Introduction

Malignancies of the skin are among the most common cancers known to man. In benign tumours, there is a proliferation of well-differentiated cells with limited growth, whereas in a malignant tumour, the dysplastic cells are undifferentiated and expand in an uncontrolled manner. The carcinogenic effect of the sun is thought to play a key role in many types of skin cancer. One hundred years ago, a tanned skin indicated outdoor work. Nowadays, many individuals deliberately seek the sun for the purposes of tanning. Longer holidays, cheap flights and a fashion to be tanned and an increasing 'hole' in the ozone layer may all have contributed to the doubling of melanoma incidence over the past decade.

High-intensity ultraviolet (UV) light can lead to sunburning episodes in fair-skinned individuals, and this is thought to be a risk factor for melanoma, the most serious form of skin cancer.

However, recently there has been an increasing global awareness concerning the dangers of strong sunlight. Public health campaigns such as 'slip slop slap' ('slip on a shirt, slop on sunscreen and slap on a hat') in Australia have been very successful at modifying people's behaviour in the sun. Skin cancer is deemed by many to be a 'preventable' form of cancer. The visible nature of skin cancer means detection should be straightforward by the trained eye, although histological confirmation is essential. Early recognition of malignant skin tumours by medical practitioners is essential in order that patients suffer minimal morbidity and avoid skin-cancer-induced mortality.

Premalignant skin tumours

Actinic keratoses

Actinic keratoses (AKs) occur on exposed skin, particularly in those who have worked outdoors or have been exposed to short intervals of high-intensity UV. AKs occur on the face (including the lip), dorsal hands, distal limbs, and bald scalp, particularly in those with fair/sun-damaged skin and increasing age (Figure 23-1). Clinically, their appearance varies from a rough area of skin to a raised keratotic lesion. They have an irregular edge and they are usually less than 1 cm in diameter. Histologically, AKs have altered keratinisation, which may lead to dysplasia and eventually invasive squamous cell carcinoma (SCC). Malignant change may be suspected in an AK that suddenly grows rapidly, becomes painful or inflamed.

Management

Treatment with liquid nitrogen (cryotherapy/cryosurgery) by a medical practitioner is usually effective for individual lesions with cure rates of around 70% (see Chapter 24). Efficacy is less effective for very hyperkeratotic lesions and those on the forearms/hands. Various topical preparations that can be applied by patients themselves are currently available. 5-Fluorouracil (5-FU) 5% cream (Efudix^®) and 0.5% solution (Actikerall^®) are useful in treating large areas of sun-damage with multiple AKs and is applied once daily for four to six weeks. The 5-FU kills any dysplastic keratinocytes and therefore produces brisk inflammation at the application site. Patients may therefore need to stop using the cream for a few days during the treatment course if discomfort is severe. Currently, 5-FU appears to be the most cost-effective treatment for AKs.

Imiquimod 5% (Aldara^®) is an immunomodulatory preparation that recruits immune cells to the area of skin where it is applied, which then attack the dysplastic cells. Imiquimod is applied three times a week for four months. 3.75% imiquimod (Zyclara^®) has recently been launched and should be used daily for two weeks, one week off and then treatment repeated for a further two weeks. There is some evidence that memory T-cells are induced by this therapy, resulting subsequently in lower numbers of clinical AKs.

Topical non-steroidal anti-inflammatory diclofenac (Solaraze^®) has been shown to be effective against small AKs if it is used regularly twice daily for three months. This treatment seems to produce less skin irritation than 5-FU or imiquimod.

Ingenol mebutate gel (Picato^®) is a recent addition to the treatment choice for AKs. It is a cytotoxic agent derived from milkweed plants that is formulated in two concentrations 0.015% (for the face once daily for three consecutive days) and 0.05% (for the trunk and limbs once daily for two consecutive days). Its effects are mediated by a brisk inflammatory reaction at the site, and the rates of clearance are reported between 34% and 42%. At 1-year follow-up, relapse rates are reported to be around 50%.

Photodynamic therapy (PDT) (see Chapter 25) has been shown to be as effective as 5-FU in the treatment of AKs. PDT is carried out by a medical practitioner rather than the patients themselves and can treat large areas of skin. The main limitation of PDT is usually the patient's ability to tolerate the burning pain felt in the skin during delivery of the treatment. Daylight PDT can also be used, with the advantage of treating larger areas of skin simultaneously and there is less pain and 'downtime'. Cosmetic outcomes for the treatment of AKs are reported to be best with photodynamic therapy and imiquimod as opposed to 5FU and cryotherapy. Any lesions not responding to the above measures should be biopsied to check for invasive malignancy.

