aEric Ehrsam, MD; bJoseph R. Kallini, MD; aDamien Lebas, MD; cAmor Khachemoune, MD; aPhilippe Modiano, MD; dHervé Cotten, MD
aService de dermatologie, université catholique de Lille, hôpital Saint-Vincent-de-Paul, Lille, France
bDepartment of Radiology, Northwestern University, Chicago, Illinois
cVeterans Affairs Medical Center, Brooklyn, New York
dAnatomopathologiste à Lille, Nordpathologie, Lille, France
Disclosure: The authors report no relevant conflicts of interest.
Abstract
Fully regressive melanoma is a phenomenon in which the primary cutaneous melanoma becomes completely replaced by fibrotic components as a result of host immune response. Although 10 to 35 percent of cases of cutaneous melanomas may partially regress, fully regressive melanoma is very rare; only 47 cases have been reported in the literature to date. All of the cases of fully regressive melanoma reported in the literature were diagnosed in conjunction with metastasis on a patient. The authors describe a case of fully regressive melanoma without any metastases at the time of its diagnosis. Characteristic findings on dermoscopy, as well as the absence of melanoma on final biopsy, confirmed the diagnosis. (J Clin Aesthet Dermatol. 2016;9(8):42–46.)
A 62-year-old man presented to our institution with a pigmented lesion on his back, which he noticed three weeks prior. The patient could not tell when the lesion first appeared. Cutaneous examination revealed a 12mm x 8mm asymmetric, variegated, pigmented patch with large slate-gray and pink discolorations (Figure 1). No ulceration, crusting, active exsanguination, or granulation was noted. Examination of the axillae was negative for palpable lymphadenopathy.
Dermoscopic examination revealed scar-like de-pigmentation and multiple blue-gray “pepper-like” papules overlying a pink macular base (Figure 2). The lesion was surgically excised under local anesthesia with a 3mm margin. The histopathologic examination revealed a flattened epidermis, residual large melanocytes confined to the basal layer of the epidermis, but no obvious nests of melanocytes were noticed, and there was no pagetoid spread. The papillary dermis was slightly edematous with some fibrosis, dilated blood vessels, and a lymphohistiocytic infiltrate, as well as the presence of many melanophages. The reticular dermis and subcutaneous tissue were normal (Figure 3). Immunohistochemical staining with Melan A was negative for nests at the dermal-epidermal junction and dermis (Figure 4). Thus, the definitive diagnosis of fully regressive melanoma was made on basis of the constellation of the clinical, dermoscopic and pathologic findings.
A re-excision of the initial lesion with a 1cm margin was performed based on depth of melanophage infiltration (less than 1mm) because Breslow index was not available. The patient underwent extensive work up for metastasis. The work up included cerebral MRI, thoracic and abdominal CT scans, and axillary ultrasonography; all were negative. The patient followed up with our service every three months for two years, followed by yearly thereafter, during which he underwent serial physical examinations with assessment of lymphadenopathy. The patient has had neither a local relapse of disease nor cutaneous metastases.
Discussion
Regression is a phenomenon in which the host immune response, via tumor infiltrate lymphocytes, attacks the primary melanocytic tumor cells and leaves behind a fibrotic component. Ten to 35 percent of cases of cutaneous melanomas may partially regress.[1] Fully regressive melanoma, in which all malignant melanocytes regress, is very rare. Only 47 cases have been reported in the literature.[2–4] Only 10 of these reported cases had included dermoscopic studies. Furthermore, regression has only been reported after the occurrence of metastasis. Partial regression, rather than full regression, is usually reported, in which malignant tumor is admixed with fibrosis. This phenomenon obliterates the tumor margin and increases the likelihood of incomplete excision. As a result, regression has once been considered a poor prognostic factor in melanoma.[5]
The cytotoxic T-cell response plays an integral role in regressive melanomas.[6–9] One study found high expression of MxA, an antiviral protein specifically induced by type I interferons, in inflamed regressive melanomas. In addition, interferon-producing dendritic cells, the interferon-induced chemokine IP10/CXCL10, CXCR3+ lymphocytes, and granzyme B+ lymphocytes were detected. In sum, the study concluded that the cytotoxic immune response is involved in spontaneous regression of melanoma and other melanocytic lesions.[6] Another study showed a correlation between ICAM-1 expression and histologic evidence of tumor regression. The expression of ICAM-1 was found to correlate with the occurrence of CD8+ cells close to the tumor cells, thus providing further evidence for the role of the cytotoxic immune response in regression of melanoma.[7] Another study showed that regressive changes of melanomas increased significantly with IFN-alpha treatment.[10]
The dermoscopic examination of fully regressive melanoma reveals many key findings. The following checklist of seven features has been constructed by Bories et al.[4]
