Cutaneous paraneoplasia

Clinics in Dermatology (2011) 29, 541–547

Cutaneous paraneoplasia Marcia Ramos-e-Silva, MD, PhD ⁎, Joana Castro Carvalho, MD, Sueli Coelho Carneiro, MD, PhD Sector of Dermatology and Post Graduation Course of Dermatology, University Hospital Clementino Fraga Filho and School of Medicine, Federal University of Rio de Janeiro, 22280-020 Rio de Janeiro, Brazil

Abstract Paraneoplasias are frequently the first sign of a subjacent malignant tumor. Although relatively rare, they need to be recognized by dermatologists to make an early diagnosis and improve the prognosis related especially to the neoplasia. This contribution presents the morphologic aspects and the differential diagnosis of the main paraneoplasias, which include acanthosis nigricans, tripe palms, LeserTrélat sign, acquired ichthyosis, acquired hypertrichosis lanuginosa, pityriasis rotunda, erythema gyratum repens, palmo-plantar keratoderma, Bazex syndrome, and dermatomyositis, hoping to contribute to the familiarity of dermatologists with the identification and early diagnosis of this group. © 2011 Elsevier Inc. All rights reserved.

Introduction The skin is the main organ through which the human being interacts with the external environment. Functions of the skin include thermal regulation and sensibility but can also be the site of several diseases. Some cutaneous alterations must be interpreted as important clues for the diagnosis of systemic diseases. When related to malignant diseases, early recognition of its cutaneous signaling is of great value, because it can anticipate the diagnosis of a neoplasia and, therefore, improve the patient's prognosis.1,2 Paraneoplasias can be defined as hormonal, neurologic, or hematologic disturbances and other clinical and biochemical alterations associated with malignant neoplasia but without being directly associated to the invasion by the primary tumor or by its metastases.3

⁎ Corresponding author. Tel.: +55 21 2286 4632. E-mail address: [email protected] (M. Ramos-e-Silva). 0738-081X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2010.09.022

Six criteria have been described for a cutaneous alteration to be considered as paraneoplastic: 1. 2. 3. 4. 5. 6.

its onset must be near to the beginning of the neoplasia, both must follow parallel courses, the dermatosis must not be part of any genetic syndrome, a specific dermatosis accompanies a specific tumor, the cutaneous disease is common, and there is a high grade of association with the neoplasia.1

At present, the two first criteria are the most relevant. Because they present parallel evolution, a recurrence of the dermatosis may indicate a recurrence of the cancer.2 The physiopathology of the lesions in relation to the tumor is not always understood.2 Mediators, such as growth factors, cytokines, or hormones, are likely involved. The lesion in the skin usually occurs at a certain distance from the primary site.1 In this contribution, paraneoplasias will be presented, especially regarding their morphologic aspects. Among them, the following will be discussed: acanthosis nigricans, tripe palms, Leser-Trélat sign, acquired ichthyosis, acquired

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hypertrichosis lanuginosa, pityriasis rotunda, erythema gyratum repens, palmoplantar keratoderma, Bazex syndrome, and dermatomyositis.

Acanthosis nigricans Acanthosis nigricans (Figure 1) is characterized by symmetrical areas4 of thickened skin with grayish brown hyperpigmentation and a velvety surface that can become verrucous and present papular lesions (acrochorda).1,2 It affects skin folds, mainly the neck and the antecubital and popliteal fossa.1,2,5 Histopathology shows hyperkeratosis, papillomatosis, and some degree of acanthosis, with increase of the stratum spinosum.1,6 Acanthosis nigricans has a benign nature in 80% of the patients, occurring in idiopathic form7 or in individuals with diseases that course with resistance to insulin, including diabetes mellitus, obesity, and polycystic ovary syndrome.1,2 Malignant acanthosis nigricans is rare,4,7 with sudden onset and quick and diffuse evolution.2 It especially affects adults in their early 50s, without preference for sex, race, or family history.4 The mucosa may present a papillomatous aspect, without hyperpigmentation.2,4 Lips and trauma sites can be affected,1 and palmoplantar keratosis may also be present.1,7 Palms may sometimes present tylosis or more evident keratosis of a wrinkled aspect known as “tripe palms,” which is associated with an underlying neoplasia in 94% of patients.1,2,5 Generalized pruritus is a frequent complaint,4 and alopecia has been described.2 The Leser-Trélat sign, characterized by sudden onset of multiple seborrheic keratoses and florid cutaneous papillomatosis, can occur simultaneously.2 The most consistent association is with intraabdominal adenocarcinoma, with 45% of the cases being gastric adenocarcinoma.2,8 Other associations described are with carcinoma of the lung, liver, uterus, breast, and ovaries, besides lymphomas and mycosis fungoides.2 Acanthosis nigricans appears simultaneously with the diagnosis of tumor in 61.3%, but can appear before (17.6%) or after (21.1%). The neoplasia probably produces cytokines, such as transforming growth factor α

