Retinoblastoma

Retinoblastoma is a malignant tumor in the retina of the eye, for its formation mutations in both alleles of the retinoblastoma gene ( located on chromosome 13, band q14 ) are the basic requirement.

This tumor is based on genetically modified immature retinal cells and untreated, leads to death. If the disease is detected early and treated, the chances of recovery are good ( about 95% of patients are cured ). Since the growth of the retinoblastoma can only come from immature retinal cells, this tumor is very rare after the age of 5. At 20,000 live births is about a case of illness, which is about 60 cases per year in Germany. In the U.S., are expected per year with about 350 cases, one goes from 5,000-8,000 new cases per year worldwide. A distinction is an inherited from a non- hereditary form. In girls and boys of the tumor occurs with equal frequency. Apart from the human species is not known so far, in which a naturally occurring retinoblastoma.

• 6.1 enucleation
• 6.2 Percutaneous radiotherapy
• 6.3 brachytherapy
• 6.4 Coagulation
• 6.5 chemotherapy
• 6.6 Thermal chemotherapy
• 6.7 New treatment method

Cause

Approximately 45% of patients have the hereditary form of retinoblastoma. These patients are heterozygous for a mutation in the retinoblastoma gene ( first mutation ). These mutations are usually the result of new mutations in the germline ( sperm or ovum ) of a parent. There is an autosomal - dominant inheritance with incomplete but high penetrance. This autosomal dominant mode of inheritance is remarkable, as it is clearly distinct from other autosomal dominant Erbgängen. On the origin of retinoblastoma, both alleles must for the retinoblastoma gene ( RB1) be mutated, this is usually a property that have autosomal recessive diseases. In the case of hereditary retinoblastoma but it takes almost 95 % of the cases of the second additional somatic mutation in retinal progenitor cells existing in the first mutation of all body cells. The mutational loss of the second, normal allele in a precursor cell of the retina triggers the formation of the tumor. This pattern of inheritance appears typical autosomal dominant with incomplete but high penetrance. Studies in this field were carried out by Alfred G. Knudson and published in 1971, after he called this theory to tumor formation " Two mutations theory according to Knudson ". Meanwhile, it is assumed that a third factor must be added so that it comes to tumor formation. Will be discussed in this context, for example, changes in chromosome structure, such as gains on the long arm of chromosome 1, or on the short arm of chromosome 6

Most patients with hereditary retinoblastoma have tumors in both eyes (two-sided retinoblastoma ). Heterozygous carriers of a mutation in the retinoblastoma gene provide them with a 50% risk to the offspring. In children who have inherited such a mutation, there is a very high risk for the development of retinoblastoma.

Approximately 55% of patients have the non- inherited form of retinoblastoma. These patients have both mutations required for tumor formation in body cells (somatic mutations), and although both mutations in the same cell must be available. Since it is statistically unlikely that this double mutation independently happens in a child in cells of the retina of both sides, the sporadic retinoblastoma is rarely bilateral. Almost all patients with non- hereditary retinoblastoma have only an affected eye ( unilateral retinoblastoma ).

Since the retinoblastoma usually occurs in young children under five years, the retinoblastoma is also known as Infantile eye tumor. The disease is found in children with bilateral retinoblastoma predominantly earlier than in children with unilateral retinoblastoma; the average age at diagnosis is the unilateral form at 23 months, at the bilateral form at 12 months. Approximately 10% of retinoblastoma are already diagnosed shortly after birth, within the first year of life about 50%, and up to 3 years approximately 90%.

Special shapes

Trilateral retinoblastoma

Trilateral retinoblastoma is known as a very rarely occurring hereditary retinoblastoma, which occurs together with a brain tumor. It is a self- tumor, not a metastasis. The histology is similar to that of retinoblastoma; the prognosis is relatively inconvenient for the patient.

Retinom ( Retinozytom )

Retinom refers to a benign ( benign ) retinal tumor that occurs in approximately 2% of patients with a mutation of the RB gene. This is probably a precursor of retinoblastoma or the remains of a healed retinoblastoma after spontaneous regression. The histology is similar to that of retinoblastoma.

