Melanoma in situ Part II. Histopathology, treatment, and clinical management H. William Higgins II, MD, MBE,a Kachiu C. Lee, MD, MPH,a Anjela Galan, MD,c and David J. Leffell, MDb Providence, Rhode Island, and New Haven, Connecticut

Learning objectives Describe appropriate treatment margins and modalities for MIS and discuss appropriate recommendations for genetic testing for patients with MIS and their family members. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Reviewer Dr Laura Ferris served as a reviewer and reported the following financial relationships: Abbott Laboratories, Principal Investigator, Other Financial Benefit; Abbott Laboratories, Consultant, Honorarium; Amgen, Principal Investigator, Other Financial Benefit; Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Institution); Boehringer Ingelheim, Principal Investigator, Other Financial Benefit (to Self); Castle Biosciences, Inc, Consultant, Honorarium; Castle Biosciences, Inc, Principal Investigator, Other Financial Benefit; Celgene Corporation, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc, Principal Investigator, Other Financial Benefit; Centocor Ortho Biotech Inc., Consultant, Honorarium; DermTech International, Principal Investigator, Other Financial Benefit; Eli Lilly and Company, Principal Investigator, Other Financial Benefit; Janssen Pharmaceuticals, Inc, Consultant, Honorarium; LEO Pharma, US, Principal Investigator, Other Financial Benefit; Medimmune, Principal Investigator, Other Financial Benefit; MelaSciences, Consultant, Honorarium; and Pfizer, Inc, Principal Investigator, Other Financial Benefit.

Melanoma in situ (MIS) poses special challenges with regard to histopathology, treatment, and clinical management. The negligible mortality and normal life expectancy associated with patients with MIS should guide treatment for this tumor. Similarly, the approach to treatment should take into account the potential for MIS to transform into invasive melanoma, which has a significant impact on morbidity and mortality. Part II of this continuing medical education article reviews the histologic features, treatment, and management of MIS. ( J Am Acad Dermatol 2015;73:193-203.) Key words: lentigo maligna; melanoma; melanoma in situ.

HISTOPATHOLOGY OF MELANOMA IN SITU Key points d

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The histopathologic diagnosis of melanoma in situ can be difficult Immunohistochemical stains may aid in the diagnosis by highlighting junctional melanocytes Microphthalmia transcription factor (MITF) and SOX10 are emerging as the preferred

From the Department of Dermatology,a Brown University School of Medicine, Providence; and the Departments of Dermatologyb and Pathology,c Yale University School of Medicine, New Haven. Funding sources: None. Conflicts of interest: None declared. Accepted for publication March 31, 2015. Correspondence to: H. William Higgins II, MD, MBE, Brown University School of Medicine, Department of Dermatology,

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immunohistochemical stains to aid in the diagnosis of melanoma in situ Atypical melanocytic hyperplasia in the setting of sun-damaged skin represents an important diagnostic challenge and can be difficult to differentiate from early melanoma in situ, particularly lentigo maligna

Melanoma in situ (MIS) is a proliferation of malignant melanocytes within the epidermis without 593 Eddy St, APC 10th fl, Providence, RI 02903. E-mail: [email protected]. 0190-9622/$36.00 Ó 2015 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2015.03.057 Date of release: August 2015 Expiration date: August 2018

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Abbreviations used: IHC: MIS: LM: MM: MMS: SEER: WLE:

immunohistochemical melanoma in situ lentigo maligna malignant melanoma Mohs micrographic surgery Surveillance, Epidemiology, and End Results wide local excision

invasion into the dermis. The criteria for histologic diagnosis include: (1) poor circumscription; (2) asymmetry; (3) a predominance of individual melanocytes over nests with (a) confluent growth along the dermoepidermal junction, (b) effacement of rete ridges, and (c) pagetoid scatter; (4) nests of atypical melanocytes with (a) confluence, (b) variability in shape and size, and (c) consumption of epidermis; (5) haphazard distribution; and (6) involvement of adnexal epithelium. The morphology of MIS may differ according to the histologic variant, which includes lentigo maligna (LM), superficial spreading, acral lentiginous, and mucosal. LM has effacement of the rete ridges and a proliferation of atypical melanocytes primarily along the basal layer with single cells predominating over nests of cells and variable pagetoid spread. Superficial spreading MIS is remarkable for pagetoid spread with single cells and groups of atypical melanocytes scattered throughout the epidermis into the granular or horny layers. Acral lentiginous MIS features a hyperplastic epidermis with lentiginous proliferation of atypical melanocytes, sometimes with prominent dendrites, that has variable density, atypia, and pagetoid scatter. Mucosal MIS shares histologic features of both acral lentiginous melanoma and LM. Occasional overlapping features between all variants of MIS may be seen, and involvement of the adnexal epithelium is a common feature.1 It can be challenging to accurately assess the number of junctional melanocytes present on microscopic evaluation of MIS. In such cases, immunohistochemical (IHC) stains may be used to help differentiate melanocytes from surrounding keratinocytes. A number of commercially available melanocytic markers exist, but their use depends on the preference or experience of the dermatopathologist. Some of the emerging preferred stains for MIS include microphthalmia transcription factor (MITF) and SOX10, which highlight the nuclei of melanocytes, thereby avoiding confusion with staining of pigmented keratinocytes that may be seen with markers of melanosome epitopes, such as Melan-A/MART-1.2,3 Fig 1 shows an example of MIS

