Radioactive phosphorus uptake test for the diagnosis of malignant melanoma of the choroid

Radioactive Phosphorus Uptake Test for the Diagnosis of Malignant Melanoma of the Choroid J.A. Shields and S. Packer

The most frequently used radioisotope in ophthalmology is radioactive phosphorus (32p). Since its introduction into ophthalmology in 1951, it has been used primarily as an aid in the diagnosis of malignant melanoma of the choroid. During the thirty years of clinical use, the indications for this test have been clearly defined. The m a x i m u m tissue penetration of

S~p is 7 m m . Surgical dissection is therefore frequently necessary to enable the ophthalmologist to place the Geiger-Muller probe on the sclera in proximity to the tumor. False positive and false negative results are unusual and the test is b e t w e e n 9 6 % and 1 0 0 % accurate,

ADIOACTIVE P H O S P H O R U S (32p) has been used to localize malignant tumors since 1939.' This followed its use as a metabolic tracer of phosphorus metabolism. 2 The rationale for the 32p test in tumor diagnosis was that incorporation of phosphorus into DNA and RNA synthesis is greater in malignant than normal tissues. Clinical applications were concerned with the diagnosis of superficial cancers? breast, 4 skin, s and testes. 6 The introduction of the gamma camera and gamma-emitting radiolabeled tracers resulted in the decline in the use of 32p as a diagnostic agent. The limited usefulness of 32p is due to the fact that it is a beta emitter with minimal tissue penetration (maximum: 7 mm). Phosphorus-32 was introduced into ophthalmo!ogy for the diagnosis of choroidal melanoma in 1951. 7.8 The detection devices were GeigerMuller probes that were placed on the anterior surface of the eye (Fig. 1), ~15-20 mm away from the tumor. Because of the lower penetration of 32p it is rather surprising that positive results were obtained clinically in some malignant tumors that were located in the posterior segment of the eye. The basic limitation of the anterior probe was the minimal tissue penetration of 32p. This limitation led to the development of posterior probes to closer approximate the counter to the base of the tumor (Fig. 1). This required surgical dissection of the conjunctiva so as to allow the probe to be placed on the sclera precisely of the base of the suspected tumor (within 1-2 mm) (Fig. 2). With this advance the test was found to be very accurate as an aid in the diagnosis of choroidal melanoma. Although, the initial enthusiasm for the accuracy of the 32p test was perhaps misleading 9 and false positives began to appear as case reports, '~ the clinical

usefulness has become more clearly defined in recent years. H

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Seminars in Nuclear Medicine, Vol. XlV, No. t (January), t 984

METHODS

Phosphorus-32, radioactive disodium phosphate (Na2HPO4), is injected intravenously in a dose of 10 ~Ci/kg body weight. The usual dose is 500-700 ttCi. Testing is performed 48 hr after injection. A surgical procedure is required for accurate localization of the tumors that are centered posterior to the ora serrata of the eye. ~2Surgery is not essential to count the activity of anteriorly located tumors. The conjunctiva is dissected for 360 ~ at the corneoscleral limbus (peritomy). Accurate localization of the tumor is done with transillumination (Fig. 3) or indirect ophthalmoscopy with scleral indentation. The sclera is marked with diathermy or dye at the periphery of the tumor. The probe is then placed on the sclera in the center of this area (Fig. 2). It is held in place by the surgeon while counting. Counts are obtained for 60-100 see. This is repeated three or four times. Because the average tissue penetration of 32p is 2-3 mm it is essential to count directly over the tumor. A normal area 180 ~ away from the tumor is then counted. O'Rourke ~3 has suggested a slightly different counting procedure. He recommends obtaining 1000 counts over tumor and control repeatedly and comparing time to gather these counts as the testing parameter. Results are expressed by the following formula: average of

From the Wills Eye tlospital, Ocular Oncology Service, Philadelphia, PA, and the Medical Department, Brookhaven National Laboratory, Upton, N Y 11973. Dr. Jerry A. Shields is currently at the Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, and is the Director of the Oncology Service, Wills Eye ttospital, Philadelphia, PA. Dr. Samuel Packer is currently affiliated with the Brookhaven National Laboratory, Upton, NY; Clinical Assistant Professor Radiology, Cornell University Medical College, New York, NY, and Chief Oncology Tumor Service, North Shore University Hospital, Manhas-~ set, NY. Address reprint requests to Samuel Packer, MD, Medical Department, Brookhaven National Laboratory, Upton, N Y 11973. 9 1984 by Grune & Stratton, Inc. 0001-2998/84/1401--0006501.00/0

