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Completely Regressed Cutaneous Melanocytic Lesion Revisited
Completely Regressed Cutaneous Melanocytic Lesion Revisited Timothy W. McCardle, Jane L. Messina, and Vernon K. Sondak
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
C
urrent Clinical Practice featured the initial case of a patient with a completely regressed cutaneous pigmented lesion of unknown biological potential in October 20091 and asked clinicians to detail how they would manage this patient. All erred on the side of caution and addressed the patient with variable conservatism. When queried, Dr Vernon Sondak and colleagues proffered the following case of their own. This case is instructive Address correspondence to Vernon K. Sondak, MD, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 3312. E-mail: vernon.sondak@ moffitt.org 0270-9295/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2009.10.003
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in that it illustrates the potential for adverse consequences when such lesions are not addressed with suspicion and confirms the wisdom of the conservative cautious approach of respondents to the initial case. Drs McCardle, Messina, and Sondak suggest a useful approach to the assessment of patients with clinically completely regressed cutaneous pigmented lesions.
THE PROBLEM A 44-year-old Caucasian woman presents to her primary care physician with a report that she had traumatized a pigmented lesion on the back of her calf while exiting an automobile, with the result that the previously enlarging lesion had now completely disappeared. Physical examination reveals a well-healed 4-mm circular scar on the back of the leg with no visible hypopigmentation, hyperpigmentation, or palpable nodularity. No popliteal or inguinal adenopathy is noted and no clinically atypical nevi or other suspicious pigmented lesions are seen.
Management Question: Should This Lesion Be Further Evaluated in Any Way? Regression of cutaneous melanocytic lesions is a well-recognized phenomenon whose frequency is almost completely undefined. Clinically, regression can occur spontaneously, without any identifiable antecedent event, or after trauma to the lesion (as in the current case), following intercurrent illness or surgery, or after immunomodulatory therapy. Regression of a pigmented lesion can be complete or partial, and may be associated with the phenomenon of a “halo” of depigmentation surrounding the re-
sidual pigmented lesion. The halo phenomenon may be seen around benign nevi, so-called halo nevi, or around primary (Figure 1) or even metastatic melanomas. The ultimate extreme of depigmentation is vitiligo— partial or total cutaneous depigmentation—which is a manifestation of autoimmunity. The clinical significance of spontaneous regression of pigmented skin lesions is virtually entirely due to the fear that such a lesion might represent a primary melanoma. Histologic evidence of regression is commonplace in clinically and histologically unequivocal primary cutaneous melanomas. Complete regression of melanoma is also a well-recognized phenomenon (although notoriously difficult to document), and unfortunately this apparent manifestation of immune recognition and rejection of the primary tumor does not preclude metastasis of a presumably resistant subclone of melanoma cells, as described below.
Case Description The patient was reassured by her primary care physician that there was no problem associated with the regression of the pigmented lesion, and it was not evaluated further. Approximately 3 years later, she developed a palpable lymph node in the ipsilateral femoral triangle. In addition to this, skin examination revealed a nonpigmented, inflamed cutaneous lesion on the anterior thigh just distal to the palpable node. The remainder of the cutaneous examination, including the site on the posterior calf, was entirely unchanged. After a trial of oral antibiotics failed to lead to resolution of either the adenopathy or the cutaneous lesion, the skin lesion was excised and found to be a squamous cell carcinoma
Seminars in Oncology, Vol 36, No 6, December 2009, pp 498-503
Completely regressed cutaneous melanocytic lesion revisited
Figure 1. Dramatic clinical appearance of a “halo” of depigmentation, in this case surrounding an extensively regressed primary melanoma discovered during physical examination of a patient referred for treatment of an “unknown primary” melanoma metastatic to the ipsilateral inguinal lymph nodes. (Photograph courtesy of Bruce Redman, DO, University of Michigan Multidisciplinary Melanoma Clinic, Ann Arbor, MI.)
in situ with surrounding inflammation. This inflammation was postulated to be causing reactive lymphadenopathy in the groin, and additional courses of antibiotics were prescribed. Ultimately, nearly a year after first noting a groin mass, she presented to a different physician with extensive, matted lymphadenopathy in the groin (Figure 2). Open biopsy revealed metastatic melanoma involving the femoral vessels and nerve, as well as the adductor musculature, and hence considered unresectable by ilioinguinal lymphadenectomy. At the time of referral to our clinic, thorough examination including pelvic, perineal, and vaginal examination, and Wood’s lamp examination of the entire visible skin surface was conducted. The small scar on the posterior calf was noted but was not hypopigmented on Wood’s lamp illumination. Nonetheless, punch biopsy of the lesion was performed to investigate if this could represent the primary tumor site. This biopsy did indeed reveal features of a regressed pigmented lesion (Figure 3).