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stained with hematoxylineeosin (Fig 1, A) and MITF (Fig 1, B). The technical quality of IHC stains is often laboratory-dependent, and it is of paramount importance that the dermatopathologist is familiar with the given laboratory’s staining patterns and pitfalls. Another obstacle in the histologic diagnosis of MIS is the recognition of pseudomelanocytic nests at the dermoepidermal junction, which may be seen in the setting of lichenoid inflammation. Pseudomelanocytic nests resemble melanocytic nests, but they label with melanocytic markers and with keratinocytic, macrophage, and T cell markers.4 Fig 1 shows pseudonests of lichenoid dermatitis stained with hematoxylineeosin (Fig 1, C ) and MITF (Fig 1, D). This pitfall highlights the importance of careful interpretation of IHC stains and close clinical pathologic correlation. In patients with LM (MIS on sun-damaged skin), atypical junctional melanocytic proliferations and melanocytic hyperplasia represent an important diagnostic challenge because they can be extremely difficult to differentiate from early MIS. These lesions consist of poorly defined proliferations of junctional melanocytes, which lack the prominent cellular atypia or density to meet the criteria of a fully developed MIS. In addition, the distinct criteria for MIS may not be present in all portions of any given MIS lesion. Some studies have attempted to define the expected background density of melanocytes in sun-damaged skin; the results suggest that chronically sun-exposed skin demonstrates increased melanocytic density.5 However, it is clear that there is a high degree of variability in melanocytic density.6 Some attempts have been made to define criteria that would help differentiate MIS from melanocytic hyperplasia of sun-damaged skin. Criteria that support a diagnosis of MIS over melanocytic hyperplasia of sun-damaged skin include the presence of melanocytic nests, an irregular distribution of melanocytes, the descent of melanocytes along the adnexal structures, the presence of melanocytes above the dermoepidermal junction, an increased number of melanocytes, pleomorphism and atypia of melanocytes, and an irregular distribution of pigment.6 However, these criteria are not fully reliable.6,7 In everyday practice, these cases are difficult and challenging because of concern about the under- or overdiagnosis of MIS. The ambiguous histopathology based on obtained biopsy specimens often mandates complete excision to establish a more definitive final diagnosis. There is occasional disagreement between experts in the diagnosis of melanocytic lesions;

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Fig 1. A, Hematoxylineeosin staining of melanoma in situ. B, Microphthalmia transcription factor immunostaining of melanoma in situ. C, Hematoxylineeosin staining of pseudonests of lichenoid dermatitis. D, Microphthalmia transcription factor immunostaining of lichenoid dermatitis. (A-D, original magnification: 310.)

however, expert review of problematic cases can improve patient care. It is imperative to recognize that partial biopsy specimens of melanocytic lesions are problematic and may be inadequate for accurate diagnosis (Table I).8 In addition, partial biopsy specimens of MIS may be misinterpreted as benign. It is well recognized that margins of MIS are difficult to evaluate on frozen sections and are not considered the best choice for the accurate assessment of surgical margins.9

CURRENT RECOMMENDATIONS AND TRENDS IN THE TREATMENT OF MELANOMA IN SITU Key points d

d

Excisional margins of 0.5 cm are considered the standard treatment for melanoma in situ, but the lack of randomized controlled trials supporting this standard is noteworthy There is evidence to support wider margins (ranging between 0.5-1.0 cm)

Because of the potential of MIS to transform into malignant melanoma (MM) and the possibility of sampling error in biopsy specimens of larger melanocytic lesions, excision with at least 0.5-cm margins is recommended.10-12 Based on

Table I. Studies examining melanoma in situ tumors with invasive component found on surgical removal

Study

Megahed et al21 Zalla et al22 Somach et al23 Weedon et al24 Bub et al36 Cohen et al112 Bosbous et al40

No. of MIS lesions

104 46 46 66 58 29 59

No. of MIS lesions found to have invasive component (% of total MIS lesions)

30 3 9 8 3 3 6

(29) (7) (20) (12) (5) (10) (10)

Surveillance, Epidemiology, and End Results (SEER) data, treatment of MIS has evolved over time, with the proportion of tumors excised with \1-cm margins increasing over the past 3 decades (Table II). This trend likely reflects consensus guidelines, released in the 1990s, suggesting 0.5-cm margins as the optimal surgical excisional margins for MIS.13-16 Different surgical excisional margins (\1 cm vs $1 cm) did not influence MIS-related survival.17 Investigations into appropriate margins for the treatment of MIS are ongoing, and will likely continue to be a topic of discussion in the coming years.

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Table II. Excisional margins of melanoma in situ, based on Surveillance, Epidemiology, and End Results data, 1973-2006 Margins

1973-1985

1986-1995

1996-2006

Excisional biopsy 1795 (58%) 1472 (10%) 3718 (5%) not otherwise specified Excisional margins 835 (27%) 7634 (53%) 43,435 (57%) \1 cm Excisional margins 485 (15%) 5343 (37%) 29,136 (38%) $1 cm Data from National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, 1973-2006.16

Current margin recommendations are largely based on clinical dogma and consensus discussion, and therefore warrant more rigorous evaluation. Guidelines in Australia and New Zealand rate the 0.5-cm excision margin recommendation as grade C, in which the ‘‘body of evidence provides some support for recommendations but care should be taken in its application.’’18 Likewise, the American Academy of Dermatology also graded the 0.5-cm margin for MIS as ‘‘III,’’ representing the lowest rank on the grading scale. Level III indicates that the recommendation was made based on ‘‘other evidence including consensus guidelines, opinion, case studies, or disease-oriented evidence.’’19 The American Academy of Dermatology guidelines recommend excisional margins between 0.5 and 1.0 cm, based on clinical judgment.19 The lack of randomized controlled trials supporting the 0.5-cm margin for MIS is striking, especially since 0.5-cm excisional margins are often considered the standard approach to treatment. The varying literature on MIS excision margins can create confusion for dermatologists. In a 2005 survey of 597 dermatologists, 55% responded that they would take #5-mm margins for a nonfacial MIS, and 33% responded that they would take [5-mm margins. For a facial MIS, 57% responded that they would take #5-mm margins, while 24% responded that they would take [5-mm margins. In this same survey, 10% of dermatologists considered MIS a premalignant/precancerous growth; 84% considered it a malignancy/cancer.20

UPSTAGING TO MALIGNANT MELANOMA Key points d

Based on the literature, a range of 5% to 29% of melanoma in situ cases are upstaged to invasive malignant melanoma after review of the pathology specimen obtained from complete excision

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Upstaging occurs more frequently after shave biopsy specimens

