Cutaneous manifestations of cancer and chemotherapy
- acral erythema
- cutaneous metastasis
- epidermal growth factor receptor inhibitors
- genodermatoses
- paraneoplastic syndromes
It is important for general physicians to be aware of cutaneous signs and symptoms that may indicate the presence of an underlying malignancy. Broadly there are four categories to consider:
cutaneous metastasis/direct tumour spread
inherited cancer syndromes with cutaneous manifestations
cutaneous markers of exposure to carcinogens, and
paraneoplastic syndromes.
Knowledge of the cutaneous manifestations of systemic and targeted cancer therapy is also important.
Cutaneous metastasis/direct tumour spread
In general, the skin is an uncommon site of distant metastases (incidence 2–4%).1The most common primary sites in men are lung (24%), colon (19%) and oral squamous cell carcinoma (12%) and in women breast (69%), colon (19%) and ovary (4%).2Lesions appear as firm, red or blue nodules, often multiple and close to the site of the primary tumour. The scalp is a well documented site of metastasis for breast, lung and renal cancer. Sister Mary Joseph's nodule refers to a periumbilical nodule that can be associated with stomach cancer.
Direct infiltration of the skin is seen with carcinoma erysipeloides, which can be misdiagnosed as cellulitis, and carcinoma en cuirasse, a hard infiltrated plaque. Both are most commonly associated with breast cancer. Paget's disease is an intra-epidermal carcinoma seen in the nipple and areola area (mammary Paget's) or anogenital and axillary skin (extramammary Paget's).3Paget's disease of the breast presents as unilateral, sharply demarcated nipple eczema or erosion, often with bleeding or nipple discharge, in association with underlying intraductal adenocarcinoma of the breast or non-invasive carcinoma. Extramammary Paget's disease is characterised by an itchy, moist, well-defined erythematous plaque, typically in the anogenital area and most common in elderly women. It is often misdiagnosed as psoriasis or Bowen's disease (squamous carcinoma in situ). It is associated with a local adnexal tumour in 25% of cases and with an internal malignancy, usually from the genitourinary (GU) or gastrointestinal (GI) tract, in a further 12%.4Vulval disease is more commonly associated with GU tract cancer and perianal disease with GI tract cancer.
Key points
Direct infiltration of the skin with cancer can mimic cellulitis (carcinoma erysipeloides) or scleroderma (carcinoma en cuirasse)
Extramammary Paget's disease presents with persistent red plaques in the anogenital or axillary area
Specific cutaneous lesions can be markers of internal cancer (inherited cancer syndromes or genodermatoses); for example, sebaceous carcinoma/adenoma can be a marker of bowel cancer in Muir-Torre syndrome
Dermatomyositis is associated with underlying malignancy in 15–41% of cases
Epidermal growth factor receptor inhibitors are associated with a papulopustular facial rash, the severity of which is positively correlated with tumour response to treatment
Inherited cancer syndromes
Genetic cancer syndromes (genodermatoses) combine characteristic cutaneous features with a predisposition to internal malignancy. These include skin-GI polyposis syndromes such as Gardner and Peutz-Jeghers syndromes. In Muir-Torre syndrome sebaceous adenomas and carcinomas are associated with cancer of the GI (61%) or GU (22%) tract.5The internal cancers can be multiple but are usually indolent.6The detailed cutaneous and internal manifestations, inheritance pattern and malignant risk of these conditions, as well as for Cowden syndrome, multiple endocrine neoplasia type 2b and neurofibromatosis, are detailed in Table 1. This list is not exhaustive; more detailed reviews, including rarer syndromes, are available.1
Cutaneous markers of exposure to environmental carcinogens
Environmental carcinogens include arsenic, ionising radiation and vinyl chloride. Cutaneous effects of exposure and associated neoplasms have been reviewed elsewhere.7
Paraneoplastic syndromes
Paraneoplastic syndromes may indicate the presence of an underlying malignancy. There are a large number of these syndromes (Table 2) and they have a variable association with malignancy. This review article will focus on pointers suggestive of underlying malignancy in selected conditions.
Cushing's syndrome
Ectopic production of adrenocorti-cotrophic hormone (ACTH) resulting in Cushing's syndrome is seen with small-cell lung cancer, carcinoid tumours, neural crest, pancreatic and medullary thyroid carcinoma and thymoma. Features suggestive of ectopic production rather than pituitary dependent Cushing's disease include:
rapid onset of progressive symptoms
weight loss
severe muscle wasting
marked hyperpigmentation
hypokalaemia
diabetes, and
plasma ACTH above 200 ng litre−−1.
Severe hirsutism or virilisation suggests an adrenal tumour, which should be associated with low or undetectable plasma ACTH. Failure of plasma cortisol levels to suppress with a high-dose dexamethasone test is seen with ectopic ACTH production or an adrenal tumour. The ACTH level will differentiate these and computed tomography scanning can help localise the tumour.
Carcinoid syndrome
Cutaneous features of carcinoid syndrome include transient deep red or purple flushing of the head and neck and oedema. Telangiectasia, cyanosis, pellagra and features of Cushing's syndrome can also be seen.7The flushing is associated with systemic features including diarrhoea, cramping abdominal pain, asthma and right-sided heart failure. GI tract carcinoid tumours account for 85% of cases.7Biologically active peptides released by these tumours are removed in the portal circulation, indicating that hepatic metastases are already present at the time of symptom onset. Bronchial and ovarian carcinoids (15% of cases) can produce symptoms early in the course of the disease.
