Cutaneous manifestations of internal malignancy

INTRODUCTION — The cutaneous manifestations of internal malignancy include a wide variety of nonmalignant skin disorders that occur in association with malignancy (paraneoplastic dermatoses) and skin disorders that represent infiltration of malignant cells into the skin due to metastatic or locoregional spread of disease or the deposition of circulating tumor cells (eg, leukemia cutis) [1,2]. When paraneoplastic dermatoses develop before an internal neoplasm is diagnosed, recognition of these disorders can aid in the diagnosis of the malignancy.

PARANEOPLASTIC DERMATOSES — Paraneoplastic dermatoses are a group of skin disorders that have strong associations with internal malignancies. Curth's postulates can aid in the classification of dermatoses as paraneoplastic (table 1) [1]. Cutaneous findings resulting from the entry of tumor cells into the skin are not considered paraneoplastic dermatoses. (See 'Non-paraneoplastic cutaneous manifestations of internal malignancy' below.)

The paraneoplastic dermatoses reviewed below are organized according to common clinical features. Some of these dermatoses may also develop in the absence of malignancy. However, the detection of a potential paraneoplastic dermatosis warrants consideration of the possibility of malignancy.

Hyperkeratotic and proliferative dermatoses — Acanthosis nigricans, florid cutaneous papillomatosis, the sign of Leser-Trélat, tripe palm, acquired ichthyosis, palmoplantar keratoderma, and Bazex syndrome are examples of paraneoplastic disorders that present with clinical features of hyperkeratosis or epidermal proliferation.

Acanthosis nigricans — Acanthosis nigricans is a reactive skin pattern that typically presents as velvety to verrucous hyperpigmented plaques in intertriginous areas (picture 1A-D). While the majority of cases of acanthosis nigricans are benign and associated with obesity and insulin resistance, the disease also can herald the onset of malignancy. (See "Acanthosis nigricans".)

Gastric cancers are the most common cause of malignant acanthosis nigricans; other cancers that have been reported in association with this disorder include hepatocellular carcinoma and adenocarcinomas of the lung, ovary, endometrium, kidneys, pancreas, bladder, breast, and other sites [2-9]. In one study of 227 patients with internal malignancy-associated acanthosis nigricans, gastric adenocarcinoma was the underlying malignancy in 55 percent [10]. Most commonly, the skin manifestations accompany the malignancy, but they can precede or follow the diagnosis of cancer. (See "Clinical features, diagnosis, and staging of gastric cancer".)

Compared with patients with obesity or insulin resistance, malignancy-associated acanthosis nigricans typically has a more striking clinical presentation. Patients tend to be older, are generally not obese, and have often experienced recent unintentional weight loss leading to a cachectic appearance. The cutaneous plaques are florid and may develop in unusual locations (eg, oral cavity, palms and soles) or in combination with the sudden appearance of multiple skin tags and eruptive seborrheic keratoses (ie, the sign of Leser-Trélat) (picture 2) [11-13] (see 'Sign of Leser-Trélat' below). In addition, acanthosis nigricans can occur in conjunction with tripe palms (see 'Tripe palm' below). (See "Acanthosis nigricans", section on 'Malignancy-associated acanthosis nigricans'.)

Suspicion for malignancy should arise when patients present with extensive or rapidly progressive acanthosis nigricans, mucous membrane involvement, prominent sole and palm involvement, or no other identifiable cause of acanthosis nigricans. Malignancy-associated acanthosis nigricans is best treated by definitive treatment of the underlying malignancy, which can lead to resolution of the skin condition [14]. (See "Acanthosis nigricans", section on 'Diagnosis and patient evaluation'.)

Florid cutaneous papillomatosis — Florid cutaneous papillomatosis is an obligatory paraneoplastic syndrome characterized by the rapid development of wart-like lesions [15-19]. Lesions often appear first on the dorsal hands but can become widespread and are often pruritic. Clinically, lesions are indistinguishable from human papillomavirus (HPV)-associated verrucae, but histopathology shows no vacuolization of keratinocytes and absence of parakeratosis and viral inclusions.

Florid cutaneous papillomatosis is associated with underlying cancer of the stomach (in the majority of cases) as well as carcinomas of the breast, bladder, ovary, uterus, prostate, and lung [17-19]. Florid cutaneous papillomatosis may co-occur with the sign of Leser-Trélat and acanthosis nigricans [17]. Florid cutaneous papillomatosis typically occurs before or concurrent with the adenocarcinoma and tends to remit with successful treatment of the neoplasm.

Sign of Leser-Trélat — The sign of Leser-Trélat, which is classically described as the explosive onset of multiple pruritic seborrheic keratoses, often with an inflammatory base, can be an ominous sign of internal malignancy [13,20-22]. The abrupt development of the seborrheic keratoses (often within three to six months) is characteristic. Acanthosis nigricans is a common associated clinical feature [23]. (See "Overview of benign lesions of the skin", section on 'Seborrheic keratosis' and 'Acanthosis nigricans' above.)

