Skin Moles

The blue skin mole is a benign neoplasm, also called blue nevus or Jadassohn-Tièche nevus, appears clinically as a dark-blue or blue-black smooth nevus formed by melanin-heavily pigmented spindle cells in the middle and lower two-thirds of the dermis. Clinically, the blue nevus appears as a slate blue or bluish black, sharply circumscribed, flat or slightly elevated nodule, occurring on any area of the body. It originates from mesodermal cells. The common blue nevus is always benign. Cellular blue nevus is larger, especially on buttocks and can degenerate into malignant melanoma.
Blue skin moles are present in fewer than 1 in 3000 newborns, in about 1 in 1000 during the first 5 years of life, and in 1 to 2 percent of white school children, and 0.5 to 4 percent of healthy white adults. They are said to be uncommon in darkly pigmented persons. The vast majority of blue skin moles are single, small, deep-blue macules or papules about 1 to 2 mm in diameter.
Common blue skin moles are usually acquired, singular, asymptomatic blue, blue-gray, or blue-black papules, usually less than 10 mm in diameter. The blue-gray color of blue skin moles is an optical effect of dermal melanin viewed through the overlying skin. The longer wavelengths of visible light penetrate the deep dermis and are absorbed by black dermal melanin, but the shorter (blue) wavelengths do not penetrate deeply enough to be absorbed by melanin and are thus reflected back to the observer's eye, giving a blue-gray cast to the deeply situated melanin. Common blue skin moles occur anywhere, but about half the reported cases present on the dorsa of hands and feet. The common blue nevus occasionally may have a target-like appearance, with a blue-gray central nodule, a flesh-colored or hypopigmented surrounding area, and a blue-black rim. The target blue nevus occurs mostly on the hands and feet but also on the back and perianal area. Common blue skin moles occasionally may have satellite lesions that may be mistaken for melanoma metastasis.
Cellular blue skin moles are blue-gray or blue-brown nodules or plaques 1 to 3 cm in diameter, occasionally larger. Their surface is usually smooth but may be irregular. About half the cases are located on the buttocks or sacrum. Malignant blue nevus may develop in contiguity with a cellular blue nevus or de novo. Malignant blue nevus presents as an expanding dermal nodule with or without ulceration.
A common blue nevus that is stable for many years in an adult usually requires no therapy. Sudden appearance of a blue nodule, expansion of a preexisting blue nodule, a congenital blue nodule, or a relatively large blue nodule or plaque greater than 10 mm in diameter demands histopathologic examination. Excision should include subcutaneous fat to ensure complete removal of deep dermal melanocytes, which are frequently present in the subcutaneous tissue of cellular blue nevus. Cellular blue nevus should be evaluated for excision because of its malignant potential.

Atypical moles are also called Dysplastic nevi. The atypical mole is a skin mole with irregular border, larger size, and has a collection of distinctive histological features.
Prevalence: 2–8% of whites have atypical moles. They begin developing during puberty and continue to appear throughout life. Atypical moles may be sporadic or have autosomal dominant inheritance (atypical mole syndrome).
Development: Hormones and sun exposure appear to be the major causative factors.
On examination: atypical moles and early malignant melanomas can be identified by the ABCDE rule; the criteria are most pronounced in malignant melanoma.
– Asymmetry.
– Border: irregular.
– Color: multiple colors.
– Diameter: more than 6mm.
– Elevating or Enlarging: a papule mole is usually harmless; a flat mole that grows or develops a nodular component is suspicious.
Atypical moles may have a “fried egg” appearance: broad flat moles (white of egg) with raised central portion (egg yolk). Sporadic atypical moles are commonly found on the palms, soles, breast, umbilicus, genital, and perianal regions.
Histopathology: The histological features of atypical moles are highly controversial. They include: Junctional proliferation of melanocytes extending beyond the dermal component of the mole (shoulder effect) often with fusion of adjacent aggregates (bridging). Melanocytes in aggregates are often spindle-shaped. Fibrosis around the aggregates (lamellar fibrosis). Lymphocytic infiltrates. Atypia of melanocytes: most controversial point; some groups say no atypia; others grade the degree of atypia (mild, moderate, severe).
NB: Many studies have shown that these criteria, greatly simplified here, are not reproducible, even between expert observers, or even by the same observer over a period of time. Almost every flat mole shows some of these features under the microscope.
Similar conditions: Common mole, malignant melanoma.
Treatment: If a patient has only one or a small number of atypical moles, excision is the simplest approach.

