Benign and Malignant Melanocytic Lesions

Question 1

What are melanomas?

Answer 1

-Malignancy of the neural crest derived melanocytes.
-Most melanomas are pigmented
-A minority (up to 30%?) of melanomas are the result of malignant change in a former ‘mole’.
-Melanomas, unlike virtually all other skin cancers metastasise early, and it is these metastases that lead to death.

-The main cause of melanoma — as with most skin cancers — is UVR exposure and sun sensitive skin.

Question 2

Epidemiology of melanomas

Answer 2

-Incidence of MM in Northern Europe is 17:100,000 with a median age of 53.
-Melanomas are more common in women than men (3:2) in some (but not all) populations.
-Melanoma is therefore much less common than non-melanoma skin cancer (NMSC), and accounts for about 10-15% of all skin cancers.

-Like all the UVR related skin cancers, the incidence of melanoma is increasing every year: for melanoma this increase is about 4% per year.
-The incidence of MM in Northern Europe is 17:100,000 with a median age of 53. Melanomas are more common in women than men (3:2) in some (but not all) populations. Melanoma is therefore much less common than non-melanoma skin cancer (NMSC), and accounts for about 10-15% of all skin cancers.

Like all the UVR related skin cancers, the incidence of melanoma is increasing every year: for melanoma this increase is about 4% per year.
-The majority of deaths from skin cancer are a result of malignant melanoma with a death rate of ~3:100,000. (2.5 K deaths)
=Melanoma has a much higher case-fatality rate (10-20%) than either SCC or BCC

Question 3

Causes of melanoma

Answer 3

-UVR and sun sensitive skin (intermittent UVR exposure)
-Acral
-Familial
-Psoralen and UVA therapy
-Immunosuppression

Question 4

Describe acral melanoma

Answer 4

-Around 10% of MM occur on the palms or soles
=Regardless of colour of their skin or sun exposure.
-Given that palmoplantar skin is sun resistant, because of the very thick epidermis, it is safe to assume that melanomas at these particular sites are not UVR related.

Question 5

Describe familial melanoma

Answer 5

-Up to 10% of MM occur in those with a family history of MM.
-Inherited in close to an autosomal dominant manner.
-Larger number of nevi (often several hundred) and these nevi look ‘atypical‘.
-Clinical clues are therefore a large number of nevi and the presence of multiple family members with melanoma (>2 or 3).
-Genetic testing

Question 6

Describe PUVA cause

Answer 6

As for squamous cell carcinoma there is some evidence that those who have received higher cumulative doses of PUVA are at an increased risk of melanoma. The evidence is far less convincing than for SCC, but that a known carcinogen like PUVA increases MM rates seems quite plausible.

Question 7

Describe immunosuppression cause

Answer 7

There appears to a be a small increased risk of melanoma in those who are immunosuppressed, particularly following organ transplantation. The increase in risk is much lower than that seen for SCC.

Question 8

Types of melanoma

Answer 8

-Superficial spreading
=Flat, spreading laterally, resemble normal flat melanocytic nevi
=Most common
=Arms, legs, back, chest, young people
=95% survival if excision early/ if thick 35-40% survival
=Intermittently exposed skin

-Nodular
=large downward/ vertical collection of malignant cells- most aggressive, worse prognosis (Breslow thickness)
=Second most common, sun-exposed skin middle aged, intermittently exposed skin
=Red or black lump which bleeds/oozes

-In situ
=confined to epidermis and cannot metastasise

-Lentigo maligna
=Chronically sun exposed skin, older people, face or back of hands, severe UVR damage, develop over many years, slow increase in area and gradual darkening of colour

-Amelanotic
=contain some melanin

-Acral
=palms, soles, subungual pigmented (Hutchinson’s sign)
=Darker skin pigmentation, rare, no UV, diagnosed late

Question 9

Prognosis of melanomas

Answer 9

-Predictor without metastatic spread at the time of diagnosis: Breslow thickness. T
-Distance measures in millimetres from the granular layer down to the deepest part of the tumour (it is not the diameter of the tumour on the skin’s surface).

-Most melanomas present as thin lesions (less than 1mm), and these have the best prognosis (>95% at 5 years).
-Melanomas with a thickness of 4mm would be considered ‘thick’ and have a much worse prognosis (55% at 5 years).

