REVIEWS
The deep penetrating nevus Lauren Strazzula, BA,a Maryanne Makredes Senna, MD,b Mariko Yasuda, MD,b and Leah Belazarian, MDb,c Worcester, Massachusetts The deep penetrating nevus (DPN), also known as the plexiform spindle cell nevus, is a pigmented lesion that commonly arises on the head and neck in the first few decades of life. Histopathologically, the DPN is wedge-shaped and contains melanocytes that exhibit deep infiltration into the dermis. Given these features, DPN may clinically and histopathologically mimic malignant melanoma, sparking confusion about the appropriate evaluation and management of these lesions. The goal of this review is to summarize the clinical and histopathological features of DPN and to discuss diagnostic and treatment strategies for dermatologists. ( J Am Acad Dermatol 2014;71:1234-40.) Key words: deep penetrating nevus; dermatopathology; malignant melanoma; melanocytic tumor of uncertain malignant potential; nevus with focal atypical epithelioid components; plexiform spindle cell nevus.
T
he deep penetrating nevus (DPN) is a darkly pigmented melanocytic lesion that exhibits deep infiltration into the reticular dermis.1 It has gained recognition over the past couple of decades because its histologic appearance is commonly confused with malignant melanoma. This nevus does not have a consistent morphology and because of its often sudden appearance and dark color, its appearance may raise concern for a malignant process among both practitioners and patients. Although the pathology literature is well-versed in the histologic features of DPN, the dermatology literature lacks a comprehensive clinical summary, and dermatologists are often forced to make clinical decisions based on isolated case reports and small series. The goal of this review is to summarize the clinical and histologic features of DPN and to discuss diagnostic and treatment issues for these elusive lesions.
with similar characteristics, which they named the ‘‘plexiform spindle cell nevus.’’ It was later accepted that these 2 reports were describing the same melanocytic lesion, and the naming of the nevus by Seab et al1 was accepted. Since then, nearly 400 lesions have been reported in the English-language literature.
CLINICAL PRESENTATION
The DPN was first described in 1989 by Seab et al,1 who reported 70 patients with a darkly pigmented nevus composed of loosely organized nests of melanocytes with deep extension into the reticular dermis. In 1991, Barnhill et al2 described a lesion
Although the age at presentation is broad (0-77 years) (Table I), DPN tend to occur in a younger patient population, most frequently in the first 3 decades of life.1,3,4 Congenital onset has been reported,3,5-7 and lesions rarely arise in patients older than 50 years.8 Females appear to have a slightly higher incidence (57.4%) compared with males (42.4%).1-3,5,6 DPN occur on the head and neck in approximately 35% of cases, on the trunk in 25%, and on the upper extremities in 20.5%. Less commonly, DPN occur on the lower extremities, and they have only rarely been described on distal extremities3,4 or mucosal surfaces.9,10 The majority of DPN are darkly pigmented dome-shaped papules or nodules that are less than 1 cm in diameter.8,11 Typically, DPN present as a solitary lesion, however, a linear arrangement of multiple DPN over the preauricular cheek has
From the University of Massachusetts Medical Schoola; and Division of Dermatology, Departments of Medicineb and Pediatrics,c University of Massachusetts Medical School, UMass Memorial Healthcare. Funding sources: None. Conflicts of interest: None declared. Accepted for publication July 19, 2014.
Reprint requests: Leah Belazarian, MD, UMass Memorial Healthcare, 281 Lincoln St, Worcester, MA 01605. E-mail: leah. [email protected]. Published online September 4, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.07.026
BACKGROUND
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been reported.12 The lesions are most frequently DPN is high, the best method of diagnosis is via a black, blue, dark brown, or gray (or often a comnarrow excision. bination of these colors) (Fig 1) but have been rarely noted to be red or pink.3 Patients may report HISTOLOGIC FEATURES a new or changing lesion because they are almost The DPN is a sharply demarcated lesion, and at always acquired. Most DPN are asymptomatic, low power is symmetric and wedged-shaped with a although pain or dysesthesia have rarely been broad base that runs parallel with the epidermis and reported.13 The vast majority an apex that is oriented toof patients have no personal wards the subcutaneous adiCAPSULE SUMMARY or family history of melapose.1-3,5,6,17 It consists of noma. A DPN developing often vertically oriented, The deep penetrating nevus is a within a medium-sized loose fascicles and nests of melanocytic lesion that may clinically congenital nevus has been spindle-shaped and epitheand histopathologically mimic malignant reported in a 3-month old lioid melanocytes extending melanoma. infant.14 into the reticular dermis in This review summarizes the clinical and a plexiform pattern (Figs 2 histopathological features and the and 3). Melanophages can be DIAGNOSIS outcomes of deep penetrating nevus found in focal interstitial DPN should be considthat have been published in the areas among the groups of ered in any young patient literature. nests and fascicles.1-3,5,6,17 presenting with a new or changing darkly pigmented There are typically a few The deep penetrating nevus is a papule or nodule. Clinically, nests or melanocytes in a controversial neoplasm that has rarely these lesions appear melanolentiginous pattern at the been associated with recurrence or cytic in nature and only dermoepidermal junction.1,3 lymph node involvement. More research rarely have been confused The papillary dermis is is needed to explore the behavior of with seborrheic keratoses or frequently spared8; however, these lesions. 3 hemangiomas. The differenthese lesions are often combined with a common tial diagnosis for such a meldermal or congenital nevus in the epidermis and anocytic lesion is broad and includes blue nevus, papillary dermis. Melanocytes tend to spread along Spitz nevus, pigmented spindle cell nevus, atypical hair follicles, blood vessels, sweat glands, and nevus, and malignant melanoma (Table II). nerves, and have been found to infiltrate the arrector The dermoscopic features of DPN have not been pili muscles in up to 88% of cases.3 Subcutaneous well established. One patient was noted to have a symmetric lesion with a homogenous ‘‘negative’’ involvement is common. Mature lymphocytes are globular pattern at baseline.15 As the lesion rapidly responsible for a mild to moderate inflammatory reaction in approximately 75% of cases.6 expanded, the globular pattern became confluent and cobblestone-like structures were noted cenMelanocytes in DPN have abundant pale cytotrally, prompting a biopsy specimen that confirmed plasm, small nucleoli, smudged chromatin, and the diagnosis.15 Subsequently, the dermoscopic large nuclear pseudoinclusions.1-3,5,6,17 Occasional features of 2 DPN were described as ‘‘polychrolow-grade cytologic atypia and random nuclear matic,’’ a term used when 3 or more colors are pleomorphism are commonly found, often seen present.16 Given these nonspecific clinical and in the deepest part of the lesion.1-3,5,6,17 Although