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Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes
DERMATOPATHOLOGY
Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes Emily A. Simons, MPH,a Jennifer T. Huang, MD,a and Birgitta Schmidt, MDb Boston, Massachusetts Background: Although only large congenital melanocytic nevi (CMN) are associated with a significantly high risk for malignant transformation, CMN of all sizes are prone to changes in clinical appearance in early childhood and thus are often biopsied or excised. While CMNs typically exhibit benign behavior, atypical histopathologic findings might be common and may prompt additional unnecessary procedures. Objective: To assess the prevalence and associated clinical outcomes of atypical histopathologic features in CMN in children. Methods: A single center retrospective study was conducted with patients 0-35 months of age with CMN diagnosed by histopathology between 1993-2013. Results: One hundred seventy-nine patients with a total of 197 CMNs were identified. Cytologic atypia, architectural disorder, or pagetoid spread were present in 73% of CMN. With a mean follow up of 7.3 years, no cases of melanoma or CMN-related deaths were identified. Limitations: Our findings were based on a largely Caucasian population and might not apply to darker skin types. Our findings might not apply to older children or adults with CMN. Conclusion: Atypical histopathologic features of cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN of young children. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2016.12.026.) Key words: congenital melanocytic nevi; dermatopathology; pediatric melanoma.
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ongenital melanocytic nevi (CMN) are benign cutaneous birthmarks found in 2%4% of children across most ethnicities.1-4 Historically, all CMNs were thought to carry a higher risk for malignant transformation than acquired melanocytic nevi.5,6 Over the past 1-2 decades, large retrospective studies have shown no increase in risk for melanoma in small- and medium-sized CMNs, which has changed our approach to the management
From the Departments of Medicinea and Pathology,b Boston Children’s Hospital, Harvard Medical School. Funding sources: None. Conflicts of interest: None declared. Previously presented: Provisional results of this study were presented as a poster at the 42nd annual meeting of The Society for Pediatric Dermatology, Minneapolis, MN, July 14-17, 2016. Accepted for publication December 16, 2016. Reprint requests: Birgitta Schmidt, MD, Boston’s Children’s Hospital, Department of Pathology, 300 Longwood Ave,
Abbreviation used: CMN:
congenital melanocytic nevus
of these lesions.7,8 However, evidence for increased risk for malignant transformation in large CMN, which can be defined as [20-cm projected adult
Boston, MA 02115. E-mail: Birgitta.Schmidt@childrens. harvard.edu. Correspondence to: Emily A. Simons, MPH, Boston Children’s Hospital, Dermatology Program, Fegan 6, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]. Published online February 24, 2017. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.12.026
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size, remains and is estimated at 2%-5% over an nodules can be challenging to distinguish from average follow-up of 4-9 years.8-13 malignancy, previously established features of proCurrently, the management of CMNs of all sizes is liferative nodules, listed in Table III, were recorded.22 variable and ranges from anticipatory counseling to For children who had a single CMN that was biopsied prophylactic excisions.14 Morphologic changes in the more than once at ages 0-35 months, the nevus was clinical appearance of CMN is common during childcaptured as a single record that included any features hood and includes development of erosions, present on any biopsy. For children who had more ulcerations, changes in color, than one CMN biopsied, each papules, nodules, and CMN was captured as a sepaCAPSULE SUMMARY plexiform neurofibroma-like rate record. plaques.15 Skin biopsy of Clinical and follow-up Congenital melanocytic nevi (CMN) often changing lesions is data, including demographic change in appearance in childhood and appropriate, yet histologic information, age at biopsy, are often excised. interpretation is often chalsize and location of nevi, realenging. Histologic features Atypical histopathologic features were sons for treatment, treatment of CMN in infants established present in 74% of 197 cases of CMN in characteristics, date of last 2-3 decades ago recognized children \3 years of age; no cases of visit, diagnosis of melanoma, the tendency of CMN to melanoma were identified after a mean and date of death were obextend into the deep dermis follow-up of 7.3 years. tained from patient medical and subcutis, involving records through April 2016. Atypical histopathologic features are vascular, adnexal, and neural Follow-up data were only recommon in CMN of young children and structures and some degree corded if patients had at least do not appear to be associated with an of cytologic atypia in 0%-30% one visit documented at least unfavorable clinical outcome. of lesions.16,17 The literature 6 months after excision or bisince has largely focused on opsy to avoid inclusion of subsets of CMN, such as blue postoperative wound evaluanevi variants and proliferative nodules, and has tions as follow-up time for development of melasuggested that atypical features are not necessarily noma. Nevus size was defined as the largest recorded indicative of malignancy.18-21 diameter before time of biopsy or, in the absence of In this study, we sought to provide an update on recorded clinical measurements, the width of excithe histopathologic spectrum of CMN and associated sion or one-third the length of excision. To classify long-term outcomes by evaluating CMN biopsied at CMN size, we used recent recommendations based our institution in children \3 years of age over a 20on projected adult size.13 year period. Study definitions Given that no single or constellation of histologic METHODS features characterize CMN to a high degree of Study design specificity, a CMN was defined by a clinical descripA retrospective study examining surgical patholtion as a pigmented lesion that was congenital, a ogy specimens and medical records was conducted birthmark, or present since birth. Blue nevus was at Boston