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Show Tournai of Cli" ical Nt'lIrtl- tll'hthalmoltlgy lin): 158- 161, 1991. Neuroblastoma Presenting as Acute Lymphoblastic Leukemia but Correctly Diagnosed After Orbital Fine- Needle Aspiration Biopsy Thomas L. Slamovits, M. D., Carl E. Rosen, M. D., and Mark J. Suhrland, M. D. © 1991 Raven Press, Ltd., New York A 31/ 2- year- old girl with a diagnosis of common acute lymphoblastic leukemia antigen ( CALLA)- positive acute lymphoblastic leukemia was noted to be hypertensive and developed a tonic- clonic seizure. Computed tomography scan of the head revealed a right orbital mass. Orbital fine needle aspiration biopsy demonstrated rosette- like arrangements of cells with fibrillar cytoplasmic processes suggesting neuroblastoma. The tumor cells were antineuron- specific enolase positive. The cytologic findings suggested neuroblastoma, a diagnosis confirmed on subsequent work- up. The difficulty in distinguishing neuroblastoma from acute lymphoblastic leukemia in the pediatric patient is discussed in terms of clinical and cytologic features. Key Words: Neuroblastoma- Acute lymphocytic leukemia- Orbit- Fine- needle aspiration biopsy. From the Departments of Ophthalmology ( T. L. S., C. E. R.) and Pathology ( M. l. S.), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, U. S. A. . Address correspondence and reprint requests to Dr. SlamoVlts at Department of Ophthalmology, Montefiore Medical Center, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, New York 10467, U. S. A. 158 In children it can be difficult to distinguish neuroblastoma from other pediatric malignancies such as acute lymphoblastic leukemia, Ewing's sarcoma, Wilms' tumor, rhabdomyosarcoma, retinoblastoma, and non- Hodgkin's lymphoma ( 1). In particular, the presenting signs and symptoms of neuroblastoma and acute lymphoblastic leukemia can be very similar ( 2). Careful attention to the details of the patient's clinical picture, as well as to the tissue and cell morphology, is essential to allow the physician to make the correct diagnosis. We report a case of neuroblastoma initially misdiagnosed as acute lymphoblastic leukemia. CASE REPORT A previously healthy 3V2- year old white girl presented to her pediatrician with a 3- week history of fatigue, leg pain, pallor, low- grade fever, and a bruise over her right eyebrow. Tests revealed a normochromic normocytic anemia ( hemoglobin, 8.2 g/ dl; hematocrit, 25.0%) and an absolute lymphocytosis ( leukocyte count, 5600/ mm3 ; differential, 26 polymorphonuclear cells, 6 bands, 59 lymphocytes, 2 monocytes, 1 eosinophil, 1 metamyelocyte, and 5 myelocytes). A pediatric oncologist performed an outpatient bone marrow biopsy which revealed Ll- type lymphoblasts. The results of flow cytometry done on the patient's bone marrow were reported to show 30% common acute lymphoblastic leukemia antigen-( CALLA, also known as COlO) positive cells that were terminal deoxynucleotidyl transferase ( TdT) negative ( 3). Total Band T cell counts were normal. Bone marrow smears revealed complete replacement with NEUROBLASTOMA PRESENTING AS ALL 159 small, round, blue malignant cells with prominent nucleoli. Bone marrow smears were negative for myeloperoxidase, butyrate esterase, and periodic acid- Schiff. A diagnosis of diploid, CALLApositive acute lymphoblastic leukemia was made. The patient was admitted to Montefiore Medical Center for chemotherapy with L- asparaginase, prednisone, and allopurinol. Vincristine was to be added days later. Hypertension was noted ranging from 130/ 80 to 140/ 90 at the time of discharge and was attributed to prednisone. Control was achieved with hydralazine. A skull series was performed and reported as normal. Three weeks after presentation a new right subconjunctival hemorrhage developed and was attributed to a fall. Eight days later she was readmitted for a tonic- clonic seizure that lasted 45 minutes. A computed tomography scan ( Fig. 1) was obtained, revealing a right orbital mass involving the sphenoid wing and lateral orbital wall, with extension into the medial cranial fossa, as well as possible involvement of the right cavernous sinus. A neuro- ophthalmology consultation was requested. Examination revealed a subconjunctival hemorrhage, periorbital ecchymosis, full extraocular movements, and normal pupillary reactions. Visual acuity was unassessable and funduscopy was normal in both eyes. A fine- needle aspiration biopsy of the right orbit ( Fig. 2) was performed. FIG. 1. Computed tomography scan dem. onst~ ating a right orbital mass involving the sphenoId wl. ng ~ nd lateral orbital wall. Other cuts showed extension IOtO the medial cranial fossa, as well as possible involvement of the right cavernous sinus. Direct smears were either fixed immediately in 95% ethanol and stained by Papanicolaou method, or air dried and stained with May- Gruenwald Giemsa. Needle rinses of all needles and syringes were performed with 0.9% saline solution, and this cell suspension was used to prepare specimens for immunocytochemistry. After concentrating the suspension to 5 x 105 cells/ mt cytocentrifuge preparations were made onto 0.05% poly L- Iysine slides ( Sigma) at 500 rpm for 5 minutes ( Shandon Cytospin II). Slides were air dried, fixed in acetone/ chloroform ( 1: 1) for 7 minutes. After several phosphate- buffered saline washes, a threestep avidin- biotin immunoperoxidase technique ( ABC Elite, Vector Laboratories) with the appropriate antibodies was used, with diaminobenzidine as chromogen and hematoxylin counter stain. Morphologic examination of the direct smears showed malignant small tumor cells in clusters with complete and incomplete rosette formation ( 2). Laboratory data obtained prior to the biopsy revealed hemoglobin 8.2 g/ d!, hematocrit 25.2%, prothrombin time 13 seconds, partial thromboplastin time 36 seconds, and a platelet count of 165,000 mm3 . Immunohistochemical studies were nonreactive with anti- CALLA and antidesmin antibodies. However, the cells were reactive with antineuron- specific enolase. These findings were consistent with a diagnosis of neuroblastoma ( 4). Further work- up revealed a right suprarenal mass, as well as positive urinary catecholamines, vanillylmandelic acid, homovanillic acid, and metanephrines. Bone marrow biopsies revealed antineuronspecific enolase- reactive tumor cells compatible with Stage IV neuroblastoma. Myelogram exhibited an extradural mass between thoracic level seven to nine and the child developed acute spinal cord compression. She underwent decompressive surgery, and laminectomies revealed metastatic neuroblastoma in the bone marrow space. Multiple courses of chemotherapy followed. Approximately 6 months after her diagnosis, the orbital mass was treated with 2,100 cGy radiation therapy divided into 12 fractions and applied to the orbits bilaterally with lateral opposed fields with dosing calculated at the midplane. Twenty- one months later a similar course of radiation was administered, this time with a dose of 2,160 cGy. Approximately 1 year after diagnosis the suprarenal mass was resected and revealed neuroblastoma with ganglioneuromatous differentiation, necrosis, calcification, and evidence of old hemorrhage. The patient died approximately 21/ 2 years after her neuroblastoma was diagnosed. 1Clin Neuro- ophthalmol. Vol. 11. No. 3, 1991 160 T. L. SLAMOVITS ET AL. FIG. 2. Light microscopy slide from fine- needle aspiration biopsy of the right orbital mass showing malignant small tumor cells in clusters with rosette formation ( incomplete in this photomicrograph) characteristic of neuroblastoma ( Papanicolau stain, xSOO). DISCUSSION Neuroblastoma is the most common malignant neoplasm of infancy and early childhood, accounting for approximately 500 new cases per year. Neuroblastoma is responsible for 50% of all malignancies found under two years of age, and approximately 30% of all malignant conditions diagnosed in the first year of life. Overall, neuroblastoma accounts for 7- 10% of childhood cancer. Leukemia is the most common form of cancer in children over 1 year of age, affecting approximately 2,500 children each year in the United States. Acute lymphoblastic leukemia accounts for approximately 80% of acute leukemia in children ( 1) with peak incidence occurring between 2 to 6 years of age. Approximately 65- 70% of all children with acute lymphoblastic leukemia have the B cell precursor type, characterized by positivity of CALLA, Major Histocompatibility Antigen Class II, and TdT ( 5). Similar ocular manifestations of neuroblastoma and acute lymphoblastic leukemia may include proptosis, periorbital ecchymosis, and subconjunctival hemorrhage ( 1,2). Bilateral lid ecchymoses when present are thought to be highly characteristic of neuroblastoma ( 6). When pediatric neoplasia is suspected, a Horner's syndrome or opsoclonus strongly suggests neuroblastoma ( 7). In a review of 18,389 pairs of eyes, Kincaid and Green ( 8) found in 233 pairs of eyes from patients diagnosed with acute lymphoblastic leukemia that 82% ( 190 of 233 cases) showed ocular involvement. In a series of children with neuroblastoma, Musarella et al. ( 7) found 19.4% ( 80 of 405 cases) of