The sign of Leser-Trélat most often occurs prior to the diagnosis of malignancy but may also be recognized after or concurrently with the malignancy diagnosis [23]. A wide variety of malignancies have been reported to occur in association with the sign of Leser-Trélat [23]. Gastrointestinal adenocarcinoma (eg, stomach, liver, colorectal, or pancreatic adenocarcinoma) is the most common class of associated malignancy. However, lymphoid malignancies (including cutaneous T cell lymphoma), breast cancer, lung cancer, and other cancers can occur in association with the sign of Leser-Trélat [20,24,25]. It is likely that various cytokines and other growth factors produced by the neoplasm are responsible for the abrupt appearance of the seborrheic keratoses. In around 50 percent of patients, the eruption resolves after treatment of the underlying malignancy [23].

Of note, there are case reports of eruptions of seborrheic keratoses occurring in association with pregnancy, benign neoplasms, and other disorders, as well as in the absence of an associated disease [23]. Inflammation of existing seborrheic keratoses and new eruptions of inflamed seborrheic keratoses have also occurred during chemotherapy [23].

Tripe palm — Tripe palm (also known as acanthosis palmaris and acquired pachydermatoglyphia [26]) refers to a characteristic velvety thickening of the palms with a ridged or rugose appearance (picture 3). The term is derived from its resemblance to the stomach mucosa of ruminants (tripe). Concurrent acanthosis nigricans is often present [27].

Tripe palm is predominantly associated with gastric or lung cancer, although it is less frequently described in association with other malignancies or as an idiopathic condition [26-28]. In some cases, tripe palm is the initial presenting feature of the underlying malignancy [27]. In a review of 77 published cases of tripe palm, improvement or resolution of tripe palm occurred in one-third of patients after beginning treatment for malignancy [27].

Acquired ichthyosis — Ichthyosis is a generalized scaling of the skin that can be either congenital or acquired. Acquired ichthyosis can be associated with inflammatory, endocrinologic, and neoplastic processes [29]. The presentation of acquired ichthyosis is similar to the inherited condition ichthyosis vulgaris, with prominent fish-like, relatively large scales adherent to the skin; however, the scaling in acquired disease may also be present on the palms and soles and in skin flexures (picture 4A-B).

Hodgkin lymphoma is the most common malignancy associated with acquired ichthyosis [2,30,31]. Less frequently reported associations include other CD30⁺ lymphoproliferative disorders (eg, anaplastic large cell lymphoma or lymphomatoid papulosis); leiomyosarcoma; multiple myeloma; cutaneous T cell lymphoma; Kaposi's sarcoma; breast, lung, or bladder carcinoma; or other malignancies [29,32]. Isolated cases in the setting of graft versus host disease following allogeneic bone marrow transplantation also have been reported [33]. Postulated mechanisms for the development of acquired ichthyosis include the secretion of keratinocyte growth factors by the tumor [28] or an autoimmune response directed against the skin [33]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

In most cases, malignancy-associated acquired ichthyosis is noted after the diagnosis of the underlying malignancy. However, there are a few reports in which recognition of acquired ichthyosis led to the diagnosis of a malignancy [30]. Acquired ichthyosis usually improves with treatment of the malignancy [34].

Palmoplantar keratoderma — Palmoplantar keratoderma is a clinical finding characterized by thickening of skin on the palms and soles. The classic form of palmoplantar keratoderma associated with malignancy is Howel-Evans syndrome (OMIM #148500), an autosomal dominant form of palmoplantar keratoderma associated with yellow, wax-like hyperkeratosis on the palms and soles (also referred to as tylosis) and markedly increased risk for squamous cell carcinoma of the esophagus (picture 5) [2,35]. Tylosis with esophageal cancer is another name for this condition. (See "Epidemiology and pathobiology of esophageal cancer", section on 'Tylosis'.)

The keratoderma of Howel-Evans syndrome primarily affects weight-bearing areas on the sole of the foot and may be accompanied by oral leukoplakia. The palmoplantar keratoderma usually becomes evident in childhood and the associated esophageal cancer is usually diagnosed in adulthood.

Sporadic cases of tylosis have also been associated with Hodgkin lymphoma, leukemia, and breast cancer [20,36]. In addition, palmoplantar keratoderma is a rare presentation of the T cell malignancy mycosis fungoides [37]. Palmoplantar keratoderma can also occur in a wide variety of conditions not associated with malignancy [38]. (See "Epidemiology and pathobiology of esophageal cancer", section on 'Epidemiology'.)

Bazex syndrome — Bazex syndrome (acrokeratosis paraneoplastica) is a rare paraneoplastic phenomenon that is strongly associated with squamous cell carcinoma of the upper aerodigestive tract, but it has also been reported with a number of other tumors [39-44]. In a systematic review of the literature that identified 77 patients with Bazex syndrome, the underlying neoplasms were squamous cell carcinoma of the head and neck in 39 percent and squamous cell carcinoma of the lung in 11 percent, followed by gastrointestinal adenocarcinoma, genitourinary tumors, lymphomas, and lung adenocarcinoma [45]. Patients present with violaceous, psoriasiform plaques predominantly located in acral areas (especially the fingers, toes, nose, and helices) (picture 6A-C) [46]. Nail dystrophy, palmoplantar keratoderma, and alopecia are common.

