Retinoblastoma is a malignant tumor of the embryonic retina. Although it is rare, it is the most common primary eye tumor of childhood. Life expectancy following treatment is now excellent, but survivors who have heritable retinoblastoma face an increased risk of a second malignant head or neck neoplasm. A second neoplasm, which often occurs in the irradiated field of the original tumor, has become the most significant threat to the survival of these patients. We report the case of a young girl who was cured of her retinoblastoma only to later develop a second nonocular tumor that metastasized to the superficial parotid gland. She underwent a superficial parotidectomy and neck dissection, but the malignancy eventually recurred and required further surgery and radiation therapy. In this article, we discuss the etiology, incidence, sites of occurrence, and management options for a second malignant neoplasm in retinoblastoma survivors. The head and neck surgeon must be vigilant in the diagnosis and management of second neoplasms in this patient population because they often occur in irradiated fields; surgical management is important to patient survival.
Retinoblastoma is the most common primary eye tumor of childhood. With advances in radiation therapy, chemotherapy, and surgery, post-treatment survival is excellent.  Yet despite this success, survivors who have heritable retinoblastoma are at an increased risk of developing a second malignant neoplasm.  This is attributable to both genetic and treatment factors. 
Because the risk of a second malignant neoplasm increases with time, the otolaryngologist has a greater role to play in the diagnosis and management of a second malignant neoplasm in the head and neck region. This is especially true given that a second malignant neoplasm occurs with greater frequency in previously irradiated areas, which makes surgical options even more important. In this article, we discuss the surgical management of a patient who was eventually cured of her retinoblastoma after enucleation and radiation therapy, only to later develop a second nonocular tumor that metastasized to the superficial parotid gland.
A white 17-month-old girl was diagnosed with bilateral Reese-Ellsworth group V retinoblastoma. During therapy for an initial finding of nasolacrimal duct obstruction, an eye examination revealed a bilateral vitreous pathology. Her right eye was blind and there was vitreous seeding in the left eye (group Vb), where some useful vision remained. Lumbar puncture, bone marrow aspirate, and computed tomography demonstrated no obvious tumor beyond the globes. The right eye was enucleated and showed retinoblastoma; there was no involvement of the optic nerve or choroid. The child's father had been blind in one eye since infancy because of a "scar covering the retina." The girl's left eye was irradiated to a total dose of 43 Gy in 23 fractions with a 4-MV photon beam in an attempt to preserve vision. This was followed by adjuvant chemotherapy (intravenous vincristine and cyclophosphamide), which was continued for approximately 1 year. At that time, no residual tumor was identified.
At the age of 31 months, the girl developed a recurrent retinoblastoma in the left eye. Despite the fact that there was less than a 10% chance of successfully controlling the tumor while preserving normal vision,  the family decided to pursue further radiation therapy. The left eye was reirradiated to 41.4 Gy (cumulative dose: 84.4 Gy). The patient responded initially, but later the same year she required enucleation for a pathologically demonstrable multifocal retinoblastoma.
The patient remained tumor-free until the age of 12 years, when she developed a left upper lid chalazion that was followed clinically. When the lesion did not resolve, the girl underwent an excisional biopsy. The lesion measured 1.0 x 1.5 cm, had distinct margins, and was firmly adherent to the tarsal plate. Pathology identified a sebaceous gland carcinoma (figure 1). The lesion later required re-excision with frozen-biopsy-controlled margins and a two-stage reconstruction of the left upper eyelid.