dilemmas that a dermatopathologist faces. Completely regressed lesions are especially difficult, since regression is not specific to melanocytic lesions and may be found in nonmelanocytic lesions such as solar lentigo and pigmented basal cell carcinomas (which may be heavily pigmented
499
with melanin as well). Usually, the dermatopathologist is looking for certain clues as to the nature of the original lesion. For example, in the case of a regressed solar lentigo, residual features of a solar lentigo (rete elongation with hyperpigmentation of basal layer at the tips of the rete) may be found at the edges of the areas of regression. Similarly, in the case of a regressed melanocytic lesion, clues may be left behind as to the nature of the primary lesion. Small banal-appearing nests of melanocytes with evidence of maturation at the edge of or within an area of regression may be reassuring that the melanocytic lesion was benign in nature. However, if features such as pagetoid spread, cytological atypia, and lack of maturation are found at the edge or within an area of regression, then a malignant lesion would be favored. Usually, there is a dense lymphocytic infiltrate in the dermis in actively regressing melanocytic lesions. This inflammation is accompanied by loss of lesional cells. The rete ridges may be lost or attenuated. The papillary
DISCUSSION Histology of Regressed Pigmented Lesions Regression of melanocytic lesions can be one of the most problematic
Figure 2. Positron emission tomography scan/computed tomography scan obtained approximately 4 years after the report of trauma-induced regression of a pigmented lesion on the posterior calf. There was no evidence of hypermetabolic activity anywhere in the lower leg (not shown), but there is extensive glucose-avid adenopathy in the groin.
500
dermis may be widened and accentuated by fibroplasia and angioplasia. Macrophages migrate in and take up the melanin pigment left behind. If any viable or degenerating tumor cells are left behind, they may be masked by the dense inflammatory infiltrate or may be misinterpreted as melanophages. In more longstanding regressed lesions, the dense inflammatory infiltrate may be replaced by fibrovascular tissue. As the inflammatory infiltrate subsides, melanophages may become more numerous or more conspicuous. The term “nodular melanosis” has been used for lesions in which the melanophages are numerous and appear to form discernable nodular masses within the dermis.2 An attempt has been made to categorize regression into early, intermediate, and late based on dense lymphocytic infiltrate progressively being replaced by melanophages and eventually fibrosis. The different histological findings in actively regressing lesions versus those found in late regressing lesions may have significant overlap and often coexist within a single lesion.3,4 One histologic mimicker of regressed melanoma is the halo nevus, a nevus surrounded by an area of depigmentation that may extend as far as several millimeters. This depigmentation lends the clinical appearance of a halo surrounding the central pigmented lesion. Microscopically, there is usually an underlying dense lymphocytic infiltrate that may invest or surround the nevus cells within the dermis (Figure 4A). If numerous histiocytes are present, the inflammation often appears granulomatous in nature.5 The nevus cells in a halo nevus may demonstrate significant reactive cytological atypia, presenting a further challenge in making the diagnosis.6 Another mimicker of a regressed melanoma worthy of note is a recurrent nevus. A recurrent nevus combines features of inflammation and fibrosis, but the pattern of fibrosis can be a tip-off to the fact that this represents proliferation
T.W. McCardle, J.L. Messina, and V.K. Sondak
Figure 3. Punch biopsy of scar on posterior calf approximately 4 years after the patient reported trauma-induced regression of a progressively enlarging pigmented lesion at that site. At low power (not shown), the biopsy demonstrated a broad zone of dermal pigment deposition, while at higher power, fibrosis, angioplasia, and melanin-laden macrophages are evident (hematoxylin & eosin, original magnification 400⫻). Immunohistochemical stains for S-100 and Melan-A failed to demonstrate definitive evidence of malignancy.