Bowen's disease

Bowen's disease is SCC in situ; SCC occurs in the epidermis with no evidence of dermal invasion. Bowen's disease is more common in the elderly and is seen most frequently on the trunk and limbs. Risk factors for Bowen's disease include solar radiation, human papillomavirus warts (HPV 16), radiotherapy, ingestion of arsenic in 'tonics' and exposure to chemicals. Clinically, Bowen's disease is characterised by well-defined, erythematous patches with slight crusting (Figure 23-2). Lesions enlarge slowly and may reach up to 3 cm in diameter. After many years, invasive carcinoma may develop. Bowen's disease may be confused with a patch of eczema or superficial basal cell carcinoma (BCC). Erythroplasia of Queyrat is a similar process occurring on the glans penis or prepuce.

Skin biopsy can confirm the diagnosis histologically. Management includes excision, curettage and cautery, cryotherapy, 5-FU, imiquimod 5% and PDT (see Chapters 24 and 25).

Malignant skin tumours

Basal cell carcinoma (BCC)

This is the most common cancer in humans with a lifetime risk of around 30%. Known risk factors for BCC include increasing age, fair skin, high-intensity UV exposure, radiation, immunosuppression, previous history of BCCs and congenital disorders such as Gorlin's syndrome. Sun-exposed skin in the 'mask area' of the face is most frequently affected. Typically, lesions start as small papules that slowly grow. Lesions often have a 'pearly' shiny translucent quality. Colour varies from clear to deeply pigmented. The tumour is composed of masses of dividing basal cells that have lost the capacity to differentiate any further. As a result, no epidermis is formed over the tumour and the surface breaks down to form an ulcer, the residual edges of the nodule forming the characteristic 'rolled edge'. Once the basal cells have invaded the deeper tissues the rolled edge disappears.

Types of BCC

Nodular lesions appear as small papules or nodules with a rolled edge (Figure 23-3) and frequently a central depression that may become ulcerated. The nodules are pearly and may have dilated telangiectatic vessels on their surface. The histological features of BCC show collections of basaloid tumour cells (Figure 23-4), the pattern of which determines the histological type (i.e. nodular, superficial, morphoeic, cystic, etc.). Determining the tumour type histologically prior to definitive treatment ensures that the most appropriate management plan can be devised for each patient. If the initial tumour is incompletely excised/inadequately treated, then the BCC can recur (Figure 23-5). Many BCCs on the face are now treated routinely with Mohs' micrographic surgery to ensure that the tumour is fully resected (see Chapter 24) at the primary procedure.

Superficial lesions appear as an erythematous patch on the skin, often on the trunk. They may be mistaken for a patch of eczema or tinea but are not usually pruritic and slowly enlarge (Figure 23-6). A firm 'whipcord' edge may be present.

Pigmented lesions can lead to confusion with naevi, seborrhoeic keratoses and melanoma (Figure 23-7).

Morphoeic or sclerosing type appears as a superficial atrophic scar in the skin. There is loss of the normal skin markings and the edge is usually indistinct (Figure 23-8). This can lead to incomplete excision of these infiltrative BCCs and therefore Mohs' micrographic surgery may be indicated (see Chapter 24) to ensure surgical cure.

Management of BCC's

The growth pattern determined histologically usually guides management, so most tumours are biopsied prior to definitive treatment. The site and the size of the BCC, comorbidities, and patient preference all guide what treatment option is most suitable. Treatment options include excision (including Mohs' micrographic surgery), excision and grafting, curettage and cautery, radiotherapy, cryotherapy, imiquimod 5% and PDT for large superficial BCCs (see Chapters 24 and 25). For advanced or metastatic BCCs unsuitable for surgery/radiotherapy oral Vismodegib (ErivedgeVISHAL) 150 mg daily can be taken. Erivedge has been shown to shrink 30-40% of tumours by blocking the abnormal signalling found in the Hedgehog pathway (present in 90% of BCCs).

Decisions as to the optimum therapy for each individual patient is complex and is therefore frequently discussed with the patient at a multidisciplinary skin cancer meeting including dermatologists, plastic surgeons, oculoplastic surgeons, oncologists, and specialist cancer nurses.

As a rule, surgical scars will improve with time compared to radiotherapy sites which tend to deteriorate cosmetically. Mohs' micrographic surgery is becoming the 'gold standard' for complete excision of BCCs on the face/scalp, particularly those near the eyes and other vital structures where identifying clear tumour margins is essential to preserve normal tissue and function. Large nasal tip lesions may be more optimally treated with radiotherapy as this can be a difficult site for grafting.

