Small malignant melanomas: Clinicopathologic correlation and DNA ploidy analysis

Beacham et al. 4. Wilkinson DS, Kirton V, Wilkinson JO. Perioral dermatitis: a 12-year review. Br J Dermatol 1979;101:245-62. 5. Wilkinson D. What is perioral dermatitis? Int J Dermatol 1981 ;20:485-6. 6. Mellette JR, AelingJL, Nuss DD. Fluoridetoothpaste: a cause of perioral dermatitis. Arch Oermato1 1976;112: 730-1. 7. Grattan CEH, PeacheyRD. Contact sensitization to toothpaste flavouring. J R Call Gen Pract 1985;35:498. 8. Fisher AA. Contactstomatitis. Dermatol Clin 1987;5:70917. 9. Gosselin RE, Hodge HC, Smith RP, et al. eds. Clinical toxicology of commercialproducts, acute poisoning. 4th ed. Baltimore: Williams & Wilkens, 1976:ii-83.

Journal of the American Academy of Dermatology

10. Jones HE, Lewis CW, McMartin SL. Allergiccontact sensitivityin atopic dermatitis. Arch Dermatol 1973;107:21722. 11. Grove OI, Reid lG, Forbes 11. Humoral and cellular immunity in atopic eczema. Br 1 Dermatol197S;92:611-8. 12. Strannegard IL, Lindholm L, Strannegard O. T lymphocytes in atopic children. Int Arch Allergy App1 Immunol 1976;50:684-92. 13. Fisher AA, ed. Contact dermatitis. 3rd ed. Philadelphia: Lea & Febiger, 1986:131-40. 14. Miura Y, Lobitz we. Histochemical studies in atopic dermatitis: responses following controlled strip injury. J Invest DermatoI1964;42:115-7.

Small malignant melanomas: Clinicopathologic correlation and DNA ploidy analysis Hideko Kamino, MD,a Hiromaro Kiryu, MD,a, * and Howard Ratech, MDb, ** New York, New York, and Philadelphia, Pennsylvania Among the various clinical and histologic criteria used to differentiate between benign and malignant melanocytic neoplasms, emphasis has been placed on the size of the lesion. Malignant melanomas, when diagnosed, are usually larger than 6 mm in diameter whereas most acquired melanocytic nevi tend to be smaller. We tested this size criterion with a retrospective clinicopathologic study of 30 proliferations of atypical melanocytes within the epidermis and dermis that measured less than 6 mm in diameter. Nineteen cases fulfilled all 15 established histologic criteria for the diagnosis of malignant melanoma. The remaining 11 cases fulfilled 14 of 15 criteria. Four of eight of these small malignant melanomas analyzed by multiparameter flow cytometry were aneuploid (DNA ploidy index =50.9or 2::: 1.1). The sex ratio, race, and anatomic sites associated with these small melanomas were similar to those described in patients with malignant melanomas larger than 6 mm in diameter. Furthermore, one melanoma metastasized to a regional lymph node and another recurred. We conclude that small malignant melanomas less than 6 mm in diameter can have histologic features, DNA abnormalities, clinical presentations, and biologic potentials similar to larger lesions. (J AM ACAD DERMATOL 1990;22:1032-8.)

From the Dermatopathology Section, Departments of Dermatology andPathology, New York University Medical Center," and the Department of Pathology, Fox Chase CancerCenter, Philadelphia," Supported byNational Institutes ofHealthgrantNo. CA06927 andan appropriation from theCommonwealth of Pennsylvania. Accepted forpublication Sept. 8, 1989. Reprint requests: Hideko Kamino, MD, Dermatopathology Section, New York University Medical Center, 530 First Avenue, Suite 71, New York, NY 10016. *Dr. Kiryu was a Visiting Fellow in Dermatopathology, New York University Medical Center. **Present address: Department of Pathology, Columbia University, College of Physicians andSurgeons, New York, NY 10032. 16/1/16673

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In general, acquired melanocytic nevi are described as less than 6 mm in diameter, round, well circumscribed, smooth surfaced, and of relatively uniform pigmentation. In contrast, when malignant melanomas are first clinicallyidentified,they tend to be asymmetric with irregular borders, variegated, and usually greater than 6 mm in diameter.!" During the past severalyears we have seen several small proliferations of atypical melanocytes within the epidermis and dermis that fulfilled most of the histologic criteria for the diagnosis of malignant melanorna.? except that all of them were less than 6