1. “Scar-like” depigmentation, defined as hypopigmented to depigmented macules
2. Pink macules
3. Linear, irregular vessels
4. Globular vessel patterns
5. Hyperpigmented macular remnants
6. Blue-gray “peppered” papular remnants
7. White transverse bands.
In all cases, scar-like depigmentation and a pink background are found. Linear, irregular vessels and remnants of pigmentation (half of which are macular and the other half containing gray-blue “peppered” granules) are found in 86 percent of cases. Of note, the scar-like depigmentation and gray-blue pinpoint papules are also found in partially regressed melanoma. Less common findings are globular vessel patterns and white transverse bands.[4]
Although there have been few reports, fully regressive melanoma appears to favor the lower extremities and trunk in elderly patients (Table 1
). As Table 1 shows, all lesions were discovered with associated metastasis at the time of diagnosis. No reports to date describe a fully regressive melanoma detected without metastases. Anatomically, one cohort of 397 patients with histologic features of regression showed that the melanomas were preferentially located on the trunk in 40.6 percent (166 of 409), the lower limbs in 29.3 percent (120 of 409), and the upper limbs in 16.1 percent (66 of 409). Twelve percent (48 of 409) of the regressive melanomas were located on the head or on the neck. A total of nine percent (36 of 409) were located on the hands or feet.[1]
The clinical and dermatoscopic differential diagnosis of fully regressive melanoma are presented in Table 2 and Table 3, respectively. The approach to fully regressive melanoma remains the same as for all primary cutaneous melanomas. The diagnosis depends on hematoxylin and eosin (H&E) staining. No immunohistochemical pattern is pathognomonic for cutaneous melanoma, although melanocyte differentiation antigens (such as glycoprotein 100, tyrosinase, Melan-A, and S100) can assist in distinguishing benign from malignant tumor. If the melanoma remains very difficult to diagnose (as in the case of spitzoid melanomas or tumors that have been placed in the category of melanocytic tumors of uncertain malignant potential), molecular analysis using comparative genomic hybridization (CGH) and florescence in situ hybridization (FISH) may be used. CGH assesses the DNA copy number of malignant cells. FISH is a technique that identifies specific DNA loci; CEP6, 6p23, 6p25, and 11q13 have been found to distinguish benign nevi from malignancy.[11]
Wood’s lamp has never been cited in the minimal amount of literature discussing regressive melanoma, though this can be an invaluable tool. Wood’s lamp takes advantage of the property of ultraviolet (UV) light to be preferentially absorbed by epidermal melanin, distinguishing it from the surrounding uninvolved tissue. Because the true margins of the lesion can extend far past the visible margins, the ability of the Wood’s lamp to amplify these differences in pigmentation makes it especially invaluable in delineating unclear borders.[12]
Management depends on initial microstaging. Breslow’s thickness, the length from the stratum granulosum of the epidermis to the deepest portion of the tumor, is still the strongest predictor of survival, regardless of regression. Mitoses per square millimeter and ulceration are also important for staging the tumor. In terms of laboratory analysis, an American Academy of Dermatology task force suggests that routine blood work is optional.[13] In terms of imaging, the 2008 evidence-based clinical practice guidelines in Australia and New Zealand state that further imaging after the diagnosis of melanoma is not required if the patient is asymptomatic.[11]
Based upon the results of a World Health Organization (WHO) trial with 612 patients, melanomas less than 1mm thick (T1 lesions) should be resected with a 1cm margin of normal tissue. For melanomas 1 to 2mm thick (T2 lesions), a 2cm margin of normal tissue is resected.[14] For primary melanomas between 2 and 4mm thick (T3), a 2cm margin is excised.
After excision of fully regressive melanoma, the subsequent management is debated. One study concludes that sentinel lymph node biopsy (SLNB) was not useful for thin melanomas with Breslow thickness less than or equal to 1mm, but further larger studies on melanomas with Breslow index between 0.75 and 1mm should be conducted before concluding that SLNB is not useful in thin regressive and/or ulcerated melanomas.[15] Furthermore, it has been shown that regression in primary cutaneous melanoma is not predictive for lymph node metastasis; positive lymphadenopathy may be missed with the omission of SLNB.[16]
In sum, the authors suggest that patients with fully or partially regressive melanoma be managed in the same regard as those with any other type of melanoma. This is based on the fact that the limited cases have shown that regression is not necessarily a favorable prognostic sign and has had no correlation with lymph node involvement or metastasis. In fact, it is a poor prognostic indicator in some citations.[5] As a result, the approach to fully regressive melanoma includes a thorough cutaneous physical exam and restaging with biopsy. Blood work and imaging are not indicated unless the patient is symptomatic.
Conclusion
Fully regressive melanomas are very rare. Though the mechanism is unclear, the cytotoxic T-cell response plays an integral role in regressive melanomas. The dermoscopic examination of fully regressive melanoma reveals many key findings that include “scar-like” depigmentation, pink macules, linear vessels, globular vessel patterns, hyperpigmented macular remnants, blue-gray “peppered” papular remnants, and white transverse bands. The authors’ case in particular is unique because the diagnosis was made without metastases, whereas all cases reported in the literature were diagnosed after the incidence of metastasis.
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