Radiation Induced Malignancy in Retinoblastoma: New Pathology in a Case Report

Clara Draf, Madeleine R. Schaberg MD1, Vijay K Anand MD1, Gurston Nyquist MD1, Syed Hoda21Department of Otolaryngology, Head and Neck Surgery, Weill Cornell Medical College, New York, N.Y.

2Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, N.Y.

Introduction• 250-350 children in the United States are diagnosed with retinoblastoma annually• Retinoblastoma is a rare type of eye cancer which originates in the retina[1, 2]• Retinoblastoma is differentiated into hereditary 30- 40% and non-hereditary 60-70% [3]• The genetic basis of retinoblastoma lies in a mutation of the tumor suppressor gene Rb1, located on the long arm of chromosome 13• Treatment, including different types of radiation therapy, chemotherapy regimens, intraocular laser- and cryo-coagulation have lead to

a high rates of survival for retinoblastoma with the literature citing an average 93% 5 year survival [7, 8]• It has also been shown that the level of expression of the mutated gene may predispose to the development of a second malignant

neoplasm [9]• Patients with retinoblastoma of hereditary origin have an increased risk of developing a second malignant tumor [9] • Additionally these secondary neoplasms occur frequently in the field of radiation• We present a patient case of hereditary retinoblastoma that subsequently developed a sinonasal adenocarcinoma 27 years post

radiation therapy

Figure 4: A. H&E, 100x. Papillary adenocarcinoma typical of sino-nasal origin (arrow showing typical papillary frond). B. H&E, 400x. High power view showing foci of pseudoglandular features containing protein secretions. C. H&E, 400x. Intracytoplasmic secretory inclusions positive for alpha-1 antitrypsin (indicated by arrow) . D. H&E, 400x. Clear dural and bony invasion. (photos courtesy of C. Besanceney, MD)

AbstractObjective: Patients with a genetic history of retinoblastoma have an increased risk of developing a second neoplasm. When these secondary malignancies occur in the previously irradiated field of the primary tumor they are most commonly osteosarcomas, fibrosarcomas, and squamous cell carcinomas. We present the first case of a radiation induced adenocarcinoma in a patient after treatment for retinoblastoma. Study Design: A case report of one patient. Methods: This case study underwent a chart review, comprehensive history, physical exam, rigid nasal endoscopy, and radiographic imaging. A literature review of the MEDLINE database 1966-2009 using key words, retinoblastoma, radiation, and second malignancy was performed. Results: Our case is a 29 year old man with a past medical history significant for surgical resection followed by irradiation at age 1 for retinoblastoma who presented with right sided epistaxis and nasal obstruction. Endoscopy revealed a mass in the right nasal cavity. MRI and CT revealed a mass filling the right nasal cavity and ethmoids with erosion through the cribriform plate. The patient underwent surgical resection and pathology revealed an adenocarcinoma.Conclusions: Second malignancies in patients with retinoblastoma tend to occur in the previously irradiated field of the primary tumour and contribute significantly to long term morbidity and mortality rates. This is the first case of a sinonasal adenocarcinoma occurring in the previously irradiated field. The endoscopic skull base surgeon plays a vital role as patient survival depends on the diagnosis and surgical management.

Figure 2: A: Sagittal view of T1 weighted MRI showing large mass at anterior skullbase extending into posterior nasal cavity. B: Axial view of T1 weighted MRI showing large mass surrounding posterior septum, nasopharynx, and anterior skullbase.

Case• 29 year old male presented with a six month history of right sided nasal obstruction, rhinorrhea, epistaxis, and headaches• Past medical history: treatment at age one for unilateral right sided retinoblastoma with external beam radiation up to as dose of

45 Gy• Family history: positive for retinoblastoma in both parents and two siblings • Social history: significant for 10 pack years of tobacco use • Clinical exam: Patient with normal vision bilaterally except for small right medial visual field defect in left eye• Nasal endoscopy: revealed a mass in the right nasal cavity, lying along the floor of the nasal cavity and emanating from beneath

the middle turbinate • Computed Tomography of the paranasal sinuses identified a soft tissue mass in the right nasal cavity, extending into the ethmoid

air cells, sphenoid sinus, and eroding the cribriform plate

Conclusions• Physicians treating these patients should be aware of the increased risk of developing second

malignancies and perform life-long follow-up and screening• This is the first case study reporting a sinonasal adenocarcinoma as a secondary neoplasm in a