Volume 22

Number 6, Part I

Small malignant melanomas 1033

June 1990

Table I. Histologic criteria for the diagnosis of malignant melanoma No. of eases

positive (N=30)

Architectural pattern Asymmetry Poor circumscription Increased number of atypical melanocytes as solitary units in epidermis Scattered melanocytes in upper reaches of epidermis Nests of melanocytes not equidistant Variation in size and shape of the nests of melanocytes Nests of melanocytes tend to confluence No maturation of atypical melanocytes with progressive descent into dermis Extension of melanocytes far down epithelial structures of adnexa Asymmetric distribution of melanin Asymmetric distribution of inflammatory cells Cytologic features Atypical nuclei Mitotic figures Necrotic cells Pagetoid cells (few to many)

30

26 30

29 30 30 30 30

%

Positive

100 87 100 97 100 100 100 100

28

93

30

100 97

29 30

29 30 30

100 97 100 100

Criteria from Maize J, Ackerman AB, eds. Pigmented lesions of the skin. Philadelphia: Lea & Febiger, 1987:182-3.

mm in greatest diameter. To determine whether these small proliferations of atypical melanocytes had histologic, clinical, and prognostic similarities to malignant melanomas larger than 6 mm in diameter and to test the size criterion, we performed a retrospective study of such cases. In addition, DNA ploidy analysis was performed with multiparameter flow cytometry. MATERIAL AND METHODS

A retrospective study was performed of 30 cases of small proliferations of atypical melanocytes involving both the epidermis and the dermis, which fulfilled most of the established criteria for the histologicdiagnosisof malignant melanoma, but on histologic sections measured lessthan 6 mm in greatest diameter. Nineteen specimens were from the files of the Dermatopathology Section at New York University Medical Center and 11 cases were submitted in consultation from outside laboratories. The cases were diagnosed from 1980 to 1988. All specimens were from excisional biopsies and submitted in toto for histologic processingin two to six stepsections. In sevencases,additional deeper sectionsthrough the blocks were obtained. Clinical information and follow-up data wereobtained by contacting the referring physicians. Multiparameter flowcytometry was performed on single nuclei suspensionsfrom paraffin blocks10,11 from 8 of the 30 specimens with a new two-color staining method that detects simultaneous nuclear S-lOO protein and DNA content in melanocytes.l? DNA aneuploidy was

defined as the presence of a discrete GOG1 population differing from diploid DNA content by 10%. RESULTS

Histologic features Table I shows the frequency of cases positive for each criterion used for the histologic diagnosis of malignant melanoma described by Maize and Ackerman." Except for size, 19 of 30 lesions fulfilled all 15 criteria (Figs. 1-4). The remaining 11 lacked only a single criterion each. Although poor circumscription was the least frequently satisfied criterion, it was still present in 26 cases (87%). Additional histologic findings suggestive of malignancy included the presence of mitoses in the dermal melanocytes in 20 cases (67%) and atypical mitotic figures in 13 cases (43%). One case had evidence of partial regression. Two lesions were associated with an intradermal melanocytic nevus. The neoplasms ranged from 1.8 to 5.5 mm in diameter (mean 3.49 mm) and from 0.25 to 1.4 mm in thickness (mean 0.71 mm). Nineteen lesions measured less than 0.76 mm in thickness. Except for size, most of the conventional histologic criteria for the diagnosis of malignant melanoma were fulfilled. Therefore we diagnosed these lesions as small malignant melanomas and not as Spitz nevi 13, 14 or as epidermotropically metastatic malignant rnela-

nomas.P

Journal of the American Academy of Dermatology

1034 Kamino et at.

~~i':.', .. ~ ~~

..

_"-!1'- •

Fig. 1. On scanning magnification this malignant melanoma 3.0 mm in diameter is asymmetric. Nests of melanocytes at left tend to confluence. (Hematoxylin-eosin stain; X20.)

Fig. 2. Higher magnification of Fig. I shows atypical melanocytes as solitary units and as irregular nests in the epidermis and dermis. Large atypical mitotic figure is present in dermis. (Hematoxylin-eosin stain; X250.)