Question 10

Treatment of melanoma

Answer 10

-Excision of the primary lesion with the overall clinical goal to diagnose melanoma at an early stage before spread has occurred.
=Incision biopsy can make subsequent histopathology assessment difficult

-Lesions suspicious of melanoma should be excised with a 2mm margin, the sample examined by the histopathologist, and a further excision carried out based on the Breslow thickness if the diagnosis is confirmed.
-The further excision might require surgical margins of a further 1 to 2cm, depending on the exact Breslow thickness.

-Sentinel lymph node mapping
-Isolated limb perfusion
-Block dissection of regional lymph node groups
-Checkpoint inhibitor immunotherapy

Question 11

Major and minor diagnostic features of melanoma

Answer 11

-Change in size, shape, colour

-Diameter >=7
-Inflammation
-Oozing or bleeding
-Altered sensation

Question 12

Margins of excision related to Breslow thickness

Answer 12

0-1mm= 1cm
1-2mm= 1-2cm (depending upon site and pathological features)
2-4mm= 2-3cm (depending on site and pathological features)
>4mm= 3cm

Question 13

Why do melanocytic lesions occur?

Answer 13

-An increase in melanin within the epidermis without an increase in melanocytes (ephelides)
-An increase in melanocytes along the basement membrane of the epidermis (lentigines)
-Nests of melanocytes at the epidermal/dermal junction and/or within the dermis (moles).

Question 14

Describe congenital melanocytic naevi

Answer 14

-Present at birth, or arise within the first two years of life.
-Moles that look like congenital naevi, but appear later in life, are sometimes called ‘congenital type’ naevi.
-Congenital naevi may be small (1-5cm), medium (1.5-20cm) or rarely, giant (bathing trunk variety).
-Congenital naevi may be macular but are frequently varied in pigment, thickened (‘cobblestoned’) and hairy, particularly post adolescence in males.
-Giant naevi have a significantly increased risk of melanoma in the lesion (5-10%) or within melanocytes in the central nervous system hence surveillance should be lifelong

Question 15

Describe café-au-lait macules

Answer 15

-Flat coffee-coloured patches.
-Solitary lesions are common.
-The presence of six or more is strongly suggestive of type 1 neurofibromatosis (Lisch nodules and axillary freckles)
-Café-au-lait macules may also arise in other genetic syndromes, including Albright syndrome.
-A speckled lentiginous naevus (also called ‘naevus spilus’) is the association of a café-au-lait macule with darker lesions

Question 16

Types of café-au-lait macules

Answer 16

-Naevus spilus maculosus has dark speckles fairly evenly distributed (junctional naevi)

-Naevus spilus papulosus has dark papules of different sizes and colours and rather unevenly distributed (dermal or compound naevi)

Question 17

Describe acquired melanocytic naevi

Answer 17

-Moles/ naevocellular naevi.
-Most people have about 20 to 50 moles.
-A few naevi appear in infancy.
=These are thought to be due to spontaneous mutations in utero (tardive congenital naevi). They rarely regress.

-Sun exposure promotes new naevi to appear during adolescence and adult life, but these tend to involute after the age of 50.
-Pigment network under scope
-Intermittent exposure to ultraviolet radiation may induce B-RAF or N-RAS mutations within the melanocytes. These naevi have a higher risk of acquiring further mutations and becoming melanoma.

Question 18

Describe halo naevi

Answer 18

-Common in teenagers and are most obvious in tanned skin.
-There are junctional, compound and dermal halo naevi.
-A white ring appears around one or more normal moles (Stage 1), which gradually fade (Stage II) and eventually disappear (Stage III). It may take several years for the white marks to disappear (Stage IV).
-Multiple halo naevi are associated with vitiligo, and rarely with metastatic melanoma.
-Histologically there is a dense lichenoid infiltrate.

-Halos may also arise around atypical naevi and blue naevi; and they are also seen around non-melanocytic skin lesions such as seborrhoeic keratoses, basal cell carcinomas and inflammatory eruptions.
-An asymmetric irregular halo may develop around a primary melanoma

Question 19

Describe spitz naevi

Answer 19

-Dome-shaped papules or nodules that most often arise on the face or limbs of children and adolescents.
-They enlarge over a few months, and are often red or deeply pigmented, resembling melanoma.
-In adults, they are often excised to rule this out.

