A wide range of tumours, both benign and malignant, are found in skin. Benign skin lesions such as seborrhoeic keratoses and skin tags are often just a cosmetic nuisance, but some benign skin lesions can be a component of diseases with serious medical consequences, e.g. neurofibromatosis or LEOPARD syndrome.
Exposure to ultraviolet light (UVL) is a major factor leading to the development of both benign lesions, e.g. melanocytic naevi, and most skin cancers. Changes in dress style, increased travel abroad, use of sun tanning salons (sunbeds), and the depletion of the ozone layer have all contributed to increased exposure to UVL.
Skin cancer is the most common human cancer and its incidence continues to increase. It most commonly affects older, fair-skinned individuals who have had either acute intermittent exposure to UVL or chronic UVL exposure. Organ transplant recipients have a 200-fold increased risk of squamous cell carcinoma. About 2% of patients who develop skin cancer have a genetic predisposition, e.g. Gorlin’s syndrome in basal cell carcinoma (BCC) and familial melanoma syndromes in malignant melanoma. Mutations in the PTCH gene cause Gorlin’s syndrome, and loss of heterozygosity at that locus is also present in most sporadic BCC.
Nonmelanoma skin cancer is rarely fatal, but can cause a lot of morbidity. Malignant melanoma is a deadly skin cancer which is the 2nd most common cancer (excluding nonmelanoma skin cancer) in young women. Over the last 20 years, its incidence has been increasing faster than any other cancer, with an approximate doubling of rates every 10 years in countries with largely white populations. Early detection and excision of melanoma is the best way to reduce mortality, as there is no curative treatment for metastatic malignant melanoma.
Benign skin tumours
Benign nonmelanocytic tumours
Seborrhoeic keratoses are probably the most common benign skin tumour. These lesions are usually found on the trunk in older individuals.
The classic seborrhoeic keratosis is a dry, brown, warty plaque with a ‘stuck-on’ appearance. There is large variation in colour, including pale and darker lesions which may even simulate malignant melanoma. The sudden appearance of multiple seborrhoeic keratoses accompanied by the development of a malignancy is known as Leser–Trélat sign.
If the lesion is definitely a seborrhoeic wart the patient can be reassured. As the lesions are a cosmetic nuisance, patients may request treatment which can include cryotherapy or curettage.
Sebaceous hyperplasia is a common benign tumour of the sebaceous glands usually occurring in middle age. The lesions are usually 2 to 3 mm, skin-coloured or yellow papules with central umbilication from which a small amount of sebum can be expressed. Treatment is usually not needed, but if requested for cosmetic reasons, curettage or gentle cautery are appropriate.
Sebaceous adenomas are also derived from the sebaceous glands. Tumours present as a yellow, smooth papule or nodule usually on the face or neck and are associated with Muir–Torre syndrome. This is an autosomal dominant disorder, caused by mutations in the mismatch repair genes, MLH1 or MSH2, with an increased tendency to visceral cancers, particularly colorectal carcinoma.
Skin tags are extremely common, flesh-coloured, pedunculated skin lesions that usually occur in the flexures, particularly the neck and axillae. There is some correlation with obesity. Treatment can include cryotherapy or snip excision.
An epidermoid cyst consists of a sphere of stratified squamous epithelium buried within the dermis. These cysts occur mainly on the face, neck and chest and have a predilection for the genitalia, where they frequently calcify. A common presentation is a dermal nodule with a small pore (punctum) on the surface. The cyst wall may rupture into the dermis, causing an intense inflammatory response followed by suppuration which may require incision and drainage. If the lesion is bothersome to the patient, it may be surgically excised.
Milia present as 1 to 2 mm white papules, most commonly on the thin skin of the periorbital region in adult women. Histologically, the lesions are small epidermoid inclusion cysts. A 20 gauge needle may be used to extract milia.
Pilar (trichilemmal) cysts occur on the scalp, where they present as smooth, firm, mobile nodules with overlying hair. A punctum is not usually present and inflammation rarely occurs. Histologically, these cysts differ from epidermoid cysts in having the squamous epithelial lining without the granular layer. Surgical excision can be performed if required.
The dermatofibroma is a common dermal tumour usually occurring on the limbs. There is sometimes a history of an insect bite or other trauma. The lesions are firm, pink-brown papules that may involute with time.
This is a benign tumour of histiocytic cells which occurs predominantly in infancy and early childhood and typically regresses spontaneously. The characteristic clinical appearance is of reddish yellow papule(s) which enlarge up to 1 cm diameter and evolve into yellow-brown plaques and macules. Resolution occurs over months or years to leave small atrophic scars. Visceral involvement may occur in the lung, liver, spleen, testes, pericardium, gastrointestinal tract, and kidney, as well as in the eye. Histologically, the lesions show a mixed dermal infiltrate with histiocytes, lymphocytes, eosinophils, and other cells. A typical feature is the presence of giant cells with a wreath-like arrangement of nuclei, the Touton giant cell.