Multiparameter flow cytometry DNA ploidy analysis Four of eight small malignant melanomas analyzed for 8-100 protein and DNA content were aneuploid (Table II and Fig. 5). A control group of 14 malignant melanomas greater than 6 mm in diameter, matched for level and thickness, showed no

Fig. 3. Low-power photomicrograph of a second primary malignant melanoma (2.4 mm in diameter). Neoplasm is asymmetric and poorly circumscribed. Epidermal component extends beyond dermal component (Hematoxylin-eosin stain; X30.)

Fig. 4. Higher magnification of Fig. 3 shows numerous melanocytes in all levels of epidermis including cornified layer. There are large nests of atypical melanocytes at dermoepidermal junction. (Hematoxylin-eosin stain; X250.) significant difference in the number of aneuploid cases (Table II). A small malignant melanoma developed in one patient subsequent to a large malignant melanoma at a different anatomic site. DNA ploidy analysis did not support the diagnosis of an epidermotropically

Volume 22 Number 6, Part I Jun e 1990

Small malignant melanomas 1035

Table Il. DNA ploidy in small and large malignant melanomas Small melanoma

« 6 rnrn diameter)

Level II III

Diploid Aneuploid Diploid Aneuploid

Thickness (mm) <0.76 Diploid Aneuploid 0.76-1.5 Diploid Aneuploid

A

Large melanoma mm diameter)

(~ 6

4 2 0 2

6 4 2 2

4 2

6 4 2 2

0 2

The values represent numb er of cases analyzed by multipara meter flow cytometry. Aneuploidy wa s defined as having a DNA ploidy index :s 0.9 or 2: 1.1.

metastatic malignant melanoma. In fact, the small melanoma was considered to be a second primary because it contained a major aneuploid (DNA ploidy index [DI] = 1.55) S-100 protein-positive population, which was not present in the first large melanoma (Fig. 6). In addition, the histologic features of the smaller lesion were also consistent with those of a primary malignant melanoma, and not an epidermotropically metastatic malignant melanoma 15 (Figs. 3 and 4) .

FL1

D

E

F

Clinical features Sixteen women and 14 men were included in the study with ages ranging from 21 to 64 years (mean 39 years). Seventeen patients (57%) were younger than 40 years. All 30 patients were white. The anatomic distribution of these small lesions was similar to that seen in larger malignant melanomas, notably the lower extremity predominance in women. The duration ranged from I month to 10 years (media n 6 months) for 17 cases in which this information was available. The clinical appearance of the lesions was recorded in 20 cases. Seven were of irregular color : tan-brown, dark brown-black, or red-black-white; four "darkly" pigmented; three of irregular shape and color; three lesions of irregular shape (two were described as "changing lesions"); one lesion was tan. The reason for excision of the lesion was recorded in 20 cases. The most common was a newly discovered or changing lesion in 18 cases, 10 of which occurred during follow-up for dysplastic nevus and/or a malignant melanoma. In one patient, a pigmented lesion was noted incidentally during evaluation for a

F L2

Fig. 5. Two-color flow cytometry analysis. Panel B shows a simultaneous DNA (FL2) and S-l00 protein (FLl; dim at top, bright at bottom) contour plot. Panels A, D, E, and F show DNA histograms. Panel C shows an S-100 protein histogram.

lung mass, which was subsequently diagnosed as a pulmonary adenocarcinoma, and in another patient a pigmented lesion was discovered on the leg during sclerotherapy for varicose veins. The clinical diagnosis was recorded in 26 cases. Malignant melanoma was diagnosed, or considered in the clinical differential diagnosis, in 16 patients (62%). Five patients had a personal history of dysplastic nevi only. Two patients had a personal history of previous malignant melanoma. Three patients had a

Journal of the American Academy of Dermatology

1036 Karnino et aJ.

o

100

200

Fig. 6. DNA histogram. Arrow indicates aneuploid peak (DI = 1.55) in a small malignant melanoma (solid line), which was not present in a prior larger melanoma (dotted line).

personal history of both dysplastic nevi and a previous malignant melanoma. None had a familial history of dysplastic nevi or m alignant melanoma.

