Melanocytic nevus pathophysiology

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Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1];Associate Editor(s)-in-Chief: Qurrat-ul-ain Abid, M.D.[2] Michel C. Samson, M.D., FRCSC, FACS [3]

Overview

Melanocytic nevus is a benign growth on the skin (usually tan, brown, or flesh-colored) that contains a cluster of melanocytes and surrounding supportive tissue.

Pathophysiology

Congenital melanocytic nevi (CMN)

  • When melanocytic nevi are present at birth or within the first few months of life they are known as Congenital melanocytic nevi (CMN).
  • Congenital melanocytic nevi (CMN) are hamartomas lesions.
  • Small melanocytic nevi that appear during early childhood between three months and two years of age, resemble true CMN clinicaly and histologicaly and are known as "tardive CMN," "early-onset nevi," and "congenital nevus-like nevi.[1]
  • During embryogenesis clonal proliferations of benign melanocytes may give rise to melanocytic nevi.[2][3]
  • BRAF V600E mutations have a very high corelation with small congenital melanocytic nevi (CMN), acquired melanocytic nevi and cutaneous melanomas.[4][5]
  • While giant congenital melanocytic nevi (CMN) have somatic gain-of-function mutations in NRAS.[6][7]
  • Compared to acquired melanocytic nevi, CMN penetrate into deeper layers of dermis.[8]
  • Melanocytes in CMN follow pathyway of nerves and vessels and grow along adenxal structures (eg, hair follicles, sebaceous glands, eccrine ducts) and settle between collagen bundles in a single arrangement.[9][10]

Dermoscopic features of Congenital melanocytic nevi (CMN)

  • CMN and acquired melanocytic nevi appear as pigment network, aggregated globules, or diffuse homogeneous brown pigmentation on dermoscopy.[11]
  • Dermoscopic patterns that are commonly seen in CMN are:[12]
    • Reticular
    • Globular/cobblestoning
    • Homogenous
    • Or a mixture of these (ie, multicomponent)
  • CMN may exhibit exaggerated attributes on dermoscopy compared to acquired melanocytic nevi, they may show:[13][14][14]
    • Perifollicular hypopigmentation
    • Marked follicular structures
    • Skin hyperpigmentation
    • Hypertrichosis
    • Pigment changes surrounding follicles such as hypopigmentation

Proliferative nodules Melanocytic nevus

  • Benign melanocytic proliferations may occasionally appear within large or giant CMN.[15]
  • They may be congenital or develop in infancy or childhood.
  • They may grow rapidly with clinical characteristics of firmness or ulceration, in that case, a biopsy should be performed to eliminate melanoma.
  • Large, atypical melanocytes and mitoses may be present on microscopy that make it difficult to differentiate from Melanoma.
  • In case of difficulty in differentiating benign melanocytic proliferation from Melanoma on microscopy, an evaluation of an experienced doctor may be helpful. Other modalities of evaluation are comparative genomic hybridization or mass spectroscopy imaging proteomic analysis.[15][16]

Speckled lentiginous nevus (SLN)

  • CMN may appear as a hyperpigmented patch with, superimposed dark or brown macules and papules which is known as lentiginous nevus (SLN) or nevus spilus.
  • The "background" tan patch (café-au-lait macule-like) of an SLN is mostly present at birth or appear soon after birth, brown "spots" may appear in the lesions later.
  • SLN is of two types:[17][18]
    • With macular speckles
    • With papular and macular speckles

Acquired melanocytic nevi (moles)

  • Benign growth of a type of melanocyte known as a "nevus cell" is known as melanocytic nevi or mole.
  • Although both melanocytes and nevus cells produce the pigment melanin however Nevus cells are different from the Melanocytes due to the following characteristics:
    • Nevus cells have a tendency to cluster within the lower epidermis or dermis, while epidermal melanocyte tends to spread out in one group.
    • Nevus cells lack dendritic process
  • Appearance of moles may vary depending on their location in the skin:
    • Junctional nevi: melanocytes are at the dermal-epidermal junction.
    • Compound nevi, melanocytes are both at the dermal-epidermal junction and in the dermis.
    • Intradermal nevi, the nests of melanocytes are in the dermis.
    • Elevated and less pigmented nevi: migration of melanocytes from the dermal-epidermal junction into the dermis.

