EXTRAORDINARY CASE REPORT
Spontaneous Regression of Multiple Melanocytic Nevi After Melanoma: Report of 3 Cases José M. Martín, MD,* Isabel Pinazo, MD,* Carlos Monteagudo, PhD,†‡ Jelena Markovic, PhD,‡ Andrea Allende, MD,* and Esperanza Jordá, PhD*‡
Abstract: Complete spontaneous regression of multiple melanocytic nevi after melanoma is an extremely rare phenomenon. We report 3 cases of patients with a history of melanoma that showed regression of almost all melanocytic nevi over time. One of the patients had 2 simultaneous primary cutaneous melanomas without metastasis. In the other 2 patients, regression of the melanocytic nevi was seen after the development of metastasis in lymph nodes. These patients had spontaneously developed an efficient immune response against melanocytes, and they would represent paradigmatic examples of the spontaneous immune responses in melanoma patients. Better understanding of the mechanisms involved in the complete regression of melanocytic lesions would lead to a better selection of melanoma patients for immunotherapy. Key Words: regression, melanoma, melanocytic nevi, dermoscopy, depigmentation
right arm, respectively. Physical examination revealed a 0.7-cm irregularly hyperpigmented macule overlying his right scapula and a 0.4-cm similar lesion on his right forearm. Regional lymphadenopathy was not detected. Histopathological analysis confirmed 2 simultaneous superficial spreading melanomas associated with dysplastic nevi (Fig. 1). Breslow thickness was 0.46 mm (back) and 0.32 mm (forearm). No metastatic lesions were found in the axillary sentinel lymph node biopsy, and complementary exams also ruled out metastatic disease. He also presented several atypical melanocytic lesions, but his mother refused more excisions, and the boy was lost for follow-up. Four years later, the patient came back to revision. Surprisingly, all cutaneous melanocytic lesions had spontaneously disappeared (Fig. 2). The patient did not present any halo phenomenon and he referred that the nevi progressively faded. No tumor progression was found.
Case 2
Case 1
A 37-year-old male patient with multiple melanocytic nevi presented with a rapidly growing nodular lesion located on his left forearm. Histologic examination revealed an ulcerated nodular melanoma, 6-mm Breslow, with 12 mitoses per square millimeter. Regional lymphadenopathy was not observed. No metastatic lesions were found in whole-body computed tomography and positron emission tomography. Ten months later, an enlarged subcutaneous mass was noted on the left axillary vault. A metastasis of melanoma in a lymph node was confirmed histologically. Complementary exams also ruled out other lymph node or visceral metastatic lesions. After the development of the lymph node metastasis, almost all his nevi showed progressive depigmentation on digital dermoscopic follow-up (Figs. 3, 4). Four atypical nevi were then excised, and histopathologic examination showed dysplastic nevi with signs of regression (Fig. 5). Interestingly, an atypical melanocytic nevus had been excised in lumbar area before ganglionar metastasis, and it was histologically a dysplastic nevus without signs of regression (Fig. 6). Two years after lymph node metastasis, he developed subcutaneous, pulmonary, and multiple hepatic metastasis. BRAF mutation was positive for V600E in a subcutaneous metastasis. The patient started treatment with vemurafenib, but he died 4 months later.
A 14-year-old male patient presented with 2 clinical and dermoscopical atypical melanocytic lesions located on his back and
Case 3
(Am J Dermatopathol 2014;36:e183–e188)
INTRODUCTION Development of several types of spontaneous or therapyinduced inflammatory (eczematous) and depigmented reactions (halo nevi and vitiligo) is a phenomenon that has been reported in patients with a personal history of melanoma.1,2 It has been hypothesized that these immune responses are more frequent in patients with metastatic melanoma.1 Spontaneous complete regression of multiple melanocytic nevi after melanoma is an extremely rare phenomenon.3 We report 3 patients, 1 without distant metastasis and 2 with subcutaneous and lymph node metastasis, in which we could demonstrate the presence of multiple regressing pigmented lesions.