Skin moles
The term ‘mole’ refers to a lesion, often present at birth, which has a local excess of one or more normal constituents of the skin. Skin moles (nevi) are localized benign proliferations of melanocytes. Their classiflcation is based on the site of the aggregations of nevus cells.

Causes of skin moles.
The cause is unknown. A genetic factor is likely in many families, working together with excessive sun exposure during childhood.

Classiflcation of skin moles.
Congenital melanocytic skin moles
Acquired melanocytic skin moles
Junctional mole
Compound mole
Intradermal mole
Spitz mole
Blue mole
Atypical melanocytic mole

With the exception of congenital skin moles, most appear in early childhood, often with a sharp increase in numbers during adolescence. Further crops may appear during pregnancy, oestrogen therapy or, rarely, after cytotoxic chemotherapy and immunosuppression, but new lesions come up less often after the age of 20 years. Skin moles in childhood are usually of the junctional’ type, with proliferating melanocytes in clumps at the dermo-epidermal junction. Later, the melanocytes round off and ‘drop’ into the dermis. A ‘compound’ mole has both dermal and junctional components. With maturation the junctional component disappears so that the melanocytes in an intradermal’ mole are all in the dermis.

Presentations of skin moles.
Congenital skin moles.
These are present at birth or appear in the neonatal period and are seldom less than 1 cm in diameter. Their color varies from brown to black or blue-black. With maturity some become protuberant and hairy, with a cerebriform surface. Such lesions
can be disflguring, e.g. a ‘bathing trunk’ mole, and carry an increased risk of malignant transformation.
Junctional skin moles.
These are roughly circular macules. Their color ranges from mid to dark brown and may vary even within a single lesion. Most skin moles of the palms, soles and genitals are of this type.
Compound skin moles.
These are domed pigmented nodules of up to 1 cm in diameter. They may be light or dark brown but their colour is more even than that of junctional skin moles. Most are smooth, but larger ones may be cerebriform, or even hyperkeratotic and papillomatous; many bear hairs.
Intradermal skin moles.
These look like compound skin moles but are less pigmented and often skin-coloured.
Spitz moles (juvenile melanomas).
These are usually found in children. They develop over a month or two as solitary pink or red nodules of up to 1 cm in diameter and are most common on the face and legs. Although benign, they are often excised because of their rapid growth.
Blue moles.
So-called because of their striking slate grey-blue colour, blue skin moles usually appear in childhood and adolescence, on the limbs, buttocks and lower back. They are usually solitary.
Mongolian spots.
Pigment in dermal melanocytes is responsible for these bruise-like greyish areas seen on the lumbosacral area of most Down’s syndrome and many Asian and black babies. They usually fade during childhood.
Atypical mole syndrome (dysplastic nevus syndrome).
Clinically atypical skin moles can occur sporadically or run in families as an autosomal dominant trait, with incomplete penetrance, affecting several generations. Some families with atypical skin moles are melanoma-prone. Genes for susceptibility to melanoma have been mapped to chromosomes 1p36 and 9p13 in a few of these families. The many large irregularly pigmented skin moles are most obvious on the trunk but some may be present on the scalp. Their edges are irregular and they vary greatly in size, many being over 1 cm in diameter. Some are pinkish and an inflamed halo may surround them. Some have a mamillated surface. Patients with multiple atypical melanocytic or dysplastic skin moles with a positive family history of malignant melanoma should be followed up 6-monthly for life.