31

32

SHIELDS AND PACKER EYE PROBES TYPES GEIGER-MULLER: NEON-HALOGEN GAS SEMICONDUCTOR: SILICONE-DRIFTEDLITHIUM MODELS ANTERIOR :

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Fig. I. Eye probes. The anterior probes are infrequently used. The posterior probe is easily manipulated between dissected conjunctiva and sclera so as to be positioned on the sclera w h e r e the choroidal t u m o r is located.

counts over tumor - average of counts over control/average of counts over control x 100 = % uptake. Using this formula 60% uptake has been considered positive by most authorities.

RESULTS

Figure 4 compares the results of 32p uptake between benign lesions and malignant melanomas. t4 An uptake of >50% has a high correlation with the lesion being a malignant intraocular tumor. The limited number of false negatives and positives can be seen in Table 1.~4 It must be stressed that 3,p uptake does not differentiate melanoma from other intraocular malignancies such as choroidai metastasis from a distant primary site. The increased use of the 32p beginning in the mid-1970s has been associated with a few case reports on false positive 32p uptake test (Table 2). Shields reported false positives of lesions suspected of being malignant."

Fig. 3. Posterior eye probe placement. The curved posterior probe is placed w h e r e the tumor location h a d been marked on the sclera. Gentle apposition, rather than pressure, is maintained against the sclera while counts a r e obtained.

DISCUSSION

The accuracy of the 32p uptake test has been stated to be between 96% and 100% in differentiating benign from malignant lesions (Table 1). lus However the occasional false positive t6-2~ and false negative 9.H'~5"2Lz2results stress that this procedure must be used in conjunction with other ancillary studies before a conclusive clinical diagnosis is made. The accuracy of the 3Zp uptake test in a situation where the other methods of diagnosis were not used is not known. However, % 0

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Fig. 2. Transilluminatlon of choroidal melanoma. This is the most frequently used method of tumor localization. A f i b e r optic probe is placed 180 * from the tumor.

MELANOMAS

Fig. 4. P-32 uptake in benign lesions and malignant melanomas. T h i r t y cases of benign lesions had an a v e r a g e uptake of 9%. One hundred cases of choroidal melanoma had an average uptake o f 239%~

32p UPTAKE TEST

33

Table 1. Accuracy of a2p Test Results in Histologically Verified Choroidal a n d / o r Ciliary Body Melanomas 32pTest Result Author Lomatzsch & Guntermann (1971)21 Vogel & StrStges (1971) z2 Hagler et al. (1977) 9 Shields et al. (1978) zl Van Dijk (1978) is

Number

Positive

Negative

% Correct Diagnoses

154 91 156 226 124

152 88 156 223 122

2 3 0 3 2

99 97 100 98.7 98

Table modified from Van Dijk. TM

Shields et al. 23 has stated that atypical cases that were misdiagnosed by all other modalities were correctly identified with the J2p uptake test. An area where the 32p uptake test is less controversial is in eyes with opaque media where the suspected melanoma cannot be visualized with ophthalmoscopy. Several techniques for combining the use of the 32p probe and ultrasound have been reported. 24-26Another area that has not been fully evaluated is use of the 32p uptake test to determine the effects of treatment. One clinic and one laboratory found the 32p uptake to change from positive to negative with treatment of the melanoma by photocoagulation, 27 or iodine-125 irradiation. :8 This use may increase with the increasing popularity of radiation rather than enucleation in the treatment of choroidal melanoma. The 32p uptake test has been reliable in that it has given negative results for most benign lesions, for example, benign choroidal nevi. However, its ability to differentiate small choroidal Table 2. Diagnoses w i t h False-Posltlve a2p Uptake Tests Number of Inflammatory Lesions

Cases

Uveitis Episcleritis Scleritis Granulation Tissue Tumors Hemangioma Choristoma Leiomyoma Nevus Adenoma Melanocytoma Miscellaneous Hemorrhage Disciform Macular Degeneration Staphyloma Hyperplasia Retinal Pigment Epithelium