CASE REPORTS
From the Departments of *Dermatology, and †Pathology, Hospital Clínico Universitario, Valencia, Spain; and ‡School of Medicine, University of Valencia, Valencia, Spain. The authors declare no conflicts of interest. Reprints: José M. Martín, MD, Department of Dermatology, Hospital Clínico Universitario, Avenida Blasco Ibáñez 17, 46010, Valencia, Spain (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
A 41-year-old woman presented with left-sided axillary lymphadenopathy of 1-month duration. Fine needle aspiration cytology revealed a melanoma metastasis. Complete lymphadenectomy showed metastatic involvement in 1 of 24 lymph nodes. One month later, she presented with a subcutaneous melanoma metastasis of the right inner thigh. No visceral metastatic lesions were found in whole-body computed tomography and positron emission tomography. www.amjdermatopathology.com |
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Am J Dermatopathol Volume 36, Number 11, November 2014
FIGURE 1. Superficial spreading melanomas arising in dysplastic nevi on the back (top) and the arm (bottom) (case 1) (hematoxylin–eosin; top left ·25; bottom left ·40; top and bottom right ·200).
FIGURE 2. Clinical pictures before excision of the melanomas (left), and 4 years later (right), when all his melanocytic nevi had completely faded (case 1).
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| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
Regression of Multiple Melanocytic Nevi After Melanoma
FIGURE 3. Clinical pictures showing regression of almost all nevi on the trunk and back. Left column: before lymph node metastasis. Right column: after lymph node metastasis (case 2). Furthermore, in the subsequent follow-up visits, halo nevi developed diffusely. One year later, almost all her melanocytic nevi had completely regressed.
DISCUSSION Melanoma is among the most immunogenic of all solid cancers. In fact, melanoma demonstrates regression 6 times more often than other malignant neoplasms.4 2014 Lippincott Williams & Wilkins
Partial regression is a common finding within primary cutaneous melanoma (10%–35%). Complete histological regression in melanoma is very rare with an estimated incidence of 0.22%–0.27%.5 Explanations for regression within melanocytic tumors have been focused largely on immunologic mechanisms,4 and the histologic finding of numerous lymphocytes is thought to be indicative of such mechanism. Moreover, the presence of tumor-specific antibodies and tumor-specific cytotoxic T cells www.amjdermatopathology.com |
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Am J Dermatopathol Volume 36, Number 11, November 2014
FIGURE 4. Dermoscopic images of 6 lesions (rows 1–6) before the regression process (left column) and 9 months (center image), or 12 months (right column) after lymph node metastasis (case 2).
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| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
Regression of Multiple Melanocytic Nevi After Melanoma
FIGURE 5. Histologic findings of a dysplastic melanocytic nevus with extensive regression. Few melanocytic junctional nests are present together with numerous lymphocytes, macrophages, and lamellar fibrosis (top and bottom left). Notice the apoptotic junctural melanocytes (bottom right) (hematoxylin–eosin; top, ·100; bottom left, ·200; bottom right, ·400).
