The Location and Appearance of Second Malignancies in Patients With Bilateral Retinoblastoma

Purpose. This paper describes the clinical history and radiographic appearance of second malignancies in patients with bilateral retinoblastoma. Subjects/methods. The imaging studies and clinical data of 14 patients with a history of bilateral retinoblastoma who were treated for second malignancies were reviewed. Results. A total of 17 tumors were identified in 14 patients during the period 1978–1996. The median age of occurrence of the second malignancy was 17 years (range 10–32 years). Fourteen of the 17 malignancies occurred in the facial structures and three developed in the lower extremities. The histologies included osteosarcoma (n = 5), malignant fibrous histiocytoma (n = 3), high-grade spindle cell sarcoma (n = 3), malignant mesenchymoma (n = 1), leiomyosarcoma (n = 4) and angiosarcoma (n = 1). The tumors were locally aggressive and had a similar appearance to those found in nonretinoblastoma patients. Six of the 14 patients are alive and disease free. Discussion. Most of the adolescent and young adult retinoblastoma survivors developed second malignancies in the irradiated facial structures but some occurred in distal sites. Radiologically, these tumors do not differ in appearance from those seen in non-retinoblastoma patients with the exception of their location.


Introduction
Retinoblastom a (RB) is a rare ocular neoplasm of childhood which occurs in a sporad ic or hereditary form . W hile the sporadic form typically presents w ith unilateral disease, m ost patients with the hereditary form have bilateral retinoblastom a (BRB). T he hereditary form is asso ciated with a germ -line defect in the retinoblastom a gene, RB -1, on chrom osom e 13 and is transm itted in an autosomal dom inant pattern. Prognosis for patients with BRB is excellent w ith approxim ately 90% of patients achieving cure of the prim ary disease. 1,2 However, these sam e patients are at an increased risk of developing a second m alignancy (SM ). 3± 5 This pap er sum marizes the experience at our institution regarding second m alignancies in patients treated for BRB and describes the radiographic features.

S ubjects and m ethods
A series of 14 patients w ith BRB presenting with a SM was obtained via a search of the M emorial H ospital database. Retrospective analysis of the charts, pathology and radiologic studies were perform ed.

Results
A total of 14 patients with BRB w ere treated for a second m alignancy at our institution during the period 1978± 1996. T ables 1 and 2 sum m arize the clinical history and outcom e of these 14 patients.
Thirteen of the patients were diagnosed w ith BRB by 21 m onths of age. O ne patient (12) is included in the series because his unilateral RB was m ulti-focal and he has a fam ily history of RB. Each patient initially underw ent enucleation of one globe and m ost patients had radiation therapy given to the opposite eye. T wo of the patients had radiation therapy to both eyes. Initial radiation therapy doses ranged from 3575 cGy to 5400 cGy. T he radiation doses for six of the patients could not be ascertained as their radiation treatm ent was perform ed elsewhere. T he age at diagnosis of the SM ranged from 10 to 32 years with a m edian age of 17 years. Patient 6 was diagnosed with a SM at 16 years of age, and then developed a third m alignancy at age 18 years . This third malignancy, m alignant ® brous histiocytoma (MF H) in the right orbit, was different in location and histology than the second m alignancy, an osteosarcom a of the left tibia.
Patient 10 developed a third m alignancy, angiosarcom a of the upper lip, 16 m onths after radiation therapy for leiomyosarcom a of the right ethmoid sinus.
Patient 11 developed an osteosarcom a of the fem ur 13 years after treatment for BRB and a leiom yosarcom a within the facial radiation ® eld 22 years after irradiation.
The histologies of the m alignancies included ® ve osteosarcom as (OS), three high-grade spindle cell sarcom as (H GS), one angiosarcom a, one m alignant m esenchym om a, three m alignant ® brous histiocytom as (M FN ) and four leiomyosarcom as (LM S). F ourteen of the 17 SM occurred within the facial structures; six know n to be w ithin the radiation port. In six patients, it is highly likely that the SM occurred in the radiation port. One patient w hose SM was not in the facial bones ultimately developed a third m alignancy w ithin the radiated facial structures.
Radiograph ically, the O S in these patients had a sim ilar appearance to those in non-B RB patients. T he tum ors dem onstrated a combination of osteolysis and osteosclerosis and an asso ciated soft tissue m ass. Osteoid matrix w as also present (Fig. 1). Enhancem ent of these lesions was present on the contrast-enhanced com puted tom ography (C T) and m agnetic resonance im aging (M RI) studies. T he location of the O S, how ever, was unusual. O ne of the ® ve O S developed in the long bones (the comm on location for de novo OS) while the other four developed in the facial bones.
The MF H were heterogeneous-enhancing lesions which caused osseous destruction which was typically perm eative. Like the OS, the MF H had an appearance sim ilar to that of a de novo M FH but the location was unusual.
The three cases of H GS app eared as inhom ogeneous m asses with central necrosis and contrast enhancement on M RI and CT . T he tum ors caused destruction of the adjacent osseous structures but no m atrix was seen in the soft tissue com ponent. In one case, patient 4, the H GS started in the left orbit and caused proptosis of the left globe.
Four patients developed a LM S in our group. This heterogeneous soft tissue tum or in® ltrated the paran asal sinuses, and sometimes extended to the orbit and extended intracranially to destroy the skull base.
Intracranial extension of the tum or was not uncom m on. T hree had intracranial tumor at the time of presentation; patient 5 with M FH , patient 4 with H GS (Fig. 2) (Fig. 3) and later intrapulmonary disease.
N ine of the 14 patients in this study experienced recurrence of their tum ors.
Other radiographic features com m on to these patients are asso ciated with the therapy they received F ig.

