Cutaneous Manifestations of Internal Malignancies: An Overview
Section snippets
Acanthosis nigricans and tripe palms
Acanthosis nigricans (AN) was initially reported by Pollitzer and Janovsky separately in the same edition of Unna's famous International Atlas of Rare Skin Diseases in 1890 [2]. Pollitzer [3] described a 62-year-old woman who developed characteristic findings, including areas of skin that “project above the general level almost like papillae ... to form a diffuse, discolored warty surface.” Although some 80% of AN is associated with benign conditions such as obesity and endocrine abnormalities,
Acquired ichthyosis
Acquired ichthyosis clinically resembles ichthyosis vulgaris, and is characterized by numerous symmetrical rhomboidal or fishlike scales, primarily on the arms and legs. The flexural surfaces are relatively spared. Acquired ichthyosis may be associated with a variety of disorders, including malnutrition, hypothyroidism, sarcoidosis, leprosy, acquired immune deficiency, and certain medication use. A subset of acquired ichthyosis may also be associated with an underlying malignancy, most commonly
Pityriasis rotunda
Pityriasis rotunda is a rare skin disorder characterized by circular, sharply demarcated scaling patches that are lighter or darker than the surrounding skin. The lesions typically occur on the trunk, are generally multiple, and may become confluent. There is no associated inflammation or pruritus. Some authors believe that pityriasis rotunda may represent a form of localized acquired ichthyosis [14]. The disorder was first described in Japanese patients. In one review, more than one third of
Acrokeratosis paraneoplastica
Acrokeratosis paraneoplastica (APN) was first described by Bazex and colleagues as a marker of malignancy in 1965. Bazex and Griffiths [16] described the progression of disease in three stages. The first stage is characterized by erythema and psoriasiform scaling of the fingers, toes, and margin of the helix, as well as violaceous erythema and pityriasiform scaling over the nasal bridge. Nail changes are frequent and may include tender nailfolds, subungual hyperkeratoses, and onycholysis. In
Erythema gyratum repens
Erythema gyratum repens (EGR) is a rare disorder and is considered to be highly specific as paraneoplastic syndrome [19]. It was first described in 1952 by Gammel [20], who reported a female who had an eruption consisting of “erythema in irregular wavy bands with … marginal desquamation.” He likened the pattern of the erythema to that of graining of a knotty cypress board, and noted that the bands moved constantly at the rate of about 1 cm per day [20]. Hands and feet were spared. The rash
The sign of Leser-Trélat
The sign of Leser-Trélat refers to the abrupt onset of and rapid increase in size and number of seborrheic keratoses. As a historical note, both Leser and Trélat made their observations about a link between angioma and malignancy [26]. De Bersaques [26] reports that Holländer was the first to note an association between seborrheic keratoses and malignancy. Because both seborrheic keratoses and malignancy are more common with increasing age, many have doubted the existence of this sign [27], and
Erythroderma
Erythroderma is a condition characterized by generalized erythema and desquamation. Generalized adenopathy, hypothermia, high-output cardiac failure, and hypoalbuminemia may be present. Though most cases are related to medications or pre-existing skin conditions such as atopic dermatitis, a subset is also linked to malignancy. In one series of 82 cases [32], 20% were related to lymphoreticular neoplasm, primarily cutaneous T-cell lymphoma (CTCL). In this series, CTCL was more likely to be the
Hypertrichosis lanuginosa acquisita
Hypertrichosis lanuginosa acquisita (HLA) was first described in 1865 in a patient who had a “thick crop of short and white downy hair” suffering from breast cancer [35]. Since that time, approximately fifty additional cases have been described in the literature [36]. The disorder was termed “malignant down” by Fretzin [37], and later given the current name based on the resemblance of the observed hair to the lanugo hair present during fetal development [38]. In 73% of cases, the disorder has
Sweet's syndrome
Sweet's syndrome was first described in 1964 as “acute febrile neutrophilic dermatosis” in a series of eight patients with the features of fever, neutrophilia, painful plaques on the limbs, face, and neck, and histologically a dense dermal infiltrate of neutrophils [43]. Since then more than 500 cases have been described, with a female predominance of 4 to 1 [44]. The associated conditions are varied and include many systemic disorders [45]. In most series, approximately 20% of cases are
Dermatomyositis
Dermatomyositis (DM) is characterized by clinical and laboratory signs of a proximal muscle extensor inflammatory myopathy and a photodistributed violaceous poikiloderma involving scalp, periocular, and extensor skin sites with nailfold telangiectasias [52]. When lesions occur on the knuckles and become lichenified, they are called Gottron's papules. Subsets of the disease include polymyositis (PM), in which the cutaneous features are absent, and amyopathic dermatomyositis, where the muscles
Paraneoplastic pemphigus
The concept of paraneoplastic pemphigus (PNP) has evolved from an initial observation that pemphigus occurred more frequently in patients who had known malignancy. This led to the recognition in 1990 by Anhaltz of a unique bullous disease with a characteristic autoantibody profile. Since that time, additional autoantibodies have been detected [60]. Although the presentation can be quite variable, the most constant feature is the development of painful and persistent stomatitis [61]. Other
Necrobiotic xanthogranuloma