Benign melanocytic tumours
Freckles (ephelides) are brown macules that occur on sun-exposed areas, particularly the nose and the arms, in fair-skinned individuals. The lesions often fade in winter.
The solar lentigo is a brown patch occurring on sun-exposed skin that results from UV exposure. Multiple symmetric, hyperpigmented patches on the face, arms, and dorsa of the hands are typical.
Extensive lentigines at a young age may indicate underlying genetic disorders such as xeroderma pigmentosum, Carney’s (atrial cutaneous myxomas, lentigines, blue naevi, endocrine disorders, and testicular tumours) or LEOPARD (lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary stenosis, genital abnormalities, retardation of growth, and deafness) syndromes.
Acquired melanocytic naevi (moles)
Melanocytic naevi are benign tumours of melanocytes, and are also known as moles.
Acquired naevi tend to first appear and increase in number during childhood, reaching their maximum in early adulthood. There is some evidence that the number of acquired naevi may be related to UV exposure. Fair-skinned individuals and white people who live close to the equator have more acquired naevi than nonwhite populations. Naevi commonly darken or enlarge during pregnancy suggesting a degree of sex hormone responsiveness. Correlation in sex and age-adjusted naevus density in adolescence is higher in monozygotic twins than dizygotic twins suggesting a definite additional genetic effect. About 2% of the population have the atypical mole syndrome, which is associated with an increased risk of melanoma. Mutations in the BRAF gene, a serine/threonine kinase involved in the mitogen-activated kinase pathway, are present in about 80% of melanocytic naevi and may contribute to melanocytic hyperproliferation.
Acquired melanocytic naevi appear and change in the childhood, teenage, and early adult years. As a rule, new melanocytic naevi do not appear after the age of 40 years. Junctional naevi are usually flat, uniformly pigmented macules that appear in childhood. Histologically, nests of naevus cells appear at the dermoepidermal junction. Compound naevi are, usually, slightly elevated pigmented papules. They may have a smooth or papillomatous surface. Compound naevi usually increase in size during adolescence. Nests of naevus cells are found both at the dermoepidermal junction and in the dermis. Intradermal naevi are seen mainly after adolescence. These are skin-coloured, dome-shaped papules that most frequently occur on the face. A halo naevus is a clinical variant with a ring of depigmentation around an otherwise normal mole (Fig. 23.14.2b). A blue naevus usually occurs on the limbs. It appears blue-grey because the pigmentation is deep in the dermis. A Spitz naevus usually presents as a vascular-looking papule on the face in children. Atypical (dysplastic naevi) are usually more than 5 mm in diameter, have a macular component, and an indistinct margin, sometimes with background erythema. Recognition of atypical naevi is important as individuals with two or more atypical naevi, naevi in unusual locations (scalp, buttocks, dorsum of feet, and iris) and 100 or more naevi more than 2 mm in diameter (atypical mole syndrome) are at increased risk of developing malignant melanoma.
The malignant potential of individual naevi is low, therefore prophylactic excision of acquired melanocytic naevi to prevent transformation into melanoma is not advised. Excision of naevi is advocated where it is not possible to clinically exclude a diagnosis of melanoma. Complete excision and histological examination is advocated even when moles are removed for purely cosmetic reasons. Although the clinical differentiation of atypical naevi from melanoma is difficult, it may be facilitated by regular surveillance, automated digital imaging systems, and dermoscopy. Removal of an atypical mole is only necessary if melanoma is suspected.
Congenital melanocytic naevi
Congenital melanocytic naevi (CMN) are proliferations of nested melanocytes that are present at birth. The term is also used to describe histologically and clinically identical lesions that appear in diameter in infancy. Small CMN (<1.5 cm in diameter) are seen in 1 to 2% of neonates, intermediate-sized lesions (1.5–20 cm) in 0.6%, and large CMN (>20 cm) in about 0.02%. Large CMN are also known as ‘bathing suit naevi’ because of their distribution. The lesions are tan, brown to dark brown patches or plaques at birth. They may have a smooth, nodular, or verrucous surface which may be hair-bearing. Patients with large CMN are at increased risk of developing melanoma within the CMN, in the central nervous system, and elsewhere.
Most small and intermediate CMN may be managed by routine surveillance. The lifetime risk of malignant melanoma in a patient with a large CMN is about 7%. Parents should be instructed on proper sun avoidance and sun protection techniques including use of sunscreen and use of high-weave, sun-protective clothing. Many specialists recommend partial or complete excision of large CMN. This may require multiple surgical procedures, tissue expansion, and/or grafting. Other surgical options include curettage, dermabrasion, or laser surgery to remove the superficial naevus cells.