and not destruction of melanocytes (Figure 4B).7
Clinical Management of Regressed Lesions No algorithms have been established and validated for the management of completely or partially regressed melanocytic lesions. The initial management of this case is not criticized retrospectively; we may well have proffered the identical recommendation had the patient seen us at the outset because of a concern for malignancy. Clinically benign-appearing nevi with areas of regression or a surrounding halo do not require excisional biopsy for confirmation of benignity, but prudence would suggest educating the patient to return if the lesion develops evidence of nodularity or new pigmentation, or if regional adenopathy were to develop. Given the fact that most authorities consider regression of a primary melanoma to be a very rare event compared to regression of a benign lesion, overly aggressive management and excessively frightening the patient with the prospect of malignancy seems counterproductive. Despite decades of experience with benign pig-
mented lesions and melanoma, we have never prospectively identified a single patient with a regressed lesion that on follow-up developed evidence of recurrent or metastatic melanoma. So, recognizing all that, how could we identify the very rare patient such as this one who does indeed present after regression of a primary melanoma? If we suspect melanoma, how would we manage the case? Our suggestion is to begin with a thorough history of the nature of the lesion before regression, as well as the inciting event of the change if any. Particular attention would be paid to discerning whether there was a longstanding and unchanging pigmented lesion present and to when any changes— either increasing or decreasing pigmentation, lesion size or the development of nodularity, ulceration or bleeding— occurred in relation to the beginning of regression. When we evaluate patients who relate a history of having had a regressed lesion, we will ask if the patient or her family might have a photograph that would document the appearance of the lesion, for example, while on a family vacation or at the beach (Figure 5).
Completely regressed cutaneous melanocytic lesion revisited
Figure 4. (A) Histologic appearance of a halo nevus showing a dense lymphocytic infiltrate surrounding and focally infiltrating dermal nests of small, benign-appearing melanocytes (arrow; hematoxylin & eosin, original magnification 200⫻). (B) Histologic appearance of a recurrent nevus following an incomplete shave biopsy, showing rare melanocytes within an area of fibrosis and associated lymphocytic infiltrate. Note that the pattern of fibrosis is parallel to the epidermal surface, and is more orderly in appearance than usually seen with regressing lesions (hematoxylin & eosin; original magnification 400⫻.
We also show the patient and their family representative photographs of benign and malignant skin lesions from widely available educational pamphlets and brochures, to see if any resemble the lesion before it disappeared. In very rare cases, this has provided informative data about the original nature of the lesion. Finally, we assess the patient’s overall risk for melanoma, by inquiring about family and personal histories of cutaneous malignancies, occupational sun exposure patterns, and recreational tanning habits. Physical examination includes, in addition to inspection of the area of
regression (usually under modest magnification) for residual pigmentation or scar, Wood’s lamp evaluation to search for evidence of hypopigmentation that might substantiate that the original lesion was pigmented. The skin phototype and the presence of freckling, clinically atypical nevi, and congenital-type and banal nevi are noted. If any nevi are present, the patient and family are asked if any resemble the original appearance of the regressed lesion. Finally, the regional lymph nodes are examined and the rationale for examining the nodes is explained to the patient and family as a prelude
501
to educating them about self skin and nodal evaluation. If clinical evaluation of the regional nodes is compromised in any way (eg, obesity or prior surgery in or near the nodal basin), we will add ultrasound of the regional nodes, a technique that has recently become a part of our armamentarium for evaluating patients with known melanoma.8 Otherwise, unless something in the history, physical examination, or review of systems is abnormal, no imaging studies or laboratory evaluation would be recommended. Whether it is of value to perform excisional biopsy of the site of the regressed lesion is entirely unknown. As indicated above, this is not needed for most partially regressed or haloed lesions, and in most cases (this one included) is nondiagnostic even in the presence of established regional or distant metastases. We would be most likely to recommend a biopsy if the patient’s history was particularly worrisome (eg, if there was a description of a new, rapidly growing lesion or of a nodule or ulceration predating the regression), or if there was a small amount of residual pigmentation present that might lend itself to histologic evaluation. Wide or radical excision would never be recommended in the absence of histologic documentation of melanoma; in which case management would be based, of course, on the pathologic characteristics of the primary tumor. Follow-up recommendations would be based on the patient’s overall skin type and particularly the presence of any lesions such as atypical nevi that might require routine dermatologic follow-up but would not include routine evaluation of the regional nodes in the absence of some specific indication.
