Recurrent Retinoblastoma With Mandibular Metastasis: A Case Report

Recurrent Retinoblastoma With Mandibular Metastasis: A Case Report

Accepted Manuscript Recurrent Retinoblastoma with Mandibular Metastasis: A Case Report Vikram Shetty, MDS, MBBS, DNB, Ganapathy Sriram S., MDS, MFDS(G...

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Accepted Manuscript Recurrent Retinoblastoma with Mandibular Metastasis: A Case Report Vikram Shetty, MDS, MBBS, DNB, Ganapathy Sriram S., MDS, MFDS(Glasgow), MOMSRCS(Edinburgh) PII:

S0278-2391(16)30887-4

DOI:

10.1016/j.joms.2016.09.027

Reference:

YJOMS 57462

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 5 July 2016 Revised Date:

17 September 2016

Accepted Date: 18 September 2016

Please cite this article as: Shetty V, Sriram S. G, Recurrent Retinoblastoma with Mandibular Metastasis: A Case Report, Journal of Oral and Maxillofacial Surgery (2016), doi: 10.1016/j.joms.2016.09.027. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title: Recurrent Retinoblastoma with Mandibular Metastasis: A Case Report Author 1: Vikram Shetty, MDS, MBBS, DNB, Director, Nitte Meenakshi Institute of Cleft and Craniofacial Surgery, K. S. Hegde Charitable Hospital,

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Derlakatte, Mangalore, Karnataka – 575018 e-mail: [email protected]

Author 2: Ganapathy Sriram S., MDS, MFDS(Glasgow), MOMSRCS(Edinburgh),

K. S. Hegde Charitable Hospital,

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Derlakatte, Mangalore, Karnataka – 575018

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Surgical Fellow, Nitte Meenakshi Institute of Cleft and Craniofacial Surgery,

e-mail: [email protected] Corresponding Author:

Vikram Shetty, MDS, MBBS, DNB,

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Director, Nitte Meenakshi Institute of Cleft and Craniofacial Surgery, K.S.Hegde Charitable Hospital,

Derlakatte, Mangalore, Karnataka – 575018

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e-mail: [email protected]

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Credit Institution: Nitte Meenakshi Institute of Cleft and Craniofacial Surgery, K. S. Hegde Charitable Hospital,

Derlakatte, Mangalore, Karnataka – 575018

Conflict of Interest: None Funding Source: None Abstract word count: 83 Manuscript word count: 1260

ACCEPTED MANUSCRIPT ABSTRACT: Retinoblastoma (RB) is an aggressive intra-ocular tumor arising from the cells of the retina. Infrequently, distant metastasis occurs in the advanced stages of the disease. This case report demonstrates the metastasis of the tumor to the mandible, an extremely rare phenomenon in

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itself. As this condition was observed in a recurrent tumor in a patient who had initially undergone chemotherapy, it makes this case report unique and gives new insights into the

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Keywords: Retinoblastoma, Metastasis, Mandible

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behavior of the tumor. An overview of the management of a metastatic RB is also discussed.

INTRODUCTION: Retinoblastoma (RB) is an aggressive intra-ocular childhood tumor often resulting in blindness. The interesting feature in patients diagnosed with RB is their liability to develop second primary tumors (SPT) elsewhere in the body. This has been strongly associated with hereditary type of RB. Nearly 35 different types of SPTs have been identified1, out of which

ACCEPTED MANUSCRIPT osteosarcoma, rhabdomyosarcoma and melanoma seem to occur more frequently1,2. Three (and sometimes four or five) second primary tumors have also been reported to have occurred in RB patients 3. RB is known to spread locally and metastasis is relatively rare. Among the sites for metastasis, the Central Nervous System (CNS) is the most common and bone

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marrow infiltration occurs infrequently giving rise to distant metastasis4. The prognosis of RB after metastasis is known to be poor, thus warranting aggressive treatment. Metastasis to the craniofacial bones is extremely rare and a literature search has revealed only a few reports

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right side of the mandible in a 3-year-old child.

