Pigmentary nevi on face have unique patterns and implications: The concept of Blaschko's lines for pigmentary nevi.

BACKGROUND: Nevi are proposed to reflect the mosaicism and thus generally follow the different archetypal patterns of mosaicism. Blaschko's lines are the most common pattern of mosaicism. There have been many attempts to elucidate the Blaschko's lines on face from the distributional patterns of different nevi, but studies that evaluated exclusively pigmentary nevi are sparse. AIMS: This study attempted to evaluate the patterns followed by different pigmentary nevi on face and utilized this to elucidate the pattern of embryological pigmentation on face.
MATERIALS AND METHODS: Spatial parameters like shape, orientation, and distribution patterns of different flat pigmentary nevi on face were analyzed and graphically drawn on human facial diagram. This was compared with existing facial Blaschko's lines. All cases of palpable pigmented nevi like congenital and giant melanocytic nevi and nevus spilus were excluded.
RESULTS: A total of 68 cases of pigmentary nevi on face (male-39, female-29) were examined. The shape and distribution lines were found to have a close similarity with Blaschko's lines on face with distinct differences.
CONCLUSIONS: The concept of facial embryonic pigmentary 'segment', 'unit' and existence of separate Blaschko's lines for facial pigmentary nevi is conceived. Some insight into the pathogenesis of Blaschko's lines is also proposed in this study.

Introduction

Nevi are disorders that can be difficult to define. They can be congenital or acquired and may reflect structural or functional abnormality. Happle proposed a workable definition of nevi and proposed that all nevi reflect mosaicism.[1] Thus, expectedly, all nevi follow some specific patterns and have some defined shapes owing to the mosaicism. The patterns of mosaicism have been described by Happle et al.[2] The fact that nevi follow some regular pattern was first noticed by Sir Alfred Blaschko. He drew some imaginary lines after evaluating 170 patients with different types of nevi including some pigmentary nevi and presented his observations at the 7th German Dermatological Society Meeting in 1901.[3] These lines were named after him and at present famously known as ‘Blaschko's lines’. Now it is known that Blaschko's lines represent the commonest phenotypic pattern of mosaicism.

Blaschko's original impression on the distribution of the lines on face was repeatedly modified and enriched later by Happle et al.,[4] and Bolognia et al.,[5] Lines on lips, palate, and tongue were hypothetically drawn by Brown et al.[6] Lines similar to ‘Blaschko's lines’ have also been described in eyes and teeth.[78] Modified Blaschko's lines proposed by Happle and Assim[9] is currently the most widely accepted one for head and neck area.

Pigmentary nevi represent nevi with altered pigmentation. They can be macular or with some elevated component that may develop or progress later. For various reasons, the pigmentary nevi are distinct from other nevi. They are overall more common than any other nevi. The patterns followed by many pigmentary nevi like incontinentia pigmenti of the Bloch-Sulzberger type or the McCune - Albright syndrome are surprisingly constant and uniform.[2] Some nevi like the congenital and giant melanocytic nevi do not follow Blaschko's lines.[10] Most non-pigmentary nevi are elevated and have definite surface changes, features that assist in straightforward understanding of the shapes and patterns they follow. In contrast, less distinct color variation without any surface alteration in macular pigmentary nevi makes the assessment of spatial parameters (shape, orientation, and distribution) difficult.

So far there has been hardly any attempt to analyze these spatial parameters (shape, orientation, and distribution) exclusively of facial pigmentary nevi. The present study attempted to analyze the patterns followed by the macular (flat) pigmentary nevi on face.

Materials and Methods

Patients of both sexes and all ages presenting with different types of flat (macular) hypo or hyperpigmented nevi on any parts of face were assessed.

Outlines of the patches, either from the photographs and or directly from the patients were depicted graphically on a pre-drawn lateral and frontal view of human facial diagrams. Patterns of lines as found following examination of nevi were drawn and it denoted the common patterns of shape, orientation, and distribution of pigmentary nevi in different parts of the face and mentioned as ‘patterned lines for pigmentary nevi’. They were matched with the Blaschko's lines on face to find the similarity and dissimilarity between them. Nevi other than pigmentary nevi were not analyzed.

The purpose of the study was to analyze the distribution patterns of pigmentary nevi on face. Thus, all the nevi were diagnosed clinically. Neither routine histological characterization of the nevi nor any special staining procedure was carried out.

Results

Total patients assessed were 68. Age ranged from 13 months to 29 years. Males were slightly higher than females (M-39, F-29). Types of nevi assessed were shown in the Table 1. Most of the nevi started within few months after birth. However, onset after infancy or even later during first few years of life was also found.