Treatment and follow-up Eighteen lesions were treated, after histologic diagnosis of malignant melanoma, by wider margins of repeat excision ranging from 0.5 to 5.5 em. The clinical follow-up period ranged from 7 months to 8 years (median 1 year 4 months). The shortest follow-up period was for two patients with a previous history of malignant melanoma. Twentyfour patients are alive and well without recurrence or evidence of metastasis. One lesion recurred 3 years after the initial removal. One patient had a malignant melanoma measuring 5.5 mm in diameter and 0.6 mm in thickness, treated by wide and deep excision, which then metastasized to a regional lymph node 6 years later. The patient is alive and well with no evidence of recurrence or additional metastases 2 years after lymph node dissection. Four patients were lost to follow-up. DISCUSSION

Both the clinical and histologic criteria for distinguishing between malignant melanomas and melanocytic nevi emphasize differences based on the size of the neoplasm. Most acquired melanocytic nevi are usually less than 6 mm in diameter whereas malignant melanomas at the time of diagnosis tend to be larger than 6mm. I -8 Schmoeckel and BraunFalco' concluded that melanocytic lesions less than 5 mm in diameter can usually not be recognized as

malignant melanomas because the specific clinical and histologic features only become apparent as the tumor enlarges. We present data of a large retrospective series of melanocytic neoplasms that involve both the epidermis and the dennis and measure less than 6 mm in diameter. These tumors can be diagnosed histologically as malignant melanomas, even when they are as small as 1.8 mm in diameter. In our series, 26 of 30 malignant melanomas (87%) were less than 5 mm in diameter. In addition to identical histologic features, small malignant melanomas also share the same clinical features as larger malignant melanomas, including race, sex ratio, and distribution by anatomic site in men and women, notably the lower extremity predominance in women .16-18 Interestingly, the mean age of patients who present with small malignant melanomas in our series was 39 years. This is approximately 7 to 10 years earlier than the mean age of presentation reported for larger malignant melanomas.J'i-17 Thus it may be possible that these small malignant melanomas are present up to a decade before being recognized by the conventional size criterion. Five patients had a previous history of malignant melanoma. Therefore the differential diagnosis included a second primary malignant melanoma versus an epidermotropically metastatic malignant melanoma. IS However, the histologic features were those of a primary neoplasm and in one case the abnormal DNA ploidy indices of the first and second lesions were different. Thus the small malignant melanomas were interpreted as second primary lesions and not epidennotropically metastatic ones. Multiparameter flow cytometry DNA analysis revealed that four of eight cases of small malignant melanoma had an aneuploid S-l 00 protein-positive population. There was essentially no difference in the number of aneuploid cases in a control group of larger (> 6 mm) malignant melanomas matched for level and thickness. In addition, the percentage of aneuploid cases agrees with values reported by others for stage I malignant melanomas of compa rable level and thickness. 19-23 Because half of the cases of small « 6 mm) malignant melanomas studied for DNA content were aneuploid, this suggests that abnormal DNA stem-cell lines are present even in small, and presumably early, melanocytic neoplasms. It is important to make both clinical and histologic

Volume 22 Number 6, Part 1 June 1990

diagnoses of small malignant melanomas as early as possible because lesions that are smaller than 6 mm in diameter can extend into the dermis, recur, or even metastasize, as was found in one case each in our series. A single case of small malignant melanoma metastasized to a regional lymph node 6 years after the excision of the primary melanoma. The original lesion was 0.6 mm in thickness; this fits in well with the hazard-rate analysis of malignant melanomas made by Rogers et al.,24 in which malignant melanomas less than 0.76 mm in thickness had the maximum hazard rate during the nnd month (sixth year) of follow-up. On the basis of clinical appearance alone, the referring physicians diagnosed or suspected malignant melanoma in more than half of these small lesions. This was accomplished because the clinical criteria used for the diagnosis of larger melanomas such as asymmetry, irregular shape, and variegation I, 5-7,25-27were also identifiable in lesions smaller than 6 mm in diameter. Ten patients with a personal history of dysplastic nevi or malignant melanoma were in the high-risk group for malignant melanomas. 28-32 In these patients, close follow-up and high clinical suspicion helped in the excision of smaller malignant melanomas. Multiple primary malignant melanomas have been reported in 1.2% to 5.3% of patients with malignant melanoma. 33-38

Small malignant melanomas 1037

8.

9. 10.

11.

l2.

13.

14.

15.

16.

17.