Management of Unknown Primary Melanoma For completeness, a few words regarding the management of metastatic melanoma from an unknown primary site are in order. Initial evaluation includes all of the steps of history and physical examination
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that were employed in this patient, including evaluation for the possibility of a vulvovaginal or anorectal melanoma in case of ilioinguinal adenopathy and for the possibility of a nasal, oral, or pharyngeal melanoma in case of cervical adenopathy. Generally, however, we do not include extensive evaluations to search for the primary tumor (eg, referral to an ophthalmologist for slit lamp examination or to a gastroenterologist for endoscopy) except as dictated by the history or if appropriate for evaluating the extent of disease in a known primary melanoma of the same stage. If no evidence of a primary is found, the metastatic disease is managed in an identical fashion as for the same stage disease from a known primary, usually radical lymphadenectomy if feasible. The expectation for outcome is the same or perhaps slightly better than for samestage melanoma patients with a known primary. Clearly, not all unknown primary melanomas can be attributed to the regression of a cutaneous primary tumor. In the majority of cases, no evidence of a primary tumor is ever uncovered. The possibility of primary melanoma arising in melanocytes located within regional nodes, the gastrointestinal tract, or elsewhere in the body has been invoked, as yet with no clear supporting evidence in most cases. New molecular techniques for evaluating tumors have established that some cases of “unknown primary melanoma” presenting in the gastrointestinal tract and possibly elsewhere in the abdomen were in fact clear cell sarcomas, which possess a characteristic chromosomal translocation t(12; 22)(q13;q12), resulting in the fusion protein EWSR1/ATF1. To date, to our knowledge, no cases of this translocation have been reported in lymph nodes felt to represent metastases from unknown primary melanomas.9,10 However, in our experience, the most common explanation for “unknown primary melanoma” presenting as nodal or distant metastasis is prior excision of a cutaneous lesion
T.W. McCardle, J.L. Messina, and V.K. Sondak
Figure 5. A 63-year-old woman presented for evaluation of a completely regressed melanocytic lesion on the right upper chest. Histologic evaluation could not determine if this represented regression of a melanoma or a benign nevus, and there was no clinical evidence of residual, recurrent, or metastatic melanoma. The patient provided this photograph of the lesion’s appearance approximately 1 year earlier—the irregular shape and pigmentation suggest the possibility that this indeed represented a melanoma, and re-excision of the site was performed.
misdiagnosed as benign but actually representing the true primary. About 30% of patients we see for an unknown primary melanoma relate a history of having a pigmented lesion in the area draining the involved nodal basin(s) removed and reported as “benign” or ablated in a fashion not permitting histologic evaluation. On multiple occasions, retrieval and reevaluation of the biopsy specimen documented the presence of a primary melanoma— usually a relatively thin primary, often of the “nevoid” type. It is worth noting that this would fit with the observation in some series that patients with nodal metastases from an “unknown primary” have a favorable outcome compared to those with the same stage disease from a known primary.
SUMMARY Regression of benign melanocytic lesions is likely much more common than regression of established primary melanomas, although both can and do occur. No algorithm for the evaluation of a completely regressed primary lesion has been established, let alone validated. We suggest an approach to the evaluation of completely regressed lesions that focuses on taking a detailed history regarding the lesion and the patient’s risk factors for melanoma, performing a physical examination in-
cluding Wood’s lamp illumination, and educating the patient about the extremely rare but clinically significant development of nodal metastases from regressed primary melanomas. Indications for biopsy in partially and completely regressed lesions remain to be established; at present, few if any such lesions are actually subjected to excisional biopsy. Unknown primary melanoma is managed similar to the same stage disease from a known primary, with the addition of a history and physical examination similar to that used for evaluating a regressed melanocytic lesion and of a surgical history to identify patients in whom a previously biopsied lesion might represent the true primary melanoma. Timothy W. McCardle, MD Jane L. Messina, MD Vernon K. Sondak, MD Departments of Cutaneous Oncology and Anatomic Pathology Moffitt Cancer Center Departments of Oncology Sciences, Pathology and Cell Biology, and Dermatology University of South Florida College of Medicine Tampa, FL
REFERENCES 1. Berger AC, McClay EF, Toporcer M, Wolchok JD, Morris GJ. Current clinical practice. Completely
Completely regressed cutaneous melanocytic lesion revisited
regressed cutaneous melanocytic lesion: was it benign or was it malignant? Semin Oncol. 2009;36: 375–9. 2. Flax SH, Skelton HG, Smith KJ, Lupton GP. Nodular melanosis due to epithelial neoplasms. A finding not restricted to regressed melanomas. Am J Dermatopathol. 1998;20:118–22. 3. Kang S, Barnhill RL, Mihm MC Jr, Sober AJ. Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol. 1993;20:126 –9. 4. Velez A, Walsh D, Karakousis CP. Treatment of unknown primary melanoma. Cancer. 1991;68:2579–81.
