Retinoblastoma

Epidemiology

The retinoblastoma is the most common intraocular tumor in childhood, with an incidence of approximately one new case in 18–20,000 live births/year. Thus in Germany there are 60 new cases per year, 200 to 300 in the United States, ³ and worldwide there are some 5,000 to 8,000 new cases per year. ⁴

The incidence is very similar in all western countries. There is no predilection with regard to sex or ethnic origin. Since the tumor consists of primitive retinal cells, which as a result of differentiation disappear in the first few years of life, the vast majority of retinoblastomas occur before the fifth to eighth year of life. ⁴ Later manifestations are possible, but very rare. Within the last 100 years the mortality rate of retinoblastoma has decreased from 95% to below 5%. ¹ However, it must be emphasized that even today an untreated tumor is nearly always fatal as spontaneous regression occurs very rarely (see “Retinoma” below).

Symptoms

Leukocoria is a pathognomonic symptom indicating, among others, retinoblastoma ( ▶ Fig. 11.1). When an examination light is shone through the pupil, a red-orange reflection from a healthy ocular fundus is normal; a white-yellow reflection is caused by pathologic intraocular changes such as white retinoblastoma tissue. Due to the frequently associated visual impairment, secondary strabismus can occur. If the duration of these symptoms is unclear, the parents of affected children should be asked for old photographs from which to check whether a squint or leukocoria had been present before. In advanced stages of the disease, secondary glaucoma can occur. Because leukocoria is not present in every case of retinoblastoma, bilateral funduscopy (dilated pupil) should be carried out in every newly diagnosed case of strabismus in young children. Orbital extension with proptosis and a unilateral unresponsive pupil is a potential complication and carries a poor prognosis, especially in developing countries. Immediate investigation is strongly recommended to differentiate retinoblastoma from other sight threatening diseases such as congenital cataract, retinopathy of prematurity (ROP), idiopathic primary hyperplastic vitreous (PHPV), or Coats’s disease.

Depending on the symptoms and findings at initial presentation, an ophthalmologic and strabological examination (in case of strabismus) has to be made. A binophthalmoscopic funduscopy is mandatory. As retinoblastoma is most frequently diagnosed within the first 2 years of life (bilateral retinoblastoma is usually detected 10–12 months earlier than unilateral retinoblastoma because of bilateral symptoms) an urgent presentation in a specialized eye hospital for an examination under a general anesthesia with ultrasonography should be arranged if retinoblastoma is suspected. ⁵

Retinoblastomas can arise unilaterally or bilaterally, unifocally or multifocally. The growth pattern of retinoblastomas is either exophytic (i.e., under the retina), endophytic (i.e., in the vitreous chamber with secondary involvement of the anterior chamber), or mixed. Vitreous seeding can take place in an early stage of the disease, when the tumor is still rather small. In cases with diffuse infiltration of the vitreous or the aqueous humor (“pseudohypopyon”), these findings can be falsely interpreted as an intraocular inflammation. In this event an echography should be carried out. Intraocular calcifications give a hint for the diagnosis of retinoblastoma. In assumed retinoblastoma, intraocular biopsy should be avoided to prevent seeding of retinoblastoma tumor cells with considerable deterioration of the prognosis. If a retinoblastoma is suspected or confirmed, patient must be presented to a national reference center for the treatment of retinoblastoma (in Germany, e.g., the Department of Ophthalmology, University Hospital Essen).

Genetics

The genesis of retinoblastoma is triggered by the inactivation of both alleles of the retinoblastoma gene (RB1, chromosome 13q) in still-undifferentiated retinal precursor cells. About 45% of patients have a heritable form of retinoblastoma (heritable retinoblastoma); in ~55% of patients there is a nonheritable form, which frequently occurs unilaterally. ^{6,​ 7}

Investigation of the genetics of retinoblastoma was pioneered by A.G. Knudson in 1971. He was the first to describe the two-mutation theory, confirmed later by genetic studies. ⁸ According to this theory a new mutation of the RB1 gene (tumor suppressor gene, chromosome 13) occurs in the germ cells of one of the parents (germinal mutation). Thus all body cells carry the genetic mutation in the form of an inactivated allele. If, during the course of embryological development in the immature retinal precursor cells, the second allele is lost, then the development of retinoblastoma is the result. This is the reason for the bilateral appearance of heritable retinoblastoma. Multifocal tumor growth is typical.

In the nonheritable form of retinoblastoma both mutations required for tumor development occur in body cells (somatic mutation). Both mutations have to be present in the same cell. This being a very rare event, usually only one eye is affected with a predominantly monofocal growth pattern.

In heritable retinoblastoma, in family members usually both eyes are affected. ⁹ These members are at risk of passing on the mutated RB1 gene in ~50% to their offspring. However, with incomplete penetrance, the risk of developing the disease is lower. In some of these families, only unilateral and unifocal retinoblastomas occur as a result of reduced expression.

When a retinoblastoma has been conclusively diagnosed, genetic testing and counseling of the family must always be undertaken to identify the carriers of an RB1 gene mutation. Patients may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently.

