Unna's and Miescher's nevi: two different types of intradermal nevus: hypothesis concerning their histogenesis

In 1991, we tentatively introduced the classification of Ackerman and Magana-García for acquired melanocytic nevi in our laboratory. We soon realized that every acquired intradermal melanocytic nevus might be easily classified into either Unna's or Miescher's patterns and that this classification had both clinical implications and significant histological differences. The decisive discriminative feature between Unna's and Miescher's nevi is that Unna's nevus is an almost purely adventitial lesion confined to expanded papillary dermis and, many times, to the perifollicular dermis too. In Miescher's nevus melanocytes diffusely infiltrate both adventitial and reticular dermis in a wedge-shaped pattern. With these concepts in mind, every acquired intradermal melanocytic nevus can be easily classified as either Unna's or Miescher's. We studied 751 acquired melanocytic nevi; 458 (61%) of them were intradermal; of these, 234 were Unna's nevi and 224 were Miescher's nevi. Eighty- three per cent of the nevi from the head and neck were intradermal nevi, whereas on the trunk and limbs junction and compound nevi were the most frequent (56%). When intradermal nevi were divided into Unna's and Miescher's patterns, it resulted that 91% of Miescher's nevi located on the face and 94% of intradermal nevi on the face were Miescher's nevi. In contradistinction, 87% of the Unna's nevi located on the neck, trunk, and limbs, and 96% of intradermal nevi from these locations were Unna's nevi. Only on the scalp was there no clear predominance of one type of intradermal nevus. A series of other histological characteristics were significantly predominant (P = 0.000) in either Unna's or Miescher's nevi. Unna's nevi had more: junctional nests above the intradermal component (40% versus 20%), a radial pattern of intradermal nests (38% versus 0%), vascular-like clefts lined by nevus cells (48% versus 4%), and in depth maturation (94% versus 0%). Miescher's nevi had more: pilosebaceous follicles within the nevus (100% versus 51%), subnevis folliculitis (12% versus 1%), large isolated melanocytes along the basal epidermal layer (47% versus 11%), multinucleated nevocytes (89% versus 44%), and adipocytes within the nevus (53% versus 11%). In conclusion, Unna's and Miescher's nevi are 2 subsets of acquired melanocytic nevus with clinical implications and significant histological differences. A histogenetic hypothesis is proposed on the basis of their histological structure.     

Perifollicular hypopigmentation. A cause of variegate pigmentation and irregular border in melanocytic nevi.

BACKGROUND AND DESIGN--Clinical and histologic features of perifollicular hypopigmentation within melanocytic nevi are described. RESULTS--Perifollicular hypopigmentation was observed in congenital and acquired melanocytic nevi. When the area of hypopigmentation was found within the nevus, it was circular. When the hypopigmentation was located at the edge of the nevus, however, it formed a half circle that resulted in a notch in the outline of the lesion. The phenomenon occurred in nevi with terminal hairs as well as nevi with vellus hairs. In biopsy specimens from 15 melanocytic nevi, one or more of the following findings were observed around hair follicles when compared with the remainder of the nevus: decrease in the number of junctional melanocytes as nests and solitary units (n = 12), decrease in pigment within keratinocytes (n = 14), decrease in the number of melanocytes in the papillary dermis (n = 6), and decrease in the number of melanophages (n = 6). CONCLUSIONS--Perifollicular hypopigmentation is a cause of variegate pigmentation and irregular border in melanocytic nevi.     

The relationship between melanocytes and peripheral nerve sheath cells (Part I): melanocytic nevus (excluding so-called "blue nevus") with peripheral nerve sheath differentiation

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).     

Histologic features of melanocytic nevi seen in association with mycosis fungoides

BACKGROUND: Many different tumors have been reported to occur simultaneously as collision lesions. To date, no such events have been reported between mycosis fungoides (MFs) and melanocytic neoplasms. METHODS: Two cases are presented in which patches of MF were superimposed on melanocytic nevi. In addition, 967 biopsies of MF from 411 patients were identified in an 8-year retrospective database search. Patient pathology history summaries were reviewed to identify inflamed nevi, atypical nevi, and melanoma submitted for histologic evaluation from this population. RESULTS: The occurrence of MF in a congenital nevus was associated with a halo phenomenon restricted to the affected region of the nevus in one patient. In the other patient, nests of two morphologies (lymphocytic and melanocytic) in the same biopsy presented a potentially confusing histologic picture. No other cases of MF superimposed on a nevus were identified in 967 biopsies from 411 patients with a histological diagnosis of MF seen over the past 8 years. In this population, 57 biopsies of melanocytic lesions were identified from 28 patients, including three atypical nevi and three melanomas. CONCLUSIONS: The presence of MF superimposed on a nevus is rare and may lead to confounding histologic features or the development of a halo nevus phenomenon.     

