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Background
This is the pigmented nevus or mole, sometimes called a nevocellular nevus or melanocytic nevus. The term nevus is often used synonymously for a mole but it actually means any congenital lesion of the skin. Clinically, most nevi are small, usually less than 6 mm. They are usually flat or slightly raised and have even pigmentation or flesh coloration with sharply circumscribed borders. Many of the clinical variants are listed in the commonly used terms.
Under the microscope, nests of melanocytes grow and proliferate along the dermoepidermal junction. If these melanocytes are localized to this junction, it is called a junctional nevus. With time, the nests of melanocytes may descend into the underlying dermis and is termed a compound nevus. In older lesions, the melanocytic nests completely descend into the dermis without any junctional nests and is termed a dermal nevus. With progressive descent and age of the nevi, the melanocytes may become spindled and fusiform, resembling schwann cells of the nervous system.
There is a consistent rise in the risk of malignant melanoma of the skin with an increasing number of nevi. It is estimated that 50% of melanomas have an acquired nevus as a precursor lesion. Thus, recent cancer control trails have focused on reducing acquired nevi in children. A recent trial of 309 white children in Vancouver, British Columbia conducted over a period of 3 years, randomized half to a group receiving SPF 30 sunscreen and the other half to a control group not receiving sunscreen. The sunscreen group developed fewer nevi than children in the control group (median counts 24 vs 28 P=0.048). In addition, children with freckles developed 30-40% fewer nevi when they received sunscreen indicating a significant interaction between freckling and the study group.
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Nevocellular nevus
Melanocytic nevus
MoleINCIDENCE Associated factors in the prevalence of more than 50 common melanocytic nevi, atypical melanocytic nevi, and actinic lentigines: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society.
Garbe C, Buttner P, Weiss J, Soyer HP, Stocker U, Kruger S, Roser M, Weckbecker J, Panizzon R, Bahmer F, et al.
Department of Dermatology, University Medical Center Steglitz, Free University of Berlin, Germany.
J Invest Dermatol 1994 May;102(5):700-5 Abstract quote
Several case-control studies identified common and atypical melanocytic nevi as major risk indicators for the development of cutaneous melanoma. The present investigation was planned to detect factors associated with the prevalence of these melanoma risk markers.
Whole-body examination findings and interview data of 513 melanoma patients and 498 age- and sex-matched control subjects were analyzed. Existence of more than 50 common melanocytic nevi and the presence of atypical melanocytic nevi were significantly related to age and gender, with significantly elevated relative risk for their prevalence before the age of 60 and in males. Additionally, sunburns before the age of 20 were significantly associated with both more than 50 common melanocytic nevi (relative risk = 1.7) and the presence of atypical melanocytic nevi (relative risk = 1.5). Actinic lentigines were found more frequently with increasing age, and the presence of actinic lentigines was significantly related to a tendency of freckling in adolescence (relative risk = 2.0) and to two or more sunburns after the age of 20 (relative risk = 1.6).
In conclusion, sunburns before the age of 20 contribute to the development of multiple melanocytic nevi and atypical melanocytic nevi. In adulthood, this type of sun exposure is associated with the development of actinic lentigines. The relative risk of developing cutaneous melanoma increases in association with the development of these benign melanocytic lesions.
ADOLESCENTS
Evolution of melanocytic nevi on the faces and necks of adolescents: a 4 y longitudinal study.Siskind V, Darlington S, Green L, Green A.
Population & Human Genetics Division, Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
J Invest Dermatol 2002 Mar;118(3):500-4 Abstract quote All melanocytic nevi on the faces and necks of a cohort of students, initially aged 12-14 y, were mapped and photographed annually for 4 y. The features of each nevus were charted yearly noting changes in size and profile, and the appearance or disappearance of any nevi on a student's face and neck was recorded. Nevi were classified by size (small, < 2 mm; medium, 2-5 mm; large, > 5 mm), and by profile (flat, raised). Data from 20 adolescents selected randomly from the cohort for detailed analysis showed males had about twice as many nevi as females, but there was little difference between sexes in their patterns of nevus development. Approximately half the nevi were small in all years; under 5% were large.
Over the 4 y of follow-up the proportion of flat nevi dropped from 70% to 57%, whereas nevus numbers increased by 47% in year 1, with smaller increases in older students. Most new or disappearing nevi were small and flat, although both incident and disappearing nevi could be larger and/or raised. Of the existing nevi that altered in the follow-up period, the tendency was towards an increase in size among raised but not among flat nevi; a lowering of profile among small nevi; and a raising of profile among larger nevi; but there were many exceptions to this pattern.
Among several host factors examined, inability to tan after sun exposure was found to be significantly negatively associated with the propensity of nevi to change size over the study period.
Overall our findings indicate that, contrary to conventional belief, there is a measurable turnover among melanocytic nevi even in early life.
Longitudinal study of melanocytic nevi in adolescents.Darlington S, Siskind V, Green L, Green A.
Population and Clinical Sciences Division, Queensland Institute of Medical Research.
J Am Acad Dermatol 2002 May;46(5 Pt 1):715-22 Abstract quote BACKGROUND: Although melanocytic nevi are the strongest known risk factors for melanoma, their etiology is not well understood.
OBJECTIVES: This study was performed to assess the roles of constitutional pigmentary factors and sun exposure in the development of new nevi in adolescents.
METHODS: A cohort of 111 school children, aged 12 and 13 years at baseline, were followed up for 5 years. Whole-body counts of nevi of all sizes and detailed sun exposure histories were updated each year. Analyses of full-body nevus counts and of nevus counts on the face and neck region and on the shoulder and back region were undertaken by means of log-linear regression, allowing for repeated measures.
RESULTS: Mean whole-body nevus counts were 130.1 (SD = 69.9) in 1990 and 215.5 (SD = 127.1) in 1994. Shoulder and back counts were consistently higher than face and neck counts. Subjects with heavy shoulder freckling had increased nevus counts on all sites investigated, with a means ratio for whole-body counts of 1.11 (95% CI, 1.03-1.19), compared with those with no freckling. Those who spent all of their school lunch times in the midday sun had a means ratio of 1.62 (95% CI, 1.15-2.29) compared with those who spent very little time in the sun during the lunch period. Summer holiday sun exposure was not significantly associated with development of nevi in this adolescent cohort.