Children’s Hospital. The study was defined as a dermal proliferation of variably pigapproved by the institutional review board (IRBmented, spindle-shaped dendritic melanocytes. P00007909). Spindle and epithelioid nevus (ie, Spitz nevus) was All surgical pathology reports containing the terms defined by the presence of spindled and/or epithe‘‘congenital’’ and ‘‘nevus’’ for patients 0-35 months of lioid melanocytes. Deep-pigmented nevus was age from 1993-2013 were obtained. Additional includefined by the presence of wedge-shaped nests of sion criteria were a clinical record describing the pleomorphic melanocytes and macrophages connevus as congenital or present since birth. Exclusion taining melanin granules extending from the upper criteria included histology findings that favored an dermis into the subcutaneous fat tissue along alternative diagnosis, missing histology specimens, adnexal structures. and insufficient tissue quantity. An experienced Architectural disorder was defined by irregular pathologist specialized in pediatric dermatopatholposition and size of nevus nests and the presence of ogy (Dr Schmidt) obtained and analyzed the histopagetoid spread of melanocytes within the logic sections that were stained with hematoxylin and epidermis. Cytologic atypia was considered present eosin in each case and recorded gross morphologic when intraepidermal melanocytes demonstrated features listed in Table I. Because proliferative d
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Table I. Histologic features of congenital melanocytic nevi (n = 196 nevi) Characteristic
Typical features Depth of invasion Epidermis Reticular dermis Deep dermis Extracutaneous involvement- Any Perivascular Periadnexal Perineural Combined features- Any Blue nevus Spindle and epithelioid (Spitz) Deep pigmented (deep penetrating) Atypical features- Any Cytologic atypia- Any Mild Moderate Severe Architectural disorder- Any Mild Moderate Severe Pagetoid spread Bridging Fibrosis First procedure In setting of prior procedure Mitotic figures ($1 per 1 mm2) Regression Inflammation
Table II. Size and location of congenital melanocytic nevus (n = 179 patients) Nevi, N (% of total)
179 193 90 194 187 188 127 79 70 20 1
(91) (98) (46) (99) (95) (96) (65) (40) (36) (10) (1)
152 138 124 37 4 131 105 43 5 121 39
(78) (70) (63) (19) (2) (67) (54) (22) (3) (62) (20)
6 16 2 0 2
(3) (8) (1) (0) (1)
variable and discontinuous nuclear atypia (ie, the degree of nuclear atypia varied from cell to cell). Cytologic atypia was graded as mild, moderate, or severe. Mild cytologic atypia referred to some retraction of the cytoplasm and minimal increase in melanocyte size compared with the nuclei from a keratinocyte in the spinous layer. Large melanocyte nuclei with occasional nucleoli was classified as moderate atypia. Severe atypia was characterized as increased melanocyte cytoplasm, enlarged nucleoli, and enlarged nuclei approaching up to twice the size of a keratinocyte. Statistical analysis Each distinct congenital nevus was considered a unit of observation. Descriptive statistics were calculated for each variable and presented in Tables I and II. Statistical analyses were conducted with STATA 13.23 Linear regression was performed to assess differences in number of atypical histologic features
Projected adult size of largest CMN13 Small (\1.5 cm) Medium, M1 (1.5-10 cm) Medium, M2 ([10-20 cm) Large, L1 ([20-30 cm) Large, L2 ([30-40 cm) Giant ([40 cm) Missing Location Head Trunk Extremities Missing
N (% with data) 3 (2) 91 (58) 31 (20) 18 (11) 6 (4) 9 (6) 21 N (% with data) 71 (40) 57 (32) 49 (28) 2
CMN, Congenital melanocytic nevus.
across clinical characteristics, including nevus size category, location, and age in years at biopsy, and length of follow-up time by histologic feature. Logistic regression was performed to assess associations between histopathologic features and differences in follow-up time by histopathologic feature.
RESULTS During 1993-2013, surgical pathology records (n = 268) were identified that contained the words ‘‘congenital’’ and ‘‘nevus,’’ of which 242 were nevi described clinically as congenital. Twenty-eight records were excluded as described in Fig 1, leading to 214 accessions representing 197 nevi in 179 patients. The average age at biopsy or excision was 17 months (range 4 days-35 months). Patients were 51% (92/179) female. Of those with data available, 80% (40/50) had skin types I-II, and 90% (104/116) reported race as Caucasian. Clinical characteristics CMNs were predominantly medium in size (Table II), with a projected adult size of 1.5-10 cm in 58% (91/158) of patients, 41 of whom had lesions 1.5-5 cm and 50 of whom had lesions [5-10 cm in projected adult size.13 The majority of CMN (72%; 128/177) had an axial distribution involving the head or trunk. Of 214 accessions, 5 were obtained by punch biopsy and 209 by surgical excisions. Dermatologists obtained 9 (4%) specimens, while 190 (89%) were obtained by plastic surgeons and 14 (7%) were obtained by general surgeons. Sixty-three of 136 (46%) patients whose nevus was excised by a surgeon did not see a dermatologist within our institution. Data on referral patterns for these 63 patients were limited, with referral from an outside dermatologist mentioned for only 3 patients. Reasons stated
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Fig 1. Congenital melanocytic nevus (CMN) identification and exclusion criteria.
Fig 2. A, Congenital melanocytic nevus with architectural disorder, superficial papillary dermal fibrosis, and lentiginous proliferation of melanocytes with focal pagetoid spread of atypical melanocytes. B, Congenital melanocytic nevus demonstrating architectural disorder and pagetoid spread. (A and B, Hematoxylin-eosin stain; original magnification: A, 34; B, 340.)
for excision or biopsy of nevus included physician concern for malignant transformation in 94 patients, change in appearance in 21 patients, disfigurement in 5 patients, size and location in 5 patients, and parental request in 5 patients. The reason for excision was not discernible for 49 patients. Histopathologic features Histologic features almost universally included involvement of reticular dermis and extracutaneous structures, including vascular, adnexal, and neural tissue (Table I). Combined histologic patterns of a blue nevus, spindle and epithelioid (Spitz) nevus, or a deep penetrating nevus were identified in 79 (40%) of CMN.