Pointillist nevi

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.     

Utilization of polarized microscopy to differentiate deep penetrating nevus from equine type melanomas

Equine type melanoma can mimic deep penetrating nevus (DPN), making histologic diagnosis challenging. We sought to investigate if the pattern of collagen polarization could be helpful in this setting. A total of 52 specimens were reviewed with polarized microscopy to determine whether refractile collagen was present within melanocytic nests vs. surrounding but not within the nests. Seven of eight (87.5%) equine type melanomas demonstrated refractile collagen within melanocytic nests in part or all of the lesion. In contrast, DPN showed no refractile collagen within the melanocytic nests. Instead, 12 (100%) DPNs and 14 of 16 (87.5%) common combined nevi (DPN plus banal nevus) demonstrated refractile collagen only surrounding melanocytic nests. The entrapment of refractile collagen, as seen with polarized microscopy, within melanocytic nests can support a diagnosis of equine type melanoma.     

Lobulated intradermal nevus. Report of three cases

We report the cases of three patients with lobulated intradermal nevi. Biopsy specimens showed similar findings, that is, fatty infiltration within nests of nevus cells, neuroid differentiation of nevus cells, and dermal fibrosis. Our cases probably represent an unusual form of regressing melanocytic nevus.     

Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms.

Neurofibromas are often clinically, as well as histologically, indistinguishable from completely neurotized melanocytic nevi. We tested the hypothesis that immunologic markers would differentiate the perineural fibroblasts and Schwann cells of neurofibromas from the neurotized cells of melanocytic origin. We examined eight partially neurotized acquired melanocytic nevi, three partially neurotized congenital melanocytic nevi, and five neurofibromas, with antibodies directed against S-100 protein, Leu-7(HNK-1), glial fibrillary acid protein (GFAP), and myelin-basic protein (MBP). A histologic diagnosis of neurofibroma was based on identification of a dermal proliferation of spindle-shaped cells with wavy nuclei, in a background of loose reticulated collagen. Neurotized nevi were diagnosed upon recognition of scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions otherwise indistinguishable from neurofibromas. The congenital nevi were all large melanocytic nevi known to be present at birth. S-100 stained the majority of neoplastic cells in all neurofibromas, neurotized acquired nevi, and neurotized congenital nevi. Neurofibromas showed focal staining for Leu-7, GFAP, and MBP. In contrast, neurotized acquired and congenital nevi failed to express these markers. We believe that Leu-7, GFAP, and MBP may be helpful in differentiating neurofibromas from completely neurotized melanocytic nevi. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these neoplasms are histogenically distinct, despite their similar histologic appearance.     

Histological features and outcome of inverted type‐A melanocytic nevi

The presence of enlarged epithelioid/spindled nests located deep in the reticular dermis of a biphasic melanocytic neoplasm can mimic melanoma arising in a pre‐existing nevus, causing over‐interpretation of malignancy. We aimed to define the clinicopathologic significance of epithelioid/spindled nests in melanocytic nevi. Retrospectively using clinical and histologic information, we characterized 121 patients with a single lesion showing epithelioid/spindled melanocytes in the reticular dermis or subcutaneous fat, surrounded by melanophages, sometimes blending in with the adnexa. The majority of nevi occurred in women in the ages of 10 to 39 years, where the most frequent presentation was a changing mole. While 78% of the lesions displayed an anatomic (Clark’s) level of IV‐V, there was no ulceration, significant regression or inflammation. Up to 2 mitoses were found in only 12% of the cases, not correlating with the severity of cytological atypia. No recurrence or metastasis occurred during 45.5 months (mean) of clinical follow up in 26 patients. Notwithstanding the deep dermal extension, these findings suggest a benign histopathology and clinical outcome. Having compared the overlapping histopathology and clinical features between deep penetrating/clonal nevus and combined nevus, we posit that “inverted type‐A nevus” might be considered a variant of the two.     

