EXTRAORDINARY CASE REPORT
Lentigo Maligna Melanoma With Local and Distant Blue Nevus-like Metastases David S. Baird, MD,* Michael D. Ioffreda, MD,*† Klaus Helm, MD,*† Catherine G. Chung, MD,*† and Sara Ferguson, MD*
Abstract: Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically, presenting a diagnostic pitfall for both the clinician and the dermatopathologist. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases followed by a distant metastasis, heralding widespread systemic metastases. Key Words: melanoma, blue nevus-like melanoma, local metastasis, distant cutaneous metastasis (Am J Dermatopathol 2015;37:e126–e128)
insufficient tissue present to perform fluorescent in situ hybridization studies, and molecular studies to analyze for BRAF or C-KIT mutations. Local excision with 1-cm clinical margins was performed, showing residual lentigo maligna with clear margins. Over the next year, the patient developed crops of at least 10 localized metastases over 4 separate occasions, characterized by blue–gray macules resembling blue nevi (Fig. 3). Biopsy was performed each time, with the histopathologic findings of predominantly dendritic melanocytes intermixed with melanophages within the upper dermis dispersed between collagen bundles. Several of the dermal melanocytes were characterized by irregular epithelioid contours, consistent with blue, nevus-like metastatic melanoma (Fig. 4A). Melan-A immunostains diffusely decorated the dermal melanocytes (Fig. 4B). A sentinel node biopsy was obtained at the first evidence of localized metastasis based on the consensus of the
INTRODUCTION Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically. Given their clinical and histologic similarity to blue nevi, these cutaneous metastases can be a diagnostic pitfall. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases without evidence of systemic involvement. This was followed by a distant metastasis, heralding widespread systemic involvement.
CASE REPORT An 80-year-old man presented with a 5-mm black macule of unknown duration on his left cheek (Fig. 1). A complete review of systems and lymph node examination were unremarkable. Biopsy of the lesion revealed an invasive lentigo maligna melanoma (depth of 0.68 mm), characterized by an asymmetric proliferation of unevenly spaced, pleomorphic single and nested melanocytes along the dermal-epidermal junction and within the underlying dermis on heavily sun-damaged skin (Fig. 2). The melanoma was additionally observed to have 1 mitosis per square millimeter. Ulceration and perineural invasion were not identified. Some of the dermal melanocytes appeared to contain intracytoplasmic pigment and were distributed between adnexal structures and dermal collagen bundles, in a pattern often encountered in blue nevi. The dermal melanocytes decorated positively with Melan-A and MITF immunostains. Additional immunohistochemistry was not performed. There was From the Departments of *Dermatology, and †Dermatopathology, Penn State Milton S. Hershey Medical Center, Hershey, PA. The authors declare no conflicts of interest. Reprints: David S. Baird, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Dr, Mail Code HU16, PO Box 850, Hershey, PA 17033 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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FIGURE 1. Lentigo maligna melanoma: a 5-mm, irregular brown macule in a chronically sun-exposed area. Am J Dermatopathol Volume 37, Number 10, October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 10, October 2015
Lentigo Maligna Melanoma
FIGURE 2. Hematoxylin and eosin, ·100. Lentigo maligna melanoma characterized by irregular nests of atypical melanocytes within the epidermis and in the underlying dermis. A background blue nevus-like area is identified in the dermis, characterized by spindled and ovoid pigmented melanocytes and melanophages interstitially dispersed between collagen bundles. treatment team and was negative. Multiple, consecutive wide local excisions were attempted for surgical control. He also received local radiation therapy and ipilimumab. Multiple positron emission tomography/computed tomography (CT) and brain magnetic resonance imaging scans showed no evidence of systemic involvement after each occurrence of localized metastases. Fifteen months after his initial presentation, the patient developed a blue nevus-like macule on his left flank. Biopsy was again consistent with blue nevus-like melanoma metastasis. Review of systems and lymph node examination were negative. However, positron emission tomography/CT imaging revealed diffuse lytic bone lesions and liver masses. Bone marrow biopsy revealed a small focus of atypical cells with positive immunostaining for S100, HMB-45, and Melan-A, confirming metastatic melanoma. CTguided core needle biopsy of a lytic bone lesion from the L4 vertebra revealed aggregates of heavily pigmented, pleomorphic epithelioid melanocytes (Fig. 5). The patient died of his disease shortly thereafter, 26 months after initial presentation.