In most patients, the cutaneous manifestations of Bazex syndrome precede the diagnosis of malignancy [45-47]. In a 1995 review of the literature that identified 109 reported cases of Bazex syndrome preceding malignancy, the average time to the discovery of the malignancy was 12 months (range 1 to 72 months) [46]. Malignancy is diagnosed concurrently or before Bazex syndrome manifestations in approximately one-third of patients [44].

The lesions of Bazex syndrome are usually resistant to targeted therapies, but treatment of the neoplasm usually leads to resolution of the cutaneous findings [40,47]. However, there are reports of patients for whom the cutaneous manifestations persist following successful tumor therapy [48].

The best approach to the treatment of patients with incurable malignancy or persistent symptoms is unclear. Treatment with different topical and systemic agents, as well as psoralen plus ultraviolet A (PUVA) phototherapy, has been described in case reports with varying responses. Clinically significant improvement with oral acitretin has been described in multiple case reports [49-51].

Inflammatory dermatoses — Inflammation manifesting as erythematous or violaceous skin eruptions is a primary feature of multiple paraneoplastic dermatoses. Examples include Sweet syndrome, dermatomyositis, erythroderma, erythema gyratum repens, necrolytic migratory erythema, and pancreatic panniculitis.

Sweet syndrome — Sweet syndrome (acute febrile neutrophilic dermatosis) consists of a cutaneous eruption characterized by a dermal nonvasculitic neutrophilic infiltration, fever, and peripheral neutrophilia [52]. It is associated with an underlying disease in up to 50 percent of patients. Sweet syndrome has a female predominance, except in cases associated with malignancy where no female predominance is noted [53].

Approximately 20 percent of patients with Sweet syndrome have an underlying malignancy [54]. Histiocytoid Sweet syndrome, a distinct histologic variant of Sweet syndrome, has a higher risk of underlying malignancy (approximately 40 percent of patients) [55]. In a retrospective study of 52 patients with Sweet syndrome, malignancy-associated Sweet syndrome was more likely to present with anemia, leukopenia, and thrombocytopenia than non-malignancy-associated Sweet syndrome [56]. The most common malignancies associated with Sweet syndrome are acute myelogenous leukemia and myelodysplastic syndrome.

In malignancy-associated Sweet syndrome, hematologic malignancies outnumber solid malignancies by a ratio of 4:1 to 8:1 [57]. Occurrences with solid tumors, lymphomas, and plasma cell dyscrasias also have been reported. Sweet syndrome may precede, follow, or appear concurrently with a diagnosis of malignancy and may be an indicator of malignancy recurrence. Sweet syndrome is discussed in detail elsewhere. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

The cutaneous eruption consists of tender, well-demarcated, erythematous to violaceous papules and plaques with an irregular pseudo-vesiculated surface (picture 7A-C). The plaques may have a central yellowish discoloration, creating a targetoid appearance, and pustulation and blistering can occur. The plaques may cause pain and a burning sensation, but usually are not pruritic. Pathergy can occur in Sweet syndrome, with lesions developing at sites of skin injury.

The papules and plaques of Sweet syndrome are most often found on the face, neck, and upper extremities, especially the dorsum of hands, but can occur anywhere. Oral manifestations are uncommon but may occur in approximately 10 percent of patients with hematologic malignancy-associated Sweet syndrome. Oral lesions present as pseudo-vesicular or pustular initially and later may ulcerate and resemble aphthae [53]. On the lower extremities, Sweet syndrome can resemble erythema nodosum (picture 8). Fever, leukocytosis, arthralgias, and episcleritis accompany the skin lesions. Infection must be ruled out in all cases.

The frequency with which malignancy-associated Sweet syndrome resolves with treatment of the malignancy is unknown. The standard and most effective therapy is prednisone. However, the disease may recur upon discontinuation of prednisone. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Management and prognosis".)

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, an autoinflammatory disease that may present with findings of Sweet syndrome, has also occurred in association with hematologic malignancy. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)

Dermatomyositis — Dermatomyositis is a condition that presents with numerous cutaneous findings and, in most cases, an associated inflammatory myopathy (clinically amyopathic dermatomyositis is also described and linked with malignancy). The skin findings of dermatomyositis include scaly violaceous papules overlying the bony prominences of the hands (Gottron papules), violaceous patches on the periorbital skin (heliotrope eruption), photodistributed poikilodermatous patches and plaques, scaly plaques on the scalp and lateral thighs, periungual telangiectasia, and ragged cuticles (picture 9A-E). The myopathy usually presents with a progressive, symmetric, proximal weakness. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

Adults with dermatomyositis have increased risk for malignancy. In a systematic review and meta-analysis, the following factors were associated with an increased risk of malignancy: older age, male sex, cutaneous necrosis, and higher erythrocyte sedimentation rate and C-reactive protein levels [58]. Certain autoantibodies are also associated with increased risk for malignancy. (See "Malignancy in dermatomyositis and polymyositis", section on 'Serum autoantibodies'.)