In a review of the literature, approximately 5% to 29% of MIS lesions actually proved to have at least 1 focus of invasion upon surgical excision. This finding upstaged the initial diagnosis of MIS to MM, but varied widely because of study sample sizes, which ranges from 66 to 104 patients. When combining data from all of the studies, approximately 19% of MIS lesions were upstaged to MM (Table II).8,21-24 This may be due to inadequate sampling within a mottled lesion with multiple morphologies resulting in a nonrepresentative biopsy specimen. Upstaging after biopsy occurs most frequently after shave biopsies compared to punch or excisional biopsies. In a review of 609 patients, 59 (10%) of patients were upstaged after surgical excision. Of these cases, 64% had been obtained by shave biopsy, compared to 27% obtained by punch biopsy.25 Therefore, it is prudent for physicians to obtain multiple scouting biopsy specimens in a lesion with multiple morphologies or in a large lesion with concern of focal invasion. Biopsy specimens should always include a portion of the lesion with the most concerning morphology.

TREATMENT: SURGICAL REMOVAL Key points d

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Surgical removal may be performed by wide local excision, staged excision with expedited permanent sections, or Mohs micrographic surgery Margins of 0.5 to 0.6 cm result in varying clearance rates and wider margins may be necessary for tumor removal

Various surgical options can be used for the treatment of MIS. These include wide local excision (WLE), staged excision, and Mohs micrographic surgery (MMS). WLE aims to remove the clinically apparent tumor and a surrounding margin of normal tissue. Staged excision removes the clinically apparent lesion and uses rushed permanent sections to identify the excised tissue for margin control. If margins are positive, additional tissue is surgically removed. Final closure of the wound bed is delayed until permanent sections show clear margins. MMS uses frozen sections to examine all portions of the epidermis. This technique can be combined with IHC stains to better delineate surgical margins. Because of unpredictable subclinical extension commonly associated with MIS, particularly on sun-damaged skin or for LM, WLE with 0.5-cm margins may be inadequate for tumor extirpation. Table III shows the margins needed for clearance of

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Table III. Surgical margins required for clearance of melanoma in situ Study

Surgical removal

Sectioning

Margin size (cm)

Clearance rates (%)

Agarwal-Antal et al38 Bienert et al27 Albertini et al26

Sample size

92 97 42

MMS MMS MMS

Permanent Frozen and permanent Frozen

Zalla et al22

46

MMS

Frozen

Bricca et al28

331

MMS

Frozen

1120

MMS

Frozen

0.5 0.5 0.5 0.6 #0.6 #1 #1.2 #1.5 #1.9 0.6 0.9 1.2 2.4 0.6 0.9 1.2 1.5 3

42 0 24 41 50 83 91 96 98 89 98.5 98.8 100 86 98.9 99.4 99.6 100

Kunishige et al29

Data from Kunishige et al.29 MMS, Mohs micrographic surgery.

MIS in various studies. Margin clearance rates with 0.5- to 0.6-cm margins range from 0% to 89%.22,26-29 Therefore, the currently accepted 0.5-cm margins for the treatment of MIS, recommended based on a consensus conference, may be inadequate.30,31 The size and type of the initial tumor should also be taken into consideration when determining excisional margins. LMs often have subclinical margins, and are more likely to be incompletely excised compared to non-LM MIS.32 Robinson et al33 found that larger LMs often required a wide margin for excision, with tumors [3 cm requiring a margin of #1 cm for resection. In contrast, tumors \2 cm required margins \1 cm.

STAGED EXCISION Key points d

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Staged excision is a means of improving margin control through sequential surgical removal of tissue after examination of the edges by pathology using permanent sections Methods of staged excision include the square technique and the spaghetti technique

Occasionally, because of the finding of positive margins after initial excision, additional tissue needs to be removed. Staged surgical excision with permanent section avoids the limitations of removal by MMS, which is an approach that has not yet been standardized. Several approaches and techniques

have been reported for staged excision of MIS. Johnson et al34 developed a square technique for LM in which the tumor is first illuminated with a Wood’s lamp. Next, a double-lined square is outlined with a 0.5- to 1-cm margin from the tumor. Afterward, the outer perimeter of the square is excised and closed. Positive margins are marked on a map, and the patient returns for reexcision of these areas. When all margins are clear, the central bulk of the tumor is excised as the last step.34 The spaghetti technique is similar to the square technique, except that outlines are drawn to match the clinical contour of the lesion, instead of in a square. The central tumor is also excised as the last step.35 Several other staged surgical excision techniques have been described, with varying geographic shapes and contours used to excise the tumor.34,36-46

MOHS MICROGRAPHIC SURGERY Key points d

d

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Mohs surgery for melanoma in situ has shown variable clearance rates and success Because of the difficulty of accurately visualizing melanocytes on frozen sections, its success is dependent on the skill of the technician and surgeon Immunohistochemical stains have been employed to better delineate melanocytes on frozen sections

In order to preserve tissue in locations where MIS frequently occurs, some have proposed using the

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Table IV. Studies examining recurrence rates of melanoma in situ treated with Mohs micrographic surgery Study

No. of MIS lesions

Surgery type

Follow-up time (months)

Recurrence rate (%)

184 76 331 116 26 77 92 38 125 55 49 50 35 109 11 42 49 31

MMS MMS MMS, HMG-45 in 33% of lesions MMS, frozen and permanent sections MMS MMS MMS Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision Staged excision

50 33 58 63 58 22 48 25 38 57 14 96 0 32 4.7 31 26 42

0.5 0 0.3 1.8 2.2 1 0 2.6 2 3.6 0 7 0 3.7 0 0 1.7 10

Zitelli et al116 Bienert et al27 Bricca et al28 Bene et al117 Cohen et al112 Clayton et al115 Agarwal-Antal et al38 Hill et al118 Huilgol et al113 Bub et al36 Moller et al44 Walling et al46 Johnson et al34 Malhotra et al119 Mahoney et al120 Jejurikar et al121 Bosbous et al40 Lee et al122

Data from McLeod et al.114 FS, Frozen section; HMG, human melanoma black; PS, permanent section.

