259

Journal of Pediatric Genetics 3 (2014) 259–269 DOI 10.3233/PGE-14107 IOS Press

Pediatric genetic ocular tumors Behnaz Rouhania and Aparna Ramasubramanianb,∗ a Department b Moran

of Ophthalmology, Drexel University, Philadelphia, PA, USA Eye Center, University of Utah, Salt Lake City, UT, USA

Received 9 September 2014 Revised 15 September 2014

Abstract. Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome, and nevoid basal cell carcinoma syndrome. It is important to screen for ocular tumors both for visual prognosis and also for systemic implications. The phakomatosis comprise of multitude of benign tumors that are aysmptomatic but their detection can aid in the diagnosis of the syndrome. Retinoblastoma is the most common malignant intraocular tumor in childhood and with current treatment modalities, the survival is more than 95%. It is transmitted as an autosomal dominant fashion and hence the offsprings of all patients with the germline retinoblastoma need to be screened from birth. This review discusses the various pediatric genetic ocular tumors discussing the clinical manifestation, diagnosis and treatment. Keywords: Tumors, genetic, retinoblastoma, tuberous sclerosis, von Hippel-Lindau syndrome, neurofibromatosis, Gardner syndrome, Gorlin-Gotz syndrome, optic nerve glioma

1. Introduction Most cancers do not have a genetic basis but there are some cancer syndromes that are linked to a gene and are transmitted in a family. Retinoblastoma (Rb) is considered as the prototype of inherited cancers and the Knudson’s two hit hypothesis was developed based on observations on this tumor. Development of cancer can be a result of either activation of a proto-oncogene or a result of deactivation of a tumor suppressor gene (as occurs in the case of retinoblastoma). The phakomatoses are a group of congenital hereditary developmental anomalies that selectively involve tissues of ectodermal origin. These disorders usually affect the central nervous system, eye and skin to various degrees. The phakomatoses include neurofibromatosis (NF), tuberous sclerosis (TS), ataxia ∗ Corresponding author: Aparna Ramasubramanian, MD, Moran Eye Center, University of Utah, 65 Mario Capecchi, Drive, Salt Lake City, Utah, 84132, USA. E-mail: Aparna ramasubramanian@hsc. utah.edu.

telangiectasia, Sturge-Weber syndrome, von HippelLindau syndrome (VHLS), incontinentia pigmenti, nevoid basal cell carcinoma syndrome and WyburnMason syndrome. In this review, we will be discussing only the phakomatoses that predispose patients to benign or malignant tumors.

2. Rb Rb is the most common pediatric intraocular malignancy. It represents approximately 3% of all pediatric malignancies with an estimated incidence of 1 in 15,00020,000 live births resulting in approximately 9,000 new cases every year worldwide [1]. 2.1. Clinical features The presenting features of retinoblastoma are most often leukocoria (Fig. 1A) or strabismus [2]. The tumor appears as one or multiple yellow-white retinal

2146-4596/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

Downloaded by: NYU. Copyrighted material.

Accepted 12 October 2014

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

Fig. 1. (A) Exophytic retinoblastoma (Rb) presenting as leukocoria. (B) Intraretinal Rb tumor appearing as a yellow white retinal lesion. (C) Endophytic Rb with extensive vitreous seeding. (D) Ultrasound of a large Rb demonstrating multiple hyperreflective echoes suggestive of calcification.

lesions with a feeding retinal artery and draining vein (Fig. 1B). There is often surrounding subretinal fluid, subretinal seeds, or vitreous seeds (Fig. 1C). Rb growth patterns include intraretinal, endophytic, exophytic, and diffuse [3]. Intraretinal Rb is limited to the retina and appears as a white nodular thickening (Fig. 1B). Endophytic Rb is characterized by fluffy vitreous seeding overlying the retinal mass (Fig. 1C). Exophytic Rb produces a retinal detachment surrounding or overlying the mass [4] (Fig. 1A). 2.2. Genetics Rb originates from germ line and/or somatic mutations that inactivate both alleles of the RB1 gene located on chromosome 13q14. The most common chromosomal abnormalities detected in Rb are deletions at 13q14 [5]. Rb was the first disease demonstrating a genetic basis for cancer development initiated by bi-allelic inactivation of the RB1 gene [6]. Another genetic form of Rb has been discovered, which was initiated by amplification of the MYCN gene. The inherited form of Rb can result in tumors either unilateral or bilateral, whereas the non-heritable form leads only to unilat-