CONCLUSION: The degree of freckling, especially on the shoulders, and habitual midday sun exposure, rather than holiday sun exposure, are significant determinants of melanocytic nevi in Queensland adolescents.
DISEASE ASSOCIATIONS CHARACTERIZATION CHEMOTHERAPY Prevalence of naevocytic naevi after chemotherapy for childhood cancer.
de Wit PE, de Vaan GA, de Boo TM, Lemmens WA, Rampen FH.
Center of Paediatric Oncology South-East Netherlands, Sint Radboud Hospital, The Netherlands.
Med Pediatr Oncol 1990;18(4):336-8 Abstract quote
The frequency of naevocytic naevi (moles) in patients with childhood haematologic malignancies was studied.
All patients had received multiple chemotherapy. The majority had also received cranial irradiation as part of their central nervous system leukaemia/lymphoma prophylaxis. Total body mole counts of the patients were compared with those of their healthy brothers and sisters. The median number of moles in the patient group was 20.0 (n = 79), in the healthy sibs 11.0 (n = 88). In two subgroups mole counts of male and female patients were compared with those of their closet brother or sister. There were 19 male and 19 female pairs for comparison.
Median numbers of moles were significantly higher in both patient groups than in the controls (P less than 0.05). It is suggested that multiple chemotherapy (and/or cranial irradiation) may induce or activate naevocytic naevi.
These findings may have important implications with regard to the aetiology of melanoma.
EPIDERMOLYSIS BULLOSA Large melanocytic nevi in hereditary epidermolysis bullosa
Johann W. Bauer, etal.
J Am Acad Dermatol 2001;44:577-84 Abstract quote
Large melanocytic nevi occurring in areas of former blistering in patients with hereditary epidermolysis bullosa (EB) pose a problem to the clinician with regard to prognosis and therapy because they may show clinical and histopathologic features strikingly resembling malignant melanoma.
To investigate clinical and histologic criteria as well as the biologic behavior of these nevi, pigmented lesions of 12 patients (EB simplex, n = 1; junctional EB, n = 7; dystrophic EB, n = 4) of the Austrian EB registry were analyzed. Clinically, the nevi are up to palm sized, are initially very dark, and may exhibit stippled pigmentation and irregular borders that outline areas of former blisters. Over time they usually lose pigment, the surface gets papillomatous, and finally they acquire a shagreen-like appearance. Histopathologically, the nevi frequently exhibit a compound congenital or persisting nevus/pseudomelanoma pattern. Despite this combination of features, no malignant transformation of the nevi has been seen by us even after 20 years of prospective surveillance.
Because nevi with these criteria do not fit in any of the known categories, we suggest the term EB nevi.
PREGNANCY Does pregnancy alter melanocytic nevi?
Caron M. Grin, Adriana I. Rojas and Jane M. Grant-Kels
Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut, USA
J Cutan Pathol 2001;28 (8), 389-392 Abstract quote
The effect of pregnancy on melanocytic nevi and malignant melanoma remains extremely controversial. In some reports, melanocytic nevi were observed to change during pregnancy. However, these studies were based on patients’ observations rather than on objective criteria. Earlier studies also suggested that pregnancy had an adverse effect on the prognosis of patients with melanoma. However, several more recent controlled studies were unable to confirm this purported negative effect of pregnancy on the prognosis of malignant melanoma. It is known that pregnancy is marked by dramatic endocrinologic changes. One of the physiologic changes noted during pregnancy is increased pigmentation of the skin. Hyperpigmentation of the areola, linea alba, axilla, and genitalia is commonly observed and well documented during pregnancy. A related phenomenon that has been noted to occur during pregnancy is the darkening of melanocytic nevi. However, few studies have objectively documented the effect of pregnancy on pigmented nevi. In this paper, we will review the pertinent articles concerning the clinical and histopathologic changes reported in melanocytic nevi and then attempt to draw conclusions based on the available data.
PATHOGENESIS CHARACTERIZATION BASEMENT MEMBRANE Melanocytes in nevi and melanomas synthesize basement membrane and basement membrane-like material. An immunohistochemical and electron microscopic study including immunoelectron microscopy
G.Schaumburg-Lever, I.Lever, B.Fehrenbacher, H.Möller, B.Bischof, E.Kaiserling, C.Garbe and G.Rassner
J Cutan Pathol 2001;27 (2), 67-75 Abstract quote
Light microscopic studies have shown that nevus cell nests and melanoma nests are surrounded by basement membrane (BM) material containing type IV collagen and laminin.
This study confirms this by electron microscopy and relates it to proteins which interact with the basement membrane.
Nevi except for dysplastic and Spitz nevi, malignant melanomas, and melanoma metastases were studied by immunohistopathology, routine electron microscopy (EM), and immunoelectron microscopy. The lesions were incubated with monoclonal antibody (moAb) against type IV collagen, laminin, and the integrin a6 and studied by light microscopy. In addition, melanomas were studied by immuno-EM after incubation with a moAb against matrix metalloproteinase-2 (MMP-2). Nevus cell nests and melanoma nests are surrounded by BM material containing type IV collagen and laminin by immuno-EM. The BM material various in thickness and is amorphous.
Type IV collagen, laminin, and MMP-2 are synthesized by melanoma cells as well as adjacent fibroblasts. Destruction or loss of the BM is not mandatory for melanoma invasion or even metastasis. Possibly the BM material is a protective wall for melanoma cells. Interactions between melanocytes and the extracellular matrix of which the BM is a part, can be traced back to the migration of melanocytes from the neural crest.
CLONALITY Assessment of clonality in melanocytic nevi
Pei Hui, etal.
J Cutan Pathol 2001;28 (3):140-144 Abstract quote
Background: Melanocytic nevi are among the most common lesions in man; however; their pathogenesis remains largely unknown. While often held to be neoplastic, this hypothesis has not been conclusively verified. Alternatively, some authorities have held that melanocytic nevi are hamartomas. More practically, difficulty may be encountered in the histologic discrimination of melanocytic nevi from melanoma. It was reported that nevi may be differentiated from melanoma in females by polymerase chain reaction (PCR) analysis of loci of human androgen receptor gene on the X-chromosome. However, contradictory findings have also been reported, suggesting that both acquired nevi and melanoma are clonal.