Differential diagnosis of skin moles.
* Malignant melanomas. This is the most important part of the differential diagnosis. Melanomas are very rare before puberty, single and more variably pigmented and irregularly shaped.
* Seborrhoeic keratoses. These can cause confusion in adults but have a stuck-on appearance and are warty. Tell-tale keratin plugs and horny cysts may be seen with the help of a lens.
* Lentigines. These may be found on any part of the skin and mucous membranes. More profuse than junctional skin moles, they are usually grey-brown rather than black, and develop more often after adolescence.
* Ephelides (freckles). These are tan macules less than 5 mm in diameter. They are confined to sun-exposed areas, being most common in blond or red-haired people.
* Hemangiomas. Benign proliferations of blood vessels, including hemangiomas and pyogenic granulomas, may be confused with a vascular Spitz mole or an amelanotic melanoma.

Histology of skin moles.
Most acquired lesions are orderly nests of benign nevus cells that are seen in the junctional region, in the dermis, or in both. However, some types of skin moles have their own distinguishing features.
In congenital skin moles the nevus cells may extend to the subcutaneous fat, and hyperplasia of other skin components (e.g. hair follicles) may be seen.
A Spitz mole has a histology worryingly similar to that of a melanoma. It shows dermal oedema and dilatated capillaries, and is composed of large epithelioid and spindle-shaped nevus cells, some of which may be in mitosis.
In a blue mole, nevus cells are seen in the mid and deep dermis.
The main features of clinically atypical (‘dysplastic’) skin moles are lengthening and bridging of rete ridges, and the presence of junctional nests showing melanocytic dysplasia (nuclear pleomorphism and hyperchromatism). Fibrosis of the papillary dermis and a lymphocytic inflammatory response are also seen.

Complications of skin moles.
* Inflammation. Pain and swelling are common but are not features of cancerous transformation. They are caused by trauma, bacterial folliculitis or a foreign body reaction to hair after shaving or plucking.
* Depigmented halo. So-called ‘halo moles’ are uncommon but benign. There may be vitiligo elsewhere. The mole in the centre often involutes spontaneously before the halo repigments.
* Malignant change. This is extremely rare except in congenital skin moles, where the risk has been estimated at between 3 and 6% depending on their size, and in the atypical skin moles of melanoma-prone families. It should be considered if the following changes occur in a skin mole:
* itch;
* enlargement;
* increased or decreased pigmentation;
* altered shape;
* altered contour;
* inflammation;
* ulceration; or
* bleeding.
If changing lesions are examined carefully, remembering the ‘ABCDE’ features of malignant melanoma, few malignant melanomas should be missed.

Treatment of skin moles.
Excision is needed when:
1- a mole is unsightly;
2- malignancy is suspected or is a known risk, e.g. in a large congenital mole; or
3- a mole is repeatedly inflamed or traumatized.

The ABCDE of cancerous transformation in a skin mole
Asymmetry
Border irregularity
Colour variability
Diameter greater than 0.5 cm
Elevation irregularity