Features considered atypical were very common, with 152/197 (77%) nevi demonstrating at least 1 atypical finding and a mean of 2.6 (range 0-7) atypical features per nevus. Even when excluding mild cytologic atypia or architectural disorder, 145/ 197 (74%) nevi exhibited at least 1 and 75/197 (38%) exhibited 2 or more of the remaining atypical features. Cytologic atypia, architectural disorder, and pagetoid spread were the most frequent features (Figs 2-4) present in 144/197 (73%) of nevi and were also closely associated. Lesions demonstrated concordance between presence of cytologic atypia and architectural disorder in 181/197 (92%) CMN and between presence of cytologic atypia and pagetoid spread in 173/197 (88%) CMN. Bridging was less
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Table III. Features of proliferative nodules (n = 9) Features
Sharply demarcated Symmetric Expansile growth Effacement of epidermis Focal pagetoid spread Variable pleomorphism With $1 mitotic figures per 10 HPF
Nodules, N (% of total)
6 6 4 4 0 1 1
(67) (67) (44) (44) (0) (11) (11)
HPF, High power field.
Fig 3. Congenital melanocytic nevus of markedly pigmented intraepidermal nevus nests composed of atypical nevus cells with architectural disorder. (Hematoxylineosin stain; original magnification: 310.)
Fig 4. Congenital melanocytic nevus demonstrating pagetoid spread of atypical melanocytes. (Hematoxylineosin stain; original magnification: 360.)
frequent, in 39/197 (20%) CMN, but was also typically present with the former features. Nevi with bridging had a 4.6 and 4.2 times greater odds of demonstrating cytologic atypia and architectural disorder, respectively, than nevi without bridging (P = .001 and P = .001.) Mitotic figures were present in 2/197 (1%) CMN, both with 2 figures per 1 mm2. Regression was not observed and inflammation was rare, in 2/179 (1%) CMN. Fibrosis was present in 6/163 (4%) CMN that had not been disrupted by prior procedures, such as placement of tissue expanders. No significant difference in the number of atypical histopathologic features was observed across CMN size category (P = .23) or age at biopsy (P = .99) using linear regression. Nevi involving the head had significantly fewer atypical features compared with nevi involving the trunk or extremities (2.1 vs 2.9 respectively, P = .003). Proliferative nodules were present in 9 (5%) nevi, with characteristic histologic findings shown in Table III. We noted a low mitotic frequency (\2 mitotic figures) in 1 of the proliferative nodules.
Clinical outcomes Outcome data was available for 130 patients who had at least 1 recorded visit after their nevus was excised or biopsied. More than 1 procedure was performed on 56% (73/130) patients, with a mean of 2.7 procedures (range 1-18) per patient. General anesthesia was administered to 121/130 (93%) patients, with 71/130 (55%) receiving general anesthesia more than once. All 130 patients, including 26 with large CMN and 8 with proliferative nodules, were alive and had not been diagnosed with melanoma after a mean followup of 8.4 years (range 7 months-21.3 years), to a mean age of 9.7 years (range 11 months-22.6 years). Margins at last excision were positive in 53/130 (41%) patients overall and were positive in 20/26 (77%) large CMN. Patients with positive margins were followed up for similar periods of time compared with the remainder of the cohort (7.8 years vs. 8.4 years, P = .39.) Recurrence of pigmentation after complete excision was reported in 7 patients, 3 of which achieved clear margins after re-excision and 4 of which did not have reports of further surgical management.
DISCUSSION In contrast to earlier studies, we found that atypical histopathologic features were exceedingly common in CMN biopsied or excised at our institution in the last 20 years.16,17 Specifically, CMN frequently demonstrated cytologic atypia, architectural disorder, and pagetoid spread while mitotic figures were rare. Despite the prevalence of these histologic features, all patients had healthy outcomes in 8.4 years of mean follow-up, even among those with positive margins or large CMN. While malignant transformation of CMN should be promptly recognized and treated, the significant morbidity associated with over-diagnosis should also be considered. Excision of larger CMN might require serial excisions under general anesthesia, the use of tissue expanders, and grafts. Though the duration of
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each procedure is typically short, surgical risks are nonetheless present, including the controversial potential for general anesthesia to affect neurologic development.24 In addition, the psychological burden of a melanoma diagnosis on a patient and family cannot be underestimated. Thus, accurate characterization and interpretation of CMN histology is critical to the management of these patients. Specifically, recognition of atypical histologic features associated with benign behavior might alleviate unnecessary concerns and minimize further intervention for patients with CMN. A recent assessment of genital CMN in children that were \10 cm in projected adult size found no melanoma or adverse outcome after 1.5 years of follow-up, suggesting that routine biopsy or prophylactic excision of these lesions in children is not warranted.25 Our study supports this conclusion in CMNs of other locations. We also noted a low rate of proliferative nodules, similar to recent studies finding proliferative nodules in about 3% of large-to-giant CMN.22,26 Proliferative nodules in congenital nevi can simulate invasive melanoma, with shared features including increased cellularity, cytologic atypia, and mitotic figures. All patients with proliferative nodules in our study, however, had healthy outcomes, supporting prior reports that proliferative nodules are not necessarily indicative of malignancy and must be interpreted in the context of other clinicopathologic features.27,28 Our study was limited by the retrospective nature of data collection, which was restricted to medical records within our institutional network and more limited prior to the 2000s. Children could have received a diagnosis of melanoma or treatments elsewhere. Our cohort was limited by the lack of diversity in skin type and reported race, so our findings might not reflect the histologic features or clinical outcomes found in darker skin types. Because nevi were biopsied or excised for a variety of concerns, our findings are not representative of all CMN. A single dermatopathologist reviewed slides for the purposes of our study and we acknowledge that histologic findings are subject to a range of interpretation. In addition, without any cases of melanoma in our cohort, our study could not identify histopathologic features associated with malignant transformation. Lastly, we recognize that surgical excision provides important benefits not captured by our study, notably correction of potential disfigurement.29 In conclusion, we demonstrate that atypical histopathologic findings of cytologic atypia, architectural disorder, and pagetoid spread are common in CMN of all sizes in young children and are associated with benign outcomes. While the high frequency of atypical features suggests that the term atypical might
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not be relevant for the histopathology of CMN in young children, these features are critical for diagnosis of malignancy in other contexts. Our findings highlight the importance of clinical context in interpretation of histopathologic findings. The diagnosis of malignant melanoma should be made with great caution in this population and the presence of the above histopathologic features alone should not be interpreted as evidence for potential malignant behavior or serve as grounds for further excision. Greater recognition that cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN could facilitate conservative management strategies that are often preferred for young children. The authors thank Drs Johanna Sheu and Cary Crall for their assistance with data collection.
