shields JA. The expanding role of laser photocoagulation for intraocular tumors. The 1993 H, Christian Zweng Memorial Lecture. Retina 1994;14(4):310322
11 Shields CL, Santos MC, Diniz W, Gündüz K, Mercado G, Cater JR, Shields JA. Thermotherapy for retinoblastoma. Arch Ophthalmol 1999;117(7):885893
12 Acland GM, Aguirre GD, Ray J, Zhang Q, Aleman TS, Cideciyan AV, PearceKelling SE, Anand V, Zeng Y, Maguire AM, Jacobson SG, Hauswirth WW, Bennett J. Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 2001;28(1):9295
13 Sheilds CL, Meadows AT, Leahey AM, Sheilds JA. Continuing challenges in the management of retinoblastoma with chemotherapy. Retina 2004;24(6):849862
来源：首席医学网 |