FIGURE 4. Hematoxylin and eosin, ·200. Histopathology of a blue nevus-like metastasis from Figure 3. A, Superficial dermal infiltrate of spindle-shaped melanocytes intermixed with melanophages, interstitially dispersed between collagen bundles. Several melanocytes have irregular epithelioid contours, further highlighted by (B) Melan-A stain, ·200. No epidermal involvement is identified.
DISCUSSION
FIGURE 3. Blue nevus-like melanoma metastases near the primary excision scar. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Both primary and metastatic melanoma can rarely mimic blue nevi clinically and/or histologically. The majority of these cases arise within a preexisting, cellular blue nevus and is often referred to as malignant blue nevi.1–4 Less frequently, melanoma not arising within a cellular blue nevus can subsequently develop metastases that resemble blue nevi clinically and histologically.1,5–7 Given their clinical and histologic similarity to blue nevi, these cutaneous metastases can be a diagnostic pitfall. In our case, a blue nevus-like area was identified on histopathology in the background of the primary melanoma. In patients with potential, blue nevuslike metastasis, review of the original pathology looking for blue nevus-like areas can be a helpful clue in distinguishing blue nevi from blue nevi-like metastasis. Busam1 has suggested that the findings of epithelioid cells, dermal mitoses, and a brisk inflammatory infiltrate may be suggestive of a melanoma metastasis in the setting of a blue nevus-like lesion. www.amjdermatopathology.com |
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Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Baird et al
Am J Dermatopathol Volume 37, Number 10, October 2015
between benign and malignant pigmented lesions, including blue nevi.13 High-resolution ultrasonography has also been reported to be useful in differentiating these lesions.14 Our patient adds to the small number of reported cases of melanoma who subsequently developed blue nevus-like melanoma metastases. Our case is unique in the large number of localized metastases resembling blue nevi both clinically and histologically, and the appearance of a distant cutaneous metastasis heralding systemic metastasis. In addition to the histologic features suggested by Busam and review of the primary melanoma for evidence of blue nevus-like areas, a new blue nevus-like lesion in the vicinity of a primary melanoma should raise suspicion for blue nevus-like melanoma metastasis and may herald systemic involvement. REFERENCES
However, these findings cannot be relied on to exclude melanoma, because they were not present in all lesions. The histopathologic differential diagnosis for a blue nevus-like melanoma metastasis or blue nevus includes desmoplastic melanoma, given that these lesions are dermal-based, spindled melanocytic neoplasms, and may be characterized by sclerotic collagen. These entities may be particularly difficult to distinguish in the case of nonpigmented blue nevi or blue nevus-like melanoma metastasis. Differentiation between desmoplastic melanoma and blue nevi can be aided by Melan-A (MART1) immunohistochemistry, because blue nevi are consistently positive, whereas desmoplastic melanoma has rarely been positive.8,9 Ki-67 has also been reported to strongly stain some desmoplastic melanomas compared with only weak staining of nonpigmented blue nevi.9 Previous reports of blue nevus-like melanoma have not focused on immunohistochemical profiles of these lesions, and therefore the role of immunostains including Melan-A and Ki-67 is less clear in these cases. It is worth noting, however, that in our case, immunohistochemistry with Melan-A was not helpful in differentiating a blue nevi-like metastasis from a blue nevus given diffuse positive Melan-A staining. More recently, the use of fluorescent in situ hybridization to differentiate blue nevus-like metastasis from blue nevi has been described.10,11 Maize et al12 showed that comparative genomic hybridization can reliably distinguish between blue nevi and melanoma in histologically unequivocal lesions, whereas histologically equivocal lesions showed an heterogeneous pattern of chromosomal abberations. RNA gene expression profiling is being developed to differentiate