eral tumors. All bilateral Rbs are inherited and tend to present at an earlier age. All inherited Rbs result from bi-allelic RB1 inactivation; the first RB1 mutation (M1) is constitutional, and the second mutation (M2) occurs somatically in one or more retinal cells [7]. Constitutional mutation of the RB1 gene predisposes individuals to second cancers later in life, such as osteosarcoma, fibrosarcoma and melanoma [8]. The heritable nature and second cancer susceptibility associated with Rb translates into a need for life-long follow up, such as genetic testing and counseling for families and offspring to determine heritable risk and to monitor for and treat second cancers [9]. 2.3. Imaging Rb is primarily diagnosed by funduscopy and ultrasound, which typically demonstrates an intraocular vascularized and calcified mass (Fig. 1D). Computed tomography (CT) scan can be useful to identify calcification (which is seen in 90% of cases) but is avoided due to the risk of radiation. Magnetic resonance imaging (MRI) is primarily employed to image the pineal and suprasellar region. Patients with bilateral Rb have

Downloaded by: NYU. Copyrighted material.

260

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

2.4. Treatment Several classifications of Rb have been employed to assist in prediction of globe salvage. The Reese Ellsworth classification was conceived in the 1960 s during the era when external beam radiotherapy was commonly used for treatment. The International Classification of Rb (ICRB) was introduced in 2003 to more simply and appropriately identify the disease staging during the era of chemoreduction for Rb [11]. The treatment options for Rb include [12–15]: (a) Local therapy; photocoagulation, transpupillary thermotherapy or cryotherapy, (b) Chemotherapy; chemotherapy could be; (1) Local like subtenon or intravitreal, (2) Intraarterial (chemotherapy delivered to the ophthalmic artery following catheterization of the femoral artery),and (3) Systemic, (c) Radiation therapy; plaque radiation therapy or external beam radiation therapy, (d) Enucleation, (e) Exenteration is required in orbital Rb, Rb is a curable cancer. If detected while still occupying the globe and without optic nerve, choroid, or scleral invasion, the child will nearly always survive with appropriate treatment. Enucleation could be a straightforward method to long-term safety. Of course, not all Rbs require enucleation. The treatment is tailored to each patient depending on the age, laterality, family history, location, and extend of tumor. The tumor requires close monitoring till at least 3 yr following therapy and all these children need life long monitoring for recurrence and for occurrence of second cancers in patients with germline mutation. With current treatment modalities, the life prognosis is close to 95% in developed countries but unfortunately in underdeveloped countries the mortality is still very high secondary to delayed diagnosis and insufficient access to health care. 2.5. Systemic implications Patients with unilateral or bilateral Rb infrequently may develop an additional intracranial neuroblastic

tumor, usually in the pineal gland, which characterizes the trilateral Rb (TRb) syndrome. The origin of intracranial tumors in Rb patients is still uncertain. The possibilities of tumor origin from ectopic foci of retinal cells in the floor of the third ventricle or from pineal photoreceptors, which are functionally and morphologically similar to retinal photoreceptors, have been suggested for pineal lesions [16]. Postlaminar optic nerve invasion is considered to be one of the most important risk factors for metastasis [17]. Also patients with germline mutation are at increased risk for second cancers of which the most common ones are osteosarcoma, fibrosarcoma and melanoma.

3. TS TS is a disease with multiple organ involvement. It is characterized by astrocytic tumors of the central nervous system (CNS), seizures, retinal astrocytic hamartoma, cutaneous lesions and mental retardation. The prevalence of TS in the general population is approximately 1 case per 10,000 persons. About two thirds are sporadic and one third of cases are familial with no racial predilection. Males and females are affected equally. Signs and symptoms of TS usually begin by 6 yr of age [18]. The retinal astrocytoma is a benign neoplasm that arises from astrocytes of the sensory retina. In patients with tuberous sclerosis, these lesions are most commonly multifocal and bilateral. In contrast, most unilateral, unifocal retinal astrocytomas occur as isolated lesions in patients who have no underlying systemic disorder [19]. 3.1. Genetics TS genes have been identified on loci on chromosome 9 (9q32–34), 11q, 16 (16p13), and 12 (12q22–24). Of these loci, the 9q32–34 locus has been the most consistent and is associated with about one third to one half of all familial cases [20]. 3.2. Clinical features TS is associated with benign cysts in various visceral organs, including the kidneys, liver, and lungs. The most distinctive visceral tumor in TS is the benign cardiac rhabdomyoma. The most common visceral tumor in TS is angiomyolipoma of the kidney. Cutaneous