Six months later, the patient developed a left preauricular mass. Findings on fine-needle aspiration were consistent with a sebaceous gland carcinoma, which was presumed to be metastatic. There was no clinical evidence of involvement of the VIIth cranial nerve and no palpable neck adenopathy. Computed tomography showed a 1 x 2 cm preauricular mass contiguous with the superficial parotid lobe and neck. Magnetic resonance imaging confirmed a 1 x 2-cm cystic lesion (figure 2). The patient's whole-body bone scan was negative. She underwent an uneventful left superficial parotidectomy with preservation of the VIIth cranial nerve and a left modified radical neck dissection. Pathology was consistent with a metastatic sebaceous gland carcinoma (figure 3). Because the lateral parotid region had been included in the original radiotherapy field, reirradiation would have subjected the patient to an increased risk of soft tissue and bone radio-necrosis, as well as an increased chance of a secondary malignancy. Therefore, because these potential risks outweighed the uncertain benefits of reirradiation, no further treatment was administered at that time.
One year later, the patient returned with a painful, enlarging left preauricular mass. She underwent a revision parotidectomy, which revealed a recurrent sebaceous gland carcinoma. The frontal and zygomatic branches of the facial nerve were encased by tumor, and these branches were sacrificed. The result was an impaired eyelid closure around the orbital prosthesis. The patient's lower facial symmetry and tone were preserved. The decision was made to administer postoperative radiation to the preauricular area. The choice of portals was based on a computer-assisted reconstruction of the previously treated field, three-dimensional treatment planning, and surgical margins. Using electrons and photons, 56 Gy were given. To date, there has been no evidence of recurrence.
Approximately 200 new cases of retinoblastoma are diagnosed each year in the United States.  Retinoblastoma can occur either unilaterally or bilaterally, and it can be either familial or sporadic. This malignancy is associated with a mutation that leads to an inactivation of a tumor suppressor gene located on the long arm of chromosome 13 [5.6] A single chromosome defect predisposes the patient to retinoblastoma, but when a "second hit" affects the other allele, the suppressive function of the gene is lost. As a consequence, malignant transformation can occur. Because the occurrence of a mutation in the second allele is so common, hereditary retinoblastoma appears to follow a dominant inheritance pattern, with a penetrance of 80 to 90%.  Hereditary or "genetic" cases represent between 25 and 40% of all retinoblastoma cases; they are usually bilateral and multifocal, and they occur at a younger age than do sporadic cases.
It has been well established that survivors of genetic retinoblastoma have an increased risk of developing a second nonocular tumor. In one series, 97% of second tumors occurred in patients who had genetic retinoblastoma.  The relative risk (RR) of death from a second tumor in patients with bilateral retinoblastoma (RR: 60) is much higher than that in patients who have unilateral disease (RR: 3.8).  There is no definitive evidence that patients with nongenetic retinoblastoma have a particularly high risk of a second malignant neoplasm. 
The increased risk of a second malignant neoplasm in patients with genetic retinoblastoma might be attributable to their increased susceptibility to the carcinogenic effects of radiation. [5'8] Fibroblasts obtained from these patients have been shown to have an increased sensitivity to radiation and a defective DNA repair mechanism.  Sagerman et al showed that the higher incidence of secondary tumors in these patients is dose-dependent.  The increased risk following radiation has been confirmed in several large studies. For example, in a study of 215 patients with bilateral retinoblastoma, Roarty et al found that the 30-year cumulative incidence of a second malignant neoplasm was 35% in 137 patients who received radiation therapy, compared with only 5.8% in 78 patients who did not.  The incidence of a second tumor occurring in the irradiated field was 29.3%, while the incidence of a second tumor occurring outside the field was only 8.1%. The latter incidence was comparable to that seen in nonirradi ated patients (5.8%).
Although genetic factors and radiation are known to play a role in the increased risk of a second malignant neoplasm in these patients, other factors might also be involved.  Studies suggest that chemotherapeutic agents such as cyclophosphamide might increase the risk of a second malignant neoplasm.  In an extensive review of genetic retinoblastoma, Draper et al reported that the estimated incidence of a second malignancy 12 years following diagnosis for tumors in the field of radiation was 4.2% among patients who received chemotherapy and 2.9% for those who did not. 
