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Allopurinol-induced suppressor T cell dysfunction
Volume 7 Number 5 November, 1982
Correspondence
present since birth and not with the complaint of nevus cells in the reticular dermis and/or adnexae.
Gaily W. Cage, M.D. 5411 W. Cedar Lane, Suite 102A Bethesda, MD 20014
REFERENCE 1. Mark GJ, Mihm MC, Litelpo MC, Reed RJ, Clark WH: Congenital melanocytic nevi of the small and garment type. Hum Pathol 4:395-418, 1973.
Reply To the Editor: Dr, Cage emphasizes that there are no perfect methods of ascertainment for congenital nevi. We agree. He argues that up to 90% of lesions found to have "congenital" histologic features may be acquired lesions. Perhaps so. He also notes that our own data support the possibility that "congenital" histologic features are associated with an increased risk of melanoma. Again, we agree. Finally Dr. Cage concludes that patients with small congenital nevi are not at increased risk for melanoma. It is here that we disagree. 1'2 It may be true that patients with small congenital nevi have the same risk as patients with acquired nevi that have "congenital" histologie features. However, finding such acquired nevi is a surgical shell game that we do not recommend. In other words, we do not know how to macroscopically identify acquired nevi with "congenital" microscopic features. Furthermore, we are unable to predict which nevi with "congenital" features are at greatest risk for melanoma. The most we can do is to seek out "recognizable" varieties of nevi most likely to have the kinds of histologic features associated with melanocytic tumors detected in contiguity with cutaneous melanoma. Nevi with "congenital" histologic features appear to be only one variety of potential melanoma precursors. Others include lentigo maligna 3 and dysplastic nevi. 4 We agree with Dr. Cage that congenital means "existing at birth," documented by parents or medical records. (Medical records are known to be unreliable for documenting the presence of congenital nevi at birth. 5) It is unlikely that melanoma arising in association with a well-documented small congenital nevus is a chance occurrence. We do not suggest that our histologic investigations constitute a "proof" of this association. However, the presence of "congenital" histologic features in some melanoma-associated nevi in an unselected series of cases I is consistent with historic data provided by patients and their parents in other
687
studies. 2 Of 134 patients with primary cutaneous melanoma closely questioned about preexisting pigmented lesions at the tumor site, 20 attributed the origin of their melanomas to nevi present since birth. In 5 of these 20 patients, history was directly available from parents; in 2 of these 5, family photographs in the first 6 months of life corroborated parental history. 2 Given the penalties for error (i.e., removing too many congenital nevi in order to prevent some melanomas, versus not removing congenital nevi and perhaps missing potential precursors), even our descriptive histologic and historic data are useful for decisionmaking. Based on these data, we propose that the observed association between small congenital nevi and melanoma is greater than expected on the basis of body surface area considerations and a 1% prevalence of small congenital nevi. Until more reliable data are available, we suggest that all small congenital nevi be considered for prophylactic excision.
Arthur R. Rhodes, M.D. The Children's Hospital Medical Center 300 Longwood Ave. Boston, MA 02115
REFERENCES 1. Rhodes AR, Sober AJ, Day CL, Melski JW, Harrist TJ, Mihm MC, Fitzpatrick TB: The malignant potential of small congenital nevocellular nevi: An estimate of association based on a histologic study of 234 primary cutaneous melanomas. J AM ACADD~RMATOL6:230-241, 1982. 2. Rhodes AR, Melski JW: Small congenital nevoceltular nevi and the risk of cutaneous melanoma. J Pediatr 100:219-224, 1982. 3. Clark WH, Folberg R, Ainsworth AM: Tumor progression in primary human cutaneous malignant melanomas, in Clark WH Jr, Goldman LI, Mastrangelo MJ, editors: Human malignant melanomas. New York, 1979, Grune & Stratton, Inc., pp. 15-31. 4. Greene MH, Clark WH, Tucker MA, Elder DE, Kraemer KH, Fraser MC, Bondi EE, Guerry D, Tuthill R, Hamilton R, LaRossa D: Precursor nevi in cutaneous malignant melanoma: A proposed nomenclature. Lancet 2:1024, 1980. 5. Alper J, Holmes LB, Mihm MC: Birthmarks with serious medical significance. J Pediatr 95:696-700, 1979.