Downloaded by: NYU. Copyrighted material.

a 10% risk of developing primitive neuroectodermal tumor (pineoblastoma or trilateral Rb). The utility of MRI is limited in assessing the extent of intraocular involvement and extraocular spread [10].

261

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

lesions include ash leaf spots, which are congenital white or hypopigmented skin macules ranging in size from about 1 mm to several centimeters in diameter resembling ash leaf [21]. The classic ophthalmic feature of TS is the retinal astrocytoma or astrocytic hamartoma (Fig. 2A). Approximately 50% of all patients with TS develop at least one retinal astrocytoma in one eye. In the individuals who have TS and develop retinal astrocytomas, multiple lesions in both eyes occur in 40–50% of cases. Astrocytoma of the retina tends to arise early in life and is frequently detected during childhood or adolescence. However, some lesions are not noted until adulthood. Malignant transformation may happen but is rare. Shedding of tumor cells into the overlying vitreous has been reported in a few cases [21]. The retinal astrocytoma usually appears as a white, superficial retinal lesion. It may present as a faint translucent intraretinal patch or a nodular, whitish deeper lesion or as a dense calcified mulberry-like tumor. These three types may present simultaneously. These lesions are vascularized from the retina, and they can arise from any location. However, the postequatorial location is more common. Patients usually have no visual symptoms unless the tumor involved the macula. 3.3. Diagnosis Systemic evaluation of individuals with suspected TS includes fundus examination, dermatological evaluation to identify characteristic skin lesions, CT or MRI of the brain and abdomen. Clinical diagnosis is primarily based on recognition of the characteristic fundus features. Fluorescein angiography of a classic retinal astrocytoma typically shows relatively slow filling of the vasculature of the lesion, absence of dilated afferent and efferent retinal vascular channels, and limited late staining of the tumor. Isolated retinal astrocytomas characteristically have prominent surface vascularity, which helps differentiate these lesions from amelanotic choroidal melanomas that have retinal invasion [19]. Optical coherence tomography (OCT) is also helpful in diagnosis of these lesions. OCT of the smaller lesions can show the tumor to be limited to the inner retina and sometimes reveals subtle retinal lesions not clear on ophthalmoscopy. CT and MRI can reveal characteristic CNS lesions of tuberous sclerosis. Occasionally, fine-needle aspiration biopsy can help to establish

the diagnosis of an atypical retinal astrocytoma [22]. Retinal astrocytoma shares some characteristics with Rb, toxocara granuloma and amelanotic choroidal melanoma. 3.4. Prognosis The life expectancy of patients with TS is reduced compared to the normal population. The most common cause of early death is renal failure secondary to angiomyolipomas. The second most common cause of death is obstructive hydrocephalus or any CNS involvement, causing enlargement of one or more of the CNS astrocytomas. Astrocytomas of the retina usually remain stable or enlarge to a limited extent during long-term follow-up. These tumors have extremely limited malignant potential and do not metastasize. Lesions adjacent to the foveola may result in progressive retinal degeneration and vision loss [23]. However, in most cases, retinal astrocytoma is associated with normal visual acuity. 3.5. Treatment Most of the retinal astrocytomas require no treatment. For patients whose intraocular tumor enlarges progressively and causes blind, painful eye, enucleation seems to be the only effective treatment [24]. Some retinal astrocytomas associated with secondary retinal detachment have been treated successfully by photodynamic therapy, with stabilization or partial regression of the tumor and partial to complete resolution of the retinal detachment [25]. Radiotherapy by plaque or charged particle beam has not been shown to be effective in most cases. Inhibitors of the mTOR (serine/threonine protein kinase) biochemical signaling pathway have shown some promise in controlling progression of central nervous system tumors associated with tuberous sclerosis; however, no beneficial impact of this therapy has been reported to date [26].

