More than a quarter century ago, Curth proposed the following criteria to define a paraneoplastic syndrome:
The malignancy and syndrome must appear at the same time, and their clinical courses should not significantly differ
Remote cutaneous manifestations should be specific to the tumor causing them
Paraneoplastic syndromes should be uncommon relative to the prevalence of the cancer
The paraneoplastic syndrome and the cancer should be demonstrably associated
These criteria have remained valid but are perhaps overly stringent, because cancers are often difficult to detect and may exert subtle physiologic influence without their presence being known. Study of these syndromes has contributed to the understanding of the effect of cancerous biology on the skin.  This article focuses on cutaneous paraneoplastic syndromes caused by solid tumors.
A wide range of cutaneous signs may be related to internal malignancy. These include the following:
Metastasis - Eg, leukemia cutis, cutaneous T-cell lymphoma, and Paget disease of the breast
Nonspecific metabolic effects related to inanition - Eg, wasting, alopecia, and xerosis
Infections related to immunosuppression  - Eg, herpes zoster
Signs resulting from compromise or dysfunction of the affected organ - Eg, jaundice
Paraneoplastic syndromes - Diverse dermatologic entities that signal the presence of a remote malignancy
Cutaneous manifestations may develop before a diagnosis of malignancy is determined; thus, these findings may aid the physician in the early identification of malignancy.
See the image below.
Acanthosis nigricans (AN) manifests as a hyperpigmented, velvety thickening of the skin that usually occurs in the intertriginous zones, including the axillae, groin, neck, and inframammary folds. AN may develop in areas subjected to trauma, such as the extensor surfaces of the knees and elbows. As many as 30% of patients also have papillomatous thickening of the oral mucosa. Patients who have AN associated with malignancies also have skin changes involving the scalp, areolae, and eyelids.
The appearance of paraneoplastic AN usually coincides with the presence of malignancy, but it can precede or follow the diagnosis of cancer and thus may signal a relapse in patients with a history of cancer.
The diagnosis of AN is based on clinical findings alone and can be supported by the histopathologic changes of hyperkeratosis and papillomatosis of the epidermis. Acanthosis is seldom present, and hyperpigmentation is related to hyperkeratosis, not melanin deposition; therefore, the condition is misnamed.
Not all patients with AN have a paraneoplastic syndrome. Familial AN, drug-induced AN, AN occurring in hyperinsulinemic states (eg, diabetes, obesity), AN associated with polycystic ovary disease, and AN associated with a spectrum of autoimmune disease in women should be considered before AN is determined to represent a paraneoplastic syndrome.
Clinical features suggestive of paraneoplastic AN include the development of AN in nonobese elderly persons and the rapid extensive progression of florid skin lesions in unusual locations, such as the mucosal membranes, palms, and soles of the feet. Other paraneoplastic syndromes that commonly occur with AN include tripe palms and the sign of Leser-Trélat (which are discussed below). [3, 4]
In a patient presenting with AN, key features of the medical history should include age of onset, history of diabetes or hyperandrogenism, new medication (steroids, oral contraceptives, estrogen replacement) use, cancer risk assessment, and family history.
Most cases of paraneoplastic AN involve an adenocarcinoma, most commonly one arising in the gastrointestinal tract (stomach or liver  ) and less commonly in the lungs, ovaries, uterus, breasts, kidneys, prostate or bladder.  Case reports have described AN associated with hematologic malignancies, including acute myeloid leukemia, and even benign gastrointestinal neoplasms.
The pathomechanism of paraneoplastic AN is unknown. Benign conditions associated with AN involve insulin resistance and hyperinsulinemia, but insulin levels are not elevated in persons with paraneoplastic AN. One well-studied patient with AN had elevated levels of transforming growth factor (TGF)–alpha; surgical excision of the malignancy was associated with a decline in TGF-alpha levels and resolution of the AN. Activation of signaling pathways by binding of growth factors to specific skin receptors could play a primary role in the pathogenesis of paraneoplastic AN, but more study is needed.
No specific effective therapies are available for AN. Treatment should be directed at the associated underlying condition. Although isolated reports have described combination chemotherapy aiding distressing symptoms associated with paraneoplastic AN,  the condition often does not improve with treatment of the underlying cancer. However, complete remission of AN has been reported with tumor regression, while the recurrence of AN has been associated with progression of internal malignancy. 
The persistence of skin lesions in patients with paraneoplastic AN does not necessarily indicate that the cancer treatment has failed. Calcipotriene, retinoids, and urea have been used as topical therapy; no single treatment is considered effective.
Acquired ichthyosis (AI) is extremely rare and is virtually clinically indistinguishable from autosomal dominant ichthyosis vulgaris.  Both conditions manifest with small, whitish to brownish, polygonal scales that lift up at the free edge and are widely distributed on the trunk and extensor surfaces of the extremities. The palms and soles are usually spared. This condition is associated with a variety of chronic illnesses, including malignancy.
Malignancy-associated AI may occur at any point in the course of the cancer. In the case of Hodgkin disease, AI often precedes the diagnosis of lymphoma and may be the initial manifestation.
The diagnosis of paraneoplastic AI is based on history and clinical findings. An adult onset of ichthyosis is critical in establishing the diagnosis of AI; a family history of scaling and early onset (age 3mo) supports a diagnosis of congenital AI. Skin biopsy findings are not diagnostic, but sometimes they can support the clinical impression.
The epidermis has moderate orthohyperkeratosis and parakeratosis. Sometimes, mild acanthosis and thinning of the granular layer are present or the granular layer may be absent. Superficial perivascular lymphohistiocytic infiltrates may be present in the dermis.
Patient demographics are not significantly different from those expected with the associated underlying cancer. The cause of AI is not ascertainable by means of clinical examination of the skin alone. As with AN, unless cancer is strongly suggested based on clinical findings, nonmalignant disease associations, which are far more common than malignant associations, should be excluded first. Thus, the diagnosis of paraneoplastic AI becomes a diagnosis of exclusion.
The differential diagnosis of AI includes xerosis or asteatotic eczema. Some drugs, including lansoprazole, niacin, retinoids, and the statin class of lipid-lowering drugs, cause clinically significant, generalized xerosis. As a paraneoplastic syndrome, AI is often impossible to distinguish from drug-induced ichthyosis; thus, the patient's history remains critical in the diagnosis.
Associated noncancerous conditions
AI is associated with a number of chronic, nonmalignant conditions, including the following:
Acquired immunodeficiency syndrome (AIDS)
Systemic lupus erythematosus
Autoimmune disease - Eg, dermatomyositis and mixed connective-tissue disease
Endocrine abnormalities - Eg, hyperparathyroidism and hypothyroidism
Infectious etiologies - Eg, tuberculosis and leprosy
Use of certain medications - Eg, nicotinic acid, cimetidine, and clofazimine
Among malignancies, AI is most strongly associated with Hodgkin lymphoma; as many as 70% of cases of paraneoplastic AI involve Hodgkin disease. Other AI-associated malignancies include Kaposi sarcoma, cutaneous T-cell lymphoma,  non-Hodgkin lymphoma, leukemias, and solid tumors (including those arising in breasts, lungs, or bladder). Rare cases of AI associated with graft versus host disease (GVHD) have been reported after allogeneic bone marrow transplantation. 
Hypovitaminosis A and hypocholesterolemia have been proposed, but not confirmed, as possible causes of the skin changes in AI. Other postulated mechanisms include an autoimmune response directed against the skin (as is seen in GVHD) and the secretion of keratinocyte growth factors by solid tumors (transitional cell carcinoma of the kidney  ).
Paraneoplastic AI responds to successful treatment of the underlying malignancy. The mainstay of symptomatic treatment of AI includes hydration of the skin and prevention of evaporation. This is achieved through the topical application of alpha-hydroxy acids (eg, lactic, glycolic, and pyruvic acids) and emollients (eg, urea creams, propylene glycol). Topical corticosteroids are not useful.
Acrokeratosis paraneoplastica (Bazex syndrome)
In 1965, Bazex described the development of eczematous or psoriasiform plaques on acral surfaces in association with an underlying cancer. The clinical features of Bazex syndrome include symmetrical, scaly, violaceous plaques on the acral surfaces, with severe forms progressing to bullae. The lesions predominantly occur on the hands, feet, ear helices, nose tip, and scalp. Skin changes may spread to involve the knees, elbows, and malar surface of the face.  Bazex syndrome occurs more commonly in men older than 40 years. 