Table 1

Types of nevi assessed

Size of the nevi ranged from very small patches [Figure 1a] to larger ones, thin lines to broad bands, single patch to multiple bands with intervening normal skin and regular to bizarre shaped nevi.

Figure 1a

Periorbital nevi extending laterally: The figure shows three small hypo and hyperpigmentary nevi at the outer margin of the eye with classical patterns of distribution

Nevi were found to have some preferential location and distributional pattern on face. These were periorbital, central (cheek), perioral, and periaural segments.

Although there were some distributional intimacy between the nevi and important facial structural landmarks like orbital and oral opening or ear, they did not exactly conform to any of the known anatomical structures, segments or dermatomes.

Most common location was found to be the periorbital areas. Nevi starting around periorbital area extended laterally over the temporal area, zygomatic area, or downwards on the cheek in a curved fashion. Nevi starting below the periorbital area extended from the nose (commonly the root of nose) extended downwards on the cheek usually without involving the eyelids. Nevi on forehead were not found in this study [Figure 1b,c].

Figure 1b

Periorbital nevi extending downwards and laterally: The figure shows larger hypo and hyperpigmentary nevi that started almost at midline, progressed laterally around eye and extended over zygoma in a downward and lateral curved direction

Figure 1c

Nevi on central or cheek area: The figure shows hypo and hyperpigmentary nevi mostly involving cheek (i-v) or around ear (vi). First two were nevus of Ota (i, ii). They (i-v) started medially close to root of nose, progressed over cheek, some also involved eye lid (i, iv, v-not seen in picture). Some (iii, v) were composed of multiple patches with intervening normal band of skin

Further downward, many nevi started around oral opening like on upper lip, angle of mouth or lower lip and progressed laterally and downward in a similar curved fashion. They were generally limited by the nasolabial furrow above [Figure 1e].

Figure 1e

Perioral nevi: The figure shows hypo and hyperpigmentary nevi in perioral regions. All had a downward and lateral curved direction

Nevi in periorbital, central, and perioral segments started medially at midline and then extended laterally and downward in a curved fashion with a upward convexity [Figure 1a, b].

Nevi encircling the ear (periaural area) were relatively rarer than other types. The anterior ramus of the nevi was distributed over mandible as a band and sometimes reached up to angle of mouth. [Figure 1c].

Nevi hardly ever crossed the hypothetical boundary of the individual embryonic pigmentary segment (defined in discussion). However distribution of over multiple segments was seen. They appeared bizarre and mentioned here as ‘conjoint nevi’[Figure 1d].

Figure 1d

The figure shows ‘conjoint nevi’ distributed over more than one ‘embryonic pigmentary segments’

The shape and orientation of the nevi was fairly constant, but size varied considerably. The outlines of the nevi have been graphically presented in Figure 2. These lines were compared with existing facial Blaschko's lines [Figure 3]. They had a strikingly similar distributional pattern with some noticeable differences.

Figure 2

The figure shows embryonic pigmentary segments and the outlines of the nevi in each segment. (i-periorbital and perioral segments, ii-central (cheek) segment, iii-periaural and mendibular segment)

Figure 3

Comparison of existing facial Blaschko's lines (i, ii) with proposed facial Blaschko's lines for pigmentary nevi (iii, iv)

Discussion

‘Mosaicism’ is defined as presence of a clone of aberrant cells admixed with normal cells when both develop from a same cell lineage. This results from some genetic aberration in one or few primitive cells due to post-zygotic mutation or rarely due to gametic half chromatid mutation; the last being occurring even before fertilization.[11] Mosaicism is thus clearly different from chimera that by definition develops from genetically different zygotes. Presence of mosaicism has been confirmed in segmental hyper[12] and hypomelanotic lesions,[13] segmental acne,[14] epidermolytic nevus,[15] and segmental Darier disease[16]. However, this is yet to be confirmed in other nevi. The theory of mosaicism was proven in monogenic keratin disorders.[15] Later, multiple cell lines of entire skin were found to follow the same.[17] Segmental lentiginosis and nevus of Ota were shown in this study to follow the Blaschko's line.