Methods: Fifteen examples of melanocytic nevus were analyzed via PCR for pattern of X-chromosome inactivation as indicated by the methylation status of the human androgen receptor gene.
Results: Among 15 nevi analyzed, 11 cases provided informative polymorphism at the androgen receptor loci. Nine of these 11 cases revealed a non-random pattern of X-chromosome inactivation.
Conclusions: These findings suggest that melanocytic nevi are clonal/neoplastic lesions. As such, they cannot be discriminated from melanoma on the basis of clonality.
EMBRYOGENESIS Migration of melanocytes during embryogenesis Melanocytes originate in the neural crest and migrate to the basal layer of the epidermis MATRIX METALLOPROTEINASES
MMP-2, TIMP-2 and MT1-MMP are differentially expressed in lesional skin of melanocytic nevi and their expression is modulated by UVB-light.Krengel S, Alexander M, Brinckmann J, Tronnier M.
Department of Dermatology, Medical University Lubeck, Lubeck, Germany.
J Cutan Pathol 2002 Aug;29(7):390-6 Abstract quote BACKGROUND: In malignant melanoma, recent studies have demonstrated an important role of matrix-metalloproteinase 2 (MMP-2), its co-activating enzyme membrane-type matrix-metalloproteinase 1 (MT1-MMP), and the endogenous inhibitor of MMP-2, tissue-inhibitor of matrix metalloproteinase 2 (TIMP-2). Melanocytic nevi are benign neoplasms of the melanocytic lineage, but may exhibit dysplastic features that can be difficult to distinguish from early stage melanoma. As shown in earlier studies, nevi show important morphological and phenotypical changes in response to ultraviolet light (UVB) irradiation. OBJECTIVE: To clarify the role of MMP-2, TIMP-2 and MT1-MMP in UVB-irradiated vs. non-irradiated melanocytic nevi. METHODS: Immunohistochemical comparison of the MMP-2, TIMP-2 and MT1-MMP expression pattern. RESULTS: MMP-2 is expressed by lesional keratinocytes and its expression is up-regulated by UVB-irradiation. MMP-2 expression was not observed in melanocytic cells. TIMP-2, by contrast, is predominantly expressed by melanocytic nevus cells, and its expression is in part down-regulated by UVB-irradiation. MT1-MMP is expressed by basal keratinocytes and to a weaker extent by melanocytic nevus cells. CONCLUSIONS: MMP-2 expression by keratinocytes in nevi probably represents the result of activation of keratinocyte turnover in lesional epidermis. MMP-2 could play a role in the downward movement of junctional nevus cells into the dermis. The reduction of TIMP-2 expression in melanocytic cells by UV-light together with the enhanced expression of MMP-2 in the adjacent epidermis may promote basement membrane degradation. The expression pattern of MT1-MMP in close proximity to epithelial-mesenchymal interfaces underlines the synergistic role of MT1-MMP in this process.
PERIPHERAL NERVE SHEATH The relationship between melanocytes and peripheral nerve sheath cells (Part I): melanocytic nevus (excluding so-called "blue nevus") with peripheral nerve sheath differentiation.
Misago N.
Institute for Dermatopathology, Jefferson Medical College, Philadelphia, Pennsylvania, USA.
Am J Dermatopathol 2000 Jun;22(3):217-29 Abstract quote
Among thousands of specimens of melanocytic nevi, not including giant congenital melanocytic nevus or blue nevus, 42 melanocytic nevi that showed peripheral nerve sheath differentiation were collected.
The patterns of melanocytic nevi with peripheral nerve sheath differentiation may be classified into three groups: 1) "neurotized and neural nevi" with nests of "neuroid cords" and "nevic corpuscles" (the most common pattern); 2) nerve fascicle-like structures with no relation to neurotized and neural nevi; and 3) palisading melanocytes of a nevus in nests of conventional melanocytic nevi (a rare pattern). Each pattern may represent a different expression of nerve sheath differentiation in melanocytic nevi. Some melanocytic nevi with nerve fascicle-like structures show discrete structures closely resembling authentic nerve fascicles, confirming a close relationship between melanocytes and peripheral nerve sheath cells (Schwann cells and probably perineurial cells in part) and suggesting derivation of the two types of cells from common precursor cells of the neural crest and their de novo development in the dermis rather than by Abtropfung of melanocytes from the epidermis. In addition, the high prevalence of Unna, Miescher, and superficial congenital nevi in melanocytic nevi with peripheral nerve sheath differentiation suggests a different character or process for these congenital melanocytic nevi than for Clark and Spitz nevi (junctional and compound types).
PROLIFERATION Growth dynamics of acquired melanocytic nevi. Higher reactivity of proliferating cell nuclear antigen in junctional and compound nevi than intradermal nevi.
Tokuda Y, Saida T, Mukai K, Takasaki Y.
Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
J Am Acad Dermatol 1994 Aug;31(2 Pt 1):220-4 Abstract quote
BACKGROUND: The histogenesis of acquired melanocytic nevi is still a matter of debate.
OBJECTIVE: To provide data on the histogenesis, we investigated the lesional area of acquired melanocytic nevi and the proliferative activity of the nevus cells.
METHODS: Proliferative activity was examined with a monoclonal antibody against proliferating cell nuclear antigen (PCNA). The lesional area of the nevus was estimated in histologic sections.
RESULTS: Intradermal nevus was the largest of the acquired melanocytic nevi but had few PCNA-positive nevus cells. In contrast, junctional nevi were smallest and showed the highest PCNA positivity. Statistical analysis showed a significant inverse correlation between the largest lesional area and PCNA positivity.
CONCLUSION: The findings of the present study are in accordance with an epidermal melanocytic origin of acquired melanocytic nevi.
GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION VARIANTS DISSEMINATED ERUPTIVE Disseminated eruptive nevocellular nevi.
Bong HW, Lee SJ, Lee KH, Chung KY.
Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
J Dermatol 1995 Apr;22(4):292-7 Abstract quote
A 13-year-old boy suddenly developed about 2,000 dark brown to black colored papules on his face and neck and about 500 lesions on his trunk and upper extremities during a six month period. Histopathologic features were compatible with junctional nevus. The results of alpha melanocyte stimulating hormone (MSH), proliferating cell nuclear antigen (PCNA), and epidermal growth factor receptor (EGF/R) studies are presented.
To the best of our knowledge, this report represents an outbreak of the highest number of nevocellular nevi in a short period without any malignant nature or evident triggering factor.
HYPERMELANOTIC Hypermelanotic nevus: clinical, histopathologic, and ultrastructural features in 316 cases.
Cohen LM, Bennion SD, Johnson TW, Golitz LE.
Dermatology and Pathology Services, Denver General Hospital, Colorado, USA.
Am J Dermatopathol 1997 Feb;19(1):23-30 Abstract quote
We report on a series of benign melanocytic nevi that have unique clinical, histopathologic, and ultrastructural features.
Between March 1993 and February 1994, 316 examples of hypermelanotic nevi were received by the dermatopathology laboratory at Denver General Hospital. Our study identified the clinical characteristics, histopathologic criteria, and ultrastructure of this lesion.
Clinically, the lesions were dark brown to black macules or papules. The most common location was the back. There was a slight female predominance, and the mean age of our patients was 40 years.
Histopathologically, the nevus showed the following characteristics: (a) melanin within a compact stratum corneum, (b) small nests of nevus cells at the dermal-epidermal junction and (in 52% of the cases), nests within the papillary dermis, (c) heavy melanin within keratinocytes in the lower epidermis, (d) a sparse to moderate lymphocytic infiltrate and melanophages in the superficial dermis, and (e) an absence of cytologic atypia. Electron microscopy revealed that abundant melanin was packaged in melanosome complexes within keratinocytes. Less pigmented melanocytes and nevus cells contained well-developed dendritic processes and golgi, indicative of efficient melanin transfer.
According to our retrospective case control analysis, patients with hypermelanotic nevi were older and more likely to be male than those with ordinary nevi. Hypermelanotic nevi were more likely than controls to be junctional nevi; they were smaller, dark brown or black in color, and clinically suspicious for melanoma. We propose the name "hypermelanotic nevus" to describe this benign lesion, which is often biopsied to exclude melanoma.
PANDA NEVUS The panda naevus: management of synchronous upper- and lower-eyelid pigmented naevi.
Yap LH, Earley MJ.
The Paediatric Craniofacial Unit, The Children's Hospital, Dublin, Ireland.
Br J Plast Surg 2001 Mar;54(2):102-5 Abstract quote
We report four patients presenting with rare synchronous upper- and lower-eyelid naevi. The distributions and appearances of these naevi resemble the distinctive periorbital pigmentation of the panda.
The possible embryological origin of this naevus and an approach to management are discussed.
SPECKLED LENTIGINOUS NEVUS Speckled Lentiginous Nevus Within the Spectrum of Congenital Melanocytic Nevi Arch Dermatol. 2001;137:172-178
Once called nevus spilus to describe a hyperpigmented patch with superimposed darker speckles
A speckled lentiginous nevus can be likened to a melanocytic garden, and within this garden a variety of lesions can grow, from junctional nevi to blue nevi to melanoma
Varied in size from 2 cm in diameter to extensive zosteriform lesions
These patients had lesions that existed in either spatial or temporal contiguity with classic congenital nevi
Opinion of the authors that both speckled lentiginous nevi and spotted grouped pigmented nevi fall within the spectrum of congenital melanocytic nevi
Recommendation:
Perform baseline photographic documentation followed by serial clinical observation and education of the patient and family regarding the clinical signs of melanomaRecommend that a biopsy of any suspicious area be performed
Melanoma arising within speckled lentiginous nevus Arch Dermatol. 1990;126:500-505.
Int J Dermatol. 1990;29:583-584.
Arch Dermatol. 1991;127:1240-1241.
J Cutan Pathol. 1992;19:423-428.
Cutis. 1998;61:287-289.
Int J Dermatol. 1997;36:499-502
Cutaneous melanomas developed within speckled lentiginous nevi
There have been at least 20 such cases reported
Suggests that speckled lentiginous nevi may actually present a greater risk, noting that of more than 2000 melanomas seen at one pigmented lesion clinic during a 15-year period, more arose from speckled lentiginous nevi than from large classic congenital melanocytic nevi
POINTILLIST NEVUS Pointillist nevi
Phung M. Huynha, Earl J. Glusac, MD, Jean L. Bolognia, MD
New Haven, Connecticut
J Am Acad Dermatol 2001;45:397-400 Abstract quote
Background: Atypical melanocytic nevi and cutaneous melanoma are often marked by variation in color. However, there are examples of “benign” explanations for irregularities in pigmentation, such as perifollicular hypopigmentation or hyperpigmentation.
Objective: The purpose of this study was to correlate the clinical and histologic features of 3 unusual melanocytic nevi consisting exclusively of multiple, tiny, dark brown to black dots on a skin-colored background, which we have termed pointillist nevi.
Methods: Histologic examination was performed of the single pointillist nevus from each of 3 patients (all women; aged 28, 39, and 47 years).
Results: The diameters of the pointillist nevi were 2, 3.5, and 5.5 mm. Individual dots were approximately 0.1-0.25 mm. Each of the 3 nevi showed a different histologic correlate for the dots, either (1) discrete, densely pigmented, junctional melanocytic nests; (2) isolated dermal pigmented melanocytic nests; or (3) discrete clusters of melanophages in the papillary dermis.
Conclusion: Pointillist nevi are benign melanocytic nevi with histologic correlates similar to those of the “brown globules” observed by dermoscopy in uniformly pigmented nevi. However, the dots seen in pointillist nevi can be visualized without magnification. The clinical and histologic features of pointillist nevi add to the spectrum of unusual patterns of pigmentation that may be encountered in benign melanocytic lesions.