Alopecia and nail changes are common and can be early findings. Subungual hyperkeratosis, onychodystrophy, and white flaking of the nail surface are the usual manifestations. These changes may progress to the point that the nail sheds.
Histopathologic analysis of samples from the affected sites reveals nonspecific changes, including hyperkeratosis, acanthosis, parakeratosis, and dyskeratotic keratinocytes. Perivascular lymphocytic infiltrates are variably present with eosinophils and neutrophils. Direct immunofluorescence is also nonspecific. The diagnosis is based on the characteristic distribution of skin changes.
The main entity in the differential diagnosis is acral psoriasis, with the entire ear typically affected. Acrokeratosis paraneoplastica is almost always noted on the nose tip and ear helices.
Skin eruptions often precede detection of the cancer, with a reported median interval of as long as 1 year between the onset of skin changes and the diagnosis of malignancy. The development of the lesions also tends to parallel the course of malignancy; skin manifestations arise in 3 well-characterized stages that parallel the dissemination of the underlying cancer. The lesions may regress with successful cancer therapy and may recur with relapses, thus serving as a marker for status.
Acrokeratosis paraneoplastica is often associated with other paraneoplastic syndromes, including dermatomyositis (DM), AN, and the sign of Leser-Trélat.
Epidemiology and associated cancers
Bazex syndrome appears to be exclusively associated with malignancy; therefore, its presence should prompt an extensive search for an occult cancer. The prevalence appears to be increased in men older than 40 years; in one review, as many as 96% of cases involved men. This finding is likely related to the specific cancers that occur with greater frequency in males.
Acrokeratosis paraneoplastica is most commonly associated with squamous cell carcinomas of the upper aerodigestive tract, including the tongue, floor of the mouth, palate, tonsils, pyriform sinus, larynx, pharynx, esophagus, and lungs  (which are not limited to squamous cell subtype).
Cancers in other sites are also reportedly associated with acrokeratosis paraneoplastica; these include adenocarcinoma of the colon and breast [14, 15] and Hodgkin lymphomas. In 2006, an unusual case of Bazex syndrome associated with a liposarcoma was reported, with associated dermatologic findings in parallel with subsequent recurrences of the tumor. 
The pathogenesis of acrokeratosis paraneoplastica is not understood. Suggested mechanisms include cross-reactivity between the tumor antigens and the basement membrane or epidermal antigens, leading to basement membrane damage. Other possibilities include tumoral production of growth factors (eg, TGF-alpha, insulinlike growth factor), low serum levels of vitamin A, and zinc deficiency.
In as many as 90% of patients, the condition improves with resection or treatment of the underlying malignancy. In severe cases, the lesions have regressed after treatment with topical and systemic steroids, oral retinoids, and oral psoralen given together with ultraviolet-A (UV-A) phototherapy.
Extramammary Paget disease
Paget disease is characterized by a solitary, pruritic (but painless), sharply demarcated, erythematous, superficial, eczematous, slightly infiltrated plaque, which usually appears on the areola. The lesion of extramammary Paget disease (EMPD) is clinically indistinguishable from that of Paget disease, except for its location; lesions in persons with EMPD typically appear on the apocrine gland–bearing perianal or vulvar skin. Occasionally, cases involving the face  and male external genitalia are described. [18, 19, 20, 21]
A second form of EMPD (30%), which consists of depigmented, whitish macules or papules, is also described. These lesions either may coexist with the classic erythematous lesions or may be the only presenting sign of EMPD.
EMPD is more common in women (1.4:1) than in men, and it predominantly affects patients older than 50 years. 
Lesions clinically suggestive of EMPD may be diagnosed with certainty by means of punch biopsy. The diagnostic Paget cell is round with abundant pale cytoplasm and a large, central, reticulated nucleus; it is located in the epidermis. The cell reacts with sialomucin, and the cytoplasm stains positively with periodic acid-Schiff dye. A lymphocytic infiltrate consistent with chronic inflammation is present in the dermis. Results of immunocytochemical studies are negative for S-100 and positive for Ber-EP4,  CK8/18, CK7, MUC1, and carcinoembryonic antigen.
The clinical differential diagnosis of EMPD includes Bowen disease, amelanotic superficial spreading malignant melanoma, and eczematous dermatitis.
Clinical course and prognosis
Skin lesions slowly increase in size. Over time, the lesions may progress from pruritic to painful, and they may become ulcerated. Regional lymph nodes may become involved. The general course of the disease depends on the presence of an underlying internal cancer.
EMPD patients have a 5-year survival rate of 72-85%. Patients with EMPD without an internal malignancy may have extremely protracted, long-term survival. In contrast, EMPD associated with local internal cancer has a poorer outcome; the median patient survival is reported to be as short as 1.5 years.
The association of EMPD with cancer is controversial. EMPD is itself a malignant lesion, involving an intraepithelial adenocarcinoma. An increased incidence of internal malignancy has been reported in association with EMPD; in one review, 32% of 178 cases of invasive EMPD and 35% of cases of in situ EMPD were associated with internal malignancy.
Data concerning the temporal relationship and response to therapy (items useful in distinguishing a paraneoplastic process) are lacking. Although the data concerning EMPD as a paraneoplastic process are inconclusive, several clinical features may be useful in treating patients with this entity.
Most of the associated malignancies are anatomically related and are usually directly subjacent. These malignancies tend to be mucin-secreting adenocarcinomas of the rectum, mucin-secreting endocervical carcinomas, or transitional cell carcinomas of the bladder. In men, extragenital skin cancers (squamous cell carcinoma and melanoma) and prostate cancer are also associated with EMPD. In women, breast cancer is associated with the disease.
The most common sites of metastasis are the lungs and para-aortic lymph nodes. Patients who present with EMPD should undergo investigation for an internal malignancy, in which the anatomic relationship described above is considered.
EMPD usually represents an intraepithelial adenocarcinoma that is believed to originate from pluripotent cells in the epidermis. The malignant cells infiltrate the epidermis, including the appendages, and then invade the dermis. Eventually, the lesions involve the regional lymph nodes.
How an internal malignancy is related to this dermal process was previously poorly understood. Evidence now indicates that tumor growth depends on the ability of tumor cells to migrate by proteolysis and angiogenesis. The matrix metalloproteinase enzymes are implicated in both of these processes, and expression levels of some subclasses may predict for the presence of secondary Paget disease.  In addition, complementary deoxyribonucleic acid (cDNA) array data suggest that overexpression of the apoptotic genes PIG7 and LITAF may play a role in the pathogenesis of EMPD. 
Unlike other lesions discussed in this article, EMPD is a malignancy and therapy directed at the skin changes is usually required. Localized lesions may be treated with surgery (general or Mohs) or radiation, although the surgical margin is not correlated to local recurrence.
Nonresectable lesions may benefit from chemotherapy, which may include topical bleomycin or systemic administration of purine analogues. The response of EMPD to the therapy of the related internal cancers varies, but treatment strategies usually include those specifically directed at the skin lesions.
Florid cutaneous papillomatosis
First described by Pollitzer in 1891, florid cutaneous papillomatosis (FCP) is characterized by the eruption of pruritic papules, which are indistinguishable from common viral warts, in patients with cancer. Lesions first appear on the dorsal aspects of the hands and wrists and then spread to the trunk and occasionally to the face. Fewer than 30 cases of FCP have been reported in the literature. The verrucous lesions of FCP may appear concomitantly with AN and the sign of Leser-Trélat.
The appearance of the skin lesions coincides with the presence of an underlying cancer. The severity of the lesions tends to parallel the course of the underlying malignancy. For instance, tumor regression is associated with recrudescence of skin changes, whereas cancer progression is associated with worsening of the lesions.
The rapid and progressive course of FCP and its frequent association with other paraneoplastic syndromes helps in its clinical distinction from viral warts. The histopathologic findings are nonspecific; they include hyperkeratosis, acanthosis, and papillomatosis.
FCP is most often associated with gastric adenocarcinoma and other intra-abdominal cancers. However, cases involving cancers of the breasts, ovary, uterus, lungs, prostate, bladder, hepatobiliary tract, and lymph nodes have also been reported.
The clinical manifestations of FCP can be explained by a diffuse disturbance of keratinization. FCP may be related to tumor-induced elevation of serum growth factors, including TGF-alpha and epidermal growth factor (EGF), but few data support this hypothesis. Human papillomavirus has been sought, but not found, in FCP lesions.
Systemic and local therapies directed at the skin lesions seem to be of little benefit. However, the cutaneous manifestations of FCP tend to improve with tumor regression. Symptomatic treatment may include topical 5-fluorouracil. Other options include steroids, retinoic acid, urea, salicylic acid, podophyllotoxin, and liquid nitrogen. 