Solar keratoses (also known as actinic keratoses) are erythematous scaling lesions between 2 and 10 mm in diameter, seen in fair-skinned individuals on areas of maximal sun exposure such as the face, ears, dorsum of the hands, forearms, and lower legs. Histologically, these lesions show dysplasia of the basal keratinocytes. The estimated risk of transformation into squamous cell carcinoma (SCC) is very low, approximately 1% per annum. Some small lesions resolve spontaneously, particularly with photoprotection. Treatment options include cryotherapy, topical diclofenac, 5-fluorouracil, or imiquimod, a topical immune modifier.
Bowen’s disease (squamous cell carcinoma (SCC) in situ) presents as an asymptomatic, enlarging, erythematous, scaly plaque. Approximately 5% progress to invasive SCC. Bowen’s disease affecting the glans penis is called erythroplasia of Queyrat. Bowen’s disease may be misdiagnosed as tinea, psoriasis, or discoid eczema. Biopsy of a typical lesion shows full-thickness dysplasia of the epidermis. Treatment can include cryotherapy, topical 5-fluorouracil, or photodynamic therapy.
Malignant skin tumours
Basal cell carcinoma
The most common factor involved in the pathogenesis of BCC is exposure to ultraviolet light (UV). Fair-skinned individuals who burn easily and tan poorly are at greatest risk of developing BCC. Both cumulative lifetime UV exposure and intermittent intense sun exposure are risk factors. Other sources of UV include sunbeds and psoralen ultraviolet A (PUVA) for psoriasis. Other environmental factors leading to the development of BCC include ionizing radiation given for benign conditions (e.g. acne, tinea capitis) and arsenic ingestion. Organ transplant recipients have a 10-fold increased risk of BCC.
A number of genetic syndromes of increased susceptibility to BCC have been described. The most significant is Gorlin’s syndrome (naevoid basal cell carcinoma syndrome) which is characterized by the appearance of BCCs before the age of 20, an autosomal dominant family history, palmar/plantar pits, odontogenic keratocysts, and bilamellar calcification of the falx cerebri. Mutations are present in the human PTCH gene, the human homologue of the drosophila patched gene Ptch1. Ninety per cent of sporadic nodular BCCs have loss of heterozygosity at chromosome 9q21-q31, where the PTCH gene is located and 70% of nodular BCCs have detectable PTCH gene mutations. This gene negatively regulates the hedgehog signalling pathway, which is important in epithelial cell growth during hair follicle development, and an inactivating mutation allows uncontrolled hedgehog signalling. Activating mutations in the SMO gene (smoothened) similarly allow for unregulated hedgehog signalling in BCC. About 40% of BCC have UV-induced transition mutations in p53. Polymorphisms in genes activated by exposure to UV, such as reactive oxygen species (GST, CYP450) or DNA repair (xeroderma pigmentosum), are also significantly associated with risk of BCC development.
The major histological patterns of BCC are nodular, micronodular, superficial, and morphoeic BCC. The nodular type is characterized by well-defined islands of basaloid cells with well-defined peripheral palisading. The superficial type has foci of tumour extending from the epidermis into the papillary dermis. The morphoeic subtype has tumour islands of varying size with surrounding fibrosis.
Basal cell carcinoma most commonly occurs in white, fair-skinned individuals and rarely occurs in darker skin types. Although BCC more commonly occurs in men, the incidence of BCC continues to rise in women because of increased UV exposure due to changes in dress and lifestyle, including ‘sun holidays’ and use of sunbeds.
The most important risk factor is cumulative lifetime UV exposure. Avoidance of exposure to UV radiation is encouraged. Helpful preventive measures include avoidance of midday/afternoon sun, wearing a broad-brimmed hat during outdoor activities, and using sunscreens with sun protection factor (SPF) of 15 or greater. Patient education about the appearance of new lesions to maximize early detection should be encouraged.
Approximately 50% of BCCs occur on the head and neck, 30% on the upper trunk, and the remainder elsewhere. The clinical variants of BCC include nodular/nodulocystic, morphoeic, superficial, and pigmented BCCs. The nodular subtype represents about 60% of BCCs and presents as a small, pink nodule, with a translucent, pearly appearance with telangiectasia. As the lesion enlarges, central ulceration may occur (‘rodent ulcer’). Although slow-growing, if neglected, these tumours may enlarge and extend deeply causing significant damage to eyelids, nose, or ears. Superficial BCC accounts for about 20% of BCCs and is more commonly found on the trunk and extremities. Typically, the lesion is a slightly scaly, pink plaque with a threadlike, translucent, raised border. Multiple lesions may be present. Melanin pigmentation may occur in both superficial and nodular BCCs, giving a pigmented variant which is more common in individuals with dark skin. Morphoeic (infiltrative) BCCs present as an indurated, ivory plaque, often resembling a scar. The name is derived from its resemblance to a plaque of localized scleroderma (morphoea). This variant of BCC is notable for its tendency to extend beyond the apparent clinical borders and a high local recurrence rate after treatment.
Differential diagnoses of nodulocystic BCC to consider include intradermal naevi and rarer tumours derived from appendageal structures.