Squamous cell carcinoma (SCC)

SCC is the second commonest skin cancer after BCC. Risk factors for SCC are similar to BCCs but in addition SCC may develop in any chronic wound or scar (Marjolin's ulcer), and HPV is thought to play a significant role in the pathogenesis. Transplant recipients who are medically immunosuppressed seem to be particularly susceptible to the development of SCCs which may be HPV mediated.

Dysplastic proliferations of abnormal keratinocytes may arise de novo or in pre-existing skin lesions such as AKs or Bowen's disease. By definition, SCCs have invasive tumour cells within the dermis. Seventy percent of lesions occur on the head and neck. Clinical suspicion of an SCC arises when lesions are rapidly growing, painful, and markedly hyperkeratotic (Figures 23-9 23-10 23-11 ). SCCs are usually nodular with surface changes including crusting, ulceration, or the formation of a cutaneous horn. Some lesions can be verrucous and therefore mistaken for viral warts, or indeed arise from a chronic viral wart. High risk sites for metastases include SCC on the lip, ear, hands/feet, and genitalia.

Keratoacanthoma is thought to be a variant of SCC, and current thinking dictates these should be treated as if they are indeed SCCs. These lesions typically appear rapidly over a few weeks and have a characteristic central crater within the nodule (Figure 23-12). They may spontaneously regress, leaving a significant scar which has led to debate about their exact nature and how they should be managed. Histologically, they look malignant and most specialists feel comfortable treating them as for an SCC.

Regional lymph nodes should be palpated to look for local metastases for any lesions suspicious of an SCC; in addition, involvement of other organs such as the liver, lung, or brain may occur. A computed tomography (CT) scan may be indicated for very large or aggressive lesions before decisions concerning management.

Management of SCC's

Management of these patients should ideally be discussed at a multidisciplinary team meeting with the patient (see section on management of BCC).

Surgical options. Ideally lesions should be excised with a 4-6 mm margin. Skin grafting may be required depending on the size of the lesion and the site. Tumour curettage and cautery (three passes over the affected area) can be highly successful in experienced hands.

Medical options. Radiotherapy can provide excellent results for tumours not amenable to surgery. Radiotherapy does, however, involve multiple trips to the hospital and symptoms of pain at the site during healing. In patients who develop multiple SCCs such as renal transplant patients, secondary prophylaxis with oral retinoids may be considered. These have been shown to reduce the number of new lesions appearing if taken indefinitely.

Moles/naevi: benign or malignant?

The term naevus (mole) is derived from the Greek word meaning 'nest', which is formed by a proliferation of melanocytes. Benign moles generally develop minor changes over the years as they mature (becoming slightly more protuberant). More rapid changes can occur during pregnancy. However, rapid change may indicate transformation into melanoma. The ABCDE acronym is a useful guide for assessing the malignant potential of a mole: asymmetry, border (irregular), colour (irregular), diameter (>0.5 cm), evolving (Box 23-1). Any symptoms such as pain, crusting, ulceration, or bleeding may also indicate malignant transformation. Patients can be educated about what changes to look for in their own moles, particularly the 'ugly duckling sign' which has been shown to be very helpful. A medical practitioner should always try to examine all the patient's skin and look for any mole that 'stands out from the crowd' (ugly duckling sign).

Dysplastic naevi

These are moles that look atypical ('funny-looking moles'). They are often deeply pigmented and have an irregular margin (Figure 23-13). Clinically and histologically, they have features of very early malignant change and therefore could progress to melanoma. Thirty percent of superficial spreading melanomas are thought to arise from pre-existing moles, 70% of melanomas appear de novo.

Some patients have multiple atypical moles and may have the so-called dysplastic naevus syndrome. Usually, there is a family history of dysplastic moles. During adolescence, these patients acquire multiple pigmented moles most frequently on the trunk. Compared to normal moles, these naevi are larger and their pigment more heterogeneous. These patients often need regular monitoring by a skin specialist.