Mosaicism results in genetic heterogeneity with distinctive phenotypic expression and distributional patterns. Nevus is one such expression. The known distributional patterns are Blaschko's line (thin or type 1a, thick or 1b), checkerboard pattern, phylloid pattern, and patchy pattern without midline separation.[2] A concept of lethal mutation surviving by mosaicism was proposed[18] as a mechanism for type 1b and later confirmed by others.[19] Two more patterns and three new shapes of nevi has been proposed later by Torrelo et al., who evaluated a large number of nevi of different types.[20] This study depicted the morphological and distributional patterns of pigmentary nevi on face. This ‘patterned lines of the pigmentary nevi’ was found to be actually representing the facial Blaschko's lines. However, some minor but noticeable distributional differences were also detected. While including the cases of different pigmentary nevi as mentioned in Table 1, it was found that unlike hypo or depigmented nevi, there remained a dearth of well accepted terminologies for many pigmented nevi.

In a normal individual (without pigmentary nevi), the shape, distribution and orientation of an area (an ‘embryological pigmentary unit’) that develops from a particular primitive melanocytic precursor cannot be delineated. Genetic aberration in the primitive melanocytic precursor cell is transferred to the clones of melanocytic cells that develop from the altered primitive cell is manifested in the form of pigmentary nevi (hypo and hyperpigmented). Thus, a pigmentary nevus provides us the only opportunity to delineate the shape and pattern of an ‘embryonic pigmentary units’ in post natal life. This is why, the shapes and distributional patterns of a nevi is fairly constant for any particular location. However, size is variable. Earlier the aberration, higher is the number of affected clones and larger is the size of the nevi. Later the aberration, smaller is the nevi. Possible existence of ‘embryonic pigmentary segment’ also hypothesized here. A ‘segment’ was hypothesized to be formed by a group of closely apposed ‘embryonic pigmentary units’ those had remarkable similarity in orientation, shape and distribution pattern. Shape and orientation of the ‘units’ were different in different ‘segments’. This was as evident in the phenotypic expression of the nevi. This clearly indicated that marked difference exists in the embryological origin and growth pattern of the melanocytes in different ‘segments’ from very early period.

The nevi were generally restricted within a segment [Figure 2]. The ‘conjoint nevi’ simultaneously involving multiple segments was rarely found and it most possibly developed due to more primitive aberration or simultaneous occurrence of multiple genetic aberrations in different primitive cells of different segments.

Although the melanocytes are migrant cells in epidermis, such migration process is complete very early before organogenesis. So, different pigmentary segments that develop due to further melanocytic differentiation locally had some spatial relations with important anatomical landmarks like periorbital area, perioral and peiaural areas, infraorbital curve, and nasolabial furrow. Preferential concentric location around facial orifices like periorbital, perioral and periaural locations was thus conspicuous.

The patterned lines of the pigmentary nevi had striking similarity to the facial Blaschko's lines. Based on that, it was hypothesized that facial pigmentary nevi followed facial Blaschko's lines. The present study provided an improvized facial ‘Blaschko's lines with more intricate details. However, accepting the slight but noticeable differences it had with the Blaschko's lines, it was also hypothesized that the facial ‘Blaschko's lines for pigmentary nevi’ are somewhat different from the existing ‘Blaschko's lines that represented nevi line for all forms of nevi’. Distant origin, different replication rate, and the different initial developmental course of melanocytic precursors from the precursors of other cutaneous cellular components can be proposed as logical explanation for the slight variation in the final phenotypic expression of the concerned cell lines. It should be remembered in this context that no nevi other than pigmentary nevi were analysed in this study. The whole concept of separate lines for pigmentary nevi was made on the basis of observed differences in distribution pattern of the pigmentary nevi with the existing Blaschko's line that represented nevi line for all forms of nevi.

As mentioned at the beginning, the ‘patterned lines for pigmentary nevi’ assessed were basically the outlines of the pigmentary nevi. This was in clear distinction to the situation in other types of elevated nevi like epidermal nevi where the distribution of the nevi represented the Blaschko's line.

Thus it can be said that the ‘Blaschko's lines for pigmentary nevi’ possibly indicate the outer margin of an embryonic pigmentary ‘unit’ where the shapes and patterns of the lines depend on the final shape of the nevi that developed from the aberrant clone of cells. Innumerable lines are possible in a ‘concentric’ fashion, to encircle the nevi that can have wide range of sizes depending on the timing of mutation maintaining the specific shape, pattern and orientation. This seems to explain the observed findings in a better way than the existing hypothesis that says the Blaschko's lines indicate the ‘pathways for dorso-ventral migration’ of the embryonic cells[21] like the cells of neuroectodermal origin e.g. melanocytes[22] .

This study represents the first of its kind on the analysis of distribution, shape, and orientation of facial pigmentary nevi. The observed results yielded many hypothetical conclusions that may be validated in future studies.