dermoscopic findings, establishing the diagnosis of mitoses are rare, 0 to 1.2 mitoses/mm2 is posa DPN purely based on appearance with or without a sible.5 dermoscope is nearly impossible, and pathologic Approximately two thirds of DPN have a comexamination of the lesion is essential. bined appearance3; most often acquired nevi are An excisional biopsy specimen is the ideal way to associated.3 Frequently, the acquired nevus can be evaluate DPN to examine the lesion in its entirety. seen occupying the most superficial part of the Heavy pigmentation may be noted on gross examlesion, whereas the characteristics of the DPN can ination of the excised tissue, a finding that is also not be seen extending into the reticular dermis. Less unusual to see with blue nevi.3 If a ‘‘scoop shave’’ commonly, components of blue nevi and Spitz nevi can be found in association with DPN.5 Some experts removal is performed, the clinician is occasionally alarmed to see dark pigment at the deep edge of the believe that the term ‘‘deep penetrating nevus’’ biopsy site, which might raise concern for malignant should be reserved for those lesions that are not melanoma. Therefore if the clinical suspicion for combined.18 d
d
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Table I. Summary of deep penetrating nevus found in the literature No. of reported cases Age range, y Patient sex: No. female (%) No. male (%) No. unknown (%) No. of lesions on: Head and neck (%) Trunk (%) Upper extremity (%) Lower extremity (%) Unknown (%) No. of cases of recurrence (%) No. of cases of ‘‘metastasis’’ (%) Range follow-up, y
380 0-77 218 (57.4) 161 (42.4) 1 (0.3) 133 (35.0) 95 (25.0) 78 (20.5) 61 (16.1) 13 (3.4) 2 (0.5)* 1 (0.3)y 0.3-23
*One additional recurrence reported in a case of a melanocytic nevus with focal atypical epithelioid components.23 y This case was diagnosed as a ‘‘malignant deep penetrating nevus’’ given the fact that melanocytic foci were present in regional lymph nodes; however, the diagnosis was controversial among dermatopathologists.
Occasionally DPN may exhibit more atypical features such as more than 2 mitoses/mm2, asymmetry, prominent nucleoli, expansile growth, and pleomorphism. This group of highly controversial lesions has also been referred to as ‘‘deep penetrating nevus with atypical features,’’ ‘‘borderline melanomas,’’ or ‘‘melanocytic tumor of uncertain malignant potential’’ and is associated with potential locoregional metastatic spread.18-21 The classification, nature, and behavior of these lesions are highly debated.18 This variant does need study but is beyond the scope of this review. It has been suggested that the melanocytic nevus with focal atypical epithelioid components, also known as a clonal nevus, is a variant of the DPN.22,23 Although the nevus with focal atypical epithelioid components does not extend deep into the dermis, similarities exist between these 2 entities including their age predilection, benign nature, and histologic morphology.22,23 It has been postulated that these lesions exist on a continuum.22,23 Others have proposed that the DPN may be a variant of the blue nevus because both lesions are predominantly located in the dermis, are associated with deep heavy pigmentation, and often have human melanoma black 45 (HMB45) positivity.4,18,24,25 Recent research has demonstrated that up to 83% of blue nevi have a mutation in the GNAQ gene.4,26 This mutation has never been demonstrated in DPN, suggesting that these 2 lesions are molecularly distinct.4,26 In contrast, the DPN and the
Spitz nevus, which both have enlarged nuclei, spindle cells, and nuclear pseudoinclusions,18 also reportedly share mutations in the HRAS gene.4 Because of small sample size and low frequency of observed mutations, the data remain inconclusive.4 One of the biggest challenges for dermatopathologists is differentiating DPN from malignant melanoma, 2 diagnoses that have vastly different prognoses and treatments. DPN can be easily mistaken for the vertical growth phase of a nodular melanoma because of the deep infiltration and presence of cytologic atypia. Conversely, Ridha et al27 described a child who was initially given a diagnosis of DPN and ultimately found to have metastatic malignant melanoma. Several publications have attempted to address the histologic differences between DPN and malignant melanoma. Unlike malignant melanoma, the architecture of a DPN is generally symmetric, and the depth of the lesion is usually greater than the width.1 In DPN, the melanocytic infiltration into adnexal structures and the collagen framework of the dermis is nondestructive.2 The atypia is typically mild and random, not throughout the lesion. The number of mitoses in DPN is low compared with the often marked atypia and numerous atypical mitoses observed in malignant melanoma.1 DPN do not typically involve the epidermis, but often have an overlying benign nevus component in the epidermis and dermis. Although nests of cells are periodically found at the dermoepidermal junction, these nests are discrete and well demarcated. Malignant melanoma usually originates at the dermoepidermal junction and destroys the underlying architecture leading to a prominent stromal reaction consisting of plasma cells, lymphoid aggregates, inflammation, or a combination of these.1-3,5,6,17 It has been suggested that any area of necrosis should raise concerns for malignant melanoma.28 Whenever there is diagnostic histologic uncertainty, it is reasonable to obtain a second opinion.
IMMUNOHISTOCHEMISTRY AND ADDITIONAL STUDIES Because both DPN and malignant melanoma stain positively with S100 and HMB45,1 researchers have searched for other cytologic markers that could help distinguish these 2 entities. Mehregan et al29 demonstrated that proliferating cell nuclear antigen stained less than 5% of the total volume of melanocytes in DPN compared with 25% to 75% of the melanocytes in malignant melanoma, a finding that has not yet been incorporated into routine clinical practice. Roesch et al30 suggested that the ataxia telangiectasia-mutated gene may serve as a
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Fig 1. Clinical photographs of deep penetrating nevus. A 1-cm blue-gray nodule on the scalp of a 15-year-old girl (A). A 6-mm brown papule with foci of white and blue pigment on the back of the shoulder of a 59-year-old man (B).
diagnostic marker that can differentiate DPN from malignant melanoma as this was slightly elevated in nodular malignant melanoma. Scolyer et al31 reported that comparative genomic hybridization or fluorescence in situ hybridization can be used to distinguish malignant melanoma from benign melanocytic lesions because more than 95% of malignant melanoma contain some loss or gain of chromosomes, whereas melanocytic nevi generally contain no chromosomal abnormalities. A more recent study has also demonstrated that fluorescence in situ hybridization may be useful in distinguishing ambiguous blue nevi/DPN from blue nevuselike melanomas32; however, because of the unknown sensitivity of fluorescence in situ hybridization in the identification of all malignant melanoma, this diagnostic tool should still be used in conjunction with standard diagnostic methods.32 Despite these potentially promising findings, routine hematoxylin-eosin is currently the most cost-effective and regularly practiced method of distinguishing DPN from malignant melanoma.