Symptoms

Not infrequently the tumor stands out due to so-called leukocoria. Here, the in the eye incident (flash ) light is not like the normal eye from the retina to the underlying choroid reflected ( this results in the typical " red eye" in photographs ), but by the Retinoblastomgewebe ( thus there is a whitish- yellowish reflection of the light, see figure). In Retinoblastompatienten that are clinically apparent later by other symptoms, can not be rare on earlier photographs already the phenomenon of leukocoria watch. If at the same time on the eye also a tumor-related " blindness" ( amaurosis ) before, so one speaks also of " amaurotic cat's eye ".

In addition to the leukocoria a squint (strabismus ) of the eyes is the most common symptom. Rare finds a painful redness of the eye, glaucoma ( glaucoma ), partial loss of vision, inflammation in the eye socket ( orbital cellulitis ), very rarely a unilateral dilatation of the pupil (unilateral mydriasis), discoloration of the iris ( heterochromia ), white Iris spots or blood in the anterior chamber of the eye ( hyphema ).

Diagnostics

Common methods of investigation, especially the eyes mirroring ( ophthalmoscopy) and sonography. In certain cases, also a computed tomography or magnetic resonance imaging is performed at an advanced stage of the disease, a study of cerebrospinal fluid and bone marrow in order to identify a metastasis can.

Reese - Ellsworth classification

This most commonly used for the retinoblastoma classification system was developed in the 1960s at Columbia Presbyterian Medical Center. This is not a traditional staging system, in which patients of Group I of progressing to the higher groups. Instead, it was designed to predict the prognosis of tumors after percutaneous radiotherapy: the higher the classification, the further forward in the eye sits a tumor and the worse the treatment success. With the increasing trend to other therapies, this classification system is increasingly being called into question; other systems have so far not yet taken off.

• Ia. - Solid tumor <4 discus - Ø, on or behind the equator
• Ib. - Multiple tumors <4 discus - Ø, on or behind the equator
• IIa. - Solid tumor, 4-10 discus - Ø, on or behind the equator
• IIb. - Multiple tumors, 4-10 discus - Ø, on or behind the equator
• IIIa -. All lesions before the equator
• IIIb. - Solid Tumor > 10 discus - Ø behind the equator
• IVa. - Multiple tumors > 10 discus - Ø
• IVb. - All lesions rostral to the ora serrata
• Va. - tumor take about a half of the retina
• Vb. - Vitreous seeding

Therapy

The chance of cure and on receipt of the vision is very much dependent on the spread of the tumor in and outside of the eye. The main objective in every case is the salvation of the patient, which amounts to a complete removal of the tumor. If it is possible, while trying to maintain the eyeball and as much of the visual acuity.

Enucleation

In advanced disease, the tumor can be completely eliminated only by the removal of the affected eye. In this enucleation of the eye with a large a part of the optic nerve (via the spread of metastases is possible in the brain ) surgically removed. The eye muscles and the remaining contents of the orbit are preserved. Tumor and optic nerve are examined histologically after the enucleation in order to determine a possible metastasis can.

Following the removal of the eyeball, an implant is inserted into the eye socket, to which a prosthesis can be placed eyes.

Percutaneous radiotherapy

Retinoblastoma is extremely sensitive to radiation. Therefore, the percutaneous radiotherapy ( irradiation of the tumor through the skin under the recess of the lens) was for a long time, the standard therapy. However, we now know that there is an increased risk of secondary tumors by irradiation ( especially when hereditary retinoblastoma and an irradiation in the first year of life ) by a factor of 3-6. Today, we used the percutaneous radiotherapy especially with vitreous seeding, metastasis, or when chemotherapy has proven ineffective or intolerable. Possible side effects are caused by radiation damage to the parts of the eye such as the retina ( radiation retinopathy ), the optic nerve ( optic atrophy and Strahlenopticusneuropathie ), the lens ( cataract rays ) or lacrimal gland and disorders of bone growth.