4. Gardner syndrome and congenital hypertrophy of the retinal pigment epithelium (CHRPE) CHRPE is a flat and well-defined lesion of the retinal pigment epithelium (Fig. 2B). It is almost always benign and asymptomatic and its prevalence in the normal population is 0.3–40% [27]. Multifocal, unilateral

Downloaded by: NYU. Copyrighted material.

262

263

Fig. 2. (A) Astrocytic hamartoma in a patient with tuberous sclerosis. (B) Congenital hypertrophy of retinal pigment epithelium. (C) Large caf´e-au-lait spot. (D) Magnetic resonance imaging showing a large optic nerve glioma.

clustered lesions are the most common type, occurring in about 1% of individuals. Unilateral, unifocal CHRPE lesions are slightly less common, seen in about 0.5% of individuals. Individuals of both genders are affected equally with no racial predilection. Any new or bilateral CHPRE-like finding should raise the suspicion for familial adenomatous polyposis (FAP). The sensitivity of this finding in FAP ranges from 65 to 84% and the specificity greater than 94%. In fact, some studies showed 100% specificity when multiple bilateral CHRPEs are present [28]. Multiple bilateral CHPRE lesions have also been reported in patients with other polyposis syndromes including Turcot’s syndrome and Gardner syndrome (GS). Typical, unifocal, unilateral CHRPE lesions and the lesions of grouped pigmentation are not linked to any of the FAP syndromes. Patients with colorectal cancer have a higher incidence of CHRPE than healthy controls (19.5 versus 7.5%). In FAP, multiple precancerous colonic polyp usually become evident at a mean age of 16 yr. By age 35 yr, 95% of patients have polyps [29]. GS is a sub-

group of FAP with extracolonic manifestations, such as pigmented ocular fundus lesions that resemble congenital hypertrophy of the retinal pigment epithelium. GS is an autosomal dominant variant of colorectal polyposis with complete penetrance. It is distinguished from the other polyposis syndromes by its delayed age at onset, the number of polyps, and its extracolonic manifestations. The presence of epidermal cysts, bony osteomas, dermoid tumors, and dental anomalies are distinguishing features of this syndrome. 4.1. Ocular manifestations CHRPE lesions are usually asymptomatic and are noted incidentally during dilated fundus examination. The typical unifocal CHRPE is a grayish, well-defined, round to oval shape ranging from 0.1-2.00 mm in diameter. They may become partially hypopigmented with aging, developing the intralesional atrophic foci known as lacunae that tend to enlarge and coalesce over the years [30]. Most lesions are located in the peripheral

Downloaded by: NYU. Copyrighted material.

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

fundus, temporally. Rarely they may appear white in clusters and are referred as bear tracks. The CHRPE lesions in patients who have familial colonic adenomatous polyposis syndrome tend to be irregularly shaped, multifocal, widely separated rather than clustered, and are usually bilateral [31]. 4.2. Diagnosis No ophthalmic diagnostic studies are necessary. However, further diagnostic studies should be considered if any of the following is suspected: (a) (b) (c) (d)

Massive gliosis of retina, Combined hamartoma of retina, Melanotic choroidal nevus or melanoma, Syndrome of bilateral diffuse uveal melanocytic proliferation associated with systemic carcinoma, (e) Adenoma or adenocarcinoma of retinal pigment epithelium, (f) Metastatic melanoma to retina.

4.3. Genetics GS, Turcot’s syndrome, and FAP are different variable phenotypic expressions of the same genotypic disorder. The gene for familial colonic adenomatous polyposis is localized to chromosome 5q21-q22. The precise site of gene mutation seems to correlate with the presence or absence of CHRPE lesions. Most of the affected individuals have multiple lesions in both eyes [32]. About a third of families who have FAP do not have CHRPE lesions. Any individual with multifocal, bilateral hypertrophy of the retinal pigment epithelium, family history should be reviewed and comprehensive colonic evaluation needs to be arranged. 4.4. Treatment No treatment is necessary for these retinal lesions. Fundus photographs and periodically monitoring for enlargement of these lesions or any other changes are recommended.

lium has been reported to arise from several classic CHRPE lesions, but this is not common [33].