REFERENCES 1. Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr. 2012; 161(2):240-245. 2. Haveri FT, Inamadar AC. A cross-sectional prospective study of cutaneous lesions in newborn. ISRN Dermatol. 2014;2014: 360590. 3. Boccardi C, Cecchettini A, Caselli A, et al. A proteomic approach to the investigation of early events involved in vascular smooth muscle cell activation. Cell Tissue Res. 2007; 328(1):185-195. 4. Kueakhai P, Changklungmoa N, Riengrojpitak S, et al. Vaccine potential of recombinant saposin-like protein 2 against Fasciolosis gigantica in mice. Vaccine. 2013;31(47):5518-5523. 5. Reed WB, Becker SW Sr, Becker SW Jr, Nickel WR. Giant pigmented nevi, melanoma, and leptomeningeal melanocytosis: a clinical and histopathological study. Arch Dermatol. 1965;91:100-119. 6. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr. 1982;100(2):219-224. 7. Sahin S, Levin L, Kopf AW, et al. Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol. 1998;39(3):428-433. 8. Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 1-epidemiology, phenotype and outcomes. Br J Dermatol. 2009;160(1):143-150. 9. Egan CL, Oliveria SA, Elenitsas R, Hanson J, Halpern AC. Cutaneous melanoma risk and phenotypic changes in large congenital nevi: a follow-up study of 46 patients. J Am Acad Dermatol. 1998;39(6):923-932. 10. Hale EK, Stein J, Ben-Porat L, et al. Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevieresults from the NYU-LCMN registry. Br J Dermatol. 2005;152(3):512-517. 11. Bittencourt FV, Marghoob AA, Kopf AW, Koenig KL, Bart RS. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics. 2000;106(4):736-741. 12. Castilla EE, da Graca Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol. 1981;104(3): 307-315.
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13. Krengel S, Scope A, Dusza SW, Vonthein R, Marghoob AA. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013;68(3):441-451. 14. Hassanein AH, Rogers GF, Greene AK. Management of challenging congenital melanocytic nevi: outcomes study of serial excision. J Pediatr Surg. 2015;50(4):613-616. 15. Schaffer JV. Update on melanocytic nevi in children. Clin Dermatol. 2015;33(3):368-386. 16. Barnhill RL, Fleischli M. Histologic features of congenital melanocytic nevi in infants 1 year of age or younger. J Am Acad Dermatol. 1995;33(5 Pt 1):780-785. 17. Everett MA. Histopathology of congenital pigmented nevi. Am J Dermatopathol. 1989;11(1):11-12. 18. Martinez-Barba E, Polo-Garcia LA, Ferri-Niguez B, Ruiz-Macia JA, Kutzner H, Requena L. Congenital giant melanocytic nevus with pigmented epithelioid cells: a variant of epithelioid blue nevus. Am J Dermatopathol. 2002;24(1): 30-35. 19. Schaffer JV, Chang MW, Kovich OI, Kamino H, Orlow SJ. Pigmented plexiform neurofibroma: distinction from a large congenital melanocytic nevus. J Am Acad Dermatol. 2007; 56(5):862-868. 20. Leech SN, Bell H, Leonard N, et al. Neonatal giant congenital nevi with proliferative nodules: a clinicopathologic study and literature review of neonatal melanoma. Arch Dermatol. 2004; 140(1):83-88. 21. Herron MD, Vanderhooft SL, Smock K, Zhou H, Leachman SA, Coffin C. Proliferative nodules in congenital melanocytic nevi:
22.
23. 24.
25.
26.
27.
28.
29.
a clinicopathologic and immunohistochemical analysis. Am J Surg Pathol. 2004;28(8):1017-1025. Chen AC, McRae MY, Wargon O. Clinical characteristics and risks of large congenital melanocytic naevi: a review of 31 patients at the Sydney Children’s Hospital. The Australasian journal of dermatology. 2012;53(3):219-223. Stata Statistical Software: Release 13 [computer program]. College Station, TX: StataCorp LP; 2013. Davidson AJ, Becke K, de Graaff J, et al. Anesthesia and the developing brain: a way forward for clinical research. Paediatr Anaesth. 2015;25(5):447-452. Hunt RD, Orlow SJ, Schaffer JV. Genital melanocytic nevi in children: experience in a pediatric dermatology practice. J Am Acad Dermatol. 2014;70(3):429-434. Yun SJ, Kwon OS, Han JH, et al. Clinical characteristics and risk of melanoma development from giant congenital melanocytic naevi in Korea: a nationwide retrospective study. Br J Dermatol. 2012;166(1):115-123. van Houten AH, van Dijk MC, Schuttelaar ML. Proliferative nodules in a giant congenital melanocytic nevus-case report and review of the literature. J Cutan Pathol. 2010;37(7):764-776. Nguyen TL, Theos A, Kelly DR, Busam K, Andea AA. Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall. Am J Dermatopathol. 2013;35(1):e16-21. Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 2eevaluation of treatments. Br J Dermatol. 2009;160(2):387-392.
Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes Emily A. Simons, MPH,a Jennifer T. Huang, MD,a and Birgitta Schmidt, MDb Boston, Massachusetts Background: Although only large congenital melanocytic nevi (CMN) are associated with a significantly high risk for malignant transformation, CMN of all sizes are prone to changes in clinical appearance in early childhood and thus are often biopsied or excised. While CMNs typically exhibit benign behavior, atypical histopathologic findings might be common and may prompt additional unnecessary procedures. Objective: To assess the prevalence and associated clinical outcomes of atypical histopathologic features in CMN in children. Methods: A single center retrospective study was conducted with patients 0-35 months of age with CMN diagnosed by histopathology between 1993-2013. Results: One hundred seventy-nine patients with a total of 197 CMNs were identified. Cytologic atypia, architectural disorder, or pagetoid spread were present in 73% of CMN. With a mean follow up of 7.3 years, no cases of melanoma or CMN-related deaths were identified. Limitations: Our findings were based on a largely Caucasian population and might not apply to darker skin types. Our findings might not apply to older children or adults with CMN. Conclusion: Atypical histopathologic features of cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN of young children. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2016.12.026.) Key words: congenital melanocytic nevi; dermatopathology; pediatric melanoma.
C
ongenital melanocytic nevi (CMN) are benign cutaneous birthmarks found in 2%4% of children across most ethnicities.1-4 Historically, all CMNs were thought to carry a higher risk for malignant transformation than acquired melanocytic nevi.5,6 Over the past 1-2 decades, large retrospective studies have shown no increase in risk for melanoma in small- and medium-sized CMNs, which has changed our approach to the management
From the Departments of Medicinea and Pathology,b Boston Children’s Hospital, Harvard Medical School. Funding sources: None. Conflicts of interest: None declared. Previously presented: Provisional results of this study were presented as a poster at the 42nd annual meeting of The Society for Pediatric Dermatology, Minneapolis, MN, July 14-17, 2016. Accepted for publication December 16, 2016. Reprint requests: Birgitta Schmidt, MD, Boston’s Children’s Hospital, Department of Pathology, 300 Longwood Ave,
Abbreviation used: CMN:
congenital melanocytic nevus
of these lesions.7,8 However, evidence for increased risk for malignant transformation in large CMN, which can be defined as [20-cm projected adult
Boston, MA 02115. E-mail: Birgitta.Schmidt@childrens. harvard.edu. Correspondence to: Emily A. Simons, MPH, Boston Children’s Hospital, Dermatology Program, Fegan 6, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]. Published online February 24, 2017. 0190-9622/$36.00 Ó 2016 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2016.12.026
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size, remains and is estimated at 2%-5% over an nodules can be challenging to distinguish from average follow-up of 4-9 years.8-13 malignancy, previously established features of proCurrently, the management of CMNs of all sizes is liferative nodules, listed in Table III, were recorded.22 variable and ranges from anticipatory counseling to For children who had a single CMN that was biopsied prophylactic excisions.14 Morphologic changes in the more than once at ages 0-35 months, the nevus was clinical appearance of CMN is common during childcaptured as a single record that included any features hood and includes development of erosions, present on any biopsy. For children who had more ulcerations, changes in color, than one CMN biopsied, each papules, nodules, and CMN was captured as a sepaCAPSULE SUMMARY plexiform neurofibroma-like rate record. plaques.15 Skin biopsy of Clinical and follow-up Congenital melanocytic nevi (CMN) often changing lesions is data, including demographic change in appearance in childhood and appropriate, yet histologic information, age at biopsy, are often excised. interpretation is often chalsize and location of nevi, realenging. Histologic features Atypical histopathologic features were sons for treatment, treatment of CMN in infants established present in 74% of 197 cases of CMN in characteristics, date of last 2-3 decades ago recognized children \3 years of age; no cases of visit, diagnosis of melanoma, the tendency of CMN to melanoma were identified after a mean and date of death were obextend into the deep dermis follow-up of 7.3 years. tained from patient medical and subcutis, involving records through April 2016. Atypical histopathologic features are vascular, adnexal, and neural Follow-up data were only recommon in CMN of young children and structures and some degree corded if patients had at least do not appear to be associated with an of cytologic atypia in 0%-30% one visit documented at least unfavorable clinical outcome. of lesions.16,17 The literature 6 months after excision or bisince has largely focused on opsy to avoid inclusion of subsets of CMN, such as blue postoperative wound evaluanevi variants and proliferative nodules, and has tions as follow-up time for development of melasuggested that atypical features are not necessarily noma. Nevus size was defined as the largest recorded indicative of malignancy.18-21 diameter before time of biopsy or, in the absence of In this study, we sought to provide an update on recorded clinical measurements, the width of excithe histopathologic spectrum of CMN and associated sion or one-third the length of excision. To classify long-term outcomes by evaluating CMN biopsied at CMN size, we used recent recommendations based our institution in children \3 years of age over a 20on projected adult size.13 year period. Study definitions Given that no single or constellation of histologic METHODS features characterize CMN to a high degree of Study design specificity, a CMN was defined by a clinical descripA retrospective study examining surgical patholtion as a pigmented lesion that was congenital, a ogy specimens and medical records was conducted birthmark, or present since birth. Blue nevus was at Boston Children’s Hospital. The study was defined as a dermal proliferation of variably pigapproved by the institutional review board (IRBmented, spindle-shaped dendritic melanocytes. P00007909). Spindle and epithelioid nevus (ie, Spitz nevus) was All surgical pathology reports containing the terms defined by the presence of spindled and/or epithe‘‘congenital’’ and ‘‘nevus’’ for patients 0-35 months of lioid melanocytes. Deep-pigmented nevus was age from 1993-2013 were obtained. Additional includefined by the presence of wedge-shaped nests of sion criteria were a clinical record describing the pleomorphic melanocytes and macrophages connevus as congenital or present since birth. Exclusion taining melanin granules extending from the upper criteria included histology findings that favored an dermis into the subcutaneous fat tissue along alternative diagnosis, missing histology specimens, adnexal structures. and insufficient tissue quantity. An experienced Architectural disorder was defined by irregular pathologist specialized in pediatric dermatopatholposition and size of nevus nests and the presence of ogy (Dr Schmidt) obtained and analyzed the histopagetoid spread of melanocytes within the logic sections that were stained with hematoxylin and epidermis. Cytologic atypia was considered present eosin in each case and recorded gross morphologic when intraepidermal melanocytes demonstrated features listed in Table I. Because proliferative d
