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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.
OUTLINE
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.
ECZEMA Is high mole count a marker of more than melanoma risk? Eczema diagnosis is associated with melanocytic nevi in children.
Dellavalle RP, Hester EJ, Stegner DL, Deas AM, Pacheco TR, Mokrohisky S, Morelli JG, Crane LA.
Veterans Affairs Medical Center, Department of Dermatology, University of Colorado, Denver, CO 80262, USA.
Arch Dermatol. 2004 May;140(5):577-80. Abstract quote
BACKGROUND: The number of melanocytic nevi is the best single marker of increased melanoma risk. In a previous study, adults with severe eczema were reported to have significantly fewer nevi than adults without eczema.
OBSERVATIONS: In a nested case-control design within a randomized, controlled interventional trial of additional sun protection vs standard care in 269 children, a history of eczema was reported by the parents of 44 (16%) of the children. More nevi were found in children with a parental report of previous eczema diagnosis than in children without reported eczema (median, 7.5 nevi vs 5.0 nevi; P =.01). Eczema diagnosis was most significantly associated with more melanocytic nevi in children with lightly pigmented skin (8.5 nevi vs 6.0 nevi; P <.001). In multivariate logistical regression analysis, including assessment of hair color, sun protection practices, and study assignment (intervention vs standard care), eczema status remained significantly predictive of nevi number in children (P <.001).
CONCLUSIONS: In contrast to a previous study that associated severe eczema with fewer nevi in adults, in the present study children with a reported history of eczema had more nevi than children without a reported history of eczema.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.
MYCOSIS FUNGOIDES NEUROFIBROMATOSIS
- Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas. A study of 226 cases*.
Ball NJ, Kho GT.
Departments of Pathology and Medicine (Dermatology), The University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada.
J Cutan Pathol. 2005 Sep;32(8):523-32. Abstract quote
Background: Neurofibromatosis, type 1, is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described.
Methods: This retrospective case-control study was designed to see if neurofibromas in patients with neurofibromatosis, type 1 (NF-1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF-1 were compared with 112 SN and 300 intradermal melanocytic nevi (IDN).
Results: Small lentiginous melanocytic nevi were identified over 13 NF-1 (11%) but no SN (P = 0.0002). Compared with other NF-1, NF-1 with nevi were more frequently associated with melanocytic hyperplasia, giant melanosomes and diffuse neurofibroma (P < 0.03). Compared with SN, NF-1 were also more frequently associated with melanocytic hyperplasia, lentigo simplex-like changes, diffuse neurofibroma and plexiform neurofibroma (P < 0.001). Sebaceous hyperplasia (14%), dermal elastosis (9%), lipomatous change (8%), epithelial cysts (4%) and keratin granulomas or folliculitis (3%) were not significantly different in prevalence between NF-1, SN and the control group of IDN.
Conclusions: This study suggests that there is a difference in the potential for melanocytic proliferation in NF-1 compared with SN. NF-1, SN and IDN are associated with a similar range of incidental histologic changes.PREGNANCY
Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
For many years, clinicians have been concerned about a potential adverse effect of pregnancy-associated hormones and exogenous hormones on melanocytic nevi and malignant melanoma.
Today, these issues are more significant as women have delayed childbearing into their 30's and 40's, and the likelihood of diagnosis with melanoma during pregnancy is enhanced.
More recent clinical, epidemiologic, and laboratory studies have shed some light on the relationship among hormones, nevi, and melanoma in 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 GENERAL
Department of Dermatology, Ludwig-Maximilian University of Munich, Munich, Germany.
Background: Basic fibroblast growth factor (bFGF) and stem cell factor (SCF) are essential growth factors for melanocytes which carry the receptors FGFR-1 for bFGF and c-kit for SCF. Because both factors may be involved in melanoma development, the expression of bFGF/FGFR-1 and SCF/c-kit was investigated in melanocytic tumors of different progression stages.
Methods: Fifty primary melanomas and 44 melanocytic nevi were analyzed for the expression of SCF, c-kit, bFGF, and FGFR-1 by immunohistochemistry.
Results: In melanoma, SCF and c-kit were expressed in 76 and 84%, respectively, and coexpressed in 66%. bFGF and FGFR-1 were expressed in 45 and 86%, respectively, and coexpressed in 46%. In melanocytic nevi, SCF was expressed in 23% and c-kit in 70% while coexpression was more common in dysplastic (39%) than non-dysplastic subtypes (8%). bFGF and FGFR-1 were expressed in 55 and 67%, respectively, while coexpression was found in 47% but varied considerably between different histological subtypes.
Conclusions: SCF and c-kit were frequently expressed by melanomas and dysplastic nevi suggesting an autocrine growth mechanism as described for bFGF. In both nevi and melanoma, c-kit was almost exclusively found in the epidermis while bFGF was more common in the dermis. Thus the growth factor/receptor expression seems to depend on the cutaneous localization of the melanocytic tumors.
- Expression profiles of melanogenesis-related genes and proteins in acquired melanocytic nevus.
Hashimoto Y, Ito Y, Kato T, Motokawa T, Katagiri T, Itoh M.
The First Department of Dermatology, Toho University School of Medicine, Omori-nishi, Tokyo, Japan.
J Cutan Pathol. 2006 Mar;33(3):207-15. Abstract quote
We used three types of AMN to investigate the expression profiles of melanogenesis-related genes [tyrosinase, tyrosinase-related protein-1 (TRP1), dopachrome tautomerase (TRP2), Pmel-17/gp100, P-protein, and microphthalmia-associated transcription factor (MITF)], as well as tyrosinase, TRP1, Pmel-17/gp100, and MITF proteins.
Results: All melanogenesis-related genes examined in the junctional type were expressed in the basal epidermal layer. In the compound and intradermal types, mRNA for tyrosinase, TRP2, and MITF was expressed in all of the AMN cells. However, the expression of TRP1, P-protein, and Pmel-17/gp100 in the compound type and TRP1 in the intradermal type became weaker in accordance with the depth of the dermis layer, as compared to those levels in the basal to upper dermis layer. Although tyrosinase and Pmel-17/gp100 mRNA in the compound and intradermal types was expressed in the intraepidermal and dermal components, immunohistochemical staining showed that tyrosinase proteins were not detected in the lower dermis layer and Pmel-17/gp100 proteins were not detected in the dermis.