Mohs microscopically controlled surgery approach. In this method, surgeons examine frozen sections of tissue cut to allow for visualization of 100% of the epidermis. Frozen sections are often not suitable for the accurate diagnosis of melanocytic lesions.9 Therefore, IHC stains, such as HMB-45, MEL-5, MITF, and MART-1, are often used to better delineate melanocytes on frozen sections.47-51 Several studies have examined recurrence rates of MIS after treatment with MMS, varying from 0% to 10% (Table IV). The use of MMS is limited by several factors, including the experience of the treating surgeon, the skill of the laboratory technician in cutting and staining the tissue for frozen sections, and avoiding freeze artifact.52 In frozen sections, melanocytes lack the shrinkage artifact often seen in permanent sections, and instead appear plump with prominent cytoplasm that can be easily mistaken for keratinocytes.47,50 Because the MMS approach to treating MIS has not been standardized and depends to a large degree on the skill of the surgeon and histopathology technician, evaluating the outcomes from different centers is difficult.52-54

TOPICAL THERAPY Imiquimod Key points d Imiquimod is not FDA approved for the treatment of melanoma in situ; its use is therefore considered off-label d Clearance rates with imiquimod can vary widely

There are several case reports and open-label studies of the use of imiquimod 5% cream for treatment of MIS, LM subtype.55 Imiquimod is an immune response modifier that works by activating Toll-like receptor 7 (TLR-7) and causes a localized immune response at the targeted site(s). It is approved by the US Food and Drug Administration for the treatment of superficial basal cell carcinoma, actinic keratosis, and genital warts. Its use for MIS is considered off-label but has been described in the literature.56 Clearance rates with imiquimod vary widely, with some MIS lesions failing to respond at all and others clearing 100% with no evidence of recurrence.57-69 Treatment regimens also varied widely, with some using the medication several days a week and others using it only once weekly. Similarly, the treatment period ranged from 4 to 36 weeks. In some cases, tumor recurred as LM melanoma, highlighting the risk that imiquimod may not treat deeper components of the tumor.66,70 A rigorous protocol using daily applications of imiquimod for 12 weeks has been proposed for the treatment of MIS. There must be clinical erythema during a minimum of 10 of the 12 weeks.71 Of note, residual clinical hyperpigmentation can still be present in lesions treated with imiquimod, even with histologic clearance of MIS.63,71-73 In addition to the use of imiquimod as monotherapy, this medication can also be used in conjunction with tazarotene and surgical excision.59,74-76 In 1 study of 40 patients, use of

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imiquimod 5 times a week for 3 months before staged excision resulted in no recurrences at 18 months.75 Patients who use imiquimod plus tazarotene may have even better responses compared to the use of imiquimod alone.59 However, there is a lack of randomized controlled trials examining the use of imiquimod with or without tazarotene before surgery compared with surgery alone. Therefore, definitive conclusions cannot be drawn. The well-known adverse effects of pruritus, erythema, irritation, and flu-like systemic symptoms, though tolerable, also need to be considered when choosing imiquimod for the treatment of MIS.77-79 While the use of imiquimod 5% cream has been examined in several case series of LM on facial locations, its use in non-LM MIS is infrequently reported. Three case reports were found in a review of the literature. In 2 of the cases, the tumor was recurrent after several treatments, including MMS, at which point imiquimod 5% cream was used.66,80 In 1 case, the tumor developed an invasive component during the course of imiquimod treatment.66 Use of imiquimod for primary treatment of MIS, non-LM types is poorly studied and therefore is not advisable as off-label monotherapy.

Intralesional interferon-alfa Key point d Intralesional interferon-alfa has been successfully used for the treatment of melanoma in situ in several case reports Several reports have examined the use of interferon-alfa (IFN-a) for the treatment of MIS. Carucci and Leffell81 successfully treated recurrent MIS of the upper and lower eyelid with 3 million units of intralesional IFN-a 3 times per week (39 million units total). Posttreatment biopsy specimens revealed clearance of the tumor.81 Cornejo et al82 achieved biopsy-proven clearance in 9 of 11 cases treated with IFN-a. Their treatment regimen included 3 million units for tumors #2.5 cm and 6 million units for tumors [2.5 cm, 3 times per week. The mean treatment duration was 15.4 months (range, 4-40 months).82 Turner et al83 reported a woman with xeroderma pigmentosa and 10 MIS lesions. Tumors were treated with either 1 million units of IFN-a or placebo and surgically excised for histologic examination. MIS treated with IFN-a showed no evidence of residual MIS, whereas those treated with placebo showed the presence of a tumor.83

Other topical medications Key point d There are case reports regarding the use of other topical medications for the treatment of melanoma in situ 5-Flurouracil,84-86 azelaic acid,87-94 and retinoic acid derivatives59,95,96 have also been investigated as treatments for MIS. These are mostly small case series or case reports and should not be considered first-line treatments for MIS.

RADIATION Key point d

There are limited studies on the use of radiation for melanoma in situ

There are a limited number of studies investigating the use of radiation for MIS. Grenz rays and fractionated radiotherapy have varying degrees of success.97,98 Recurrence rates range from 0% to 20%, and side effects include radiation dermatitis, telangiectasias, hypo- or hyperpigmentation, erythema, and the development of other neoplasms, such as basal and squamous cell carcinoma.98-102 Radiation therapy is not considered a first-line treatment but may be appropriate depending on other factors, such as lesion size, anatomic site, and patient comorbidity.