The malignancies associated with dermatomyositis include a wide range of tumor types. Ovarian, cervical, breast, uterine, lung, gastric, colorectal, and pancreatic cancers are frequently reported. Associated malignancies are usually detected within three years of diagnosis, and the majority are detected within one year. Muscle disease is more likely to improve with treatment of an underlying cancer than skin disease [1,2]. The risk for malignancy and the diagnostic workup and follow-up for malignancy in patients with dermatomyositis is reviewed elsewhere. (See "Malignancy in dermatomyositis and polymyositis".)

Erythroderma — Erythroderma or exfoliative erythroderma syndrome is defined as a diffuse and generalized erythema of the skin that may involve over 90 percent of the body surface area. Severe pruritus, ectropion, and generalized lymphadenopathy are not uncommon, and superficial desquamation usually ensues. (See "Erythroderma in adults".)

The most common cause of erythroderma is a preexisting skin disease, such as atopic dermatitis or psoriasis [59], followed by drug hypersensitivity reactions. Most cases of erythroderma linked to malignancy are associated with lymphoid malignancies, particularly cutaneous T cell lymphoma. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Drug eruptions" and "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Less commonly, acute myeloid leukemia and solid tumors (eg, lung, prostate, thyroid, liver, ovaries, rectum, or skin) are associated with paraneoplastic erythroderma [60]. Paraneoplastic dermatomyositis may also be initially confused with diffuse erythroderma [61]. (See "Malignancy in dermatomyositis and polymyositis".)

The diagnostic workup of an erythrodermic patient should involve a detailed history and physical examination, with special attention to medication history and the history of preexisting skin conditions, systemic disorders, and neoplasia. Erythroderma usually resolves with treatment of the associated malignancy [2]. The evaluation to determine the underlying cause of erythroderma and the management of patients with erythroderma are reviewed in detail separately. (See "Erythroderma in adults", section on 'Determining the underlying cause' and "Erythroderma in adults", section on 'Treatment'.)

Erythema gyratum repens — Erythema gyratum repens is characterized by concentric rings of rapidly migrating erythematous plaques covering a large percentage of the body surface (picture 10A-C). A trailing collarette of scale is evident, and lesions are moderately to severely pruritic. In the vast majority of cases (70 to 80 percent), there is an associated internal malignancy, most often a bronchogenic carcinoma, less commonly esophageal or breast cancer [62-64]. The cutaneous eruption may precede, occur with, or follow the diagnosis of malignancy. Improvement often correlates with successful treatment of the underlying cancer.

Erythema gyratum repens has also been reported in the setting of benign conditions, such as pulmonary tuberculosis, psoriasis, pityriasis rubra pilaris, and autoimmune disorders [65].

Necrolytic migratory erythema — Necrolytic migratory erythema (NME) is a transient, weeping eczematous or psoriasiform eruption that occurs in approximately 70 percent of patients with glucagon-secreting pancreatic islet cell tumors (glucagonomas). The eruptions primarily occur around body orifices, in skin flexures, and in acral sites (picture 11A-C) [66]. Anemia, weight loss, stomatitis, abdominal pain, diarrhea, and thromboembolic phenomena are additional common features. The diagnosis of NME is indicated by the presence of characteristic clinical features, an elevated serum glucagon level, and radiographic or histologic evidence of a glucagon-secreting pancreatic tumor. (See "Glucagonoma and the glucagonoma syndrome", section on 'Diagnosis'.)

Although NME has been described as pathognomonic for glucagonoma, some patients with this condition do not have glucagon-producing tumors. These patients are categorized as having pseudoglucagonoma syndrome [67]. Examples of other disorders that have been associated with NME include celiac disease, cirrhosis of the liver, and inflammatory bowel disease [68]. Various extrapancreatic malignancies, such as hepatocellular, lung, and duodenal cancer, and tumors that secrete insulin or insulin-like growth factor-2 also have been linked to NME.

Treatment with octreotide controls NME effectively, but does not appear to affect the underlying malignancy [69]. Surgical removal of the tumor, when feasible, can result in the resolution of NME [66,70]. (See "Glucagonoma and the glucagonoma syndrome", section on 'Treatment'.)

Pancreatic panniculitis — Pancreatic panniculitis, a form of lobular panniculitis, is a rare condition in which necrosis of fat within the panniculus and other distant foci occurs in the setting of chronic pancreatitis [71]. Pancreatic panniculitis also has occurred in patients with acinar and islet cell pancreatic cancers [71-76]. The term "lipase hypersecretion syndrome" is used to describe the development of pancreatic panniculitis, inflammation of nearby joints, and eosinophilia in the setting of acinar cell carcinoma, often in association with liver metastasis [77-79]. (See "Pathology of exocrine pancreatic neoplasms", section on 'Acinar cell carcinoma' and "Panniculitis: Recognition and diagnosis", section on 'Enzymatic destruction'.)