The classification of retinoblastoma was elaborated in the decades after the Reese–Ellsworth classification was developed in the 1960s. As this classification does not contain a classic staging system, new classifications, such as the ABC classification, are now being developed that follow current therapeutic guidelines.

Trilateral Retinoblastoma

In approximately 5 to 10% of children with heritable retinoblastoma, a simultaneous pineoblastoma can develop. This rare event is associated with a very poor prognosis. Pineal gland cyst detected by MRI must be distinguished from these malignant tumors.

Retinoma

Retinoma or retinocytoma is a retinoblastoma that has spontaneously regressed. However, this condition is only found in ~2% of family members of children suffering from retinoblastoma. Clinically, this tumor presents like a retinoblastoma in regression. ⁹ Patients with a retinoma should likewise have regular clinical and ophthalmologic check-ups and be provided with genetic counseling.

Orbital Involvement of Retinoblastoma

The earlier the diagnosis of a retinoblastoma is made, the better the prognosis with respect to life expectancy and visual acuity. As in all malignant tumors, retinoblastoma bears the risk of tumor invasion and spread. Depending on the tumor’s location, it can spread into all areas of the eye, predominantly into the choroid, the ocular vessels, and the optic nerve. It should be noted that extraocular tumor growth via the posterior ciliary circulation or the other vascular systems is rather rare. Most often extraocular tumor growth occurs along the optic nerve. ¹⁰ Tumors that extend beyond the lamina cribrosa are usually associated with a poor prognosis. If there is evidence for optic nerve involvement after enucleation, further imaging and cytopathologic diagnosis is necessary including assessment of the cerebrospinal fluid. As well as the local tumor invasion into the orbit, there is a risk for distant metastases depending on the duration of the disease. Today the prognosis of the disease and the risk for other relatives to be affected can be determined by pathological and molecular genetic examination of fresh tumor specimen and of serological samples.

Treatment of Unilateral Retinoblastomas

Because of mild symptoms the diagnosis of unilateral retinoblastomas is often delayed, so that at the initial examination the disease can be in an advanced stage. Treatment options are mainly guided by the localization of the tumor or tumors and how the prognosis is assessed. Enucleation of the affected eye is the treatment of choice if the tumor is at an advanced stage with de facto blindness, or if the primary tumor has developed in such an unfavorable location that usable visual acuity cannot be achieved by another form of treatment. ⁵

An attempt of eye-saving treatment is indicated for solitary tumors, for those tumors in favorable location, and if an acceptable visual acuity can be preserved. Therapeutic approach consists of brachytherapy using ruthenium 106/rhodium 106, iodine 125, or iridium 192 plaques or of repeated photocoagulation and cryocoagulation of very small tumors. Treatment options should be discussed in detail with the parents of the patient.

Patients should be monitored lifelong with ophthalmologic and medical examination.

Treatment of Bilateral Retinoblastomas

Treatment of bilateral (heritable) retinoblastomas usually combines surgical and medical therapeutic approaches. Percutaneous radiotherapy, which was often carried out in earlier times, has been abandoned due to the high risk of subsequent neoplasms (such as osteogenic sarcoma) occurring at a later age. ⁵

Primary polychemotherapy in combination with local photocoagulation, transpupillary laser hyperthermia, or cryocoagulation can be associated with a higher recurrence rate. For this reason the treatment strategy must be determined in each case individually, according to the findings of both eyes, and discussed with the parents.

If seeding of tumor cells into the vitreous body of the more affected eye has occurred and this eye is virtually blind, attempts to preserve the eye are usually unsuccessful and primary enucleation is inevitable. However, if significant tumor regression can be expected following chemotherapy even in the more severely affected eye, and if there is the potential for visual improvement, enucleation can be postponed until final tumor regression can be assessed. If preservation of the eye and of a useful visual acuity is then an option, subsequent brachytherapy (e.g., ruthenium 106/rhodium 106) or treatment by adjuvant photocoagulation and/or transpupillary laser hyperthermia can be given.

In the less affected eye (i.e., the eye with better visual acuity), monitoring of the effect of polychemotherapy, followed by local therapy (brachytherapy, photocoagulation, etc.) if necessary, is justified. In all cases, however, close follow-up is mandatory as recurrences are to be expected.

Recently, at the Departments of Ophthalmology and Pediatrics at the University of Essen, Germany, a successful outcome to primary treatment was achieved in 75% of the eyes by administration of a chemotherapy regimen modified from an established protocol using cyclophosphamide, vincristine, etoposide, and carboplatin. Although tumors in categories A and B were controlled in 75% (of 56 eyes) and 85%, respectively, the failure rate was significantly higher (83%) in larger tumors of categories D/E. ¹¹ Recently, Abramson and coworkers from the Memorial Sloan Kettering Cancer Center in New York published the 2-year results of intra-arterial chemotherapy with melphalan, topotecan, and carboplatin (superselective intra-arterial chemotherapy, 76 eyes of 67 patients). ¹² With this therapeutic approach the rate of enucleation could be significantly reduced and eyes could be salvaged in 83%.