Conclusions: Our results suggest that all nevus cells that constitute AMN tissue originate from melanocytes. Further, there may be differences in the transcription levels of melanogenesis-related genes as well as in their post-transcriptional regulation between nevus cells located in the basal epidermal to upper dermis layer and those in the lower dermis layer.
- Nevogenesis--new thoughts regarding a classical problem.
Krengel S.
Department of Dermatology, University of Lubeck, Germany.
Am J Dermatopathol. 2005 Oct;27(5):456-65. Abstract quote
The development of melanocytic nevi is a multifactorial and heterogeneous biologic process that involves prenatal and postnatal steps. As a consequence, there are two main perspectives to nevi: that of a hamartoma and that of a benign tumor.
In this review, dermatopathological studies on congenital and acquired nevi, including studies on age-related and location-dependent changes, are analyzed. These studies have lead to different hypothetical concepts on the evolution of individual lesions.
In the light of findings from experimental embryology and stem cell biology, we discuss the histogenesis of nevi with special reference to the temporospatial sequence of melanocyte-basement membrane interactions and hair follicle genesis. Regarding the mechanisms of postnatal nevus development, epidemiological studies demonstrate the importance of constitutional and environmental influences, especially ultraviolet light.
Possible molecular pathways of solar nevogenesis involve ultraviolet-induced alterations of the cellular microenvironment (eg, changes in the expression of cytokines and melanocyte adhesion molecules). Recent results and future directions of clinical and experimental research are presented.APOPTOSIS
- Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi.
Florell SR, Bowen AR, Hanks AN, Murphy KJ, Grossman D.
Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
J Cutan Pathol. 2005 Jan;32(1):45-9. Abstract quote
Background: Apoptosis is important for maintenance of tissue homeostasis and often dysregulated in cutaneous neoplasms. The apoptosis inhibitor survivin is expressed in melanoma and non-melanoma skin cancers and benign keratinocytic lesions. Its expression has not been studied in melanocytic nevi.
Objective: We determined the expression pattern of survivin in benign melanocytic nevi in comparison to markers of proliferation and apoptosis.
Methods: Six cases of each of the following melanocytic nevi were retrieved from a dermatopathology archive: compound dysplastic nevus, intradermal nevus, compound nevus, neurotized intradermal nevus, and Spitz nevus. Survivin expression was evaluated by in situ hybridization. Apoptotic and proliferation indices were calculated by counting immunoreactive cells in terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling and proliferating cell nuclear antigen immunostained sections, respectively.
Results: All nevi, regardless of histologic type, expressed survivin. Compound melanocytic lesions expressed survivin in both epidermal and dermal compartments. The apoptotic rate was low for dysplastic, compound, and Spitz nevi, and apoptotic cells were not identified in any neurotized nevus. The proliferative index was highest for Spitz nevi, while all other nevi demonstrated rare positive cells.
Conclusions: Survivin is consistently expressed in benign melanocytic lesions, while apoptotic cells are rarely identified, suggesting the dysregulation of apoptotic pathways with the accumulation of cells in these neoplasms.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 INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 2 Expression of insulin-like growth factor-binding protein 2 in melanocytic lesions
Huamin Wang, Steven S. Shen, Hua Wang, A. Hafeez Diwan, Wei Zhang3, Gregory N. Fuller and Victor G. Prieto
J Cutan Pathol 2003;30:599-605 Abstract quote
Background: Insulin-like growth factor-1 (IGF-1) is one of the most critical proteins required for the survival, migration, and growth of melanoma cells. IGF-binding protein 2 (IGFBP2), which binds and regulates the function of IGF-1, is upregulated in a dose-dependent manner in melanoma cells treated with IGF-1, suggesting a possible role of IGFBP2 in the pathogenesis of melanoma.Methods: Tissue microarrays were constructed using formalin-fixed, paraffin-embedded archival tissue blocks from 94 melanocytic lesions: 20 benign nevi, 20 dysplastic nevi, 23 primary melanomas, and 31 metastatic melanomas. IGFBP2 expression was evaluated immunohistochemically using a polyclonal antibody against the C-terminus of IGFBP2. The number of cells and labeling intensity were assessed semiquantitatively.
Results: Positive IGFBP2 labeling was observed in 5.0% of benign nevi, which was significantly lower than in dysplastic nevi (35.0%), primary melanomas (52.2%), or metastatic melanomas (54.8%) (p < 0.05). Among the IGFBP2-positive cases, moderate-to-strong immunostaining was observed in 64.7% of metastatic melanomas and 33.3% of primary melanomas. But none of the dysplastic nevi had moderate-to-strong immunostaining (p < 0.05).
Conclusions: Our study shows that IGFBP2 expression increases from benign and dysplastic nevi to primary and metastatic melanomas and suggests that it may play a role in melanoma progression.
MATRIX METALLOPROTEINASES
- Implication of MT1-MMP in the maturation steps of benign melanocytic nevi.
Perez LJ, Penas PF, Atienzar M, Garcia-Diez A.
Department of Dermatology, Hospital Universitario de Albacete, Spain.
J Cutan Pathol. 2006 Feb;33(2):139-44. Abstract quote
Background: Metalloproteinases (MMPs) are proteins involved in extracellular matrix breakdown and have been implicated in stages of migration and metastasis. MT1-MMP is an MMP anchored to the cell membrane. During maturation, melanocytic nevi penetrate the extracellular matrix and express MMPs.
Methods: We studied 10 junctional, 10 compound, and 10 intradermal nevi diagnosed by clinical and histological studies and by performing immunohistochemical study to assess MT1-MMP activity.
Results: We found evidence of MT1-MMP expression in melanocytic nevus cells, particularly around the entire border of cell nests. Expression was more intense in junctional nevi and gradually decreased with acquisition of intradermal component and became nonexistent in nevi in the deep dermis.
Conclusions: MT1-MMP is expressed in the membrane of nevus cells, with expression greater in nest cells in contact with the extracellular matrix. The intensity of expression correlated inversely with the maturation phase of the nevus, being very high in junctional nevi and low in intradermal nevi.
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.
PTEN
PTEN expression in normal skin, acquired melanocytic nevi, and cutaneous melanoma.
Tsao H, Mihm MC Jr, Sheehan C.