(TGF-α),9 that stimulate the proliferation of keratinocytes. Thus, treatment of the tumor usually results in an improvement in the cutaneous picture .1,2 Other medications proposed are acitretin,10 oral isotretinoin,1,5 tretinoin, and topic ammonium lactate.7,11

Tripe palms Tripe palms, also known as acanthosis palmaris and acanthosis nigricans of the palms,1 represents an accentuation of the dermatoglyphs,2 providing a wrinkled and grooved appearance to the skin of the palms. It can also affect the plantar region.12 In more than 90%, it is associated with malignancies.2 It usually coexists with acanthosis nigricans and sometimes with the Leser-Trélat sign, suggesting that those alterations may be related.12 TGF-α may be involved in its pathogenesis as well as in acanthosis nigricans. Both present parallel evolution to cancer and similar histopathologic alterations.1 The occurrence of tripe palms in the absence of acanthosis nigricans should lead to the suspicion of pulmonary squamous cell carcinoma.12

Leser-Trélat sign The Leser-Trélat sign (Figure 2) corresponds to the sudden appearance of multiple seborrheic keratoses with quick evolution in size and numbers1 secondary to the presence, known or unknown, of a neoplasia. It affects especially the trunk, followed by the extremities, face, abdomen, and neck.1,5 Many patients complain about pruritus.2 Because the appearance of seborrheic keratoses and malignancies increases with age, the value of that sign is still controversial. 2,12 About 20% of the patients also present with acanthosis nigricans,1,9 and in those cases, TGF-α produced by tumoral cells13 may be involved in the pathogenesis.1 Other proposed causes are the rupture in epidermal cellular turnover and reduction in host defenses.2 The Leser-Trélat sign is associated with adenocarcinomas, mainly gastric, but also of the colon, breast,1,9 lung, ovary, uterus,2 kidney, liver, and pancreas.13 Lymph-proliferative disorders respond for 20% of the cases.1 It may occur in benign conditions as during pregnancy9 and in some benign tumors.7 Every patient with the Leser-Trélat sign should be evaluated for a hidden neoplasia.13 Histopathology is similar to the usual seborrheic keratoses. There is no specific therapy1; however, proper treatment of the neoplasia leads to the regression of the seborrheic keratoses in approximately half of the patients.2

Acquired ichthyosis

Fig. 1

Acanthosis nigricans.

Acquired ichthyosis (Figures 3 and 4) clinically resembles vulgar ichthyosis, with cutaneous xerosis14 and a great quantity of rhomboid scales similar to fish scales. It mainly

Cutaneous paraneoplasia

Fig. 2 Leser-Trélat sign (photograph courtesy of Dr Tania Cestari, Porto Alegre, Brazil).

affects the extensor regions of upper and lower limbs1 and trunk.4 The region of the folds, palms, and soles are spared in most patients.1,4 Ichthyosis vulgaris is a autosomal-dominant genetic disorder2 that begins in childhood.4 The acquired form usually appears in adults and may be associated with benign disorders such as malnutrition, hypothyroidism, sarcoidosis, and leprosy, as well as with acquired immunodeficiencies such as AIDS, graft-versus-host disease, and bone marrow transplant. It can also appear after the use of certain medications, including niacin. When paraneoplastic, the main neoplasia found is Hodgkin disease, representing about 70% of the cases.1,4 It can also be related to multiple myeloma, cutaneous

Fig. 3

Acquired ichthyosis.

543 lymphomas of the T cells, and other lymph-proliferative disorders.1 Solid tumors, such as of the breast, lung, ovary, cervix, and liver,4 and leiomyosarcoma and Kaposi sarcoma, represent a small portion of the cases.1 The cutaneous alterations frequently appear some weeks or months after the manifestations of the neoplasia1,2 Men seem to be more affected, but there is no genetic influence or racial preference.2 Ichthyosis occurs when an alteration of the keratinization process of the epidermis occurs that results in hyperkeratosis, desquamation, and abnormalities in the function of the stratum corneum barrier.14 The pathophysiology remains unknown; however, when associated with Hodgkin disease, the deficiency is likely to be related to poor vitamin A absorption.1 The synthesis of lipids in the skin, increased in ichthyosis vulgaris, seems normal in the acquired form associated with lymphoma.2 In Hodgkin disease, the synthesis of lipids is reduced regardless of the presence or not of ichthyosis.2 The histopathologic examination reveals contact or laminar orthokeratosis,14 moderate acanthosis, and thinning or absence of the granular layer,1 without dermal inflammatory infiltrate.4,14 Ichthyosis vulgaris may occur simultaneously with other paraneoplastic syndromes such as dermatomyositis, erythema gyratum repens, and Bazex syndrome. The treatment must focus on the basic disease. Symptomatic therapy consists in skin hydration and removal of the scales with the use of topical medications such as salicylic acid, αhydroxyacids, or urea.1