HISTOLOGICAL TYPES CHARACTERIZATION VARIANTS There are several body sites where benign nevi have atypical architectural features with intraepithelial scatter, confluent junctional nests, and occasionally dense lymphocytic infiltrates with melanocytes containing pale staining cytoplasm
Some of these sites include:
Umbilicus
Genitalia
Conjunctiva
Acral
EarsACRAL SKIN J Cutan Pathol 1991;18:378 (Abstract)
Histopathol 1995;27:549-555
Am J Surg Pathol 1999;23:283-287
Am J Dermatopathol 2001;22:556-558
Suprabasal scatter of single melanocytes and poor lateral circumscriptionScant lymphocytic infiltrates
Part of the architectural atypia may be secondary to the plane of section. On acral skin, there parallel ridges and furrors. If sections of the lesional skin are examined perpendicular to the dermatoglyphic lines, features of symmetry, circumscription, and benignity may be more easily ascertained
COMBINED NEVUS Histologic classification of the combined nevus. Analysis of the variable expression of melanocytic nevi.
Pulitzer DR, Martin PC, Cohen AP, Reed RJ.
Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana 70112.
Am J Surg Pathol 1991 Dec;15(12):1111-22 Abstract quote
The designation combined nevus gives recognition to mixed cytologic patterns. In the common variant, plump, pigmented spindle cells form fascicles among nests of ordinary nevus cells. In other variants, one or several cellular components that share cytologic features with either a blue nevus or a Spitz nevus are represented.
Ninety-five cases, 49% of which were of the common type, were studied. Grossly, most of the lesions were darkly pigmented papules or nodules. The clinical diagnosis in three-fourths of the cases was nevus, blue nevus, or melanoma. Fifteen percent had concomitant histologic features of melanocytic dysplasia, and most of these lesions were of the common type. For the common variant, the cytologic features, pattern of apparent infiltration, and variable representation of the features of a premalignant melanocytic dysplasia often mislead a pathologist in interpreting and predicting biologic potential.
In combined nevi, the phenotypic diversity and genetic lability of melanocytic nevus cells is manifested.
DESMOPLASTIC NEVUS Desmoplastic nevus: a distinct histologic variant of mixed spindle cell and epithelioid cell nevus.
Barr RJ, Morales RV, Graham JH.
Cancer 1980 Aug 1;46(3):557-64 Abstract quote
From a series of 75 cases of mixed spindle cell and epithelioid cell nevi, 14 were designated as desmoplastic nevi. Junctional activity, theque formation, and pigmentation were uncommon features. As a result, desmoplastic nevi may be confused with a variety of fibrohistiocytic lesions.
Well defined intranuclear invaginations of cytoplasm occurred in 12 cases, and were helpful in differentiating desmoplastic nevi from these lesions.
Desmoplastic malignant melanoma must also be considered in the microscopic differential diagnosis, but distinguishing features of desmoplastic melanoma include the presence of preexisting lentiginous melanoma, and necrosis of tumor cells and collagen.
Desmoplastic nevus was compared to the ordinary variants of mixed spindle cell and eipthelioid cell nevus in an attempt to define etiologic factors responsible for a desmoplastic reaction. No satisfactory explanation could be found since the clinical variables examined were not statistically different.
EPITHELIOID FEATURES Melanocytic nevi with focal atypical epithelioid cell components: a review of seventy-three cases.
Ball NJ, Golitz LE.
Department of Dermatology, Denver General Hospital, CO 80204.
J Am Acad Dermatol 1994 May;30(5 Pt 1):724-9Abstract quote
BACKGROUND: We report a variant of melanocytic nevus that may be confused with melanoma.
OBJECTIVE: The purpose of this study is to describe the clinical, histologic, and biologic features of nevi with focal atypical epithelioid cell components (clonal nevi).
METHODS: Seventy-three cases were retrieved by reviewing lesions previously diagnosed as clonal, combined, deep penetrating, and inverted type-A nevi. Histologic features were assessed and referring physicians received a questionnaire about the presentation and outcome of each case.
RESULTS: Histologically, all cases had a biphasic pattern characterized by an ordinary nevus that contained a darkly pigmented collection of large distinct epithelioid melanocytes in the superficial dermis. Immunostains identified mutant p53 proteins in 50% of dermal clones (9 of 18) but not in ordinary nevus cells adjacent to the clones. We are not aware of any patient developing a malignant melanoma (mean follow-up 24.5 months), including 41 cases that were initially incompletely excised.
CONCLUSION: Clonal nevi are a distinct variant of melanocytic nevi and should be distinguished from malignant melanoma arising in a preexisting nevus.
HALO NEVUS Halo nevus or halo phenomenon? A study of 142 cases.
Mooney MA, Barr RJ, Buxton MG.
Division of Dermatology, UMDNJ-New Jersey Medical School, Newark, USA.
J Cutan Pathol 1995 Aug;22(4):342-8 Abstract quote
One hundred and forty-two (142) halo nevi were reviewed.
For 66 cases the diagnosis of halo nevus was made both clinically and pathologically, and for 76 cases the diagnosis was based on histological grounds alone. The nevi were classified by type and by degree of atypia. Of the 142 nevi, all were compound, junctional, or intradermal nevi except for one case of a Spitz nevus and two cases that could not be further classified.
For those with a clinicopathological diagnosis of halo nevus, 11% exhibited moderate atypia; 16% exhibited minimal atypia to only focally moderate atypia; 24% minimal atypia; and 49% exhibited no significant atypia. For those cases where the diagnosis was pathological only, there was also a broad spectrum of atypia identified, with 8% exhibiting focally severe or severe atypia.
This study supports the concept that the halo nevus should not be regarded as a single clinicopathological entity, but rather that the halo phenomenon occurs in a wide spectrum of nevus types exhibiting a wide spectrum of histological atypia. The pathologist is therefore encouraged to classify halo nevi on the basis of the nevus cell population alone, using whatever classification normally utilized.
JUNCTIONAL ATYPIA Benign atypical junctional melanocytic hyperplasia associated with intradermal nevi: a common finding that may be confused with melanoma in situ.
Okamura JM, Barr RJ, Cantos KA.
Department of Dermatology, University of California, Irvine, USA.