LASER THERAPY Key point d

Recurrence after laser therapy can be as high as 38%

Several lasers have been used to treat MIS in case reports and case series. These lasers include CO2, Q-switched neodymium-doped yttrium aluminium garnet, Q-switched ruby, argon, and alexandrite. Combinations of these laser modalities have also been tried. The largest case series involved 22 patients treated with the Q-switched neodymiumdoped yttrium aluminium garnet laser. Recurrence rates were 23% after a follow-up of \3 months.103 When evaluated as a class of treatment, recurrence rates of MIS treated with laser were as high as 38%, with some progressing to LM melanoma.103-111 A major challenge with laser therapy is the absence of histopathology to evaluate the presence of invasive components and confirmation of complete extirpation of the tumor. In conclusion, our understanding of melanoma in situ and its treatment is evolving. The histopathologic diagnosis of MIS continues to be challenging, even to expert dermatopathologists. Pseudomelanocytic nests, lichenoid inflammation, and a background of

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sun-damaged skin also add to the diagnostic challenge. In addition, obtaining an incomplete biopsy specimen can lead to sampling error, which may result in upstaging to invasive melanoma. The treatment paradigm for MIS continues to improve with time. Surgical excision remains the standard of care for the treatment of MIS. In addition to wide local excision with at least 0.5-cm margins, staged surgical excision and MMS with frozen section IHC stains may be useful. However, the use of MMS for this purpose requires additional study and is variable depending on the skill of the physician and histotechnician. Second-line treatments—topical agents, intralesional IFN-a, radiation, and laser therapy—may have roles in the primary treatment of patients who are unable to tolerate surgery or as treatment adjuvant to excision. Until the efficacy of these modalities is better proven in the literature, we do not recommend their use as monotherapy. REFERENCES 1. Tan MAL, Ackerman AB. Criteria for histopathologic diagnosis of melanoma, 1947-2000: a critique in historical perspective. Dermatopathol Pract Conceptual. 2001;7:39-53. 2. Buonaccorsi JN, Prieto VG, Torres-Cabala C, Suster S, Plaza JA. Diagnostic utility and comparative immunohistochemical analysis of MITF-1 and SOX10 to distinguish melanoma in situ and actinic keratosis: a clinicopathological and immunohistochemical study of 70 cases. Am J Dermatopathol. 2014;36:124-130. 3. Kim J, Taube JM, McCalmont TH, Glusac EJ. Quantitative comparison of MiTF, Melan-A, HMB-45 and Mel-5 in solar lentigines and melanoma in situ. J Cutan Pathol. 2011;38:775-779. 4. Silva CY, Goldberg LJ, Mahalingam M, Bhawan J, Wolpowitz D. Nests with numerous SOX10 and MiTF-positive cells in lichenoid inflammation: pseudomelanocytic nests or authentic melanocytic proliferation? J Cutan Pathol. 2011;38:797-800. 5. Madden K, Forman SB, Elston D. Quantification of melanocytes in sun-damaged skin. J Am Acad Dermatol. 2011;64:548-552. 6. Barlow JO, Maize J Sr, Lang PG. The density and distribution of melanocytes adjacent to melanoma and nonmelanoma skin cancers. Dermatol Surg. 2007;33:199-207. 7. Weyers W, Bonczkowitz M, Weyers I, Bittinger A, Schill WB. Melanoma in situ versus melanocytic hyperplasia in sun-damaged skin. Assessment of the significance of histopathologic criteria for differential diagnosis. Am J Dermatopathol. 1996;18:560-566. 8. Scolyer RA, Thompson JF, McCarthy SW, Strutton GM, Elder DE. Incomplete biopsy of melanocytic lesions can impair the accuracy of pathological diagnosis. Australas J Dermatol. 2006;47:71-73. 9. Prieto VG, Argenyi ZB, Barnhill RL, et al. Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions? Am J Clin Pathol. 2003;120:203-208. 10. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005;365:687-701. 11. Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351:998-1012.

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12. National Comprehensive Cancer Network. NCCN guidelines for melanoma. Fort Washington (PA): National Comprehensive Cancer Network; 2014. 13. Kroon BB, Bergman W, Coebergh JW, Ruiter DJ. Consensus on the management of malignant melanoma of the skin in The Netherlands. Dutch Melanoma Working Party. Melanoma Res. 1999;9:207-212. 14. Sober AJ. Diagnosis and management of early melanoma: a consensus view. Semin Surg Oncol. 1993;9:194-197. 15. National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, January 27-29, 1992. Am J Dermatopathol. 1993; 15:34-43. 16. Diagnosis and treatment of early melanoma. NIH Consensus Development Conference. January 27-29, 1992. Consens Statement / NIH Consensus Development Conference National Institutes of Health Consensus Development Conference. 1992; 10:1-25. 17. Mocellin S, Nitti D. Cutaneous melanoma in situ: translational evidence from a large population-based study. Oncologist. 2011;16:896-903. 18. Australian Cancer Network Melanoma Guidelines Revision Working Party. Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand. Cancer Council Australia and Australian Cancer Network Sa. 19. Bichakjian CK, Halpern AC, Johnson TM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. 2011;65:1032-1047. 20. Charles CA, Yee VS, Dusza SW, et al. Variation in the diagnosis, treatment, and management of melanoma in situ: a survey of US dermatologists. Arch Dermatol. 2005; 141:723-729. 21. Megahed M, Schon M, Selimovic D, Schon MP. Reliability of diagnosis of melanoma in situ. Lancet. 2002;359: 1921-1922. 22. Zalla MJ, Lim KK, Dicaudo DJ, Gagnot MM. Mohs micrographic excision of melanoma using immunostains. Dermatol Surg. 2000;26:771-784. 23. Somach SC, Taira JW, Pitha JV, Everett MA. Pigmented lesions in actinically damaged skin. Histopathologic comparison of biopsy and excisional specimens. Arch Dermatol. 1996;132: 1297-1302. 24. Weedon D. A reappraisal of melanoma in situ. J Dermatol Surg Oncol. 1982;8:774-775. 25. Egnatios GL, Dueck AC, Macdonald JB, et al. The impact of biopsy technique on upstaging, residual disease, and outcome in cutaneous melanoma. Am J Surg. 2011;202: 771-777. discussion 7-8. 26. Albertini JG, Elston DM, Libow LF, Smith SB, Farley MF. Mohs micrographic surgery for melanoma: a case series, a comparative study of immunostains, an informative case report, and a unique mapping technique. Dermatol Surg. 2002;28:656-665. 27. Bienert TN, Trotter MJ, Arlette JP. Treatment of cutaneous melanoma of the face by Mohs micrographic surgery. J Cutan Med Surg. 2003;7:25-30. 28. Bricca GM, Brodland DG, Ren D, Zitelli JA. Cutaneous head and neck melanoma treated with Mohs micrographic surgery. J Am Acad Dermatol. 2005;52:92-100. 29. Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. J Am Acad Dermatol. 2012;66: 438-444. 30. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA. 1992;268:1314-1319.