5. Neurofibromatosis NF consists of type 1 and 2 with phenotypic overlap. Both have autosomal dominant inheritance and are characterized by neuro-ectodermal tumors that arise in multiple organs. NF is the most common phakomatosis, affecting approximately 1 case per 3,500 persons in the general population. NF-1 is the more common of than NF-2, affecting approximately 1 person per 3,500–4,000 people in the general population. NF-2 affects no more than 1 person per 40,000–50,000 people. There is no racial predilection for either type of the disease and men and women appear to be affected with equal frequency. Many features do not appear until late childhood or early adulthood. The severity of the syndrome varies. Many patients who have limited forms of NF are probably not identified [19]. The gene for NF-1 is localized to chromosome 17q11, and that for NF-2 is localized to chromosome 22q12. 5.1. Systemic manifestations NF-1 known as peripheral NF or von Recklinghausen’s disease, is characterized by cutaneous caf´e-au-lait spots (Fig. 2C), axillary and inguinal freckling, Lisch nodules, cutaneous neurofibromas, optic nerve gliomas (Fig. 2D), and neurofibromas. Six or more caf´e-au-lait spots larger than 1.5 cm in diameter are generally considered diagnostic of NF-1. Axillary and inguinal freckling are present in 90–95% of affected individuals. Subcutaneous neurofibromas in NF-1 tend to arise in multiple locations and can be either nodules or diffuse plexiform lesions [34]. NF-2 or central NF is typified by bilateral vestibular schwannomas (acoustic neuromas) and neurofibromas, meningiomas, gliomas, and schwannomas. The most consistent extraophthalmic problem suffered by patients affected by NF-2 is sensorineural deafness caused by the vestibular schwannomas. 5.2. Diagnostic criteria for NF-1

4.5. Prognosis Most CHRPEs enlarge minimally if at all over period of time. Adenocarcinoma of the retinal pigment epithe-

Six or more caf´e-au-lait spots, 1.5 cm or larger in postpubertal individuals or 0.5 cm or larger in prepubertal patients, two or more neurofibromas of any type

Downloaded by: NYU. Copyrighted material.

264

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

or one or more plexiform neurofibroma, freckling in the axilla or groin, optic nerve glioma, two or more Lisch nodules of the iris, a distinctive bony abnormality such as scoliosis, dysplasia of sphenoid bone, dysplasia or thinning of long bone cortex and/or a first-degree relative with NF-1.

265

bromas, and optic nerve gliomas occur occasionally but are not generally present. The most consistent ocular findings in patients who have NF-2 are combined hamartomas of the retina and juvenile posterior subcapsular or cortical lens opacities. 5.5. Systemic evaluation

5.3. Diagnostic criteria for NF-2

5.4. Ocular manifestations Ophthalmologic findings in NF-1 are subcutaneous pedunculated and plexiform neurofibromas of the eyelids, optic nerve gliomas, Lisch nodules of the iris, choroidal nevi. Lisch nodules have been described as melanocytic hamartomas of the iris stroma. These lesions appear as tan nodules that stud the iris surface They tend to develop in the second to third decade of life in over 95% of persons who have NF-1. Histopathologically, Lisch nodules consist of spindle-shaped melanocytes or closely packed dendritic lesions within the anterior layers of iris stroma. These lesions are not nevi as they are normal uveal melanocytes. Some patients develop multifocal choroidal melanocytic nevi bilaterally, and these patients appear to have an increased cumulative lifetime risk for the development of a uveal melanoma. Neurofibromas of the eyelids can be either nodular or plexiform. They usually develop early in life and can enlarge progressively. Gliomas of the optic nerve develop in 10–15% of affected patients. They can occur either unilaterally or bilaterally and frequently involve the optic chiasm. Optic nerve gliomas in the orbit result in progressive proptosis and optic atrophy and frequently cause blindness [35]. Those that involve the brain and the chiasm can cause bilateral visual loss as well as intracranial mass effects. Patients with NF-1 may have pulsating exophthalmos caused by anomalous development of the sphenoid bone. Congenital and infantile glaucoma is common in patients who have this syndrome. Ophthalmologic findings in NF-2 are relatively uncommon. Lisch nodules of the iris, eyelid neurofi-

