Sinonasal Small Cell Neoplasm Developing After Radiation Therapy for Retinoblastoma: An Immunohistologic, Ultrastructural, and Cytogenetic Study DAISY SAW, JAISHREE AND

MD, JOHN K. C. CHAN,

JAGIRDAR,

MICHAEL

LEE,

MD,

M.

ALBA

MRCPATH, GRECO,

Patients with retinohlastoma have an increased risk of developing second primary tumors. Only a few examples of sinonasal small cell neoplasms developing after radiation therapy for retinohlastoma have been reported. We report one such case that developed 18 years after treatment for retinoblastoma. Histologic examination revealed a small, blue, round cell tumor without rosettes or cytoplasmic glycogen. Immunohistochemically, the tumor cells were positive for neuron-specific enolase, synaptophysin, and S-100 protein, but negative for epithelial and mesenchymal markers, sug gesting that this was a primitive neuroectodermal tumor. Cytogenetic studies of this tumor failed to reveal the chromosome 13 abnormality typical of retinoblastoma and the t(l1:22) translocation typical of the group of peripheral neuroepitheliomas. HUM PATHOL 23:896-899. Copyright 0 1992 by W.B. Saunders Company

Survivors of retinoblastoma are prone to develop second primary tumors on long-term follow-up.‘-4 The relative risk is particularly high in those patients with bilateral retinoblastoma, positive family history, retinoblastoma susceptibility gene, and history of radiation ‘-” The most common second primary tumor is osteosLcoma,1.2~‘0.1 ’ both within and outside the field of radiation. We describe the immunohistologic, ultrastructural, and cytogenetic findings of a rare sinonasal small cell neoplasm developing in a patient with retinoblastoma.

REPORT

In April 1990, the patient was hospitalized for a bout of epistaxis that was controlled by packing the nose. She presented to our hospital in June 1990 for nasal obstruction. On examination, a bulky, fleshy, grey, soft tissue tumor was found filling the left nostril. Computerized tomography and magnetic resonance imaging showed extensive tumor filling the left nose and the ethmoid, sphenoid, and frontal sinuses, with extension into the frontal lobe. The cribriform plate was not visible. Examination under general anesthesia revealed that the tumor had also extended into the previously reconstructed left orbit. The nasal tumor was biopsied. The patient refused further treatment.

MATERIALS

AND METHODS

Fresh tumor tissue was taken for flow cytometric analysis and cytogenetic studies. Some tissue was fixed in glutaraldehyde for electron microscopy. The remainder of the biopsy specimen was fixed in buffered formalin and processed in the usual manner for paraffin embedding. Sections 4 pm in thickness were cut and stained with hematoxylin-eosin and periodic acid-Schiff with and without diastase. Immunohistochemical studies with a panel of antibodies (Table 1) were performed on paraffin sections using the peroxidase-antiperoxidase method. The slides or paraffin blocks of the original eye operation

OF A CASE

A 1 g-year-old in the left nostril. the left eye, which Radiation therapy no record of the

MD,

MD

were not available for review.

RESULTS Pathologic

woman presented in June 1990 with a mass She had a past history of retinoblastoma of was enucleated when she was 1 year of age. was subsequently given. However, there was pathology report or the dose of radiation

administered. There was no known family history. Over the years the patient had multiple plastic reconstructions of her face because of improper bone growth. The last reconstruction was in February 1990. From the Departments of Surgical Pathology and Pediatric Pathology, New York University Medical Center, New York, NY; the Department of Clinical Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY; and the Institute of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong. Accepted for publication October 3, 1991. Key wor&: sinonasal neoplasm, immunohistochemistry, radiation, retinoblastoma. Address correspondence and reprint requests to Daisy Saw, MD, Department of Pathology, Booth Memorial Medical Center, 56-45 Main St, Flushing, NY 11355. Copyright 0 1992 by W.B. Saunders Company 0046.8177/92/2308-0010$5.00/O

a96

Findings

Histologic examination showed a cellular tumor composed of sheets and clumps of small, round, darkly stained cells lying in a fibrous stroma (Figs 1 and 2). The cells had scanty cytoplasm. The nuclei were round or irregular and hematoxyphilic, and had finely dispersed chromatin with indistinct nucleoli. Molding of nuclei was observed. The mitotic count averaged 1 per high-power field. Rosettes and fibrillary matrix were not observed. No cytoplasmic glycogen was demonstrated. The stroma was poorly cellular and poorly vascularized.