Acquired diffuse palmoplantar keratoderma
Acquired diffuse palmoplantar keratoderma (PPK) is believed to represent a paraneoplastic process. Skin changes are characterized by uniform, yellow, hyperkeratotic thickening of the palms and soles. The hyperkeratosis leads to an irregular, cobblestone appearance of the skin and a disruption of the normal dermatoglyphic skin markings.
Other syndromes of PPK are associated with an increased prevalence of cancer, but these are not paraneoplastic in nature. These syndromes include the hereditary forms of diffuse and punctate PPK. Howel-Evans syndrome (an inherited PPK) has been most strongly associated with squamous cell carcinoma. Skin changes with inherited forms of PPK manifest during childhood, but cancer, if it occurs, appears decades later. The cancer risk in inherited forms of PPK likely involves genes that are closely linked to the genetic defect responsible for the skin changes. Therefore, inherited forms of PPK are better classified as genodermatoses rather than paraneoplastic processes.
A punctate form of acquired PPK often occurs after exposure to arsenic. Some reports suggest that the prevalence of cancer is increased in patients with punctate lesions, but this finding is debatable. Any increase in the frequency of cancer is likely related to the role of arsenic as a carcinogen, as opposed to the skin lesions, which represent a paraneoplastic manifestation.
Acquired diffuse PPK often occurs with other paraneoplastic syndromes, such as AN, hypertrophic osteoarthropathy (HOA), and acrokeratosis paraneoplastica. This form has also been associated with autoimmune disorders, including systemic lupus erythematosus and myasthenia gravis, in addition to multiple myeloma. 
The course of the skin lesions in acquired diffuse PPK tends to follow that of the underlying malignancy. Their appearance usually coincides with the presence of the associated tumor, and lesions often regress with effective cancer therapy.
The diagnosis of acquired diffuse PPK is based on the presence of new-onset hyperkeratotic thickening of the palms and soles, on which a cobblestone appearance disguises the normal dermatoglyphic skin markings. In making the diagnosis, other causes of PPK must be ruled out, including underlying autoimmune disease, thyroid disease, medications, malnutrition, and menopausal hormonal changes.
Associated cancers and noncancerous conditions
Acquired palmar hyperkeratosis has been linked with a variety of cancers. Breast, lung, and gastric cancers, in addition to leukemias and lymphomas, have been associated with this dermatologic syndrome. One case of Brunauer-Fohs-Siemens syndrome (striated nonepidermolytic PPK) was associated with acral melanoma. 
Case reports have described this entity in association with severe hypothyroidism, systemic lupus erythematosus, and myasthenia gravis.
Tumor-induced growth factor production is believed to underlie the skin changes, and elevated growth hormone levels have been documented.
Lesions improve with treatment of the underlying malignancy. Chronic cutaneous lesions that do not respond to treatment of the underlying malignancy have been successfully treated with oral retinoic acid combined with topical betamethasone/salicylic acid.  Punctate PPK has been successfully treated with a combination of oral retinoids and topical calcipotriol. Conservative treatment options also include topical urea, salicylic acid, and lactic acid. 
Pityriasis rotunda is an eruption characterized by scaly, strikingly circular, hyperpigmented patches on the trunk, buttocks, and thighs. Lesions are 1-3cm or larger. Skin changes begin insidiously as round, well-demarcated lesions, but they may become confluent and develop a polycyclic appearance. The scaling is uniform throughout the lesions, and the quality of the scale is similar to that of ichthyosis vulgaris. The lesions are hyperpigmented in dark-skinned individuals and are hypopigmented in light-skinned individuals. 
Findings persist for months to decades. The size of the lesions may have seasonal variation; lesions that worsen in winter and regress in summer have been reported.
Pityriasis rotunda is a rare condition in North America and Northern Europe. It is common among native Japanese individuals, South African Bantu peoples, and West Indian blacks.
A substantial percentage of patients with pityriasis rotunda have serious underlying medical conditions, including cancer. In one study, 9 (5%) of 181 patients with pityriasis rotunda had an underlying malignancy. The prevalence of pityriasis rotunda among 63 South African black patients with hepatocellular carcinoma was 16%, whereas the average prevalence among several control groups was 3%. Among the few cases of pityriasis rotunda described in light-skinned patients, almost all of these individuals were free of associated illness.
The unique clinical appearance of pityriasis rotunda distinguishes it from other papulosquamous disorders. The histopathologic findings are similar to those of ichthyosis vulgaris (ie, hyperkeratosis and a sparse or absent granular cell layer), but they differ from those of ichthyosis in that hyperpigmentation is present in the basal cell layer.
The differential diagnosis includes tinea corporis, tinea versicolor, autosomal dominant ichthyosis vulgaris, and parapsoriasis. Pityriasis rotunda is usually differentiated from other conditions based on characteristic biopsy findings and by examining potassium hydroxide wet mounts of scales from the lesions. Down-regulation of filaggrin and loricrin expression in affected skin compared with adjacent normal tissue may serve as a useful diagnostic marker.
Paraneoplastic pityriasis rotunda most often occurs with hepatocellular and gastric carcinoma, but it has also been identified in association with leukemia, lymphoma, upper gastrointestinal carcinomas, and prostate cancer. No specific clinical features are helpful in distinguishing paraneoplastic pityriasis rotunda from other conditions.
Pityriasis rotunda is also reported in healthy individuals without any precipitating conditions and in families as a genetic condition.
The cause of primary pityriasis rotunda is unknown. One postulation is that genetic predisposition, infections, or nutritional causes may play a role. Down-regulated expression of filaggrin and loricrin suggests that dysfunctional terminal differentiation processes may contribute to hyperkeratosis.
Lesions usually improve with treatment of the underlying condition, but topical treatment with emollients, retinoids, or ammonium lactate lotion is helpful.
Sign of Leser-Trélat
The sign of Leser-Trélat, originally reported as eruptive hemangioma, is now defined as the rapid increase in the number and size of seborrheic keratoses in patients with an internal malignancy. Lesions can develop anywhere, but they are most common in the usual distribution of seborrheic keratoses; ie, the chest and back (76% of cases). Patients either are asymptomatic or have symptoms limited to pruritus (50% of cases).
The sign of Leser-Trélat occurs with an unexpectedly high frequency in association with other paraneoplastic syndromes, including AN (as many as 35% of cases), tripe palms, and FCP.
Eruptive seborrheic keratoses are not clinically or histopathologically distinctive. The diagnosis is based on the recognition of characteristic clinical features, such as the abrupt development of seborrheic keratoses that increase in size and number over a short period (15 weeks on average but ranging from several days to a year).
Associated noncancerous conditions
Eruptive seborrheic keratoses have been described in association with nonmalignant inflammatory conditions, such as acute drug eruptions, human immunodeficiency virus (HIV) infection, and exfoliative erythroderma, in addition to benign neoplasms and pregnancy. No clinical or histologic feature seems to reliably distinguish paraneoplastic from nonmalignant cases.
Because of the high prevalence of seborrheic keratoses and cancer in elderly persons, the predictive value of the sign of Leser-Trélat has been questioned. Findings from case-control and autopsy studies have failed to confirm a relationship between seborrheic keratoses and cancer. The results are unconvincing, however, because the studies did not take into account the eruptive quality of the seborrheic keratoses in the clinical history and because genuine examples of the sign of Leser-Trélat are rare and likely would not be ascertained in even a large study of seborrheic keratoses or cancer.
The notion that the sign of Leser-Trélat is an independent paraneoplastic syndrome is supported by convincing reports of eruptive seborrheic keratoses in young patients with cancer, the observation that lesions resolve after the associated malignancy is treated, and the strong association of the sign with other, better-recognized paraneoplastic syndromes.
Most authors believe that rapidly erupting seborrheic keratoses do represent a paraneoplastic process and should prompt an investigation for occult malignancy. The sign of Leser-Trélat has been linked to a variety of solid tumors, but most cases involve adenocarcinomas, especially those of the stomach, lungs, colon, rectum,  or breasts. Of note, cases have been reported to arise in the presence of chemotherapeutic agents such as cytarabine, in that the seborrheic keratoses become inflamed with treatment.
The pathomechanism of the sign of Leser-Trélat is unknown. Alterations in serum levels of human growth factors, including TGF-alpha, TGF-beta, and epidermal growth factor (EGF), have been implicated in the pathogenesis but not proven. The roles of platelet-derived growth factor (PDGF) and human papillomavirus are being explored.