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Table I. Histologic features of congenital melanocytic nevi (n = 196 nevi) Characteristic
Typical features Depth of invasion Epidermis Reticular dermis Deep dermis Extracutaneous involvement- Any Perivascular Periadnexal Perineural Combined features- Any Blue nevus Spindle and epithelioid (Spitz) Deep pigmented (deep penetrating) Atypical features- Any Cytologic atypia- Any Mild Moderate Severe Architectural disorder- Any Mild Moderate Severe Pagetoid spread Bridging Fibrosis First procedure In setting of prior procedure Mitotic figures ($1 per 1 mm2) Regression Inflammation
Table II. Size and location of congenital melanocytic nevus (n = 179 patients) Nevi, N (% of total)
179 193 90 194 187 188 127 79 70 20 1
(91) (98) (46) (99) (95) (96) (65) (40) (36) (10) (1)
152 138 124 37 4 131 105 43 5 121 39
(78) (70) (63) (19) (2) (67) (54) (22) (3) (62) (20)
6 16 2 0 2
(3) (8) (1) (0) (1)
variable and discontinuous nuclear atypia (ie, the degree of nuclear atypia varied from cell to cell). Cytologic atypia was graded as mild, moderate, or severe. Mild cytologic atypia referred to some retraction of the cytoplasm and minimal increase in melanocyte size compared with the nuclei from a keratinocyte in the spinous layer. Large melanocyte nuclei with occasional nucleoli was classified as moderate atypia. Severe atypia was characterized as increased melanocyte cytoplasm, enlarged nucleoli, and enlarged nuclei approaching up to twice the size of a keratinocyte. Statistical analysis Each distinct congenital nevus was considered a unit of observation. Descriptive statistics were calculated for each variable and presented in Tables I and II. Statistical analyses were conducted with STATA 13.23 Linear regression was performed to assess differences in number of atypical histologic features
Projected adult size of largest CMN13 Small (\1.5 cm) Medium, M1 (1.5-10 cm) Medium, M2 ([10-20 cm) Large, L1 ([20-30 cm) Large, L2 ([30-40 cm) Giant ([40 cm) Missing Location Head Trunk Extremities Missing
N (% with data) 3 (2) 91 (58) 31 (20) 18 (11) 6 (4) 9 (6) 21 N (% with data) 71 (40) 57 (32) 49 (28) 2
CMN, Congenital melanocytic nevus.
across clinical characteristics, including nevus size category, location, and age in years at biopsy, and length of follow-up time by histologic feature. Logistic regression was performed to assess associations between histopathologic features and differences in follow-up time by histopathologic feature.
RESULTS During 1993-2013, surgical pathology records (n = 268) were identified that contained the words ‘‘congenital’’ and ‘‘nevus,’’ of which 242 were nevi described clinically as congenital. Twenty-eight records were excluded as described in Fig 1, leading to 214 accessions representing 197 nevi in 179 patients. The average age at biopsy or excision was 17 months (range 4 days-35 months). Patients were 51% (92/179) female. Of those with data available, 80% (40/50) had skin types I-II, and 90% (104/116) reported race as Caucasian. Clinical characteristics CMNs were predominantly medium in size (Table II), with a projected adult size of 1.5-10 cm in 58% (91/158) of patients, 41 of whom had lesions 1.5-5 cm and 50 of whom had lesions [5-10 cm in projected adult size.13 The majority of CMN (72%; 128/177) had an axial distribution involving the head or trunk. Of 214 accessions, 5 were obtained by punch biopsy and 209 by surgical excisions. Dermatologists obtained 9 (4%) specimens, while 190 (89%) were obtained by plastic surgeons and 14 (7%) were obtained by general surgeons. Sixty-three of 136 (46%) patients whose nevus was excised by a surgeon did not see a dermatologist within our institution. Data on referral patterns for these 63 patients were limited, with referral from an outside dermatologist mentioned for only 3 patients. Reasons stated
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Fig 1. Congenital melanocytic nevus (CMN) identification and exclusion criteria.
Fig 2. A, Congenital melanocytic nevus with architectural disorder, superficial papillary dermal fibrosis, and lentiginous proliferation of melanocytes with focal pagetoid spread of atypical melanocytes. B, Congenital melanocytic nevus demonstrating architectural disorder and pagetoid spread. (A and B, Hematoxylin-eosin stain; original magnification: A, 34; B, 340.)
for excision or biopsy of nevus included physician concern for malignant transformation in 94 patients, change in appearance in 21 patients, disfigurement in 5 patients, size and location in 5 patients, and parental request in 5 patients. The reason for excision was not discernible for 49 patients. Histopathologic features Histologic features almost universally included involvement of reticular dermis and extracutaneous structures, including vascular, adnexal, and neural tissue (Table I). Combined histologic patterns of a blue nevus, spindle and epithelioid (Spitz) nevus, or a deep penetrating nevus were identified in 79 (40%) of CMN.
Features considered atypical were very common, with 152/197 (77%) nevi demonstrating at least 1 atypical finding and a mean of 2.6 (range 0-7) atypical features per nevus. Even when excluding mild cytologic atypia or architectural disorder, 145/ 197 (74%) nevi exhibited at least 1 and 75/197 (38%) exhibited 2 or more of the remaining atypical features. Cytologic atypia, architectural disorder, and pagetoid spread were the most frequent features (Figs 2-4) present in 144/197 (73%) of nevi and were also closely associated. Lesions demonstrated concordance between presence of cytologic atypia and architectural disorder in 181/197 (92%) CMN and between presence of cytologic atypia and pagetoid spread in 173/197 (88%) CMN. Bridging was less
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Table III. Features of proliferative nodules (n = 9) Features
Sharply demarcated Symmetric Expansile growth Effacement of epidermis Focal pagetoid spread Variable pleomorphism With $1 mitotic figures per 10 HPF
Nodules, N (% of total)
6 6 4 4 0 1 1
(67) (67) (44) (44) (0) (11) (11)
HPF, High power field.