in the peripheral blood of melanoma patients has also been well established.6 Many proteins expressed by melanocytes are strongly immunogenic, and they can be expressed on the surface of
FIGURE 6. Junctural dysplastic nevi with no evidence of regression (hematoxylin–eosin; ·100). 2014 Lippincott Williams & Wilkins
melanocytes in the context of major histocompatibility complex class I molecules and, as such, may potentially be recognized by antigen-specific CD8+ T cells.7 Descriptions of spontaneous responses to several tumor antigen–derived peptides, including Melan-A/MART1 and gp-100 in human leukocyte antigen A 0201–positive melanoma have been provided. Moreover, in vitro experiments demonstrated that cytotoxic T lymphocytes generated from melanoma tissue could also target differentiation antigens shared by normal melanocytes.6,7 One of our patients had 2 simultaneous primary cutaneous melanomas without metastasis. Regarding the other 2 cases, as melanoma progresses from primary to metastatic disease, the immune system may recognize a change in the level of antigen load and become capable of reacting against neoplastic cells in the invaded lymph nodes.8 Some data have associated complete regression in primary malignant melanoma with concurrent nodal metastases. These observations led some authors to hypothesize that the presence of metastatic melanoma within a regional lymph node may stimulate an immune response, resulting in regression of the primary lesion, and other melanocytic lesions www.amjdermatopathology.com |
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sharing the same antigens. In favor of this hypothesis, in 1 of our cases, several atypical nevi that were excised after lymph node metastasis showed regression histologically, whereas lesions excised before metastasis did not. In 2 of our patients, this regression was only clinically apparent by dermoscopic follow-up pictures as no depigmented halos around the disappearing nevi were observed. Most descriptions of depigmentation in melanocytic lesions involve the presence of a whitish halo around the lesion. However, dermoscopic studies have demonstrated different patterns of regression of melanocytic nevi, including depigmentation without the formation of a visible halo.9 A T-cell mediated immune response seems also to be strongly implicated in the pathogenesis of regressing nevi. Unfortunately, cases in which the immune system cannot develop an effective immunosurveillance are much more frequent. Given that primary melanomas likely harbor genetically diverse population of neoplastic melanocytes with diverse immunogenicity, the presence of partial regression of a melanoma may simply signify the elimination of 1 subpopulation of tumor cells with persistence of others bearing unpredictable capabilities. Despite their presence in metastatic lesions, T cells equipped with the right T-cell receptor and expressing the phenotype of memory effector cells mostly fail to cause a significant tumor destruction. Melanoma cells escape T-cell immune-mediated destruction by a variety of mechanisms including production of suppressive cytokines that inhibit effector T-cell responses and by down-regulation of the expression of class I human leukocyte antigen.10 As a conclusion, we postulate that normal melanocytes sharing the same antigens of melanoma cells became acutely antigenic, inciting an inflammatory reaction. T cells can continue
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| www.amjdermatopathology.com
Am J Dermatopathol Volume 36, Number 11, November 2014
to proliferate until the antigenic element that induced the immune response was completely eliminated, suggesting a breakdown of immune tolerance. The evaluation of this subset of melanoma patients may contribute to increase our knowledge of the mechanisms involved in the regression of melanocytic lesions and to a better selection of patients for immunotherapy. REFERENCES 1. Elenitsas R, Halpern AC. Eczematous halo reaction in atypical nevi. J Am Acad Dermatol. 1996;34:357–361. 2. Speeckaert R, Van Geel N, Lambert J, et al. Immune mediated mechanisms of melanocyte destruction. Paving the way for efficient immunotherapeutic strategies against melanoma. Oncoimmunology. 2012;1:526–528. 3. Speeckaert R, van Geel N, Luiten RM, et al. Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma. Anticancer Res. 2011;31:3697–3703. 4. High WA, Steward D, Wilbers CH, et al. Completely regressed primary cutaneous malignant melanoma with nodal and or visceral metastases: a report of 5 cases and assessment of the literature and diagnostic criteria. J Am Acad Dermatol. 2005;53:89–100. 5. Emanuel PO, Mannion M, Phelps RG. Complete regression of primary malignant melanoma. Am J Dermatopathol. 2008;30:178–181. 6. Garbelli S, Mantovani S, Palermo B, et al. Melanocyte-specific, cytotoxic T cell responses in vitiligo: the effective variant of melanoma immunity? Pigment Cell Res. 2005;18:234–242. 7. Anichini A, Maccalli C, Mortarini R, et al. Melanoma cells and normal melanocytes share antigens recognized by HLA-A2-restricted cytotoxic T cell clones from melanoma patients. J Exp Med. 1993;177:989–998. 8. Mortarini R, Piris A, Maurichi A, et al. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res. 2003;63: 2535–2545. 9. Martin JM, Nuñez J, Lopez V, et al. Descriptive melanocytic study of depigmentation in melanocytic nevi without a visible halo [in Spanish]. Actas Dermosifiliogr. 2011;102:344–353. 10. Zindl CL, Chaplin DD. Tumor immune evasion. Science. 2010;328:697–698.