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31. Tzellos T, Kyrgidis A, Mocellin S, Chan A, Pilati P, Apalla Z. Interventions for melanoma in situ, including lentigo maligna. Cochrane Database Syst Rev. 2014;12:CD010308. 32. Akhtar S, Bhat W, Magdum A, Stanley PR. Surgical excision margins for melanoma in situ. J Plast Reconstr Aesthet Surg. 2014;67:320-323. 33. Robinson JK. Margin control for lentigo maligna. J Am Acad Dermatol. 1994;31:79-85. 34. Johnson TM, Headington JT, Baker SR, Lowe L. Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the ‘‘square’’ procedure. J Am Acad Dermatol. 1997;37:758-764. 35. Gaudy-Marqueste C, Perchenet AS, Tasei AM, et al. The ‘‘spaghetti technique’’: an alternative to Mohs surgery or staged surgery for problematic lentiginous melanoma (lentigo maligna and acral lentiginous melanoma). J Am Acad Dermatol. 2011;64:113-118. 36. Bub JL, Berg D, Slee A, Odland PB. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol. 2004;140: 552-558. 37. Clark GS, Pappas-Politis EC, Cherpelis BS, et al. Surgical management of melanoma in situ on chronically sun-damaged skin. Cancer Control. 2008;15:216-224. 38. Agarwal-Antal N, Bowen GM, Gerwels JW. Histologic evaluation of lentigo maligna with permanent sections: implications regarding current guidelines. J Am Acad Dermatol. 2002;47:743-748. 39. Abdelmalek M, Loosemore MP, Hurt MA, Hruza G. Geometric staged excision for the treatment of lentigo maligna and lentigo maligna melanoma: a long-term experience with literature review. Arch Dermatol. 2012;148: 599-604. 40. Bosbous MW, Dzwierzynski WW, Neuburg M. Staged excision of lentigo maligna and lentigo maligna melanoma: a 10-year experience. Plast Reconstr Surg. 2009;124: 1947-1955. 41. Raziano RM, Clark GS, Cherpelis BS, et al. Staged margin control techniques for surgical excision of lentigo maligna. G Ital Dermatol Venereol. 2009;144:259-270. 42. Walling HW. Lentigo maligna: current concepts in diagnosis and management. G Ital Dermatol Venereol. 2009;144: 149-155. 43. Then SY, Malhotra R, Barlow R, et al. Early cure rates with narrow-margin slow-Mohs surgery for periocular malignant melanoma. Dermatol Surg. 2009;35:17-23. 44. Moller MG, Pappas-Politis E, Zager JS, et al. Surgical management of melanoma-in-situ using a staged marginal and central excision technique. Ann Surg Oncol. 2009;16: 1526-1536. 45. 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;58:142-148. 46. Walling HW, Scupham RK, Bean AK, Ceilley RI. Staged excision versus Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol. 2007;57: 659-664. 47. Bricca GM, Brodland DG, Zitelli JA. Immunostaining melanoma frozen sections: the 1-hour protocol. Dermatol Surg. 2004;30:403-408. 48. Cherpelis BS, Moore R, Ladd S, Chen R, Glass LF. Comparison of MART-1 frozen sections to permanent sections using a rapid 19-minute protocol. Dermatol Surg. 2009;35:207-213.

Higgins et al 201

49. Glass LF, Raziano RM, Clark GS, et al. Rapid frozen section immunostaining of melanocytes by microphthalmiaassociated transcription factor. Am J Dermatopathol. 2010;32: 319-325. 50. Hendi A, Brodland DG, Zitelli JA. Melanocytes in long-standing sun-exposed skin: quantitative analysis using the MART-1 immunostain. Arch Dermatol. 2006;142: 871-876. 51. Kimyai-Asadi A, Ayala GB, Goldberg LH, Vujevich J, Jih MH. The 20-minute rapid MART-1 immunostain for malignant melanoma frozen sections. Dermatol Surg. 2008;34:498-500. 52. Zitelli JA, Moy RL, Abell E. The reliability of frozen sections in the evaluation of surgical margins for melanoma. J Am Acad Dermatol. 1991;24:102-106. 53. Kimyai-Asadi A, Katz T, Goldberg LH, et al. Margin involvement after the excision of melanoma in situ: the need for complete en face examination of the surgical margins. Dermatol Surg. 2007;33:1434-1439. discussion 9-41. 54. Barlow RJ, White CR, Swanson NA. Mohs’ micrographic surgery using frozen sections alone may be unsuitable for detecting single atypical melanocytes at the margins of melanoma in situ. Br J Dermatol. 2002;146:290-294. 55. Ellis LZ, Cohen JL, High W, Stewart L. Melanoma in situ treated successfully using imiquimod after nonclearance with surgery: review of the literature. Dermatol Surg. 2012;38: 937-946. 56. Navi D, Huntley A. Imiquimod 5 percent cream and the treatment of cutaneous malignancy. Dermatol Online J. 2004; 10:4. 57. Kallini JR, Jain SK, Khachemoune A. Lentigo maligna: review of salient characteristics and management. Am J Clin Dermatol. 2013;14:473-480. 58. Wong JG, Toole JW, Demers AA, Musto G, Wiseman MC. Topical 5% imiquimod in the treatment of lentigo maligna. J Cutan Med Surg. 2012;16:245-249. 59. 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: 592-596. 60. Situm M, Buljan M. Surgical and histologic pitfalls in the management of lentigo maligna melanoma. G Ital Dermatol Venereol. 2012;147:21-27. 61. Noel B, Kunzle N. Image in clinical medicine. Lentigo maligna. N Engl J Med. 2005;353:2176. 62. Wolf IH, Cerroni L, Kodama K, Kerl H. Treatment of lentigo maligna (melanoma in situ) with the immune response modifier imiquimod. Arch Dermatol. 2005;141:510-514. 63. Kamin A, Eigentler TK, Radny P, Bauer J, Weide B, Garbe C. Imiquimod in the treatment of extensive recurrent lentigo maligna. J Am Acad Dermatol. 2005;52:51-52. 64. Kupfer-Bessaguet I, Guillet G, Misery L, Carre JL, Leroy JP, Sassolas B. Topical imiquimod treatment of lentigo maligna: clinical and histologic evaluation. J American Acad Dermatol. 2004;51:635-639. 65. Powell AM, Russell-Jones R. Amelanotic lentigo maligna managed with topical imiquimod as immunotherapy. J Am Acad Dermatol. 2004;50:792-796. 66. Fisher GH, Lang PG. Treatment of melanoma in situ on sun-damaged skin with topical 5% imiquimod cream complicated by the development of invasive disease. Arch Dermatol. 2003;139:945-947.

