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Figure.
Effect of Topical 5% Imiquimod Cream on Melanocyte Density Counts
Effect of Topical 5% Imiquimod Cream on Melanocyte Density Counts

LM indicates lentigo maligna. The data shown is the melanocyte density count (MDC) per 400 × magnification in 52 participants with LM treated with neoadjuvant topical imiquimod 5% cream compared with negative controls. A total of 44 of 52 cases showed a decrease in MDC after 5% topical imiquimod treatment compared with the control biopsy specimens.

Table.  
Statistical Summary of Study Data for 52 Cases of LM Treated With Neoadjuvant Topical Imiquimod 5% Cream Compared With Concomitant Negative Controls
Statistical Summary of Study Data for 52 Cases of LM Treated With Neoadjuvant Topical Imiquimod 5% Cream Compared With Concomitant Negative Controls
1.
Tsao  HS, Sober  AJ. Acquired precursor lesions and marker of increased risk for cutaneous melanoma. In: Balch  CMH, Houghton  AN, Sober  AJ, Soong  SJ, eds.  Cutaneous Melanoma. 4th ed. St. Louis, MO: Quality Medical Publishing Inc; 2003:121-133.
2.
Bowen  AR, Thacker  BN, Goldgar  DE, Bowen  GM.  Immunohistochemical staining with Melan-A of uninvolved sun-damaged skin shows features characteristic of lentigo maligna.  Dermatol Surg. 2011;37(5):657-663.PubMedGoogle ScholarCrossref
3.
Gorman  M, Khan  MA, Johnson  PC, Hart  A, Mathew  B.  A model for lentigo maligna recurrence using melanocyte count as a predictive marker based upon logistic regression analysis of a blinded retrospective review.  J Plast Reconstr Aesthet Surg. 2014;67(10):1322-1332.PubMedGoogle ScholarCrossref
4.
Hazan  C, Dusza  SW, Delgado  R, Busam  KJ, Halpern  AC, Nehal  KS.  Staged excision for lentigo maligna and lentigo maligna melanoma: a retrospective analysis of 117 cases.  J Am Acad Dermatol. 2008;58(1):142-148.PubMedGoogle ScholarCrossref
5.
Hyde  MA, Hadley  ML, Tristani-Firouzi  P, Goldgar  D, Bowen  GM.  A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions.  Arch Dermatol. 2012;148(5):592-596.PubMedGoogle ScholarCrossref
6.
Gautschi  M, Oberholzer  PA, Baumgartner  M, Gadaldi  K, Yawalkar  N, Hunger  RE.  Prognostic markers in lentigo maligna patients treated with imiquimod cream: a long-term follow-up study.  J Am Acad Dermatol. 2016;74(1):81-87.e1, e81.PubMedGoogle ScholarCrossref
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Research Letter
April 2018

Comparison of Melanocyte Density Counts in Topical Imiquimod-Treated Skin Surrounding Lentigo Maligna vs Control Biopsy Specimens

Author Affiliations
  • 1University of Utah School of Medicine, Huntsman Cancer Institute, Salt Lake City, Utah
JAMA Dermatol. 2018;154(4):482-484. doi:10.1001/jamadermatol.2017.5632

Lentigo maligna (LM) is the most common subtype of melanoma in situ, usually occurring in the head and neck regions.1 Several treatment approaches include wide local excisions, staged excisions (confirmation of negative histologic margins prior to surgical reconstruction), radiotherapy, or topical imiquimod 5% cream. The distinction between the surgical border of LM and surrounding background melanocytic hyperplasia common to chronically sun-exposed skin can be ambiguous. Of all the histologic features of LM, only melanocyte density counts (MDC) are statistically significant in making a distinction between LM and background melanocytic hyperplasia.2,3 In 1 study,2 the mean (SD) MDC for the negative control group was 25.6 (9.3) compared with 82.7 (29.3) cells per 400 × magnification for LM. The average margin requirement for LM removal is reportedly 7.2 mm.4 When used in the neoadjuvant setting, topical imiquimod 5% cream enables the removal of most LM tumors with 2-mm margins.5 Gautschi et al6 reported that the risk for local recurrence after topical imiquimod treatment correlates with the total number of melanocytes per millimeter in the original biopsy specimen. We sought to evaluate MDCs in imiquimod-treated LM and negative control biopsy specimens to determine if there was a measurable difference in melanocyte density.