lmmunohistochemical

Findings

The tumor cells were strongly immunoreactive for synaptophysin and neuron-specific enolase, and scattered cells were weakly reactive for S-100 protein. The cells did not stain for cytokeratin, epithelial membrane antigen, leukocyte common antigen, glial fibrillary acidic protein, vimentin, muscle-specific actin, desmin,

POSTRETINOBLASTOMA

TABLE 1.

SINONASAL

Antibodies for lmmunohistochemical Studies, Their Sources, and Dilutions Used Dilution

Antibodies

1:50 1:800 1:50

DAK0

1:800 1:800

DAK0 DAK0

1:200 1:lOO 1:8,000

Biogenex (Dublin, CA) Biogenex Enzo Diagnostics (New York, NY) Enzo Diagnostics

(AEl, AE3)

1:800

Keratin

(CAM 5.2)

1:5

Synaptophysin Chromogranin Epithelial membrane antigen Desmin Glial fibrillary acidic protein Leukocyte-common antigen S-l 00 protein Carcinoembryonic antigen Vimentin Neuron-specific enolase Actin (HHF 35)

1:50 1:400 1:200

Melanoma

1:4,000

(HMB 45)

chromogranin, munoreactions those found in that the tumor antigen, B-cell

DISCUSSION Sinonasal undifferentiated neoplasms developing in patients with a history of retinoblastoma are rare. In view of a past history of retinoblastoma, the possibility of local recurrence has to be considered. However, this is most unlikely because recurrence of retinoblastoma usually occurs within 9 years of diagnosis, whereas the time lag in the present case is 18 years.12 Furthermore, Flexner-Wintersteiner rosettes (found in approximately 50% of retinoblastomas), chromosome 13 abnormality, and ultrastructural features typical of retinoblastoma are lacking. The presence of neural differentiation in this small cell tumor should also raise the possibility of olfactory neuroblastoma. However, in contrast to the latter, the stroma was much less vascularized, and S-l 00 protein-positive sustentacular cells enveloping the tumor lobules could not be demonstrated.r3 We therefore believe this tumor represents an unusual “primitive neuroectodermal tumor,” but appears to be distinguishable from peripheral neuroepithelioma, Ewing’s sarcoma, or Askin’s tumor by the absence of the 11:22 chromosomal translocation.r4 Only three similar cases of sinonasal small cell tumor have been previously characterized.14s’” These tumors developed 22, 35, and 37 years after radiotherapy for retinoblastoma. Two cases were considered to show dual epithelial and neural differentiation; the third case was considered to show epithelial, neural, and myogenic differentiation. These tumors behaved aggressively, with

or HMB 45. Table 2 compares the imof the previously reported cases15*r6 with our case. Flow cytometric analysis showed cells were negative for leukocyte common markers, and T-cell markers.

Electron Microscopy Electron microscopy showed tumor cells with microtubules and filaments. There were no electron-dense granules in the cytoplasm. No definite epithelial, neural, or mesenchymal differentiation was found. Cytogenetic

(Saw et al)

of group G. Intrachromosomal banding patterns revealed no consistent deviations from normal. A number of random chromosome breaks and translocations were noted, and probably represented aberrations arising in rapidly growing tumor cultures. No deletion was seen at the 650+ band level of resolution at band 13q14, the site of the retinoblastoma gene.