1. Busam KJ. Metastatic melanoma to the skin simulating blue nevus. Am J Surg Pathol. 1999;23:276–282. 2. Granter SR, McKee PH, Calonje E, et al. Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called “malignant blue nevus”. Am J Surg Pathol. 2001;25:316–323. 3. Martin RCW, Murali R, Scolyer RA, et al. So-called “alignant blue nevus”: a clinicopathologic study of 23 patients. Cancer. 2009;115: 2949–2955. 4. Mehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus: a report of eight cases. J Dermatol Sci. 1992;4:185–192. 5. Lee HY, Na SY, Son YM, et al. A malignant melanoma associated with a blue nevus of the lip. Ann Dermatol. 2010;22:119–124. 6. King R, Lyons J, Meyers AL, et al. Primary invasive melanoma and basal cell carcinoma (collision tumor) with blue nevus-like cutaneous metastases. J Cutan Pathol. 2007;34:629–633. 7. Wieselthier JS, White WL. Cutaneous metastasis of ocular malignant melanoma. An unusual presentation simulating blue nevi. Am J Dermatopathol. 1996;18:289–295. 8. Busam KJ, Chen Y-T, Old LJ, et al. Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg Pathol. 1998;22:976–982. 9. Kucher C, Zhang PJ, Pasha T, et al. Expression of Melan-a and Ki-67 in desmoplastic melanoma and desmoplastic nevi. Am J Dermatopathol. 2004;26:452–457. 10. Busam KJ, Fang Y, Jhanwar S, et al. Diagnosis of blue nevus-like metastatic uveal melanoma confirmed by fluorescence in situ hybridization (FISH) for monosomy 3. J Cutan Pathol. 2012;39:621–625. 11. Gammon B, Beilfuss B, Guitart J, et al. Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma. J Cutan Pathol. 2011;38:335–341. 12. Maize JC, McCalmont TH, Carlson JA, et al. Genomic Analysis of blue nevi and Related dermal melanocytic proliferations. Am J Surg Pathol. 2005;29:1214–1220. 13. Rock C, E CL, Warf MB, et al. Development and validation of a gene expression signature to distinguish malignant melanoma from benign nevi. Paper presented at: ASCO, Chicago, IL; October 13, 2014. Available at: http://meetinglibrary.asco.org/content/92108? media=vm. Accessed October 13, 2014. 14. Samimi M, Perrinaud A, Naouri M, et al. High-resolution ultrasonography assists the differential diagnosis of blue nevi and cutaneous metastases of melanoma. Br J Dermatol. 2010;163:550–556.
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FIGURE 5. Hematoxylin and eosin, ·200. Vertebral melanoma metastasis. Core needle biopsy of L4 vertebral lytic lesion reveals an aggregate of heavily pigmented epithelioid melanocytes.
| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Lentigo Maligna Melanoma With Local and Distant Blue Nevus-like Metastases David S. Baird, MD,* Michael D. Ioffreda, MD,*† Klaus Helm, MD,*† Catherine G. Chung, MD,*† and Sara Ferguson, MD*
Abstract: Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically, presenting a diagnostic pitfall for both the clinician and the dermatopathologist. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases followed by a distant metastasis, heralding widespread systemic metastases. Key Words: melanoma, blue nevus-like melanoma, local metastasis, distant cutaneous metastasis (Am J Dermatopathol 2015;37:e126–e128)
insufficient tissue present to perform fluorescent in situ hybridization studies, and molecular studies to analyze for BRAF or C-KIT mutations. Local excision with 1-cm clinical margins was performed, showing residual lentigo maligna with clear margins. Over the next year, the patient developed crops of at least 10 localized metastases over 4 separate occasions, characterized by blue–gray macules resembling blue nevi (Fig. 3). Biopsy was performed each time, with the histopathologic findings of predominantly dendritic melanocytes intermixed with melanophages within the upper dermis dispersed between collagen bundles. Several of the dermal melanocytes were characterized by irregular epithelioid contours, consistent with blue, nevus-like metastatic melanoma (Fig. 4A). Melan-A immunostains diffusely decorated the dermal melanocytes (Fig. 4B). A sentinel node biopsy was obtained at the first evidence of localized metastasis based on the consensus of the
INTRODUCTION Melanoma or melanoma metastases can rarely mimic blue nevi clinically and/or histologically. Given their clinical and histologic similarity to blue nevi, these cutaneous metastases can be a diagnostic pitfall. We report a case of an invasive lentigo maligna melanoma with subsequent development of multiple, cutaneous blue nevus-like localized metastases without evidence of systemic involvement. This was followed by a distant metastasis, heralding widespread systemic involvement.
