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SIGNS OF INTERNAL MALIGNANCY, AND PARANEOPLASTIC SYNDROMES

A number of dermatoses are linked with internal neoplasia (Table 12.7). Some are rather non-specific and may have many other non-neoplastic causes (e.g. acquired ichthyosis), some have a sufficiently frequent link with malignancy generally that screening is appropriate (e.g. adult dermatomyositis), while others have such a close link that the site of associated malignancy can almost be assumed (e.g. acrokeratosis paraneoplastica). Selected examples are discussed here; direct metastases to the skin are covered in Chapter 33. Superior vena cava obstruction (Fig.12.52) is a mechanical problem rather than paraneoplastic but is conveniently illustrated here.

Figure 12.52 Superior vena cava obstruction causing dilated veins and plethora of the upper trunk and neck in a patient with bronchial carcinoma. Patients with superior vena cava obstruction are occasionally referred to dermatologists with suspected contact allergy (eyelid swelling) or angioedema (facial or hand swelling).

Acanthosis nigricans

The benign endocrine-associated form of AN, the most common type, was discussed earlier in this chapter. AN also occurs as a paraneoplastic phenomenon, usually in elderly patients, and is most frequently associated with adenocarcinoma of stomach. By contrast to the insulin-resistant type of AN, patients with paraneoplastic AN are usually older, losing weight, and have more florid AN (often involving oral and conjunctival mucosae, and the palms) of recent onset (Figs 12.53 – 12.55; compare with Figs 12.24 – 12.26).

Figure 12.53 Malignant acanthosis nigricans in the axilla. The lesions are much more warty than those occurring in the hyperandrogenic or insulin-resistant types, and occurrence in a thin, elderly patient is highly suspicious of gastrointestinal carcinoma.

Figure 12.54 Palmar markings and fingerprints are exaggerated in malignant acanthosis nigricans, and are known as tripe palms. This is the fingertip of the patient shown in Fig. 12.53.

Figure 12.55 Warty lesions on the eyelids of the same patient as in Fig. 12.53. She also had warty areas of the oral mucosa.

Dermatomyositis

About 25% of patients with dermatomyositis have an underlying malignancy, with approximately equal proportions diagnosed before, after, and at the time of the skin eruption. This disorder and the approach to diagnosis and evaluation are discussed in more detail in Chapter 13, but dermatomyositis is included here as it is one of the more characteristic paraneoplastic eruptions. Bronchial, colonic, breast, and genitourinary carcinomas are the most frequent associations with dermatomyositis.

Sign of Leser–Trélat

This sign is the sudden appearance of seborrheic keratoses in association with an internal malignancy (usually a gastrointestinal adenocarcinoma). It is somewhat subjective, as older patients (in whom most cancers occur) tend to have multiple seborrheic keratoses. In some cases, regression of keratoses after treating the malignancy supports the diagnosis. Screening all patients with multiple or itchy seborrheic keratoses is unlikely to be cost-effective, but suspicion is reasonable if the keratoses are multiple, small, itchy, and of concurrent recent onset (Fig. 12.56). They must not be confused with the small, eruptive acanthomas that occur during the resolution of erythrodermic disorders.

Figure 12.56 The sign of Leser–Trélat. This is sometimes overestimated, as multiple seborrheic keratoses are common in elderly patients, and this is the age group with the highest cancer risk. The important aspect is that the keratoses are eruptive and itchy. In this case, they occurred over a few months in a young adult who was found to have an ovarian carcinoma.

Glucagonoma syndrome

This is due to glucagon-producing tumors, usually arising in the pancreatic a  cells but occasionally at other sites in the gastrointestinal tract. It occurs mainly in middle-aged or older women. The rash it produces is known as necrolytic migratory erythema (Figs 12.57 and 12.58). It typically affects the perineum and other flexures, causing expanding macular lesions with erosions and crusting, which may resemble pemphigoid. Postinflammatory pigmentation may occur. Angular cheilitis and glossitis are common, and weight loss, diarrhea, glucose intolerance, and anemia are typical. The rash may precede the other symptoms by many years, and suspicion is required for any biopsy of a rash that shows histologic evidence of necrolysis in the superficial epidermis.