The atypical mole is a special kind of dysplastic melanocytic nevus, with clinical and microscopic features suggestive of an intermediate form between the common acquired mole and melanoma. Atypical skin moles are important markers for both familial and non familial melanoma. As many as 50% of patients with “sporadic” melanoma have been observed to have atypical skin moles. The incidence of atypical skin moles in the general population has been estimated to be 1.8% to 10% and possibly as high as 19%. The presence of atypical skin moles has been established as an independent risk factor for melanoma, along with several other cutaneous traits, including red or blonde hair, solar lentigines, skin type 1 or 2, and increased numbers of common acquired melanocytic nevi. One study found the adjusted relative risk of melanoma to be 2 for a single atypical mole and 12 for 10 or more atypical skin moles. Another found a relative risk of 1.6 when one to four atypical skin moles were counted and 6.1 for five or more atypical skin moles. The risk ofmelanoma attributable to atypical skin moles may be further exacerbated by the coexistence of other melanoma risk factors, such as skin type 1 or 2. The increased risk for melanoma is particularly true in the setting of the atypical mole syndrome (AMS). AMS encompasses individuals with multiple atypical skin moles arising sporadically or in a setting of a family history of atypical skin moles or melanoma. AMS has been divided into a number of forms. Type A is sporadic atypical mole without melanoma; type B is familial atypical mole without melanoma; type C is sporadic atypical mole with a personal history of melanoma; type D-l is familial atypical mole with one family member with melanoma; and type D-2 is familial atypical mole with two or more family members with melanoma. Meticulous screening of family members may demonstrate that presumptive cases of sporadic AMS are actually familial. All patients with AMS have an increased risk for developing melanoma, although the magnitude of the risk varies among the AMS types. The relative risk of melanoma is least in patients with AMS types A and B, and has been estimated to be 7 with a cumulative lifetime risk of 6%. The relative risk of melanoma in type D-2 patients may be as high as 1000 or greater compared with the general population. Individuals with AMS also appear to be at an increased risk for multiple primary cutaneous melanomas.One study found a 35.5% cumulative 10-year risk of developing a second melanoma in those with AMS and a history of melanoma as compared with a 17% 10-year risk of developing a second melanoma in those with a history of melanoma but without AMS. Patients with AMS may also be at increased risk of conjunctival and intraocular melanoma. The recognition of AMS may allow early detection of melanoma and identification of those at risk and provide the opportunity for the initiation of preventive measures. A great deal of discussion has centered on the validity of the atypical mole as a distinct entity and its potential for progression to melanoma. Much disagreement over its nature stems from a lack of uniform clinical and microscopic criteria to define it. Atypical skin moles generally demonstrate both clinical and microscopic evidence of distorted and disordered architecture.  

Common features:
Typical acquired skin moles vary considerably in their gross features. In general, appearance to the naked eye is orderly; i.e., lesions have a homogeneous surface and coloration pattern, round or oval shape, regular outlines, and relatively sharp border. Typical acquired skin moles may be papillomatous, dome-shaped, pedunculated, or flat-topped and usually are flesh-colored, pink, or brown.
Clinico-pathological correlation:
More elevated acquired skin moles tend to be more lightly pigmented, and flatter acquired skin moles tend to be more darkly pigmented. More elevated and less pigmented lesions tend to have a prominent intradermal nevus component, whereas flatter and darker lesions have a more prominent junctional component and a less prominent dermal component. Skin moles on palms and soles, even compound skin moles, may not distort the skin surface, perhaps because of a thickened stratum corneum in these sites.
Special features:
Dark pigmentation:
Very dark brown and black are unusual colors for typical acquired skin moles in lightly pigmented people. In contrast, dark pigmentation is usual for Typical acquired skin moles in people who have darkly pigmented skin. Very dark brown and black in skin moles on acral and mucosal surfaces and nail apparatus should be viewed with suspicion regardless of normal skin color.
Other colors:
Blue, gray, red, and white areas in a mole are not typical features and ought also to be viewed with suspicion.
Hair quality:
The surfaces of skin moles may reveal hair that is less than, equal to, or greater than that of surrounding skin. Hair in skin moles may be coarser, longer, and darker than that in surrounding skin.
Site specific:
Lesions on palms and soles are usually hairless. Size, shape, skin markings, and hair quality of skin moles in darkly pigmented races are similar to those in whites.
Extent of lesion:
Skin moles of the nail apparatus may be a dark or light brown, extending from the nail matrix to the distal edge of the nail plate; extension of the pigmentation onto the skin of the nail fold or beyond the distal nail groove should be considered suspicious for melanocytic dysplasia or malignant melanoma.

Any skin mole, by definition, is benign. A skin mole, is a benign proliferation of melanocytes in the epidermis, epidermis and dermis, or dermis alone. In general, a skin mole is a small (less than 6 mm), symmetric, well-circumscribed proliferation of nested melanocytes, and the melanocytes that are deepest in the dermis are smaller than superficial melanocytes, a process known as maturation.

Typical Acquired Mole is a proliferation of nevomelanocytes in the epidermis (junctional), dermis (intradermal), or both areas (compound). The nevomelanocytes forming these lesions often do not demonstrate normal melanocytic differentiation and hence the term nevomelanocytes. The extent of melanocytic proliferation, spectrum and type of differentiation, location of cells, and age of the lesion all may influence clinical and histopathologic features.