Methods

The institutional review board of the University of Utah School of Medicine approved this prospective study of 52 cases of LM treated with off-label neoadjuvant topical imiquimod 5% cream 5 days per week for 8 weeks followed by conservative staged excisions with 2-mm margins. Because the study was conducted along standard-of-care guidelines, informed consent was not required. All patients were treated by 1 Mohs surgeon at the Huntsman Cancer Institute at the University of Utah School of Medicine. A period of 2 to 4 months was allowed for recuperation between topical treatment and surgery. All patients had a 10-mm long fusiform biopsy taken as a negative control to establish a baseline MDC. The negative control was sampled from an ipsilateral site showing similar actinic changes as did the LM site. The mean distance of the negative control was 6 cm from the LM site. Frozen sections were prepared on radially sectioned LM specimens and stained with hematoxylin and eosin, Mart-1 (Cell Marque A103), and SOX10 (BioCare Medical BC34). The LM sites were located on the head (n = 47), neck (n = 3), and upper extremities (n = 2). Each resected LM lesion was quadrisected. The MDCs were simultaneously counted by the authors (S.F. and G.B.) viewing the specimens under a light microscope at 400 × magnification at 3 sites per quadrant and independently recorded. The MDCs for the negative control and all 4 quadrants of the resected LM were then averaged and compared.

Results

A total of 52 specimens were assessed. (13 women and 39 men; mean age, 67 years). The median (SD) MDC from the negative controls was 20.0 (6.2) (range, 9.0-36.7). The median (SD) MDC from the postimiquimod treatment sites was 14.4 (5.4) (range, 0.5-26.6). Using the 2-tailed paired t test, the results showed statistical significance (P < .001) (Figure) (Table). Of 52 participants, 44 (85%) showed decreased MDCs compared with the negative control group. Residual LM was observed in the central areas of 9 (17%) specimens, whereas 43 (83%) had no residual LM. One specimen had an averaged count of 0.5 MDC per 400 × magnification on all 4 quadrants of the specimen compared with a 32.4 MDC on the negative control specimen (0.02:1). Positive controls to verify Mart-1 and SOX10 immunostaining were used in all cases.

Discussion

Neoadjuvant topical imiquimod 5% cream applied 5 times weekly for 8 weeks was associated with decreased MDCs in LM treatment sites compared with the MDCs of negative control sites. The decreased melanocytic hyperplasia in imiquimod-treated sites reduced ambiguity in making a distinction between the border of the excised LM and background melanocytic hyperplasia.

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Article Information

Corresponding Author: Glen M. Bowen, MD, University of Utah School of Medicine, Huntsman Cancer Institute, 30 N 1900 E, 4A 330 School of Medicine, Salt Lake City, UT 84132 (glen.bowen@hci.utah.edu).

Accepted for Publication: November 15, 2017.

Published Online: February 16, 2018. doi:10.1001/jamadermatol.2017.5632

Author Contributions: Dr Bowen and Ms Flores had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bowen.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Administrative, technical, or material support: Luby.

Study supervision: Bowen.

Conflict of Interest Disclosures: None reported.

Meeting Presentation: This study was presented at the 2018 American Academy of Dermatology Annual Meeting; February 16, 2018; San Diego, California.

Additional Contributions: We thank Kenneth Boucher, PhD, of the Huntsman Cancer Institute, who provided expertise with regard to statistical analysis. He was not compensated.

References
1.
Tsao  HS, Sober  AJ. Acquired precursor lesions and marker of increased risk for cutaneous melanoma. In: Balch  CMH, Houghton  AN, Sober  AJ, Soong  SJ, eds.  Cutaneous Melanoma. 4th ed. St. Louis, MO: Quality Medical Publishing Inc; 2003:121-133.
2.
Bowen  AR, Thacker  BN, Goldgar  DE, Bowen  GM.  Immunohistochemical staining with Melan-A of uninvolved sun-damaged skin shows features characteristic of lentigo maligna.  Dermatol Surg. 2011;37(5):657-663.PubMedGoogle ScholarCrossref
3.
Gorman  M, Khan  MA, Johnson  PC, Hart  A, Mathew  B.  A model for lentigo maligna recurrence using melanocyte count as a predictive marker based upon logistic regression analysis of a blinded retrospective review.  J Plast Reconstr Aesthet Surg. 2014;67(10):1322-1332.PubMedGoogle ScholarCrossref
4.
Hazan  C, Dusza  SW, Delgado  R, Busam  KJ, Halpern  AC, Nehal  KS.  Staged excision for lentigo maligna and lentigo maligna melanoma: a retrospective analysis of 117 cases.  J Am Acad Dermatol. 2008;58(1):142-148.PubMedGoogle ScholarCrossref
5.
Hyde  MA, Hadley  ML, Tristani-Firouzi  P, Goldgar  D, Bowen  GM.  A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions.  Arch Dermatol. 2012;148(5):592-596.PubMedGoogle ScholarCrossref
6.
Gautschi  M, Oberholzer  PA, Baumgartner  M, Gadaldi  K, Yawalkar  N, Hunger  RE.  Prognostic markers in lentigo maligna patients treated with imiquimod cream: a long-term follow-up study.  J Am Acad Dermatol. 2016;74(1):81-87.e1, e81.PubMedGoogle ScholarCrossref
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