Proliferation, apoptosis, and survivin expression in a spectrum of melanocytic nevi

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.     

The dysplastic melanocytic nevus: a prevalent lesion that correlates poorly with clinical phenotype

We estimated the prevalence of persons with histologic dysplasia in at least one of two nevi examined by biopsy to be 53% in Utah's caucasians. This apparently high prevalence indicates that such lesions may represent a normal variant of a melanocytic nevus, perhaps those in the process of active proliferation. Regardless of the apparent ubiquity of these lesions, examination of biopsy specimens led to a grading scheme of histologic dysplasia that may reflect chronologic stages in the neoplastic development of melanocytic nevi. Comparison of these histologic findings with the clinical examination yielded the unexpected result that dysplasia and lesion size are independent of each other. Lesions 3 mm in diameter or smaller were as likely to be dysplastic as those much larger. There was, however, a statistically significant relationship between histologic dysplasia of a nevus examined by biopsy and the person's total number of melanocytic lesions. This finding indicates that the pathology grading scheme may be useful. The high prevalence of dysplastic nevi dilutes the clinical significance of a dysplastic nevus as an isolated finding and thereby lessens the importance of pathologic findings in the diagnosis of dysplastic nervus syndrome.     

Trichoadenoma associated with an intradermal melanocytic nevus: a combined malformation

Melanocytic nevi have been associated with epidermal hyperplasia, adnexal hyperplasia with follicular and sebaceous differentiation, cysts, and tumors of epidermal or adnexal origin. We report a combined cutaneous hamartoma in a 29-year-old woman that comprised a trichoadenoma within an intradermal melanocytic nevus. Clinical diagnosis was a malignant transformation of a melanocytic nevus. Histopathologically, multiple keratinous cysts together with solid islands or masses of eosinophilic epithelial cells were closely intermingled with the nevus cells. Occasional nests of basaloid cells were present. Although to our knowledge this association has not been previously reported, it is worth considering that trichoadenoma and desmoplastic trichoepithelioma are the two ends of a spectrum of lesions. This combined hamartoma reported herein is important because growth of these lesions could be clinically misinterpreted as malignant transformation of a preexisting lesion. Histologic study will reveal the correct diagnosis in such cases.     

Clinical diagnosis of dysplastic melanocytic nevi: A clinicopathologic correlation

A prospective, community practice-based, clinicopathologic correlation was undertaken in 165 melanocytic nevi excised from a group of forty-three patients, each patient having previously had at least one clinically suspected and histologically confirmed dysplastic melanocytic nevus. Eighty-two percent of seventy-two lesions with histologic evidence of mild dysplasia had been diagnosed correctly as such clinically. The accuracy of clinical diagnosis of moderate dysplasia was low (20%); however, all cases of severe dysplasia with or without in situ melanoma were diagnosed correctly. In 75% of all cases in which dysplasia of any degree was diagnosed clinically, histologic evidence of dysplasia was found. In order to investigate further the clinical features of these nevi, 175 color enlargements of histologically confirmed dysplastic melanocytic nevi were examined. The following clinical features were found to be most common: ill-defined border (90%), irregularly distributed pigmentation (84%), maximum diameter greater than 5.0 mm (72%), erythema (64%), and accentuated skin markings (63%). Increasing darkness and confluence of pigmentation in these dysplastic melanocytic nevi correlated with increasing severity of dysplasia. We conclude that careful clinical examination of individual melanocytic nevi will separate severe dysplasia with or without in situ melanoma from low-grade (mild or moderate) dysplasia in a high percentage of nevi from patients with the dysplastic nevus syndrome. Clinical examination will yield a diagnosis of dysplasia in approximately 75% of nevi from such patients in whom histologic evidence of dysplasia is present. Clinical examination constitutes a practical and sufficiently reliable method for the assessment of melanocytic nevi in patients with the dysplastic nevus syndrome.     

Intradermal melanocytic nevus with prominent schwannian differentiation.

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.     