5. Denianke KS, Gottlieb GJ. Granulomatous inflammation in nevi undergoing regression (halo phenomenon): a report of 6 cases. Am J Dermatopathol. 2008;30:233–5. 6. Mooney MA, Barr RJ, Buxton MG. Halo nevus or halo phenomenon? A study of 142 cases. J Cutan Pathol. 1995;22:342– 8. 7. King R, Hayzen BA, Page RN, Googe PB, Zeagler D, Mihm MC Jr. Recurrent nevus phenomenon: a clinicopatholgoic study of 357 cases and histologic comparison with melanoma with regression. Mod Pathol. 2009;22:611–7. 8. Starritt EC, Uren RF, Scolyer RA,
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Quinn MJ, Thompson JF. Ultrasound examination of sentinel nodes in the initial assessment of patients with primary cutaneous melanoma. Ann Surg Oncol. 2005;12:18 –23. 9. Lyle PL, Amato CM, Fitzpatrick JE, Robinson WA. Gastrointestinal melanoma or clear cell sarcoma? Molecular evaluation of 7 cases previously diagnosed as malignant melanoma. Am J Surg Pathol. 2008;32:858 – 66. 10. Joo M, Chang SH, Kim H, Gardner JM, Ro JY. Primary gastrointestinal clear cell sarcoma: report of 2 cases, one case associated with IgG4-related sclerosing disease, and review of literature. Ann Diagn Pathol. 2009;13:30 –5.
At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor
C
urrent Clinical Practice featured the initial case of a patient with a completely regressed cutaneous pigmented lesion of unknown biological potential in October 20091 and asked clinicians to detail how they would manage this patient. All erred on the side of caution and addressed the patient with variable conservatism. When queried, Dr Vernon Sondak and colleagues proffered the following case of their own. This case is instructive Address correspondence to Vernon K. Sondak, MD, Moffitt Cancer Center, 12902 Magnolia Dr, Tampa, FL 3312. E-mail: vernon.sondak@ moffitt.org 0270-9295/09/$ - see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2009.10.003
498
in that it illustrates the potential for adverse consequences when such lesions are not addressed with suspicion and confirms the wisdom of the conservative cautious approach of respondents to the initial case. Drs McCardle, Messina, and Sondak suggest a useful approach to the assessment of patients with clinically completely regressed cutaneous pigmented lesions.
THE PROBLEM A 44-year-old Caucasian woman presents to her primary care physician with a report that she had traumatized a pigmented lesion on the back of her calf while exiting an automobile, with the result that the previously enlarging lesion had now completely disappeared. Physical examination reveals a well-healed 4-mm circular scar on the back of the leg with no visible hypopigmentation, hyperpigmentation, or palpable nodularity. No popliteal or inguinal adenopathy is noted and no clinically atypical nevi or other suspicious pigmented lesions are seen.
Management Question: Should This Lesion Be Further Evaluated in Any Way? Regression of cutaneous melanocytic lesions is a well-recognized phenomenon whose frequency is almost completely undefined. Clinically, regression can occur spontaneously, without any identifiable antecedent event, or after trauma to the lesion (as in the current case), following intercurrent illness or surgery, or after immunomodulatory therapy. Regression of a pigmented lesion can be complete or partial, and may be associated with the phenomenon of a “halo” of depigmentation surrounding the re-
sidual pigmented lesion. The halo phenomenon may be seen around benign nevi, so-called halo nevi, or around primary (Figure 1) or even metastatic melanomas. The ultimate extreme of depigmentation is vitiligo— partial or total cutaneous depigmentation—which is a manifestation of autoimmunity. The clinical significance of spontaneous regression of pigmented skin lesions is virtually entirely due to the fear that such a lesion might represent a primary melanoma. Histologic evidence of regression is commonplace in clinically and histologically unequivocal primary cutaneous melanomas. Complete regression of melanoma is also a well-recognized phenomenon (although notoriously difficult to document), and unfortunately this apparent manifestation of immune recognition and rejection of the primary tumor does not preclude metastasis of a presumably resistant subclone of melanoma cells, as described below.
Case Description The patient was reassured by her primary care physician that there was no problem associated with the regression of the pigmented lesion, and it was not evaluated further. Approximately 3 years later, she developed a palpable lymph node in the ipsilateral femoral triangle. In addition to this, skin examination revealed a nonpigmented, inflamed cutaneous lesion on the anterior thigh just distal to the palpable node. The remainder of the cutaneous examination, including the site on the posterior calf, was entirely unchanged. After a trial of oral antibiotics failed to lead to resolution of either the adenopathy or the cutaneous lesion, the skin lesion was excised and found to be a squamous cell carcinoma
Seminars in Oncology, Vol 36, No 6, December 2009, pp 498-503
Completely regressed cutaneous melanocytic lesion revisited
Figure 1. Dramatic clinical appearance of a “halo” of depigmentation, in this case surrounding an extensively regressed primary melanoma discovered during physical examination of a patient referred for treatment of an “unknown primary” melanoma metastatic to the ipsilateral inguinal lymph nodes. (Photograph courtesy of Bruce Redman, DO, University of Michigan Multidisciplinary Melanoma Clinic, Ann Arbor, MI.)