The Melanocyte is a melanin-producing cell in the skin, that determines its color. Color is determined by the activity of the melanocytes. Melanin production takes place in melanosomes (tiny sub-structures within the cell). Darkly pigmented skin have melanosomes that contain more melananin.

Melanosomes are a network of microtubules that rearrange themselves within the cell in response to external factors such as ultraviolet rays. Melanosomes usually cluster together near the center of the cell but can rapidly redistribute themselves to the ends of dendritic (tooth-like) processes projecting from the cell. Each melanocyte supplies melanin to approximately 30 nearby keratinocytes via its dendrites along microtubules.

The nevus cell differs from melanocytes in a number of ways. The nevus cell is larger, lacks dendrites, has more abundant cytoplasm, and contains coarse granules. Nevus cells aggregate in groups (nests) or proliferate in a nonnested pattern in the basal region at the dermoepidermal junction. Nevus cells in the dermis are classified into types A (epithelioid), B (lymphocytoid), and C (neuroid). Through a process of maturation and downward migration, type A epidermal nevus cells develop into type B cells and then into type C dermal nevus cells.

Skin Moles Causes: There has been a continual debate as to the origin of skin moles. Although many theories have been proposed and some supporting data are available, the critical events leading to mole development remain a mystery. A number of hypotheses have been proposed. These include:
(1) transformation from epidermal melanocytes and subsequent deposition/migration into the dermis. Evidence for this hypothesis includes the demonstration of basement membrane around nevomelanocytes in the dermis based on routine, ultrastructural, and immunohistologic features, suggesting structural contiguity of dermal nevomelanocytes with epidermis. These studies would suggest that nevomelanocytes extend down from the epidermis along with the basement membrane.
(2) dual origin, i.e., nevomelanocytes in the epidermis and upper dermis being derived from epidermal melanocytes, and nevomelanocytes in the lower dermis being derived from Schwann cells of nerves. Evidence for this hypothesis is based on differences in differentiation of nevomelanocytes. This includes positive staining by a monoclonal antibody to the Schwann cell–associated antigen for nevomelanocytes in the lower dermis and negative staining for nevomelanocytes in the epidermis and upper and middle dermis. Moreover, nevomelanocytes in the epidermis and papillary dermis Typically resemble epithelioid cells, aggregate in nests, demonstrate tyrosinase activity but not cholinesterase activity, stain weakly for neuron-specific enolase, and contain melanin. Nevomelanocytes in the deep dermis tend to resemble fibroblasts or Schwann cells or form concentrically arranged and loosely layered structures becoming skin molesc corpuscles that resemble Meissner corpuscles, are usually disposed as single cells, demonstrate minimal tyrosinase activity, have abundant cholinesterase activity, and Typically stain positively for neuron-specific enolase. This hypothesis would suggest that the phenotypic differences in the nevomelanocytes are due to different origins (melanocytes and Schwann cells).
(3) hamartomatous change affecting many cell types. Evidence for this hypothesis includes changes in the associated epidermis, including lentiginous, seborrheic, or epidermal nevus type patterns, and aberrations of appendageal and neurovascular structures, particularly in congenital skin moles. These findings reinforce the notion that skin moles are benign hamartomas involving multiple tissue elements. The fourth hypothesis is based on the existence of defective melanoblasts that may lead to defective differentiation. Neural crest–derived melanoblasts migrate to the dermis and basal layer of the epidermis before 40 days of estimated gestational age. These cells are thought to take up residence in the epidermis and/or superficial dermis (or the deep dermis, panniculus, and adnexal structures in the case of congenital skin moles). Melanocytic “precursor” cells have been shown to be present in adult human skin. Theoretically, these cells could aberrantly proliferate and differentiate, giving rise to melanocytic neoplasms. Depending on the defect, timing, and local tissue influences, a variety of different melanocytic neoplasias could be created.
(4) benign neoplastic proliferation originating from a defect in melanoblast/neural crest cells.
This fourth hypothesis is supported by data showing that human acquired skin moles are clonal.