Treatment of Retinoblastoma with Orbital Involvement

Orbital involvement of a retinoblastoma is a rare occurrence in developed countries. A transscleral spread is regarded as an extraocular manifestation because the risk of a further spread of the tumor into the meninges, the brain, and the cerebrospinal fluid. The risk of distant metastases is significantly elevated, accompanied by a poor prognosis. There are no proven treatment protocols for orbital retinoblastoma. An individual multimodal therapeutic approach is needed. According to the recommendations of the National Cancer Institute in the United States, surgical treatment should be postponed until the response to polychemotherapy can be assessed. Further treatment options are surgery (enucleation of the eye, orbital exenteration), additional chemotherapy, and external beam radiation therapy (40–45 Gy). ¹³

Follow-ups and Prognosis

Once the treatment has been completed, regular ophthalmological and pediatric-oncologic check-ups should be performed (approximately on a 4-weekly basis, where applicable under general anesthesia). If a recurrence is diagnosed early, the tumor can be brought under control by means of local treatment. Depending on the findings and the age of the patient, the follow-up intervals can then be extended. Regular check-ups, however, should take place up to the fifth year of life. These should always include binophthalmoscopic fundus examinations. Additionally, in patients with heritable retinoblastoma, regular MRI follow-up images should be obtained in collaboration with the pediatric and radiological departments to exclude trilateral retinoblastoma.

As mentioned above, the chances of curing a retinoblastoma have dramatically improved over the recent decades due to the development of interdisciplinary treatment strategies and close controls. Today, through early diagnosis, adequate interdisciplinary therapy, and regular follow-ups, success rates of over 95% can be achieved.

Choroidal Melanoma

Epidemiology

Choroidal melanoma is the most common primary malignant intraocular tumor in adults. While it is extremely rare in blacks, the incidence in whites is between 6 (USA) and 8 (Scandinavia) new cases per year and 1,000,000 inhabitants. ^{5,​ 14} There is no clear gender predilection. Whereas females under the age of 40 years are affected more frequently, more males are affected in the older age group. ¹⁴ Choroidal melanoma is rarely found in children or young adults. The prevalence in patients under the age of 20 years is 1.1%. ¹⁵ From the fifth decade of life onward, choroidal melanoma occurs more often, reaching its maximum between sixth and eighth decades. Thus it is a typical, most commonly unilateral tumor of middle and older age.

Etiological factors for choroidal melanomas are unclear. In particular, risk factors for cutaneous melanoma (e.g., exposure to UV radiation) have not been shown to be significant for the development of choroidal melanoma. ^{16,​ 17,​ 18} The two tumors are distinct from each other. The risk for transformation of choroidal nevi into a choroidal melanoma depends on the prominence of the lesion (>2 mm), the presence of subretinal fluid, clinical symptoms, orange pigment, and tumor margins within 3 mm of the optic disc. ¹⁹ There are reports of isolated cases of higher familial clustering. Occupational and chemical exposure may increase risk in certain professions, ²⁰ as well as a presumed pathogenetic relevance of exposure to electromagnetic radiation. ²¹

Symptoms

The extent and course of the symptoms depend considerably on the location of the tumor and concomitant diseases. Melanomas located in the ciliary body and in the peripheral retina may remain without symptoms for a long time, whereas patients notice visual disturbances earlier if the macula is involved, due to direct tumor growth or serous detachment. Thus, peripheral melanomas are often discovered accidentally during a routine examination or at an advanced stage when either the optical axis is obscured or a compression-induced cataract develops. Often patients indicate only nonspecific symptoms of visual deterioration, while pain is not a typical complaint related to melanoma unless intraocular inflammation, extraocular growth, or neovascular glaucoma occur in advanced stages. There is previous history of malignancy in 6 to 10% of all patients with choroidal melanoma. Patients should therefore be asked whether they have had other neoplasms in the past. ¹⁴

Binophthalmoscopic funduscopy can be regarded as the standard procedure for diagnosis. More than 90% of choroidal melanomas can be identified with this technique ( ▶ Fig. 11.2). Typical characteristics are pigmentation on the tumor´s surface, “orange pigment,” and the occasional visualization of the tumor’s own vascular system as well as an accompanying serous detachment in melanomas with a prominence more than 3 to 4 mm. Dilatation and increased tortuosity of episcleral veins can be observed in peripheral melanomas, predominantly in the ciliary body. If a ciliary body melanoma is suspected, gonioscopy can help to evaluate whether the tumor has already infiltrated the iridocorneal angle. In ophthalmoscopy, and more so in ultrasound, a mushroom or collar-button shape of the tumor is pathognomonic. Unfortunately, however, there are melanomas that do not present this typical form.

Genetics

Usually choroidal melanomas are genetically homogeneous with specific cytogenetic aberrations. ¹⁴ Several studies have shown that these variations in the primary tumors influence their metastasizing potential. In some tumors monosomy of chromosome 3 has been demonstrated. ²² This particular chromosomal aberration correlates with a higher risk of distant metastases and with a poor survival rate. Today it is possible to predict this risk by means of molecular-genetic investigations and chromosomal analyses. ²³ It must be discussed whether patients wish the results of this analysis to be disclosed. ⁵

Diagnostics

In most cases clinically suspected choroidal melanoma can be confirmed by A- and B-mode ultrasonography. In A-mode-sonography choroidal melanomas demonstrate a typical medium to low internal echoes with sound attenuation as well as vascular pulsations. Whereas the measurement of the thickness can often be determined more precisely in A-mode sonography, B-mode sonography is advantageous to assess the dimensions of the tumor.