patients exhibited ophthalmological involvement, with ocular symptoms as the presenting signs in 8.1% ( 33 or 405 cases). Proptosis or periorbital ecchymosis secondary to orbital metastases was the most frequent ocular sign, reported in 14.8%. The bone marrow biopsy or peripheral blood smears obtained prior to our patient's hospitalization at Montefiore Medical Center were not available to us for review. We can therefore only suggest possible causes for some of the potentially confusing or misleading preadmission laboratory data. It was only after orbital fine- needle aspiration biopsy that reexamination of previously biopsied bone marrow tissue displayed the presence of characteristic neuroblastoma cell clusters and Homer- Wright rosette formation, rather than the dispersed- cell pattern typical of acute lymphoblastic leukemia ( 2,4). Unfortunately, staining with neuron- specific enolase was not done on the original outpatient bone marrow biopsy. Although CALLA staining is helpful in diagnosing leukemia, neither the distribution nor the behavior of NEUROBLASTOMA PRESENTING AS ALL 161 CALLA is specific for leukemic cells as demonstrated by binding of anti- CALLA immunoglobulin to granulocytes, fibroblasts, and cells of melanoma cell lines. In addition, the presence of a CALLA- like molecule has been identified on or in normal human kidney cells, small intestine, and breast ( 9). Pediatric bone marrow displays a higher CALLA reactivity ( approximately 34%) than adult bone marrow ( approximately 4.5%) ( 10), and in adult peripheral blood CALLA reactivity is as low as 0.001% ( 11). To our knowledge, there are no reports of CALLA- positive neuroblastoma cells. Incomplete review of the slides or incorrect gate settings on flow cytometry could have contributed to an erroneous CALLA- positive reading. Repeat CALLA testing after the orbital fine- needle aspiration biopsy confirmed that the tumor cells in fact were CALLA negative. Other supporting data included tumor cells that stained positive for neuron- specific enolase, which is present in up to 95% of patients with widespread neuroblastoma. The reported myelocytic precursors in the peripheral blood smear may have actually been neuroblastoma cells. The difficulty in distinguishing leukemic cells from neuroblastoma cells in the peripheral blood has been previously discussed ( 12,13). Hypertension of unknown cause in children should raise concern about possible neuroblastoma ( 4,14). Therefore, in retrospect, our patient's hypertension was clinically relevant and should have warranted investigation, since it is unlikely that a short course of prednisone could have caused the blood pressure elevation. In summary, this patient's case history outlines the considerable pitfalls and challenges in distinguishing between acute lymphoblastic leukemia and neuroblastoma. Both can present with similar systemic and ophthalmic signs, and the features of peripheral blood smears and bone marrow biopsies can be difficult to differentiate. To avoid making a misdiagnosis, careful review of bone marrow and peripheral blood smears for characteristic cytologic features is in order, as is assessment of cellular CALLA staining. Clustering of tumor cells around fibrillar material is suggestive of neuroblas-toma. Antineuron- specific enolase immunoglobulin studies are also useful if neuroblastoma is being considered. Finally, hypertension should increase the suspicion for neuroblastoma and lead to a work- up including urinary catecholamines, vanillylmandelic acid, homovanillic acid, and metanephrines, as well as abdominal imaging studies. Acknowledgment: This work was supported in part by an unrestricted departmental grant to the Department of Ophthalmology, Albert Einstein College of Medicine, Montefiore Medical Center from Research to Prevent Blindness Inc., New York, New York. REFERENCES 1. Rudolph AM, Hoffman JIE. Pediatrics. 18th ed. Norwalk, CT: Appleton & Lange, 1987: 1096- 100, 1113- 5. 2. Raney RB, Lyon GM, Porter FS. Neuroblastoma simulating acute leukemia. I Pediatr 1976; 89: 433- 5. 3. Letarte M, Vera 5, Iran R, et al. Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. I Ex- p Med 1988; 168: 1247- 53. 4. Finkelstein J2. Neuroblastoma: The challenge and frustration. Hematol Oneol Clin North Am 1987; 1: 675- 93. 5. Miller, DR. Childhood acute lymphoblastic leukemia: 1. biological features and their use in predicting outcome of treatment. Am I Pediatr Hematol Oneol 1988; 2: 163- 73. 6. Miller NR. In: Walsh and Hoyt's Clinical Neuro- Ophthalmology. 4th ed. 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