2014 Lippincott Williams & Wilkins
Spontaneous Regression of Multiple Melanocytic Nevi After Melanoma: Report of 3 Cases José M. Martín, MD,* Isabel Pinazo, MD,* Carlos Monteagudo, PhD,†‡ Jelena Markovic, PhD,‡ Andrea Allende, MD,* and Esperanza Jordá, PhD*‡
Abstract: Complete spontaneous regression of multiple melanocytic nevi after melanoma is an extremely rare phenomenon. We report 3 cases of patients with a history of melanoma that showed regression of almost all melanocytic nevi over time. One of the patients had 2 simultaneous primary cutaneous melanomas without metastasis. In the other 2 patients, regression of the melanocytic nevi was seen after the development of metastasis in lymph nodes. These patients had spontaneously developed an efficient immune response against melanocytes, and they would represent paradigmatic examples of the spontaneous immune responses in melanoma patients. Better understanding of the mechanisms involved in the complete regression of melanocytic lesions would lead to a better selection of melanoma patients for immunotherapy. Key Words: regression, melanoma, melanocytic nevi, dermoscopy, depigmentation
right arm, respectively. Physical examination revealed a 0.7-cm irregularly hyperpigmented macule overlying his right scapula and a 0.4-cm similar lesion on his right forearm. Regional lymphadenopathy was not detected. Histopathological analysis confirmed 2 simultaneous superficial spreading melanomas associated with dysplastic nevi (Fig. 1). Breslow thickness was 0.46 mm (back) and 0.32 mm (forearm). No metastatic lesions were found in the axillary sentinel lymph node biopsy, and complementary exams also ruled out metastatic disease. He also presented several atypical melanocytic lesions, but his mother refused more excisions, and the boy was lost for follow-up. Four years later, the patient came back to revision. Surprisingly, all cutaneous melanocytic lesions had spontaneously disappeared (Fig. 2). The patient did not present any halo phenomenon and he referred that the nevi progressively faded. No tumor progression was found.
Case 2
Case 1
A 37-year-old male patient with multiple melanocytic nevi presented with a rapidly growing nodular lesion located on his left forearm. Histologic examination revealed an ulcerated nodular melanoma, 6-mm Breslow, with 12 mitoses per square millimeter. Regional lymphadenopathy was not observed. No metastatic lesions were found in whole-body computed tomography and positron emission tomography. Ten months later, an enlarged subcutaneous mass was noted on the left axillary vault. A metastasis of melanoma in a lymph node was confirmed histologically. Complementary exams also ruled out other lymph node or visceral metastatic lesions. After the development of the lymph node metastasis, almost all his nevi showed progressive depigmentation on digital dermoscopic follow-up (Figs. 3, 4). Four atypical nevi were then excised, and histopathologic examination showed dysplastic nevi with signs of regression (Fig. 5). Interestingly, an atypical melanocytic nevus had been excised in lumbar area before ganglionar metastasis, and it was histologically a dysplastic nevus without signs of regression (Fig. 6). Two years after lymph node metastasis, he developed subcutaneous, pulmonary, and multiple hepatic metastasis. BRAF mutation was positive for V600E in a subcutaneous metastasis. The patient started treatment with vemurafenib, but he died 4 months later.
A 14-year-old male patient presented with 2 clinical and dermoscopical atypical melanocytic lesions located on his back and
Case 3
(Am J Dermatopathol 2014;36:e183–e188)
INTRODUCTION Development of several types of spontaneous or therapyinduced inflammatory (eczematous) and depigmented reactions (halo nevi and vitiligo) is a phenomenon that has been reported in patients with a personal history of melanoma.1,2 It has been hypothesized that these immune responses are more frequent in patients with metastatic melanoma.1 Spontaneous complete regression of multiple melanocytic nevi after melanoma is an extremely rare phenomenon.3 We report 3 patients, 1 without distant metastasis and 2 with subcutaneous and lymph node metastasis, in which we could demonstrate the presence of multiple regressing pigmented lesions.