Mod Pathol 2000 Aug;13(8):857-60 Abstract quote
Over the past few years, consultation cases thought to represent melanoma in situ have been received that consisted of otherwise normal intradermal nevi with an abnormal but benign junctional proliferation of melanocytes that we have termed benign atypical junctional melanocytic hyperplasia.
In order to evaluate the incidence of this feature, 400 cases of intradermal nevi were reviewed. Of these, 25 (6.2%) qualified for inclusion, making this a rather common phenomenon. Clinically, patient ages ranged from 18 to 64 years (mean, 35 years), with a male to female ratio of 1:1. Face (40%) and back (32%) were the most common locations.
Histologically, the lesions were predominantly dome-shaped with an intradermal component consisting of conventional nevus cells. Most importantly, each lesion exhibited prominent individual nevomelanocytic cells dispersed at uneven intervals along the dermoepidermal junction in insufficient numbers to be considered compound nevi. The cells exhibited abundant pale to clear cytoplasm, an increased nuclear:cytoplasmic ratio, and often exhibited prominent nucleoli. However, these lesions could be distinguished from melanoma in situ by the lack of several features including lateral spread, upward epidermal migration, marked cytologic atypia, finely granular "smoky" melanin pigment, mitotic figures, and a subjacent host inflammatory response.
All cases behaved in a benign fashion. Although benign atypical junctional melanocytic hyperplasia is a relatively common histological curiosity, it is a potential pitfall in the diagnosis of pigmented lesions.
KERATOTIC Keratotic melanocytic nevus: a clinicopathologic and immunohistochemical study.
Horenstein MG, Prieto VG, Burchette JL Jr, Shea CR.
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Cutan Pathol 2000 Aug;27(7):344-50 Abstract quote
BACKGROUND: Epidermal hyperplasia in melanocytic nevi is a common but little-investigated phenomenon.
METHODS: We prospectively examined all melanocytic nevi diagnosed in our department over an 8-month period, for the criteria of keratotic melanocytic nevus (KMN), namely the presence of marked epidermal hyperplasia with or without horn pseudocyst formation, hyperkeratosis, and papillomatosis. In addition to routine histologic review, we studied 12 representative cases with immunohistochemistry to examine expression of Ki-67, epidermal growth factor receptor (EGFR), Bcl-2, and Bax.
RESULTS: From a total of 1,527 melanocytic nevi, 95 were KMN (prevalence 6%). The average age was 34 years, with a male:female ratio of 1:2. The predominant location was the trunk (76%), followed by head and neck (20%), and extremities (4%). Clinical diagnoses were atypical nevus (44%), nevus not otherwise specified (43%), and others including seborrheic keratosis, acrochordon, and basal cell carcinoma. Two KMN were junctional, 44 compound, and 49 intradermal. Twenty-three KMN (24%) had histologic features suggesting congenital onset, and 15 (16%) had mild to moderate dysplastic features. Two cases demonstrated induction of sebaceous glands. Significantly increased Ki-67 expression was detected in the hyperplastic epidermis, particularly in deeper areas related to keratinous cysts and hair follicles. Bcl-2 and Bax (anti- and pro-apoptosis proteins, respectively) and EGFR were expressed similarly in both normal and hyperplastic epidermis overlying the KMN.
CONCLUSIONS: KMN are commonly biopsied skin lesions, mostly located on the trunk. Many such lesions are clinically considered atypical, in contrast to their benign histologic appearance. The epidermal hyperplasia on top of KMN demonstrates increased cellular proliferation, in the context of adequately regulated apoptosis and EGFR expression. The cellular proliferation seems to commence in hair follicles.
MYXOID CHANGE Nodular myxoid change in melanocytic nevi. A report of two cases.
Mehregan DR, Mehregan DA, Mehregan AH.
Pinkus Dermatopathology Laboratory, Monroe, MI 48161-0360, USA.
Am J Dermatopathol 1996 Aug;18(4):400-2 Abstract quote
Mucin deposition has been reported in a variety of cutaneous neoplasms, including melanocytic nevi.
We describe a series of melanocytic nevi with nodular myxoid change.
NEUROCUTANEOUS MELANOCYTOSIS J Am Acad Dermatol 1996;35:529-538
J Am Acad Dermatol 1991;24:747-755
J Am Acad Dermatol 1994;31:423-429Affects 10% of patients with LCMN
Characterized by LCMN or multiple (3 or more) small to medium sized congenital melanocytic nevi, accompanied by benign and/or malignant growth of melanocytes in the central nervous system5 year cumulative life table risk of developing NCM is 2.5%
RECURRENT NEVUS Recurrent melanocytic nevus: a histologic and immunohistochemical evaluation
Mai P. Hoang1, Victor G. Prieto2, James L. Burchette3 and Christopher R. Shea3
1 Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA, 2 Department of Pathology, The University of Texas-M.D. Anderson Cancer Center, Houston, Texas, USA, 3 Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
Journal of Cutaneous Pathology 2001;28 (8), 400-406 Abstract quote
Background: Recurrent melanocytic lesions may histologically resemble malignant melanoma.
Methods: We evaluated the original nevi (ON) and recurrent nevi (RN) of 15 patients by routine histology and immunohistochemistry (IHC), examining expression of S-100 protein, gp100 (with HMB-45), MART-1, tyrosinase, and the Ki-67 proliferation marker.
Results: Compared with ON, RN had a dermal scar, a significantly greater number of melanophages, and a greater extent of cellular atypia including prominent nucleoli and larger cell size. Architecturally, RN showed significantly less symmetry than ON; however, the percentage of junctional cohesive nests, the presence of suprabasal spread, and the degree of confluence were similar between ON and RN. Both ON and RN showed a decrease in expression of gp100 and tyrosinase with increasing depth (“maturation gradient”) and low proliferative activity in both the junctional (4.6% for ON vs. 4.13% for RN) and the dermal components (0.93% for ON vs. 1.45% for RN).