J Am Acad Dermatol. 2003 Nov;49(5):865-72. Abstract quote
BACKGROUND: Although various studies have shown mutations of the tumor suppressor gene, PTEN/MMAC1, in primary, metastatic, and cultured cutaneous melanoma specimens, little is known about the pattern of PTEN protein expression in early melanocytic tumor progression.
OBJECTIVE: To further investigate the role of PTEN in melanocytic tumor development.
METHODS: We assessed the level and distribution of PTEN in normal skin, 39 acquired melanocytic nevi, and 30 primary cutaneous melanomas, including lentigo malignas, by immunostaining.
RESULTS: We found high levels of PTEN expression in cutaneous muscles, nerves, and muscular arteries, and moderate-to-high amounts of PTEN in the epidermis, follicular epithelium, and sebaceous and eccrine glands. PTEN staining in cutaneous lymphatics, dermal and periadnexal adventitial fibroblasts, and chondrocytes were variably absent. Junctional melanocytes and chondrocytes frequently exhibited preferential nuclear staining. We found uniformly strong PTEN expression in the cytoplasm of almost all benign and dysplastic nevi. However, there was some evidence of nuclear PTEN loss even in the benign melanocytic proliferations. In addition, out of 30 primary cutaneous melanomas and lentigo malignas, we detected diffuse expression of PTEN in 11 (37%) tumors, widespread loss of PTEN in 11 (37%) tumors and mixed PTEN expression in 8 (27%) lesions. In the primary cutaneous melanomas, PTEN was largely localized to the cytoplasm.
CONCLUSIONS: The presence of PTEN in benign melanocytic tumors and the absence of PTEN in a significant proportion of primary cutaneous melanomas support a role for PTEN loss in the pathogenesis of melanoma.
LABORATORY/
RADIOLOGYCHARACTERIZATION DERMOSCOPY
- Morphologic changes of acquired melanocytic nevi with eccentric foci of hyperpigmentation ("Bolognia sign") assessed by dermoscopy.
Pizzichetta MA, Massone C, Grandi G, Pelizzo G, Soyer HP.
Division of Medical Oncology C-Preventive Oncology, National Cancer Institute, Aviano, Italy
Arch Dermatol. 2006 Apr;142(4):479-83. Abstract quote
BACKGROUND: Melanocytic nevi with eccentric foci of hyperpigmentation ("Bolognia sign") can be considered as a melanoma-simulating type of acquired melanocytic nevus. We report on the morphologic changes of this type of melanocytic nevus over a 39-month period of dermoscopic follow-up.
OBSERVATIONS: A 5-year-old girl had a 4-mm brown papule with a peripheral blue-black area on her right upper arm. The eccentric focus of the hyperpigmentation corresponded dermoscopically to a blue-gray area of pigmentation associated with irregular brown-black globules or dots and partially with a superficial black network. After 39 months, a globular type of acquired melanocytic nevus was detectable, which clinically and dermoscopically appeared to be completely benign. A nearly identical situation was observed in 5 other melanocytic nevi, underlining the involution of the pigmented foci in these nevi. The histopathologic diagnoses of 2 lesions were consistent with a compound type of acquired melanocytic nevus with eccentric foci of hyperpigmentation.
CONCLUSIONS: Dermoscopy allows identification of a morphologic pathway of modifications, probably typical for this type of melanocytic nevus in children, and therefore enables avoidance of surgical excision with attendant hypertrophic scarring in children. Conversely, in adults, when dermoscopic follow-up of melanocytic nevi reveals eccentric foci of hyperpigmentation, surgical excision of the lesion is indicated.
- Anatomical and histopathological correlates of the dermoscopic patterns seen in melanocytic nevi on the sole: a retrospective study.
Miyazaki A, Saida T, Koga H, Oguchi S, Suzuki T, Tsuchida T.
Department of Dermatology, Shinshu University School of Medicine, Matsumoto, Japan.
J Am Acad Dermatol. 2005 Aug;53(2):230-6. Abstract quote
BACKGROUND: Anatomical and histopathologic correlates of the unique dermoscopic patterns seen in melanocytic nevi on acral volar skin is yet to be clarified.
OBJECTIVE: Our aim was to investigate the relation between the dermoscopic patterns and anatomical and histopathological characteristics of melanocytic nevi on the sole.
METHODS: The precise locations of 298 melanocytic nevi on the sole from 278 patients were retrospectively investigated, with attention paid to each dermoscopic pattern. In addition, 35 nevi showing each typical dermoscopic pattern were excised and evaluated histopathologically.
RESULTS: Melanocytic nevi showing the parallel furrow pattern or the fibrillar pattern were located on the portions of the sole with regular parallel skin markings and were not found on the arch areas of the foot. Moreover, a subtle but distinctive difference in the distribution was observed between nevi of the two patterns; the nevi with the fibrillar pattern showed a tendency for the sites directly pressed by the body's weight. Melanocytic nevi of the lattice-like pattern were mostly located on the arch areas. Histopathologically, irrespective of the dermoscopic patterns, nests of nevus cells were mainly located in the epidermal rete ridges underlying the surface sulci. In the nevi with a fibrillar pattern, the cornified layer showed a slanting arrangement, which is considered to be a histopathological background of the fibrillar pattern.
CONCLUSION: Dermoscopic patterns seen in acral melanocytic nevi could be explained by the unique anatomical and histopathological characteristics of the acral skin.DNA MICROARRAY
Gene expression profiling of melanocytic lesions.Seykora JT, Jih D, Elenitsas R, Horng WH, Elder DE.
Am J Dermatopathol 2003 Feb;25(1):6-11 Abstract quote DNA microarrays, microscopic grids of DNA, can be used to assess gene expression within a particular cell or cell population. Since DNA from thousands of genes can be hybridized and analyzed in one experiment, researchers can globally characterize genes expressed in normal and various pathologic states.
To accurately assess the differences between normal and pathologic states, one derives cDNA from control and diseased tissue specimens for genes expression profiling. For these reasons, microarray technology may be of particular interest to dermatopathologists and dermatologists interested in understanding cutaneous disease because these physicians have access to tissue specimens. In addition, microarray technology is an efficient way of identifying molecules expressed in a cell population; therefore, it can be used to search for unique immunohistologic markers.