PROGNOSIS AND MANAGEMENT The vast majority of DPN that have been described and reviewed in the literature have demonstrated benign biological behavior.1-3,7,9,10,12,13 However, perhaps because DPN can clinically and histologically appear similar to malignant melanoma, some clinicians re-excise DPN with margins. The earlier reports of DPN discuss that simple excision is curative and frequently mention that treatment is by complete excision. In 2009, the International Melanoma Pathology Study Group agreed that significant controversy still exists regarding the terminology, variants, and the malignant potential of DPN.18 The authors discuss that spread to regional lymph nodes
may occur but spread beyond the regional nodes is rare.18 They estimate that less than 2% of DPN spread to local lymph nodes if increased mitotic activity, expansile growth, or excessive nuclear pleomorphism are absent.18 There is mention of anecdotal cases of typical DPN with lymph node and/or visceral involvement occurring33 but no discussion of the cases, therefore, it is difficult to interpret this information. Rare cases of lymph node involvement can be found in the literature. A 23-year-old man presented with a lesion located on his back and was initially given a diagnosis by 3 pathologists as having nodular malignant melanoma.34 The patient underwent wide excision of the primary lesion and axillary lymph node dissection that revealed cells in 4 of 9 lymph nodes.34 The author of this case believed that the patient was given a misdiagnosis and, in fact, had a ‘‘malignant deep penetrating nevus.’’ Five-year follow-up of the patient revealed no recurrence or metastasis.34 More recent cases of metastasis from a DPN have been reported only in association with ‘‘DPN with atypical features’’ or ‘‘borderline’’ lesions.19-21,33 Although it is unclear whether these metastatic foci represent true pathogenic spread, the current consensus is that these atypical lesions have an unknown metastatic potential. Until future research reveals the pathogenesis of these neoplasms, the diagnosis and management of ‘‘DPN with atypical features,’’ ‘‘borderline’’ lesion, or melanocytic tumor of uncertain malignant potential varies on a caseby-case basis. Recurrences of pure DPN have been reported in 2 cases in the literature.5,23 The first was a 10-year-old child with a DPN excised from his toe.5 The lesion recurred within 1 year and was re-excised without
Histologic features
d
d
d
d
Sharply demarcated, wedge-shaped lesion with apex that points toward subcutis Loose fascicles and nests of epithelioidshaped melanocytes that extend into reticular dermis and along skin appendages but typically spare the epidermis Low-grade cytologic atypia common 0-1.2 Mitosis/mm2
10-30 Head and neck [ trunk, extremities Clinical appearance d \1-cm Brown to black dome-shaped papule
Age, y Site of predilection
Deep penetrating nevus
d
d
d
d
d
Sharply demarcated, wedge-shaped lesion Nests or sheets of spindled, pale melanocytes that extend along skin appendages and into the subcutis but typically spare the epidermis May be biphasic with component of common blue nevus Cytologic atypia and mitoses rare
\3-cm Blue-gray nodule
\40 Scalp, trunk
Cellular blue nevus35,36
d
d
d
d
d
d
Sharply demarcated, wedge-shaped lesion with apex towards subcutis Nests of large epithelioid or spindle cells Cell maturation seen with increasing depth Hyperkeratosis, hyperplasia, and hypergranulation commonly seen in epidermis \2 Mitosis/mm2 with rare mitoses in dermis
\1-cm Pink to brown papule or nodule
0-20 Face [ trunk, extremities
Spitz nevus36,37
d
d
d
d
d
d
\6-mm Brown to black macule or papule Starburst pattern often seen with dermoscopy Well-circumscribed, symmetric, junctional or compound melanocytic proliferation Nests of spindle-shaped melanocytes typically confined to epidermis and reticular dermis Low-grade cytologic atypia common Rare mitoses
10-30 Extremities
Pigmented spindle cell (Reed) nevus38
d
d
d
d
d
Asymmetric, poorly circumscribed nests of melanocytes with extension from the epidermis into the dermis and along skin appendages Presence of cytologic atypia Numerous mitoses Melanocyte necrosis may be present
Pink to black macule, papule, or nodule
40-60 Trunk, extremities
Malignant melanoma36
Table II. A comparison of clinical and histopathological features of lesions commonly included in the differential diagnosis of the deep penetrating nevus
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Fig 3. Histopathological features of deep penetrating nevus (DPN). A, At low power, the DPN appears fairly well circumscribed, occupying the papillary and reticular dermis, arranged in heavily pigmented nests. B, At higher power, the base of this DPN exhibits a pushing rather than an infiltrative border. C, Despite heavy pigmentation, the DPN cells do not exhibit atypia or bizarre mitoses. Fig 2. Histopathological features of deep penetrating nevus (DPN). A, At low power, the punch biopsy specimen demonstrates a well-circumscribed, wedgeshaped, pigmented dermal lesion, tapering toward the subcutaneous fat. B, DPN typically track along adnexal structures and neurovascular bundles, as shown on this high-power view. C, At high power, monomorphic pigmented dendritic melanocytes are interspersed among the larger, darkly pigmented melanophages.