Acquired hypertrichosis lanuginosa This disease is characterized in adults by the sudden and progressive development of thin lanuginous hairs. The hair is soft, thin, and nonpigmented,5 resembling velvet. Initially, the hairs cover the face and ears and rapidly disseminate to involve the entire body, except the palm-plantar,1 genital, and pubic areas.5 Findings, such as glossitis, hypertrophy of the tongue papillae, and alterations of taste and smell, can be

Fig. 4

Acquired ichthyosis.

544 found. About 73% of cases occur in women aged between 40 and 70 years.15 For being a rare syndrome, the true frequency associated with neoplasias is unknown; however, most seem to be secondary to underlying malignancies, which should be investigated.5 The most common neoplasias found are those of the colon, rectum, and lung.15 In women, hypertrichosis lanuginosa is also related to breast cancer.1,15 In most patients, the syndrome is diagnosed late during the course of the neoplasia, with the tumor metastases already having occurred. 1 Late cutaneous porphyria, AIDS, anorexia nervosa, thyrotoxicosis, and use of topical or systemic medications (cyclosporine, phenytoin, minoxidil) are nonmalignant causes of acquired hypertrichosis lanuginosa and should be excluded.15 Its etiology remains unknown, and no hormonal or biochemical abnormality has been found.1

Pityriasis rotunda Pityriasis rotunda is a rare dermatosis, usually described associated with malignant and infectious systemic diseases.16 It is clinically characterized by multiple, welldelimited hyperchromic or hypochromic lesions, with ichthyosiform desquamation of circular morphology.1,17 Pityriasis rotunda typically occurs on trunk1 but can also affect the buttocks, thighs, and the arms.17 There is no inflammation or pruritus.1 A genetic factor seems to be involved. Its pathogenesis is unknown.17 Episodes of exacerbation alternate with periods of remission.16 Pityriasis rotunda affects both men and women aged between 20 and 45 years. Tinea versicolor, erythrasma, leprosy, fixed eruption, pityriasis alba, and pityriasis rosea should be considered as differential diagnoses, and among associated disorders are urogenital tract diseases in women, tuberculosis, leprosy, hepatic diseases, and pulmonary diseases. Others include cardiopathies and neoplasias such as adenocarcinoma of the prostate, carcinoma of the palate, esophageal, hepatocellular, and gastric malignancies, chronic lymphocyte leukemia, and multiple myeloma. Remission of the dermatosis after removal of the tumor has been reported. Histology shows hyperkeratosis with a reduction or absence of the granular layer.16 Most topical treatments fail to offer a good response.1

Erythema gyratum repens Erythema gyratum repens is a dermatosis with dramatic onset and evolution18 and is a very specific sign of an underlying neoplasia.1 It is present in more than 80% of the cases,18 and patients, therefore, should be examined diligently.1 It affects more men than women, in a 2:1 ratio, with average age for onset of 63 years.18 The main lesions are erythematous serpiginous macules forming

M. Ramos-e-Silva et al. concentric rings with the characteristics of migrating at a speed of 1 cm per day.5,18 Discrete marginal scaling and bullae over the lesions can occur. The hands, feet, and the face are usually spared.5,18 There is intense and disseminated pruritus.18 Other cutaneous manifestations include palmoplantar keratosis, onychodystrophy, and ichthyosis of the acral regions.1 Its histopathology is unspecific, showing moderate hyperkeratosis, parakeratosis, acanthosis, and spongiosis with mononuclear perivascular inflammatory infiltrate in the upper dermis. Erythema gyratum repens precedes the diagnosis of cancer in 80% of patients. The main associated neoplasia is lung cancer, but others have been reported, including cancer of the esophagus, breast,18 pharynx, stomach, cervix, and colon and rectum.2 Other associated conditions are tuberculosis; pregnancy; bullosis18; calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactylia, and telangiectasia (CREST) syndrome,1 lupus erythematosus, and Sjögren syndrome.19 Its etiology is unknown; however, an immunologic mechanism is hypothesized, because there are reports of granular deposits of immunoglobulin G and C3 in the basal membrane of the epidermis at the affected sites.1 The course of the cutaneous lesions follows the underlying tumor, and tumor eradication results in improvement of the patient's condition.1,18 If treatment of the neoplasia is impossible, antihistamines, azathioprine, and topical or systemic steroids5 can be tried, usually without success.1