Further investigations such as fluorescein or ICG (indocyanine green) angiography or optical coherence tomography are only occasionally needed. Currently the role of magnetic resonance imaging for diagnosis has not been definitively clarified. It can be helpful in those cases, in which clinically and sonographically an older, prominent subretinal hemorrhage alone or camouflaging a melanoma cannot be differentiated from a melanoma alone.

Occasionally a transretinal biopsy of the tumor has to be performed, especially in amelanotic melanomas, which can mimic intraocular metastases or chorioretinal inflammatory processes. The risk of tumor cell seeding caused by the biopsy itself appears very low, ^{24,​ 25,​ 26} however, surgeons should refrain from transscleral biopsies of the tumor base. ⁵

Orbital Involvement of the Choroidal Melanoma

Melanomas can lead to orbital involvement by spreading via the emissary vessels and along the optic nerve. ²⁷ Extrascleral spread occurs in 10 to 15% of patients with choroidal melanoma, ¹⁰ associated with a significantly increased risk of distant metastases. Although fewer than 2% of patients have distant metastases at the time of diagnosis only, 40 to 50% of all patients will eventually die of distant metastases over the course of the disease. Most common sites of metastases are the liver (~90%), lungs (~24%), and bones (~16%). ²⁸ If metastases occur in the liver, the average survival time is about 6 months, with a chance of survival of 15 to 20% for 1 year and ~10% for 2 years. ^{29,​ 30} The prognosis is poor if extraocular growth and orbital involvement are present at the time of diagnosis (mortality rate between 73 and 81%). ³¹

Therapy

The earlier hypothesis that primary enucleation of the affected eye improves the survival rate of the patients was not supported by many studies. According to these studies there is no statistically significant difference for the survival rate among those patients being enucleated, with and without accompanying radiotherapy, ³² and those with primary enucleation or globe-preserving brachytherapy. ³³ Poor prognosis of choroidal melanoma is associated with multiple factors, such as older age at presentation, male sex, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, melanocytosis, extraocular tumor extension, advanced tumor staging, epithelioid cell type, high mitotic activity, higher microvascular density, higher expression of IGF-1 receptor and HLA-class-I- and -II, monosomy 3, and other factors. ³⁴ Depending on the size and location of the tumor as well as the prognosis in regard to visual acuity, eye-preserving treatment—if possible—should be discussed with the patient. However, the patient must be made aware that this form of treatment is more time-consuming and requires lifelong follow-up examinations.

A wait-and-see approach along with regular follow-ups is justified in patients with small tumors and suspected melanoma, depending on the localization and the clinical symptoms. If progression becomes evident treatment has to be initiated.

Treatment options in small tumors are photocoagulation, ³⁵ photodynamic therapy, ³⁶ transpupillary thermotherapy, ³⁷ and brachytherapy. ^{38,​ 39} Additional treatment options for tumors with a thickness of up to 6 mm is brachytherapy using ruthenium 106/rhodium 106, iodine 125, or palladium 103 plaques (cobalt 60, strontium 90, and cesium 131 have also been used), percutaneous radiation therapy with protons and helium ions, as well as the Leksell Gamma knife. ^{40,​ 41,​ 42,​ 43}

For tumors with a thickness exceeding 6 mm, iodine 125 applicators have to be used. Due to the greater thickness and the higher dose of radiation, a higher incidence of radiogenic complications such as optic nerve atrophy, cataract, secondary glaucoma, and radiation retinopathy have to be reckoned with when treating larger tumors. ^{44,​ 45} It is recommended that the scleral dose should not exceed 1,500 Gy. Further therapeutic options are transscleral local resection of the tumor in deep arterial hypotony as well as endoresection combined with adjuvant radiotherapy. ^{46,​ 47,​ 48} If an extraocular growth is suspected at the time of presentation, a combined radiotherapy and modified enucleation with tenonectomy or orbital exenteration should be planned depending on the nature of the extraocular growth (flat, nodular, suspicion of involvement of the vortex veins). ⁴⁹ If an extrascleral spread of the choroidal melanoma is discovered during the operation upon inspection of the enucleated globe, likewise a modified enucleation with tenonectomy and subsequent radiotherapy has to be carried out. A similar treatment modality is followed if extraocular involvement is not discovered until the histological examination of the enucleated eye.

Potential extension of the treatment with subsequent radiotherapy must always be discussed with the patient prior to surgery.

Follow-ups and Prognosis

Today’s operating procedures and radio-oncological methods enable better local tumor control. Despite these efforts, the survival rate of patients with choroidal melanoma has basically not changed over the last 30 years. If distant metastases develop or if they already exist at initial presentation, chemotherapy is the only therapeutic option. In spite of oncologic therapy, life expectancy in metastatic melanoma is about 6 to 9 months only. However, one should bear in mind that patients with asymptomatic metastases have a slightly longer survival time than symptomatic patients. Accordingly it should be discussed with the patient whether the limited benefits of chemotherapy outweigh the serious side effects and the reduced quality of life.