4 1 1 1

Modified from references, lo.ls-2o

5 4 2 2 1 1 3 1 1 1

melanoma from large, suspicious choroidal nevi seems doubtful. ~m5 Generally, with choroidal hemangiomas there is a negative 32p uptake test. 33 The 32p test is not recommended for iris lesions nor for small choroidal masses, <10 • 10 • 2 mm. ]~'~aThe dilemma in the management of these small pigmented tumors centers around the fact that 10% contain malignant cells and have metastatic potential. 29 The fact that the 32p uptake test does not help in the differentiation of these lesions is no surprise since pathologists frequently have difficulty determining malignancy in this group, even with histopathologic sections. 3~ Comp!ications due to the 32p uptake test are rare 24"25and mostly hypothetical. The radiation dose from 750 ~Ci of 32p is considered acceptable. ~'~3 The target organ is bone and the bone dose is 20 rad. ~3 Manipulation of the globe during the ~2p uptake test has resulted in bleeding. 3]'32 This has also been seen spontaneously with larger choroidai melanoma so that it would be difficult to indict the 32p probe placement as the cause of the bleeding. Normal rubbing of the eye by the patient also can cause a hemorrhage in an eye with a melanoma. The same argument holds for tumor dissemination. It seems unlikely that the techniques used alter the probabilities of metastasis. The primary indication for the use of the 32p uptake test is in the ease'where the diagnosis cannot be made with other noninvasive diagnostic modalities. The uncertainty that will exist after these other modalities are used will vary with the experience of the clinician. Thus the definite indications are (1) the situation with a choroidal mass that cannot be diagnosed as malignant with less invasive modalities such as fluorescein angiography and ultrasonography, (2) those eyes with opaque media and suspected tumors by ultrasonography. In other clinical

34

SHIELDS AND PACKER

situations it is a confirmatory test, an example would be with ciliary body and choroidal melanomas. Finally, its usefulness with small to medium-sized choroidal lesions relates to the magnitude of the 32p uptake. Shields ~4 recommends treatment of small to medium-sized choroidal melanomas if the 32p uptake test is greater than 100%.

REFERENCES 1. Jones HB, Chaikoff IL, Lawrence JH: Radioactive phosphorus as an indicator of phospholipid metabolism: VI. The phospholipid metabolism of neoplastic tissues (mammary carcinoma, lymphoma, lymphosarcoma, sarcoma 180). J Biol Chem 128:631-636, 1939 2. Chiewitz O, Hevesy G: Radioactive indicators in the study of phosphorus metabolism in rats. Nature 136:754755, 1935 3. Kenney JM, Marinelli LD, Woodard HQ: Tracer studies with radioactive phosphorus in malignant neoplastic disease. Radiology 37:683-687, 1941 4. Low-Beer BVA, Bell HG, McCorkie H J, Stone RS: Measurement of radioactive phosphorus in breast tumors in situ: a possible diagnostic procedure. Radiology 47:492-493, 1946 5. Bauer FK, Steffen CG: Radioactive phosphorus in the diagnosis of skin tumors, differentiation of nevi, malignant melanomas, and other skin tumors. JAMA 158:563-565, 1955 6. Roswit B, Sorrentino J, Yalow R: The use of radioactive phosphorus (P-32) in the diagnosis of testicular tumors: a preliminary report. J Urol 37:724-727, 1950 7. Dunphy EB, Selverstone B: Distribution of radioactive phosphorus in ocular tissues. Transactions of the New England Ophthalmology Society. Am J Ophthalmo134:1603, 1951 8. Thomas CI, Krohmer JS, Storaasli JP: Detection of intra-ocutar tumors with radioactive phosphorus. Arch Ophthalmol 47:276-286, 1952 9. Hagler WS, Jarrett WH 1I, Killan JH: The use of the 32p test in the management of malignant melanoma of the choroid. A five-year follow-up study. Trans Am Acad Ophthalmol 83:49-60, 1977 10. Minckler D, Font RL, Shields JA: Non-melanoma ocular lesions with positive 32p tests, in Jakobiec F (ed): Ocular and Adnexal Tumors. Aesculapius Publishing Co, 1978, pp 237-244 I 1. Shields JA: Accuracy and limitations of the 32p test in the diagnosis of ocular tumors. An analysis of 500 cases. Ophthalmology 85:950-966, 1978 12. Shields JA, Sarin LK, Federman JL, MenshehaManhart O, et ah Surgical approach to the 32p test for posterior uveal melanomas. Ophthalmol Surg 5:13-19, 1974 13. O'Rourke J: Nuclear Ophthalmology. London, WB Saunders Co Ltd, 1976, pp 100-102 14. Shields JA: Diagnostic approaches to posterior uveal melanomas in Diagnosis and Management of lntraocular