The basic diagnostic evaluation for patients with NF should consist of a complete history and comprehensive physical examination, including an ophthalmic examination. CT and MRI should be performed. 5.6. Treatment Optic nerve glioma or pilocytic astrocytomas, account for up to 10% of all intracranial neoplasms in adults and children. The majority of these cases are diagnosed during the first two decades of life. Women are affected as often as men. Many gliomas that infiltrate the chiasm also involve the hypothalamus. Up to one third may be associated with NF-1. Gliomas in adults tend to be more malignant. Eosinophilic hyalinization of apparently degenerated neuroglial cells may form elongated structures, called Rosenthal fibers. The benign tumors are more common in children, are distinct from the aggressive, malignant glioblastoma multiform that involves adults. The treatment of optic chiasmatic-hypothalamic gliomas remains controversial. Patients with gliomas that involve the chiasm alone have a mortality of 28% due to invasion to the hypothalamus or third ventricle. Invasion of the hypothalamus or third ventricle dramatically increases the mortality rate to more than 50% over 15 yr [36]. Surgical interventions would not be the definitive treatment for these tumors once there is chiasmal. Shunts are of benefit when hydrocephalus is present, and hormone replacement is indicated in patients with endocrine dysfunction. Chemotherapy for progressive chiasmal gliomas has shown promise. Radiotherapy may be considered in children over the age of 5 yr if chemotherapy has been ineffective and progression occurs [36]. 5.7. Prognosis Life expectancy is reduced substantially in patients with NF. The common causes of early death in patients with NF-1 are expansive growth of benign intracranial neoplasms and cancers [37]. Different types of cancer

Downloaded by: NYU. Copyrighted material.

A first-degree relative with NF-2, bilateral, vestibular schwannomas (acoustic neuromas), unilateral, vestibular schwannoma appearing before age 30 yr, any meningioma, glioma or schwannoma, juvenile posterior subcapsular lens opacities, juvenile cortical cataract and retinal hamartoma.

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

including neurofibrosarcoma, sarcomas, leukemia, and lymphoma, occur with increased frequency in patients who have NF-1. In patients with NF-2, the main cause of early death is expansion of a CNS neoplasm. Unilateral or bilateral blindness occurs in some individuals affected by NF-1 or NF-2, usually because of glioma of the optic nerves or chiasm (especially in NF-1) but occasionally because of intracranial growth of a vestibular schwannoma.

6. VHLS VHLS is a multi-organ disorder characterized by retinal capillary hemangiomas, CNS hemangioblastomas and various solid and cystic visceral hamartomas and renal cell carcinoma [38]. In the presence of autosomal dominant inheritance pattern, this disease runs in the family. VHLS affects both sexes equally and occurs in all racial groups. The gene is localized on chromosome 3p25-26. DNA testing is the best way to determine if an individual has VHLS. This syndrome is associated with risk of early death from intracranial hemangioma or renal cell carcinoma. The incidence is not clear. It usually presents by third decade of life. Capillary hemangiomas of the retina are usually the earliest detected manifestation of VHLS. CNS hemangioblastomas typically appear later followed by renal cell carcinomas. However, the timing of different organ involvement varies [19]. Renal cell carcinoma occurs in about 5% of VHLS patients by the age of 30 yr and in more than 40% by the age of 60 yr and is bilateral in 75% of the cases. Other neoplasms that may develop in some are pheochromocytoma, islet cell carcinoma of the pancreas, and adenomas or cysts in pancreas, ovaries or kidneys.

lary hemangioma is usually detected in only one eye of an otherwise healthy individual. Men and women are affected equally, without any racial predilection. The average age at initial detection is usually between 15 and 35 yr. The usual presenting symptom is blurred vision in the affected eye or loss of visual field. They appear as a reddish spherical lesion fed and drained by dilated tortuous retinal blood vessels. Intraretinal and subretinal exudation surrounding a retinal capillary hemangioma is common, particularly if the tumor size is more than 2-3 mm. An exudative retinal detachment may occur and frequently may lead to iris neovascularization and subsequently neovascular glaucoma. Some patients with one or more retinal capillary hemangiomas develop proliferative vitreoretinopathy. The vitreous membranes are usually strongly adherent to the hemangioma risking tractional retinal detachment [39]. Optic disc capillary hemangioma may also occur but not as common. Lesions usually have the reddish color of extrapapillary retinal capillary hemangiomas but less well defined. 6.2. Diagnosis and ancillary testing Fluorescein angiography of a typical retinal capillary hemangioma is helpful in diagnosis, showing rapid filling of the afferent artery and the retinal vascular tumor followed by intense hyperfluorescence of the vascular lesion with subsequent rapid filling of the efferent vein. An active retinal capillary hemangioma characteristically leaks fluorescein into the vitreous, often causing the late phase to be extremely hazy because of diffuse vitreous fluorescence. OCT is also very helpful in revealing the extension of retinal exudation and in monitoring the course of the disease.