To this end, we have used microarray technology to define differences in the gene expression profile of nevi and melanomas. In this manuscript, we discuss the results of our study, which confirm previously known differences in gene expression between melanoma and nevi. While a few genes appear slightly overexpressed in nevi, a number of genes involved in regulating cell proliferation were upregulated in melanoma, such as cyclin D1, cdc2-related protein kinase, c-Myc binding protein, early growth response protein 1, and pleiotrophin. "Housekeeping" genes such as glyceraldehyde 3-phosphate dehydrogenase were expressed at similar levels in melanoma and nevi.
Surprisingly, a majority of genes were expressed at similar levels in both nevi and melanoma. Based on this study, DNA microarray technology appears to be a valuable tool for identifying genes that may be specifically expressed in cutaneous lesions.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION VARIANTS AGMINATED ACQUIRED NEVI
- Agminated acquired melanocytic nevi of the common and dysplastic type.
Bragg JW, Swindle L, Halpern AC, Marghoob AA.
Department of Medicine, Lenox Hill Hospital, USA.
J Am Acad Dermatol. 2005 Jan;52(1):67-73. Abstract quote
We previously reported a single case of agminated acquired melanocytic nevi, consisting of a localized clustering of banal and atypical moles.
We now report 4 more cases, confirming that the initial case was not an isolated finding. We examined the lesions clinically, with a dermoscope, with a Wood's light, and in 3 cases with UV photography so as to exclude nevus spilus from the differential diagnosis. The presence of an underlying dysplastic nevus syndrome phenotype in 4 of the 5 cases raises the possibility that agminated nevi arise as a consequence of postzygotic loss of heterozygosity and, thus, may represent a type 2 segmental manifestation of the atypical mole syndrome phenotype.
Further studies of similar cases using microdissection techniques for analysis of loss of heterozygosity pattern are warranted.BREAST
Melanocytic nevi of the breast: a histologic case-control study.
Rongioletti F, Urso C, Batolo D, Chimenti S, Fanti PA, Filotico R, Gianotti R, Innocenzi D, Lentini M, Tomasini C, Pippione M, Rebora A.
Dermatopathology Center, Di.S.E.M., University of Genoa, Genoa, Dermatopathology Section, S. M. Annunziata Hospital, Florence, Department of Human Pathology, University of Messina, Messina, Institute of Dermatology, University 'Tor Vergata', Rome, Institute of Dermatology, University of Bologna, Bologna Institute of Dermatology, University of Bari, Bari, Institute of Dermatology, University of Milan, Milan, Institute of Dermatology, University 'La Sapienza', Rome, and Institute of Dermatology, University of Turin, Turin, Italy.
J Cutan Pathol. 2004 Feb;31(2):137-140. Abstract quote
BACKGROUND: Melanocytic nevi in the genital, acral, and flexural sites often display clinical and histologic features that may simulate melanoma. We verified whether this is the case also for nevi of the breast.
METHODS: Eleven dermatopathologists, from nine Italian Institutions, collected the specimens of melanocytic lesions from the breast and other body sites, excluding the acral, genital, and flexural areas, as controls. Cases and controls were matched for sex and age. All nevi were observed 'blindly' and simultaneously by all participants. For each lesion, 10 histological parameters were analyzed: asymmetry, absence of lateral demarcation of melanocytes, lentiginous proliferation, nested and dyshesive pattern, intraepidermal melanocytes above the basal layer, involvement of the hair follicle, absence of maturation of dermal melanocytes, melanocytic atypia, fibroplasia of the papillary dermis, and lymphocytic dermal infiltrate. Each parameter was scored 2 when present and 1 when absent or not valuable. A total score was calculated for each lesion. Results were statistically analyzed by the chi-square test and the Mann-Whitney U-test.
RESULTS: One hundred and one nevi came from the breast area and 97 from elsewhere. Breast nevi exhibited significantly more atypical features than nevi from other sites. In particular, breast nevi with intraepidermal melanocytes, melanocytic atypia, and dermal fibroplasia were significantly more numerous. We did not find any sexual difference.
CONCLUSIONS: To avoid undue concerns, dermatopathologists should be aware that melanocytic nevi of the breast may show a high degree of atypical features.CHEETAH PHENOTYPE
Numerous, small, darkly pigmented melanocytic nevi: The cheetah phenotype.Huynh PM, Glusac EJ, Alvarez-Franco M, Berwick M, Bolognia JL.
Departments of Dermatology and Pathology, Yale University School of Medicine; and Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center.
J Am Acad Dermatol 2003 May;48(5):707-13 Abstract quote BACKGROUND: The presence of multiple atypical nevi or numerous melanocytic nevi increases the risk for the development of cutaneous melanoma.
OBJECTIVE: We sought to describe a distinct clinical phenotype characterized by numerous (>100), small (</=4 mm), darkly pigmented melanocytic nevi that are uniform in color.
METHODS: Biopsy specimens from 6 patients (3 men and 3 women; age range, 44 to 81 years) with this clinical phenotype were reviewed and compared with a database of melanocytic lesions analyzed by the Yale Dermatopathology Laboratory (YDL) in the year 2000.
RESULTS: Of the 6 patients, 4 had multiple primary melanomas develop (n = 2-4), ranging from in situ to 1.0 mm in depth. The other 2 patients each had 1 nevus with severe cytologic atypia. When compared with the YDL database, our patients were more likely to have the following pigmented lesions: junctional melanocytic nevi, junctional lentiginous nevi, junctional nevi with cytologic atypia, and simple lentigines (P <.001).
CONCLUSIONS: The longitudinal evaluation of patients with this phenotype can be challenging because similar-appearing pigmented lesions (small and uniformly dark-brown to black) had a range of histologic diagnoses from simple lentigo to junctional lentiginous nevus to thin melanoma.
CONJUNCTIVAL
*Department of Ophthalmology, Massachusetts Eye and Ear Infirmary †Harvard Medical School ‡Department of Pathology, Massachusetts General Hospital, Boston, MA.
Conjunctival nevi in children and adolescents often have histologic features that can be difficult to differentiate from malignancy.
We have identified a subset of childhood nevi displaying a confluent growth pattern and a lack of maturation that we have defined as juvenile conjunctival nevi (JCN), with the aim of further describing the clinicopathologic features of these lesions. Lesions identified as conjunctival nevus in a tertiary referral hospital were reviewed and the subset of lesions identified as JCN were further evaluated.