In those patients in whom local tumor control has been achieved, lifelong follow-examinations with oncologic check-ups (including ultrasonography of the liver) are recommended.

11.1.2 Intraocular Metastases

Epidemiology

In the United States, like in other western industrial countries, after heart disease (614,348 deaths), malignancies are the second most common cause of death (591,699 deaths). ⁵⁰ In the United States, there will be an estimated 1,685,210 new cancer cases with an estimated 595,690 cancer deaths in 2016. The most frequent cancer types are breast cancer with a total of 249,260 new cases per year and lung/bronchial cancer with a total of 224,390 new cases in 2016, followed by prostate (180,890 new cases/year) and colorectal cancer (134,490 new cases/year). ⁵¹ Estimated deaths in 2016 are 158,080 due to lung/bronchial cancer, 49,190 due to colorectal cancer, and 40,890 due to breast cancer. ⁵¹

The eye and its adnexa can be affected either by metastases of a distant primary tumor or by invasion of primary tumors from adjacent anatomical structures such as the paranasal sinuses, the eyelids, the surface of the eye, or the orbit. Most frequently ocular metastases occur by hematogenous tumor cell seeding. In rare cases the eye can also be involved indirectly in paraneoplastic syndromes or by toxic adverse effects from chemotherapy.

First descriptions of a choroidal metastasis ^{52,​ 53} were given by Horner (1864) and later by Perl (1872). In an evaluation of 8,712 cancer patients, Gottfredsen reported only 6 cases (0.07%) with choroidal metastases. ⁵⁴ Accordingly, in the first half of the 20th century the frequency of intraocular metastases was regarded as relatively low. However, by systematic examination of autopsy material, in the second half of the century a markedly higher incidence of intraocular metastases was found. In their pioneering histological examination of autopsy material from 230 patients with metastasizing carcinomas, Bloch and Gartner discovered choroidal metastases in 10% of cases. ⁵⁵ Four years prior to that, Albert and colleagues had found choroidal metastases in 2.0% (bronchial carcinoma) and in 7.7% (breast cancer) by ophthalmological examinations on 213 asymptomatic patients with known metastasizing tumors. ⁵⁶ The authors concluded that the risk of choroidal metastases is apparently higher than hitherto has been assumed in the literature. ^{56,​ 57} In further studies by Nelson and coworkers as well as by Eliassi-Rad et al, previous estimates of incidence rates could be confirmed (9.3% and 12.6%). ^{58,​ 59}

Most often (82%) intraocular metastases derive from carcinoma, whereas sarcomas are less frequently the primary tumors. ⁶⁰

Breast Cancer

Between 40 and 49% of all choroidal metastases are caused by breast carcinoma. ^{60,​ 61,​ 62} As would be expected, women are affected most often, whereas choroidal metastases in men caused by breast cancer are extremely rare. ⁶⁰

The risk of metastases to the choroid is lower than into other organs such as bones, brain, kidneys, and other internal organs. The incidence is reported to be 0.07 to 37%. ⁶³ The risk of intraocular metastases rises from 5% to 11% in asymptomatic patients if more than one organ contains metastases. ⁶⁴

Lung Cancer

The second most frequent primary tumor prone for intraocular metastasis is lung carcinoma. The prevalence varies between 14 and 30%. ^{60,​ 61,​ 62} The vast majority of patients are male (67.3%); ⁶⁰ of these, 78.3% are smokers. According to a study by Singh et al, adenocarcinomas are the most frequent cause of choroidal metastases, followed by squamous cell carcinomas and small cell bronchial carcinomas. ⁶⁵

Other Primary Tumors

Other primary tumors bearing the risk of ocular metastasis are neoplasms of the gastrointestinal tract (~4%), of the kidneys (~2–4%), of the skin (0–2%), and of prostate (1.3–3.6%), cutaneous melanoma (0–4.5%), as well as others (5–20.9%). ^{60,​ 61,​ 62}

In asymptomatic cancer patients (e.g., breast and lung cancer or other primary tumors) intraocular metastases may be discovered before the actual primary tumor is diagnosed. The ensuing search for tumor can finally lead to the diagnosis. Nevertheless, in their study of 420 patients with choroidal metastases, Shields et al. did not find a primary tumor in 17% of patients (73 of 520 eyes). ⁶⁰

Clinical Findings

The most frequent intraocular site of metastases is the uvea. Although the iris or the ciliary body is involved in 4–11% of patients, the vast majority of metastases arise in the posterior choroid (88 to >90%). ^{59,​ 60,​ 61}

Anterior Uvea (Iris and Ciliary Body)