Melanoma

Melanoma is an invasive malignant tumour of melanocytes. Melanoma accounts for 4% of skin tumours but is responsible for 75% of skin cancer deaths. Most cases occur in white adults over the age of 30. Females are more commonly affected than males in the USA, but this trend is reversed in Australia. Solar radiation is a known carcinogen and is the main risk factor for melanoma, especially intermittent unaccustomed and high-intensity UV exposure particularly in childhood. Other risk factors include light skin tones, poorly tanning skin, red or fair-coloured hair, light-coloured eyes, female sex, older age, a personal or family history of melanoma, and congenital defect of DNA repair (xeroderma pigmentosum). The presence of giant congenital melanocytic naevi, one to four dysplastic naevi, multiple common moles, actinic lentigines, and change in a mole are additional risk factors for melanoma.

Incidence

The incidence of melanoma has tripled over the past 20 years. In Australia, 1 in 35 women and 1 in 25 men will develop melanoma during their lifetime. In Europe, there are 63 000 new cases of melanoma diagnosed each year, accounting for 2% of all cases. In the USA, the lifetime risk of developing melanoma is estimated to be 1 in 60.

Sun exposure

The highest incidence of melanoma occurs in countries near the equator with high-intensity UV throughout the year. However, skin type and the regularity of exposure to sun are also important. The incidence is higher in fair-skinned people who have concentrated high-intensity exposure on holiday than those with darker skin types who have regular exposure throughout the year. Sunburning episodes are thought to be a risk factor for melanoma. The most frequent site of melanoma in women is the legs while in men it is the trunk. This is thought to be a direct consequence of behaviour in the sun, that is women expose their legs and men remove their shirts.

Pre-existing moles

It is rare for ordinary moles to become malignant but giant congenital naevi and multiple dysplastic naevi are more likely to develop into melanoma. Thirty percent of melanomas are thought to arise from pre-existing moles.

Types of melanoma

Clinically, there are five main types of melanoma.

• Superficial spreading melanoma is the most common type. It is common on the back in men and on the legs in women. As the name implies the melanoma cells spread superficially in the epidermis, becoming invasive after months or years. The margin and the surface are irregular, with pigmentation varying from brown to black (Figure 23.14). There may be surrounding inflammation and signs of regression - pale areas within it/around it (Figure 23-15). Nodules may appear within the tumour when it becomes invasive, which worsens the prognosis.
• Lentigo maligna melanoma occurs characteristically on the face of elderly people. Initially, patients may have single or multiple solar lentigos which are benign and common but can look suspicious. However, over the years patients may develop a slowly growing, irregular, and larger pigmented macule (lentigo maligna) (Figure 23-16a), which if very large can be treated with imiquimod over many months rather than extensive surgery (Figure 23-16b); however, if a nodule/darker colour develops within the pigmented patch then suspect lentigo maligna melanoma (Figure 23-17).
• Nodular melanoma presents as a dark nodule from the start without a preceding in situ epidermal phase (Figure 23-18). It is more common in men than in women and is usually seen in people in their fifties and sixties. This tumour is in a vertical growth phase from the start and therefore has a correspondingly poor prognosis.
• Acral melanoma occurs on the palm and soles and near/under the nails. Benign pigmented naevi may also occur in these sites and it is important to recognise early dysplastic change (ABCDE - as above). A very important indication that discolouration of the nail is due to melanoma is 'Hutchinson's sign': pigmentation of the nail fold adjacent to the nail (Figure 23-19). It is important to distinguish talon noir, in which a black area appears on the sole or heel because of trauma - for example, sustained while playing sport - causing haemorrhage into the dermal papillae. Paring the skin gently with a scalpel will reveal distinct blood-filled papillae.
• Amelanotic melanoma. As the melanoma cells become more dysplastic and less well differentiated they lose the capacity to produce melanin and form an amelanotic melanoma (Figure 23-20). Such non-pigmented nodules may be regarded as harmless but in fact are highly malignant. A rare form but also highly malignant is the desmoplastic form of melanoma (Figure 23-21).

Prognosis

Prognosis depends on the depth to which the melanoma has penetrated below the base of the epidermis seen histologically: the so-called Breslow thickness of the lesion. This is measured histologically in millimetres from the granular layer to the deepest level of invasion. The depth alone can give an indication of prognosis: Breslow of less than 1.5 mm is associated with a 90% 5-year survival, 1.5-3.5 mm with a 75% 5-year survival and greater than 3.5 mm with only a 50% 5-year survival. These figures are based on patients in whom the original lesion had been completely excised. A recent study in Scotland has shown an overall 5-year survival of 71.6-77.6% for women and 58.7% for men. Ulceration, lymph node involvement and skin metastases are associated with a poorer prognosis and therefore accurate prognosis cannot be determined by Breslow thickness alone, Therefore, more accurate melanoma staging considers not only Breslow thickness but also ulceration, lymph node involvement, and metastases to distant organs. If melanoma is not recognised and excised, then melanoma satellites (small islands of melanoma nearby) may develop and ultimately metastases in transit (Figure 23-22) and/or distant metastases may spread haematogenously and via the lymphatics (Table 23-1).