18. We thank Dr. Alfred W. Kopf for his helpful comments in preparing the manuscript and Ms. Alice Subtelney for expert technical assistance in preparing the flow cytometry samples. REFERENCES l. Friedman RJ, Rigel DS, Kopf AW. Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA 1985;35:130-51. 2. Ackerman AB. Malignant melanoma in situ: the flat, curable stage of malignant melanoma. Pathology 1985;17:298300. 3. Schmoeckel C, Braun-Falco O. Diagnosis of early malignant melanoma: sensitivity and specificity of clinical and histological criteria. Pigment Cell 1987;8:96-106. 4. Howell JB. Spotting sinister spots. A challenge to dermatologists to examine every new patient at increased risk for signs of early melanoma. J AM ACAD DERMATOL 1986;15:722-6. 5. MacKie RM. Early recognition of malignant melanoma. J AM ACAD DERMATOL 1986;15:707-8. 6. Mihm MC Jr, Clark WC Jr, From L. The clinical diagnosis, classification and histogenetic concepts of early stages of cutaneous malignant melanomas. N Engl J Med 1971; 284: 1078-82. 7. Wick MM, Sober AJ, Fitzpatrick TB, et al. Clinical char-

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25. 26.

acteristics of early cutaneous melanoma. Cancer 1980; 45:2684-6. Kopf AW, Rodriguez-Sains RS, Rigel DS, et al. "Small" melanomas. Relation of prognostic variables to diameter of primary superficial spreading melanomas. J Dermatol Surg Oncol 1982;8:765-70. Maize J, Ackerman AB, ed. Pigmented lesions of the skin. Philadelphia: Lea & Febiger, 1987:182-3. Hedley DW, Friedlander ML, Taylor JW, et aJ. Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. J Histochem Cytochem 1983;31:1333-5. Hedley DW, Friedlander ML. Taylor IW. Application of DNA now cytometry to paraffin-embedded archival material for the study of aneuploidy and its clinical significance. Cytometry 1985;6:327-33. Kamino H, Ratech H. Improved detection of aneuploidy in malignant melanoma using multipara meter flow cytometry for S-I00 protein and DNA content. J Invest Dermatol 1989;93:392-6. Paniago-Pereira C, Maize JC, Ackerman AB. Nevus of large spindle and/or epithelioid cells (Spitz's nevus). Arch DermatoI1978;114:1811-23. Weedon W, Little JH. Spindle and epithelioid cell nevi in children and adults. A review of 211 cases of Spitz's nevus. Cancer 1977;40:217-25. Kornberg R, Harris M, Ackerman AB. Epidermotropically metastatic malignant melanoma. Differentiating malignant melanoma metastatic to the epidermis from malignant melanoma primary in the epidermis. Arch Dermatol 1978;114:67-9. Sober AJ, Rhodes AR, Mihm Me Jr, et aJ. Malignant melanoma. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al. eds. Dermatology in general medicine. New York: McGraw-Hill, 1987:947-66. Elias EG, Didollcar MS, Goel IP, et al. A clinicopathologic study of prognostic factors in cutaneous malignant melanoma. Surg Gynecol Obstet 1977;144:327-34. Kopf AW, Welkovich B, Frankel RE et aJ. Thickness of malignant melanoma: global analysis of related factors. J Dermatol Surg OncolI987;l3:345-419. Von Roenn J, KheirS, Wolter J, etal. Significance of DNA abnormalities in primary malignant melanoma and nevi,a retrospective now cytometric study. Cancer Res 1986; 46:3l92-5. Sondergaard K, Larsen JK, Muller U, et al. DNA ploidy characteristics ofhuman malignant melanoma analyzed by flow cytometry and compared with the clinical course. Virchows Arch B 1983;42:43-52. Frankfurt OS, Greco WR, Slocum HK, et al. Proliferative characteristics of primary and metastatic human solid tumors by DNA flow cytometry. Cytometry 1984;5:629-35. Buchner T, Hiddeman W, Wormann B, et aJ. Differential pattern of DNA-aneuploidy in human malignancies. Pathol Res Pract 1985;179:310-7. Kheir SM, Bines SD, Von Roenn JH, et aJ. Prognostic significance of DNA aneuploidy in stage I cutaneous melanoma. Ann Surg 1988;207:455-61. Rogers GS, Kopf AK, Rigel DS, et al. Hazard-rate analysis in stage I malignant melanoma. Arch Derrnatol 1986;122:999-1002. Mihm MC Jr, Clark WC Jr, Reed RJ. The clinical diagnosis of malignant melanoma. Semin Oncol 1975;2:105-18. Mihm MC Jr, Fitzpatrick TH, Lane Brown MM, et a1. Early detection of primary cutaneous malignant melanoma. A color atlas. N Engl ] Med 1973;289:989-96.