Fig 3. Congenital melanocytic nevus of markedly pigmented intraepidermal nevus nests composed of atypical nevus cells with architectural disorder. (Hematoxylineosin stain; original magnification: 310.)
Fig 4. Congenital melanocytic nevus demonstrating pagetoid spread of atypical melanocytes. (Hematoxylineosin stain; original magnification: 360.)
frequent, in 39/197 (20%) CMN, but was also typically present with the former features. Nevi with bridging had a 4.6 and 4.2 times greater odds of demonstrating cytologic atypia and architectural disorder, respectively, than nevi without bridging (P = .001 and P = .001.) Mitotic figures were present in 2/197 (1%) CMN, both with 2 figures per 1 mm2. Regression was not observed and inflammation was rare, in 2/179 (1%) CMN. Fibrosis was present in 6/163 (4%) CMN that had not been disrupted by prior procedures, such as placement of tissue expanders. No significant difference in the number of atypical histopathologic features was observed across CMN size category (P = .23) or age at biopsy (P = .99) using linear regression. Nevi involving the head had significantly fewer atypical features compared with nevi involving the trunk or extremities (2.1 vs 2.9 respectively, P = .003). Proliferative nodules were present in 9 (5%) nevi, with characteristic histologic findings shown in Table III. We noted a low mitotic frequency (\2 mitotic figures) in 1 of the proliferative nodules.
Clinical outcomes Outcome data was available for 130 patients who had at least 1 recorded visit after their nevus was excised or biopsied. More than 1 procedure was performed on 56% (73/130) patients, with a mean of 2.7 procedures (range 1-18) per patient. General anesthesia was administered to 121/130 (93%) patients, with 71/130 (55%) receiving general anesthesia more than once. All 130 patients, including 26 with large CMN and 8 with proliferative nodules, were alive and had not been diagnosed with melanoma after a mean followup of 8.4 years (range 7 months-21.3 years), to a mean age of 9.7 years (range 11 months-22.6 years). Margins at last excision were positive in 53/130 (41%) patients overall and were positive in 20/26 (77%) large CMN. Patients with positive margins were followed up for similar periods of time compared with the remainder of the cohort (7.8 years vs. 8.4 years, P = .39.) Recurrence of pigmentation after complete excision was reported in 7 patients, 3 of which achieved clear margins after re-excision and 4 of which did not have reports of further surgical management.
DISCUSSION In contrast to earlier studies, we found that atypical histopathologic features were exceedingly common in CMN biopsied or excised at our institution in the last 20 years.16,17 Specifically, CMN frequently demonstrated cytologic atypia, architectural disorder, and pagetoid spread while mitotic figures were rare. Despite the prevalence of these histologic features, all patients had healthy outcomes in 8.4 years of mean follow-up, even among those with positive margins or large CMN. While malignant transformation of CMN should be promptly recognized and treated, the significant morbidity associated with over-diagnosis should also be considered. Excision of larger CMN might require serial excisions under general anesthesia, the use of tissue expanders, and grafts. Though the duration of
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each procedure is typically short, surgical risks are nonetheless present, including the controversial potential for general anesthesia to affect neurologic development.24 In addition, the psychological burden of a melanoma diagnosis on a patient and family cannot be underestimated. Thus, accurate characterization and interpretation of CMN histology is critical to the management of these patients. Specifically, recognition of atypical histologic features associated with benign behavior might alleviate unnecessary concerns and minimize further intervention for patients with CMN. A recent assessment of genital CMN in children that were \10 cm in projected adult size found no melanoma or adverse outcome after 1.5 years of follow-up, suggesting that routine biopsy or prophylactic excision of these lesions in children is not warranted.25 Our study supports this conclusion in CMNs of other locations. We also noted a low rate of proliferative nodules, similar to recent studies finding proliferative nodules in about 3% of large-to-giant CMN.22,26 Proliferative nodules in congenital nevi can simulate invasive melanoma, with shared features including increased cellularity, cytologic atypia, and mitotic figures. All patients with proliferative nodules in our study, however, had healthy outcomes, supporting prior reports that proliferative nodules are not necessarily indicative of malignancy and must be interpreted in the context of other clinicopathologic features.27,28 Our study was limited by the retrospective nature of data collection, which was restricted to medical records within our institutional network and more limited prior to the 2000s. Children could have received a diagnosis of melanoma or treatments elsewhere. Our cohort was limited by the lack of diversity in skin type and reported race, so our findings might not reflect the histologic features or clinical outcomes found in darker skin types. Because nevi were biopsied or excised for a variety of concerns, our findings are not representative of all CMN. A single dermatopathologist reviewed slides for the purposes of our study and we acknowledge that histologic findings are subject to a range of interpretation. In addition, without any cases of melanoma in our cohort, our study could not identify histopathologic features associated with malignant transformation. Lastly, we recognize that surgical excision provides important benefits not captured by our study, notably correction of potential disfigurement.29 In conclusion, we demonstrate that atypical histopathologic findings of cytologic atypia, architectural disorder, and pagetoid spread are common in CMN of all sizes in young children and are associated with benign outcomes. While the high frequency of atypical features suggests that the term atypical might
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not be relevant for the histopathology of CMN in young children, these features are critical for diagnosis of malignancy in other contexts. Our findings highlight the importance of clinical context in interpretation of histopathologic findings. The diagnosis of malignant melanoma should be made with great caution in this population and the presence of the above histopathologic features alone should not be interpreted as evidence for potential malignant behavior or serve as grounds for further excision. Greater recognition that cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN could facilitate conservative management strategies that are often preferred for young children. The authors thank Drs Johanna Sheu and Cary Crall for their assistance with data collection.