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in the past five decades. We present a case of recurrent retinoblastoma with metastasis to the

CASE REPORT:

A 3-year-old boy reported to the Department of Craniofacial Surgery with an extensive swelling on the right side of the face. The boy’s parents reported that the lesion was first

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noticed at 20 months of age as a whitish-yellow plaque in the center of the right eye and was associated with diminished vision. On fundoscopic examination, he was diagnosed with retinoblastoma for which he underwent 6 cycles of chemotherapy (Vincristine, Etoposide and

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Carboplatin). After chemotherapy, the lesion was confirmed to have resolved. However, his

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vision did not improve and the patient did not report for regular follow-up. When the patient finally returned at 3 years of age, he presented with severe proptosis associated with complete blindness of the right eye (Figure 1 & 2). The patient had also developed a mandibular swelling after the chemotherapy sessions. The mandibular swelling at the time of examination was diffuse with indistinct borders and measured about 6x7 cm, extending from the corner of the mouth to the posterior border of the mandible; supero-inferiorly, it extended from the infra-orbital margin to the lower border of the mandible. On intraoral examination (Figure 3), the swelling appeared to be arising from the right side of the mandible, obliterating the mandibular buccal vestibule and extending across the buccal mucosa till the

ACCEPTED MANUSCRIPT maxillary alveolus on the right side. Antero-posteriorly, it extended from the region of the lower right canine to the retro-molar region. The lower deciduous molars were displaced medially. The mucosa on the tumor appeared highly vascular and the patient was unable to close the mouth due to impingement of the maxillary teeth on the tumor. On palpation, the

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tumor was found to be firm in consistency. Magnetic resonance imaging (MRI), computed tomography (CT) scan, bone marrow aspiration and incisional biopsy from right buccal mucosa were performed under general anesthesia.

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MRI and CT findings: The MRI (Figure 4) showed the right eye to be enlarged with an intra-conal mass filling the anterior and posterior chambers. The mass had an extra-ocular

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extension involving the extra-ocular muscles and also extending along the optic nerve, causing thickening of the nerve. Another large homogenous soft tissue mass was noted on the right side of the mandible with bilateral cortical expansion in the body and the ramus region. The mandibular mass was hyper-intense, showing bony destruction and extending into the

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muscle. CT (Figure 5 & 6) findings showed periosteal reaction.

Histopathology: Microscopic examination (Figure 7) showed several small round cells with scant cytoplasm arranged in an alveolar pattern separated by thin fibrous septae. There were

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focal areas of necrosis and high mitotic activity was evident. Immunohistochemistry studies

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showed the tumor cells to be positive to CD99 (Figure 8) and synaptophysin (Figure 9); focally positive to neuron-specific enolase (NSE, Figure 10) and p53 (Figure 11); and the Ki67 (Figure 12) proliferative index was 67%. The tumour cells were negative for Myogenin (Figure 13) and S-100 markers (Figure 14).The bone marrow aspirate showed numerous small round tumor cells. Correlating the clinical findings with the MRI, CT, and histopathological features, the final diagnosis of recurrent RB with metastasis to the right side of the mandible was concluded.

DISCUSSION:

ACCEPTED MANUSCRIPT RB is the most common intra-ocular tumor caused by the mutation of the RB1 gene and it is more prevalent in the developing world, such as in Asia and Africa5. Our patient seemed to have a sporadic mutation since no other family member presented a history of RB. It has been reported that when extra-ocular RB is clinically obvious, cure is very difficult and treatment

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should be planned with an attempt to save the child’s life 6. Since retinoblastoma patients are prone to develop SPTs, it is challenging to differentiate metastatic RB from a SPT. The case discussed here had a direct extra-ocular spread into the CNS along the optic nerve, and in

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addition, presented with a mandibular tumor which was later confirmed to be metastatic RB. When metastatic RB is suspected, it is advised to perform a full body examination which

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includes bone scintigraphy, bone marrow examination to check for distant metastasis and a lumbar puncture to check for CNS involvement. Our patient had bone marrow infiltration with extensive mandibular metastasis. However, metastases to other parts of the body were not clinically evident. Clinically, the tumor in the mandible appeared to be a direct extension

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of the ocular tumor. However, on careful radiological examination, the mandibular tumor was distinct and separated from the ocular tumor (Figure 4). The CT image clearly showed bilateral mandibular cortical expansion (Figure 6) with a cortical discontinuity in the body

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region through which the tumor proliferated into the soft tissue.