-Difficult to distinguish the biologically benign Spitz naevus from malignant melanoma.
-Histological descriptions usually refer to a symmetrical compound naevus in which maturing melanocytes are noted in the deeper dermis, and an epithelioid cell structure.
-Atypical Spitz naevus can be impossible to differentiate from melanoma, so is best removed with generous excision margins and followed up carefully.

-Melanocytes in some Spitz naevi have been shown to have H-RAS type mutations. B-RAF and N-RAS mutations seen in acquired naevi and melanoma do not occur in Spitz naevi.

Question 20

Types of spitz naevi

Answer 20

-Classic Spitz naevus
-Pigmented Spitz naevus
-Atypical Spitz naevus

Question 21

Describe Spindle cell tumour of Reed

Answer 21

-Reed naevus is sometimes classified separately from Spitz naevus but may co-exist with Spitz naevus.
-The Reed naevus also tends to be seen most often in children and present as dark brown to black papules on hands, feet or elsewhere.
-The pathology reveals spindle-shaped melanocytes in the dermis

Question 22

What are atypical naevi?

Answer 22

-Funny-looking moles.
-They may be more numerous, larger in size (over 4mm diameter), and varied in colour (usually shades of brown), shape, and contour (with an ill-defined border).
-Certain atypical naevi, classified as dysplastic naevi (also called Clark’s naevi), may resemble melanoma and may also predispose to melanoma, especially in patients with a strong family history of atypical naevi and melanoma (dysplastic naevus syndrome).
-There is an autosomal dominant mode of inheritance.

Question 23

Clinical features of dysplastic naevi

Answer 23

-Round, oval or asymmetrical shape
-Variegated colour, often including pink (due to phaeomelanin and inflammation)
-Irregular, poorly demarcated, fading border
-Fried egg or target-shaped appearance
-Flat or with central papule
-May evolve over time to become more or less atypical

=Arrangement of melanocytes in lentiginous pattern, fibroplasia, dermal lymphocytic infiltration

Question 24

Types of freckles

Answer 24

-Ephelis
=Common in redhead fair skin, fade in winter and age
=Increased melanin in basal keratinocytes

-Lentigo simplex
=Sunburn
=Pigmented elongated rete ridges, increased melanocytes along basal layer, ink-spot variety (deeply pigmented)

-Solar lentigo
=Scattered small brown lesions on sun-damaged areas/ large well-defined oval patch on face in mature individuals
=Pigmented elongated and clubbed rete ridges, increased melanocytes along basal layer, solar elastosis

Question 25

Management of moles

Answer 25

-No intervention/ sun protection

-Removed if:
=Possible malignancy: bleeding, growth or atypical features;
=Nuisance moles: irritated by clothing, comb or razor;
=Cosmetic: the mole is unsightly or the patient wishes to be rid of it.

-Shave biopsy
-Excision biopsy
=Send for pathology
=If there is concern that a lesion could be a melanoma, it should be completely excised with 2-3 mm margin. If the lesion is too big for this to be practical or the scar will be unsightly, it is preferable to send the patient to a dermatologist for a specialist opinion. Incisional biopsy should be generous (punch biopsy is best avoided).

-Hair can only be removed permanently by electrolysis, laser epilation or excision of the whole mole.

Question 26

Management of freckles

Answer 26

-Sun protection
-Anti-aging creams containing hydroquinone, peeling agents or antioxidants (alpha hydroxy acids, vitamin-C, retinoids, azelaic acid, pentapeptide);
-Superficial chemical peels (glycolic acid, Jessner’s, salicylic acid);
-Lasers or flash lamps that produce a green or red light, which are absorbed by melanin.
Results are variable but sometimes very impressive with minimal risk of scarring.
-Resurfacing lasers (carbon dioxide and Erbium:YAG) that vaporise the surface skin, and cryotherapy, should not be used to remove pigmented lesions by non-specialists. Although they may improve the appearance of lentigines, they may instead result in unsightly patchy hypopigmentation or scarring

Question 27

Describe solar lentigo

Answer 27

-Sun exposed area, flat/macular, uniform light brown
-Can look like flat SK
-Can change into lentigo maligna (change colour/ darker)