Treatment of melanoma

If melanoma is suspected it should ideally be excised urgently in its entirety with initially just a 2-mm margin for histological analysis. Definitive treatment including wide local excision margins will be guided by the Breslow thickness (determined histologically) as well as any potential risk for lymph node involvement. The higher the Breslow thickness, the more likely that the draining lymph nodes may contain melanoma metastases. If a palpable lymph node is found on examination, then a fine needle aspiration or lymph node removal for cytology/histology respectively should be undertaken. If no lymph nodes are palpable but the Breslow thickness is greater than 1 mm, then the patient may be offered sentinel lymph node biopsy (SLNB) (this is the first draining node from the melanoma skin site), or ultrasound examination of the draining nodes.

Sentinel lymph node biopsy (SLNB)

The presence or absence of nodal metastases is a significant prognostic indicator. SLNB is therefore currently offered in some centres to patients who have a melanoma of greater than 1 mm Breslow thickness. SLNB is usually undertaken simultaneously with the wide local excision. To detect the sentinel nodes lymphoscintigraphy (which maps the lymphatics using technetium-99 m) is carried out, plus methylene blue dye is infiltrated around the excision scar and a gamma probe is used to identify positive nodes. All blue nodes and those with more than 10% radioactivity are identified as sentinel nodes. The sentinel lymph node/s are examined histologically for evidence of melanoma micrometastases. A false negative rate of between 4% and 12% is reported. If the sentinel lymph node is positive for melanoma then local lymph basin clearance and/or adjuvant therapy in a clinical trial is usually offered to the patient. Unfortunately, there is no evidence that undergoing SLNB and lymph basin clearance improves survival, but it is the most accurate currently available staging method.

Adjuvant therapies for melanoma

Patients with stage 4 disease (i.e. where melanoma has spread from its original skin site as satellite lesions in the skin or distant metastases) may be suitable to have adjuvant therapy (if complete surgical resection is not possible). Currently, there are three main types: immunotherapy, targeted therapy, and cytotoxic chemotherapy.

Immunotherapy with checkpoint inhibitors has been a recent advance in the adjuvant treatment of patients with known metastatic disease. Nivolumab, which targets programmed cell death protein 1 (PD-1), is currently the agent of choice following randomised trials which showed it had a better relapse-free survival (RFS) advantage (70% at 12 months) and lower adverse effect profile (14 vs 46%) over ipilimumab (50% RFS at 12 months). These results were irrespective of BRAF mutation status, stage 3 vs 4 disease, PD-1 status, extent of lymph node involvement and if ulceration was present/absent). Nivolumab was approved by the FDA as first-line treatment in this group of patients in December 2017 (either 240 mg every two weeks or 480 mg every four weeks). Ipilimumab is a monoclonal antibody that targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).

Some trials look at combination treatment and show better survival rates when Nivolumab was given first and then ipilimumab, rather than either agent being given alone. However, there was also more toxicity in the sequential combination treatment group, which on occasion meant treatment needed to stop.

Targeted therapy currently involves detecting and targeting gene mutations within the patient's melanomas. 50% of melanomas have a single gene mutation in BRAF. BRAF is a human gene that makes a protein called B-Raf which is a cell growth signalling protein. Mutations in the BRAF gene therefore lead to switching on of tumour cell growth, and the melanoma becomes addicted to the actions of B-Raf, the so-called 'oncogene addiction'. These novel targeted therapies such as vemurafenib, dabrafenib, and trame-tinib block the production of B-Raf protein resulting in tumour shrinkage prolonging survival by an additional six months. However, despite the continuation of therapy the melanomas eventually start to grow again by finding alternative pathways to stimulate tumour growth. Side effects of BRAF inhibitors include photosensitivity, joint pains/fatigue, and an increase in non-melanoma skin cancers (in about 25% of patients on vemurafenib or dabrafenib due to paradoxical activation of the mitogen activated protein kinase (MEK) pathway) that usually require surgical excision. Trametinib (MEK inhibitor) is also highly active against tumours containing BRAF mutations and are often given in combination with BRAF inhibitors to enhance overall survival rates.