Clinical details including follow-up data were also gathered. Of the 40 conjunctival nevi identified, 33 fit the criteria for JCN. The mean age at time of excision was 10.9 years (range: 4 to 19 y). Thirty-two lesions were of the compound type; one was a junctional nevus. All showed a nested junctional growth pattern. In 17 lesions (61%), the junctional component extended beyond the subepithelial component (shoulder phenomenon). Maturation was absent in 21 of the compound nevi (66%, average age 10.3 y), and incomplete in the remaining 11 lesions (34%, average age 12.1 y). The nuclei of the subepithelial nevus cells were larger than the epithelial nevus cells in 19 nevi (59%) and the same size in 13 (41%). A lymphocytic host response was present in 17 lesions (52%). Mitotic figures were rarely seen. None of the lesions had recurred over an average follow-up period of 34 months.
Recognition of JCN as a distinct morphologic variant of a conjunctival nevus with characteristic histologic features may help to distinguish this benign lesion from melanoma.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.
EAR
- Melanocytic nevi of the auricular region: histologic characteristics and diagnostic difficulties.
Saad AG, Patel S, Mutasim DF.
Department of Dermatology, University of Cincinnati, Cincinnati, OH 45267-0592, USA.
Am J Dermatopathol. 2005 Apr;27(2):111-5. Abstract quote
We examined auricular melanocytic nevi to evaluate their architectural and cytologic features. A retrospective analysis of 21 auricular melanocytic nevi was conducted during 3 years.
The nevi were evaluated for cytologic atypia, architectural disorder, location of epidermal nests, pagetoid spread, growth pattern (symmetry versus asymmetry), demarcation of lateral borders, and host response (lymphocytic infiltrate and/or lamellar fibroplasia). Eleven cases (52.4%) measured at least 6 mm in greatest dimension and 6 cases (28.6%) were asymmetric. Fourteen cases (66.7%) were ill demarcated. Pagetoid spread was present in 12 cases (57.1%). Ten cases (47.6%) showed moderate to severe cytologic atypia. Nucleoli were prominent in 9 cases (42.8%). None of the cases showed mitoses or apoptotic melanocytes. Auricular melanocytic nevi, like those occurring in the acral, flexural, and genital areas, may exhibit some histologic features commonly found in melanomas.
Careful histologic interpretation of these lesions is recommended.
- The characteristic histopathologic features of nevi on and around the ear.
Lazova R, Lester B, Glusac EJ, Handerson T, McNiff J.
Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
J Cutan Pathol. 2005 Jan;32(1):40-4. Abstract quote
Background: Nevi on certain areas of the body such as the acral, genital, and flexural regions may exhibit uncommon but characteristic histopathologic features. The purpose of this study was to characterize the distinctive features of nevi with a junctional component located on and around the ear.
Materials and methods: A total of 101 compound and junctional nevi of the ear received at the Yale Dermatopathology Laboratory during a 10-year period were examined in this study. The most characteristic feature of the majority of these nevi was irregularity of nesting pattern, with nests, which varied in size and shape and which were sometimes located between rete ridges.
Results: Forty-two (42%) of nevi on and around the ear showed poor circumscription, lateral extension of the junctional component beyond the dermal component, and elongation of rete ridges with bridging between them. A subset of these nevi (26 cases) showed uniformly large melanocytes with large vesicular nuclei without prominent nucleoli, and abundant pale, finely granular cytoplasm. These lesions did not show a tendency to recur.
Conclusions: This study supports the existence of a subset of nevi on or near the ear that, like certain nevi located on other special sites, exhibit unusual but characteristic features, which may be misinterpreted as atypical or malignant.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.
NEVUS OF OTA
Two cases of late onset Ota's naevus.Chang SE, Kim KJ, Kim ES, Choi JH, Sung KJ, Moon KC, Koh JK.
Department of Dermatology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea
Clin Exp Dermatol 2002 May;27(3):202-4 Abstract quote Ota's naevus is among the dermal melanocytoses that show a distinct pattern involving skin innervated by the trigeminal nerve. Most cases present at birth or manifest clinically in early childhood. Cases of acquired lesions in adult onset have been reported rarely.
We present two cases of late onset Ota's naevus which were confirmed by skin biopsies. Both patients underwent Q-switched alexandrite laser treatment with a dose of 8.0 J/cm2 given four or five times at 6 weekly intervals and showed some improvement.
Nevus of Ota associated with ipsilateral deafness.
Alvarez-Cuesta CC, Raya-Aguado C, Vazquez-Lopez F, Garcia PB, Perez-Oliva N.
Departments of Dermatology and Otolaryngology, Hospital Central de Asturias.
J Am Acad Dermatol 2002 Nov;47(5 Suppl):S257-9 Abstract quote Nevus of Ota is a benign pigmentary disorder that involves the skin innervated by the first and second branches of the trigeminal nerve. It is a dermal melanocytosis frequent in Oriental persons but uncommon in white persons.
We report a case of nevus of Ota in a white woman emphasizing the wide extension of the pigmentation and its association with ipsilateral sensorineural hypoacusia.
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
- Dermoscopic features of combined melanocytic nevi.
De Giorgi V, Massi D, Salvini C, Trez E, Mannone F, Carli P.
Department of Dermatology, University of Florence, Florence, Italy.
J Cutan Pathol. 2004 Oct;31(9):600-4. Abstract quote
In order to investigate the possible role of dermoscopy in the non-invasive classification of combined nevi, we analyzed dermoscopic features of a series of combined nevi consecutively excised.
Two dermatologists expert in dermoscopy retrospectively evaluated all images based on the presence of dermoscopic findings to analyze which epiluminescence microscopy features were more frequently associated with each type of combined nevus.
Dermoscopy may provide useful information in the non-invasive diagnosis of combined nevi, allowing a conservative management, but this may be limited to combined nevi including a blue nevus component. Conversely, combined nevi including a Spitz nevus component may be difficult to classify even by dermoscopy, thus requiring careful monitoring or surgical excision.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.
DEEP PENETRATING NEVUS
Linear arrangement of multiple deep penetrating nevi: report of first case and review of literature.
Hassan AS, Schulte KW, Ruzicka T, Megahed M.
Department of Dermatology, Cairo University, Cairo, Egypt.