Brachytherapy

Brachytherapy radiation beam ( applicators ) to the sclera ( sclera ) of the eye are sewn on and removed again after reaching the required radiation dose. The applicators contain small pieces of a radioactive emitter such as ruthenium -106 or iodine -125 whose radiation can be aligned quite specifically to the tumor. Thus it is particularly suitable for medium-sized tumors away from the macula and localized vitreous seeding. Possible side effects include double vision, clouding of the lens, damage to the retina or the optic nerve or bleeding.

Coagulation

This is local therapy methods in which the tumor by heating with a laser ( photocoagulation ) or freezing ( cryotherapy ) is killed. They are used in patients with relatively early stage and small tumors that recur after radiation or chemotherapy after reduction. The tumors must be removed from this optic nerve, macula, choroid and larger vessels, so that they are not damaged by the treatment. Complications can myopia, shrinking of the dermis and damage to the retina occur.

Chemotherapy

Adjuvant ( supportive ) chemotherapy is carried out primarily by enucleation, when metastasis is present and tumor cells were found in the anterior chamber, iris or choroid, or optic nerve in the remote.

In the chemo reducing large tumors in the anterior part of the eye can be reduced by chemotherapy before they are treated with topical therapies ( brachytherapy, laser or cryotherapy ) on.

A high-dose chemotherapy is performed only at high metastasis with poor prognosis.

Increasingly, local administration of chemotherapeutic agents directly into the ophthalmic artery ( ophthalmic artery ) is applied. This systemic side effects are reduced.

In addition to the usual side effects of chemotherapy, the incidence of chemotherapy resistance is problematic, by accommodating the tumor after a while the growth.

Thermo chemotherapy

In thermal chemotherapy, makes use of the effect of a local heating of the tumor, considerably improves the effect of treatment with a chemotherapeutic agent (usually carboplatin). It is used particularly in smaller tumors in the posterior part of the eye. Possible complications are opacities of the vitreous body and damage to the retina and iris.

New Therapy Method

All current therapies are associated with a number of disadvantages: enucleation results in the loss of an eye, percutaneous radiotherapy increases the risk of secondary tumors, chemotherapy is associated with significant side effects and is of limited effectiveness, through the emergence of resistance lead, laser photocoagulation and cryotherapy to the loss of retinal areas and thereby to visual limitations. Despite a low mortality retinoblastoma is thus associated with a high morbidity. Novel therapies such as the thermo- chemotherapy or photodynamic therapy to reduce morbidity further.

History

The first description of retinoblastoma is the Leiden anatomist Pieter Pauw called Peter Parwius attributed, in his " Observationes Anatomicae Selectiores " in the " tumor oculorum " describes 1597 autopsy of a three- year-old boy, who died at a large tumor of the left eye. William Hey describes 1805 in his "Practical Observations in Surgery" in detail a " Fungus haematodes ", ie Blutschwamm. The most detailed study can be found in the " Observations on the fungus haematodes or Soft Cancer " by James Wardrop (1809 ), which describes 17 cases and for the first time the emergence in the retina and spread via the optic nerve ( optic nerve ) describes. He was the first recommended the removal of the eye. 1836 may prove the origin in the retina microscopically Langenbech, Robin and Nystin first time. Rudolf Virchow called the retinal tumor in 1864 as a glioma. Albrecht von Graefe in 1868 identifies that there is a hereditary disease. Simon Flexner (1891 ) and Hugo Winterhalter Steiner ( 1897) describe the typical rosette-like growth ( Flexner - Winter Steiner- rosettes ) and recognize the relationship with rods and cones of the retina. The term " retinoblastoma " is characterized by Fredrick Herman Verhoeff 1926, from the undifferentiated retinal cells, the retinoblasts, recognizes the origin. 1971 is the retinoblastoma as a model system for the "two- hit " hypothesis of Alfred G. Knudson, and 1987, the " retinoblastoma susceptibility gene " Lee is sequenced.