retinoblastoma survivor

References1. Abramson, D.H., et al., Retinoblastoma: survival, age at detection and comparison 1914-1958, 1958-1983. J Pediatr Ophthalmol Strabismus, 1985. 22(6): p. 246-50.2. Pendergrass, T.W. and S. Davis, Incidence of retinoblastoma in the United States. Arch Ophthalmol, 1980. 98(7): p. 1204-10.3. Vogel, F., Genetics of retinoblastoma. Hum Genet, 1979. 2: p. 1-54.4. Lai, H., F. Ma, and S. Lai, Identification of the novel role of pRB in eye cancer. J Cell Biochem, 2003. 88(1): p. 121-7.5. Perez-Ordonez, B., M. Beauchemin, and R.C. Jordan, Molecular biology of squamous cell carcinoma of the head and neck. J Clin Pathol, 2006. 59(5): p. 445-53.6. Yamasaki, L., Role of the RB tumor suppressor in cancer. Cancer Treat Res, 2003. 115: p. 209-39.7. Abramson, D.H., et al., Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced? Ophthalmology, 1984. 91(11): p. 1351-5.8. Melamud, A., R. Palekar, and A. Singh, Retinoblastoma. Am Fam Physician, 2006. 73(6): p. 1039-44.9. Roarty, J.D., I.W. McLean, and L.E. Zimmerman, Incidence of second neoplasms in patients with bilateral retinoblastoma. Ophthalmology, 1988. 95(11): p. 1583-7.10. Wenzel CT, H.E., Fisher SR., Second malignant neoplasms of the head and neck in survivors of retinoblastoma. Ear Nose Throat J. , 2001. Feb;80(2):106, 109-12.11. Albert, D.M., et al., Fibroblast radiosensitivity and intraocular fibrovascular proliferation following radiotherapy for bilateral retinoblastoma. Br J Ophthalmol, 1986. 70(5): p. 336-42.12. Malard, O., et al., Radiation-induced cancers of the pharynx and larynx: a study of five clinical cases. Clin Otolaryngol Allied Sci, 2002. 27(1): p. 68-74.13. Sale, K.A., et al., Radiation-induced malignancy of the head and neck. Otolaryngol Head Neck Surg, 2004. 131(5): p. 643-5.14. Sagerman, R.H., et al., Radiation induced neoplasia following external beam therapy for children with retinoblastoma. Am J Roentgenol Radium Ther Nucl Med, 1969. 105(3): p. 529-35.15. Halperin EC, C.L., Tarbell NJ, Kun LE, ed. Pediatric Radiation Oncology. 3rd ed. Philadelphia ed. 1999, Lippincott Williams and Wilkins. 126-62.16. Wong, F.L., et al., Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. Jama, 1997. 278(15): p. 1262-7.17. Brinton, L.A., et al., A case-control study of cancers of the nasal cavity and paranasal sinuses. Am J Epidemiol, 1984. 119(6): p. 896-906.18. Elwood, J.M., Wood exposure and smoking: association with cancer of the nasal cavity and paranasal sinuses in British Columbia. Can Med Assoc J, 1981. 124(12): p. 1573-7.19. Hayes RB, K.J., de Bruyn A., Tobacco use and sinonasal cancer: a case-control study. Br J Cancer. , 1987 Dec;56(6):843-6.20. Marees, T., et al., Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer, 2009.

Discussion• Survivors of genetically transmitted retinoblastoma have an increased risk of developing a

second nonocular tumor• In addition these patients have an increased sensitivity to carcinogenic effects of radiation• Whether a tumor is classified as radiation-induced is determined by following criteria:

• The secondary neoplasm has to be located within the irradiated volume • It must develop at least three years after the irradiation of the primary tumor • The administered dose of radiation has to exceed 2 Gy • The pathology should have excluded a metastatic tumor process [12, 13]

• A long latency period is characteristic for radiation induced tumors and within this field the most common secondary neoplasms are: osteosarcomas, fibrosarcomas and squamous cell carcinomas

• Patients who have been diagnosed with retinoblastoma have an increased susceptibility to oncogenic processes due to a genetic predisposition

• In addition, therapeutic radiotherapy also increases the risk of developing a second primary malignancy even after a substantial amount of time, in this case 27 years

A B

Figure 1: Pre-operative endoscopic view of right nasal mass. Thick Black arrow mass denotes polypoid mass emanating from right nasal cavity

Middle Turbinate Lateral nasal

wall

Figure 3: Intraoperative image of tumor removal. Posterior septectomy has been performed and thick arrow points to tumor mass.

• Magnetic resonance imaging of the brain and maxillofacial region showed a similar heterogeneous mass with dural displacement but no gross erosion

• Intra-operative findings: The bulk of the tumor was in the nasopharynxand it extended into the superior posterior right septum and filled the right ethmoids and sphenoid, extending to skull base and cribiform plate. It invaded the dura beneath the right cribiform plate

• Surgery: Endoscopic resection of tumor, bilateral ethmoidectomy,sphenoidotomy, and closure of skullbase defect with fascia lata graft, medpore implant, and left nasoseptal flap

• Pathology revealed a sinonasal adenocarcinoma with papillary features.• This was staged as a T4aN0M0 tumor and patient underwent post-

operative chemotherapy and proton beam radiation which was completed in October 2009

Figure 5: Axial (A) and Sagittal (B) T1 MRIs showing nasal cavity and skull base post endoscopic resection.