Figure 12.57 Necrolytic migratory erythema is the typical eruption of glucagonoma syndrome, and is typically crusted and rather annular, as shown here.

Figure 12.58 The sign of Leser–Trélat. This is sometimes overestimated, as multiple seborrheic keratoses are common in elderly patients, and this is the age group with the highest cancer risk. The important aspect is that the keratoses are eruptive and itchy. In this case, they occurred over a few months in a young adult who was found to have an ovarian carcinoma.

A significantly elevated plasma glucagon level confirms the diagnosis, and amino acid levels are often low, as gluconeogenesis is impaired (low valine, leucine, and isoleucine). Zinc levels may be low; the rash of zinc deficiency is similar (Fig. 12.59). Extensive radiology may be required to determine the tumor site; radioisotope localization (indium-labeled octreotide) is a recent development. Non-malignant causes of necrolytic migratory erythema with hyperglucagonemia should be excluded; these include administration of glucagon (to treat insulin-producing tumors), malabsorption (especially due to celiac disease), pancreatitis, and hepatitis.

Figure 12.59 (a,b) Acquired zinc deficiency: the skin eruption is similar to that of glucagonoma syndrome, although periorificial rash may be the only feature.

Treatment is by resection of the tumor if possible. Drug treatment includes somatostatin, octreotide, radioisotopes (indium-labeled octreotide), and chemotherapy (streptozocin); dietary supplementation with zinc and amino acids may also improve the rash.

Other paraneoplastic eruptions and clinical approach

Numerous eruptions, some rather non-specific, may on occasion be paraneoplastic. The clinical problem is often that of deciding which patients require investigation. Most tumors are commoner in older patients but, conversely, older patients generally have more reasons for some skin eruptions, and over-investigation may be detrimental. For example, itch is a feature of some malignancies, especially lymphomas, although there are numerous other causes of generalized pruritus, such as dry skin in the elderly (see Ch. 6). Itch may present as ‘eczema' or even as bruising due to scratching (Figs 12.60 and 12.61). Likewise, there are many causes of acquired ichthyosis; the clue that it is significant may be the degree, as it is sometimes dramatic, presenting as extensive asteatotic eczema (Fig. 12.62), especially in patients with lymphoma ( Fig. 12.48).

Figure 12.60 (Itch is a symptom that may be due to underlying malignancy. This patient has the butterfly sign of scratch marks confined to the areas she can reach (a). The lack of rash in the spared central back demonstrates that the visible skin lesions are secondary to the scratching rather than due to a specific rash. A chest radiograph (b) demonstrated a pleural effusion that was due to underlying malignancy.

Figure 12.61  Occasionally, itch may be sufficiently severe that patients whose response is to rub the skin rather than to scratch it may get prominent bruising. This patient had a carcinoma of the ovary.

In general, the more uncommon the pattern of eruption, then the greater the chance that it is significant (e.g. erythema gyratum repens). Other examples are given in Table 12.7.

Questions that may help to direct the approach to the patient include the following.

Figure 12.62 A rather poikilodermatous asteatotic eruption on the trunk. This was too prominent to be considered as an ordinary asteatotic eruption in an elderly man, especially on the trunk, and investigations revealed a carcinoma of the prostate.

Figure 12.63 Bazex syndrome: this is a psoriasiform paraneoplastic eruption that typically includes involvement of the nose, ears, and distal digits. It is associated with upper aerodigestive tract neoplasms.

PRACTICE POINTS

Consider an underlying systemic malignancy in any patient, especially the elderly and especially if non-specifically unwell or losing weight for unexplained reasons, and who has a rash that is:

White/Cox: Diseases of the Skin, 2ed.(c) 2006, Elsevier Inc. All rights reserved.