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May 2007: Skin changes may herald systemic disease

Which skin conditions suggest metabolic problems or malignancy?

How often do such skin changes occur without underlying disease?

When should patients with skin changes be referred?

Which skin conditions suggest metabolic problems or malignancy?

How often do such skin changes occur without underlying disease?

When should patients with skin changes be referred?

Skin changes can often be the first sign of the development of an internal malignancy or other disorder. These cutaneous markers can be divided into two major types: genetically determined syndromes with a cutaneous component (genodermatoses) and those that occur as a result of circulating factors produced by an underlying cancer (paraneoplastic syndromes).

One of the most common systemic diseases associated with skin lesions is diabetes; at least 30% of people with diabetes develop cutaneous manifestations in their lifetime,1 the most common being necrobiosis lipoidica.

In some cases this will herald the onset of the diabetes. Muller1 suggested that necrobiosis lipoidica may occur up to five years before the onset of diabetes. In other cases, investigations undertaken after the development of a skin condition may allow the early detection and possible treatment of a malignancy that would otherwise have been fatal. In the case of acanthosis nigricans, this may be the only symptom of an underlying gastrointestinal malignancy.

1 Diabetic peripheral neuropathy

Peripheral neuropathy leads to lack of sensation and an increased risk of ulceration. One UK study2 found that 5.3% of people with type 2 diabetes and 7.4% of people with type 1 or type 2 diabetes had a history of active or previous foot ulcer.

Diabetic peripheral neuropathy is more common in men and incidence increases with patient age and the severity and duration of diabetes.

The exact aetiology of diabetic peripheral neuropathy is unclear, and there are a number of theories as to its cause.

As well as diabetes there are many other causes of peripheral neuropathy, including vitamin B12 deficiency, alcohol excess, thyroid disease and vasculitic neuropathy. The pain associated with neuropathy can be severe, and treatment with tricyclic antidepressants such as amitriptyline, or anticonvulsants such as gabapentin and pregabalin, can help. More important, though, is educating sufferers about foot care to prevent injuries, such as the one in the photo, caused by cutting a toenail too short.

2 Xanthelasmata

Xanthelasma comes from the Greek xanthos (yellow) and elasma (beaten metal plate). The xanthomatoses are a group of conditions in which lipids are deposited in the skin. These lipid deposits are known as xanthelasmata. The condition usually occurs as a result of hyperlipidaemia, either as a primary genetic defect or as a result of defective metabolism of lipids.

Xanthelasmata are flat yellow/white plaques, most commonly seen around the eyes. In some cases, deposition occurs despite normal lipid profiles. Similarly, a reduction in blood lipid levels seems to have little effect on the lesions already present.

Treatment options include topical application of trichloracetic acid, argon and carbon dioxide laser ablation,3 electrodessication and cryotherapy.

3 Dupuytren's contracture

Dupuytren's contracture is a disease of the palmar fascia that causes shortening and thickening of the fibrous bands in the hands and feet, resulting in limitation of function in the fingers and toes. It can be associated with other conditions such as diabetes (5% of people with this condition have diabetes),4 and the incidence increases with increased duration of diabetes, smoking, chronic alcoholism, seizures and infection.5

The majority of cases are currently treated by surgery, but non-surgical treatments are available and include percutaneous needle fasciotomy and skeletal traction therapy.

4 Pyoderma gangrenosum

This is a rare ulcerative skin condition first described in the 1930s. In 50% of cases pyoderma gangrenosum is associated with underlying disease, such as Crohn's disease, ulcerative colitis, rheumatoid arthritis and multiple myeloma. The lesions start as tender nodules or sterile pustules and rapidly develop into large ulcers with a characteristic purple overhanging edge, as in the photo. There may be single or multiple lesions, typically on the lower legs, abdomen or face. The exact aetiology is unknown and prognosis depends on the underlying condition.

Treatment includes topical agents, such as tacrolimus ointment, systemic steroids, azathioprine, infliximab6 and hyperbaric oxygen.

5 Alopecia secondary to metastatic breast cancer

Skin secondaries can occur with a number of internal malignancies. Excluding melanoma, the most common tumour to metastasise to the skin is breast cancer, with an incidence of 23.9%.7 In this case the patient presented because she had developed areas of alopecia over her scalp. The areas looked atypical of alopecia areata, with a scar-like appearance and marked surface telangiectasia, so an incisional biopsy was taken. This revealed cells consistent with a breast malignancy; the concealed primary was subsequently located in the left breast.

6 Superficial thrombophlebitis

Presenting usually as tenderness and redness over the route of a superficial vein, superficial thrombophlebitis may be a complication of pregnancy and the early postpartum period. Increased platelet stickiness and reduced fibrinolytic activity are believed to play a role in the development of superficial thrombophlebitis. Sterile thrombophlebitis is rarely life threatening, but when simultaneous involvement of deeper veins is missed this may not be the case. Consequently deep vein involvement should always be considered until proven otherwise.

Differential diagnoses include lipodermatosclerosis, lymphoedema, lymphangitis, varicosities and soft tissue injury.

7 Acanthosis nigricans

First described in 1889, acanthosis nigricans presents as thickened, pigmented skin with a smooth velvety surface in flexures such as the axillae, under the breasts and even the hands and mouth. This rare condition is associated with underlying carcinomas of the gastrointestinal tract, especially the stomach.8 In many cases it appears in advance of other symptoms associated with the malignancy, making further investigation important once it has been diagnosed. It is common for affected areas to develop skin tags and warty lesions as well.