further recurrence at 2-year follow-up.5 The authors did not specify whether the initial excision involved clear margins.5 In the second case, clinical information was not available; however, surgical margins were involved histologically.23 There has also been a case of nevus with focal atypical epithelioid components, involving surgical margins, that has recurred.23 Overall, recurrence of a DPN is quite rare and may be more likely if associated with incomplete primary excision; although, there are also cases of DPN with positive margins that have reportedly never recurred.3 With this, there is no conclusive evidence that a pure DPN without atypical features has metastatic or
malignant potential. Given that biopsy is necessary for diagnosis, many DPN will be removed in their entirety during an excisional biopsy, if performed. If lesions are found to have positive surgical margins, re-excision may not be necessary given the rarity of clinical recurrence. However, any DPN with atypical features or foci concerning for malignant melanoma should be removed in its entirety with appropriate surgical margins. There are no current guidelines outlining follow-up recommendations for patients given a diagnosis of DPN. Occasional full-body skin examinations may be beneficial given the lack of long-term data on these lesions. Conclusions The DPN is a fairly distinct melanocytic lesion, which can mimic other lesions, most notably malignant melanoma. In most cases, the characteristic histopathologic features allow for an accurate diagnosis. We concur with the International Melanoma Pathology Study Group that further study of DPN and long-term follow-up is necessary to make more
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definitive conclusions regarding natural history and biological behavior of these lesions.18 Jennifer Rivard, MD, Mary Maloney, MD, and Jeremy Bordeaux, MD, are acknowledged for assistance in the editing of this manuscript. REFERENCES 1. Seab JA, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989;13:39-44. 2. Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell nevus; a distinct variant of plexiform melanocytic nevus. Histopathology 1991;18:243-7. 3. Cooper PH. Deep penetrating (plexiform spindle cell) nevus: a frequent participant in combined nevus. J Cutan Pathol 1992; 19:172-80. 4. Bender RP, McGinniss MJ, Esmay P, Velazquez EF, Reimann JD. Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi. Mod Pathol 2013;26:1320-8. 5. Robson A, Morley-Quante M, Hempel H, McKee PH, Calonje E. Deep penetrating nevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma. Histopathology 2003;43:529-37. 6. Mehregan DA, Mehregan AH. Deep penetrating nevus. Arch Dermatol 1993;129:328-31. 7. P erez OG, Villoldo MS, Schroh R, Woscoff A. Deep penetrating nevus. J Eur Acad Dermatol Venereol 2009;23:703-4. 8. Luzar B, Calonje E. Deep penetrating nevus: a review. Arch Pathol Lab Med 2011;135:321-6. 9. Cheng YS, Kessler H, Watkins D, Watson S. Deep penetrating nevus of cheek skin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:49-52. 10. Sanatkhani M, Mosannen-Mozaffari P, Salehinejad J, Amirchaghmaghi M, Mokhtari M. A problematic oral pigmentation: deep penetrating nevus. J Appl Sci 2011;11:2265-9. 11. Flauta VS, Lingamfelter DC, Dang LM, Lankachandra KM. Deep penetrating nevus: a case report and brief literature review. Diagn Pathol 2006;1:31. 12. Hassan AS, Schulte KW, Ruzicka T, Megahed M. Linear arrangement of multiple deep penetrating nevi. Arch Dermatol 2003;139:1608-10. 13. Gupta A, Srilatha PS, Suvarna N, Rao L. Deep penetrating nevus: a distinct variant of melanocytic nevus. Indian J Pathol Microbiol 2011;54:156-7. 14. Murphy MJ, Jen M, Chang MW, Grant-Kels JM, Makkar H. Molecular diagnosis of a benign proliferative nodule developing in a congenital melanocytic nevus in a 3-month-old infant. J Am Acad Dermatol 2008;59:518-23. 15. Guadagni M, Nazzari G. Clinical and dermoscopic features of an evolving deep-penetrating nevus. Arch Dermatol 2005;141:1490. 16. Ferrara G, Soyer HP, Malvehy J, Piccolo D, Puig S, Sopena J, et al. The many faces of blue nevus; a clincopathologic study. J Cutan Pathol 2007;34:543-51. 17. Barnhill RL, Barnhill MA, Berwick M, Mihm MC Jr. The histological spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. Hum Pathol 1991;22:52-8. 18. Barnhill RL, Cerroni L, Cook M, Elder DE, Kerl H, LeBoit PE, et al. State of the art, nomenclature, and points of consensus and controversy concerning benign melanocytic lesions: outcome of an international workshop. Adv Anat Pathol 2010;17:73-90. 19. Magro CM, Crowson AN, Mihm MC Jr, Gupta K, Walker M, Soloman G. The dermal-based borderline melanocytic proliferation: a categorical approach. J Am Acad Dermatol 2010;62: 469-79.
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20. Abraham RM, Ming ME, Elder DE, Xu X. An atypical melanocytic lesion without genomic abnormalities shows locoregional metastasis. J Cutan Pathol 2011;39:21-4. 21. McCalmont TH, Bastian BC. An unconventional deep penetrating melanocytic nevus with microscopic involvement of regional lymph nodes. J Cutan Pathol 2012;39:25-8. 22. Ball NJ, Golitz LE. Melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases. J Am Acad Dermatol 1994;30:724-9. 23. High WA, Alanen KW, Golitz LE. Is melanocytic nevus with focal atypical epithelioid components (clonal nevus) a superficial variant of deep penetrating nevus? J Am Acad Dermatol 2006;55:460-6. 24. Scolyer RA, Zhuang L, Palmer AA, Thompson JF, McCarthy SW. Combined nevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma. Pathology 2004;36:419-27. 25. LeBoit P, Burg G, Weedon D, Sarasin A, editors. World Health Organization classification of tumors: pathology and genetics of skin tumors. Lyon (France): IARC Press; 2006. pp. 95-9. 26. Van Raamsdonk CD, Bezrookove V, Green G, Bauer J, Gaugler L, O’Brien JM, et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue nevi. Nature 2009;457:599-602. 27. Ridha H, Ahmed S, Theaker JM, Horlock N. Malignant melanoma and deep penetrating nevusedifficulties in diagnosis in children. J Plast Reconstr Aesthet Surg 2007;60:1252-5. 28. Edwards S, Blessing K. Problematic pigmented lesions: approach to diagnosis. J Clin Pathol 2000;53:409-18. 29. Mehregan DR, Mehregan DA, Mehregan AH. Proliferating cell nuclear antigen staining in deep-penetrating nevi. J Am Acad Dermatol 1995;33:685-7. 30. Roesch A, Becker B, Bentink S, Spang R, Vogl A, Hagen I, et al. Ataxia telangiectasia-mutated gene is a possible biomarker for discrimination of infiltrative deep penetrating nevi and metastatic vertical growth phase melanoma. Cancer Epidemiol Biomarkers Prev 2007;16:2486-90. 31. Scolyer RA, Murali R, McCarthy SW, Thompson JF. Histologically ambiguous (‘‘borderline’’) primary cutaneous melanocytic tumors: approaches to patient management including the roles of molecular testing and sentinel lymph node biopsy. Arch Pathol Lab Med 2010;134:1770-7. 32. North JP, Garrido MC, Kolaitis NA, LeBoit PE, McCalmont TH, Bastian BC. Fluorescence in situ hybridization as an ancillary tool in the diagnosis of ambiguous melanocytic neoplasms: a review of 804 cases. Am J Surg Pathol 2014;38:824-31. 33. Cerroni L, Barnhill R, Elder D, Gottlieb G, Heenan P, Kutzner H, et al. Melanocytic tumors of uncertain malignant potential: results of a tutorial held at the XXIX Symposium of the International Society of Dermatopathology in Graz, October 2008. Am J Surg Pathol 2010;34:314-26. 34. Graham J. Malignant deep penetrating nevus. J Cutan Pathol 1996;23:76. 35. Murali R, McCarthy SW, Scolyer RA. Blue nevi and related lesions: a review highlighting atypical and newly described variants, distinguishing features and diagnostic pitfalls. Adv Anat Pathol 2009;16:365-82. 36. Bolognia JL, Jorizzo JJ, Schaffer JV, Callen JP, Cerroni L, Heymann WR, et al, editors. Dermatology, 3rd edition. London: Elsevier; 2012. 37. Zedek DC, McCalmont TH. Spitz nevi, atypical Spitzoid neoplasms, and Spitzoid melanoma. Clin Lab Med 2011;31:311-20. 38. Brinster NK, Liu V, Diwan AH, McKee PH. Pigmented spindle cell nevus (Reed nevus). In: Brinster NK, Liu V, Diwan AH, McKee PH, editors. Dermatopathology: high-yield pathology. Philadelphia (PA): Saunders; 2011. pp. 347-8.