In pancreatic panniculitis, tender, erythematous to violaceous, ulcerated nodules can occur anywhere on the body but most commonly occur on the upper and lower extremities. Unlike other panniculitides, pancreatic panniculitis nodules may undergo liquefactive necrosis leading to spontaneous ulceration and brown, viscous drainage [80]. The eruption is attributed to the massive release of lipolytic enzymes into the bloodstream [71,73,76]. Patients are systemically ill with fever and weight loss, and joint manifestations may be prominent. Serum lipase and amylase levels are elevated. In cases associated with a pancreatic neoplasm, the tumor is usually advanced by the time cutaneous lesions appear. Nevertheless, treatment may be beneficial [76]. (See "Panniculitis: Recognition and diagnosis", section on 'Enzymatic destruction'.)

Bullous dermatoses — Paraneoplastic pemphigus and mucous membrane pemphigoid with antibodies against laminin 332 are autoimmune blistering disorders with a strong association with malignancy.

Paraneoplastic pemphigus — Paraneoplastic pemphigus (also known as paraneoplastic autoimmune multiorgan syndrome or PAMS) is a paraneoplastic disorder associated with lymphoreticular malignancies or lymphoproliferative disorders in 84 percent of cases. Non-Hodgkin lymphoma is the most frequent disorder, followed by chronic lymphocytic leukemia and Castleman disease. Paraneoplastic pemphigus most frequently affects adults aged 45 to 70 years; however, children may present with the condition, especially in the setting of Castleman disease [81]. Thymoma, sarcomas, and Waldenström macroglobulinemia are also associated. (See "Paraneoplastic pemphigus".)

The most consistent clinical feature of paraneoplastic pemphigus is a painful stomatitis (picture 12). Severe pseudomembranous conjunctivitis may also occur in addition to disease of other mucosal sites. Cutaneous manifestations can include tense bullae or lesions resembling erythema multiforme or lichen planus (picture 13). Extracutaneous manifestations include ocular complications, muscle weakness, myasthenia gravis, and severe involvement of the airways leading to bronchiolitis obliterans [82,83].

The diagnosis of paraneoplastic pemphigus is made by clinical and histopathologic findings and results of direct immunofluorescence, indirect immunofluorescence of patient’s serum on murine bladder substrate, and/or enzyme-linked immunosorbent assay (ELISA) for antibodies to envoplakin or periplakin. (See "Paraneoplastic pemphigus", section on 'Diagnosis'.)

The diagnosis of malignancy precedes the diagnosis of paraneoplastic pemphigus in approximately two-thirds of patients [84]. In a patient with suspected paraneoplastic pemphigus, but without known malignancy, investigation for an underlying malignancy is indicated.

In patients with Castleman disease or thymoma, resection of the tumor frequently results in remission of paraneoplastic pemphigus. However, with other malignancies, paraneoplastic pemphigus often progresses independent of the status of the malignancy and may require treatment with immunosuppressive therapies [85]. Paraneoplastic pemphigus is discussed in greater detail elsewhere. (See "Paraneoplastic pemphigus".)

Mucous membrane pemphigoid — Mucous membrane pemphigoid (MMP) with antibodies against laminin 332 (previously known as laminin 5 or epiligrin) is an autoimmune blistering condition characterized by severe, painful blisters and erosions on the oral mucosa and skin manifestations consisting of bullae and erosions on an erythematous base. Distinction from other types of MMP is important because of an elevated risk for cancer associated with this subtype [86]. The types of cancer that occur in patients with anti-laminin 332 MMP vary; most are solid tumors. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid", section on 'Malignancy'.)

Nearly all patients have mucosal involvement, and possible severe sequelae include gingival destruction, tooth loss, blindness, dysphagia, dysphonia, and airway compromise. The diagnosis of anti-laminin 332 MMP cannot be made clinically, as features are similar to other types of MMP. The detection of antibodies bound to the dermal side of salt-split skin on indirect immunofluorescence is suggestive of this condition. However, confirmatory tests for anti-laminin 332 antibodies are limited to specialized centers and research settings. Patients with this finding should undergo age-appropriate malignancy screening. Immunosuppressive therapy may be effective for improving symptoms; however, the disease course often is progressive. (See "Clinical features and diagnosis of bullous pemphigoid and mucous membrane pemphigoid" and "Management of mucous membrane pemphigoid".)

Hyperpigmentation — Widespread hyperpigmentation can be a prominent cutaneous finding in patients with malignancy-associated ectopic Cushing's syndrome or metastatic melanoma. In addition, patients with malignancy-associated acanthosis nigricans may have hyperpigmentation in the affected areas. (See 'Acanthosis nigricans' above.)

Hyperpigmentation in ectopic Cushing's syndrome — Ectopic Cushing's syndrome is the most common hormonally induced paraneoplastic syndrome associated with internal malignancy. The syndrome is characterized by generalized hyperpigmentation (cutaneous and mucosal), muscle wasting, proximal muscle weakness, abnormal fat distribution, peripheral edema, hypokalemic metabolic alkalosis, abnormal glucose tolerance, and hypertension [87]. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

Ectopic Cushing's syndrome is caused by hypersecretion of proopiomelanocortin (POMC) from tumors outside of the pituitary gland. POMC is a prohormone of melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH). Both MSH and ACTH are capable of stimulating melanin synthesis, which leads to the development of hyperpigmentation [88]. (See "Causes and pathophysiology of Cushing syndrome".)