202 Higgins et al

67. Chapman MS, Spencer SK, Brennick JB. Histologic resolution of melanoma in situ (lentigo maligna) with 5% imiquimod cream. Arch Dermatol. 2003;139:943-944. 68. Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br J Dermatol. 2000;143:843-845. 69. Epstein E. Extensive lentigo maligna clearing with topical imiquimod. Arch Dermatol. 2003;139:944-945. 70. Woodmansee CS, McCall MW. Recurrence of lentigo maligna and development of invasive melanoma after treatment of lentigo maligna with imiquimod. Dermatol Surg. 2009;35: 1286-1289. 71. Kirtschig G, van Meurs T, van Doorn R. Twelve-week Treatment of Lentigo Maligna with Imiquimod Results in High and Sustained Clearance Rate. Acta Derm Venereol. 2015;95:83-85. 72. Fleming CJ, Bryden AM, Evans A, Dawe RS, Ibbotson SH. A pilot study of treatment of lentigo maligna with 5% imiquimod cream. Br J Dermatol. 2004;151:485-488. 73. Powell AM, Russell-Jones R, Barlow RJ. Topical imiquimod immunotherapy in the management of lentigo maligna. Clin Exp Dermatol. 2004;29:15-21. 74. Ly L, Kelly JW, O’Keefe R, et al. Efficacy of imiquimod cream, 5%, for lentigo maligna after complete excision: a study of 43 patients. Arch Dermatol. 2011;147:1191-1195. 75. Cotter MA, McKenna JK, Bowen GM. Treatment of lentigo maligna with imiquimod before staged excision. Dermatol Surg. 2008;34:147-151. 76. Osborne JE, Hutchinson PE. A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision. Br J Plast Surg. 2002;55:611-615. 77. Cannon PS, O’Donnell B, Huilgol SC, Selva D. The ophthalmic side-effects of imiquimod therapy in the management of periocular skin lesions. Br J Ophthalmol. 2011;95:1682-1685. 78. Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol. 2009;145:1431-1438. 79. Murchison AP, Washington CV, Soloman AR, Bernardino CR. Ocular effects of imiquimod with treatment of eyelid melanoma in situ. Dermatol Surg. 2007;33:1136-1138. 80. Munoz CM, Sanchez JL, Martin-Garcia RF. Successful treatment of persistent melanoma in situ with 5% imiquimod cream. Dermatol Surg. 2004;30:1543-1545. 81. Carucci JA, Leffell DJ. Intralesional interferon alfa for treatment of recurrent lentigo maligna of the eyelid in a patient with primary acquired melanosis. Arch Dermatol. 2000;136:1415-1416. 82. Cornejo P, Vanaclocha F, Polimon I, Del Rio R. Intralesional interferon treatment of lentigo maligna. Arch Dermatol. 2000; 136:428-430. 83. Turner ML, Moshell AN, Corbett DW, et al. Clearing of melanoma in situ with intralesional interferon alfa in a patient with xeroderma pigmentosum. Arch Dermatol. 1994;130:1491-1494. 84. Ryan RF, Krementz ET, Litwin MS. A role for topical 5-fluorouracil therapy in melanoma. J Surg Oncol. 1988;38:250-256. 85. Coleman WP III, Davis RS, Reed RJ, Krementz ET. Treatment of lentigo maligna and lentigo maligna melanoma. J Dermatol Surg Oncol. 1980;6:476-479. 86. Litwin MS, Krementz ET, Mansell PW, Reed RJ. Topical chemotherapy of lentigo maligna with 5-fluorouracil. Cancer. 1975;35:721-733. 87. Vereecken P, Heenen M. Recurrent lentigo maligna melanoma: regression associated with local azelaic acid 20%. Int J Clin Pract. 2002;56:68-69.