Conclusions: RN exhibit a dermal scar, a greater number of melanophages, cytologic atypia, and asymmetry than ON, features that may raise concern about the possibility of malignant melanoma. However, the area with the irregular architectural pattern is restricted to the epidermis and dermis immediately above the scar. In addition, IHC helps to distinguish RN from malignant melanoma; specifically, RN demonstrate an immunohistochemical “maturation pattern” (with HMB-45 and anti-tyrosinase) and a low proliferative index (with Ki-67).
SCHWANNIAN DIFFERENTIATION
Intradermal melanocytic nevus with prominent schwannian differentiation.Kroumpouzos G, Cohen LM.
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Am J Dermatopathol 2002 Feb;24(1):39-42 Abstract quote Features of peripheral nerve sheath differentiation such as neuroid cords, nerve corpuscles, fascicle-like structures, and, exceptionally, palisading have been reported in melanocytic nevi.
We report an intradermal melanocytic nevus with prominent Verocay-like bodies. The upper portion of the neoplasm was composed of typical round intradermal nevus cells, many of which were pigmented. Within the deeper portion, there was a nonpigmented spindle cell proliferation with prominent Verocay bodies, simulating a neurilemmoma. Typical nevus nests merged with neurilemmoma-like areas. The entire lesion stained positively for S-100 and Mart-1 proteins and negatively for HMB-45 stain. Diffuse Mart-1 positivity excluded a collision of a melanocytic lesion with a neurilemmoma.
The histopathologic features of this nevus further support a close relation between nevus cells and Schwann cells.
WITH SYRINGOMETAPLASIA An unusual melanocytic lesion associated with eccrine duct fibroadenomatosis and syringoid features.
Stefanato CM, Simkin DA, Bhawan J.
Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Am J Dermatopathol 2001 Apr;23(2):139-42 Abstract quote
The intimate association of nevomelanocytic nevi with eccrine ducts commonly seen in congenital nevi was emphasized by Mishima, who described as eccrine-centered nevi those lesions characterized by nevomelanocytic cells predominantly proliferating around and within the eccrine sweat duct walls. However, there were no changes in the overlying epidermis, dermis, or eccrine acrosyringeal or dermal duct proliferation in these lesions.
We present the case of a 16-year-old boy with a 1-year-history of a 0.6-cm diameter single tan papule on the right heel, clinically thought to be a Spitz nevus. Histopathologic examination revealed a compound nevomelanocytic nevus associated with epidermal hyperplasia, thin anastomosing cords of acrosyringeal epithelium extending within the dermis, and eccrine ductal proliferation in a syringoma-like pattern associated with a dense fibrous stroma.
Features that distinguish our case from eccrine-centered nevus are that the latter lacks epidermal and eccrine duct hyperplasia and a dense fibrous stroma. The location of the lesion on the heel in our case suggests the possibility that the pathologic changes observed could result from repetitive trauma.
SPECIAL STAINS/IMMUNOHISTOCHEMISTRY/OTHER CHARACTERIZATION CEA The carcinoembryonic antigen (CEA) family (CD66) expressed in melanocytic naevi is not expressed in blue naevuscell naevi in dendritic type.
Egawa K, Honda Y, Kuroki M, Ono T.
Department of Dermatology, Kumamoto University School of Medicine, Honjo, Japan.
J Cutan Pathol 2000 Aug;27(7):351-8 Abstract quote
BACKGROUND: Although sporadic reports have regarded the expression of the carcinoembryonic antigen (CEA) family in melanoma, there has been no information about the expression in precursor lesions of melanoma such as melanocytic naevi and blue naevi.
METHODS: The expression was immunohistochemically studied in frozen biopsy specimens of 45 acquired and 16 congenital melanocytic naevi and 20 blue naevi, using a panel of monoclonal and polyclonal antibodies that recognize different epitopes of CEA and related molecules.
RESULTS: Members of the CEA glycoprotein family were strongly expressed in all of the subtypes of melanocytic naevus. A reduced expression of the CEA glycoproteins with increased dermal depth or acquisition of a spindled morphology of naevus cells was apparent. The expression was not seen in the present blue naevi and normal epidermal melanocytes.
CONCLUSIONS: Although the significance of the expression was not clarified, this report has clearly demonstrated that the CEA family is strongly expressed in melanocytic naevi and immunoreactivity is divergent between melanocytic naevi and blue naevi and between dermal naevus cell types, suggesting that the expression may be altered with architectural changes in the melanocyte-lineage cells.
hTER
Human telomerase RNA component expression in Spitz nevi, common melanocytic nevi, and malignant melanomas.Guttman-Yassky E, Bergman R, Manov L, Sprecher E, Shaefer Y, Kerner H.
Department of Dermatology, Rambam Medical Center; Haifa, Israel The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology; Haifa, Israel Dermatopathology Unit, Rambam Medical Center, Haifa, Israel Department of Pathology, HaEmek Medical Center, Afula; Israel Department of Pathology, Rambam Medical Center, Haifa, Israel.
J Cutan Pathol 2002 Jul;29(6):341-346 Abstract quote BACKGROUND: Telomerase is a ribonucleoprotein DNA polymerase that is capable of synthesizing telomeres onto the ends of chromosomes. The cumulative loss of telomerase activity is believed to be associated with cell senescence. Telomerase activity has been shown to be higher in malignant melanomas than in common melanocytic nevi. The aim of the present study was to elucidate the pattern of expression of the human telomerase RNA (hTER) component in routinely processed specimens of Spitz nevi, malignant melanomas, and ordinary melanocytic nevi.
METHODS: Ten specimens of each type of tumor were studied, using an in situ hybridization technique.
RESULTS: All three types of tumors demonstrated moderate to high intensities of hTER expression, usually in more than half of the tumor cells, and the majority of the studied lesions in each group did not show stratification of staining. The hTER component was also detected in the epidermis, sweat glands, and pilosebaceous units.
CONCLUSIONS: hTER levels do not necessarily correlate with the level of telomerase activity, and the level and pattern of hTER expression are not useful as an adjunct to the histologic differential diagnosis of Spitz nevi from melanocytic nevi and malignant melanomas.
S-100 S100A6 preferentially labels type C nevus cells and nevic corpuscles: additional support for Schwannian differentiation of intradermal nevi D.