The lesions are benign and do not require specific therapy. They may resolve with successful cancer therapy.
Tripe palms, also known as acanthosis nigricans of the palms, pachydermatoglyphy, and acanthosis palmaris, is characterized by the appearance of hypertrophic ("velvety") papillation of the palms and soles, along with exaggerated dermatoglyphics and hyperkeratosis. Tripe palms often occurs simultaneously with other paraneoplastic syndromes, including AN and the sign of Leser-Trélat.
The skin changes of tripe palms most often predate the diagnosis of cancer, but they may occur at any point in the course of the malignancy. The median time at which tripe palms presents is 2 months prior to the diagnosis of cancer, with the actual time ranging from 15 months before to 264 months after cancer recognition. In fact, 23% of lesions occur after the malignancy, and 17% coincide with it. Lesions inconsistently respond to successful cancer therapy, but they may persist for many years despite remission of the underlying tumor. 
Although hyperkeratosis, acanthosis, and deposition of mucin in the dermis are nonspecific histologic findings, they are consistently present and support the diagnosis of tripe palms. Papillomatosis, the dermal accumulation of mucin, and an increased number of mast cells are observed in 20% of specimens.
AN occurs in approximately 75% of cases of tripe palms and raises the possibility that they are part of the same syndrome.
The differential diagnosis of tripe palms includes conditions related to HOA and endocrinopathies, such as thyroid acropachy and acromegaly. These conditions are more related to dermal overgrowth or periostitis than to epidermal changes.
Approximately 90% of cases of tripe palms are associated with malignancy, and the appearance of the skin findings should prompt an investigation for an internal cancer, with close attention to gastrointestinal and lung malignancies. Nearly 100 cases of tripe palms have been reported since its initial description in 1977. Almost all of these cases were associated with an underlying solid tumor.
A wide variety of tumor types, including cancers of the gastrointestinal tract, lungs,  head and neck, and genitourinary (ovarian  ) system, have been reported; gastric and bronchogenic carcinomas are the most common. Tripe palms in the absence of AN is more often associated with lung neoplasms, especially non–small cell carcinomas of the squamous cell type. 
The pathophysiology of tripe palms lesions is poorly understood. Tumoral production of substances that stimulate cellular proliferation and resultant thickening of the palmar surface has been proposed. Data concerning specific factors are limited and often conflicting.
However, in 1998, Chosidow et al described a case of tripe palms in the setting of systemic mastocytosis associated with elevated serum levels of TGF-alpha.  Regression of mastocytosis and skin lesions with interferon therapy was associated with the normalization of TGF-alpha levels. This parallel course between TGF-alpha and skin lesions implies that this hormone plays a role in the pathogenesis.
Finally, the role of receptor tyrosine kinases of subclass I and the oncogenes SRC and c-myc has been studied. Further data are required to fully define the importance of these signaling molecules in the pathogenesis of tripe palms.
No specific therapeutic intervention is available for tripe palms, but as many as 30% of lesions resolve with cancer-directed therapy.
Dermatomyositis (DM) is an inflammatory proximal myopathy with characteristic skin changes; it is often associated with an occult malignancy. The rash is characteristic and diagnostic and usually accompanies or precedes the onset of the myopathy.
Skin manifestations of dermatomyositis include the following:
Heliotrope rash (so named because of the similarity to the color of the blue-purple flower, the heliotrope) on the upper eyelids
A macular, red rash on the face and the V of the upper trunk that may become shiny and atrophic, with variable pigmentation and telangiectasias (poikiloderma)
Violaceous, scaly papules over the interphalangeal and metacarpophalangeal joints (ie, Gottron papules) that evolve into atrophic telangiectatic macules
Scaling, erythematous to violaceous plaques over the elbows and knees (ie, Gottron sign) and malleoli with follicular plugging
Involvement of the skin over the back and shoulders (ie, shawl sign)
Dilated capillary loops in the cuticles, with irregular, thickened, distorted cuticles
Irregular, dirty-appearing horizontal lines on the lateral and palmar surfaces of the fingers and palms (ie, mechanic's hands)
Subcutaneous calcifications that may extrude chalky material through a sinus in the skin
The myopathy produces symmetrical weakness of the limb-girdle muscles and anterior neck flexors, with or without muscle tenderness. This weakness progresses over weeks to months, with variable involvement of the pharynx, upper esophagus, or respiratory muscles.
In 1975, Bohan and Peter established laboratory criteria for the diagnosis of DM. These include the following:
Muscle biopsy findings consistent with DM (ie, evidence of necrosis in type I and type II fibers; magnetic resonance imaging [MRI] and magnetic resonance spectroscopy are now used prior to biopsy to decrease sampling error), regeneration, variation in fiber size, and perivascular inflammatory infiltrate
Elevation of skeletal muscle enzyme levels, particularly creatine kinase levels
Electromyographic changes consisting of the triad of short, small polyphasic motor units and fibrillations; positive, sharp waves and insertional irritability; and bizarre, high-frequency, repetitive discharges.
A number of autoantibodies are associated with DM and have prognostic implications, as follows:
Anti–histidyl-tRNA s- synthetase (anti-Jo-1) - Distinctive manifestations include interstitial lung diseases, Raynaud disease, fevers, mechanic's hands, and arthritis; prognosis is fair
Anti–signal recognition particle - Distinctive manifestations include palpitations, falls, severe myositis, and distal weakness; prognosis is poor
Anti–Mi-2 - Distinctive manifestations include classic DM with heliotrope rash, Gottron sign, V sign, shawl sign, and cuticular overgrowth; prognosis is better (unless associated with cancer)
Kaji et al reported evidence of a myositis-specific antibody reacting with a 155kd serum protein (anti-p155) that is associated with a greater frequency of malignancy (71% vs 11%), in 52 adult Japanese patients with dermatomyositis.  Notably, this antibody is also found in patients with juvenile dermatomyositis, but in these patients it is associated with the severity of disease instead of the risk of malignancy.
Clinical features of DM that may increase the likelihood of cancer include the following:
A normal serum creatine kinase level
Disease that is refractory to treatment
An absence of myositis antibodies
Overlap of autoimmune disease and lung disease
A review of the literature reveals that cancer risk is also associated with increased age (>65y), necrotic truncal lesions, cutaneous leukocytoclastic vasculitis,  and capillary damage seen in muscle biopsy samples. Pediatric DM is only rarely associated with internal malignancy.
The strength of the association between DM and cancer has been debated. The incidence of malignancy in association with DM varies dramatically according to one report (6-60%), as does the clinical course of DM in response to successful cancer therapy.
Although most malignancies are detected within 24 months of onset of DM, ovarian cancer is unusual in that it can occur even up to 5 years after onset. Therefore, some authors argue that DM is not a paraneoplastic syndrome.
However, a review of the literature indicates that approximately 25% of patients with DM already have or will develop cancer and that the relative risk increase for patients presenting with DM is increased 6-fold over the general population. This suggests that when DM is present, thorough history taking and physical examination, coupled with sex- and age-appropriate cancer screening, is advisable. Additionally, computed tomography (CT) scanning of the chest, abdomen, and pelvis and measurement of cancer antigen-125 levels in women are now advised.
The malignancies associated with DM are those common for the age, racial background, and sex of the patient, although incidences of ovarian, cervical, lung, and pancreatic and gastric carcinomas, in addition to non-Hodgkin lymphoma, may be unusually increased.
The increased presence of helper T-cells in the involved sites suggests that cell-mediated immunity plays a role in the pathogenesis of DM. Tumor antigens that stimulate the immune system may have cross-reactivity with self-antigens in the muscle or skin, leading to autoimmunity against these self-antigens. The involved epitopes have not been identified. Other possibilities include the presence of an infectious or toxic agent that may be causative in myositis and malignancy.
Topical corticosteroids are helpful in the treatment of the skin lesions, and oral corticosteroids help in controlling the myopathy. Steroid-sparing immunosuppressive agents are also of benefit in treating the myopathy.
Erythema gyratum repens
In 1952, Gammel first described a case of progressive circinate erythematous skin lesions that developed in the setting of breast cancer and that completely resolved after radical mastectomy. He termed this condition erythema gyratum repens (EGR), which is derived from the Latin repens, meaning creep.
Of all gyrate (circular) erythemas, EGR is almost always (>80%) indicative of an underlying malignancy.  Lesions consist of dramatic, erythematous, concentric rings with scales, which cause the classic wood-grain appearance. Lesions may be flat or slightly raised. They are localized to the trunk and proximal extremities, sparing the feet, hands, and face.