J AM ACAD DERMATOL

AUGUST 2015

88. Nazzaro-Porro M, Breathnach AS, Balus L, Passi S, Picardo M, Potenza C. A case of recurrent (following surgery x2) invasive malignant melanoma with satellitosis (stage IIIA) successfully resolving after azelaic acid treatment administered by several routes. Clin Exp Dermatol. 1996;21:321-323. 89. Rodriguez Prieto MA, Manchado Lopez P, Ruiz Gonzalez I, Suarez D. Treatment of lentigo maligna with azelaic acid. Int J Dermatol. 1993;32:363-364. 90. Nazzaro-Porro M, Passi S, Zina G, Breathnach AS. Ten years’ experience of treating lentigo maligna with topical azelaic acid. Acta Derm Venereol Suppl. 1989;143:49-57. 91. Azelaic acid in lentigo maligna. Br J Dermatol. 1987;116: 605-607. 92. McLean DI, Peter KK. Apparent progression of lentigo maligna to invasive melanoma during treatment with topical azelaic acid. Br J Dermatol. 1986;114:685-689. 93. Leibl H, Stingl G, Pehamberger H, Korschan H, Konrad K, Wolff K. Inhibition of DNA synthesis of melanoma cells by azelaic acid. J Invest Dermatol. 1985;85:417-422. 94. Nazzaro-Porro M, Passi S, Balus L, Breathnach A, Martin B, Morpurgo G. Effect of dicarboxylic acids on lentigo maligna. J Invest Dermatol. 1979;72:296-305. 95. Chimenti S, Carrozzo AM, Citarella L, De Felice C, Peris K. Treatment of lentigo maligna with tazarotene 0.1% gel. J Am Acad Dermatol. 2004;50:101-103. 96. Gaspar ZS, Dawber RP. Treatment of lentigo maligna. Australas J Dermatol. 1997;38:1-6; quiz 7-8. 97. Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. Br J Dermatol. 2002;146:1042-1046. 98. Schmid-Wendtner MH, Brunner B, Konz B, et al. Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. J Am Acad Dermatol. 2000;43: 477-482. 99. Barker CA, Lee NY. Radiation therapy for cutaneous melanoma. Dermatol Clin. 2012;30:525-533. 100. Tsang RW, Liu FF, Wells W, Payne DG. Lentigo maligna of the head and neck. Results of treatment by radiotherapy. Arch Dermatol. 1994;130:1008-1012. 101. Harwood AR. Conventional fractionated radiotherapy for 51 patients with lentigo maligna and lentigo maligna melanoma. Int J Radiat Oncol Biol Phys. 1983;9:1019-1021. 102. Harwood AR. Conventional radiotherapy in the treatment of lentigo maligna and lentigo maligna melanoma. J Am Acad Dermatol. 1982;6:310-316. 103. Madan V, August PJ. Lentigo malignaeoutcomes of treatment with Q-switched Nd:YAG and alexandrite lasers. Dermatol Surg. 2009;35:607-611. discussion 11-2. 104. Niiyama N, Niiyama S, Takasu H, Katsuoka K. Progression of lentigo maligna into lentigo maligna melanoma following laser treatment. Eur J Dermatol: EJD. 2007;17: 252-253. 105. Iyer S, Goldman M. Treatment of lentigo maligna with combination laser therapy: recurrence at 8 months after initial resolution. J Cosmet Laser Ther. 2003;5:49-52. 106. Orten SS, Waner M, Dinehart SM, Bardales RH, Flock ST. Q-switched neodymium:yttrium-aluminum-garnet laser treatment of lentigo maligna. Otolaryngol Head Neck Surg. 1999;120:296-302. 107. Chan HH, King WW, Chan ES, et al. In vivo trial comparing patients’ tolerance of Q-switched Alexandrite (QS Alex) and Q-switched neodymium:yttrium-aluminum-garnet (QS Nd: YAG) lasers in the treatment of nevus of Ota. Lasers Surg Med. 1999;24:24-28.

J AM ACAD DERMATOL

Higgins et al 203

VOLUME 73, NUMBER 2

108. Thissen M, Westerhof W. Lentigo maligna treated with ruby laser. Acta Derm Venereol. 1997;77:163. 109. Kopera D. Treatment of lentigo maligna with the carbon dioxide laser. Arch Dermatol. 1995;131:735-736. 110. Arndt KA. New pigmented macule appearing 4 years after argon laser treatment of lentigo maligna. J Am Acad Dermatol. 1986;14:1092. 111. Arndt KA. Argon laser treatment of lentigo maligna. J Am Acad Dermatol. 1984;10:953-957. 112. Cohen LM, McCall MW, Zax RH. Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. A follow-up study. Dermatol Surg. 1998;24:673-677. 113. Huilgol SC, Selva D, Chen C, et al. Surgical margins for lentigo maligna and lentigo maligna melanoma: the technique of mapped serial excision. Arch Dermatol. 2004;140: 1087-1092. 114. McLeod M, Choudhary S, Giannakakis G, Nouri K. Surgical treatments for lentigo maligna: a review. Dermatol Surg. 2011;37:1210-1228. 115. Clayton BD, Leshin B, Hitchcock MG, Marks M, White WL. Utility of rush paraffin-embedded tangential sections in the management of cutaneous neoplasms. Dermatol Surg. 2000; 26:671-678.

116. Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol. 1997;37:236-245. 117. Bene NI, Healy C, Coldiron BM. Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases. Dermatol Surg. 2008;34:660-664. 118. Hill DC, Gramp AA. Surgical treatment of lentigo maligna and lentigo maligna melanoma. Australas J Dermatol. 1999;40: 25-30. 119. Malhotra R, Chen C, Huilgol SC, Hill DC, Selva D. Mapped serial excision for periocular lentigo maligna and lentigo maligna melanoma. Ophthalmology. 2003;110:2011-2018. 120. Mahoney MH, Joseph M, Temple CL. The perimeter technique for lentigo maligna: an alternative to Mohs micrographic surgery. J Surg Oncol. 2005;91:120-125. 121. Jejurikar SS, Borschel GH, Johnson TM, Lowe L, Brown DL. Immediate, optimal reconstruction of facial lentigo maligna and melanoma following total peripheral margin control. Plast Reconstr Surg. 2007;120:1249-1255. 122. Lee MR, Ryman WJ. Treatment of lentigo maligna with total circumferential margin control using vertical and horizontal permanent sections: a retrospective study. Australas J Dermatol. 2008;49:196-201.

Answers to CME examination Identification No. JB0815 August 2015 issue of the Journal of the American Academy of Dermatology.

Higgins II HW, Lee KC, Galan A, Leffell DJ. J Am Acad Dermatol 2015;73:193-203. 1. b

2. b

Melanoma in situ: Part II. Histopathology, treatment, and clinical management.

Melanoma in situ (MIS) poses special challenges with regard to histopathology, treatment, and clinical management. The negligible mortality and normal...
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