R. Fullen1, J. A. Reed2, B. Finnerty3 and N. S. McNutt3
1 Department of Pathology, University of Michigan Hospitals, Ann Arbor, Michigan, USA, 2 Division of Dermatopathology, Department of Pathology, Baylor College of Medicine, Houston, Texas, USA, 3 Division of Dermatopathology, Department of Pathology, The New York Presbyterian Hospital-Cornell University Weill Medical College, New York, New York, USA
J Cutan Pathol 2001;28 (8), 393-399 Abstract quote
Background: Melanocytic nevi typically show a morphologic sequence of maturation from epithelioid “type A” cells to fusiform, Schwann cell-like “type C” cells with dermal descent. Nevi may also produce Wagner-Meissner-like structures (nevic corpuscles). Previous studies have shown that this maturation of intradermal nevi recapitulates intermediate stages in Schwann cell development. In intradermal nevi, we have evaluated the pattern of S100A6 protein, a form of S100 found in Schwann cells.
Methods: Formalin-fixed, paraffin-embedded archival tissues were evaluated by immunohistochemistry using antibodies specific for S100A6 and S100B in 38 intradermal nevi (IDN). Ten neurofibromas (NF), 3 Schwannomas (SCH), 2 palisaded and encapsulated neuromas (PEN), and 2 granular cell tumors (GCT) were included as positive controls since these lesions have large numbers of Schwann cells.
Results: Melanocytic nevi demonstrated preferential anti-S100A6 staining of “type C” cells (36/38; 28 strong, 8 weak) and nevic corpuscles (25/38; 19 strong, 6 weak) compared to “type A” cells (17/38; 17 weak) and “type B” cells (17/38; 4 strong, 13 weak). All NF, SCH, and PEN stained strongly with anti-S100A6. Both GCT were negative with anti-S100A6 but positive with anti-S100B.
Conclusions: The pattern of S100A6 expression in intradermal nevi further supports the hypothesis that maturation in these lesions recapitulates features of Schwann cell differentiation. The lack of S100A6 expression by both GCT suggests that these lesions have lost this feature of Schwann cells, which may play a role in their peculiar phenotypic appearance.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES ATYPIA Histologic atypia in clinically benign nevi. A prospective study.
Klein LJ, Barr RJ.
Department of Dermatology, University of California, Irvine.
J Am Acad Dermatol 1990 Feb;22(2 Pt 1):275-82 Abstract quote
Histologic features of dysplastic nevi include varying degrees of pattern atypia, cytologic atypia, and host response.
The purpose of this prospective study was to determine the prevalence of these histologic features in benign acquired nevi.
Fifty-eight junctional and compound nevi from 26 volunteer subjects were excised and examined. All nevi met each of the following criteria: 5 mm or less in diameter, symmetric, round or slightly oval, uniform pigmentation, distinct and regular margins, and no erythema.
One or more of the histologic features associated with dysplastic nevi were present in 87.8% of the lesions; two or more were present in 69%; and all three histologic features were found in 29.3%.
These results indicate that histologic features of dysplastic nevi occur in benign common acquired nevi.
Atypical histologic features in melanocytic nevi.
Urso C.
Dermatopathology Section, SM Annunziata Hospital, Florence, Italy.
Am J Dermatopathol 2000 Oct;22(5):391-6 Abstract quote
The atypical histologic features considered to be specific to dysplastic (atypical) nevi have been reported to occur in nevi that are common nevi by all other clinical and histologic features. The distribution and mutual relations among such features in nevi need to be further studied.
Six histologic features (dimension > 5 mm, lentiginous proliferation, disordered nested pattern, melanocytic dyskaryosis, dermal lymphocytic infiltrate, suprabasal melanocytes) were analyzed in 253 melanocytic nevi with different clinical appearances.
Atypical histologic features, found in 72% of nevi, occurred singly or formed numerous and highly variable combinations. Nevi formed a complex histologic spectrum comprising lesions showing a progressively increasing incidence of atypical features rather than two classes (common and dysplastic nevi). To divide the investigated lesions in objectively defined groups, we used a scoring system. In each nevus, a numeric value of 1 was assigned when each of the studied parameters was present and a value of 0 was assigned when each of these parameters was absent; on the basis of the final scores, nevi were divided in six different classes (classes 0-5).
Diagnostic categories such as dysplastic nevi and common nevi seem to be inappropriate, as they do not reflect the real histologic complexity of such lesions.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS TREATMENT Simple excision is curative Treatment of benign and atypical nevi with the normal-mode ruby laser and the Q-switched ruby laser: clinical improvement but failure to completely eliminate nevomelanocytes.
Duke D, Byers HR, Sober AJ, Anderson RR, Grevelink JM.
Dermatology Laser Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Arch Dermatol 1999 Mar;135(3):290-6 Abstract quote
OBJECTIVE: To evaluate the effect of normal-mode and Q-switched ruby laser light (694 nm) on nevomelanocytes of benign, atypical, and congenital nevi.
DESIGN: Half of the lesion of each of 31 nevi was treated with either the Q-switched ruby laser or the normal-mode ruby laser or both; the other half of the lesion was covered with aluminum foil and was not treated.
SETTING: A university-affiliated, hospital-based laser center.
PATIENTS: Sixteen patients with a total of 31 melanocytic nevi were enrolled in the study.
INTERVENTIONS: All nevi were evaluated by at least 2 dermatologists to assess the degree of clinical atypia. Photographs were taken before and immediately after treatment and at each follow-up visit. The digital imaging system was used to evaluate the number of melanocytes in a measured length of basement membrane zone.
MAIN OUTCOME MEASURE: Three individual readings (number of melanocytes per unit length) were taken on both the control and treated halves and then compared to quantitate treatment effect. All analyses used averages from 3 measurements. A Student paired t test was used to compare the treated and untreated sides.
RESULTS: Sixteen (52%) of the nevi showed a clinically visible decrease in pigment on the treatment side at the 4-week follow-up visit. CONCLUSION: No lesions had complete histologic removal of all nevomelanocytes. Therefore, 1 or 2 laser treatments are not sufficient to cause complete removal of a lesion either clinically or histologically.
JAMA 2000;283:2955-2960.
J Am Acad Dermatol 1992;26:920-926.