Although acanthosis nigricans is rare, a clinically similar condition – pseudoacanthosis nigricans – is much more common, but tends to be confined to the axillae in obese individuals and is not associated with visceral malignancy.

8 Sarcoidosis

Sarcoidosis is an uncommon, multi-organ condition with a predilection for the skin. Cutaneous involvement may be the first indication of its presence in other organs.

Other organs that may be affected include the lungs, eyes, liver, spleen, lymph nodes and bone. The cause of the condition is unknown, but biopsies of affected tissue reveal non-caseating granulomatous infiltrate with negative staining for tuberculosis and fungi. The condition may present in the skin in various ways, the most common being erythema nodosum; other variants include annular lesions, small facial papules and erythroderma. Invasion of old scars by sarcoid tissue is characteristic.

9 Toxic erythema of pregnancy

Also known as polymorphic eruption of pregnancy, and pruritic urticarial papules and plaques of pregnancy, toxic erythema of pregnancy is a common condition in which an intensely itchy eruption develops in the third trimester. It tends to affect younger women, with an incidence of 1 in 200 first pregnancies.9 It is associated with excess weight gain during pregnancy, fetal distress and postmaturity.10 The irritation tends to start in the abdominal striae and is followed by the development of symmetrical, discrete, red urticarial papules over the limbs and extremities.

Management options include general measures such as cool soothing baths, emollients, wet soaks and light cotton clothing. Patients should be reassured that the condition settles after delivery. However, it has a tendency to recur with future pregnancies.

10 Necrobiosis lipoidica diabeticorum

Muller1 found frank diabetes, related biochemical changes, glucose intolerance or positive family history of diabetes in 90% of presenting cases of necrobiosis lipoidica diabeticorum. The condition typically affects the lower legs and produces relatively symmetrical, smooth, well defined yellow plaques, often with associated telangiectasia and a waxy feel. In some cases the lesions may ulcerate.

Treatment with intralesional steroids can be of benefit, but as the lesions are usually relatively asymptomatic, unless they ulcerate many of those affected opt for no treatment. When ulceration occurs, excision of the affected areas with grafting has traditionally been the treatment of choice, but more recently infliximab has shown promise.11

11 Granuloma annulare

Often mistaken for ringworm, this skin condition has a similar appearance with well defined red annular lesions, most commonly on the hands, knuckles and feet. In the majority of cases there is no association with systemic disease. In this case, however, the patient had diabetes and the association between the two conditions is well documented.12

The aetiology is unknown but histology reveals a palisading granuloma in the dermis. The condition is twice as common in women as men and usually occurs in people under 30 years of age.

Left untreated the lesions will disappear spontaneously, or they can be treated with intralesional steroid injection or imiquimod.13 Patients need to be warned that, despite treatment, recurrence is common.

12 Striae

Stretch marks or striae, though often a non-significant idiopathic finding, may be associated with underlying adrenal overactivity, excessive stimulation by ACTH or iatrogenic steroid excess. In the case of Cushing's syndrome the striae will be associated with a plethoric moon-shaped face, increased intra-abdominal fat, hirsutism and acne. The striae are typically present on the trunk and limbs and may be purple in colour. Concern about their unsightly appearance is often the initial reason for presentation to primary care.

Dr Nigel Stollery Author

Dr Nigel Stollery
MB BS
GP, Kibworth, Leicestershire and clinical assistant in dermatology, Leicester Royal Infirmary

Diabetic peripheral neuropathy can contribute to diabetic foot ulceration Figure 1: Diabetic peripheral neuropathy Xanthelasmata. These lipid deposits usually occur as a result of hyperlipidaemia, but may be seen in people with normal lipid profiles Figure 2: Xanthelasmata Dupuytren's contracture is a disease of the palmar fascia that may be associated with diabetes, smoking, chronic alcoholism, seizures and infection Figure 3: Dupuytren's contracture Pyoderma gangrenosum is a rare skin condition that is associated with underlying disease such as Crohn's disease, ulcerative colitis, rheumatoid arthritis and multiple myeloma in 50% of cases Figure 4: Pyoderma gangrenosum Alopecia secondary to metastatic breast cancer. Excluding melanoma, breast cancer is the most common tumour to metastasise

to the skin Figure 5: Alopecia secondary to metastatic breast cancer Superficial thrombophlebitis commonly occurs during pregnancy or six weeks postpartum Figure 6: Superficial thrombophlebitis Acanthosis nigricans. This rare condition is associated with gastrointestinal cancers, especially of the stomach, and often appears in advance of other symptoms of the malignancy Figure 7: Acanthosis nigricans Sarcoidosis can affect many organs. Cutaneous involvement may be the first indication of its presence in other organs Figure 8: Sarcoidosis Toxic erythema of pregnancy. This common condition settles after delivery but tends to recur in future pregnancies Figure 9: Toxic erythema of pregnancy Necrobiosis lipoidica diabeticorum. A high proportion of cases are associated with diabetes, hence the name Figure 10: Necrobiosis lipoidica diabeticorum Granuloma annulare is not generally associated with systemic disease although there is a well documented link with diabetes

Figure 11: Granuloma annulare Granuloma annulare is not generally associated with systemic disease although there is a well documented link with diabetes Figure 12: Striae

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