Cytotoxic chemotherapy is now usually reserved as second or third line treatment for metastatic melanoma. High-dose interleukin-2 and interferon alpha treatment may help in some patients who are no longer responding to immune/targeted therapy, however there is no robust evidence showing increased overall survival.

Melanoma vaccines may provide hope for future patients with clinical trials currently underway in patients with stage 4 melanoma. Preliminary results show that by immunising patients with their own functionally mature dendritic cells that have been modified to produce interleukin-12p70 this switches on the production of cytotoxic T-cells which are directed against gp100 tumour antigen. This vaccination process boosts the patient's ability to kill tumour cells in a very specific way. Further larger studies are needed to assess response rates and 5-year survival data.

Cutaneous lymphoma

Cutaneous lymphoma results from abnormal T or B lymphocytes invading the skin.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of disorders that account for 80% of primary cutaneous lymphomas (B-cell types 20%). The most common form of CTCL is mycosis fungoides (MF), which is more common with increasing age, male sex, and black skin. MF has a relatively good overall prognosis, but some individuals may have more aggressive disease. Clinically, MF may initially resemble eczema, psoriasis, or fungal infections. Patients have scaly erythematous patches and plaques on the skin, particularly on the trunk and buttock area (Figure 23-23). These may be itchy or asymptomatic. Lesions usually remain fixed and do not respond to mild topical steroids or antifungal creams. These lesions may remain stable for many years but eventually may transform to tumour stage disease when nodules may appear in long-standing plaques or arise de novo.

Five percent of MF patients develop a generalised exfoliative erythroderma with lymphadenopathy and atypical peripheral T-cells (Sézary cells): the so-called Sézary syndrome. This is considered to be a more aggressive form of MF. A clone of malignant T-cells can be demonstrated in the skin, lymph nodes, and blood by T-cell gene rearrangement studies.

Management of early patch stage MF is usually with potent topical steroids, topical nitrogen mustard and phototherapy (psoralen ultraviolet A [PUVA]). Plaque or tumour stage disease may be managed with localised radiotherapy or for more extensive plaques/tumours total skin electron beam therapy.

Results from multiagent chemotherapy regimens have been disappointing. Over the past decade, an oral synthetic rexinoid (a subclass of retinoid that activates retinoid X receptors) bexarotene has been used to treat more advanced CTCL with an overall response rate of 75%. Adverse effects may prohibit optimal dosing in some patients who may develop hypothyroidism, raised triglycerides, abnormal liver function tests, glucose abnormalities, and neutropenia. Brentuximab vedotin (anti CD-30 antibody conjugated to a tubulin disrupting agent) can be effective at treating tumour stage disease. For erythrodermic MF in addition to the above agents alemtuzumab (anti CD52) can be of benefit.

Allogenic stem cell transplantation has been used in small numbers of patients with CTCL no longer responding to conventional therapies. High or conventional dose (non-myeloablative) chemotherapy with/without radiation therapy is given to patients prior to an infusion of donor stem cells. Small cases series report 75% of patients remaining disease free at five years; however, 25% of patients died from complications related to the stem cell transplant.

Primarycutaneous B-cell lymphomas (CBCL) arise from a malignant transformation of B-cells at different stages of their development, leading to different types including follicular, marginal zone, diffuse large B-cell 'other' and diffuse large B-cell on the leg (the latter has a worse prognosis). Clinically, lesions present as firm indurated papules, nodules, or plaques that may be erythematous, violaceous, or brown (Figure 23-24).

Management of B-cell lymphoma depends on the type but as a general rule, low-grade solitary lesions can be treated with surgical excision, localised radiotherapy, intralesional interferon alpha or intralesional rituximab. Multiple lesions can be treated with systemic rituximab. High-grade poor-prognosis CBCL may be managed with pegylated liposomal doxorubicin or CHOP chemotherapy (cyclophosphamide, hydroxydaunorubicin, oncovin (vincristine), and prednisolone).

Other cutaneous malignancies

Paget's diseaseof the nipple presents with unilateral non-specific erythematous changes on the areola/nipple spreading to the surrounding skin. The cause is an underlying adenocarcinoma of the ducts. It should be considered in any patient with eczematous changes in one breast that fail to respond to simple treatment (Figure 23-25). Extra-mammary Paget's can affect the axillae and groin.

Metastases from internal organs most commonly spread from cancers of the breast, lung, GI tract, renal tract, oral pharynx, larynx, and melanoma (originating from the retina and leptomeninges). Early recognition of cutaneous metastases may allow accurate and rapid diagnosis of internal malignancy and expedite possible curative therapies.