CASE REPORT An 80-year-old man presented with a 5-mm black macule of unknown duration on his left cheek (Fig. 1). A complete review of systems and lymph node examination were unremarkable. Biopsy of the lesion revealed an invasive lentigo maligna melanoma (depth of 0.68 mm), characterized by an asymmetric proliferation of unevenly spaced, pleomorphic single and nested melanocytes along the dermal-epidermal junction and within the underlying dermis on heavily sun-damaged skin (Fig. 2). The melanoma was additionally observed to have 1 mitosis per square millimeter. Ulceration and perineural invasion were not identified. Some of the dermal melanocytes appeared to contain intracytoplasmic pigment and were distributed between adnexal structures and dermal collagen bundles, in a pattern often encountered in blue nevi. The dermal melanocytes decorated positively with Melan-A and MITF immunostains. Additional immunohistochemistry was not performed. There was From the Departments of *Dermatology, and †Dermatopathology, Penn State Milton S. Hershey Medical Center, Hershey, PA. The authors declare no conflicts of interest. Reprints: David S. Baird, MD, Department of Dermatology, Penn State Milton S. Hershey Medical Center, 500 University Dr, Mail Code HU16, PO Box 850, Hershey, PA 17033 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
e126
| www.amjdermatopathology.com
FIGURE 1. Lentigo maligna melanoma: a 5-mm, irregular brown macule in a chronically sun-exposed area. Am J Dermatopathol Volume 37, Number 10, October 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Am J Dermatopathol Volume 37, Number 10, October 2015
Lentigo Maligna Melanoma
FIGURE 2. Hematoxylin and eosin, ·100. Lentigo maligna melanoma characterized by irregular nests of atypical melanocytes within the epidermis and in the underlying dermis. A background blue nevus-like area is identified in the dermis, characterized by spindled and ovoid pigmented melanocytes and melanophages interstitially dispersed between collagen bundles. treatment team and was negative. Multiple, consecutive wide local excisions were attempted for surgical control. He also received local radiation therapy and ipilimumab. Multiple positron emission tomography/computed tomography (CT) and brain magnetic resonance imaging scans showed no evidence of systemic involvement after each occurrence of localized metastases. Fifteen months after his initial presentation, the patient developed a blue nevus-like macule on his left flank. Biopsy was again consistent with blue nevus-like melanoma metastasis. Review of systems and lymph node examination were negative. However, positron emission tomography/CT imaging revealed diffuse lytic bone lesions and liver masses. Bone marrow biopsy revealed a small focus of atypical cells with positive immunostaining for S100, HMB-45, and Melan-A, confirming metastatic melanoma. CTguided core needle biopsy of a lytic bone lesion from the L4 vertebra revealed aggregates of heavily pigmented, pleomorphic epithelioid melanocytes (Fig. 5). The patient died of his disease shortly thereafter, 26 months after initial presentation.
FIGURE 4. Hematoxylin and eosin, ·200. Histopathology of a blue nevus-like metastasis from Figure 3. A, Superficial dermal infiltrate of spindle-shaped melanocytes intermixed with melanophages, interstitially dispersed between collagen bundles. Several melanocytes have irregular epithelioid contours, further highlighted by (B) Melan-A stain, ·200. No epidermal involvement is identified.
DISCUSSION
FIGURE 3. Blue nevus-like melanoma metastases near the primary excision scar. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Both primary and metastatic melanoma can rarely mimic blue nevi clinically and/or histologically. The majority of these cases arise within a preexisting, cellular blue nevus and is often referred to as malignant blue nevi.1–4 Less frequently, melanoma not arising within a cellular blue nevus can subsequently develop metastases that resemble blue nevi clinically and histologically.1,5–7 Given their clinical and histologic similarity to blue nevi, these cutaneous metastases can be a diagnostic pitfall. In our case, a blue nevus-like area was identified on histopathology in the background of the primary melanoma. In patients with potential, blue nevuslike metastasis, review of the original pathology looking for blue nevus-like areas can be a helpful clue in distinguishing blue nevi from blue nevi-like metastasis. Busam1 has suggested that the findings of epithelioid cells, dermal mitoses, and a brisk inflammatory infiltrate may be suggestive of a melanoma metastasis in the setting of a blue nevus-like lesion. www.amjdermatopathology.com |
e127
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Baird et al
Am J Dermatopathol Volume 37, Number 10, October 2015