The rings spread outward in a serpiginous pattern at a rapid rate; the lesions may advance at a rate of 1cm daily. Patients universally report severe pruritus, and concurrent hyperkeratosis of the palms and soles has also been reported. Marked peripheral eosinophilia may occur. Thus, EGR is a clinically specific paraneoplastic syndrome. EGR occurs more frequently in males, whites, and elderly persons.
The clinical appearance of EGR is diagnostic. Histopathologic features are nonspecific and include perivascular lymphocytic infiltrates with focal spongiosis and parakeratosis. A single study showed increased Langerhans cells in the epidermis, and several studies demonstrated direct immunofluorescence in the skin, but patterns are inconsistent.
The differential diagnosis includes other figurate erythemas, such as erythema annulare centrifugum, erythema chronicum migrans, and erythema marginatum. The most consistent distinguishing feature of EGR is the rapidity with which the lesions spread. The distinguishing features of EGR's differentials include the following:
Erythema annulare centrifugum - Spreads slowly and has a characteristic trailing scale; also, lacks the severe pruritus and widespread and nearly confluent lesions of EGR
Erythema chronicum migrans - Lesions lack scales; serum antibodies against Borrelia burgdorferi are present
Erythema marginatum - Evanescent rash associated with rheumatic fever; lacks scales and pruritus, and biopsy specimens predominantly reveal neutrophilic infiltrates
Lesions begin on the trunk or extremities and rapidly expand. The temporal relationship between skin lesions and the diagnosis of cancer varies. However, in more than 80% of reported cases, skin changes occurred at least 4-9 months prior to the recognition of an underlying malignancy.
Associated noncancerous conditions
Among patients with EGR without a detectable malignancy, diagnoses of tuberculosis, CREST (ie, calcinosis cutis, Raynaud phenomenon, bullous dermatoses, esophageal motility disorder, sclerodactyly, bone marrow transplantation, telangiectasia) syndrome, and pregnancy are thought to be related.
Dermatoses, including bullous pemphigoid, pityriasis rubra pilaris, and psoriasis, have in rare cases been reported to be associated with EGR. Some patients have no underlying condition and reportedly remain healthy at follow-up examinations.
Because EGR is almost always indicative of a malignancy, its onset should prompt an extensive search for an occult cancer. Cancers associated with EGR are transitional cell carcinoma of the kidney  and those arising in the lungs, esophagus, and breasts. 
The pathogenesis of EGR is not understood, but because of frequent improvement of the lesions upon treatment of the tumor, the underlying malignancy is thought to play a role. Interestingly, lesions disappear just before death, likely because of a markedly diminished immune response.
One postulation is that antigens directed against the tumor cross-react with normal skin proteins, resulting in a cutaneous inflammatory immune response. In one patient with lung cancer, deposition of C3, C4, and immunoglobulin G identified on affected skin and bronchial basement membranes supported this idea. Fibroblasts are also postulated to play a role in the rapid development of lesions, owing to their migration during wound healing.
Lesions typically regress with treatment of the underlying cancer. In resistant cases, systemic steroids have been variably useful. Cetirizine has been reported to be mildly effective in reducing symptoms.  Azathioprine, topical steroids, and vitamin A have shown no benefit. 
Hypertrophic osteoarthropathy and digital clubbing
Only the secondary form of hypertrophic osteoarthropathy (HOA) is associated with malignancies. The syndrome of HOA consists of digital clubbing and periostitis with polyarthralgia. Clubbing is defined as the asymptomatic thickening of the soft tissues of the distal phalanges in association with increased convexity of the nails and loss of the normal 15° angle between the nail plate and the proximal nail fold.
Patients with periostitis report periarticular pain, which most often involves the knees, wrists, ankles, and elbows. Associated swelling, warmth, erythema, and tenderness of affected sites may be present and are sometimes relieved by elevating the affected extremities. True arthritis is variably present.
Radiographs of the bones in patients with HOA show periostitis, most often in the proximal and distal ends of the tibia, fibula, and ulna, with isolated distal involvement of the femur; periostitis is associated with pain upon palpation of the involved area. Synovial effusions are prominent in the large joints.  Because of the vascularity of the lesions in persons with HOA, bone scanning results are often abnormal. However, while bone scanning is more sensitive than plain radiography, it is less specific.
The diagnosis of clubbing is based on several features. The examiner can oppose the distal phalanges of matching fingers. Typically, this maneuver creates a rectangular or rhomboid clearing in the center. However, in cases of clubbing, this clearing is obliterated. One can also use the differences in the width between the distal interphalangeal joint and the proximal end of the nail to assess clubbing. Typically, the distal interphalangeal joint is wider than the proximal nail edge; contrary findings suggest clubbing.
Histologic examination of samples from patients with clubbing reveals lymphocytic infiltration, subungual edema, and a deposition of loosely arranged connective tissue. Arteriovenous malformations are commonly found and result in increased blood flow to the fingertips.
In periostitis, new bone formation begins with subperiosteal edema and lymphocytic infiltration, which cause elevation of the periosteum. Osteoid deposition occurs in the newly created space under the periosteum, and this is eventually ossified. Vascularity is increased and accounts for the improved sensitivity of bone scanning in comparison with plain bone radiography. The increased vascularity is commonly associated with arteriovenous anastomoses in the new bone.
Associated cancers and noncancerous conditions
Among patients with acquired HOA, 90% have an underlying malignancy; the remainder have nonmalignant chronic diseases of the lungs, liver, or heart. In contrast to patients with acquired HOA, only a minority of patients with clubbing, without periostitis, have an associated cancer. Clubbing is more common with chronic hypoxemia due to lung or heart disease.
Peripheral non–small-cell lung cancer is the most commonly associated malignancy in patients with HOA. Adenocarcinoma and mesothelioma are the most common malignancies associated with clubbing. Small-cell lung cancer is rarely associated with HOA.
The combination of clubbing and HOA is thought to represent a disease continuum. Clubbing may result from alterations in local tissue oxygenation due to either the formation of platelet and megakaryocytic vascular plugs or to the abnormal production of vasoactive substances. Studies support a role for platelet-derived growth factor (PDGF), in that platelets are thought to release growth factors in the extremities.
The pathogenesis of periostitis and periosteal new bone formation is not understood, but the intriguing observation that many patients experience an immediate relief of pain and an eventual regression of new bone formation after vagotomy suggests a neural mechanism. However, because unilateral vagotomy is accompanied by bilateral disease regression, humoral mediators are also likely involved.
Finally, levels of vascular endothelial growth factor (VEGF) have been found to be elevated in patients with lung cancer,  which may account for edema formation, vascular proliferation, and new bone formation. VEGF levels decrease in response to removal of the associated cancer.
Studies of patients with primary HOA, a genetic disorder, have shown that their disease is due to mutations in the gene encoding 15-hydroxyprostaglandin dehydrogenase, the enzyme responsible for prostaglandin degradation. Homozygotes have chronically elevated levels of prostaglandin E(2) (PGE2) and pronounced physical signs compared with heterozygotes. Because some patients with lung cancers have been shown to have elevated levels of PGE2, this finding suggests a common pathway. In theory, exposure to elevated PGE2 levels could lead to platelet reactions and associated VEGF release at the digital extremities, leading to clubbing and HOA.
Treatment of the underlying malignancy usually results in the regression of the periostitis but not the clubbing. Unilateral vagotomy may be considered because it usually provides pain relief.
Multicentric reticulohistiocytosis (MRH) is a rare disorder characterized by skin-colored or reddish brown papular or nodular skin lesions in association with the progressive development of severe, destructive arthritis. Lesions may be isolated and multifocal or they may be found in crops with a cobblestone appearance. They tend to involve the upper half of the body, especially the face, hands, ears, and forearms. As many as 50% of patients have oral mucosal involvement. Pruritus is present in two thirds of patients.
The skin is often the first system affected, followed by the joints; all patients eventually develop cutaneous and arthritic manifestations of MRH. Arthritis of the hands, knees, and shoulders is typical and mimics rheumatoid disease with arthritis mutilans, with the exception that any joint may be affected. Arthritic manifestations typically wax and wane, but they can rapidly progress to joint destruction.
Lesions of MRH typically predate the diagnosis of cancer and are variably responsive to antineoplastic therapy. However, near-resolution of MRH after effective cancer treatment has been reported, and flares of MRH have been linked to cancer recurrence. Of those cases of MRH that are not related to malignancy, the natural history is that of spontaneous resolution in approximately 8 years.