REFERENCES 1. Kanada KN, Merin MR, Munden A, Friedlander SF. A prospective study of cutaneous findings in newborns in the United States: correlation with race, ethnicity, and gestational status using updated classification and nomenclature. J Pediatr. 2012; 161(2):240-245. 2. Haveri FT, Inamadar AC. A cross-sectional prospective study of cutaneous lesions in newborn. ISRN Dermatol. 2014;2014: 360590. 3. Boccardi C, Cecchettini A, Caselli A, et al. A proteomic approach to the investigation of early events involved in vascular smooth muscle cell activation. Cell Tissue Res. 2007; 328(1):185-195. 4. Kueakhai P, Changklungmoa N, Riengrojpitak S, et al. Vaccine potential of recombinant saposin-like protein 2 against Fasciolosis gigantica in mice. Vaccine. 2013;31(47):5518-5523. 5. Reed WB, Becker SW Sr, Becker SW Jr, Nickel WR. Giant pigmented nevi, melanoma, and leptomeningeal melanocytosis: a clinical and histopathological study. Arch Dermatol. 1965;91:100-119. 6. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr. 1982;100(2):219-224. 7. Sahin S, Levin L, Kopf AW, et al. Risk of melanoma in medium-sized congenital melanocytic nevi: a follow-up study. J Am Acad Dermatol. 1998;39(3):428-433. 8. Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 1-epidemiology, phenotype and outcomes. Br J Dermatol. 2009;160(1):143-150. 9. Egan CL, Oliveria SA, Elenitsas R, Hanson J, Halpern AC. Cutaneous melanoma risk and phenotypic changes in large congenital nevi: a follow-up study of 46 patients. J Am Acad Dermatol. 1998;39(6):923-932. 10. Hale EK, Stein J, Ben-Porat L, et al. Association of melanoma and neurocutaneous melanocytosis with large congenital melanocytic naevieresults from the NYU-LCMN registry. Br J Dermatol. 2005;152(3):512-517. 11. Bittencourt FV, Marghoob AA, Kopf AW, Koenig KL, Bart RS. Large congenital melanocytic nevi and the risk for development of malignant melanoma and neurocutaneous melanocytosis. Pediatrics. 2000;106(4):736-741. 12. Castilla EE, da Graca Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi: I. Incidence rates and relative frequencies. Br J Dermatol. 1981;104(3): 307-315.
J AM ACAD DERMATOL
Simons, Huang, and Schmidt 7
VOLUME jj, NUMBER j
13. Krengel S, Scope A, Dusza SW, Vonthein R, Marghoob AA. New recommendations for the categorization of cutaneous features of congenital melanocytic nevi. J Am Acad Dermatol. 2013;68(3):441-451. 14. Hassanein AH, Rogers GF, Greene AK. Management of challenging congenital melanocytic nevi: outcomes study of serial excision. J Pediatr Surg. 2015;50(4):613-616. 15. Schaffer JV. Update on melanocytic nevi in children. Clin Dermatol. 2015;33(3):368-386. 16. Barnhill RL, Fleischli M. Histologic features of congenital melanocytic nevi in infants 1 year of age or younger. J Am Acad Dermatol. 1995;33(5 Pt 1):780-785. 17. Everett MA. Histopathology of congenital pigmented nevi. Am J Dermatopathol. 1989;11(1):11-12. 18. Martinez-Barba E, Polo-Garcia LA, Ferri-Niguez B, Ruiz-Macia JA, Kutzner H, Requena L. Congenital giant melanocytic nevus with pigmented epithelioid cells: a variant of epithelioid blue nevus. Am J Dermatopathol. 2002;24(1): 30-35. 19. Schaffer JV, Chang MW, Kovich OI, Kamino H, Orlow SJ. Pigmented plexiform neurofibroma: distinction from a large congenital melanocytic nevus. J Am Acad Dermatol. 2007; 56(5):862-868. 20. Leech SN, Bell H, Leonard N, et al. Neonatal giant congenital nevi with proliferative nodules: a clinicopathologic study and literature review of neonatal melanoma. Arch Dermatol. 2004; 140(1):83-88. 21. Herron MD, Vanderhooft SL, Smock K, Zhou H, Leachman SA, Coffin C. Proliferative nodules in congenital melanocytic nevi:
22.
23. 24.
25.
26.
27.
28.
29.
a clinicopathologic and immunohistochemical analysis. Am J Surg Pathol. 2004;28(8):1017-1025. Chen AC, McRae MY, Wargon O. Clinical characteristics and risks of large congenital melanocytic naevi: a review of 31 patients at the Sydney Children’s Hospital. The Australasian journal of dermatology. 2012;53(3):219-223. Stata Statistical Software: Release 13 [computer program]. College Station, TX: StataCorp LP; 2013. Davidson AJ, Becke K, de Graaff J, et al. Anesthesia and the developing brain: a way forward for clinical research. Paediatr Anaesth. 2015;25(5):447-452. Hunt RD, Orlow SJ, Schaffer JV. Genital melanocytic nevi in children: experience in a pediatric dermatology practice. J Am Acad Dermatol. 2014;70(3):429-434. Yun SJ, Kwon OS, Han JH, et al. Clinical characteristics and risk of melanoma development from giant congenital melanocytic naevi in Korea: a nationwide retrospective study. Br J Dermatol. 2012;166(1):115-123. van Houten AH, van Dijk MC, Schuttelaar ML. Proliferative nodules in a giant congenital melanocytic nevus-case report and review of the literature. J Cutan Pathol. 2010;37(7):764-776. Nguyen TL, Theos A, Kelly DR, Busam K, Andea AA. Mitotically active proliferative nodule arising in a giant congenital melanocytic nevus: a diagnostic pitfall. Am J Dermatopathol. 2013;35(1):e16-21. Kinsler VA, Birley J, Atherton DJ. Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 2eevaluation of treatments. Br J Dermatol. 2009;160(2):387-392.