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The retina is the innermost light sensitive layer of the eye responsible for vision. It consists of several layers of neurons interconnected with synapse. Retinal glial cells are called Müller cells and they span the entire thickness of retina supporting the neurons. Retinoblastoma was initially thought to have originated from the glial cells of the retina. More recent studies have found that RB can originate either from retinal neurons or glial cells 7. Histology of a metastatic RB is non-specific and could be confused with any of the small round cell tumors like Ewings sarcoma (peripheral neuro-ectodermal tumor), rhabdomyosarcoma, lymphoma or desmoplastic small round cell tumor. Immunohistochemistry (IHC) of a metastatic RB is

ACCEPTED MANUSCRIPT complex and may vary depending on its cellular origin. It has been reported that IHC of RB shows more of neuronal characteristics than glial properties 8,9. In our case report, we arrived at the diagnosis of metastatic RB after correlating the histopathological report to the clinical features, MRI/CT findings, and bone marrow histology. The patient was immediately started

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on high dose chemotherapy. However, after 2 cycles, the patient died of respiratory complications. Regular follow-up and family support plays an important role in RB patients. Long-term follow-up of treated primary non-heritable RB is recommended to check for 10

. Our patient reported back with an

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recurrence, and heritable RB patients for SPT

inoperable metastasis into the mandible within 8 months of primary treatment. This shows

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the aggressiveness of the tumor and highlights the need for regular follow-up. Abandonment of therapy is the main cause of treatment failure in curable children, especially those whose parents are of low and middle-income status presumably because of limited resources and a perceived stigma of cancer or blindness

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. It was learned that the patient had lost hope in

CONCLUSION:

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healing.

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medical treatment after recurrence and resorted to other traditional/religious methods of

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Retinoblastoma usually occurs in infants and the child’s guardian plays an important role in seeking urgent medical attention to preserve a good quality of life for the child. Recurrence of the tumor, distant metastasis and SPT can further hamper the quality of life. Health education and awareness play an important role in successfully treating RB.

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REFERENCES: 1. Moll AC, Imhof SM, Bouter LM, Tan KE. Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet. 1997;18(1):27-34.

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2. Meadows AT, Friedman DL, Neglia JP, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009;27(14):2356-2362.

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3. Abramson DH, Melson MR, Dunkel IJ, Frank CM. Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology. 2001;108(10):1868-1876.

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4. Gündüz K, Müftüoglu O, Günalp I, Unal E, Taçyildiz N. Metastatic retinoblastoma clinical features, treatment, and prognosis. Ophthalmology. 2006;113(9):1558-1566. 5. Kivelä T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol. 2009;93(9):1129-1131.

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6. Dimaras H, Héon E, Budning A, et al. Retinoblastoma CSF metastasis cured by multimodality chemotherapy without radiation. Ophthalmic Genet. 2009;30(3):121-126. 7. Yuge K, Nakajima M, Miki H, Uyama M, Uemura Y, Tsubura A. Immunohistochemical

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features of the human retina and retinoblastoma. Virchows Arch. 1995;426(6):571-575.

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8. He W, Hashimoto H, Tsuneyoshi M, Enjoji M, Inomata H. A reassessment of histologic classification and an immunohistochemical study of 88 retinoblastomas. A special reference to the advent of bipolar-like cells. Cancer. 1992;70(12):2901-2908. 9. Kivelä T, Tarkkanen A, Virtanen I. Intermediate filaments in the human retina and retinoblastoma. An immunohistochemical study of vimentin, glial fibrillary acidic protein, and neurofilaments. Invest Ophthalmol Vis Sci. 1986;27(7):1075-1084. 10. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44 11.

Dimaras H, Kimani K, Dimba EAO, et al. Retinoblastoma. Lancet (London, England).

ACCEPTED MANUSCRIPT 2012;379(9824):1436-1446. LEGEND FOR FIGURES: FIGURE 1 & 2: Extra-oral clinical photographs

FIGURE 4: MRI showing the extent of tumor

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FIGURE 3: Intra-oral Photograph showing the site of biopsy

FIGURE 5 & 6: CT scan of the mandible showing periosteal reaction FIGURE 7: Histological section of the tumor

Synaptophysin, NSE & p53 markers respectively

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FIGURE 8, 9, 10, 11 &12: Positive IHC study of the tumour cells with CD99,

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Figure 13 & 14: Negative IHC study of the tumour cells with Myogenin & S100 markers

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