Source Boehringer and Mannheim (Indianapolis, IN) Becton Dickinson (Mountain View, CA) Boehringer and Mannheim Boehringer and Mannheim DAK0 (Santa Barbara, CA) DAK0 DAK0

Keratin

NEOPLASM

Studies

The tumor had the basic chromosome pattern of a normal female with 46 chromosomes and four members

FIGURE 1. Tumor composed of sheets and nests of small, darkstaining cells beneath the normal squamous epithelium. (Hematoxylin-eosin stain; magnification X75.)

897

HUMAN PATHOLOGY

Volume 23, No. 8 (August

the patients dying within months of diagnosis in spite of multimodal treatment. One case demonstrated deletion at the Rb 1 locus in the sinonasal tumor, but not in the normal tissue.‘” The sinonasal tumor of our case showed only immunohistochemical evidence of neural differentiation, whereas the previously reported cases were interpreted to show additional epithelial and/or myogenic difierentiation. However, it is doubtful whether immunoreactivity for cytokeratin alone can be considered conclusive evidence of epithelial differentiation, since small round cell tumors, such as Ewing’s sarcoma, olfactory neuroblastoma, and rhabdomyosarcoma, also have been reported to show cytokeratin positivity. 13*” With the application of the newer antibodies and more sensitive immunohistochemical techniques, an increasing number of small cell tumors have been shown to express markers of divergent lineages and “unexpected” antigens.14 Several series have shown that approximately 4.2% of survivors of retinoblastoma will develop second primary tumors.’ The incidence is even higher (15% to 20%) for patients with bilateral retinoblastoma.” The most common nonocular tumor is osteosarcoma,‘~2~‘0~” other tumors being fibrosarcoma, carcinoma, melanoma, lymphoma, leukemia, and undifferentiated malignant tumors. These tumors may develop either inside or outside the field of radiation.‘-4*7~8~”The relationship between radiation therapy and second malignancies was emphasized by several studies,‘*4,7,8 and Abramson et al have found radiation to increase the total incidence of second neoplasms in retinoblastoma survivors above the already high incidence in those survivors who have not received radiation.‘,” However, although radiation plays a role in the genesis of some second primary neoplasms in survivors of retinoblastoma, the occurrence of some second primary tumors in sites away from the field of radiation and in patients with no history of radiation suggests an

1992)

TABLE 2. lmmunohistochemical Reactivity of the Three Previously Reported Sinonasal Tumors and the Present Case, Occurring in Patients With a History of Retinoblastoma

Keratin AEl/AES Keratin CAM 5.2 Epithelial membrane antigen Carcinoemhryonic antigen Neuron-specific enolase s-100 Synaptophysin Chromogranin Glial fihrillary acidic protein New&lament Desmin Vimentin Actin Leukocyte-common antigen Leu-7 HMB 45 MOC 1 Abbreviations:

+ +

_ +

+ + _

NA

_

_

NA

_

_

NA ++/+++ +/++

+ + Focal _ _

_

t/+t

+ + t

_ _

ND _

NA

+ Focal

NA _

+ Focal

NA

_ _

ND _ _

ND _ _

NA NA NA

ND _

ND

ND

+t+

ND

ND _ _ _ _

NA, information

not provided;

ND

_

ND, not done

inherent susceptibility to develop tumors.“” The retinoblastoma susceptibility (Rb) gene, a suppressor gene, can provide a possible explanation for the high incidence of second tumors in these patients. The inheritance of an individual one mutated allele of Rb gene predisposes to the development of retinoblastoma with a 90% penetrance, whereas the sporadic form of retinoblastoma develops from the somatic mutation in the Rb gene. The Rb mutation also contributes to the development of other types of cancer in these individuals.‘-4.‘b

FIGURE 2. The neoplostic ceils have indistinct cell membranes, irregular nuclei, and fine chromatin. There is no attempt at glandular or rosette formation. (Hematoxylin-eosin stain; magnification X375.)