D iscussion
It has been recognized that patients with BRB are at greater risk of developing a SM . Abram son et al. determ ined that tw o-thirds of the second tum ors arise within the ® eld of radiation therapy and onethird are outside the ® eld. 2 T his suggests that radiation therapy used to treat retinoblastom a m ay play a part in the induction of the SM but there m ust also be a genetic predisposition. G enetic studies have demonstrated that the RB-1 gene w hose deletion is responsible for retinoblastom a is localized on band 14 of the long arm of chrom osom e 13. RB-1 m utations have also been identi® ed in OS. 6± 8 In our study, all the patients received radiation therapy as part of their treatm ent for BRB and developed a sarcom a within the ® eld of radiation. As with radiation-induced sarcom as in non-R B patients, the sarcom as developed after a long latency period. Our patients were diagnosed and treated for BRB in infancy. The sarcom as w hich they developed occurred one to three decades later at a m edian age of 17 years with a range of 10± 32 years. Radiation-induced sarcom as in non-R B patients have been reported to develop 4± 30 years after com pletion of radiation therapy. 10 The doses of radiation used to treat our patients were in the range which can result in osseous damage. D oses greater than 3000 cGy usually cause permanent dam age to reparative m echanisms while doses greater than 5000 cG y can cause devitalization of bones. 10 T hese num bers were determined for adult bones; children m ay m ore favorably tolerate higher doses. Kin et al. review ed the radiationinduced sarcomas of bone following therapeutic radiation at the Mem orial Sloan Kettering Cancer C enter from 1977 to 1982. 11 The age of the 10 patients in his study ranged from 9 to 52 years with ® ve patients under 18 years of age. He found both osseous and extraosseous sarcom as can develop after receiving doses ranging from 3000 to 6000 cGy, w ith a m edian dose of 4605 cGy.
W ith the exception of their location, the radiographic appearance of the sarcom as in our patients w as sim ilar to those in non-B RB patients. In our study, only two of the ® ve O S developed in a long bone. T ypically, O S arise in the m etaphyseal region of the tubular bones with 50± 75% developing around the knee. O nly 5± 10% of de novo O S develop in the¯at bones 12 yet three of the ® ve O S in our patients developed there.
The tumors were locally advanced at the time of their presentation and had a propensity to recur, w hich may account for the poor clinical outcom e for som e of these patients. At our institution, aggressive treatment for the SM is advocated. N eo-adjuvant chem otherapy produced responses in the m ajority of the patients treated and, with subsequent surgery, long periods of disease-free survival were obtained. Six of our 14 patients are alive w ithout evidence of disease, indicating that apparent cures can be achieved in a signi® cant m inority.

A cknowledgem ents
W e would like to acknowledge D r Fereshteh G havim i for her inspiration and guidance with this project, and M rs Patricia D udley and M s Lennora Spicer w ho prepared the m anuscript.