The most common cause of ectopic Cushing's syndrome is lung carcinoma, specifically the small cell neuroendocrine type. Cushing's syndrome is less frequently associated with carcinoid tumors, thymomas, and pheochromocytomas. (See "Pathobiology and staging of small cell carcinoma of the lung" and "Clinical features of carcinoid syndrome" and "Clinical presentation and management of thymoma and thymic carcinoma".)

In Cushing's syndrome, the normal diurnal variation in cortisol production is absent and most patients do not respond normally to the 48-hour dexamethasone suppression test. Surgical removal of the ACTH-producing tumor is the treatment of choice, but in the case of small cell lung cancer, chemotherapy is more often considered. (See "Establishing the cause of Cushing syndrome" and "Overview of the treatment of Cushing syndrome" and "Extensive-stage small cell lung cancer: Initial management".)

Generalized dermal melanosis — Rarely, generalized melanosis with a diffuse slate-gray color to the skin may develop in a patient with extensive metastatic melanoma [89-91]. Since malignant melanocytes are rarely detected in involved areas, pigmentation is thought to be due to dissemination of melanin pigment with uptake by dermal macrophages [92].

The pathogenesis of generalized melanosis is not well understood. Pigmentation resulting from aberrant production of melanocyte growth factors is one of multiple theories [89,91,93].

Purpura and petechiae — Purpura and petechiae are common features of vasculitis and primary (AL) amyloidosis. Both disorders can occur in the setting of an underlying malignancy.

Vasculitis — Malignancy-associated vasculitis is rare and occurs more often with hematologic malignancies than with solid malignancies [94]. The associated hematologic malignancies are typically lymphoproliferative, or less frequently, myelodysplastic.

In patients with hematologic malignancies, the most common presentation is a small vessel cutaneous leukocytoclastic vasculitis. Similar to non-malignancy-associated leukocytoclastic vasculitis, malignancy-associated leukocytoclastic vasculitis typically presents with palpable purpura that are preferentially located in dependent areas (picture 14A-B) [95,96]. Solid tumors are associated with various types of vasculitis, including polyarteritis nodosa, immunoglobulin A vasculitis (Henoch-Schönlein purpura), and small-vessel vasculitis [97,98]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis" and "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)

Vasculitis may occur a few years before diagnosis of a malignancy, closer to the time of diagnosis, or following the diagnosis of malignancy [96]. The proportion of patients with vasculitis who harbor an underlying malignancy is not well characterized but appears to be small. Workup for underlying malignancy, therefore, should be guided by associated findings on history, physical examination, or basic laboratory tests. Successful treatment of the underlying malignancy may lead to resolution of vasculitis [94,99]. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

Amyloidosis — Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low molecular weight subunits (5 to 25 kD) of a variety of low molecular weight serum proteins. In primary (AL) amyloidosis, fragments of monoclonal light chains with or without heavy chains are deposited in the kidney and other tissues, including the skin. AL amyloidosis can occur alone or in association with plasma cell dyscrasias such as multiple myeloma, and less frequently, Waldenström macroglobulinemia. In patients with multiple myeloma, the myeloma is typically diagnosed before or concurrently with the amyloidosis diagnosis. Rarely, multiple myeloma develops more than six months after evident amyloidosis. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Relation to other plasma cell disorders'.)

The most common mucocutaneous findings in amyloidosis are purpura, petechiae, and ecchymoses following minor trauma ("pinch purpura") (picture 15). A classic finding is the appearance of periorbital purpura following a Valsalva maneuver or dependent positioning of the head. Macroglossia (picture 16), waxy papules and plaques, enlarged shoulder pads, bullous lesions, and sclerodermatous changes in the skin may also be seen.

The diagnosis and management of AL amyloidosis is reviewed in detail separately. (See "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis" and "Treatment and prognosis of immunoglobulin light chain (AL) amyloidosis".)

Scleroderma-like dermatoses — Scleromyxedema and scleredema are rare connective tissue disorders that have been associated with paraproteinemias [100,101].

Scleromyxedema — Scleromyxedema is characterized by waxy yellow-red papules often arranged in a linear fashion. The cutaneous findings occur most commonly on the face, neck, forearms, and hands (picture 17A-B). When the papules coalesce, induration similar to sclerodermatous changes may be noted [102]. Associated findings may include sparse eyebrow, axillary, and pubic hair and leonine facies. Middle-aged adults are most commonly affected. (See "Scleromyxedema".)

Scleromyxedema typically occurs in the presence of paraproteinemia. Scleromyxedema without paraproteinemia is considered an atypical presentation. A monoclonal gammopathy characterized by an IgG lambda paraprotein is commonly detected, but myeloma is rare [103,104].

A variety of agents have been used to induce remission of scleromyxedema; however, results are inconsistent. Successful treatment of scleromyxedema does not appear to be dependent upon the resolution of the paraproteinemia. (See "Scleromyxedema", section on 'Treatment'.)