A small shave or punch biopsy is usually sufficient to confirm the diagnosis and histological subtype of BCC. In some centres, scrapings for cytology can be performed to confirm the diagnosis.
Treatments are influenced both by tumour factors (the size, site, margin, and subtype of the BCC) and patient factors (such as age, coexisting illnesses (bleeding diathesis, anticoagulant therapy, or susceptibility to bacterial endocarditis), access to specific treatments locally, and patient preference. Options for superficial BCC include topical 5-fluorouracil, cryotherapy, or more recently, imiquimod. Nodular BCC can be treated by curettage and cautery or simple excision. Morphoeic BCCs or nodular BCCs in high-risk sites ideally should be treated with Mohs’ micrographic surgery, which is performed in stages with examination of the histological margins, but wide excision can be performed if this is not available. Photodynamic therapy may be useful for thin BCCs at cosmetically difficult sites. Radiotherapy can be useful in older patients where surgery is not feasible.
With appropriate patient selection, the treatments described above will give cure rates exceeding 95%. Patients who have had one BCC have a 20% risk of developing a further BCC over the following 5 years.
It is likely that over the next 5 to 10 years, further BCC tumour suppressor genes will be identified. The use of imiquimod for superficial BCC will also become more widespread. Small-molecule inhibitors of the hedgehog signalling pathway currently in clinical trials, such as cyclopamine, may well be used routinely as topical therapy in the future.
Squamous cell carcinoma
Squamous cell carcinoma (SCC) is the second most common form of skin cancer and usually occurs on sun-exposed areas in older individuals.
SCC is a malignant tumour of epidermal keratinocytes. The development of SCC is multifactorial, involving both genetic predisposition and environmental factors. The majority of SCCs occur on sun-exposed areas (head and neck, dorsum of hands). Individuals with type I and II skin types (who burn easily) are at greatest risk. Africans with oculocutaneous albinism, who have lost their protective melanin, also have an increased risk of SCC.
The amount of chronic cumulative sun exposure is a major risk factor for SCC. The highest incidence of SCC worldwide is in Australia, a country with a large white population and year-round sunshine. Absorption of UVB by DNA in skin keratinocytes induces unique mutations at the site of pyrimidine dimers. Ultraviolet B (UVB) irradiation also leads to the activation of cell cycle checkpoint controls and apoptotic pathways. The repair and/or elimination of such apoptotic and mutated cells from the epidermis by ‘gatekeeper genes’ such as p53 is important, as clonal proliferation of mutated cells may eventually lead to cancer development. Mutations in p53 are found in up to 90% of SCCs. Mutations in p16INK4a and p14ARF, as well as hypermethylation without mutation, have also been documented in SCC. Finally, mutations in HRAS and KRAS have also been demonstrated in SCC. UVA also plays a role in SCC carcinogenesis through DNA damage, modulation of protein kinase C, and immunosuppression.
There is evidence that human papillomavirus (HPV) may play a causal role in SCC (Chapter 7.5.19). Epidermodysplasia verruciformis, a rare inherited disorder with a high risk of SCC is associated with susceptibility to infection with specific HPV types, called ‘EV types’, including the oncogenic HPV-5. Organ transplant recipients are highly susceptible to HPV infection, particularly warts, and have a c.200-fold risk of SCC compared to the immunocompetent population. Up to 80% of transplant SCCs have detectable EV-type HPV DNA. HPV E6 protein inhibits UV-induced apoptosis by abrogation of the proapoptotic protein, Bak, enhancing tumour survival. HPV E6 and E7 proteins also functionally inactivate p53. Azathioprine and UVA radiation have recently been shown to generate oxidative DNA damage which may be a further risk factor in organ transplant recipients.
Other documented risk factors include arsenic ingestion and exposure to chemical carcinogens such as polycyclic aromatic hydrocarbons found in soot and tar (a historical example of this is SCC of the scrotum in chimney sweeps). Other conditions predisposing to SCC include chronic ulcers (known as Marjolin’s ulcer), recessive dystrophic epidermolysis bullosa (an inherited blistering disease which heals with extensive scarring), skin damage from ionizing radiation, thermal injury, and lymphoedema. Chronic infection and chronic inflammation, such as discoid lupus erythematosus, erosive lichen planus, and lichen sclerosus et atrophicus, also increase the predisposition to SCC. Mutations in nucleotide excision repair genes in xeroderma pigmentosum causing defective DNA repair result in a 1000-fold increased risk of skin cancers (both nonmelanoma and melanoma).
The incidence of SCC has doubled over the last 40 years. The British Association of Dermatology estimates that there are 25 000 new cases of SCC in the United Kingdom annually, representing about one-quarter of nonmelanoma skin cancers. Men are affected 2 to 3 times more than women probably because of outdoor occupations, less protective clothing, and a greater lifetime cumulative UV radiation exposure. The success of organ transplantation and immunosuppression has also contributed to the increased incidence of SCC.