Necrobiotic xanthogranuloma (NXG) was first described in 1980 by Kossard and Winkelmann [65]. This disease is characterized by multiple yellowish or xanthomatous plaques and subcutaneous nodules, often found in a periorbital distribution. A subset of lesions may ulcerate, and there is a predilection for lesions to develop in scars. Most cases are asymptomatic. In one review of 48 cases, 80% of cases in which protein electrophoresis was performed revealed an abnormality [66]. The majority had an
Multicentric reticulohistiocytosis
Multicentric reticulohistiocytosis (MR) is a rare disorder characterized by joint symptoms and papulonodular skin lesions. Fewer than 200 cases have been published [68]. About 40% of cases present with joint symptoms first [68]. A symmetric arthritis typically affects the hands. The skin lesions are typically skin-colored, dome-shaped, symmetrical papules or nodules. They are found on the upper half of the body, with hands being the most common site, followed by the face. The characteristic
Amyloidosis
Amyloidosis represents a diverse group of disorders that share the common feature of extracellular deposition of pathologic fibrillar proteins. The classificiation of amyloidosis is based on the nature of the precursor protein. In primary amyloidosis, clonal plasma cells produce immunoglobulins, usually lambda light chains that are amyloidogenic. The clinical features vary on the organs primarily affected. Renal failure is reported in 28% of cases, congestive heart failure in 17%, carpal tunnel
Scleromyxedema
Scleromyxedema or lichen myxedematosus was first reported by Dubreuilh in 1906 under the name “fibromes militaries folliculares” [5]. Specifically, scleromyxedema refers to the generalized variant of lichen myxedematosus with four features: (1) papular and sclerodermoid lesions, (2) mucin deposition and fibrosis with fibroblast proliferation, (3) monoclonal gammopathy, and (4) the absence of thyroid disease [74]. It is an uncommon disease with no gender predilection, which presents as a
Scleredema
Scleredema adultorum of Buschke is an uncommon dermatosis most frequently associated with diabetes mellitus; however, it has been reported to be a paraneoplastic syndrome in lymphomas and myeloma [78], [79], [80], [81]. Initially described in 1752 by Curzio, it was formalized in 1902 when Buschke described a patient who had progressive skin hardening that began at the neck after influenza [78]. It presents as firm, indurated non-pitting edema around the neck and upper back, and can progress to
Vasculitis and cryoglobulinemia
Purpura, which manifests as non-blanching violaceous or erythematous lesions secondary to red blood cell extravasation, may be rarely associated with underlying malignancy. The purpura may either be caused by vasculitis or cryoglobulinemia. According to a review by Wooten and Jasin [87], 1% of cases of vasculitis were associated with a lymphoproliferative disorder. The most common association is a leukocytoclastic vasculitis, of which palpable purura, particularly of the lower extremities, is
Hypertrophic osteoarthropathy
Clubbing refers to focal enlargement of the connective tissue in the terminal phalanges of the digits, especially on the dorsal surfaces. Clubbing is associated with a variety of underlying cardiopulmonary diseases. Hypertrophic osteoarthropathy (HOA) is a systemic disorder of the bones, joints, and soft tissues. It is characterized by clubbing of the digits, periosteal new bone formation, particularly of the distal extremities, and symmetric arthritis-like changes in the joints and
Necrolytic migratory erythema
Necrolytic migratory erythema (NME), or the cutaneous manifestation of the glucagonoma syndrome, was first described in 1942 by Becker and colleagues [5]. It is a widespread eruption that presents as irregular patches of erythema with superficial erosions, vesicles, and bullae. These lesions may have arcuate or polycyclic forms, and tend to be more prominent on the central areas of the body, often concentrating on the groin [90]. NME may also show lesions around the mouth, and patients may have
Carcinoid syndrome
Carcinoid tumors are derived from neuroendocrine cells most commonly found in the small intestine. Carcinoid tumors located within the gastrointestinal tract rarely cause cutaneous manifestations unless the tumor is metastatic to the liver. Carcinoid tumors outside of the gastrointestinal tract may produce symptoms in the absence of metastasis. In patients who have carcinoid syndrome, approximately 85% will have episodic flushing of the face, neck, and upper chest [102]. Over time, with
Cushing's syndrome
Cushing's syndrome is seen in the setting of either endogenous or exogenous elevated glucocorticoids. The majority of cases of endogenous glucocorticoid excess are caused by an anterior pituitary tumor; however, a small proportion are caused by tumors, which ectopically produce adrenocorticotropin hormone. Typical features of Cushing's syndrome include altered subcutaneous fat distribution leading to a “buffalo hump” over the dorsal neck and “moon facies,” as well as central obesity. In
Pruritus
When the lengthy list of nonmalignant causes is carefully eliminated, cancer as a cause of itch must be sought. Numerous malignancies are associated with pruritus as a paraneoplastic manifestation, including breast carcinoma, carcinoid syndrome, cutaneous T-cell lymphoma, and gastrointestinal cancers [104]; however, generalized itching without an associated eruption has most frequently been associated with Hodgkin's disease and may occur in more than 25% of these patients [105]. The etiology of
Summary
This article summarizes the clinical and histologic features of many cutaneous disorders that may be associated with underlying malignancies. For some of these conditions, such as erythema gyratum repens, the likelihood of malignancy can be quite high. For others, such as acquired ichthyosis, the strength of association is considerably weaker. Recognition of any of the paraneoplastic skin disorders reviewed here should raise suspicion for an occult malignancy. The decision to pursue further
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