CASE REPORTS
From the Departments of *Dermatology, and †Pathology, Hospital Clínico Universitario, Valencia, Spain; and ‡School of Medicine, University of Valencia, Valencia, Spain. The authors declare no conflicts of interest. Reprints: José M. Martín, MD, Department of Dermatology, Hospital Clínico Universitario, Avenida Blasco Ibáñez 17, 46010, Valencia, Spain (e-mail: [email protected]). © 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
A 41-year-old woman presented with left-sided axillary lymphadenopathy of 1-month duration. Fine needle aspiration cytology revealed a melanoma metastasis. Complete lymphadenectomy showed metastatic involvement in 1 of 24 lymph nodes. One month later, she presented with a subcutaneous melanoma metastasis of the right inner thigh. No visceral metastatic lesions were found in whole-body computed tomography and positron emission tomography. www.amjdermatopathology.com |
e183
Martín et al
Am J Dermatopathol Volume 36, Number 11, November 2014
FIGURE 1. Superficial spreading melanomas arising in dysplastic nevi on the back (top) and the arm (bottom) (case 1) (hematoxylin–eosin; top left ·25; bottom left ·40; top and bottom right ·200).
FIGURE 2. Clinical pictures before excision of the melanomas (left), and 4 years later (right), when all his melanocytic nevi had completely faded (case 1).
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| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
Regression of Multiple Melanocytic Nevi After Melanoma
FIGURE 3. Clinical pictures showing regression of almost all nevi on the trunk and back. Left column: before lymph node metastasis. Right column: after lymph node metastasis (case 2). Furthermore, in the subsequent follow-up visits, halo nevi developed diffusely. One year later, almost all her melanocytic nevi had completely regressed.
DISCUSSION Melanoma is among the most immunogenic of all solid cancers. In fact, melanoma demonstrates regression 6 times more often than other malignant neoplasms.4 2014 Lippincott Williams & Wilkins
Partial regression is a common finding within primary cutaneous melanoma (10%–35%). Complete histological regression in melanoma is very rare with an estimated incidence of 0.22%–0.27%.5 Explanations for regression within melanocytic tumors have been focused largely on immunologic mechanisms,4 and the histologic finding of numerous lymphocytes is thought to be indicative of such mechanism. Moreover, the presence of tumor-specific antibodies and tumor-specific cytotoxic T cells www.amjdermatopathology.com |
e185
Martín et al
Am J Dermatopathol Volume 36, Number 11, November 2014
FIGURE 4. Dermoscopic images of 6 lesions (rows 1–6) before the regression process (left column) and 9 months (center image), or 12 months (right column) after lymph node metastasis (case 2).
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| www.amjdermatopathology.com
2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 11, November 2014
Regression of Multiple Melanocytic Nevi After Melanoma
FIGURE 5. Histologic findings of a dysplastic melanocytic nevus with extensive regression. Few melanocytic junctional nests are present together with numerous lymphocytes, macrophages, and lamellar fibrosis (top and bottom left). Notice the apoptotic junctural melanocytes (bottom right) (hematoxylin–eosin; top, ·100; bottom left, ·200; bottom right, ·400).
