**1. History**

### **1.1 Introduction**

Different tumors that resembled retinoblastoma were described in the past, the first of which was by Pieter Pawius of Amsterdam in 1597 [1]. The Dutch anatomist described a malignancy involving the left eye, temporal bone, and cranium [1]. Pawius described the tumor as "filled with substance like brain tissue mixed with thick blood and like crushed stone." The crushed stone may have represented retinoblastoma classic calcifications. Then, in 1767, Hayes described another case of a child who had presented with the appearance "cat's eyes in the dark" [2]. This was the first description of leukocoria in the scientific literature. In the last two centuries, retinoblastoma had different names. "Fungus haematodes" was the term used in the early 1800s. This term was used to describe a fungating vascular tumor that affected different parts of the body including the globe. Before the era of ophthalmoscopy, no one thought the tumor originated from the globe except

James Wardrop who had a different opinion. He believed "fungus haematodes" of the globe originated from the retina and should be recognized as a distinct entity [3]. Wardrop, who was a Scottish surgeon, reached this conclusion based on his dissections. However, at that time, Wardrop's explanation and observation were not acknowledged. Wardrop was also the first surgeon to perform enucleation for retinoblastoma [3]. In 1854, Virchow suggested the term "glioma of the retina" [4]. Flexner and later Wintersteiner noticed tumor rosettes on histopathology which resembled the photoreceptors of the retina [5, 6]. Flexner proposed the name neuroepithelioma, and both thought that the photoreceptors were the origin of the tumor [5]. Finally, in 1922, Verhoeff coined the term retinoblastoma after he noticed the histologic similitude between the disease and embryonic retina [7]. Four years later, the American Ophthalmological Society decided to adopt the term retinoblastoma. In 1970, Tso described the appearance of fleurettes which represent advanced photoreceptor differentiation [8].

#### **1.2 Retinoblastoma variants**

Hirschberg categorized the disease per its growth into endophytum and exophytum [9]. In 1960, Schofield described few cases who had presented with hypopyon and no macroscopic evidence of retinoblastoma [10]. After enucleation, histological exam showed malignant cells and rosettes were found within the retina. He described the cases as having "diffuse infiltrating retinoblastoma" [10]. He gave the credit to Ashton who first used the term in 1958 after personal communication with him. Schofield stressed on including retinoblastoma as part of the differential diagnosis of hypopyon. In 1998, Grossniklaus was the first to use the name "anterior variant of diffuse retinoblastoma" [11]. He reported a case that was misdiagnosed as anterior uveitis. After the eye was enucleated, the tumor was found to be in the peripheral retina, iris, ciliary body, and anterior vitreous. In 1982, Bader et al. described three cases of trilateral retinoblastoma [12]. He found out retinoblastoma-like tumors in the suprasellar or parasellar region few months before the detection of intraocular retinoblastoma in each of the three cases. He concluded the association was more than a coincidence and having retinoblastoma gene may confer the risk of having other "ectopic" malignancies.

#### **1.3 The history of genetics**

In the 1800s, retinoblastoma was thought to be an autosomal dominant hereditary disease. Alfred Knudson, a cancer geneticist, had observed that patients with hereditary retinoblastoma developed multiple tumors in both eyes, while patients with the non-hereditary form had unilateral tumors. In 1971, Knudson proposed the two-hit hypothesis. It states that a second sporadic mutation should occur in patients with hereditary retinoblastoma before the development of retinoblastoma [13]. The other type described by Knudson was non-hereditary retinoblastoma. In non-hereditary retinoblastoma, two sporadic mutations in both alleles of retinal cells should take place. In 1986, RB gene was the first tumor suppressor gene to be identified in medical history.