Allopurinol-induced suppressor T cell dysfunction To the Editor: In his editorial, "Allopurinol-Induced Suppressor T Cell Dysfunction: A Hypothesis" (J AM ACAD D~RMATOL 5:607-608, 1981), Berken suggests that in patients with renal impairment oxipurinol plasma concentrations may rise to levels capable of inhibiting
688
Journal of the American Academy of Dermatology
Correspondence
human purine nucleoside phosphorylase (PNP). He does not indicate that it requires an oxipurinol concentration of 0.8 raM, or 12 mg/dl, for 50% inhibition of PNP in vitro? This is four- to sixfold higher than those oxipurinol plasma concentrations observed even in complete renal failure, z In patients receiving 300 mg of allopurinol daily, we have observed that in those with impaired renal function, with a creatinine clearance in the range of 9.8 to 20 ml/min, the plasma oxipurinol level ranged from 0.9 to 3.0 mg/dl. 2 Therefore, we doubt that oxJpurinol plasma concentrations achievable in patients with reduced renal function are ever high enough to completely suppress PNP activity.
G. B. Elion, D.Sc. T. E. Williams, M.D. Departments of Experimental Therapy and Clinical h~vestigation Wellcome Research Laboratories Research Triangle Park, NC 27709
REFERENCES 1. Krenitsky TA, Elion GB, Henderson AM, Hitchings GH: Inhibition of human purine nucleoside phosphorylase. J Biol Chem 234:2876-2881, 1968. 2. Elion GB, Benezra FM, Beardmore TD, Kelley WN: Studies with allopurinol in patients with impaired renal function, in Rapado A, Watts RWE, DeBruyn Chris HMM, editors: Purine metabolism in man. IIIA. Clinical and therapeutic aspects. New York, 1980, Plenum Publishing Corp., pp. 263-267.
Reply To the Editor: Among the data that S. B. Howell submitted at the 1981 meeting of the American Society of Clinical Oncology to supplement the information in the abstract, "Selective Modulation by Oxipurinol of 5FU Toxicity to Human Marrow, Lymphocyte and Tumor Colony Forming Units In Vitro" (Proc Am Soc Clin Oncol 22:364, 1981) was that oxallopurinol was toxic to lymphocytes in culture at a concentration of 10 -4 M. He showed that this concentration was achieved in normal human subjects from hours 2 through 8 following a single 300-mg dose of allopurinol. It is not unreasonable to assume from these data that patients with significant renal impairment who have had repeated 300-rag doses of allopurinol can achieve the oxallopurinol plasma concentration of 8 × 10 -4 M reported by Dr. Elion to produce 50% inhibition of purine nucleoside phosphorylase (PNP), This degree of PNP inhibition may be responsible for the observed lymphocyte toxicity. Arthur Berken, M.D, 4277 Hempstead Tpke. Bethpage, NY 11714
Methotrexate guidelines and liver biopsies To the Editor: In regard to the article "Methotrexate Guidelines-Revised" by Roenigk, Auerbach, Maibach, and Weinstein (J AM ACAD DERMATOL 6:145-155, 1982), the recommendation for percutaneous liver biopsies before beginning methotrexate and periodically while methotrexate is being administered has an authoritative force which the practicing dermatologist may have difficulty in withstanding. Nonetheless, I believe, with a procedure with a mortality rate of one in 5,000, l and which is certainly not morbidity-free, that some thought must be given as to whether liver biopsies are of sufficient help in the day-to-day management of psoriatic patients on long-term methotrexate therapy. I am not sure that a careful review of the literature on the subject shows the procedure to be helpful in the management of the individual case, although there can be no question about the value of the research studies which have been done to date on this problem. I know of no other medicine used by physicians in which a liver biopsy is proposed as a baseline and periodic recheck tool. Obviously, the risk and expense make it a procedure which cannot be used very often, and the information obtained at such infrequent intervals may not be worth the risk and trouble. The recommended guidelines seem to impale the practitioner on a professional, moral, and medicolegal dilemma. If he has percutaneous liver biopsies done as baseline and interval evaluations on his methotrexatetreated psoriatics and then a complication results, the indications for the procedure may appear tenuous. If he does not have this procedure performed on these patients and hepatic damage occurs, then he has not done what the experts have chosen to represent as guidelines for methotrexate usage in psoriasis. Perhaps guidelines are not such a good idea here. Richard D. Cart, M.D. 1840 Zollinger Rd. Columbus, OH 43221
REFERENCE 1. Isselbacher KJ, LaMont JT: Diagnostic procedures in liver disease, in Isselbacher KJ, et al, editors: Harrison's Principles of internal medicine. New York, 1980, McGrawHill Book Co., p. 1453.
Reply To the Editor: Liver biopsies before and during management o f psoriasis with methotrexate (MTX) are no longer the exercise of a research project but are essential in the day-to-day management of psoriasis.