in the peripheral blood of melanoma patients has also been well established.6 Many proteins expressed by melanocytes are strongly immunogenic, and they can be expressed on the surface of
FIGURE 6. Junctural dysplastic nevi with no evidence of regression (hematoxylin–eosin; ·100). 2014 Lippincott Williams & Wilkins
melanocytes in the context of major histocompatibility complex class I molecules and, as such, may potentially be recognized by antigen-specific CD8+ T cells.7 Descriptions of spontaneous responses to several tumor antigen–derived peptides, including Melan-A/MART1 and gp-100 in human leukocyte antigen A 0201–positive melanoma have been provided. Moreover, in vitro experiments demonstrated that cytotoxic T lymphocytes generated from melanoma tissue could also target differentiation antigens shared by normal melanocytes.6,7 One of our patients had 2 simultaneous primary cutaneous melanomas without metastasis. Regarding the other 2 cases, as melanoma progresses from primary to metastatic disease, the immune system may recognize a change in the level of antigen load and become capable of reacting against neoplastic cells in the invaded lymph nodes.8 Some data have associated complete regression in primary malignant melanoma with concurrent nodal metastases. These observations led some authors to hypothesize that the presence of metastatic melanoma within a regional lymph node may stimulate an immune response, resulting in regression of the primary lesion, and other melanocytic lesions www.amjdermatopathology.com |
e187
Martín et al
sharing the same antigens. In favor of this hypothesis, in 1 of our cases, several atypical nevi that were excised after lymph node metastasis showed regression histologically, whereas lesions excised before metastasis did not. In 2 of our patients, this regression was only clinically apparent by dermoscopic follow-up pictures as no depigmented halos around the disappearing nevi were observed. Most descriptions of depigmentation in melanocytic lesions involve the presence of a whitish halo around the lesion. However, dermoscopic studies have demonstrated different patterns of regression of melanocytic nevi, including depigmentation without the formation of a visible halo.9 A T-cell mediated immune response seems also to be strongly implicated in the pathogenesis of regressing nevi. Unfortunately, cases in which the immune system cannot develop an effective immunosurveillance are much more frequent. Given that primary melanomas likely harbor genetically diverse population of neoplastic melanocytes with diverse immunogenicity, the presence of partial regression of a melanoma may simply signify the elimination of 1 subpopulation of tumor cells with persistence of others bearing unpredictable capabilities. Despite their presence in metastatic lesions, T cells equipped with the right T-cell receptor and expressing the phenotype of memory effector cells mostly fail to cause a significant tumor destruction. Melanoma cells escape T-cell immune-mediated destruction by a variety of mechanisms including production of suppressive cytokines that inhibit effector T-cell responses and by down-regulation of the expression of class I human leukocyte antigen.10 As a conclusion, we postulate that normal melanocytes sharing the same antigens of melanoma cells became acutely antigenic, inciting an inflammatory reaction. T cells can continue
e188
| www.amjdermatopathology.com
Am J Dermatopathol Volume 36, Number 11, November 2014
to proliferate until the antigenic element that induced the immune response was completely eliminated, suggesting a breakdown of immune tolerance. The evaluation of this subset of melanoma patients may contribute to increase our knowledge of the mechanisms involved in the regression of melanocytic lesions and to a better selection of patients for immunotherapy. REFERENCES 1. Elenitsas R, Halpern AC. Eczematous halo reaction in atypical nevi. J Am Acad Dermatol. 1996;34:357–361. 2. Speeckaert R, Van Geel N, Lambert J, et al. Immune mediated mechanisms of melanocyte destruction. Paving the way for efficient immunotherapeutic strategies against melanoma. Oncoimmunology. 2012;1:526–528. 3. Speeckaert R, van Geel N, Luiten RM, et al. Melanocyte-specific immune response in a patient with multiple regressing nevi and a history of melanoma. Anticancer Res. 2011;31:3697–3703. 4. High WA, Steward D, Wilbers CH, et al. Completely regressed primary cutaneous malignant melanoma with nodal and or visceral metastases: a report of 5 cases and assessment of the literature and diagnostic criteria. J Am Acad Dermatol. 2005;53:89–100. 5. Emanuel PO, Mannion M, Phelps RG. Complete regression of primary malignant melanoma. Am J Dermatopathol. 2008;30:178–181. 6. Garbelli S, Mantovani S, Palermo B, et al. Melanocyte-specific, cytotoxic T cell responses in vitiligo: the effective variant of melanoma immunity? Pigment Cell Res. 2005;18:234–242. 7. Anichini A, Maccalli C, Mortarini R, et al. Melanoma cells and normal melanocytes share antigens recognized by HLA-A2-restricted cytotoxic T cell clones from melanoma patients. J Exp Med. 1993;177:989–998. 8. Mortarini R, Piris A, Maurichi A, et al. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. Cancer Res. 2003;63: 2535–2545. 9. Martin JM, Nuñez J, Lopez V, et al. Descriptive melanocytic study of depigmentation in melanocytic nevi without a visible halo [in Spanish]. Actas Dermosifiliogr. 2011;102:344–353. 10. Zindl CL, Chaplin DD. Tumor immune evasion. Science. 2010;328:697–698.
2014 Lippincott Williams & Wilkins