Arch Dermatol. 2003 Dec;139(12):1608-10. Abstract quote
BACKGROUND: Deep penetrating nevus is a recently described variant of melanocytic nevi with clinical and histopathological features that may be confused with malignant melanoma, blue nevus, pigmented Spitz nevus, or congenital melanocytic nevus. We report a case with linear arrangement of multiple deep penetrating nevi. To our knowledge, such presentation has never been reported in the literature.
OBSERVATIONS: We describe a patient with multiple darkly pigmented lesions in the right periauricular area, above and behind the ear. The histopathological features of these lesions were consistent with deep penetrating nevus.
CONCLUSIONS: To our knowledge, this is the first report of linear arrangement of multiple deep penetrating nevi. We consider this case a unique presentation of deep penetrating nevus.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.
GENITAL NEVUS
*Department of Pathology, Brigham and Womenʼs Hospital, and Harvard Medical School †Department of Pathology, Childrenʼs Hospital, and Harvard Medical School ‡Dermatopathology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA §Sedona, AZ ∥Department of Pathology, Western General Hospital and The University of Edinburgh, Edinburgh, UK.
Atypical genital nevi are rare melanocytic lesions that most commonly arise on the vulva of young women. They are currently regarded as nevi of special sites, in that despite histologically worrisome features, their clinical behavior is reportedly benign. However, only few studies with limited follow-up data are available.
To better characterize the clinical presentation and behavior of these lesions and to further delineate their histologic features, we retrieved 56 atypical genital nevi arising in the lower female genital tract from our departmental and consultation files. The 56 lesions arose in 55 female patients with a median age of 26 years (range, 6 to 54 y).
The dominant histologic feature was a lentiginous and nested junctional component composed of prominent round or fusiform nests, which often showed retraction artifact and/or cellular dyscohesion. Cytologic atypia was mild in 11 cases (20%), moderate in 34 (60%), and severe in 11 (20%). Ten cases (18%) showed focal pagetoid spread, with extension to the granular layer and stratum corneum in 1 case. The atypical junctional melanocytic proliferation was associated with a large common dermal nevus component that dominated the lesion in 26 cases (46%). Adnexal spread (46%) and nuclear atypia of melanocytes situated in the superficial dermis (39%) were relatively common, but dermal mitoses (7%) were uncommon and maturation was present in all cases. A broad zone of dense eosinophilic fibrosis within the superficial dermis was a frequent finding (41%).
Clinical follow-up was available in 45 cases (80%) with a median follow-up period of 3.5 years (range, 1 to 16 y). Only 1 lesion recurred, 1.5 years after the initial excision. The original nevus in this patient had only mild cytologic atypia and was present at the margins of excision. The recurrent/persistent nevus was reexcised, and there was no further clinical recurrence in 11.5 additional years of follow-up.
Our data support the hypothesis that atypical genital nevi have a benign clinical course despite their occasionally striking cytologic and architectural atypia. Awareness and recognition of this group of melanocytic lesions is important to avoid over diagnosis as melanoma with subsequent wide excision and possibly sentinel lymph node biopsy.HALO NEVUS
Halo nevus, rather than vitiligo, is a typical dermatologic finding of turner's syndrome: clinical, genetic, and immunogenetic study in 72 patients.
Brazzelli V, Larizza D, Martinetti M, Martinoli S, Calcaterra V, De Silvestri A, Pandolfi R, Borroni G.
Department of Human and Hereditary Pathology, Institute of Dermatology, University of Pavia and IRCCS Policlinico S. Matteo, Italy.
J Am Acad Dermatol. 2004 Sep;51(3):354-8. Abstract quote
Turner's syndrome (TS) is a genetic disorder caused by numeric and/or structural abnormalities of the X chromosome; it is characterized by short stature, gonadal dysgenesis, and frequently by webbed neck, cubitus valgus, and lymphedema at birth. TS has been associated with several cutaneous abnormalities including an increased frequency of pigmented nevi, but few reports consider nevi in detail.
Halo nevus (HN) is clinically defined as a melanocytic nevus surrounded by a halo of depigmentation. Vitiligo, a dermatologic disorder characterized by the presence of depigmented patches on the skin, has been described in the list of cutaneous findings associated with TS. The aim of this study was to determine the prevalence of HN and vitiligo in TS and to evaluate if a correlation between major histocompatibility complex genes, karyotype, autoimmunity, therapies, and the presence of HN exists.
Of the 72 patients with TS examined, 13 had HN, a prevalence of 18.05%, which was significantly higher than in our control group (1%; P=.000001). On the contrary, only 2 patients with TS (2.77%, P=not significant) had vitiligo. By comparing the distribution of HLA class I alleles between patients with TS who did (13 of 72) and did not (59 of 72) have HN, we observed a significantly higher frequency of HLA-Cw6 in patients with TS and HN than in those without HN (26.92% vs 6.78%, respectively; P=.0067; odds ratio=5.06). The study of HLA class II genomic polymorphisms showed that the DRB1(*)0701 and DQB1*02 alleles for patients with TS and HN were overrepresented when compared with those without HN (34.61% vs 11.86%, respectively, P=.0078, odds ratio=3.93; and 34.61% vs 19.49%, respectively, P=.1386, odds ratio=2.19).
In conclusion, this study is the first to demonstrate an increased prevalence of HN for patients with TS. Furthermore, the data suggest that a HN putative susceptibility gene in TS is located close to the HLA-C locus.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.
MITOTIC FIGURES
Frequent mitotic activity in banal melanocytic nevi uncovered by immunohistochemical analysis.
Glatz K, Hartmann C, Antic M, Kutzner H.Institute for Pathology, University Hospital, Basel, Switzerland.
Am J Dermatopathol. 2010 Oct;32(7):643-9.
Abstract
The presence and distribution of mitotic figures is an important discriminatory parameter in the assessment of melanocytic lesions.
We evaluated the number and distribution of mitotic figures in 353 randomly collected melanocytic nevi of various subtypes by hematoxylin and eosin (H&E) staining and immunohistochemically with the 2 mitotic markers Phospho-Histone H3 Ser28 (PHH3) and MPM2. At least 1 mitotic figure was present in 19.5%, 31.3%, and 42.8% of H&E-, PHH3-, and MPM2-stained lesions, respectively. In common compound nevi, the mean number of dermal mitoses amounted to 0.024/mm dermal surface area in the H&E staining (PHH3: 0.061; MPM2: 0.087) and to 0.175/mm in Spitz nevi (PHH3: 0.325; MPM2: 0.45). Nevi exhibiting mitotic figures were significantly more frequent in the youngest age group (0-20 years) than in patients older than 50 years (P < 0.0001). In the upper half of the dermis, mitotic activity was roughly 3 times as frequent as compared with the lower half. Clusters of mitotic figures within the dermis were not observed.