Regardless of the predisposing factors, second malignant neoplasms are a significant contributor to morbidity and mortality in retinoblastoma survivors. In a large series of 1,730 retinoblastoma patients after 40 years of follow-up, the cumulative mortality from all second tumors was found to be 26% in patients who had bilateral tumors and 1.5% in those with unilateral tumors.  Among the patients with bilateral retinoblastoma, the cumulative mortality from a second malignant neoplasm was 6% for nonirradiated patients and 30% for irradiated patients. This high mortality demonstrates the need to detect a second malignant neoplasm early and treat it aggressively, especially in an irradiated patient.
The otolaryngologist should be familiar with the incidence, sites of occurrence, and patterns of spread of various second malignant neoplasms in retinblastoma survivors. The incidence of a second malignant neoplasm increases in a time-dependent fashion, with a mean latency period of 10 to 13 years.  Wong et al showed that the cumulative incidence of a second tumor increases with time, reaching 58% at 50 years in irradiated patients with heritable retinoblastoma versus 27% in patients who were not irradiated.  Other studies have shown that the latency period prior to the development of a second malignant neoplasm is approximately 5 years shorter in irradiated patients than in nonirradiated patients.  The pattern of second malignancies that occur in the irradiated field is slightly different from those that arise outside the field. The most common second malignant neoplasms that develop within irradiated fields are osteosarcomas, fibrosarcomas, squamous cell carcinomas, and other spindle cell carcino mas. Outside the fields, the common second malignant neoplasms include osteosarcomas and soft tissue sarcomas as well as malignant melanomas and thyroid. [1,2]
Although we know that second malignant neoplasms in genetic retinoblastoma patients more often occur in irradiated fields, the site of occurrence is highly variable. In one series of 882 retinoblastoma patients, 30 patients developed a second malignant neoplasm in irradiated fields. The most common site reported for this group was the orbit (eight patients); other second malignancies occurred in the forehead (melanoma), temple (leiomyosarcoma), eyelid (sebaceous carcinoma), and the nasal bones and maxilla (osteosarcoma).  There have been no large studies showing trends in the most common sites of occurrence because there is such a diverse variety of second malignant neoplasms. Several cases of sebaceous gland carcinoma of the eyelid, such as was seen in our patient, have been reported. [13,14]
As both survival and susceptibility to second tumors increases, the role of otolaryngologists in the management of retinoblastoma patients has become more important. Not only is surgery often the treatment of choice for nonirradiated tumors, but the fact that many of these tumors occur in or metastasize to irradiated areas often makes surgical treatment more favorable than reirradiation. In our case study, the patient had already received in excess of 80 Gy to the area of the first metastasis. Reirradiation might have induced osteoradionecrosis or yet another tumor, or it might have carried other attendant radiation-associated risks. Even in nonirradiated patients, an aggressive surgical approach to a second malignant neoplasm is sometimes more favorable to long-term outcomes than radiation. We performed a modified neck dissection in conjunction with a parotidectomy because our patient's tumor--a sebaceous gland carcinoma-is known to behave in an aggressive manner. The choice of options from among surgery, r adiotherapy, and chemotherapy must be made for each case in light of the particular tumor, its location, and other clinical factors.
In summary, although the treatment of retinoblastoma is highly successful, with a cure rate of 85 to 90% in the U.S., the development of a second malignant neoplasm has become more problematic and is a more significant threat to survival.  The head and neck surgeon now has a greater role in the diagnosis and management of a second malignant neoplasm in retinoblastoma survivors. Otolaryngologists not only should be vigilant in the diagnosis and treatment of second primaries, both in and outside irradiated fields, we should also monitor our patient closely for metastatic disease and recurrence following our treatment of these tumors.
From the Division of Otolaryngology--Head and Neck Surgery, Department of Surgery, Duke University Medical Center, Durham, N.C.
Reprint requests: Samuel R. Fisher, MD, Division of Otolaryngology- Head and Neck Surgery, Department of Surgery, Duke University Medical Center, Box 3805, Durham, NC 27710. Phone: (919) 684-4201; fax: (919) 681-7949; e-mail: email@example.com
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