Recommendations include photoprotection against UVA and UVB, patient education about warning signs, regular skin examination, and treatment of actinic keratoses. Systemic chemoprevention with oral retinoids may be an option for high-risk patients, e.g. organ transplant recipients with multiple SCCs.
The classical SCC is a pink, keratotic papule or nodule appearing on the head and neck regions on sun-damaged skin. Surface changes may include ulceration, crusting, scaling, or the presence of a cutaneous horn. As the lesion progresses, it will become nodular and/or ulcerated. These lesions are frequently tender to compression. SCC of the lip generally occurs on the vermilion border of the lip in men with a background of actinic cheilitis (the lower lips are scaly, irregularly pigmented, and atrophic). SCC of the anogenital region may present with pruritus, a palpable lump, or erosion. A full skin examination and palpation of regional lymph nodes is important.
The common differential diagnoses of SCC include keratoacanthoma, hypertrophic actinic keratosis, verruca vulgaris, and basal cell carcinoma.
In most patients, the clinical diagnosis of SCC is confirmed by excision and histopathology. Where there is diagnostic doubt, a small biopsy will confirm the diagnosis.
Simple excision with a 4 mm margin of normal surrounding skin is adequate treatment for most low-risk SCC. High-risk tumours (>2 cm in diameter, depth more than 4 mm, located on ears, lip, nose, or scalp, poorly differentiated, perineural, or subcutaneous invasion and recurrent tumours) should be removed with a margin of 6 mm or ideally using Mohs’ micrographic surgery. Selected small, low-risk SCCs can be treated with curettage and cautery or cryotherapy after a confirmatory biopsy. Radiotherapy can be used for nonresectable tumours.
The 5-year cure rate after simple excision of SCC is 92%. The overall risk of metastasis from SCC is in the range of 2 to 5%. High-risk SCCs have the greatest risk of metastasis. Chronically immunosuppressed patients also have an increased rate of metastasis. The overall 5-year survival after regional metastasis is just 25%. In addition, patients are at risk of developing a second primary skin cancer. Within 5 years, 12% cent of patients will have developed a new SCC, 43% a new BCC, and 2% a malignant melanoma.
It is likely that over the next 5 to 10 years, the use of genomic and proteomic technology will identify new therapeutic targets in cutaneous and metastatic SCC. Cyclo-oxygenase-2 inhibitors and antioxidants, e.g. green and black tea compounds, may be potentially useful as chemopreventative agents in patients with multiple actinic keratoses. There will be more aggressive management of patients with high-risk SCC, including sentinel lymph node mapping. If a role for HPV in SCC development is validated, there may be randomized clinic trials of vaccination against EV-type HPV in high-risk groups such as organ transplant recipients. The use of sirolimus, an mTOR inhibitor, instead of azathioprine in transplant immunosuppression regimes may reduce the incidence of post-transplantation cancer.
Keratoacanthoma is a clinically and genetically distinct subtype of SCC. A nodule with a central keratin crater develops rapidly over several weeks, stabilizes in size, and then spontaneously resolves over several months. Histologically and clinically (apart from the history), it is difficult to distinguish from a well-differentiated SCC. There are minimal mitoses or cellular atypia. Ferguson Smith syndrome is an autosomal dominant disorder presenting with multiple keratoacanthomas at a young age. Hundreds of eruptive keratoacanthomas occur in the Grzybowski variant. Keratoacanthomas are also found in Muir–Torre syndrome.
Malignant melanoma (MM) is a melanocyte-derived tumour located predominantly in the skin, but also found in the eyes, leptomeninges, and oral, genital, and rectal mucous membranes. Melanoma accounts for only 4% of all skin cancers, but causes about 80% of skin cancer-related deaths worldwide.
The development of MM is multifactorial. Risk factors include fair skin phenotype (blonde/red hair, freckles easily, blue eyes), blistering sunburn in childhood or adolescence, history of excessive UV exposure, greater than 100 melanocytic naevi, greater than 5 atypical/dysplastic naevi, personal or family history of MM, and changing moles. The presence of the atypical mole syndrome (also known as familial atypical mole melanoma syndrome) or xeroderma pigmentosum increases the risk by 500 to 1000-fold. More than 60% of melanomas arise de novo (no pre-existing lesion).
BRAF mutations occur in 70% of melanomas arising in intermittently sun-exposed sites. The receptor tyrosine kinase gene, KIT, is mutated in 20% of acral and mucosal melanomas. Melanocortin 1 receptor variants that cause red hair and freckling are associated with a small increase in melanoma risk (two–threefold) and an increased risk of melanoma with BRAF mutations. There are probably at least three other genes which underlie predisposition to familial melanoma. The most common is a gene on chromosome 9, CDKN2A, which codes for p16INK4a, an inhibitor of the cyclin-dependent kinases 4 and 6. In the United Kingdom, 50% of families with three or more melanoma cases have CDKN2A mutations, but only 12% of families with two or fewer cases. The second is the CDK4 gene. A rare, dominant activating mutation in this gene renders it insensitive to p16 inhibition. The third is p14ARF, a second product of the CDKN2A locus. Very rare deletions of this gene have been shown to underlie susceptibility to melanoma and neural tumours. Melanoma may also occur as a second tumour in familial retinoblastoma and in the Li–Fraumeni syndrome (associated with sarcomas, brain, and breast tumours).