MRH affects women more frequently than men of middle age (female-to-male ratio of 3:1). No clinical features of MRH are specific to patients with cancer. Therefore, extensive searches for occult malignancy in patients with MRH are unwarranted. Thorough history taking and physical examination with age-appropriate cancer screening and a focused investigation based on the findings seem reasonable.
The clinical appearance of MRH may not be diagnostic, but the histopathologic features are; collections of tartrate-resistant acid phosphatase–positive (TRAP) histiocytes, which are often RANK-L (receptor activator of nuclear factor kappa-B ligand) positive, and characteristic atypical multinucleated giant cells are present in the dermis. These giant cells have eosinophilic cytoplasm, which has a ground-glass appearance and stains positively with the periodic acid-Schiff reagent.
Immunohistochemical markers OKM1, M02, and lysozyme can be used to identify the histiocytes as macrophages; negative results with S-100 and OKT6 (CD1) stains exclude a Langerhans cell origin and the diagnosis of histiocytosis X.
The clinical differential diagnosis of MRH includes malignant histiocytosis, progressive nodular histiocytosis, lepromatous leprosy, rheumatoid arthritis,  granuloma annulare,  and sarcoidosis, all of which can be easily distinguished with biopsy coupled with an appropriate history and physical examination.
Associated cancers and noncancerous conditions
Approximately one third of MRH cases are associated with malignancy. This high association rate has led some authorities to designate MRH as a paraneoplastic syndrome, but others argue that this is questionable because of the fact that the 2 diseases do not always run in parallel and are not associated with a specific malignancy. A wide variety of tumors have been reported, including cancers of the breasts, lungs, muscles, gastrointestinal and genitourinary tracts, and hematologic system.
Other systemic diseases, including tuberculosis, and a number of autoimmune disorders, including diabetes mellitus, hypothyroidism, and primary biliary cirrhosis, have been associated with MRH.
The pathogenesis of MRH is unknown, but evidence suggests that an underlying reactive disorder that stimulates histiocyte production may be important. An increase in the number of macrophages, endothelial cell interleukins (including interleukins 12, 6, and 1B), and tumor necrosis factor-alpha have all been described. The finding that some mononuclear cells are positive for RANK-L, TRAP, and cathepsin K supports the concept that the differentiation of histiocytes to osteoclasts occurs and, thus, may contribute to bony erosions.
The self-limited nature of MRH makes identifying the regression of skin changes and arthritis in response to cancer therapy difficult and further confounds its characterization as a paraneoplastic process. Owing to the rarity of the disease, treatment has largely been empirical.
The early use of cytotoxic and immunosuppressive agents has shown mixed results. These agents include systemic steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), chlorambucil, cyclophosphamide, methotrexate, hydroxychloroquine, and cyclosporine. In addition, the use of bisphosphonates and anti–tumor necrosis factor agents has demonstrated marked disease regression. [46, 47] Because first-line therapies consist of immunosuppressive agents, an underlying malignancy or infection should be excluded or treated prior to initiation of these treatment modalities.
Necrolytic migratory erythema
Necrolytic migratory erythema (NME)  was first described by Becker and colleagues in 1942 in a woman with an alpha-cell tumor of the pancreas, hypoaminoacidemia, and elevated serum glucagon levels in the presence of a distinct rash. The skin and mucous membranes are affected, with painful, migratory, erythematous, polycyclic patches or plaques with superficial pustules, vesicles, or bullae being present. The lesions are typically widespread, but they are accentuated in the intertriginous areas, lower abdomen, and proximal parts of the lower extremities. It is often present in a triad with NME, glucose intolerance, and hyperglucagonemia. 
Lesions begin as erythematous papules; coalesce into patches or plaques; evolve into vesicles, flaccid bullae, and pustules; and then become erosions and crusts. Patients may have stomatitis and signs of systemic illness, including weight loss and anemia. It is commonly complicated by Candida albicans or Staphylococcus aureus infection.
The typical patient with NME is middle aged, has diabetes, and has the characteristic rash. The diagnosis is often overlooked for many years, and patients may be debilitated by the time the underlying disease is recognized. A family history of endocrine neoplasms may be uncovered in cases of glucagonoma associated with multiple endocrine neoplasia.
The diagnosis of NME and glucagonoma syndrome  is often difficult and usually occurs several years after the initial skin manifestations are noticed. The most common scenario involves repeated attempts at treating a presumed benign inflammatory dermatosis by using topical antifungal agents or steroids. This approach is unsuccessful, and patients eventually undergo diagnostic skin biopsy, which reveals NME.
The differential diagnosis of NME includes nonneoplastic conditions such as acrodermatitis enteropathica, chronic mucocutaneous candidiasis, pemphigus foliaceus, and acquired zinc deficiency.
In NME, the characteristic clinical appearance is accompanied by the nearly diagnostic microscopic appearance of a biopsy specimen. Biopsy of involved sites may reveal edema, patchy acanthosis with spongiosis, basal cell hyperplasia, subcorneal clefts, and midepidermal clefts. Fusiform keratinocytes with pyknotic nuclei are also found. Acantholysis is usually absent.
Confirming a diagnosis of paraneoplastic NME is achieved by performing specific laboratory tests and imaging studies to localize the pancreatic tumor. Elevated serum glucagon levels (and occasionally insulin levels), an abnormal glucagon response to arginine infusion, glucose intolerance, and hypoaminoacidemia all contribute to the diagnosis of glucagonoma syndrome.
Imaging studies are used to localize the pancreatic tumor. Celiac arteriography, which reveals the characteristic hypervascularity of the tumor, is believed to be more sensitive than CT scanning for identifying the primary lesion.
The usual delay in the diagnosis of NME likely contributes to the high prevalence of metastatic disease (50%) in patients with glucagonoma. Surgical resection or effective chemotherapy of the tumor is accompanied by resolution of the dermatitis. The median patient survival after the diagnosis of glucagonoma syndrome is 2 years.
Associated cancers and noncancerous conditions
NME is unique among paraneoplastic syndromes in that it is almost always associated with a glucagon-secreting alpha-cell neoplasm of the pancreas, although it may rarely occur in the presence of jejunal and rectal adenocarcinomas, villous atrophy of the small intestine, hepatitis B,  or myelodysplastic syndrome. Of patients with symptomatic glucagonomas, an estimated 67-90% have NME.
The pathogenesis of NME is believed to involve glucagon-induced hypoaminoacidemia. Glucagon may act to directly induce skin necrosis and is also thought to lower serum amino acid levels by stimulating the liver to increase the uptake and use of certain amino acids. The success of amino acid infusions in treating NME supports this hypothesis.
Other contributing conditions may include nutritional deficiencies, autoimmune conditions, liver disease, inflammatory mediators (arachidonic acid), and generalized malabsorption. Interestingly, one patient with non–small-cell lung cancer developed NME after administration of ZD1839 (Iressa), a tyrosine kinase anti–epidermal growth factor (anti-EGF) receptor that blocks signal transduction pathways involved in cell proliferation.
Surgical resection or effective cancer chemotherapy with dacarbazine usually leads to resolution of the dermatitis. Patients who are not candidates for cancer-directed therapy or whose conditions are unresponsive to it may benefit from other interventions. Skin lesions regress with treatments involving the somatostatin analogue octreotide or amino acid infusions. The response to octreotide usually occurs within 7 days. Octreotide infusion has a variable effect on serum glucagon levels and possibly exerts its effect directly on skin somatostatin receptors.
In 1964, Robert Sweet described a syndrome involving an acute onset of febrile neutrophilic dermatosis in 8 women he encountered over a 15-year period. At the time, the classic patient was a middle-aged woman in good general health whose skin lesions developed within days of an upper respiratory tract infection or minor illness. While this entity came to be known by the eponym Sweet syndrome, it has now been expanded to include older patients with an underlying internal malignancy.
Sweet syndrome is characterized by fever, neutrophilia, and sterile erythematous plaques or nodules that respond to steroid therapy. Skin lesions most commonly involve the upper extremities and face and begin as tender, erythematous plaques or nodules. The lesions may evolve into vesicles, bullae, or pustules.
Extracutaneous manifestations are not infrequent and commonly involve the eyes, lungs, liver, kidneys, muscles, and bones. Laboratory features include neutrophilia, anemia, and an elevated erythrocyte sedimentation rate.
In cases associated with malignancy, Sweet syndrome typically appears shortly before or coincident with the diagnosis of cancer, although the timing varies. Lesions may wax and wane, but they typically persist until the proper therapy is administered. The symptoms resolve with systemic steroid and/or successful cancer-directed therapy. Recurrences are described and may herald relapse of an underlying malignancy.