Scleredema — Scleredema is characterized by firm, stiff indurated skin on the posterior and lateral portion of the neck and the upper back (picture 18). The stiffness is caused by increased mucin deposition in the skin. Although scleredema most commonly follows a viral upper respiratory infection or the onset of diabetes mellitus, patients with persistent scleredema often have an associated monoclonal gammopathy [105]. Others have reported the development of myeloma in such patients [106,107]. (See "Scleredema".)

Since cutaneous manifestations can precede the monoclonal gammopathy, immunoelectrophoresis should be performed routinely in patients with scleredema, especially if diffuse. It is uncertain whether treatment of the associated underlying disease alters the clinical course of scleredema. (See "Scleredema", section on 'Diagnosis' and "Scleromyxedema", section on 'Treatment'.)

Hair and nail changes — Paraneoplastic dermatoses associated with hair or nail disorders include hypertrichosis lanuginosa and hypertrophic osteoarthropathy. Nail changes are also a common finding in Bazex syndrome. (See 'Bazex syndrome' above.)

Hypertrichosis lanuginosa — Hypertrichosis lanuginosa (malignant down) refers to the appearance of fine hair growth, which is predominantly localized to the head and neck but may spread to the torso, arms, and legs (picture 19) [108-110]. A strong association of this unusual hair growth has been described with adenocarcinomas arising in the large bowel, breast, lung, and kidney [20,108].

Hypertrichosis lanuginosa usually presents in patients with advanced or metastatic cancer; rare early and very delayed presentations also have been reported [111,112]. Removal of the malignancy may lead to resolution of the excess hair growth. (See "Pathophysiology and causes of hirsutism".)

In addition, there is a congenital form of hypertrichosis lanuginosa that is not associated with malignancy. Congenital hypertrichosis lanuginosa is present at birth [113].

Hypertrophic osteoarthropathy — Hypertrophic osteoarthropathy, which is characterized by the development of clubbed fingers, periostitis of long tubular bones, and arthritis, can occur secondary to chronic pulmonary or cardiac conditions producing peripheral hypoxia (picture 20A-B and figure 1 and image 1A-B). There is also an association with lung cancer, primarily non-small cell lung cancer [114,115]. Symptoms may improve with treatment of the associated lung cancer [115,116]. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

Hypertrophic osteoarthropathy secondary to pulmonary or cardiac disorders should be distinguished from primary hypertrophic osteoarthropathy, a hereditary disorder that presents with similar features. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

Other paraneoplastic dermatoses

Pruritus — In patients with generalized pruritus who are not jaundiced, a search for systemic diseases should be initiated to rule out associated disorders such as thyroid disease and hepatic and renal insufficiency [117]. Malignant neoplasms may underlie some cases of generalized, refractory pruritus, most commonly lymphoma (particularly Hodgkin lymphoma), multiple myeloma, leukemia, and carcinoid tumor involving the stomach [118]. In contrast to the usually nonpruritic intermittent cutaneous flushing associated with intestinal carcinoid tumors, the intermittent "histamine" flush associated with atypical gastric carcinoid tumors tends to be pruritic. Occasionally, pruritus presents years before the diagnosis of a malignancy. Malignancy-associated pruritus may improve with treatment of the underlying malignancy [119]. (See "Pruritus: Etiology and patient evaluation", section on 'Malignancy'.)

The evaluation of patients with generalized pruritus is reviewed separately. (See "Pruritus: Etiology and patient evaluation", section on 'Generalized pruritus without primary skin lesions'.)

Multicentric reticulohistiocytosis — Multicentric reticulohistiocytosis (MRH) is a rare multisystem disease consisting of a cutaneous histiocytosis and destructive polyarthritis. MRH is associated with an underlying malignancy in one-quarter of patients. A variety of malignancies have been linked to MRH; breast, hematologic, and gastric cancers are most common [120].

Flesh-colored to yellow-brown papules and nodules are seen with a predilection for the upper body, and most frequently occur on the face, hands, forearms, and ears. Lesions around the fingernails have a "coral bead" appearance (picture 21). In addition, xanthelasma has been noted in one-third of patients with MRH. The arthritis of MRH can be rapidly destructive and progress to arthritis mutilans in half of the patients. Other associated symptoms include fever, weight loss, and weakness. Although resolution of MRH following treatment of the underlying cancer has been reported, it is debated whether there is a clear correlation between disease activity in MRH and successful treatment of the associated malignancy [121].

Plane xanthomas — Plane xanthomas can occur in patients with lipid disorders, but may also herald the presence of monoclonal gammopathy, multiple myeloma, or less frequently, other hematologic malignancies or lymphoproliferative disorders [122]. The term normolipemic plane xanthoma is used to refer to the development of plane xanthomas in patients who lack concomitant hyperlipidemia.