Predisposing factors for the development of acquired melanocytic nevi

  • Factors influencing to the development of all acquired nevi except blue and Spitz nevi are:[19][20][21]
    • Heredity, with a familial propensity to have many moles.[22]
    • Intense sun exposure during childhood. Other factors that may affect the development of acquired melanocytic nevi in children include lichen sclerosus, immunosuppression, chemotherapy, and endocrine disorders.[23][24][25]
    • Phenotypic attributes such as skin type, with more nevus in individuals with light skin. Dark skinned people have few nevi. Children with dark hair tend to have more moles compared to people with very fair skin and red hair. [24][21][26]

Complications of Melanocytic nevi

Melanoma

  • Melanoma may arise as a complication within congenital melanocytic nevi(CMN), the lifetime risk is lower than 1%.[2]
  • Melanoma arises at the dermal-epidermal junction, in giant CMN they may arise in the deeper layers.
  • In large or giant CMN, there is 2 to 5 percent lifetime risk of developing either cutaneous or extracutaneous melanoma.[27]
  • Half of the Melanoma may arise within the first five years of life.[28][29]
  • Early identification and assessment may be difficult in giant CMN, becuase of there subepidermal location in cutaneous melanomas.
  • Palpation of the lesion during physical exam may help in detecting deeper nodules.
  • Primary melanoma may arise in the central nervous system (CNS) or retroperitoneum.
  • Posterior axial giant CMN have the greateset risk of developing Melanomas, nevi of head and extrimities are less likely to develop melanomas.

Neurocutaneous melanosis

  • Rarely in CMN neurocutaneous melanosis(NCM) may arise, it is the growth of melanocytes in CNS and skin.
  • Neurocutaneous melanosis (NCM) includes leptomeningeal melanosis and CNS melanosis.[30]
  • NCM is diagnosed on MRI as it may stay asymptomatic or produce minimal symptoms.[28]
  • Symptomatic NCM has a poor prognosis with high mortality rate.[27]
  • Risk factors for NCM are:[31][32][33]
    • A large CMN >40 cm and in a posterior axial location
    • Multiple satellite nevi
    • Greater than two medium-sized CMN
  • According to a study CMN with >20 satellites had a fivefold increased risk for NCM compared with those with ≤20 satellites.[34]
  • NCM may cooccur with the structural abnormalities of CNS such as Dandy-Walker malformation/posterior fossa cysts, defects of the vertebrae or skull, and intraspinal lipomas.[34]
  • MRI with gadolinium contrast can pick NCM.[32]
  • Symptomatic NCM may present with hydrocephalus, seizures that may be consequence of intracranial hemorrhage, impaired cerebrospinal fluid circulation, spinal cord compression, or malignant transformation of the melanocytes.[35]
  • If symptomatic NCM have poor prognosis even with abscence of malignant changes.[36]

