Types Of Second Malignancy

The most common SMN, osteogenic sarcoma (Figures 5.2 and Figure 5.3), occurs at about the same age as in the normal population, around the second decade.42-44 The frequency of bone and soft tissue sarcomas is not surprising, since many of these tumors seem to harbor Rb-I mutations.45,46 The osteogenic sarcoma incidence in the literature varies from 19 to 54% of all

FIGURE 5.5. Extensive esthesioneuroblastoma developed in the left orbit and nasal cavity following enucleation and postoperative irradiation of the left socket for recurrent bilateral Rb.

FIGURE 5.3. Axial magnetic resonance images from the same patient depicting the osteogenic sarcoma (T) compressing onto the left globe; arrows indicate remnants of calcified Rb. (A) Tl-weighted image. (B) T2-weighted image.

SMNs.23'26 Hawkins et al., whose survey included at least 90% of children with cancer in the United Kingdom, estimated that the relative risk of bone tumors increased 4l5 times in patients with Rb.47 Soft tissue tumors (Figures 5.4 and 5.5) are ranked as the second most common SMN, with an estimated increased relative risk of 130 times.47

Mortality from cutaneous melanoma as an SMN seen in Rb survivors is also far above the age-matched expected levels.47,48 The increased incidence of melanoma is a rather unexpected finding, since melanoma

Orbital Tumors
FIGURE 5.4. Large rhabdomyosarcoma originating from the inferior orbital rim and mandible, following EBRT for bilateral Rb. (Courtesy of Dr. Barrett Haik, Memphis, Tennessee.)

FIGURE 5.5. Extensive esthesioneuroblastoma developed in the left orbit and nasal cavity following enucleation and postoperative irradiation of the left socket for recurrent bilateral Rb.

has not been shown to harbor Rb-I mutations and more often develops outside the radiotherapy site.49 Many SMNs, including osteogenic and soft tissue sarcomas and carcinomas of breast and other sites, have proven to have somatic mutations of Rb-I; this is thought to be the common pathway of oncogenesis in the development of SMNs in children with Rb.50 The carriers of Rb-I may have a dramatic increase in susceptibility to other common cancers when the usual age of onset of these neoplasms is approached.

At present few reliable data are available on patients older than 40 years of age. Two studies of family members of patients with bilateral Rb, however, revealed more deaths due to stomach, bronchial, bladder, and breast carcinoma than expected in the normal population, particularly in first-degree rela-tives.51,52 Data indicate that the observed excess mortality due to SMNs is far above the incidence of that expected to occur in the same age group of the normal population. What is not clear, however, is what happens as these patients proceed through life. Is the risk lifelong? If it is, the risk represents a unique situation for Rb patients, since more than 90% of these patients are cured of their primary neoplasm.

The SMN issue is rapidly becoming a significant public health concern, claiming a large segment of the population living with a history of a "cured" malignancy after exposure to chemotherapy, radiation, or both. In the early 1990s it was projected that at the end of the year 2000, one of every 900 individuals in the United States between the ages of 16 and 44 years would be a survivor of a childhood malignancy.53 In general, it is estimated that 70% of children with a diagnosis of malignancy survive 5 years. In Rb, however, the percentage of survivors and the length of the survival period are greater than for other malignancies. Recent data suggest that 95% of these patients do not develop metastatic disease and are cured of Rb for life.54 Although the rate of metastasis varies from one series to another, Shields and Shields seem to be correct in their estimate that the mortality rate in Rb today due to the primary disease is less than 5%.54-56

Even the small percentage of patients who develop metastatic disease survive longer with aggressive chemotherapy.57

The increased risk of developing additional malignancies in the survivors of childhood cancer may well be lifelong. However, from the standpoint of implications for public health, the age range to concentrate on is between I5 and 45 years. After the fourth decade, the overall incidence of malignancies rises sharply in the general population. Whether survivors of Rb are at a higher risk to develop malignancies than the general population over 50 years of age is not yet known; accumulation of data for another 20 to 25 years is needed to provide the answer.

The occurrence of third and additional nonocular malignancies in Rb survivors is another interesting aspect of this problem. Abramson reported that approximately 1% of hereditary Rb patients develop second nonocular neoplasm each year. Approximately 50% of these patients die as a result of these tumors.58 It is becoming more and more apparent that the survivors of SNMs are at risk for the development of third, fourth, and even fifth nonocular malignancies.59,60 Abramson and coworkers reported a series of 211 (19 unilateral, 192 bilateral) Rb patients who had developed second malignant neoplasms. One hundred forty-two of these patients died within approximately 2 years as a result of their cancers. In 28 patients, a third nonocular tumor developed; all but one had received EBRT for the initial treatment of Rb. A fourth and a fifth tumor developed in 6 and 2 patients, respectively, out of the total of 211 Rb patients.

Another interesting finding is the higher mortality from SMNs in females. In the study of Eng and coworkers, death from second malignancies in females, was reported to be significantly higher than in males.23 Although there are biological differences between genders, the increased mortality in females is quite striking and difficult to explain. Again, more studies are needed to qualify the gender issue.

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