Plane xanthomas usually present as yellowish to reddish macules, papules, patches, or slightly elevated plaques that have a predilection for the face, neck, upper trunk, and intertriginous areas (picture 22). In some cases, plane xanthoma precedes the appearance of a hematologic disorder by several years [122]. It is theorized that the myeloma proteins interfere with lipid metabolism, leading to cutaneous deposition. In our experience, plane xanthomas often persist after treatment of the associated malignancy. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)

Acquired cutis laxa — Cutis laxa can be inherited or acquired and results in loose, wrinkled, and redundant skin due to defects in elastic tissue. Internal manifestations may occur and include intestinal diverticula, pulmonary emphysema, hernias, and cardiovascular dilatations.

Acquired cutis laxa develops later in life and has been attributed to infections, medications, inflammatory dermatoses, and plasma cell dyscrasias [123]. The progression is often cephalocaudal in the generalized, acquired form with the development of "hound dog" facies preceding lax skin of the trunk and extremities. Localized forms have also been described, including acral acquired cutis laxa affecting the fingertips associated with plasma cell dyscrasia.

Biopsy of the skin will show elastolysis and elastophagocytosis by giant cells. Deposition of myeloma-associated immunoglobulins on elastic fibers of the skin has been demonstrated, likely leading to elastic fiber destruction [124].

Patients with adult onset of loose, redundant skin should be biopsied and if decreased elastic fibers are evident, should be evaluated for plasma cell dyscrasia by serum protein electrophoresis and immunofixation, along with assessment for other causes (infection, medication reactions, coexistent or preceding dermatoses). In generalized forms, evaluation for internal manifestations is recommended.

NON-PARANEOPLASTIC CUTANEOUS MANIFESTATIONS OF INTERNAL MALIGNANCY — Cutaneous disorders that represent tumoral infiltration into the skin are not considered paraneoplastic dermatoses. Examples include cutaneous metastases and leukemia cutis.

Cutaneous metastases — Occasionally, internal cancers metastasize to the skin through hematogenous or lymphatic spread of tumor cells. Tumor cells from an internal cancer may also appear in the skin as a result of direct tissue invasion or iatrogenic implantation [125].

Estimates for the frequency of cutaneous metastasis range from less than 1 percent to 10 percent of patients with internal cancers [125,126]. The clinical manifestations vary widely. Patients may develop papules, plaques, nodules, or ulcers (picture 23).

In some cases, cutaneous metastasis is the initial sign that leads to the diagnosis of an internal malignancy [126]. Cutaneous metastases often herald a poor prognosis [126].

Leukemia cutis — Leukemia cutis describes the cutaneous manifestations that result from the entry of neoplastic leukocytes into the skin. The disorder is more common in patients with acute myeloid leukemia than in patients with chronic myeloproliferative disease [127]. (See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia", section on 'Skin'.)

The clinical manifestations of leukemia cutis vary. Affected patients typically present with single or multiple red-brown, violaceous, or hemorrhagic papules, nodules, or plaques (picture 24) [127].

HERITABLE CONDITIONS ASSOCIATED WITH SKIN DISORDERS AND MALIGNANCY — Several inherited conditions that predispose to internal malignancy have associated cutaneous manifestations. These include:

●Cowden syndrome – Trichilemmomas (adnexal tumors (picture 25)) with multiple hamartomatous lesions and an increased risk of early-onset breast and thyroid cancer. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Mucocutaneous'.)

●Peutz-Jeghers syndrome – Multiple hamartomatous polyps in the gastrointestinal tract (with malignant potential) in association with distinctive mucocutaneous pigmentations (picture 26). (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)

●Muir-Torre syndrome – Multiple sebaceous gland and skin tumors, including keratoacanthomas, in conjunction with visceral cancers [128-130]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)

●Gardner syndrome – Desmoid tumors, sebaceous or epidermoid cysts, lipomas, osteomas supernumerary teeth, gastric polyps, juvenile nasopharyngeal angiofibromas, and intestinal adenocarcinomas. (See "Gardner syndrome".)

●Neurofibromatosis type 1 – Cutaneous and subcutaneous neurofibromas, café-au-lait macules with optic pathway gliomas, and other tumors involving the nervous system. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Examples of other heritable conditions associated with malignancy and prominent cutaneous findings include Birt-Hogg-Dubé syndrome and multiple endocrine neoplasia syndromes. In addition, some patients with a strong family history of melanoma have an increased risk for pancreatic cancer. (See "Hereditary kidney cancer syndromes", section on 'Birt-Hogg-Dubé syndrome' and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Inherited susceptibility to melanoma", section on 'CDKN2A gene' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis", section on 'Tumors'.)

SUMMARY

●Overview – A wide variety of cutaneous disorders can occur in the setting of malignancy. Skin conditions that are associated with neoplastic disorders, but do not represent cutaneous infiltration of malignant cells constitute the paraneoplastic dermatoses. (See 'Introduction' above.)

●Clinical relevance – Knowledge of the paraneoplastic dermatoses is of value in the clinical setting. The presence of unexplained cutaneous findings consistent with a paraneoplastic disorder can indicate the need to evaluate a patient for an underlying internal malignancy. (See 'Paraneoplastic dermatoses' above.)

For some paraneoplastic dermatoses, successful treatment of the underlying malignancy results in resolution of the dermatosis. (See 'Paraneoplastic dermatoses' above.)