Correspondence
present since birth and not with the complaint of nevus cells in the reticular dermis and/or adnexae.
Gaily W. Cage, M.D. 5411 W. Cedar Lane, Suite 102A Bethesda, MD 20014
REFERENCE 1. Mark GJ, Mihm MC, Litelpo MC, Reed RJ, Clark WH: Congenital melanocytic nevi of the small and garment type. Hum Pathol 4:395-418, 1973.
Reply To the Editor: Dr, Cage emphasizes that there are no perfect methods of ascertainment for congenital nevi. We agree. He argues that up to 90% of lesions found to have "congenital" histologic features may be acquired lesions. Perhaps so. He also notes that our own data support the possibility that "congenital" histologic features are associated with an increased risk of melanoma. Again, we agree. Finally Dr. Cage concludes that patients with small congenital nevi are not at increased risk for melanoma. It is here that we disagree. 1'2 It may be true that patients with small congenital nevi have the same risk as patients with acquired nevi that have "congenital" histologie features. However, finding such acquired nevi is a surgical shell game that we do not recommend. In other words, we do not know how to macroscopically identify acquired nevi with "congenital" microscopic features. Furthermore, we are unable to predict which nevi with "congenital" features are at greatest risk for melanoma. The most we can do is to seek out "recognizable" varieties of nevi most likely to have the kinds of histologic features associated with melanocytic tumors detected in contiguity with cutaneous melanoma. Nevi with "congenital" histologic features appear to be only one variety of potential melanoma precursors. Others include lentigo maligna 3 and dysplastic nevi. 4 We agree with Dr. Cage that congenital means "existing at birth," documented by parents or medical records. (Medical records are known to be unreliable for documenting the presence of congenital nevi at birth. 5) It is unlikely that melanoma arising in association with a well-documented small congenital nevus is a chance occurrence. We do not suggest that our histologic investigations constitute a "proof" of this association. However, the presence of "congenital" histologic features in some melanoma-associated nevi in an unselected series of cases I is consistent with historic data provided by patients and their parents in other
687
studies. 2 Of 134 patients with primary cutaneous melanoma closely questioned about preexisting pigmented lesions at the tumor site, 20 attributed the origin of their melanomas to nevi present since birth. In 5 of these 20 patients, history was directly available from parents; in 2 of these 5, family photographs in the first 6 months of life corroborated parental history. 2 Given the penalties for error (i.e., removing too many congenital nevi in order to prevent some melanomas, versus not removing congenital nevi and perhaps missing potential precursors), even our descriptive histologic and historic data are useful for decisionmaking. Based on these data, we propose that the observed association between small congenital nevi and melanoma is greater than expected on the basis of body surface area considerations and a 1% prevalence of small congenital nevi. Until more reliable data are available, we suggest that all small congenital nevi be considered for prophylactic excision.
Arthur R. Rhodes, M.D. The Children's Hospital Medical Center 300 Longwood Ave. Boston, MA 02115
REFERENCES 1. Rhodes AR, Sober AJ, Day CL, Melski JW, Harrist TJ, Mihm MC, Fitzpatrick TB: The malignant potential of small congenital nevocellular nevi: An estimate of association based on a histologic study of 234 primary cutaneous melanomas. J AM ACADD~RMATOL6:230-241, 1982. 2. Rhodes AR, Melski JW: Small congenital nevoceltular nevi and the risk of cutaneous melanoma. J Pediatr 100:219-224, 1982. 3. Clark WH, Folberg R, Ainsworth AM: Tumor progression in primary human cutaneous malignant melanomas, in Clark WH Jr, Goldman LI, Mastrangelo MJ, editors: Human malignant melanomas. New York, 1979, Grune & Stratton, Inc., pp. 15-31. 4. Greene MH, Clark WH, Tucker MA, Elder DE, Kraemer KH, Fraser MC, Bondi EE, Guerry D, Tuthill R, Hamilton R, LaRossa D: Precursor nevi in cutaneous malignant melanoma: A proposed nomenclature. Lancet 2:1024, 1980. 5. Alper J, Holmes LB, Mihm MC: Birthmarks with serious medical significance. J Pediatr 95:696-700, 1979.