References

  1. ↑ Makkar HS, Frieden IJ (August 2002). "Congenital melanocytic nevi: an update for the pediatrician". Curr. Opin. Pediatr. 14 (4): 397–403. PMID 12130901.
  2. ↑ 2.0 2.1 Tannous ZS, Mihm MC, Sober AJ, Duncan LM (February 2005). "Congenital melanocytic nevi: clinical and histopathologic features, risk of melanoma, and clinical management". J. Am. Acad. Dermatol. 52 (2): 197–203. doi:10.1016/j.jaad.2004.07.020. PMID 15692463.
  3. ↑ Price HN, Schaffer JV (2010). "Congenital melanocytic nevi-when to worry and how to treat: Facts and controversies". Clin. Dermatol. 28 (3): 293–302. doi:10.1016/j.clindermatol.2010.04.004. PMID 20541682.
  4. ↑ Ichii-Nakato N, Takata M, Takayanagi S, Takashima S, Lin J, Murata H, Fujimoto A, Hatta N, Saida T (September 2006). "High frequency of BRAFV600E mutation in acquired nevi and small congenital nevi, but low frequency of mutation in medium-sized congenital nevi". J. Invest. Dermatol. 126 (9): 2111–8. doi:10.1038/sj.jid.5700366. PMID 16691193.
  5. ↑ Wu J, Rosenbaum E, Begum S, Westra WH (December 2007). "Distribution of BRAF T1799A(V600E) mutations across various types of benign nevi: implications for melanocytic tumorigenesis". Am J Dermatopathol. 29 (6): 534–7. doi:10.1097/DAD.0b013e3181584950. PMID 18032947.
  6. ↑ Dessars B, De Raeve LE, Morandini R, Lefort A, El Housni H, Ghanem GE, Van den Eynde BJ, Ma W, Roseeuw D, Vassart G, Libert F, Heimann P (January 2009). "Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis". J. Invest. Dermatol. 129 (1): 139–47. doi:10.1038/jid.2008.203. PMID 18633438.
  7. ↑ Charbel C, Fontaine RH, Malouf GG, Picard A, Kadlub N, El-Murr N, How-Kit A, Su X, Coulomb-L'Hermine A, Tost J, Mourah S, Aractingi S, Guégan S (April 2014). "NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi". J. Invest. Dermatol. 134 (4): 1067–1074. doi:10.1038/jid.2013.429. PMID 24129063.
  8. ↑ Mark GJ, Mihm MC, Liteplo MG, Reed RJ, Clark WH (September 1973). "Congenital melanocytic nevi of the small and garment type. Clinical, histologic, and ultrastructural studies". Hum. Pathol. 4 (3): 395–418. PMID 4756859.
  9. ↑ "Precursors to malignant melanoma. National Institutes of Health Consensus Development Conference Statement, Oct. 24-26, 1983". J. Am. Acad. Dermatol. 10 (4): 683–8. April 1984. PMID 6715623.
  10. ↑ Kokta V, Hung T, Al Dhaybi R, Lugassy C, Barnhill RL (April 2013). "High prevalence of angiotropism in congenital melanocytic nevi: an analysis of 53 cases". Am J Dermatopathol. 35 (2): 180–3. doi:10.1097/DAD.0b013e318260908c. PMID 22771898.
  11. ↑ Haliasos EC, Kerner M, Jaimes N, Zalaudek I, Malvehy J, Hofmann-Wellenhof R, Braun RP, Marghoob AA (2013). "Dermoscopy for the pediatric dermatologist part III: dermoscopy of melanocytic lesions". Pediatr Dermatol. 30 (3): 281–93. doi:10.1111/pde.12041. PMID 23252411.
  12. ↑ Changchien L, Dusza SW, Agero AL, Korzenko AJ, Braun RP, Sachs D, Usman MH, Halpern AC, Marghoob AA (August 2007). "Age- and site-specific variation in the dermoscopic patterns of congenital melanocytic nevi: an aid to accurate classification and assessment of melanocytic nevi". Arch Dermatol. 143 (8): 1007–14. doi:10.1001/archderm.143.8.1007. PMID 17709659.