Mitotic activity in obviously benign melanocytic nevi is not rare even in the deep dermal part. More than 2 mitotic figures per lesion can usually be explained either by the nevus subtype, young patient age, traumatization, or inflammation. PHH3 and MPM2 are a valuable diagnostic adjunct in the evaluation of melanocytic tumors allowing more sensitive and faster recognition of mitotic figures and their distribution.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%
ONCOCYTIC CHANGE
Oncocytic metaplasia occurring in a spectrum of melanocytic nevi.Jih DM, Morgan MB, Bass J, Tuthill R, Somach S.
Am J Dermatopathol 2002 Dec;24(6):468-72 Abstract quote Oncocytosis is defined as a metaplastic change characterized by the presence of cells with finely granular eosinophilic cytoplasm caused by the accumulation of mitochondria. Although this histologic feature can be found in normal tissues, it can also be seen pathologically as a degenerative phenomenon, where an accumulation of mitochondria is thought to compensate for an uncoupling of oxidative metabolism secondary to cellular aging. Oncocytic metaplasia can be observed in a variety of cutaneous lesions but, to our knowledge, has not been described in melanocytic nevi.
We retrospectively reviewed 87 melanocytic nevi from 83 patients that showed significant oncocytic change. We obtained patient clinical history through surveys completed by the patients' physicians. Ultrastructural studies were performed on 4 representative nevi to confirm the presence of increased mitochondria. We prospectively reviewed 100 randomly selected nevi looking for oncocytic changes.
We subsequently did not find any correlation with patient demographics or medical histories. Histologic evaluation showed granular eosinophilic cytoplasm in 75% or greater of lesional cells in two thirds of cases. This phenomenon occurred in all types of melanocytic nevi. Ultrastructural studies revealed melanocytes with numerous mitochondria in close apposition to melanosomes. Focal oncocytic change was identified prospectively in 38 of 100 randomly selected melanocytic nevi.
We conclude that oncocytosis in melanocytic nevi is a relatively common and underrecognized phenomenon.
RECURRENT NEVUS Recurrent nevus phenomenon: a clinicopathologic study of 357 cases and histologic comparison with melanoma with regression
Roy King1,2,3, Brett A Hayzen1, Robert N Page1,2,3, Paul B Googe1,2,3, Deborah Zeagler4 and Martin C Mihm Jr5
- 1Knoxville Dermatopathology Laboratory, Department of Pathology, University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA
- 2University of Tennessee, Graduate School of Medicine, Knoxville, TN, USA
- 3Vanderbilt Medical School, Nashville, TN, USA
- 4Florida Hospital Waterman, Tavares, FL, USA
- 5Massachusetts General Hospital, Boston, MA, USA
Correspondence: Dr R King, Department of Pathology, University of Tennessee, Graduate School of Medicine, Knoxville Dermatopathology Laboratory, 315 Erin Dr, Knoxville, TN 37919, USA.
Modern Pathology (2009) 22, 611–617; doi:10.1038/modpathol.2009.22; Abstract quote
Recurrent nevus phenomenon and regression in melanoma may have overlapping histologic features. The clinical findings and histologic changes in 357 cases of recurrent nevus phenomenon were compared with 34 cases of melanoma with regression. Regression was defined as (1) Early: dense lymphoid infiltrates replacing nests of melanocytes, (2) Intermediate: absence/ loss of tumor with replacement by mix of lymphocytes and melanophages and early fibrosis, and (3) Late: tumor absence with extensive fibrosis and telangiectasia, melanophages and epidermal effacement.
Four broad histologic patterns of recurrent nevus were identified and classified into type 1: junctional melanocytic hyperplasia with effacement of the retiform epidermis and associated dermal scar, type 2: compound melanocytic proliferation with effacement of the retiform epidermis and associated dermal scar, type 3: junctional melanocytic hyperplasia with retention of the retiform epidermis, and type 4: compound melanocytic hyperplasia with retention of the retiform epidermis and scar.
Melanomas with early and intermediate regression were recognizable due to the presence of residual melanoma. Melanomas with late regression had overlapping features of type 1 and 2 recurrent nevi. Type 3 recurrent nevi resembled primary melanoma with scar/fibrosis.
Histologically, the vast majority of recurrent nevi are readily identifiable; however, partial biopsies or cases without prior knowledge of the original biopsy may lead to misdiagnosis. This is especially true in recurrent nevus and regression in malignant melanoma, where these two lesions share overlapping histologic features. Correlation with the clinical findings and prior biopsy will avoid these pitfalls.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).
ROSETTE
Rosette formation within a proliferative nodule of an atypical combined melanocytic nevus in an adult.Hoang MP, Rakheja D, Amirkhan RH.
Am J Dermatopathol 2003 Feb;25(1):35-9 Abstract quote Rosette formation is a feature that has not been described as occurring in melanocytic neoplasms.
We present such a unique case. A 59-year-old man presented with an asymptomatic, soft, hairy 3.0 x 2.0-cm pigmented lesion that had been present for many years in the right external ear, extending from the conchal bowl onto the antitragus area.
Examination of histologic sections showed a proliferation of nonatypical and heavily pigmented melanocytes in the superficial dermis and around deep adnexal structures, characteristic of a congenital nevus. In other areas, pigmented spindled and dendritic cells infiltrated thickened collagen bundles in a pattern of a blue nevus. A nodular proliferation of epithelioid melanocytes was seen within the deep dermis and subcutaneous tissue. The periphery of the nodule merged with the surrounding nevus cells. Neoplastic cells with nuclear atypia, melanin pigment, pseudonuclear inclusions, and balloon cell change were present. In addition, there was rosette formation by the tumor cells, with a central aggregate of coarse cell processes. Neuroid cords were also noted. No prominent mitotic figures, necrosis, or significant inflammatory infiltrate were noted.