Histologically, a MM is an asymmetric lesion consisting of single or nested melanocytes in the epidermis (pagetoid spread), appendageal structures, and dermis. The tumour melanocytes do not mature as they descend into the dermis. The distribution of melanin is irregular and the melanocytes display atypia and mitoses. An initial radial growth phase (melanocytes proliferating in the epidermis and papillary dermis) is followed by a more aggressive vertical growth phase with more extensive spread deep into the dermis.
Malignant melanoma is the most serious type of skin cancer and is primarily a disease of white individuals. It rarely occurs in black and Asian individuals. There are about 8000 new cases of MM in the United Kingdom annually and about 1800 melanoma related deaths (Cancer Research UK statistics). In the age group 20 to 39, melanoma is the second most common cancer (excluding BCC and SCC). The incidence of melanoma increases with age with a peak in the 5th decade.
The general public should be encouraged to avoid sunburn and other excessive UV exposure. At risk individuals should use sunblock and wear protective clothing. Health care professionals and patients should be educated about the features of early MM as early detection of thin melanoma is the best method of reducing mortality.
The major clinical characteristic of melanoma is a changing mole. The seven-point checklist is useful. Major features are change in size, irregular colour, and irregular shape, while minor features are inflammation, oozing, change in sensation, and diameter 7 mm or less. Lesions with any of the major features or three of the minor features are suspicious of melanoma. The mnemonic ABCDE is also used which stands for asymmetry, border irregularity, colour variegation, diameter more than 6 mm, and evolving (changing).
Four major clinicopathological variants of MM have been identified. Superficial spreading melanoma represents about 70% of melanomas and occurs most commonly on the legs in women and on the trunk in men. It presents as a flat, pigmented lesion with variegation in colour and an irregular border. Nodular melanoma accounts for about 15 to 20% of melanomas and presents as a papule or nodule on the trunk (usually in men) or limbs. There is frequently a history of rapid growth. This variant is more likely to be amelanotic (no pigmentation) and there may be a delay in diagnosis. Lentigo maligna, also known as Hutchinson’s melanotic freckle, occurs on the head and neck of older people who have been heavily exposed to sunlight. These are slow-growing in situ melanomas with the potential to progress to invasive melanoma (lentigo maligna melanoma) and metastasize. Acral lentiginous melanoma occurs on palmoplantar skin or the nail bed. It occurs in all races and therefore does not appear to be caused by exposure to the sun. A tendency to delayed diagnosis gives this variant a poor prognosis.
At presentation, 10% of cutaneous melanomas will have metastasized. The primary lesion may regress, leaving a hypopigmented patch, or the primary can be noncutaneous. Although systemic metastasis is predominantly to the lung, liver, brain, and bone, lesions can arise anywhere including bowel, kidney, and muscle. Localized skin metastasis is also common.
Atypical naevi, deeply pigmented seborrhoeic warts, and pigmented BCC may all simulate melanoma. Dermoscopy may be helpful in discriminating between melanocytic and nonmelanocytic lesions. Features of MM include a broadened pigment network, multiple colours, a blue-white veil, pseudopods, and peripheral black dots and globules.
The diagnosis should always be based on a full thickness excisional biopsy down to fat with a margin of 2 mm of normal skin around the lesion. Patients with Stage IIB melanoma or higher (Breslow’s thickness 2.01–4 mm without ulceration, or >4 mm or any Breslow’s thickness with metastases) will require further investigation including full blood count, liver function tests, chest X-ray, lactate dehydrogenase, and CT of chest/abdomen/pelvis.
The definitive treatment of localized disease is wide excision of the tumour with a normal skin margin of 0.5 cm for in situ melanoma (confined to the epidermis), 1 cm for tumours with a Breslow’s thickness of 1 to 2 mm and 2 to 3 cm for thicker lesions. Sentinel node (initial draining lymph node) biopsy with selective complete clearance of regional nodes is now performed in many centres for lesions with a Breslow’s thickness of more than 1 mm but remains an area of controversy.
Adjuvant therapy should be considered for those with positive lymph nodes or thick primary tumours who should be entered into available clinical trials. Multiple approaches have been tried including immunotherapy, vaccine therapy, and chemotherapy. High-dose interferon prolongs relapse-free survival, but no clear benefit in overall survival and carries significant systemic side effects.