#### **1.4 The treatment history**

Wardrop advocated enucleation in 1809 as the only treatment [3]. However, Wardrop's patients failed to survive despite enucleation. Von Graefe suggested the optic nerve should be excised during enucleation. This resulted in better survival rates. One of the major turn points in the history of retinoblastoma was

**5**

*History and Genetics of Retinoblastoma DOI: http://dx.doi.org/10.5772/intechopen.89035*

introduction of ophthalmoscope, which allowed earlier detection of retinoblastoma. Retinoblastoma was a fatal disease, so the primary was aim to save life of affected patients. The first radiation treatment for retinoblastoma was reported, in 1903, by Hilgartner in Texas [14]. Hilgartner reported the survival of the patient but not the eye following a series of X-rays. Verhoeff, in 1921, used radiotherapy to cure retinoblastoma [15]. However, 60 years following radiation therapy, Verhoeff's patient developed lid basal cell carcinoma and recurrence of retinoblastoma [16]. In 1930, Moore used surgically inserted radioactive radon seed to cure retinoblastoma [17]. Weve introduced the use of diathermy for treating retinoblastoma [18]. However, it resulted in major complications including large chorioretinal scarring and scleral thinning. Then, Stallard established plaque brachytherapy [19]. External beam radiotherapy (EBRT) was used and resulted in improvement in eye survival rates [20]. However, EBRT cause second cancers in patients with germline muta-

Schwickerath used xenon arc photocoagulation to treat retinoblastoma [23]. Harvey Lincoff developed cryotherapy for the treatment of small retinoblastoma tumors [24]. In 1953, Kupfer was the first to use chemotherapy, nitrogen mustard, along with radiotherapy for retinoblastoma [25]. To decrease systemic side effects of chemotherapy, the idea of local chemotherapy came up. Kaneko used intraarterial chemotherapy for retinoblastoma, which resulted in substantially higher drug concentration in the eye [26, 27]. Retinoblastoma mortality rate decreased substantially from 100 to 2% in the last 50 years [25]. Indeed, retinoblastoma is a

Retinoblastoma (RB) is the most common intraocular malignancy in children affecting 1 in 18,000 live births which occurs as a result of biallelic inactivation of RB1 gene [28]. Hereditary RB is due to heterozygous germline mutation in one copy of the RB1 gene, hence is inherited as an autosomal dominant trait. In this form, all body cells have a dysfunctional RB1 allele and, thus, are vulnerable to neoplasia. The non-hereditary form of RB is consequent to somatic mutations, which is known

In these patients, RB development requires a second, somatic, mutation in the same cells that renders the other allele nonfunctional. The cumulative incidence rates of non-ocular tumors reach up to 90% at 30 years in patients who were

exposed to radiation vs. 68% at 32 years in patients without radiation exposure [30]. The aim of this chapter is to provide a valuable summary of retinoblastoma genetics that is essential for genetic counseling and estimation of short-term (multifocal and bilateral ocular tumors) and long-term (secondary tumors) risks with an overall improvement of healthcare planning and management of our patients.

The RB1 gene located on the long arm of chromosome 13 (13q14) is a negative regulator element in the cell cycle process and was the first tumor suppressor gene identified [31]. This gene codes for the RB protein which has multiple cellular functions; it prevents the dividing cells from uncontrollable cycles in the mitosis stage and has a role in genomic stability, apoptosis, and differentiation [32]. Inactivation of the RB protein is usually caused by deletions and nonsense mutations [33].

tions by causing the second hit described by Knudson [21, 22].

story of success and there is still more to come.

to affect both RB1 alleles in retinal cells [29].

**2.2 The RB1 gene and protein function**

**2. Genetics of retinoblastoma**

**2.1 Introduction**

#### *History and Genetics of Retinoblastoma DOI: http://dx.doi.org/10.5772/intechopen.89035*

*Retinoblastoma - Past, Present and Future*

advanced photoreceptor differentiation [8].

confer the risk of having other "ectopic" malignancies.

**1.2 Retinoblastoma variants**

**1.3 The history of genetics**

identified in medical history.