The deep penetrating nevus Lauren Strazzula, BA,a Maryanne Makredes Senna, MD,b Mariko Yasuda, MD,b and Leah Belazarian, MDb,c Worcester, Massachusetts The deep penetrating nevus (DPN), also known as the plexiform spindle cell nevus, is a pigmented lesion that commonly arises on the head and neck in the first few decades of life. Histopathologically, the DPN is wedge-shaped and contains melanocytes that exhibit deep infiltration into the dermis. Given these features, DPN may clinically and histopathologically mimic malignant melanoma, sparking confusion about the appropriate evaluation and management of these lesions. The goal of this review is to summarize the clinical and histopathological features of DPN and to discuss diagnostic and treatment strategies for dermatologists. ( J Am Acad Dermatol 2014;71:1234-40.) Key words: deep penetrating nevus; dermatopathology; malignant melanoma; melanocytic tumor of uncertain malignant potential; nevus with focal atypical epithelioid components; plexiform spindle cell nevus.
T
he deep penetrating nevus (DPN) is a darkly pigmented melanocytic lesion that exhibits deep infiltration into the reticular dermis.1 It has gained recognition over the past couple of decades because its histologic appearance is commonly confused with malignant melanoma. This nevus does not have a consistent morphology and because of its often sudden appearance and dark color, its appearance may raise concern for a malignant process among both practitioners and patients. Although the pathology literature is well-versed in the histologic features of DPN, the dermatology literature lacks a comprehensive clinical summary, and dermatologists are often forced to make clinical decisions based on isolated case reports and small series. The goal of this review is to summarize the clinical and histologic features of DPN and to discuss diagnostic and treatment issues for these elusive lesions.
with similar characteristics, which they named the ‘‘plexiform spindle cell nevus.’’ It was later accepted that these 2 reports were describing the same melanocytic lesion, and the naming of the nevus by Seab et al1 was accepted. Since then, nearly 400 lesions have been reported in the English-language literature.
CLINICAL PRESENTATION
The DPN was first described in 1989 by Seab et al,1 who reported 70 patients with a darkly pigmented nevus composed of loosely organized nests of melanocytes with deep extension into the reticular dermis. In 1991, Barnhill et al2 described a lesion
Although the age at presentation is broad (0-77 years) (Table I), DPN tend to occur in a younger patient population, most frequently in the first 3 decades of life.1,3,4 Congenital onset has been reported,3,5-7 and lesions rarely arise in patients older than 50 years.8 Females appear to have a slightly higher incidence (57.4%) compared with males (42.4%).1-3,5,6 DPN occur on the head and neck in approximately 35% of cases, on the trunk in 25%, and on the upper extremities in 20.5%. Less commonly, DPN occur on the lower extremities, and they have only rarely been described on distal extremities3,4 or mucosal surfaces.9,10 The majority of DPN are darkly pigmented dome-shaped papules or nodules that are less than 1 cm in diameter.8,11 Typically, DPN present as a solitary lesion, however, a linear arrangement of multiple DPN over the preauricular cheek has
From the University of Massachusetts Medical Schoola; and Division of Dermatology, Departments of Medicineb and Pediatrics,c University of Massachusetts Medical School, UMass Memorial Healthcare. Funding sources: None. Conflicts of interest: None declared. Accepted for publication July 19, 2014.