898

POSTRETINOBLASTOMA

SINONASAL

NEOPLASM

(Saw

et al)

7. Forrest AW: Tumors following radiation about the eye. Trans Am Acad Ophthalmol Otolaryngol 65:694-717, 1961 8. Sagerman RH, Cassady JR, Tretter P, et al: Radiation induced neoplasm following external beam therapy for children with retinoblastoma. Am J Roentgen01 Radium Ther Nucl Med 105:529-535, 1969 9. Abramson DH, Ronner HJ, Ellsworth RM: Second tumors in nonirradiated bilateral retinoblastoma. Am J Ophthalmol 87:624-627, 1979 10. Shah IC, Arlen M, Miller C: Osteogenic sarcoma developing after radiotherapy for retinoblastoma. Am Surg 40:485-490, 1974 11. Amendola BE, Lamm FR, Markoe AM, et al: Radiotherapy of retinoblastoma-A review of 63 children treated with different irradiation techniques. Cancer 66:21-26, 1990 12. Abramson DH, Ellsworth RM, Grumbach N, et al: Retinoblastoma: Survival, age at detection and comparison 19 14-l 958, 19581983. J Pediatr Ophthalmol Strabismus 22:246-250, 1985 13. Frierson HF, Ross GW, Mills SE, et al: Olfactory neuroblastoma, additional immunohistochemical characterization. Am J Clin Pathol 94:547-553, 1990 14. Gerald WI,, Battifora H, Miettinen M, et al: Intraabdominal desmoplastic small round-cell tumor, report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol 15:499-5 13, 1991 15. Frierson HF, Ross GW, Stewart FM, et al: Unusual sinonasal small-cell neoplasms following radiotherapy for bilateral retinoblastomas. Am J Surg Pathol 13:947-954, 1989 16. Greger V, Schirmacher P, Bohl J, et al: Possible involvement of the retinoblastoma gene in undifferentiated sinonasal carcinoma. Cancer 66: 1954-1959, 1990 17. Mole R, Lee I, Gould VE, et al: Immunocytochemical analysis of Ewing’s tumors, patterns of expression of intermediate filaments and desmosomal proteins indicate cell type heterogeneity and pluripotential differentiation. Am J Pathol 127:288-304, 1987

Recognition of these rare sinonasal small cell tumors that develop in patients with retinoblastoma is important because they are aggressive. These unusual second primary tumors may have arisen from a primitive cell capable of multidirectional differentiation. However, it is unclear whether they are radiation therapy related or whether they arise in a setting of genetic susceptibility in patients with retinoblastoma. Acknowledgment. We express our gratitude to Dr M. A. Perle for performing the cytogenetic studies and to Sunanda Goswani for performing the immunocytochemical studies.

REFERENCES 1. Abramson DH, Ellsworth RM, Kitchin FD, et al: Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced? Ophthalmology 91:1351-1355, 1984 2. Draper GJ, Sanders BM, Kingston JE: Second primary neoplasms in patients with retinoblastoma. BrJ Cancer 53:661-671, 1986 3. Lueder GT, Judisch GF, O’Gorman TW: Second nonocular tumors in survivors of heritable retinoblastoma. Arch Ophthalmol 104:372-373, 1986 4. Winther J, Olsen JH, de Nully Brown P: Risk of nonocular cancer among retinoblastoma patients and their parents. Cancer 62: 1458-1462, 1988 5. Reese AB, Merriam GR, Martin HE: Treatment of bilateral retinoblastoma by irradiation and surgery. Report on 15 year results. Am J Ophthalmol 32: 175-l 90, 1949 6. Tebbet RD, Vickery RD: Osteogenic sarcoma following irradiation for retinoblastoma. Am J Ophthalmol 35:811-818, 1952

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Sinonasal small cell neoplasm developing after radiation therapy for retinoblastoma: an immunohistologic, ultrastructural, and cytogenetic study.

Patients with retinoblastoma have an increased risk of developing second primary tumors. Only a few examples of sinonasal small cell neoplasms develop...
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