The neoplastic cells were positive for S-100 protein, Mart-1, tyrosinase, neuron-specific enolase, and vimentin. HMB-45 and Ki-67 (MIB-1) labeled only rare neoplastic cells within the proliferative nodule. The tumor cells were negative for synaptophysin, protein gene product 9.5, CD57, epithelial membrane antigen, CD31, and CD34. The central cell processes of the rosettes were negative for trichome, type IV collagen, neurofilament protein, glial fibrillary acidic protein, and tyrosine hydroxylase.
We also retrospectively examined 78 congenital nevi of 65 pediatric patients at our institution. Rosette formation was not seen in any of these cases.
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.
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.
TREATMENT RELATED CHANGES
- The effects of gp100 and tyrosinase peptide vaccinations on nevi in melanoma patients.
Cassarino DS, Miller WJ, Auerbach A, Yang A, Sherry R, Duray PH.
Department of Pathology Stanford University Medical Center, Stanford, CA, USA.
J Cutan Pathol. 2006 May;33(5):335-42. Abstract quote
Background: A new approach to prevent disease recurrence in high-risk melanoma patients involves immunization with gp100 and tyrosinase peptides. This is the first study to examine the effects of such treatments on nevi.
Design: We studied biopsies of 'clinically atypical' nevi from 10 patients before and after peptide vaccination. All had a cutaneous melanoma measuring at least 1.5 mm in depth, satellite metastases, or at least one positive lymph node. We performed immunohistochemical stains for CD3, CD4, CD8, MHC-I, MHC-II, CD1a, HMB-45, MART-1, tyrosinase, bcl-2, p53, and Ki-67 (mib-1).
Results: Immunohistochemistry showed no differences in staining due to vaccination in either the immunologic or melanocytic markers. However, there was a significant increase in both p53 and bcl-2 staining, and a trend toward decreased Ki-67 staining, in the nevi post-treatment.
Discussion: The primary goal of peptide vaccinations with gp100 and tyrosinase is to activate melanoma-specific T cells in order to prevent melanoma recurrence. Nevi were studied in order to assess the effects on benign melanocytes. No significant changes in lymphocytes, langerhans cells, expression of MHC antigens, or melanocytic markers were found. The increase in p53 and bcl-2 raises the possibility that vaccination with melanocytic antigens stimulates a response in benign melanocytes.
SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRYCHARACTERIZATION 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.
FATTY ACID SYNTHASE
Mod Pathol. 2005 Aug;18(8):1107-12. Abstract quote
Mammalian fatty acid synthase is a multifunctional enzyme complex involved in de novo synthesis of saturated fatty acids, and inhibitors of fatty acid synthase are being evaluated as potential therapeutic agents. Increased fatty acid synthase expression has been demonstrated in subsets of malignancies, including colon, breast, endometrium, prostate and ovarian carcinomas, and recently malignant melanomas.
We evaluated the immunohistochemical expression of fatty acid synthase in 155 cutaneous melanocytic lesions. They included 30 congenital nevi, 19 compound nevi, 40 Spitz nevi, 48 primary melanomas, and 18 metastatic melanomas. Fatty acid synthase expression was stronger in malignant melanomas in comparison to conventional nevi and Spitz nevi, and was the highest for metastatic melanoma. Of the primary malignant melanomas, mean fatty acid synthase scores were significantly greater for Clark levels IV and V compared to Clark levels I and II (P<0.001). In addition, melanomas with Breslow thickness 0.75-1.50 mm and >1.50 mm showed significantly higher mean fatty acid synthase scores compared with those with Breslow thickness <0.75 mm (P=0.013 and <0.001, respectively).
Of interest, congenital melanocytic nevi also showed strong fatty acid synthase expression, similar to that seen in metastatic melanoma. This may represent persistence of or regression to a fetal phenotype since normal fetal tissues are known to express high levels of fatty acid synthase.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.
WT-1
Perry BN,School of Medicine, Department of Dermatology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
BACKGROUND: Pigmented lesions are common, yet they present diagnostic and therapeutic challenges. They range from nevi, which are clinically stable, to melanomas, which are notorious for distant metastasis and death. Both nevi and melanomas arise from melanocytes, which are neural crest derivatives, and melanocyte precursors migrate from the paraspinal area to their eventual location at the dermoepidermal junction. Atypical nevi have been clinically considered to be precursors of melanoma, and recently, biochemical abnormalities have been found that are present in both nevi and melanomas, including inactivation of the p16INK4a tumor suppressor gene and mutations in B-raf. These mutations suggest not only that nevi and melanomas share a common origin but also that additional events are required for transformation to malignant melanoma.
OBSERVATIONS: We performed a Panomics protein array comparing a radial growth melanoma cell line with a vertical growth melanoma cell line and found that the transcription factor Wilms tumor 1 is highly expressed in the vertical growth cell line compared with the radial growth cell line. Using immunohistochemical analysis, we compared expression of archival nevi and melanomas in a tissue microarray.
CONCLUSION: We found that Wilms tumor 1 is expressed in most melanomas but is nearly absent in nevi. Immunohistochemical analysis for Wilms tumor 1 may be clinically useful in distinguishing nevi from melanoma.
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 AgNOR COUNTS
Argyrophilic staining of nucleolar organizer region count and morphometry in benign and malignant melanocytic lesions.Li LX, Crotty KA, Palmer AA, Kril JJ, Scolyer RA, Thompson JF, McCarthy SW.
Am J Dermatopathol. 2003 Jun;25(3):190-7. Abstract quote Differentiation between malignant melanomas (MMs) and benign nevi based on histologic features can sometimes be difficult.
This study evaluated the diagnostic effectiveness of argyrophilic staining of nucleolar organizer regions (AgNORs) in separating benign nevi from MMs by assessing 27 compound nevi (CN), 20 dysplastic nevi (DN), 10 Spitz nevi (SN), and 24 MMs. Both AgNOR count and morphology variables were measured from the superficial, middle, and deep zones of the lesions using video image analysis. Malignant melanomas had a significantly greater AgNOR number per nucleus, mean AgNOR area per nucleus, and variation in AgNOR area per nucleus compared with all types of benign nevi (p < 0.05). In multivariate discriminant analysis using a combination of four AgNOR counts and morphometric parameters, all CN and DN, 8 of 10 SN, and 23 of 24 MMs could be correctly classified as benign or malignant.
The results suggest that both AgNOR count and morphology help to separate benign and malignant melanocytic lesions and that the combination of both sets of parameters improves their discriminating ability.
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.
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