Allopurinol-induced suppressor T cell dysfunction To the Editor: In his editorial, "Allopurinol-Induced Suppressor T Cell Dysfunction: A Hypothesis" (J AM ACAD D~RMATOL 5:607-608, 1981), Berken suggests that in patients with renal impairment oxipurinol plasma concentrations may rise to levels capable of inhibiting
688
Journal of the American Academy of Dermatology
Correspondence
human purine nucleoside phosphorylase (PNP). He does not indicate that it requires an oxipurinol concentration of 0.8 raM, or 12 mg/dl, for 50% inhibition of PNP in vitro? This is four- to sixfold higher than those oxipurinol plasma concentrations observed even in complete renal failure, z In patients receiving 300 mg of allopurinol daily, we have observed that in those with impaired renal function, with a creatinine clearance in the range of 9.8 to 20 ml/min, the plasma oxipurinol level ranged from 0.9 to 3.0 mg/dl. 2 Therefore, we doubt that oxJpurinol plasma concentrations achievable in patients with reduced renal function are ever high enough to completely suppress PNP activity.
G. B. Elion, D.Sc. T. E. Williams, M.D. Departments of Experimental Therapy and Clinical h~vestigation Wellcome Research Laboratories Research Triangle Park, NC 27709
REFERENCES 1. Krenitsky TA, Elion GB, Henderson AM, Hitchings GH: Inhibition of human purine nucleoside phosphorylase. J Biol Chem 234:2876-2881, 1968. 2. Elion GB, Benezra FM, Beardmore TD, Kelley WN: Studies with allopurinol in patients with impaired renal function, in Rapado A, Watts RWE, DeBruyn Chris HMM, editors: Purine metabolism in man. IIIA. Clinical and therapeutic aspects. New York, 1980, Plenum Publishing Corp., pp. 263-267.
Reply To the Editor: Among the data that S. B. Howell submitted at the 1981 meeting of the American Society of Clinical Oncology to supplement the information in the abstract, "Selective Modulation by Oxipurinol of 5FU Toxicity to Human Marrow, Lymphocyte and Tumor Colony Forming Units In Vitro" (Proc Am Soc Clin Oncol 22:364, 1981) was that oxallopurinol was toxic to lymphocytes in culture at a concentration of 10 -4 M. He showed that this concentration was achieved in normal human subjects from hours 2 through 8 following a single 300-mg dose of allopurinol. It is not unreasonable to assume from these data that patients with significant renal impairment who have had repeated 300-rag doses of allopurinol can achieve the oxallopurinol plasma concentration of 8 × 10 -4 M reported by Dr. Elion to produce 50% inhibition of purine nucleoside phosphorylase (PNP), This degree of PNP inhibition may be responsible for the observed lymphocyte toxicity. Arthur Berken, M.D, 4277 Hempstead Tpke. Bethpage, NY 11714
Methotrexate guidelines and liver biopsies To the Editor: In regard to the article "Methotrexate Guidelines-Revised" by Roenigk, Auerbach, Maibach, and Weinstein (J AM ACAD DERMATOL 6:145-155, 1982), the recommendation for percutaneous liver biopsies before beginning methotrexate and periodically while methotrexate is being administered has an authoritative force which the practicing dermatologist may have difficulty in withstanding. Nonetheless, I believe, with a procedure with a mortality rate of one in 5,000, l and which is certainly not morbidity-free, that some thought must be given as to whether liver biopsies are of sufficient help in the day-to-day management of psoriatic patients on long-term methotrexate therapy. I am not sure that a careful review of the literature on the subject shows the procedure to be helpful in the management of the individual case, although there can be no question about the value of the research studies which have been done to date on this problem. I know of no other medicine used by physicians in which a liver biopsy is proposed as a baseline and periodic recheck tool. Obviously, the risk and expense make it a procedure which cannot be used very often, and the information obtained at such infrequent intervals may not be worth the risk and trouble. The recommended guidelines seem to impale the practitioner on a professional, moral, and medicolegal dilemma. If he has percutaneous liver biopsies done as baseline and interval evaluations on his methotrexatetreated psoriatics and then a complication results, the indications for the procedure may appear tenuous. If he does not have this procedure performed on these patients and hepatic damage occurs, then he has not done what the experts have chosen to represent as guidelines for methotrexate usage in psoriasis. Perhaps guidelines are not such a good idea here. Richard D. Cart, M.D. 1840 Zollinger Rd. Columbus, OH 43221
REFERENCE 1. Isselbacher KJ, LaMont JT: Diagnostic procedures in liver disease, in Isselbacher KJ, et al, editors: Harrison's Principles of internal medicine. New York, 1980, McGrawHill Book Co., p. 1453.
Reply To the Editor: Liver biopsies before and during management o f psoriasis with methotrexate (MTX) are no longer the exercise of a research project but are essential in the day-to-day management of psoriasis.