  13. ↑ Seidenari S, Pellacani G, Martella A, Giusti F, Argenziano G, Buccini P, Carli P, Catricalà C, De Giorgi V, Ferrari A, Ingordo V, Manganoni AM, Peris K, Piccolo D, Pizzichetta MA (July 2006). "Instrument-, age- and site-dependent variations of dermoscopic patterns of congenital melanocytic naevi: a multicentre study". Br. J. Dermatol. 155 (1): 56–61. doi:10.1111/j.1365-2133.2006.07182.x. PMID 16792752.
  14. ↑ 14.0 14.1 Ingordo V, Iannazzone SS, Cusano F, Naldi L (2006). "Dermoscopic features of congenital melanocytic nevus and Becker nevus in an adult male population: an analysis with a 10-fold magnification". Dermatology (Basel). 212 (4): 354–60. doi:10.1159/000092286. PMID 16707885.
  15. ↑ 15.0 15.1 Phadke PA, Rakheja D, Le LP, Selim MA, Kapur P, Davis A, Mihm MC, Hoang MP (May 2011). "Proliferative nodules arising within congenital melanocytic nevi: a histologic, immunohistochemical, and molecular analyses of 43 cases". Am. J. Surg. Pathol. 35 (5): 656–69. doi:10.1097/PAS.0b013e31821375ea. PMID 21436676.
  16. ↑ Lazova R, Yang Z, El Habr C, Lim Y, Choate KA, Seeley EH, Caprioli RM, Yangqun L (September 2017). "Mass Spectrometry Imaging Can Distinguish on a Proteomic Level Between Proliferative Nodules Within a Benign Congenital Nevus and Malignant Melanoma". Am J Dermatopathol. 39 (9): 689–695. doi:10.1097/DAD.0000000000000849. PMC 5647999. PMID 28248717.
  17. ↑ Happle R (March 2009). "Speckled lentiginous naevus: which of the two disorders do you mean?". Clin. Exp. Dermatol. 34 (2): 133–5. doi:10.1111/j.1365-2230.2008.02966.x. PMID 19040513.
  18. ↑ Schaffer JV, Orlow SJ, Lazova R, Bolognia JL (February 2001). "Speckled lentiginous nevus: within the spectrum of congenital melanocytic nevi". Arch Dermatol. 137 (2): 172–8. PMID 11176689.
  19. ↑ Oliveria SA, Satagopan JM, Geller AC, Dusza SW, Weinstock MA, Berwick M, Bishop M, Heneghan MK, Halpern AC (January 2009). "Study of Nevi in Children (SONIC): baseline findings and predictors of nevus count". Am. J. Epidemiol. 169 (1): 41–53. doi:10.1093/aje/kwn289. PMC 2720704. PMID 19001133.
  20. ↑ Aalborg J, Morelli JG, Mokrohisky ST, Asdigian NL, Byers TE, Dellavalle RP, Box NF, Crane LA (September 2009). "Tanning and increased nevus development in very-light-skinned children without red hair". Arch Dermatol. 145 (9): 989–96. doi:10.1001/archdermatol.2009.193. PMC 2924169. PMID 19770437.
  21. ↑ 21.0 21.1 De Giorgi V, Gori A, Greco A, Savarese I, Alfaioli B, Grazzini M, Rossari S, Papi F, Scarfi F, Janowska A, D'Errico A, Salvati L, Covarelli P, Gandini S (October 2018). "Sun-Protection Behavior, Pubertal Development and Menarche: Factors Influencing the Melanocytic Nevi Development-The Results of an Observational Study of 1,512 Children". J. Invest. Dermatol. 138 (10): 2144–2151. doi:10.1016/j.jid.2018.02.046. PMID 29614272.
  22. ↑ Orlow I, Satagopan JM, Berwick M, Enriquez HL, White KA, Cheung K, Dusza SW, Oliveria SA, Marchetti MA, Scope A, Marghoob AA, Halpern AC (April 2015). "Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC)". Br. J. Dermatol. 172 (4): 1081–9. doi:10.1111/bjd.13467. PMC 4382400. PMID 25307738.
  23. ↑ Dulon M, Weichenthal M, Blettner M, Breitbart M, Hetzer M, Greinert R, Baumgardt-Elms C, Breitbart EW (November 2002). "Sun exposure and number of nevi in 5- to 6-year-old European children". J Clin Epidemiol. 55 (11): 1075–81. PMID 12507670.
