Management of nevi 4 x 4 x 6 rule

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Main PageBenign Melanocytic lesionsManagement of nevi 4 x 4 x 6 rule
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Author(s) Michael Kunz · Teresa Deinlein · Giuseppe Argenziano · Aimilios Lallas · Iris Zalaudek
Responsible author Iris Zalaudek→ send e-mail
Status unknown
Status update June 4, 2017
Status by Ralph P. Braun

The dermoscopic diagnosis of pigmented melanocytic nevi relies on the assessment of 4 main criteria: (1) color, (2) overall pattern, (3) pigment distribution, and (4) patterns related to special sites [1]. Each of the 4 criteria has 4 variables, thus the term 4x4 is a good memory prompt for the criteria and their variables.


With some exceptions, pigmented nevi generally exhibit only 1 or 2 of the following 4 colors:

  • black
  • brown
  • gray
  • blue

Colors allow estimation of the location of pigmented cells in the skin. Colors are due to the presence of pigmented melanocytes or pigment-laden melanophages at different levels of the skin.
Black and brown are due to pigmentation within the epidermis and are the most common colors seen in nevi with a prevailing epidermal component.

Gray and blue represent pigmentations found in the upper and middle dermis, respectively, and are often seen in nevi with dermal involvement. Gray and blue may also be due to pigment-laden melanophages in the upper dermis.The combination of gray or blue with white (blue-white structures or granularity) is highly suggestive of regression, in which the white color corresponds histopathologically to fibrosis. Because regression may occur in nevi and melanoma, lesions showing a combination of blue and/or gray and white should always raise the index of suspicion. This is especially the case when a lesion shows a large amount of regression features (ie, 10% of the lesion surface).

The evaluation of color alone is insufficient to rule out melanoma, but the basic principle “the more colors, the more suspect” is useful for identifying atypical melanocytic proliferations.


The presence of uniform and regularly distributed globular, reticular, starburst, and homogeneous blue patterns identify a given lesion as a melanocytic nevus (ie, per defi- nition absence of melanoma-specific patterns). Each pattern corresponds to a specific underlying histopathologic correlate.

Based on the most common dermoscopic patterns associated with melanocytic nevi, a new nevus classification has been proposed that includes 4 main categories:

  • globular
  • reticular
  • starburst
  • homogeneous blue nevi

In this classification system, small congenital nevi, compound nevi, and dermal nevi are lumped together in the globular category based on their common dermoscopic-histopathologic features (globules correspond to predominantly dermal nests of melanocytes). With the exception of congenital nevi of the lower extremities, reticular nevi correspond typically to junctional or lentiginous nevi. The starburst nevus category includes both pigmented Spitz nevi and Reed nevi based on their striking dermoscopic features (ie, regular peripheral streaks). Finally, the fourth category includes blue nevi typified dermoscopically by homogeneous structureless blue pigmentation without additional dermoscopic features.


Pigment distribution in nevi may be:

  • uniformly distributed
  • multifocal (patchy distribution of small islands of hyperpigmentation and hypopigmentation)
  • central (central area of hyperpigmentation or hypopigmentation),
  • eccentric (eccentric foci of hyperpigmentation or hypopigmentation).


Nevi located on the face, palms and/or soles, nails, and mucosal areas (mostly genitalia) exhibit peculiar clinical, dermoscopic, and histopathologic features that are related to the specific anatomic structure of the skin in these locations. Therefore, these nevi are referred to as nevi of special body sites and show a pseudonetwork pattern (face), parallel furrow pattern (acral areas), regular band- like pattern (nails), and a globular mixed pattern (mucosa), illustrates the dermoscopic patterns of nevi on special body sites.

Among nevi located on special body sites, acral nevi are those best described in terms of dermoscopic patterns. They typically reveal pigmented parallel lines located within the furrows of skin markings (parallel furrow pattern), whereas melanoma shows pigmentation on the ridges (parallel ridge pattern). The differentiation between parallel furrow and parallel ridge pattern may be at times difficult (particularly in the center of the lesion); for these cases, the furrow ink test represents a practical aid for correct diagnosis. Although the dermoscopic pattern of subungual, facial, and genital nevi have been described in various case series, they are much less well defined, and their assessment and interpretation often requires a high level of expertise.

MULTIPLE NEVI Most patients with multiple nevi exhibit various degrees of clinical and dermoscopic atypia in a number of their lesions. In these cases a comparative approach would be much more useful. As demonstrated by Gachon et al and Scope et al, the immediate diagnostic opinion of dermatologist is mainly based on an unconscious reference to the overall pattern compared with the common nevi but also compared with the other nevi on the individual (the ugly duckling sign) rather than on an analytic process applied to an isolated lesion. The key point in the examination of individuals with multiple nevi is therefore the identification of his or her predominant nevus pattern (defined as the pattern seen in more than 30% of all nevi), which then permits the identification of atypical lesions that deviate from this pattern (recommendation 2). Increasing evidence suggests that both the prevalent nevus pattern and patterns of single nevi are influenced by age, skin type, history of melanoma, UV exposure, pregnancy, and growth dynamics.

Context (6 Factors)

Age-Related Nevus Pattern

In prepubertal children, most nevi exhibit a globular or homogeneous pattern, while the most frequent pattern in adults is the reticular (network) pattern. Nevi with a globular pattern are more often located on the head and neck area and upper trunk than are reticular nevi, which can be seen in any areas of the trunk and extremities.