Eruptive large melanocytic nevus in a patient with hereditary epidermolysis bullosa simplex

Hereditary epidermolysis bullosa (HEB) is a group of genetically determined mechanobullous disorders characterized by blister formation following minor trauma. Unusual melanocytic lesions may be a rare feature of all major categories of HEB. We report a large melanocytic nevus, clinically simulating malignant melanoma, which developed at a site of healing blisters in an 8-year-old male with recessive generalized epidermolysis bullosa simplex (EBS). Histological findings were consistent with a compound nevus. This is the third reported case of an eruptive melanocytic nevus developing in EBS. Due to their unique features, it has been suggested that these nevi may represent a distinct variant, referred to as epidermolysis bullosa nevi. Despite the atypical picture, no malignant transformation of HEB nevi has been seen. Therefore, after histologic verification, regular long-term follow-up rather than radical surgery is recommended.     

Incidence of congenital melanocytic nevi in newborn babies in Denmark

Three hundred fourteen unselected babies were examined within 96 hours of delivery. Three (1%) of the infants had clinically recognizable pigmented lesions. Two of the lesions (mean, 0.6%; range, 0.1%-2.3%; 95% confidence limits) proved histologically to be compound melanocytic nevi. The histology displayed almost identical patterns, with large nests of melanocytes at the dermoepidermal junction and only few nevus cells in the papillary dermis. A 0.6% incidence rate corresponds to 330 congenital melanocytic nevi in Denmark each year (range, 55-1265; 95% confidence limits). Because histology does not seem to be an accurate diagnostic tool to sort out the malignant potential of the small congenital melanocytic nevi, prospective studies are needed to characterize the premalignant melanocytic nevi, whether congenital or acquired.     

BRAF(V600E)基因突变与儿童先天性色素痣的增殖活性及组织病理学特征的相关性研究

目的:明确先天性色素痣(congenital melanocytic nevi, CMN)中BRAF(V600E)基因突变对其增殖活性和组织病理学的影响。方法:回顾分析2018年12月至2020年12月我院皮肤科诊治的185例CMN患儿，所有患儿均进行基因检测、病理检查和Ki67免疫组化检测。根据基因检测结果是否存在BRAFV600E突变，将入选患儿分为突变组和对照组，然后再根据性别、年龄、皮损大小和皮损部位进行配对后进一步研究。结果:突变组Ki67指数、痣细胞累及深度、痣细胞巢个数、痣细胞巢大小与对照组比较差异均有统计学意义(均P<0.05)。与BRAF V600E阴性的CMN相比，BRAF(V600E)阳性CMN通常在表真皮交界部位形成黑素细胞巢，且巢较大。痣细胞累及深度和痣细胞巢个数与Ki67指数之间成正相关(均P<0.05)。结论:BRAF(V600E)基因突变使CMN的增殖活性明显升高，并对其组织病理学有特殊的影响。     

Histopathological features of flexural melanocytic nevi: a study of 40 cases

Melanocytic nevi in certain locations such as the genital and acral sites may have atypical histologic features simulating melanoma. We studied the microscopic findings of 40 melanocytic nevi of flexural sites (axilla, umbilicus, inguinal creases, pubis, scrotum and perianal area) to verify if flexural nevi show distinctive features similar to melanocytic nevi of the genital skin. The patients were young (mean age 20 years), the lesions were mostly removed for cosmetic reasons and we are not aware of any deaths or complications related to the removed nevi. We found that 22 (55.5%) out of 40 flexural nevi had "a nested and dyshesive pattern" similar to the melanocytic nevi of genital skin. This pattern was characterized by the confluence of enlarged nests with variation in size, shape and position at the dermo-epidermal junction and by the diminished cohesion of melanocytes. Dermatopathologists should pay attention to the "nested and dyshesive pattern" of flexural nevi that may mimick histologic changes of melanoma.     

Implication of MT1-MMP in the maturation steps of benign melanocytic nevi

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.     

Solitary small active junctional nevi in juvenile patients

Solitary small very dark and papular pigmented nevi, less than 4 mm, are seen commonly in the second decade of life and have a distinctive histologic pattern. Microscopically these lesions show abundant intraepidermal melanin, included within the keratin layer, and proliferating single melanocytes or nevus cell nests. Prominent nucleoli in the melanocytic cells, occasional mitoses, and the invariable presence of moderate numbers of dermal melanophages and lymphocytes indicated the activity of the pathologic process. The benignity of the lesions in nine patients is supported by a benign course over a one- to three-year evaluation period after limited excisional biopsy procedures. The clinical and pathologic evidence of activity in these nevi suggests yet another possible precursor of malignant melanoma. The B-K mole syndrome and the dysplastic nevi syndrome differ from these cases both clinically and histologically.