Reprint requests: Leah Belazarian, MD, UMass Memorial Healthcare, 281 Lincoln St, Worcester, MA 01605. E-mail: leah. [email protected]. Published online September 4, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.07.026
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been reported.12 The lesions are most frequently DPN is high, the best method of diagnosis is via a black, blue, dark brown, or gray (or often a comnarrow excision. bination of these colors) (Fig 1) but have been rarely noted to be red or pink.3 Patients may report HISTOLOGIC FEATURES a new or changing lesion because they are almost The DPN is a sharply demarcated lesion, and at always acquired. Most DPN are asymptomatic, low power is symmetric and wedged-shaped with a although pain or dysesthesia have rarely been broad base that runs parallel with the epidermis and reported.13 The vast majority an apex that is oriented toof patients have no personal wards the subcutaneous adiCAPSULE SUMMARY or family history of melapose.1-3,5,6,17 It consists of noma. A DPN developing often vertically oriented, The deep penetrating nevus is a within a medium-sized loose fascicles and nests of melanocytic lesion that may clinically congenital nevus has been spindle-shaped and epitheand histopathologically mimic malignant reported in a 3-month old lioid melanocytes extending melanoma. infant.14 into the reticular dermis in This review summarizes the clinical and a plexiform pattern (Figs 2 histopathological features and the and 3). Melanophages can be DIAGNOSIS outcomes of deep penetrating nevus found in focal interstitial DPN should be considthat have been published in the areas among the groups of ered in any young patient literature. nests and fascicles.1-3,5,6,17 presenting with a new or changing darkly pigmented There are typically a few The deep penetrating nevus is a papule or nodule. Clinically, nests or melanocytes in a controversial neoplasm that has rarely these lesions appear melanolentiginous pattern at the been associated with recurrence or cytic in nature and only dermoepidermal junction.1,3 lymph node involvement. More research rarely have been confused The papillary dermis is is needed to explore the behavior of with seborrheic keratoses or frequently spared8; however, these lesions. 3 hemangiomas. The differenthese lesions are often combined with a common tial diagnosis for such a meldermal or congenital nevus in the epidermis and anocytic lesion is broad and includes blue nevus, papillary dermis. Melanocytes tend to spread along Spitz nevus, pigmented spindle cell nevus, atypical hair follicles, blood vessels, sweat glands, and nevus, and malignant melanoma (Table II). nerves, and have been found to infiltrate the arrector The dermoscopic features of DPN have not been pili muscles in up to 88% of cases.3 Subcutaneous well established. One patient was noted to have a symmetric lesion with a homogenous ‘‘negative’’ involvement is common. Mature lymphocytes are globular pattern at baseline.15 As the lesion rapidly responsible for a mild to moderate inflammatory reaction in approximately 75% of cases.6 expanded, the globular pattern became confluent and cobblestone-like structures were noted cenMelanocytes in DPN have abundant pale cytotrally, prompting a biopsy specimen that confirmed plasm, small nucleoli, smudged chromatin, and the diagnosis.15 Subsequently, the dermoscopic large nuclear pseudoinclusions.1-3,5,6,17 Occasional features of 2 DPN were described as ‘‘polychrolow-grade cytologic atypia and random nuclear matic,’’ a term used when 3 or more colors are pleomorphism are commonly found, often seen present.16 Given these nonspecific clinical and in the deepest part of the lesion.1-3,5,6,17 Although dermoscopic findings, establishing the diagnosis of mitoses are rare, 0 to 1.2 mitoses/mm2 is posa DPN purely based on appearance with or without a sible.5 dermoscope is nearly impossible, and pathologic Approximately two thirds of DPN have a comexamination of the lesion is essential. bined appearance3; most often acquired nevi are An excisional biopsy specimen is the ideal way to associated.3 Frequently, the acquired nevus can be evaluate DPN to examine the lesion in its entirety. seen occupying the most superficial part of the Heavy pigmentation may be noted on gross examlesion, whereas the characteristics of the DPN can ination of the excised tissue, a finding that is also not be seen extending into the reticular dermis. Less unusual to see with blue nevi.3 If a ‘‘scoop shave’’ commonly, components of blue nevi and Spitz nevi can be found in association with DPN.5 Some experts removal is performed, the clinician is occasionally alarmed to see dark pigment at the deep edge of the believe that the term ‘‘deep penetrating nevus’’ biopsy site, which might raise concern for malignant should be reserved for those lesions that are not melanoma. Therefore if the clinical suspicion for combined.18 d
d
d
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Table I. Summary of deep penetrating nevus found in the literature No. of reported cases Age range, y Patient sex: No. female (%) No. male (%) No. unknown (%) No. of lesions on: Head and neck (%) Trunk (%) Upper extremity (%) Lower extremity (%) Unknown (%) No. of cases of recurrence (%) No. of cases of ‘‘metastasis’’ (%) Range follow-up, y
380 0-77 218 (57.4) 161 (42.4) 1 (0.3) 133 (35.0) 95 (25.0) 78 (20.5) 61 (16.1) 13 (3.4) 2 (0.5)* 1 (0.3)y 0.3-23
*One additional recurrence reported in a case of a melanocytic nevus with focal atypical epithelioid components.23 y This case was diagnosed as a ‘‘malignant deep penetrating nevus’’ given the fact that melanocytic foci were present in regional lymph nodes; however, the diagnosis was controversial among dermatopathologists.
Occasionally DPN may exhibit more atypical features such as more than 2 mitoses/mm2, asymmetry, prominent nucleoli, expansile growth, and pleomorphism. This group of highly controversial lesions has also been referred to as ‘‘deep penetrating nevus with atypical features,’’ ‘‘borderline melanomas,’’ or ‘‘melanocytic tumor of uncertain malignant potential’’ and is associated with potential locoregional metastatic spread.18-21 The classification, nature, and behavior of these lesions are highly debated.18 This variant does need study but is beyond the scope of this review. It has been suggested that the melanocytic nevus with focal atypical epithelioid components, also known as a clonal nevus, is a variant of the DPN.22,23 Although the nevus with focal atypical epithelioid components does not extend deep into the dermis, similarities exist between these 2 entities including their age predilection, benign nature, and histologic morphology.22,23 It has been postulated that these lesions exist on a continuum.22,23 Others have proposed that the DPN may be a variant of the blue nevus because both lesions are predominantly located in the dermis, are associated with deep heavy pigmentation, and often have human melanoma black 45 (HMB45) positivity.4,18,24,25 Recent research has demonstrated that up to 83% of blue nevi have a mutation in the GNAQ gene.4,26 This mutation has never been demonstrated in DPN, suggesting that these 2 lesions are molecularly distinct.4,26 In contrast, the DPN and the
Spitz nevus, which both have enlarged nuclei, spindle cells, and nuclear pseudoinclusions,18 also reportedly share mutations in the HRAS gene.4 Because of small sample size and low frequency of observed mutations, the data remain inconclusive.4 One of the biggest challenges for dermatopathologists is differentiating DPN from malignant melanoma, 2 diagnoses that have vastly different prognoses and treatments. DPN can be easily mistaken for the vertical growth phase of a nodular melanoma because of the deep infiltration and presence of cytologic atypia. Conversely, Ridha et al27 described a child who was initially given a diagnosis of DPN and ultimately found to have metastatic malignant melanoma. Several publications have attempted to address the histologic differences between DPN and malignant melanoma. Unlike malignant melanoma, the architecture of a DPN is generally symmetric, and the depth of the lesion is usually greater than the width.1 In DPN, the melanocytic infiltration into adnexal structures and the collagen framework of the dermis is nondestructive.2 The atypia is typically mild and random, not throughout the lesion. The number of mitoses in DPN is low compared with the often marked atypia and numerous atypical mitoses observed in malignant melanoma.1 DPN do not typically involve the epidermis, but often have an overlying benign nevus component in the epidermis and dermis. Although nests of cells are periodically found at the dermoepidermal junction, these nests are discrete and well demarcated. Malignant melanoma usually originates at the dermoepidermal junction and destroys the underlying architecture leading to a prominent stromal reaction consisting of plasma cells, lymphoid aggregates, inflammation, or a combination of these.1-3,5,6,17 It has been suggested that any area of necrosis should raise concerns for malignant melanoma.28 Whenever there is diagnostic histologic uncertainty, it is reasonable to obtain a second opinion.