Skin Type–Related Nevus Pattern

Individuals with skin type I exhibit a predominant nevus type characterized by light brown color and central hypopigmentation. In contrast, nevi in patients with skin type IV tend to be dark brown with a central hyperpigmentation (so-called black or hypermelanotic nevi). Nevi of skin types II and III are prone to be light to dark brown with multifocal pigmentation.

Notably, the stereotypical nevus type in persons with skin type IV (also known as hypermelanotic or black nevus) is commonly excised because the clinical black appearance raises the clinician’s concern. Dermoscopically, this nevus shows a dark brown reticular pattern and central hyperpigmentation caused by a central black blotch (“black lamella”) corresponding histopathologically to a pigmented parakeratosis. The black lamella may hide the underlying regular network and cause some diagnostic difficulty, but it can be easily removed by tape stripping, which allows visualization of the underlying network and a more confident diagnosis of a reticular nevus.

Melanoma-Related Nevus Pattern

Patients with melanoma more frequently have nevi with a mixed pattern (reticular-globular pattern or homogeneous-globular pattern) vs the more uniform pattern seen in healthy individuals.

UV-Related Nevus Pattern

Nevi exposed to UV radiation reveal reversible changes of dermoscopic features including darkening of pigmentation, fading of pigment network, increase in size, erythema, and new development of irregular dots, globules, or blotches. Regarding surveillance, it is generally recommended to avoid skin cancer screening in patients with tanned skin because the UV irradiation that tanned the skin may also have caused atypical changes in the dermoscopic pattern of nevi that could lead to false-positive results using various dermoscopic algorithms. Because these changes generally reverse themselves 1 to 3 months after discontinuation of UV exposure, reexamination should be scheduled for that time.

Pregnancy-Related Nevus Pattern

During pregnancy, nevi reveal reversible changes including lightening or darkening, progressive reduction of thickness and prominence of reticular pattern, new appearance of dots or globules, increased vascularization, and increase in size (regardless of the location but most prominently on the abdomen). Pregnancy also induces nevus changes that may cause diagnostic difficulties. It has been shown that these changes linearly increase with the length of pregnancy and are most evident during the third trimester and at the time of delivery. These changes also reverse themselves approximately 3 to 6 months after delivery, and so reexamination of nevi at that time is usually recommended. Since any change during a 3-month interval must be considered suspect, the physiologic changes of nevi should be taken into account when performing shortterm digital follow-up.

Growth Dynamics

Globular nevi

Evolving nevi, which are typically seen in pubescent adolescents and continue developing through the second decade of life, are dermoscopically characterized by a peripheral rim of small brown globules. During digital dermoscopic follow-up, these nevi show symmetric enlargement, disappearance of peripheral globules, and consequent stabilization of lesion size. The dual concept of nevogenesis suggests that nevi showing variations of the globular pattern belong to a spectrum of melanocytic proliferations with dermal origin that develop in early childhood along endogenous pathways. Globular nevi seem to grow vertically rather than horizontally and are clinically characterized by progressive elevation of the nevus until stabilization is reached. Once stable, the nevi will persist, and after years to decades will acquire the stereotypical appearance of a dermal nevus. In contrast to globular nevi, we consider reticular nevi to be primarily epidermal proliferations that reveal a dynamic life cycle, increasing steadily in number from pu- berty until the fourth decade of life and decreasing in number later in life. In support of this theory is the high number of nevi with a peripheral rim of brown globules found on patients younger than 20 years. These peripheral globules seem to be particularly evident in evolving reticular or complex-pattern (reticular-globular) nevi, until the final disappearance of peripheral globules indicates stabilization of growth. This nevus life cycle may explain why the most common pattern of nevi in adults is the reticular or reticular-globular pattern. The decline in number of acquired nevi after the fifth decade of life can be explained by a progressive involution, regression, or apoptosis of these nevi. Thus an evolving nevus showing a peripheral rim of globules should be considered a highly unusual finding in individuals older than 60 years and should always raise suspicion.

Spitz and Reed nevi

Spitz and Reed nevi reveal different patterns, depending on the growth phase of the lesion. After an initial globular pattern, Spitz and Reed nevi tend to show the classic starburst pattern. The final phase is represented by the homogeneous pattern, although some Spitz and Reed nevi may even completely disappear. Spitz and Reed nevi can be easily differentiated from globular nevi because their globules are usually irregular in size and color. Epidemiologic data indicate a high frequency of Spitz nevi in childhood that continues until the third decade of life but their number declines later in life. It must be emphasized that some melanomas may have a starburst pattern. Since no single criterion allows differentiating such spitzoid-appearing melanomas from Spitz or Reed nevi with sufficient accuracy, excision of all spitzoid lesions, particularly in adults, is always recommended.

Blue nevi

Conversely, homogeneous blue nevi seem to be highly stable lesions that persist throughout a lifetime. This stability of blue nevi is an important, although subjective, clue for the diagnosis because blue color alone is a highly unspecific feature that may occur also in nodular melanoma, melanoma metastases, or pigmented basal cell carcinoma.Therefore, the diagnosis of blue nevi should always be based on the combination of the dermoscopic pattern and a convincing subjective history of no changes, while the combination of blue color with a history of changes should always lead to further evaluation for melanoma or basal cell carcinoma. When a reliable history is difficult to obtain, excision, not monitoring, must be performed.

  1. Zalaudek et al.: Using dermoscopic criteria and patient-related factors for the management of pigmented melanocytic nevi. Arch Dermatol 2009;145:816-26. PMID: 19620566. DOI.
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