in situ with surrounding inflammation. This inflammation was postulated to be causing reactive lymphadenopathy in the groin, and additional courses of antibiotics were prescribed. Ultimately, nearly a year after first noting a groin mass, she presented to a different physician with extensive, matted lymphadenopathy in the groin (Figure 2). Open biopsy revealed metastatic melanoma involving the femoral vessels and nerve, as well as the adductor musculature, and hence considered unresectable by ilioinguinal lymphadenectomy. At the time of referral to our clinic, thorough examination including pelvic, perineal, and vaginal examination, and Wood’s lamp examination of the entire visible skin surface was conducted. The small scar on the posterior calf was noted but was not hypopigmented on Wood’s lamp illumination. Nonetheless, punch biopsy of the lesion was performed to investigate if this could represent the primary tumor site. This biopsy did indeed reveal features of a regressed pigmented lesion (Figure 3).
dilemmas that a dermatopathologist faces. Completely regressed lesions are especially difficult, since regression is not specific to melanocytic lesions and may be found in nonmelanocytic lesions such as solar lentigo and pigmented basal cell carcinomas (which may be heavily pigmented
499
with melanin as well). Usually, the dermatopathologist is looking for certain clues as to the nature of the original lesion. For example, in the case of a regressed solar lentigo, residual features of a solar lentigo (rete elongation with hyperpigmentation of basal layer at the tips of the rete) may be found at the edges of the areas of regression. Similarly, in the case of a regressed melanocytic lesion, clues may be left behind as to the nature of the primary lesion. Small banal-appearing nests of melanocytes with evidence of maturation at the edge of or within an area of regression may be reassuring that the melanocytic lesion was benign in nature. However, if features such as pagetoid spread, cytological atypia, and lack of maturation are found at the edge or within an area of regression, then a malignant lesion would be favored. Usually, there is a dense lymphocytic infiltrate in the dermis in actively regressing melanocytic lesions. This inflammation is accompanied by loss of lesional cells. The rete ridges may be lost or attenuated. The papillary
DISCUSSION Histology of Regressed Pigmented Lesions Regression of melanocytic lesions can be one of the most problematic
Figure 2. Positron emission tomography scan/computed tomography scan obtained approximately 4 years after the report of trauma-induced regression of a pigmented lesion on the posterior calf. There was no evidence of hypermetabolic activity anywhere in the lower leg (not shown), but there is extensive glucose-avid adenopathy in the groin.
500
dermis may be widened and accentuated by fibroplasia and angioplasia. Macrophages migrate in and take up the melanin pigment left behind. If any viable or degenerating tumor cells are left behind, they may be masked by the dense inflammatory infiltrate or may be misinterpreted as melanophages. In more longstanding regressed lesions, the dense inflammatory infiltrate may be replaced by fibrovascular tissue. As the inflammatory infiltrate subsides, melanophages may become more numerous or more conspicuous. The term “nodular melanosis” has been used for lesions in which the melanophages are numerous and appear to form discernable nodular masses within the dermis.2 An attempt has been made to categorize regression into early, intermediate, and late based on dense lymphocytic infiltrate progressively being replaced by melanophages and eventually fibrosis. The different histological findings in actively regressing lesions versus those found in late regressing lesions may have significant overlap and often coexist within a single lesion.3,4 One histologic mimicker of regressed melanoma is the halo nevus, a nevus surrounded by an area of depigmentation that may extend as far as several millimeters. This depigmentation lends the clinical appearance of a halo surrounding the central pigmented lesion. Microscopically, there is usually an underlying dense lymphocytic infiltrate that may invest or surround the nevus cells within the dermis (Figure 4A). If numerous histiocytes are present, the inflammation often appears granulomatous in nature.5 The nevus cells in a halo nevus may demonstrate significant reactive cytological atypia, presenting a further challenge in making the diagnosis.6 Another mimicker of a regressed melanoma worthy of note is a recurrent nevus. A recurrent nevus combines features of inflammation and fibrosis, but the pattern of fibrosis can be a tip-off to the fact that this represents proliferation
T.W. McCardle, J.L. Messina, and V.K. Sondak
Figure 3. Punch biopsy of scar on posterior calf approximately 4 years after the patient reported trauma-induced regression of a progressively enlarging pigmented lesion at that site. At low power (not shown), the biopsy demonstrated a broad zone of dermal pigment deposition, while at higher power, fibrosis, angioplasia, and melanin-laden macrophages are evident (hematoxylin & eosin, original magnification 400⫻). Immunohistochemical stains for S-100 and Melan-A failed to demonstrate definitive evidence of malignancy.