Journal of the American Academy of Dermatology

Kamino et al. 27. Milton GW. Clinical diagnosis of malignant melanoma. Br J Surg 1968;55:755-7. 28. Clark WH Jr, Reimer RR, Greene M, et al. Origin of familial malignant melanomas from heritable melanocytic lesions. "The B-K mole syndrome." Arch Dermatol 1978;114:732-8. 29. Elder DE, Goldman LI, Goldman SC, et al. Dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma. Cancer 1980;46: 1787-94. 30. Elder DE, Clark WC Jr. Developmental biology of malignant melanoma. In: Elder DE, ed. Pathobiology of malignant melanoma. Basel: Karger, 1987;8:22-5. 31. Rhodes AR, Weinstock MA, Fitzpatrick TB, et at. Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals. lAMA 1987; 258 :3146-54. 32. Titus-ErnstoIfL, Duray PH, Ernstolf MS, et al. Dysplastic

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nevi in association with multiple primary melanoma. Cancer Res 1988;48:1016-8. Pack GT, Schamagel 1M, Hillyer RA. Multiple primary melanoma. A report of sixteen cases. Cancer 1952;5: 1110-5. McLeod R, Davis NC, Herron JJ, et al. A retrospective survey of 498 patients with malignant melanoma. Surg Gynecol Obstet 1968;126:99-108. Cascinelli N, Fontana V, Cataldo I, et al. Multiple primary melanoma. Tumori 1975;61:481-6. Beardmore GL, Davis NC. Multiple primary cutaneous melanomas. Arch Dermatol 1975; I I :603-9. Veronesi U, Cascinelli N, BufalinoR. Evaluation of the risk of multiple primaries in malignant cutaneous melanoma. Tumori 1976;62:127-30. Moseley HS, Giuliano AE, Storm FK III, et at. Multiple primary melanoma. Cancer 1979;43:939-44.

Relation of application time to bioactivity of a potent topical glucocorticoid formulation Richard B. Stoughton, MD, and Karen Wullich, JD La Jolla, Calzfornia The vasoconstrictorassay in human beings was used to assess bioavailability during different time periods of exposure when 0.05% clobetasolpropionate cream (Temovate) was applied and left on for periods of 0.5, 1.0, 1.5, and 16.0 hours and subsequently washed. Maximal responses were achieved by 1.5 hours of exposure, but there was no significant differencein intensity of vasoconstriction between 1.0, 1.5, and 16.0hours of exposurebefore washing the sites. Exposures to 0.05% clobetasolpropionate cream for 0.5 hour were not significantly different from 16-hour exposures to 0.05% fiuocinonide cream, but exposuresto 0.05% clobetasol propionate cream for 1,0, 1.5, and 16.0hours all resulted in significantincreasesin vasoconstriction responses compared with f1.uocinonide cream applied and left on for 16 hours. Topical exposures to a superpotent topical steroid for a short time give vasoconstrictor responses equivalent to long time exposures. (J AM ACAD DERMATOL 1990;22: 1038-41.) What is the relationship between the length of time a glucocorticoid formulation is on the skin and its biologic activity? Official labeling for a topical steroid usually suggests twice-a-day applications without any attempt to remove the formulation other than by the bathing schedule of the patient. From the Division of Dermatology,School of Medicine, University of California at San Diego. Supported in part bya grant from Glaxo, Inc., Research Triangle Park, N.C. Accepted for publication Sept. 13, 1989. Reprint requests: Richard B. Stoughton, MD, Division of Dcrmatology/M-023C, School of Medicine, University of California at San Diego, La Jolla, CA 92093. 16/1/16761

1038

Does exposure for 16 hours after application, followed by removal, give a better result than exposure for 0.5 or 1 or 1.5 hours? Unfortunately, few data indicate the relationship of bioavailability of glucocorticoids during various time periods of exposure in vivo in human beings. It is generally assumed that there is a brief lag period for saturation of the stratum corneum and then a steady-state rate of penetration as long as the surface supply of the drug is adequate. Vickers 1 showed a biologically significant and long-lasting reservoir of glucocorticoids in vivo in human skin. Another example of the reservoir effect is the "minutes technique" of Schaefer et al. 2 for treating psoriasis with anthralin. Recent work sug-