Studies Of The Gene For Rb

After the cloning of Rb-I for Rb, which is now considered to be a member of a family of genes including p107 and p130, it became evident that mutations of the Rb tumor suppressor gene were also present in a wide variety of other human neoplasms.11-18 As is the case in retinoblastomatoma, all Rb-I mutations in other neoplasms lead either to loss of expression of Rb protein (pRB) or the production of malfunctioning protein.19-22 The understanding of the Rb suppressor gene in tumors led to other practical insights. Patients with the hereditary form of Rb were recognized to be at a greater risk than the general population to develop a second malignant neoplasm (SMN) later in life. Today, with early detection and improved treatment modalities' second' third' and even fourth malignant neoplasms are increasingly becoming the leading cause of mortality among Rb survivors. Since second malignant tumor is the most commonly encountered presentation of these multiple tumor-harboring patients in this chapter the term "second malignant neoplasms" designates these lesions.

Prior to the advent of genetic experimentation and examination of the molecular basis of susceptibility to multiple malignancies, the development of second tumors had been reported sporadically as the result of clinical observations. The most startling report was by Abramson and coworkers indicating that the incidence of SMNs in the hereditary form of Rb was 20% after 10 years, 50% after 20 years, and 90% after 30 years.23 Although the SMN incidences were exaggerated, this paper was significant in attracting attention to the second malignancy issue in Rb, and more reports were published throughout the 1980s.22-30 Draper and coworkers conducted a population-based study using records from cancer registries and hospitals in England, Scotland, and Wales.26 All cases listed with the National Cancer Registration Scheme between 1962 and 1977 were included. Their base was 882 patients with Rb, 2% of whom developed an SMN at 12 years' follow-up, and 4.2% at 18 years' follow-up. Three hundred eighty-four of these instances of Rb were determined to be hereditary, and the incidence of SMN in the hereditary group was 8.4% at 18 years.16

Abramson's group adjusted their figures to an SMN incidence of 16% at 35 years. The same group later published a more conclusive retrospective cohort study examining the second malignancy mortality rate among long-term survivors of Rb.31 In the new study, 1603 patients were enrolled at one year after the diagnosis of Rb. A total of 305 deaths was recorded: 167 from Rb, 96 from SMNs, and 42 from other causes. The great majority of Rb deaths (143 of 167 patients) occurred between the first and ninth year after initial diagnosis, agreeing with other studies and indicating the rarity of late mortality due to Rb.31 Nine hundred nineteen (57%) of the 1603 patients had unilateral disease. The most common second primary malignancies were bone and soft tissue sarcomas, followed by cutaneous melanoma and brain tumors. When the relative risk of mortality was calculated, it was found to exceed the expected rates 300-fold for malignant tumors of bone and soft tissues,32-34 100-fold for melanoma, and 24-fold for brain tumors. At 40 years of follow-up, the cumulative mortality for all SMNs was 26 ± 3.5% (expected 1.3%) for bilateral Rb and 1.5 ± 0.7% (expected 1.1%) for unilateral Rb. In the bilateral Rb patients, external beam radiotherapy (EBRT) further increased the risk of mortality (Figure 5.1). The cumulative mortality from SMNs among patients who received radiotherapy was 30.3 ± 4.8% as opposed to 6.4 ± 3.8% for those who did not receive EBRT. Acute leukemias have also been reported among the patients who survive Rb.35,36 Several investigators have restricted their studies of Rb, some focusing on the bilateral form37-38 and others on the hereditary.25,28 Desjardins and coworkers reported nine SMNs in 80 bilateral Rb patients who had been followed for more than 30 years. Six of these SMNs may have been radiation induced.37 Roarty and coworkers reported cumulative SNN incidence in bilateral disease ranging from 4.4% (10 years postdiagnosis) to 26.1% (30 years postdiagnosis).38

FIGURE 5.1. (A) Socket atrophy, scarring, and contraction of the eyelid tissues, and charring of the skin with loss of eyelashes and eyebrow hair (white arrow) following EBRT for Rb. (B) Extensive scarring and neovascularization (black arrow) of the external eye, secondary to EBRT for Rb.

FIGURE 5.2. A 13-year-old girl with osteogenic sarcoma (T) originating from the superior lateral rim of the orbit. The patient had been treated with EBRT for bilateral Rb at the age of 2.

FIGURE 5.1. (A) Socket atrophy, scarring, and contraction of the eyelid tissues, and charring of the skin with loss of eyelashes and eyebrow hair (white arrow) following EBRT for Rb. (B) Extensive scarring and neovascularization (black arrow) of the external eye, secondary to EBRT for Rb.

FIGURE 5.2. A 13-year-old girl with osteogenic sarcoma (T) originating from the superior lateral rim of the orbit. The patient had been treated with EBRT for bilateral Rb at the age of 2.

Among studies based exclusively on nonhereditary (unilateral and bilateral) cases, Minoda reported a cumulative SMN incidence of 4.8 and 15.7%, respectively, at 10 and 20 years after diagnosis.39 In another study that included only hereditary Rb patients, Lueder and coworkers reported cumulative SMN incidences of 6, 14, and 14 at 10, 20, and 30 years after diagnosis, respectively.28 In another group that included only hereditary disease patients, DerKinderen and coworkers reported a cumulative SMN incidence of 19% in Rb patients at the age of 35 years.25

Other studies include both unilateral and bilateral, and hereditary and nonhereditary patients as mixed groups. In a joint study conducted in Europe, DeSut-ter and coworkers reported a cumulative SMN incidence ranging from 10 to 30% in the Rb population with 40% bilateral disease.40 In another European study that included approximately 35% hereditary Rb patients, Winther et al. reported a relative risk for SMN development as 15.4% for hereditary and 1.7% for nonhereditary Rb patients.29 Smith and coworkers in the United States studied 53 Rb patients, 79% of whom were reported as hereditary; their actuarial SMN incidence was 6, 19, and 38% after 10, 20, and 30 years, respectively.41

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