and not destruction of melanocytes (Figure 4B).7
Clinical Management of Regressed Lesions No algorithms have been established and validated for the management of completely or partially regressed melanocytic lesions. The initial management of this case is not criticized retrospectively; we may well have proffered the identical recommendation had the patient seen us at the outset because of a concern for malignancy. Clinically benign-appearing nevi with areas of regression or a surrounding halo do not require excisional biopsy for confirmation of benignity, but prudence would suggest educating the patient to return if the lesion develops evidence of nodularity or new pigmentation, or if regional adenopathy were to develop. Given the fact that most authorities consider regression of a primary melanoma to be a very rare event compared to regression of a benign lesion, overly aggressive management and excessively frightening the patient with the prospect of malignancy seems counterproductive. Despite decades of experience with benign pig-
mented lesions and melanoma, we have never prospectively identified a single patient with a regressed lesion that on follow-up developed evidence of recurrent or metastatic melanoma. So, recognizing all that, how could we identify the very rare patient such as this one who does indeed present after regression of a primary melanoma? If we suspect melanoma, how would we manage the case? Our suggestion is to begin with a thorough history of the nature of the lesion before regression, as well as the inciting event of the change if any. Particular attention would be paid to discerning whether there was a longstanding and unchanging pigmented lesion present and to when any changes— either increasing or decreasing pigmentation, lesion size or the development of nodularity, ulceration or bleeding— occurred in relation to the beginning of regression. When we evaluate patients who relate a history of having had a regressed lesion, we will ask if the patient or her family might have a photograph that would document the appearance of the lesion, for example, while on a family vacation or at the beach (Figure 5).
Completely regressed cutaneous melanocytic lesion revisited
Figure 4. (A) Histologic appearance of a halo nevus showing a dense lymphocytic infiltrate surrounding and focally infiltrating dermal nests of small, benign-appearing melanocytes (arrow; hematoxylin & eosin, original magnification 200⫻). (B) Histologic appearance of a recurrent nevus following an incomplete shave biopsy, showing rare melanocytes within an area of fibrosis and associated lymphocytic infiltrate. Note that the pattern of fibrosis is parallel to the epidermal surface, and is more orderly in appearance than usually seen with regressing lesions (hematoxylin & eosin; original magnification 400⫻.
We also show the patient and their family representative photographs of benign and malignant skin lesions from widely available educational pamphlets and brochures, to see if any resemble the lesion before it disappeared. In very rare cases, this has provided informative data about the original nature of the lesion. Finally, we assess the patient’s overall risk for melanoma, by inquiring about family and personal histories of cutaneous malignancies, occupational sun exposure patterns, and recreational tanning habits. Physical examination includes, in addition to inspection of the area of
regression (usually under modest magnification) for residual pigmentation or scar, Wood’s lamp evaluation to search for evidence of hypopigmentation that might substantiate that the original lesion was pigmented. The skin phototype and the presence of freckling, clinically atypical nevi, and congenital-type and banal nevi are noted. If any nevi are present, the patient and family are asked if any resemble the original appearance of the regressed lesion. Finally, the regional lymph nodes are examined and the rationale for examining the nodes is explained to the patient and family as a prelude
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to educating them about self skin and nodal evaluation. If clinical evaluation of the regional nodes is compromised in any way (eg, obesity or prior surgery in or near the nodal basin), we will add ultrasound of the regional nodes, a technique that has recently become a part of our armamentarium for evaluating patients with known melanoma.8 Otherwise, unless something in the history, physical examination, or review of systems is abnormal, no imaging studies or laboratory evaluation would be recommended. Whether it is of value to perform excisional biopsy of the site of the regressed lesion is entirely unknown. As indicated above, this is not needed for most partially regressed or haloed lesions, and in most cases (this one included) is nondiagnostic even in the presence of established regional or distant metastases. We would be most likely to recommend a biopsy if the patient’s history was particularly worrisome (eg, if there was a description of a new, rapidly growing lesion or of a nodule or ulceration predating the regression), or if there was a small amount of residual pigmentation present that might lend itself to histologic evaluation. Wide or radical excision would never be recommended in the absence of histologic documentation of melanoma; in which case management would be based, of course, on the pathologic characteristics of the primary tumor. Follow-up recommendations would be based on the patient’s overall skin type and particularly the presence of any lesions such as atypical nevi that might require routine dermatologic follow-up but would not include routine evaluation of the regional nodes in the absence of some specific indication.