Limited metastatic disease can be managed with excision or carbon dioxide laser ablation. Extensive recurrent disease in a limb can be treated with isolated limb perfusion with melphalan. About 15 to 20% of patients with visceral metastatic disease will have a temporary response to interleukin 2 (IL-2) or dacarbazine.
Breslow’s thickness is the distance from the granular layer to the deepest level of the tumour and is the most important prognostic factor in MM. Patients with lesions confined to the epidermis (melanoma in situ) have an approximate 5-year survival rate of 100%; those less than 1 mm, 95 to 100%; between 1 and 2 mm, 80 to 96%; between 2.1 and 4 mm, 60 to 75%; and lesions of more than 4 mm in depth, 50%. If a single lymph node is involved the 5-year survival is 45 per cent, if two lymph nodes are involved, the survival rate is 28%, but this rate drops to 9% if more than four lymph nodes are involved. The median survival time following metastasis is between 5 and 16 months.
It is likely that over the next 5 to 10 years, immunotherapy may provide hope for those patients with metastatic disease. In a recent study using autologous T cells transduced with high-affinity tumour antigen (MART-1), specific T-cell receptors produced dramatic remission in metastases in 2 out of 15 patients with metastatic melanoma. Clinical trials of targeted inhibitors, e.g. Raf and Kit inhibitors, in combination with chemotherapy will continue. Advances in genomic technology should provide new targets for investigation.
Other cutaneous malignancies
Cutaneous lymphomas are rare lymphoproliferative disorders of the skin, mainly of T or B-cell origin. The most common cutaneous lymphoma is mycosis fungoides (MF), a T-cell lymphoma.
Clonal lymphocyte proliferation has been ascribed to viral infection, chromosomal alterations, overexpression of oncogenes, or environmental toxins. Chromosomal aberrations associated with cutaneous T-cell lymphoma include losses on chromosomes 1p (38%) and 17p (21%) and gains on chromosomes 4/4p, 18, and 17q/17. These loci contain two well-known tumour suppressor genes, p53(17p) and PTEN(10q).
Biopsy of a patch or plaque lesion in MF shows prominent atypical lymphocyte invasion of the epidermis (epidermotropism), formation of intraepidermal collections called Pautrier’s microabscesses, and a band-like infiltrate in the papillary dermis. The clonal nature of the lymphocyte infiltration can be confirmed by demonstration of rearrangement of the TCRB gene by polymerase chain reaction. However, clonal T-cell populations are also found in inflammatory dermatoses. Immunohistochemistry shows that the lymphocytic infiltrate expresses T-cell antigens (CD2, CD3, CD4, CD5) with loss of CD7 and CD26.
Mycosis fungoides most commonly occurs in the fourth to fifth decade and is approximately twice as common in black individuals as it is in white individuals.
Mycosis fungoides—the typical clinical presentation of MF is with brownish-red patches and plaques. Some lesions may have an annular or serpiginous configuration and poikiloderma (telangiectasia, pigmentation and atrophy), particularly on the breasts and buttocks. Some patients will progress to develop thicker plaques and tumours. Widespread erythroderma with ulcerated tumours is the final stage of the disease. Other clinical variants that may have the immunophenotypic features of MF include granulomatous slack skin disease, follicular mucinosis and large plaque parapsoriasis.
Sézary’s syndrome—this is part of the spectrum of MF and is characterized by generalized erythroderma (‘red man’) with scaling and pruritus, lymphadenopathy, and circulating atypical lymphoid cells (Sézary cells) which have cerebriform nuclei (usually >1000 atypical lymphocytes/mm3).
Adult T-cell leukaemia/lymphoma—this is a high-grade CD4-positive lymphoproliferative disorder associated with infection with human T-lymphotropic virus 1 (HTLV-1). It is most common in Japan and in the Caribbean and in immigrants from these regions. The cutaneous manifestations include patches, plaques, and tumours. Atypical lymphocytes (clover leaf cells) are commonly seen in the peripheral blood. Extracutaneous manifestations include lymphadenopathy, hypercalcaemia, splenomegaly, pulmonary infiltrates, and opportunistic infections.
B-cell lymphoma—cutaneous B-cell lymphoma usually presents as grouped dermal nodules, sometimes in an annular configuration. These generally progress slowly and remain confined to the skin.
Other inflammatory skin disorders may simulate MF including psoriasis, eczema, and parapsoriasis.
A clinical diagnosis of MF is confirmed by a skin biopsy. Initial histology may be subtle and several biopsies may be required to see the histological features of MF. Initial clinical investigation of a newly diagnosed patient with MF should include a thorough history (looking for systemic symptoms such as fever, weight loss, night sweats) and examination (looking for lymphadenopathy or hepatosplenomegaly). Routine investigations should include full blood count/blood film, liver function tests, lactate dehydrogenase (an indicator of tumour load), and HTLV-1 antibodies. If lymph node enlargement is present, a lymph node aspirate/biopsy should be performed. Patients with an elevated lactate dehydrogenase (LDH), abnormal full blood count, or rapidly progressive disease should have a staging CT of chest, abdomen, and pelvis and bone marrow biopsy.