Typical acquired skin moles have not been followed systematically from their progression to regression. Therefore, dynamic evolution of acquired skin moles must be suggested from static information or short-term follow-up studies. It has been stated that during the early years of life, virtually all skin moles are composed primarily of junctional moles, that nevomelanocytes in these junctional moles eventually push their way to the dermis and finally lose their epidermal contact as they continue to grow into the dermis and become intradermal skin moles, and that in the intermediate stage of this process there are junctional moles in the epidermis and sheets and nests of nevomelanocytes in the dermis (i.e., compound skin moles). This argument suggests that because skin moles in adults are primarily of the dermal type and because skin moles in children are primarily of the junctional type, skin moles evolve by a process of “dropping down” of nevus cells from the epidermis into the dermis. The precise nature of the “dropping down” process has not been defined. It is likely that acquired skin moles evolve through a life cycle, first becoming apparent after infancy in the vast majority of cases, peaking in number during the second and third decades of life, and then disappearing by the seventh to ninth decades. Regression of skin moles is believed to occur by degeneration. The formation of degenerative structures in aging skin moles suggests an end stage in differentiation and not a source of origin of intraepidermal skin moles. Transepidermal elimination of nevomelanocytes rarely occurs. Rarely, nevomelanocytes have been documented to show spontaneous disappearance. Skin moles also may involute during the course of inflammatory halo depigmentation (halo moles). There may be relatively sudden changes in skin moles that are unrelated to cancerous transformation. Any single mole that is noted to suddenly change independently should be a cause for concern. Causes of sudden changes in a mole (color, surface, or size, with or without pain, itching, ulceration, or bleeding) over days or weeks include cystic dilatation of a hair follicle, epidermal cyst formation, folliculitis, abscess formation, trauma, hemorrhage, and, in the case of a pedunculated mole, strangulation and thrombosis. These benign causes of sudden change may require close observation until resolution occurs over the course of 7 to 10 days (in the case of trauma or inflammation) or histopathologic examination. Cases have been described of the eruptive appearance of skin moles after blistering skin disease, immunosuppression, or chemotherapy. The vast majority of acquired skin moles are harmless, growing in proportion to body growth, with physiologic spurts of enlargement during early childhood and puberty.
A cancerous mole risk appears to be related to the number and size of skin moles; patients with numerous skin moles, atypical skin moles, and a personal or family history of a cancerous mole should be considered for periodic surveillance examinations.

Typical acquired skin moles develop after birth, slowly enlarge symmetrically, stabilize, and persist or regress later in life. The majority of Typical acquired skin moles appear to develop during the second and third decades of life, although some lesions may appear in the first 6 to 12 months of life.
A number of studies have measured the number of typical acquired skin moles in different age groups. The average number of skin moles per person peaked at 43 for males and 27 for females during the second and third decades, respectively, and decreased to very few in the sixth and seventh decades. A similar age-related prevalence rate for skin moles has also been documented. A difference in frequency distribution of skin moles according to gender is not clear, although most series show a close to equal prevalence in males and females. The prevalence of skin moles varies according to race. In blacks, the overall prevalence of skin moles (regardless of size) tends to be higher in those with lighter skin versus those with darker skin. When prepubertal whites were examined for skin moles, a significant association for excess skin moles was documented for pale skin, blue or green eyes, blond or light-brown hair, and a tendency to sunburn, but not a tendency to freckle. Other studies show variable relationships to these same parameters. Environmental exposure to UV light appears to be a critical exacerbating factor for the development of skin moles. Mole density has been shown to increase with increasing sun intensity of UV light. Further, the use of UV blocking sunscreens has been shown to decrease the number of new moles in children. Genetics plays a role in mole development. There is evidence that the size, frequency, and distribution patterns of acquired skin moles tend to aggregate in families. This observation is well documented for atypical skin moles in the setting of familial cutaneous melanoma and congenital skin moles.