IMMUNOHISTOCHEMISTRY AND ADDITIONAL STUDIES Because both DPN and malignant melanoma stain positively with S100 and HMB45,1 researchers have searched for other cytologic markers that could help distinguish these 2 entities. Mehregan et al29 demonstrated that proliferating cell nuclear antigen stained less than 5% of the total volume of melanocytes in DPN compared with 25% to 75% of the melanocytes in malignant melanoma, a finding that has not yet been incorporated into routine clinical practice. Roesch et al30 suggested that the ataxia telangiectasia-mutated gene may serve as a
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Fig 1. Clinical photographs of deep penetrating nevus. A 1-cm blue-gray nodule on the scalp of a 15-year-old girl (A). A 6-mm brown papule with foci of white and blue pigment on the back of the shoulder of a 59-year-old man (B).
diagnostic marker that can differentiate DPN from malignant melanoma as this was slightly elevated in nodular malignant melanoma. Scolyer et al31 reported that comparative genomic hybridization or fluorescence in situ hybridization can be used to distinguish malignant melanoma from benign melanocytic lesions because more than 95% of malignant melanoma contain some loss or gain of chromosomes, whereas melanocytic nevi generally contain no chromosomal abnormalities. A more recent study has also demonstrated that fluorescence in situ hybridization may be useful in distinguishing ambiguous blue nevi/DPN from blue nevuselike melanomas32; however, because of the unknown sensitivity of fluorescence in situ hybridization in the identification of all malignant melanoma, this diagnostic tool should still be used in conjunction with standard diagnostic methods.32 Despite these potentially promising findings, routine hematoxylin-eosin is currently the most cost-effective and regularly practiced method of distinguishing DPN from malignant melanoma.
PROGNOSIS AND MANAGEMENT The vast majority of DPN that have been described and reviewed in the literature have demonstrated benign biological behavior.1-3,7,9,10,12,13 However, perhaps because DPN can clinically and histologically appear similar to malignant melanoma, some clinicians re-excise DPN with margins. The earlier reports of DPN discuss that simple excision is curative and frequently mention that treatment is by complete excision. In 2009, the International Melanoma Pathology Study Group agreed that significant controversy still exists regarding the terminology, variants, and the malignant potential of DPN.18 The authors discuss that spread to regional lymph nodes
may occur but spread beyond the regional nodes is rare.18 They estimate that less than 2% of DPN spread to local lymph nodes if increased mitotic activity, expansile growth, or excessive nuclear pleomorphism are absent.18 There is mention of anecdotal cases of typical DPN with lymph node and/or visceral involvement occurring33 but no discussion of the cases, therefore, it is difficult to interpret this information. Rare cases of lymph node involvement can be found in the literature. A 23-year-old man presented with a lesion located on his back and was initially given a diagnosis by 3 pathologists as having nodular malignant melanoma.34 The patient underwent wide excision of the primary lesion and axillary lymph node dissection that revealed cells in 4 of 9 lymph nodes.34 The author of this case believed that the patient was given a misdiagnosis and, in fact, had a ‘‘malignant deep penetrating nevus.’’ Five-year follow-up of the patient revealed no recurrence or metastasis.34 More recent cases of metastasis from a DPN have been reported only in association with ‘‘DPN with atypical features’’ or ‘‘borderline’’ lesions.19-21,33 Although it is unclear whether these metastatic foci represent true pathogenic spread, the current consensus is that these atypical lesions have an unknown metastatic potential. Until future research reveals the pathogenesis of these neoplasms, the diagnosis and management of ‘‘DPN with atypical features,’’ ‘‘borderline’’ lesion, or melanocytic tumor of uncertain malignant potential varies on a caseby-case basis. Recurrences of pure DPN have been reported in 2 cases in the literature.5,23 The first was a 10-year-old child with a DPN excised from his toe.5 The lesion recurred within 1 year and was re-excised without
Histologic features
d
d
d
d
Sharply demarcated, wedge-shaped lesion with apex that points toward subcutis Loose fascicles and nests of epithelioidshaped melanocytes that extend into reticular dermis and along skin appendages but typically spare the epidermis Low-grade cytologic atypia common 0-1.2 Mitosis/mm2
10-30 Head and neck [ trunk, extremities Clinical appearance d \1-cm Brown to black dome-shaped papule
Age, y Site of predilection
Deep penetrating nevus
d
d
d
d
d
Sharply demarcated, wedge-shaped lesion Nests or sheets of spindled, pale melanocytes that extend along skin appendages and into the subcutis but typically spare the epidermis May be biphasic with component of common blue nevus Cytologic atypia and mitoses rare
\3-cm Blue-gray nodule
\40 Scalp, trunk
Cellular blue nevus35,36
d
d
d
d
d
d
Sharply demarcated, wedge-shaped lesion with apex towards subcutis Nests of large epithelioid or spindle cells Cell maturation seen with increasing depth Hyperkeratosis, hyperplasia, and hypergranulation commonly seen in epidermis \2 Mitosis/mm2 with rare mitoses in dermis
\1-cm Pink to brown papule or nodule
0-20 Face [ trunk, extremities
Spitz nevus36,37
d
d
d
d
d
d
\6-mm Brown to black macule or papule Starburst pattern often seen with dermoscopy Well-circumscribed, symmetric, junctional or compound melanocytic proliferation Nests of spindle-shaped melanocytes typically confined to epidermis and reticular dermis Low-grade cytologic atypia common Rare mitoses
10-30 Extremities
Pigmented spindle cell (Reed) nevus38
d
d
d
d
d
Asymmetric, poorly circumscribed nests of melanocytes with extension from the epidermis into the dermis and along skin appendages Presence of cytologic atypia Numerous mitoses Melanocyte necrosis may be present
Pink to black macule, papule, or nodule
40-60 Trunk, extremities
Malignant melanoma36
Table II. A comparison of clinical and histopathological features of lesions commonly included in the differential diagnosis of the deep penetrating nevus
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Fig 3. Histopathological features of deep penetrating nevus (DPN). A, At low power, the DPN appears fairly well circumscribed, occupying the papillary and reticular dermis, arranged in heavily pigmented nests. B, At higher power, the base of this DPN exhibits a pushing rather than an infiltrative border. C, Despite heavy pigmentation, the DPN cells do not exhibit atypia or bizarre mitoses. Fig 2. Histopathological features of deep penetrating nevus (DPN). A, At low power, the punch biopsy specimen demonstrates a well-circumscribed, wedgeshaped, pigmented dermal lesion, tapering toward the subcutaneous fat. B, DPN typically track along adnexal structures and neurovascular bundles, as shown on this high-power view. C, At high power, monomorphic pigmented dendritic melanocytes are interspersed among the larger, darkly pigmented melanophages.