Management of Unknown Primary Melanoma For completeness, a few words regarding the management of metastatic melanoma from an unknown primary site are in order. Initial evaluation includes all of the steps of history and physical examination
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that were employed in this patient, including evaluation for the possibility of a vulvovaginal or anorectal melanoma in case of ilioinguinal adenopathy and for the possibility of a nasal, oral, or pharyngeal melanoma in case of cervical adenopathy. Generally, however, we do not include extensive evaluations to search for the primary tumor (eg, referral to an ophthalmologist for slit lamp examination or to a gastroenterologist for endoscopy) except as dictated by the history or if appropriate for evaluating the extent of disease in a known primary melanoma of the same stage. If no evidence of a primary is found, the metastatic disease is managed in an identical fashion as for the same stage disease from a known primary, usually radical lymphadenectomy if feasible. The expectation for outcome is the same or perhaps slightly better than for samestage melanoma patients with a known primary. Clearly, not all unknown primary melanomas can be attributed to the regression of a cutaneous primary tumor. In the majority of cases, no evidence of a primary tumor is ever uncovered. The possibility of primary melanoma arising in melanocytes located within regional nodes, the gastrointestinal tract, or elsewhere in the body has been invoked, as yet with no clear supporting evidence in most cases. New molecular techniques for evaluating tumors have established that some cases of “unknown primary melanoma” presenting in the gastrointestinal tract and possibly elsewhere in the abdomen were in fact clear cell sarcomas, which possess a characteristic chromosomal translocation t(12; 22)(q13;q12), resulting in the fusion protein EWSR1/ATF1. To date, to our knowledge, no cases of this translocation have been reported in lymph nodes felt to represent metastases from unknown primary melanomas.9,10 However, in our experience, the most common explanation for “unknown primary melanoma” presenting as nodal or distant metastasis is prior excision of a cutaneous lesion
T.W. McCardle, J.L. Messina, and V.K. Sondak
Figure 5. A 63-year-old woman presented for evaluation of a completely regressed melanocytic lesion on the right upper chest. Histologic evaluation could not determine if this represented regression of a melanoma or a benign nevus, and there was no clinical evidence of residual, recurrent, or metastatic melanoma. The patient provided this photograph of the lesion’s appearance approximately 1 year earlier—the irregular shape and pigmentation suggest the possibility that this indeed represented a melanoma, and re-excision of the site was performed.
misdiagnosed as benign but actually representing the true primary. About 30% of patients we see for an unknown primary melanoma relate a history of having a pigmented lesion in the area draining the involved nodal basin(s) removed and reported as “benign” or ablated in a fashion not permitting histologic evaluation. On multiple occasions, retrieval and reevaluation of the biopsy specimen documented the presence of a primary melanoma— usually a relatively thin primary, often of the “nevoid” type. It is worth noting that this would fit with the observation in some series that patients with nodal metastases from an “unknown primary” have a favorable outcome compared to those with the same stage disease from a known primary.
SUMMARY Regression of benign melanocytic lesions is likely much more common than regression of established primary melanomas, although both can and do occur. No algorithm for the evaluation of a completely regressed primary lesion has been established, let alone validated. We suggest an approach to the evaluation of completely regressed lesions that focuses on taking a detailed history regarding the lesion and the patient’s risk factors for melanoma, performing a physical examination in-
cluding Wood’s lamp illumination, and educating the patient about the extremely rare but clinically significant development of nodal metastases from regressed primary melanomas. Indications for biopsy in partially and completely regressed lesions remain to be established; at present, few if any such lesions are actually subjected to excisional biopsy. Unknown primary melanoma is managed similar to the same stage disease from a known primary, with the addition of a history and physical examination similar to that used for evaluating a regressed melanocytic lesion and of a surgical history to identify patients in whom a previously biopsied lesion might represent the true primary melanoma. Timothy W. McCardle, MD Jane L. Messina, MD Vernon K. Sondak, MD Departments of Cutaneous Oncology and Anatomic Pathology Moffitt Cancer Center Departments of Oncology Sciences, Pathology and Cell Biology, and Dermatology University of South Florida College of Medicine Tampa, FL
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