between benign and malignant pigmented lesions, including blue nevi.13 High-resolution ultrasonography has also been reported to be useful in differentiating these lesions.14 Our patient adds to the small number of reported cases of melanoma who subsequently developed blue nevus-like melanoma metastases. Our case is unique in the large number of localized metastases resembling blue nevi both clinically and histologically, and the appearance of a distant cutaneous metastasis heralding systemic metastasis. In addition to the histologic features suggested by Busam and review of the primary melanoma for evidence of blue nevus-like areas, a new blue nevus-like lesion in the vicinity of a primary melanoma should raise suspicion for blue nevus-like melanoma metastasis and may herald systemic involvement. REFERENCES
However, these findings cannot be relied on to exclude melanoma, because they were not present in all lesions. The histopathologic differential diagnosis for a blue nevus-like melanoma metastasis or blue nevus includes desmoplastic melanoma, given that these lesions are dermal-based, spindled melanocytic neoplasms, and may be characterized by sclerotic collagen. These entities may be particularly difficult to distinguish in the case of nonpigmented blue nevi or blue nevus-like melanoma metastasis. Differentiation between desmoplastic melanoma and blue nevi can be aided by Melan-A (MART1) immunohistochemistry, because blue nevi are consistently positive, whereas desmoplastic melanoma has rarely been positive.8,9 Ki-67 has also been reported to strongly stain some desmoplastic melanomas compared with only weak staining of nonpigmented blue nevi.9 Previous reports of blue nevus-like melanoma have not focused on immunohistochemical profiles of these lesions, and therefore the role of immunostains including Melan-A and Ki-67 is less clear in these cases. It is worth noting, however, that in our case, immunohistochemistry with Melan-A was not helpful in differentiating a blue nevi-like metastasis from a blue nevus given diffuse positive Melan-A staining. More recently, the use of fluorescent in situ hybridization to differentiate blue nevus-like metastasis from blue nevi has been described.10,11 Maize et al12 showed that comparative genomic hybridization can reliably distinguish between blue nevi and melanoma in histologically unequivocal lesions, whereas histologically equivocal lesions showed an heterogeneous pattern of chromosomal abberations. RNA gene expression profiling is being developed to differentiate
1. Busam KJ. Metastatic melanoma to the skin simulating blue nevus. Am J Surg Pathol. 1999;23:276–282. 2. Granter SR, McKee PH, Calonje E, et al. Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called “malignant blue nevus”. Am J Surg Pathol. 2001;25:316–323. 3. Martin RCW, Murali R, Scolyer RA, et al. So-called “alignant blue nevus”: a clinicopathologic study of 23 patients. Cancer. 2009;115: 2949–2955. 4. Mehregan DA, Gibson LE, Mehregan AH. Malignant blue nevus: a report of eight cases. J Dermatol Sci. 1992;4:185–192. 5. Lee HY, Na SY, Son YM, et al. A malignant melanoma associated with a blue nevus of the lip. Ann Dermatol. 2010;22:119–124. 6. King R, Lyons J, Meyers AL, et al. Primary invasive melanoma and basal cell carcinoma (collision tumor) with blue nevus-like cutaneous metastases. J Cutan Pathol. 2007;34:629–633. 7. Wieselthier JS, White WL. Cutaneous metastasis of ocular malignant melanoma. An unusual presentation simulating blue nevi. Am J Dermatopathol. 1996;18:289–295. 8. Busam KJ, Chen Y-T, Old LJ, et al. Expression of melan-A (MART1) in benign melanocytic nevi and primary cutaneous malignant melanoma. Am J Surg Pathol. 1998;22:976–982. 9. Kucher C, Zhang PJ, Pasha T, et al. Expression of Melan-a and Ki-67 in desmoplastic melanoma and desmoplastic nevi. Am J Dermatopathol. 2004;26:452–457. 10. Busam KJ, Fang Y, Jhanwar S, et al. Diagnosis of blue nevus-like metastatic uveal melanoma confirmed by fluorescence in situ hybridization (FISH) for monosomy 3. J Cutan Pathol. 2012;39:621–625. 11. Gammon B, Beilfuss B, Guitart J, et al. Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma. J Cutan Pathol. 2011;38:335–341. 12. Maize JC, McCalmont TH, Carlson JA, et al. Genomic Analysis of blue nevi and Related dermal melanocytic proliferations. Am J Surg Pathol. 2005;29:1214–1220. 13. Rock C, E CL, Warf MB, et al. Development and validation of a gene expression signature to distinguish malignant melanoma from benign nevi. Paper presented at: ASCO, Chicago, IL; October 13, 2014. Available at: http://meetinglibrary.asco.org/content/92108? media=vm. Accessed October 13, 2014. 14. Samimi M, Perrinaud A, Naouri M, et al. High-resolution ultrasonography assists the differential diagnosis of blue nevi and cutaneous metastases of melanoma. Br J Dermatol. 2010;163:550–556.
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
FIGURE 5. Hematoxylin and eosin, ·200. Vertebral melanoma metastasis. Core needle biopsy of L4 vertebral lytic lesion reveals an aggregate of heavily pigmented epithelioid melanocytes.
| www.amjdermatopathology.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