Many primary tumors are able to metastasize into the iris and the ciliary body. Regardless of the histology of the primary malignancy, choroidal metastases appear relatively similar as yellowish-orange to brownish lesions, sometimes with exact margins, but often with unclear boundaries to the surrounding iris stroma ( ▶ Fig. 11.3, ▶ Fig. 11.4, ▶ Fig. 11.5). Metastases in the ciliary body and the iridocorneal angle can lead to a subsequent occlusion of epibulbar vessels. If congestion of scleroconjunctival vessels cannot be attributed to an extraocular disease, one should always search for an intraocular malignancy. In the initial stage of the disease this can quite often only be assessed by gonioscopy or ultrasound biomicroscopy. Occasionally metastases of the ciliary body, and even more so iris metastases, can be associated with symptoms such as an anterior chamber hematoma (hyphema), pseudohypopyon ( ▶ Fig. 11.6, ▶ Fig. 11.7), rubeosis iridis, anterior and posterior synechiae, displacement of the iridocorneal angle with ocular hypertension and uveitis.

Depending on the history and the age of the patient, there should be consideration of primary iris and ciliary body tumors such as amelanotic melanoma, iris cysts, or retinoblastoma; inflammatory diseases such as a granulomatous uveitis; and granulomas after foreign body injury.

Posterior Uvea (Choroid)

As mentioned earlier, in the vast majority of cases metastases occur in the posterior choroid. Although choroidal metastases occur more frequently than previously thought (5–9%), the majority of patients report a painless impairment of vision and defects in the visual field.

Irrespective of the underlying primary tumor most choroidal metastases are flat or slightly prominent and of gray-whitish to yellow-whitish and plaquelike appearance. They can occur monofocally or, quite often, multifocally or confluently, unilaterally or bilaterally; they usually exhibit only minimal pigment changes; and they are rarely associated with retinal or vitreous hemorrhage ( ▶ Fig. 11.8, ▶ Fig. 11.9, ▶ Fig. 11.10). In a study by Shields et al ⁶⁰ choroidal metastases were accompanied by an exudative retinal detachment in 73% of eyes. While even an extensive associated retinal detachment can remain without any clinical symptoms if located in the periphery, minimal accumulation of subretinal/intraretinal fluid in the center of the retina can lead to early visual deterioration. After regression of choroidal metastases, often lesions with fuzzy margins and overlying pigment epithelial changes or subretinal fluid remain funduscopically visible.

Differential diagnosis should include, among other possibilities, inflammatory diseases (e.g., granulomatous uveitis, chorioretinitis, Vogt–Koyanagi–Harada syndrome, Pneumocystis carinii infection) as well as osteoma, choroidal hemangioma, amelanotic melanomas, and nevi.

Optic Disc and Optic Nerve

Metastases of the optic disc/nerve are rather rare at ~4.5% of cases. ⁶⁵ Beside a primary involvement of the optic disc or the spread of a metastatic lesion from the choroid into the disc and into the optic nerve or, vice versa, an intraocular extension of a metastasis primarily located in the optic nerve to the disc is also possible. Shields et al observed an associated juxtapapillary choroidal lesion in 74% of eyes. ⁶⁵

Symptoms and the clinical picture are usually nonspecific. Hence many patients complain of a gradual, sometimes even acute deterioration of vision and visual field defects as well as of color vision disturbances. A relative afferent pupillary defect occurs quite often. Clinical signs are an edematous optic disc with flamelike hemorrhages and tortuosity of congested venous blood vessels ( ▶ Fig. 11.11, ▶ Fig. 11.12). In late stages, atrophy of the optic disc can develop.

Differential diagnosis comprises optic neuritis, acute anterior ischemic optic neuropathy, papilledema, optic disc drusen, and capillary hemangiomas.

Retina

Retinal metastases are extremely rare. They arise either by local infiltration of choroidal metastases or by direct hematogenous tumor cell seeding into the retina. Usually they appear as circumscribed, mostly whitish lesions, occasionally with accompanying retinal hemorrhages, adjacent vitreoretinal changes such as periretinal membrane formation, and vitreous body infiltration/hemorrhage, as well as traction and exudative retinal detachment ( ▶ Fig. 11.13, ▶ Fig. 11.14).

Retinitis, proliferative vitreoretinopathy with traction retinal detachment, and retinal vessel occlusions have to be considered in the differential diagnosis.

Vitreous Body

Tumor cell infiltration of the vitreous body can occur secondary to a ciliary or retinal metastasis. Also primary hematogenic tumor cell seeding of the vitreous body associated with, for example, skin melanoma or non-Hodgkin’s lymphoma have been described ( ▶ Fig. 11.15). Occasionally, secondary vitreous hemorrhages can occur after intraocular metastases.

Differential diagnosis may be challenging especially in those cases, where no involvement of other ocular structures is evident. Intravitreal inflammatory disorders such as endophthalmitis, posterior uveitis, or iridocyclitis should be considered. Sometimes a diagnostic vitrectomy with cytopathologic investigation of the vitreous cell aspirate may be mandatory in order to be able to make the correct diagnosis.

Metastases of the Conjunctiva, the Sclera, and the Eyelids

In rare cases (<1%) metastases can manifest in the conjunctiva; they usually present as yellowish-orange prominent lesions. Primary metastases of the sclera are extremely rare, but the sclera may be secondarily involved after invasion or spread of intraocular or intraorbital tumors.