Potent topical corticosteroids are usually the initial treatment for limited patch or plaque stage cutaneous T-cell lymphoma (CTCL). Topical nitrogen mustard is also effective in adults with patch or plaque stage disease but application is time-consuming. Superficial (patch stage) disease also responds well to narrowband UVB, but psoralen ultraviolet A (PUVA) is better for plaque stage disease. Combined treatment with α-interferon improves the duration of response. Total skin electron beam therapy is a further option. Bexarotene, a synthetic retinoid-X receptor agonist, is a promising new therapy for CTCL with response rates of up to 70%, even in tumour stage disease. Bexarotene-related toxicity includes marked hypertriglyceridaemia and hypercholesterolaemia. Photopheresis and denileukin diftitox are other options for more advanced disease. Patients with resistant early stage disease or advanced disease should be offered entry into clinical trials where available.
Patients with early stage disease have a similar life expectancy to their peers. Patients presenting with tumours or erythroderma have a 10-year survival of approximately 40% (tumour-node-metastasis (TMN) Stage III or higher). Poor prognostic factors include presentation with extensive thick plaques, tumours, or erythroderma, a late age of onset, or folliculotropic histology.
There are many newer agents in development/trials directed at receptors, tumour-specific genes, or signalling pathways. These include alemtuzumab, a humanized anti-CD52 antibody that targets a cell surface antigen expressed on normal and malignant T-cells, individualized dendritic cell-based vaccines, depsipeptide, a histone deacetylase inhibitor molecule (in Phase I-II clinical trials), topical tazarotene, and allogenic haematopoietic stem cell transplant.
Leukaemic infiltrates of skin are known as leukaemia cutis. Leukaemia cutis is most commonly associated with myeloid subtypes of leukaemia, particularly acute monocytic or myelomonocytic leukaemias, but may also herald the transformation of myelodysplastic syndrome to leukaemia. It is less commonly associated with lymphatic leukaemia. The most characteristic lesions of leukaemia cutis are red-brown to violaceous papules, nodules, and plaques which may be purpuric from thrombocytopenia. The lesions may localize to sites of skin trauma or surgical scars. A granulocytic sarcoma (or chloroma) presents as a rapidly growing, firm nodule that at times has a green hue. This tumour is usually associated with acute myeloid leukaemia, and the greenish colour is related to myeloperoxidase in the granulocytes. Leukaemia cutis is usually an indicator of advanced disease. If there is diagnostic doubt, immunophenotyping of a skin biopsy may be helpful.
Skin metastases usually occur at a late stage of disease and indicate a poor prognosis. The most common skin tumour to metastasize to the skin is malignant melanoma. Frequent visceral primary sites that metastasize to skin include breast, stomach, lung, uterus, colon, kidney, prostate gland, and ovary. Metastases from other organs are transferred via lymphatic or haematogenous spread and this occurs in about 3% of cancer cases. The presenting lesions are often rather inflammatory in appearance. The most common presentation is isolated or multiple nodules. Intra-abdominal metastasis may produce an umbilical nodule, known as Sister Mary Joseph’s nodule. The primary cancer is often ovarian or gastric and this may be the presenting sign. Metastases from renal cell carcinoma are often very vascular. In breast carcinoma, metastases may present as inflammatory plaques resembling erysipelas (carcinoma erysipeloides). Breast cancer may also cause dermal oedema which resembles orange peel (peau d’orange). Rarely, infiltrative breast cancer metastases can cause scarring alopecia. The presenting lesion is usually excised to confirm the diagnosis. Immunohistochemistry can be performed with tumour-specific markers to confirm the primary source.
Paget’s disease of the nipple is the presenting feature of about 2% of breast cancers, usually intraductal carcinoma. It occurs most frequently in the 5th or 6th decade. Early changes may be very minimal, e.g. only a very small amount of nipple discharge. An erythematous plaque subsequently develops over the nipple and areola which may simulate eczema. The main differential diagnosis is nipple eczema which is almost always bilateral. A biopsy will confirm the diagnosis.
Langerhans cell histiocytosis
Langerhans cell histiocytosis is a rare disease of unknown aetiology, but characterized histologically by a proliferation of Langerhans cells expressing CD1a and CD207, and with the presence of Birbeck granules on electron microscopy. The clinical presentation varies with the nature of organ involvement and whether it is single system or multi system disease. Skin, bone, and lymph node are the most common sites of involvement, but other systems include liver, lung, gastrointestinal, endocrine, nervous system, and haematological. The characteristic skin presentation is the presence of greasy scales on the scalp, reminiscent of seborrhoeic dermatitis. On the trunk, the lesions are discrete, yellow-brown, scaly papules, often with areas of purpura. Ulceration in the flexures and groin is a common presentation in adults.