6.1. Ocular manifestations

6.3. Baseline systemic evaluation

The classic ocular manifestation of VHLS is the retinal capillary hemangioma. About 50–60% of patients develop retinal capillary hemangiomas and about one half of these individuals have multiple retinal capillary hemangiomas in both eyes. The retinal capillary hemangioma is a benign vascular tumor that arises from the retina or optic disc. It may be multifocal or unifocal affecting one or both of the eyes. It tends to enlarge progressively, and it may lead to exudative or tractional retinal detachment. In the isolated form of the disease, a single retinal capil-

Individuals who have a family history of bilateral retinal capillary hemangiomas, vascular CNS tumors, or renal cell carcinoma have VHLS until proved otherwise. These individuals should undergo comprehensive evaluation for features of VHLS. Family members are recommended to have a complete ophthalmic examination. MRI of brain and spinal cord should be done every 3 yr to age 50 yr in the presence of CNS tumors and every 5 yr thereafter. Annual renal imaging should also be done at least every 3 yr or more frequently if multiple

Downloaded by: NYU. Copyrighted material.

266

B. Rouhani and A. Ramasubramanian / Genetic ocular tumors

6.4. Treatment The necessity for treatment depends on the nature, location and size of the lesion. Photocoagulation of the vascular tumor is commonly done. This treatment is particularly effective against tumors of about 2 mm or smaller. Involution and atrophy of the hemangioma is expected after this treatment. Cryotherapy is used for peripheral retinal capillary hemangiomas or larger post-equatorial lesions. Focal tumor irradiation using a radioactive plaque is usually helpful for medium- to large-sized retinal capillary hemangiomas located more than 3 mm from the disc. Irradiation beam is effective for juxtapapillary tumors [39]. Verteporfin photodynamic therapy has also been used to treat selected retinal capillary hemangiomas. This treatment may reduce exudative macular edema; however, it does not result in obliteration of the retinal hemangioma [40]. In patients with exudative or tractional retinal detachment associated with multiple retinal capillary hemangiomas, pars plana vitrectomy, membrane peeling and endophotocoagualtion of the tumor is usually required. Penetrating diathermy, transcleral tumor resection, and even transvitreal endoresection are the other alternatives that may be done [41]. 6.5. Prognosis Progression of retinal capillary hemangioma is highly variable. Tumor enlargement, intraretinal and intravitreal bleeding, exudation, gliosis, and retinal detachment may develop. These may result in profound visual loss or even phthisis bulbi. Some may remain stable for months to years. Ophthalmic treatment in a timely manner usually preserves good vision in at least one eye.

ectopic calcifications, facial dysmorphism, palmar and plantar pits, ophthalmic or neurological abnormalities may also be seen. Associated neoplasms are medulloblastoma, astrocytoma, menigioma and ovarian fibroma. The incidence is estimated 1 in 50,000 with no sex predilection [42]. 7.1. Genetics Gorlin-Goltz syndrome is also known as fifth phacomatosis. The gene involved in this disease is located on the long arm of chromosome 9 (q22.3-q31). Loss or mutations of human patched gene (PTCH1 gene) may also occur. About 20% to 40% of cases result from a de novo mutation of this gene [43]. Diagnosis is based upon presence of major and minor clinical and radiological criteria and confirmed by deoxyribonucleic acid analysis [42]. This disease usually affects patients between 17 to 35 yr of age. Early diagnosis of Gorlin-Goltz syndrome is important due to susceptibility of patients to develop multiple neoplasms in early age [44]. 7.2. Systemic implementation Major criteria include: more than two basal cell carcinoma or one in patient

Pediatric genetic ocular tumors.

Pediatric genetic ocular tumors include malignancies like retinoblastoma and phakomatosis like neurofibromatosis, tuberous sclerosis, von Hippel-Linda...
336KB Sizes 0 Downloads 6 Views