Likewise metastases of the eyelids are rare and constitute only 0.3–1.1% of lid tumors. In a study conducted by Mansour et al, metastatic lid lesions were discovered earlier than the underlying primary tumors in 45% of cases. ⁶⁶ Clinically, these lesions frequently appear as isolate nodular epidermal tumors with occasional ulcerations. The primary tumors are often breast cancer, lung cancer, or cutaneous melanoma.

Diagnosis

Because patients present with rather nonspecific symptoms such as vision loss, photophobia, metamorphopsia, or vitreous floaters (mouches volantes), obtaining a thorough history, especially of previous cancer, is crucial. The complete ophthalmologic examination can be supplemented in patients with suspected intraocular metastases by further investigational procedures such as A- and B-mode ultrasonography, ultrasound biomicroscopy, fluorescein/ICG angiography, and optical coherence tomography (OCT).

Ultrasonographic Examination

Ultrasonography provides an important means if opaque optic media and unclear retinal/choroidal lesions are present, particularly if space-occupying intraocular disease processes are being masked by associated hemorrhages, exudations, or exudative retinal detachment. Ultrasonography is a rapid and simple method and has the advantage of minimal stress for the patients, suitability for follow-up examinations, and low cost. Due to the minimal thickness of intraocular metastases, it can be challenging with ultrasound evaluation to depict the internal characteristics of suspected lesions even when the investigator is very experienced. Normally they show a high internal and frequently irregular reflectivity pattern. These sonographic patterns differ significantly from those of other intraocular tumors, such as choroidal melanoma. In A-mode sonography the latter typically shows an initial prominent spike, followed by a homogenous low-to-medium internal reflectivity and typical sound attenuation. Vascular pulsations can be seen as fine oscillations of the internal spiking pattern within the lesion. In B-mode ultrasound, occasionally the typical collar-button or dome-shape of choroidal melanoma can be depicted.

Ultrasound biomicroscopy can be helpful to investigate disease processes in the iris and the ciliary body. A major drawback is the low penetration depth (e.g., to distinguish cystic from solid structures) so that examination of subjacent structures is limited.

Fluorescein and ICG Angiography

Fluorescence angiography can be helpful in distinguishing between intraocular metastases, inflammatory processes, and other chorioretinal pathologies, such as choroidal neovascularization. In contrast to primary ocular neoplasms, intraocular metastases are often hypofluorescent in the early stages of the angiogram. Depending on the ophthalmoscopic findings (presence of pigment epithelial changes) in the course of the angiogram, an inhomogeneous, sometimes pinpoint leakage can develop associated with blockage phenomena. In late stages, frequently a diffuse hyperfluorescence may be present in the area of the lesion. Indocyanine green (ICG) angiography often reveals nonspecific subtle, occult lesions.

Because of frequent nonspecific angiographic findings, fluorescein angiography often has only documentary value in patients with intraocular metastases. Nevertheless, it can provide significant differential diagnostic information in particular cases. ^{67,​ 68}

Further Diagnostic Procedures

Further diagnostic procedures include computed tomography, MRI, and positron emission tomography (PET). For further diagnostic purposes, fine needle aspiration biopsy or tissue biopsy are suitable.

Therapy

The type and scope of the treatment depend strongly on the size, number, and localization of intraocular metastases. When discussing therapy of intraocular metastases the basic oncologic therapy (the chemotherapy and radiotherapy modality), the age of the patient and the prognosis must be taken into account. The therapeutic decision is therefore influenced by many individual factors.

If chemotherapy is administered, usually a response should be awaited. Often, metastases (e.g., in breast or prostate carcinoma) regress over the course of chemotherapy. ⁶⁹ Even without treatment, choroidal metastases can remain stable and asymptomatic for a long time.

Further treatment options are available if metastases are unresponsive to medical therapy or show progression and if the patient is compromised by ocular symptoms or visual disturbances. ⁷⁰

A promising treatment modality is available with percutaneous radiotherapy (external beam radiotherapy, EBRT), which is effective, cost-effective, and, as a rule, less stressful for patients. Because local EBRT does not treat the primary tumor, a precise interdisciplinary therapy schedule should be elaborated in order to coordinate the different treatment modalities. Usually, percutaneous radiotherapy is applied with a linear accelerator in the lateral portal with a target volume dose of 30–40 Gy in fractions of 2–3 Gy. Local tumor control can be achieved in 33 to 89% of cases, ⁷¹ depending on the underlying primary tumor. For a comprehensive review of radiation therapy see Chapter ▶ 14.

In most studies it was possible to achieve stabilization or even improvement of visual acuity as frequently the exudative retinal detachment responds very well to radiotherapy. ⁷² Radiogenic cataract formation, radiation retinopathy, and dry eyes are known side effects. After regression of choroidal metastasis, in many cases there is atrophy of the choroid and of the retinal pigment epithelium, combined with pigment epithelium accumulation.