Necrolytic migratory erythema
A persistent erythematous scaly rash with annular borders, particularly affecting perioral, genital and flexural areas, is characteristic of necrolytic migratory erythema. There is often a painful glossitis and angular stomatitis. It is associated with glucagonoma of the pancreas. Over 50% of patients have metastases at the time of presentation.
Acanthosis nigricans
Acanthosis nigricans, a diffuse, velvety hyperpigmentation and thickening of flexural areas (eg axillae, groin, neck, inframammary area), progresses to a condition with a verrucous or papillo-matous appearance. Pointers that suggest a malignant cause include:
onset after 40 years
more extensive and severe involvement
mucosal lesions
exaggeration of normal skin markings on the knuckles and palms (tripe hands), and
weight loss and wasting.
Associated malignancies include GI (particularly stomach) or GU tract, breast, lung or lymphoma. Onset of the disease can predate or mirror the onset of the malignancy.
Dermatomyositis
Adult-onset dermatomyositis can be associated with malignancy. Estimates of the risk vary from 15–41%.8,9 The most common associated cancers are breast, lung, colon, pancreas and ovary. They may be diagnosed at the same time as or after the diagnosis of dermatomyositis.9Cutaneous manifestations include:
a heliotrope periorbital rash, often with associated oedema
Gottron's papules over the knuckles
periungual telangiectasia, and
poikiloderma (a triad of atrophy, pigmentation and telangiectasia).
Paraneoplastic pemphigus
A form of pemphigus, paraneoplastic pemphigus, is seen predominantly with haematological malignancy. It presents with particularly severe mucous membrane ulceration, blisters and erosions, predominantly on the upper body and palmoplantar target lesions. Diagnosis is made on histological and immunofluorescence findings.
Cutaneous manifestations of systemic and targeted cancer therapy
Non-specific cutaneous manifestations of traditional cytotoxic chemotherapy such as alopecia, xerosis and mucositis are well-known. Other cutaneous side effects include extravasation, hyperpigmentation of skin, hair, mucosae or nails, and acral erythema. Acral erythema (palmar-plantar erythrodysaesthesia syndrome/hand-foot syndrome) is most commonly seen with 5-fluorouracil and its prodrug capecitabine, as well as with doxorubicin and cytarabine.10It presents with a prodrome of tingling on the palms and soles, progressing over the course of a few days to burning pain, tenderness and oedema associated with well demarcated erythematous plaques. It resolves following cessation of chemotherapy, often with peeling.
New targeted cancer therapies include signal transduction inhibitors, encompassing epidermal growth factor receptor (EGFR) inhibitors and multik-inase inhibitors (Table 3). Both groups have well documented cutaneous side effects.
Epidermal growth factor receptor inhibitors
EGFR is a transmembrane protein inducing cell proliferation, migration and angiogenesis via a variety of signalling mechanisms. EGFR inhibitors are used in the advanced stages of malignancies which overexpress the receptor, including colorectal cancer and squamous cell carcinoma of head neck (cetuximab), pancreatic cancer (erlotinib) and non-small cell lung cancer (erlotinib and gefitinib). EGFR is constitutively expressed in many normal epithelial tissues including the skin and hair follicles, and cutaneous side effects of treatment are common (Table 4). The most frequent cutaneous side effect is a papulopustular eruption, affecting 24–91% of patients, depending on the drug used.11It is most common in patients treated with cetuximab and is characterised by multiple follicular or pustular lesions on the face, scalp, upper chest and back but may extend to the extremities and abdomen.12Crusting is seen in severe cases and an absence of comedones. There is a dose-dependent relationship between severity and incidence of the eruption. Several studies have shown a relationship between severity of the eruption and length of progression free and overall survival benefit following treatment. The eruption typically begins in the first two weeks of treatment and is reversible following treatment withdrawal.13
Case reports and reviews have described benefit with emollients, antibiotic treatment for secondary infection, standard acne treatments (topical retinoids and antibiotics, oral tetracy-clines) and, if necessary, dose reduction or cessation. Isotretinoin treatment of cetuximab eruptions has been described in three case reports.
Other cutaneous side effects of EGFR inhibitors include xerosis, nail changes (paronychia and pyogenic granuloma), hair abnormalities (brittle, fine, curly scalp hair, long eyebrows), pigmentary change and telangiectasia.14
Multikinase inhibitors
Multikinase inhibitors include imatinib and second-generation agents used in chronic myeloid leukaemia and GI stromal tumours, and sorafenib and sunitinib used in renal cell carcinoma. A rash/desquamation and acral erythema develop in two-thirds of patients treated with sorafenib and mild-to-moderate facial oedema is reported in 50% patients given sunitinib.11
Conclusions
An awareness of cutaneous manifestations of cancer can mean earlier diagnosis and possibly improved survival of affected patients. Cutaneous manifestations of cancer include metastasis, paraneoplastic syndromes and genetic cancer syndromes; these may present to general physicians in a variety of specialties. Cutaneous manifestations of systemic cancer therapies include specific side effects of targeted therapies, such as the papulopustular eruption seen with EGFR inhibitors and characteristic clinical presentations such as acral erythema.
- © 2009 Royal College of Physicians
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