Overall, Sweet syndrome is 4 times more common in women than in men. However, when cases related to an underlying malignancy are considered, the frequencies in males and females are equal.
The diagnosis of Sweet syndrome is based on the clinical presentation and characteristic findings at skin biopsy. Histologic evaluation reveals a neutrophilic infiltrate in the dermis, without evidence of infection, vasculitis, or malignant cells. Patients frequently have a positive perinuclear antineutrophil cytoplasmic antibody titer.
The clinical syndrome can mimic several other entities; the differential diagnosis includes erythema multiforme, cellulitis, and leukemia cutis. Sweet syndrome can usually be distinguished from these other conditions on the basis of the biopsy results; however, patients are often initially treated for an infectious process before the proper diagnosis is realized.
Associated cancers and noncancerous conditions
Sweet syndrome is associated with an underlying cancer in 20% of cases. Approximately 80% of these cases involve hematologic malignancies; acute myeloid leukemia is most common. Cases involving solid tumors are also described, usually in association with adenocarcinomas of the breast or gastrointestinal and genitourinary tracts. 
Nonmalignant conditions that have been linked to Sweet syndrome include the following:
Autoimmune diseases - Ie, relapsing polychondritis 
Infections - Ie, with mycobacteria
Hematologic diseases - Eg, myelodysplastic syndrome
The exact mechanism for the development of lesions in Sweet syndrome is unclear. Although the infiltrate is neutrophilic, the syndrome may well be driven by T-cell abnormalities. This is supported by evidence of disease response to infliximab and cyclosporine, agents that act to modulate T-cell response.
Several theories have been proposed, including abnormalities in neutrophil chemotaxis, autoantibodies directed against neutrophils, and alteration in cytokine levels (including interleukin 6 and endogenous granulocyte colony-stimulating factor (G-CSF). Notably, a case of Sweet syndrome has been reported in a healthy donor patient receiving G-CSF, suggesting a possible etiology.  Patients may be perinuclear antineutrophil cytoplasmic antibody positive, but this is believed to be an epiphenomenon.
Although Sweet syndrome is often linked to acute myeloid leukemia as a paraneoplastic process, skin lesions in the syndrome do not directly involve malignant cells. Abnormalities in cytokine production or response in the presence of leukemia are believed to underlie the neutrophilic invasion of the dermis. On the other hand, dermal infiltration with leukemic cells is a separate entity referred to as leukemia cutis.
Systemic steroid therapy and/or treatment of the underlying malignancy are usually effective. Steroid-sparing agents, including NSAIDs, cyclosporine, dapsone, metronidazole, methotrexate, and potassium iodide, have all been used in alternative approaches, with some success.
Paraneoplastic pemphigus is a member of a heterogeneous group of autoimmune paraneoplastic syndromes. It is characterized by painful, intractable, erosive ulcerative stomatitis and a polymorphic cutaneous eruption consisting of erythema, papules, iris lesions, bullae, and erosions. 
In approximately two thirds of cases, paraneoplastic pemphigus occurs in patients with a known, preexisting neoplasm. However, one third of patients develop the mucocutaneous disease before the neoplasm is detected. Paraneoplastic pemphigus usually resolves in 6-18 months; the resolution is accompanied by a reduction in autoantibody titer (discussed below), with the resection of benign tumors, such as thymoma and Castleman tumor.
Paraneoplastic pemphigus is most commonly found in adults and elderly patients; it is only rarely reported in children.
The diagnosis of paraneoplastic pemphigus is based on a compatible clinical picture that includes the following classic criteria:
Painful mucosal erosions and a polymorphous skin eruption
Histopathologic features of intraepidermal acantholysis, dyskeratosis, and vacuolar interface dermatitis
Direct immunofluorescence findings of intracellular epidermal immunoglobulin G and complement with or without granular linear complement deposition along the basement membrane zone
Serum autoantibodies, detected by indirect immunofluorescence, that bind cell surfaces of stratified squamous epithelia, as well as simple, columnar, and transitional epithelium
Serum immunoprecipitation with a complex of 4 proteins of 250, 230, 210, and 190kd
Immunofluorescence studies of biopsy specimens demonstrate the presence of autoantibodies to desmoglein 1 and 3, periplakin, and envoplakin. The target antigens are not all localized to the skin, suggesting that this is an autoimmune multiorgan paraneoplastic syndrome. Sensitive and specific tests include indirect immunofluorescence labeling of rat or mouse bladder transitional epithelium to patient serum antigens and immunoblot analysis of patient sera demonstrating antibodies directed against envoplakin and periplakin.
When paraneoplastic pemphigus is associated with malignant neoplasms, the prognosis is grim; only 10% of patients survive 2 years. Deaths are attributed to the complications of therapy or to pulmonary failure resulting from autoantibodies binding to the bronchial epithelium.
Associated cancers and noncancerous conditions
Paraneoplastic pemphigus is most often associated with B-cell lymphoproliferative disorders, especially non-Hodgkin lymphoma (80%). The condition's skin changes are also linked to chronic lymphocytic leukemia, Castleman disease, [57, 58] thymoma, and Waldenström macroglobulinemia. An association with solid tumors is extremely rare, yet case reports have described an association with uterine cancer, melanoma, primary liver and spleen tumors, spindle cell sarcomas, and renal cell carcinoma.
The cause of paraneoplastic pemphigus is not known, but it is thought to have a cellular and humoral component. Cellular cytotoxicity is mediated by monocytes/macrophages, natural killer cells, and CD8+ cells.
The presence of autoantibodies directed against certain desmosome-associated proteins appears to be necessary and sufficient for disease expression. Desmogleins 1 and 3 and members of the plakin family, most notably envoplakin and periplakin, are the most common targets. The presence of these autoantibodies, in addition to bullous pemphigoid antigen 2 and an unknown 170kd antigen, are unique to this entity and aid in distinguishing this condition from other autoimmune acantholytic diseases, such as cicatricial pemphigoid and pemphigus vulgaris.
The pathogenesis of immunobullous disorders such as pemphigus vulgaris is believed to be associated with the inheritance of particular HLA alleles. Evidence indicates that patients with alleles HLA-Cw14 and HLA-DRB103 may be susceptible to developing paraneoplastic pemphigus. [59, 60]
Eradication of the tumor may not parallel a decrease in bullous disease activity. Paraneoplastic pemphigus is resistant to therapy, and combined immunosuppressive treatment with steroids and cyclosporine is usually required. More aggressive treatment, including the use of agents such as cyclophosphamide or processes such plasmapheresis, may be beneficial. Many other agents have been tried, including intravenous immunoglobulin, rituximab, thalidomide, gold, dapsone, and mycophenolate mofetil, with little success.
Carcinoid tumors are of neuroendocrine origin and may occur anywhere in the body. Although most of these tumors are benign, a small fraction of them are malignant. The presence of carcinoid syndrome, an uncommon manifestation of carcinoid tumors, signifies the presence of a malignant carcinoid tumor (ie, one that has already metastasized to the liver).
Carcinoid syndrome is manifested by flushing, diarrhea, and, variably, bronchospasm, cardiac valve dysfunction, and pellagralike skin changes. Of the patients with symptomatic carcinoid tumors, an estimated 10% develop carcinoid syndrome.
Flushing, which occurs in 75% of cases and lasts as long as 30 minutes, usually manifests in the face and the central part of the body. The skin may be diffusely affected or mottled, with or without accompanying edema. Recurrent episodes of flushing may lead to long-lasting skin changes, including telangiectasias and plethora. Flushing may be precipitated by stress or the consumption of hot foods, chocolate, alcohol, or cheese.
The dermatitis of carcinoid syndrome is characterized by skin findings that are identical to those of pellagra, a disease characterized by dermatitis, diarrhea, and dementia resulting from niacin deficiency. The dermatitis starts as an erythematous, phototoxic eruption on sun-exposed regions. Bullae supervene and heal with hyperpigmentation, which leads to the characteristic peeling-paint appearance. The prominence of the sebaceous glands, which results in an appearance referred to as goose skin, develops on the face and chest. The band of dermatitis around the neck is referred to as the Casal necklace.
Because liver metastases are required for the development of carcinoid syndrome, most cases are unresectable at the time of diagnosis.
Abdominal CT scanning usually readily depicts metastatic spread, but identifying small primary (often submucosal) lesions may be difficult. The use of indium-111 (111 In)–labeled octreotide that acts to bind somatostatin receptors (SSTRs) 1-5, expressed on the tumor surface, has a role in identifying primary tumors.