  24. ↑ 24.0 24.1 Wiecker TS, Luther H, Buettner P, Bauer J, Garbe C (February 2003). "Moderate sun exposure and nevus counts in parents are associated with development of melanocytic nevi in childhood: a risk factor study in 1,812 kindergarten children". Cancer. 97 (3): 628–38. doi:10.1002/cncr.11114. PMID 12548604.
  25. ↑ Harrison SL, MacLennan R, Buettner PG (September 2008). "Sun exposure and the incidence of melanocytic nevi in young Australian children". Cancer Epidemiol. Biomarkers Prev. 17 (9): 2318–24. doi:10.1158/1055-9965.EPI-07-2801. PMID 18768500.
  26. ↑ Luther H, Altmeyer P, Garbe C, Ellwanger U, Jahn S, Hoffmann K, Segerling M (December 1996). "Increase of melanocytic nevus counts in children during 5 years of follow-up and analysis of associated factors". Arch Dermatol. 132 (12): 1473–8. PMID 8961877.
  27. ↑ 27.0 27.1 Vourc'h-Jourdain M, Martin L, Barbarot S (March 2013). "Large congenital melanocytic nevi: therapeutic management and melanoma risk: a systematic review". J. Am. Acad. Dermatol. 68 (3): 493–8.e1–14. doi:10.1016/j.jaad.2012.09.039. PMID 23182059.
  28. ↑ 28.0 28.1 Watt AJ, Kotsis SV, Chung KC (June 2004). "Risk of melanoma arising in large congenital melanocytic nevi: a systematic review". Plast. Reconstr. Surg. 113 (7): 1968–74. PMID 15253185.
  29. ↑ Kinsler VA, Birley J, Atherton DJ (January 2009). "Great Ormond Street Hospital for Children Registry for congenital melanocytic naevi: prospective study 1988-2007. Part 1-epidemiology, phenotype and outcomes". Br. J. Dermatol. 160 (1): 143–50. doi:10.1111/j.1365-2133.2008.08849.x. PMID 18811688.
  30. ↑ Foster RD, Williams ML, Barkovich AJ, Hoffman WY, Mathes SJ, Frieden IJ (April 2001). "Giant congenital melanocytic nevi: the significance of neurocutaneous melanosis in neurologically asymptomatic children". Plast. Reconstr. Surg. 107 (4): 933–41. PMID 11252085.
  31. ↑ DeDavid M, Orlow SJ, Provost N, Marghoob AA, Rao BK, Wasti Q, Huang CL, Kopf AW, Bart RS (October 1996). "Neurocutaneous melanosis: clinical features of large congenital melanocytic nevi in patients with manifest central nervous system melanosis". J. Am. Acad. Dermatol. 35 (4): 529–38. PMID 8859278.
  32. ↑ 32.0 32.1 Kinsler VA, Chong WK, Aylett SE, Atherton DJ (September 2008). "Complications of congenital melanocytic naevi in children: analysis of 16 years' experience and clinical practice". Br. J. Dermatol. 159 (4): 907–14. doi:10.1111/j.1365-2133.2008.08775.x. PMID 18671780.
  33. ↑ Lovett A, Maari C, Decarie JC, Marcoux D, McCuaig C, Hatami A, Savard P, Powell J (November 2009). "Large congenital melanocytic nevi and neurocutaneous melanocytosis: one pediatric center's experience". J. Am. Acad. Dermatol. 61 (5): 766–74. doi:10.1016/j.jaad.2008.11.022. PMID 19766348.
  34. ↑ 34.0 34.1 Marghoob AA, Dusza S, Oliveria S, Halpern AC (February 2004). "Number of satellite nevi as a correlate for neurocutaneous melanocytosis in patients with large congenital melanocytic nevi". Arch Dermatol. 140 (2): 171–5. doi:10.1001/archderm.140.2.171. PMID 14967788.
  35. ↑ Di Rocco F, Sabatino G, Koutzoglou M, Battaglia D, Caldarelli M, Tamburrini G (January 2004). "Neurocutaneous melanosis". Childs Nerv Syst. 20 (1): 23–8. doi:10.1007/s00381-003-0835-9. PMID 14576958.
  36. ↑ Schaffer JV, McNiff JM, Bolognia JL (2001). "Cerebral mass due to neurocutaneous melanosis: eight years later". Pediatr Dermatol. 18 (5): 369–77. PMID 11737677.


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