further recurrence at 2-year follow-up.5 The authors did not specify whether the initial excision involved clear margins.5 In the second case, clinical information was not available; however, surgical margins were involved histologically.23 There has also been a case of nevus with focal atypical epithelioid components, involving surgical margins, that has recurred.23 Overall, recurrence of a DPN is quite rare and may be more likely if associated with incomplete primary excision; although, there are also cases of DPN with positive margins that have reportedly never recurred.3 With this, there is no conclusive evidence that a pure DPN without atypical features has metastatic or
malignant potential. Given that biopsy is necessary for diagnosis, many DPN will be removed in their entirety during an excisional biopsy, if performed. If lesions are found to have positive surgical margins, re-excision may not be necessary given the rarity of clinical recurrence. However, any DPN with atypical features or foci concerning for malignant melanoma should be removed in its entirety with appropriate surgical margins. There are no current guidelines outlining follow-up recommendations for patients given a diagnosis of DPN. Occasional full-body skin examinations may be beneficial given the lack of long-term data on these lesions. Conclusions The DPN is a fairly distinct melanocytic lesion, which can mimic other lesions, most notably malignant melanoma. In most cases, the characteristic histopathologic features allow for an accurate diagnosis. We concur with the International Melanoma Pathology Study Group that further study of DPN and long-term follow-up is necessary to make more
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definitive conclusions regarding natural history and biological behavior of these lesions.18 Jennifer Rivard, MD, Mary Maloney, MD, and Jeremy Bordeaux, MD, are acknowledged for assistance in the editing of this manuscript. REFERENCES 1. Seab JA, Graham JH, Helwig EB. Deep penetrating nevus. Am J Surg Pathol 1989;13:39-44. 2. Barnhill RL, Mihm MC Jr, Magro CM. Plexiform spindle cell nevus; a distinct variant of plexiform melanocytic nevus. Histopathology 1991;18:243-7. 3. Cooper PH. Deep penetrating (plexiform spindle cell) nevus: a frequent participant in combined nevus. J Cutan Pathol 1992; 19:172-80. 4. Bender RP, McGinniss MJ, Esmay P, Velazquez EF, Reimann JD. Identification of HRAS mutations and absence of GNAQ or GNA11 mutations in deep penetrating nevi. Mod Pathol 2013;26:1320-8. 5. Robson A, Morley-Quante M, Hempel H, McKee PH, Calonje E. Deep penetrating nevus: clinicopathological study of 31 cases with further delineation of histological features allowing distinction from other pigmented benign melanocytic lesions and melanoma. Histopathology 2003;43:529-37. 6. Mehregan DA, Mehregan AH. Deep penetrating nevus. Arch Dermatol 1993;129:328-31. 7. P erez OG, Villoldo MS, Schroh R, Woscoff A. Deep penetrating nevus. J Eur Acad Dermatol Venereol 2009;23:703-4. 8. Luzar B, Calonje E. Deep penetrating nevus: a review. Arch Pathol Lab Med 2011;135:321-6. 9. Cheng YS, Kessler H, Watkins D, Watson S. Deep penetrating nevus of cheek skin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:49-52. 10. Sanatkhani M, Mosannen-Mozaffari P, Salehinejad J, Amirchaghmaghi M, Mokhtari M. A problematic oral pigmentation: deep penetrating nevus. J Appl Sci 2011;11:2265-9. 11. Flauta VS, Lingamfelter DC, Dang LM, Lankachandra KM. Deep penetrating nevus: a case report and brief literature review. Diagn Pathol 2006;1:31. 12. Hassan AS, Schulte KW, Ruzicka T, Megahed M. Linear arrangement of multiple deep penetrating nevi. Arch Dermatol 2003;139:1608-10. 13. Gupta A, Srilatha PS, Suvarna N, Rao L. Deep penetrating nevus: a distinct variant of melanocytic nevus. Indian J Pathol Microbiol 2011;54:156-7. 14. Murphy MJ, Jen M, Chang MW, Grant-Kels JM, Makkar H. Molecular diagnosis of a benign proliferative nodule developing in a congenital melanocytic nevus in a 3-month-old infant. J Am Acad Dermatol 2008;59:518-23. 15. Guadagni M, Nazzari G. Clinical and dermoscopic features of an evolving deep-penetrating nevus. Arch Dermatol 2005;141:1490. 16. Ferrara G, Soyer HP, Malvehy J, Piccolo D, Puig S, Sopena J, et al. The many faces of blue nevus; a clincopathologic study. J Cutan Pathol 2007;34:543-51. 17. Barnhill RL, Barnhill MA, Berwick M, Mihm MC Jr. The histological spectrum of pigmented spindle cell nevus: a review of 120 cases with emphasis on atypical variants. Hum Pathol 1991;22:52-8. 18. Barnhill RL, Cerroni L, Cook M, Elder DE, Kerl H, LeBoit PE, et al. State of the art, nomenclature, and points of consensus and controversy concerning benign melanocytic lesions: outcome of an international workshop. Adv Anat Pathol 2010;17:73-90. 19. Magro CM, Crowson AN, Mihm MC Jr, Gupta K, Walker M, Soloman G. The dermal-based borderline melanocytic proliferation: a categorical approach. J Am Acad Dermatol 2010;62: 469-79.
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