Positron emission tomography (PET) scanning using amine precursors has been described in case reports to successfully localize the tumor. Elevated urinary levels of 5-hydroxyindole acetic acid (5-HIAA), a breakdown product of serotonin, confirm the diagnosis of carcinoid syndrome.
Although numerous agents are released from carcinoid tumors (eg, amines, proteins, prostaglandins), the clinical findings in patients with carcinoid syndrome result from the abnormal metabolism of tryptophan.
The essential amino acid tryptophan is absorbed from the gut via neutral amino acid transporters. Typically, in healthy patients, approximately 1% of dietary tryptophan is used to make serotonin, which is metabolized to 5-HIAA and is excreted in the urine. The rest is used to make proteins or niacin ribonucleotide, which is further metabolized to nicotinamide adenine dinucleotide (NAD) and NAD phosphate. These cofactors are critical in many oxidation-reduction reactions, in electron transport, and in adenosine triphosphate (ATP) production.
In patients with carcinoid syndrome, approximately 60% of dietary tryptophan is shunted into the production of serotonin. The resulting interference with energy metabolism is believed to be responsible for the gastrointestinal and central nervous system symptoms of carcinoid syndrome.
Phototoxic dermatitis may be related to impairment in the thioredoxin-mediated quenching of free radicals. Tumor biology and proteomics research suggest emerging roles for p53, vascular endothelial growth factor (VEGF), multiple endocrine neoplasia type 1 (MEN1), platelet-derived growth factor (PDGF), and the apoptotic factor bcl-2 in the pathogenesis of this malignancy.
Surgery should be considered in all patients. In patients with unresectable disease due to diffuse metastases, palliation may still be achieved if the primary tumor is causing local problems. The use of chemoembolization to induce necrosis of hepatic lesions may produce long-term palliation of symptoms; however, no survival benefit, versus surgical resection, is gained.
Chemotherapy for carcinoid generally has yielded disappointing results, although favorable results using a combination of lomustine and 5-fluorouracil have been reported. Targeted nuclear treatments, including uptake of iodine-131 (131 I) metaiodobenzylguanidine and radiolabeled octreotide, have shown promising results for selected patient populations.
Symptomatic relief may be achieved with the use of histamine 2 or alpha1-receptor blocking agents to decrease flushing, opiates and serotonin-blocking agents for diarrhea, and chlorpromazine or corticosteroids to decrease bronchospasm. Octreotide, a long-acting somatostatin analogue, improves symptoms and decreases levels of 5-HIAA.
Hypertrichosis lanuginosa acquisita
Hypertrichosis lanuginosa acquisita associated with a malignancy is rare.
Patients with hypertrichosis lanuginosa acquisita grow lanugo-type (ie, fetal) hair near their eyebrows and on their forehead, ears, and nose. Some patients have extensive involvement that includes the extremities, axillae, and trunk, but the palms, soles, and perineum are spared. The hair, referred to as malignant down, is fine, thin, and unpigmented, unlike the robust, pigmented terminal hairs characteristic of hirsutism. Although the hair may grow to considerable length, it is easily pulled out.
Hypertrichosis lanuginosa acquisita associated with malignancy is sometimes concurrent with acanthosis nigricans (AN), papillary hypertrophy of the tongue, glossitis, and disturbances of smell or taste.
Hair growth typically ranges from 2.5 years before the tumor is identified to 5 years after diagnosis. Patients usually have metastatic disease at the time of diagnosis and, therefore, a poor prognosis. However, successful tumor therapy is associated with regression of the hair growth.
Women are affected by hypertrichosis lanuginosa acquisita more often than men. The age of onset (40-70y) mirrors the age of onset of the associated malignancies. 
The clinical appearance of hypertrichosis lanuginosa acquisita is unique and diagnostic. Histopathologic findings are consistent with lanugo-type hair.
However, a thorough patient history must be taken to distinguish hypertrichosis lanuginosa acquisita associated with malignancy from that associated with noncancerous conditions. For example, hypertrichosis lanuginosa acquisita may be an adverse effect of medications, such as phenytoin or cyclosporine, or it may be associated with systemic diseases, such as AIDS, hyperthyroidism, or toxic shock syndrome. These forms of the disease are clinically indistinguishable from those cases associated with malignancy, but the presence of otherwise unexplained hypertrichosis lanuginosa acquisita should prompt an extensive search for occult malignancy.
Associated cancers and noncancerous conditions
Although this condition is most often paraneoplastic, it may also be associated with AIDS, thyrotoxicosis, porphyria, or medication use. Most cancers associated with hypertrichosis lanuginosa acquisita are of solid tumor origin, although case reports have described a range of both solid and liquid malignancies. Most commonly, lung (small cell and non–small cell cancers) and colorectal tumors are seen; in women, breast malignancies are also associated.
Abnormalities in virilizing hormones or other hormone-driven growths of lanugo hair have been suggested but have not been conclusively supported in limited studies.
Hypertrichosis lanuginosa acquisita may regress with cancer-directed therapy; otherwise, cosmetic management with shaving or mechanical or chemical depilation may be used.
Trousseau syndrome is an acquired coagulopathy that results in migratory thrombophlebitis (MTP), a condition that is often seen in the setting of an underlying malignancy. In 1865, Trousseau first described an association between recurrent MTP and cancer.
Since then, a variety of coagulation abnormalities related to malignancy have been described; these include disseminated intravascular coagulation, thrombotic endocarditis (ie, marantic endocarditis), pulmonary embolism, venous gangrene, and bleeding tendencies. These physiologic phenomena are believed to be secondary to an imbalance in the clotting cascade induced by the underlying malignancy.
Trousseau syndrome (or MTP) is characterized by the development of recurrent superficial thrombophlebitis. Thrombi may occur in either the arterial system or the venous system. Lesions consisting of tender, erythematous cords or nodules typically appear in the subcutaneous fat over the trunk or extremities.
Biopsy specimens of involved sites show veins containing occlusive thrombi and an inflammatory infiltrate in the vessel wall.
The lesions in patients with Trousseau syndrome may be clinically similar to those in a variety of conditions, such as cellulitis, erythema nodosum, lymphangitis, and vasculitis. Once the presence of MTP is established, the differential diagnosis includes other conditions known to induce hypercoagulable states, including lupus anticoagulant syndrome, Buerger disease, Behçet disease, and inflammatory bowel disease.
Conventional imaging diagnostics are able to identify the underlying malignancy in most cases. However, PET scanning has been gaining a diagnostic role in cases in which these other modalities are unsuccessful.
Approximately 50% of cases of MTP are associated with cancer. Therefore, in the absence of other causes of hypercoagulability, a search for an occult malignancy is warranted. Various cancers have been associated with Trousseau syndrome; most often, these are solid tumors of the adenocarcinoma type. Pancreatic cancer, especially that of the body or tail, seems to be associated with the highest risk of MTP, but lung cancers are most commonly reported, probably because of the relatively greater frequency of pulmonary carcinomas.
Proposed mechanisms for the induction of a prothrombotic state by tumor cells include the following:
The expression of a tissue factor, an activator of the extrinsic clotting pathway
The release of a tumor-derived cysteine proteinase, the so-called cancer procoagulant, which directly activates factor X independent of factor VII
The induction of a state of relative resistance to activated protein C
The direct activation of platelets by fragments of tumor cell membranes
The indirect effects of tumor-derived or tumor-induced cytokines on the expression of tissue factor, thrombomodulin, and other factors
Heparin therapy is usually required because cases are often refractory to vitamin-K antagonists, such as warfarin. Anticoagulation must be continued until the underlying cancer is eliminated, at which time the hypercoagulability often resolves. The emerging role of long-term low–molecular weight heparin as the primary therapy for malignancy-associated thromboembolic events has simplified outpatient management of MTP.
Cutaneous paraneoplastic syndromes represent a heterogenous group of dermopathies, the recognition of which may allow the early detection of occult malignancies. In some cases, the relationship between skin findings and the underlying cancer is clearly established, and even the specific type of cancer may be revealed. In other cases, however, the significance of the given dermatologic syndrome is controversial.
A great challenge to the clinician is deciding when an aggressive evaluation for an occult malignancy is warranted and when conservative management is appropriate. Approximately 70% of cancers in patients with a presumed paraneoplastic condition can be detected with simple history taking, physical examination, and sex- and age-appropriate cancer screening. Unfortunately, most cutaneous paraneoplastic syndromes are associated with unresponsive cancers, and the prognosis is often poor.