Brachytherapy is a treatment option in solitary metastases, particularly if they are localized in the periphery of the choroid. Regression in 94% of cases can be achieved. ⁷³ In the posterior eye segment, ruthenium 106 and iodine 125 plaques are particularly used; for tumors of the anterior segment, cobalt 60 plaques have been widely used.

Further therapeutic options include transpupillary thermotherapy, or in exceptional cases, local resection of a solitary metastasis in combination with brachytherapy. ^{72,​ 74,​ 75}

In cases of advanced metastatic disease with severe vision loss or pain caused by secondary glaucoma, enucleation should be discussed with the patient if an improvement of the situation cannot be expected. The indication for enucleation should be discussed in terms of the general prognosis. If life expectancy is only a few months and the progression is minimal, patients can be treated by alternative modalities such as a retrobulbar alcohol injection, sparing them from the psychological trauma of enucleation.

Prognosis

Metastases probably represent the most common intraocular malignancy. The prognosis in patients with intraocular metastases depends on the nature of the primary tumor and the extent of metastatic disease. Median survival time of 2–32 months after diagnosis of metastases is reported. ^{61,​ 76,​ 77,​ 78,​ 79,​ 80} Survival time for patients with breast carcinoma is reported to be the longest, at 18–32 months, while it is significantly less in patients with gastrointestinal and lung cancer, with an average of 5 months. ^{71,​ 77,​ 81}

As asymptomatic metastases, in particular choroidal metastases, occur more often than previously thought, all patients with malignancies should routinely have ophthalmologic check-ups. Diagnosis of intraocular metastases can be made by means of a slit lamp examination and by simple binocular ophthalmoscopy. Further diagnostic investigations and interdisciplinary collaboration can be initiated if the ophthalmologic work-up has disclosed intraocular metastases.

11.2 Tumors of the Lacrimal Glands and Lacrimal Ducts

H.-J. Welkoborsky

Tumors of the lacrimal glands are rare. Only 0.1% of all tumors occurring in people are localized in the lacrimal glands or ducts. ⁸² Their incidence amounts to ~0.07 per 100,000. ⁸³ It is necessary to differentiate between pseudo tumors, benign and malignant epithelial tumors, and malignant lymphomas.

11.2.1 Tumors of the Lacrimal Glands

Pseudo Tumors

Pseudo tumors include the dermoids or dermoid cysts most commonly. In the true meaning of the word these are not tumors of the lacrimal glands themselves; dermoids are rather congenital lesions that are often localized in the area of the orbital edge and here in particular in the upper outer quadrant. They often arise in places, in which embryonal clefts close and cystic lesions can result through the migration of epithelium from the epidermis; however, a traumatic origin is also possible. They can contain hair, several layers of squamous cell epithelium, or callus material. The tumors appear in early childhood and, due to their typical clinical appearance together with the ultrasound diagnostic findings, do not cause any diagnostic difficulties. Dermoids appear as smooth circumscribed, firm elastic space-occupying lesions that can often be easily moved. Sonography (see Chapter ▶ 4.6) exhibits a circumscribed, anechoic space-occupying mass with dorsal enhancement. Depending on the nature of the contents of the cyst there may be some intralesional echoes, which correspond to the callus material or cell debris in the cyst’s fluid. A displacement of the eye globe occurs only in very extensive lesions. Treatment consists of complete excision. The prognosis is good.

Sjögren’s disease is an autoimmune disease. Women over 40 years of age are mostly affected. Clinically, there is a reduced tear and saliva production with dryness of the mouth and eyes in the foreground. The large salivary glands and the lacrimal glands are mostly swollen on both sides and can thus simulate a tumor. The histological characteristic is a lymphocytic and plasma cellular infiltration of the salivary and lacrimal glands, which are then destroyed by this. As a rule, diagnosis presents no difficulties due to the very typical clinical signs and the characteristic sonographic finding. Treatment consists in giving corticosteroids. Sjögren’s syndrome is associated in some cases with lymphoproliferative diseases.

Benign Tumors

Essentially the same benign tumors occur in the lacrimal glands as in the salivary glands. The most common benign tumor is the pleomorphic adenoma, which forms over 50% of all tear gland tumors. ^{84,​ 85} Clinically, a unilateral, coarse, easily movable space-occupying mass appears on the lateral upper lid. A displacement of the eye globe occurs in the nasal caudal direction only in extended tumors ( ▶ Fig. 11.16). As with pleomorphic adenomas of the large salivary glands, the etiology of the tumor is currently unknown. Molecular genetic studies indicate numerical and structural aberrations in diverse chromosome areas, predominantly on the short arm of chromosome 9 (9p23-p22.3). The PLAG1 oncoprotein, among others, is coded in this area. ⁸⁶ Sonographically a well-defined anechoic space-occupying mass appears that is often circumscribed and polycyclic, with dorsal enhancement. Magnetic resonance imaging can be used for further diagnostics. Here the tumor spread, in particular toward the dorsal orbital compartments, can be assessed. Treatment consists of complete tumor resection. Since the tumors are surrounded by a fine capsule, which at the same time often exhibits small eversions, particular care is indicated in preparation. An injury to the capsule that opens up the tumor can lead to tumor cell seeding, with the result of recurrences. ⁸⁴

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