Tumors. St. Louis, C.V. Mosby Co., 1983 pp 194-207, 210-254 15. Van Dijk RA: The 3,p test and other methods in the diagnosis of intraocular tumors. Doe OphthalmoI 46:1-132, 1978 16. Williams AT, Font RL, Van Dyke HJL, Riekhot FT: Osseous choristoma of the choroid simulating a choroidal melanoma. Arch Ophthalmol 96:1874-1977, 1978 17. Gass JDM, Guerry RK, Jack RL, Harris G: Choroidal osteoma. Arch Ophthalmol 96:428-435, 1978 18. Feldon SE, Sigelman J, Albert DM, Smith TR: Clinical manifestations of brawny scleritis. Am J Ophthalmol 85:781-787, 1978 19. Benson WE, Shields JA, Tasman WS, Crandall AS: Posterior scleritis. Arch Ophthalmo197:1482-1486, 1979 20. Coston TO, Wilkinson CP: Choroidal osteoma. Am J Ophthalmol 86:368-372, 1978 21. Lommatzsch P, Guntermann S: Uber den Klinischen weft des 32P-Testes bei der diagnistik intraokular Tumoren. Ophthalmologica 163:393-402, 1971 22. Vogel MH, Str~Stges MW: Der wert des ~2P-Testes bei der diagnose intraokularer Aderhautmelanome. Kiln Mbl Augenbeilk 159:375-382, 1971 23. Shields JA, Hagler WS, Federman JL, Jarrett WH, et al: The significance of the a2p test in the diagnosis of posterior uveal melanomas. Trans Am Acad Ophthalmol Otolaryngol 79:296-306, 1975 24. Lommatzsch P, Ulrich CL, Guntermann J, Millner R: 0ber Eine Neue Mensonde zur Diagnostik lntraocular Tumoren. AIb v Graetes Arch Kiln Exp Ophthalmol 172:105-107, 1969 25. Shields JA, Canny CLB: Ultrasonography and the 32p test in the diagnosis of choroidal melanoma with massive vitreous hemorrhage. Am J Ophthalmol 12:230-234, 1977 26. Packer S, Goldberg H, Feldman M: Ultrasoundguided P-32 test. Ann Ophthalmol 10:1411-1420, 1978 27. Shields JA, Annesley WH Jr, Federman JL, Sarin LK: Fluorescein angiography and 32p studies in photocoagulated choroidal melanomas, in L'Esperance FA (ed): Current Diagnosis and Management of Chorioretinal Disease. St. Louis, C.V. Mosby Co., 1977 28. Packer S, Rotman M, Fairchild R, et ah Irradiation of choroidal melanoma with iodine-125 ophthalmic plaque. Arch Ophthalmol 98:1453-1457, 1980 29. Davidorf FH, Lang JR: The natural history of malignant melanoma of the ehoroid: Small vs large tumors. Trans Am Acad Ophthalmol Otolaryngol 79:310-320, 1975 30. Gass JDM: Problems in the differential diagnosis of choroidal nevi and malignant melanoma. Am J Ophthalmol 83:299-315, 1977 31. Burton TC: lataogenic breaks in Bruch's membrane in choroidal melanomas. Trans Am Acad Ophthalmol Otolaryngol 81:841-845, 1976 32. Packer S: Hemorrhage of a choroidal melanoma. A complication of the radioactive phosphorus uptake test. NY State J Med 77:2274-2275, 1977 33. Lanning RC, Shields JA: Comparison of the radioactive phosphorus uptake test in comparable sized choroidal melanomas and hemangiomas. Am J Ophthalmol 87:769772, 1979