**1.4 The treatment history**

James Wardrop who had a different opinion. He believed "fungus haematodes" of the globe originated from the retina and should be recognized as a distinct entity [3]. Wardrop, who was a Scottish surgeon, reached this conclusion based on his dissections. However, at that time, Wardrop's explanation and observation were not acknowledged. Wardrop was also the first surgeon to perform enucleation for retinoblastoma [3]. In 1854, Virchow suggested the term "glioma of the retina" [4]. Flexner and later Wintersteiner noticed tumor rosettes on histopathology which resembled the photoreceptors of the retina [5, 6]. Flexner proposed the name neuroepithelioma, and both thought that the photoreceptors were the origin of the tumor [5]. Finally, in 1922, Verhoeff coined the term retinoblastoma after he noticed the histologic similitude between the disease and embryonic retina [7]. Four years later, the American Ophthalmological Society decided to adopt the term retinoblastoma. In 1970, Tso described the appearance of fleurettes which represent

Hirschberg categorized the disease per its growth into endophytum and exophytum [9]. In 1960, Schofield described few cases who had presented with hypopyon and no macroscopic evidence of retinoblastoma [10]. After enucleation, histological exam showed malignant cells and rosettes were found within the retina. He described the cases as having "diffuse infiltrating retinoblastoma" [10]. He gave the credit to Ashton who first used the term in 1958 after personal communication with him. Schofield stressed on including retinoblastoma as part of the differential diagnosis of hypopyon. In 1998, Grossniklaus was the first to use the name "anterior variant of diffuse retinoblastoma" [11]. He reported a case that was misdiagnosed as anterior uveitis. After the eye was enucleated, the tumor was found to be in the peripheral retina, iris, ciliary body, and anterior vitreous. In 1982, Bader et al. described three cases of trilateral retinoblastoma [12]. He found out retinoblastoma-like tumors in the suprasellar or parasellar region few months before the detection of intraocular retinoblastoma in each of the three cases. He concluded the association was more than a coincidence and having retinoblastoma gene may

In the 1800s, retinoblastoma was thought to be an autosomal dominant hereditary disease. Alfred Knudson, a cancer geneticist, had observed that patients with hereditary retinoblastoma developed multiple tumors in both eyes, while patients with the non-hereditary form had unilateral tumors. In 1971, Knudson proposed the two-hit hypothesis. It states that a second sporadic mutation should occur in patients with hereditary retinoblastoma before the development of retinoblastoma [13]. The other type described by Knudson was non-hereditary retinoblastoma. In non-hereditary retinoblastoma, two sporadic mutations in both alleles of retinal cells should take place. In 1986, RB gene was the first tumor suppressor gene to be

Wardrop advocated enucleation in 1809 as the only treatment [3]. However, Wardrop's patients failed to survive despite enucleation. Von Graefe suggested the optic nerve should be excised during enucleation. This resulted in better survival rates. One of the major turn points in the history of retinoblastoma was

**4**

introduction of ophthalmoscope, which allowed earlier detection of retinoblastoma. Retinoblastoma was a fatal disease, so the primary was aim to save life of affected patients. The first radiation treatment for retinoblastoma was reported, in 1903, by Hilgartner in Texas [14]. Hilgartner reported the survival of the patient but not the eye following a series of X-rays. Verhoeff, in 1921, used radiotherapy to cure retinoblastoma [15]. However, 60 years following radiation therapy, Verhoeff's patient developed lid basal cell carcinoma and recurrence of retinoblastoma [16]. In 1930, Moore used surgically inserted radioactive radon seed to cure retinoblastoma [17]. Weve introduced the use of diathermy for treating retinoblastoma [18]. However, it resulted in major complications including large chorioretinal scarring and scleral thinning. Then, Stallard established plaque brachytherapy [19]. External beam radiotherapy (EBRT) was used and resulted in improvement in eye survival rates [20]. However, EBRT cause second cancers in patients with germline mutations by causing the second hit described by Knudson [21, 22].

Schwickerath used xenon arc photocoagulation to treat retinoblastoma [23]. Harvey Lincoff developed cryotherapy for the treatment of small retinoblastoma tumors [24]. In 1953, Kupfer was the first to use chemotherapy, nitrogen mustard, along with radiotherapy for retinoblastoma [25]. To decrease systemic side effects of chemotherapy, the idea of local chemotherapy came up. Kaneko used intraarterial chemotherapy for retinoblastoma, which resulted in substantially higher drug concentration in the eye [26, 27]. Retinoblastoma mortality rate decreased substantially from 100 to 2% in the last 50 years [25]. Indeed, retinoblastoma is a story of success and there is still more to come.