Palmoplantar keratoderma The several groups of palmoplantar keratodermas (Figures 5 and 6) represent an abnormal thickening of the horny layer of palms and soles secondary to alterations in the keratinization process.4,20 They can have a hereditary or acquired character and can be classified according to their histopathology (presence or absence of epidermolysis) or by the type of involvement (focal, diffuse, or punctata).4 Tripe palms, mentioned earlier, fit in this group.4 The skin is hardened and yellowish, and this is usually associated with hyperhidrosis.4,20 Among the inherited forms that may be transmitted by dominant autosomal or regressive heritage, the diffuse forms are usually present at birth or soon after, with generalized keratosis of palms and soles, as in epidermolytic hyperkeratosis. The focal forms, however, appear later in childhood with thickening only in the pressure areas, as occurs in the Howel-Evans syndrome.4 Palmoplantar keratoderma punctata, or dotted (as the name suggests), presents with areas of punctual keratoses forming translucent papules that can become opaque or verrucous in acral regions, especially on pressure points, and become evident after puberty.4,20 The acquired keratodermas are asymmetric and do not affect all palmoplantar regions. They appear in later phases and can have several triggering factors.20

Cutaneous paraneoplasia

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Many clinical variants of palmoplantar keratodermas, whether inherited or acquired, are associated with different malignant diseases. Howel-Evans syndrome, for instance, has dominant-autosomal heritage and is associated with a familial predisposition to squamous cell carcinoma of the esophagus.4

Paraneoplastic acrokeratosis (Bazex syndrome) Bazex syndrome is a rare dermatosis, obligatorily paraneoplastic, characterized by the appearance of papulosquamous and psoriasiform plaques in the acral regions.2,4,21 It is especially associated with squamous cell carcinomas of the upper aerodigestive tract; however, an association with other malignancies has been reported, including cancer of the prostate, lung, breasts, colon, and bladder, as well as liposarcoma.21-23 It mostly affects white men in their 40s.4 An erythematous-purplish desquamating eruption, affecting the fingers and feet, appears initially, followed by involvement of the nose and ears. Periungual hyperkeratosis with onycholysis and ungual dystrophy occurs later.21 During the evolution of the disease, lymph node involvement and dissemination of the lesions to the trunk, elbows, and knees can occur.4,21 In most cases, there is no pruritus or other symptoms.23 Histopathologic findings are unspecific, with moderate acanthosis, hyperkeratosis with focal parakeratosis, and lymphocytic infiltrate in the upper dermis.21

Fig. 5

Palmo-plantar keratoderma.

Fig. 6

Palmo-plantar keratoderma.

Cutaneous manifestations precede the diagnosis of neoplasia in about 70%.21,23 Treatment of the neoplasia brings important improvement in 90% to 95% of patients, including total remission of the lesions. Its reappearance indicates recurrence of the tumor. There is no improvement with the use of steroids or topical keratolytic agents.21

Dermatomyositis Dermatomyositis (Figures 7 to 10) is an inflammatory myopathy associated with malignancies in 15% to 25% of

Fig. 7

Dermatomyositis: Gottron sign.

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Fig. 10

Fig. 8 Dermatomyositis: poikiloderma (atrophy depigmentation and telangiectasia) in photo-exposed areas of sudden onset.

the cases. It is characterized by a cutaneous eruption and progressive symmetrical weakening of the proximal muscles.24 Muscular involvement can be mild or absent in some patients, a picture known as hypoamyopathic dermatomyositis. Polymyositis is characterized by muscular involvement without cutaneous alterations.1,24 The most commonly related cancer is found in the ovary, but others have also been associated with dermatomyositis, including lung, pancreas, stomach, and colon-rectal cancers, and nonHodgkin lymphoma.24 The most typical cutaneous lesions are Gottron papules and heliotrope. Gottron sign is characterized by papules and purple plaques, with discreet desquamation located over

Dermatomyositis: periungual telangiectasia.

joints, mainly the metacarpophalangeal, distal, or proximal interphalangeal joints. Heliotropus consists of an erythematous purple eruption, with or without edema, that is symmetric and located in the periorbital region. Other cutaneous alterations that can occur are malar erythema, poikiloderma (atrophy, depigmentation, and telangiectasia) in photo-exposed areas, erythematous purple coloration on extensor surfaces, periungual telangiectasia, cuticular hypertrophy, and noncicatricial alopecia. The lesions usually cause intense pruritus. The presence of erythematous purple psoriasiform dermatitis in scalp is relatively common.24 More rare cutaneous manifestations, such as vesicled or bullae, lesions resembling pityriasis rubra pilaris, vasculitis, erosive lesions, exfoliative erythroderma, and other characteristics such as sudden onset of the picture, absence of the Raynaud phenomenon, and an increase of herpes simplex infection and cutaneous necrosis, can indicate a paraneoplastic form of dermatomyositis.1,24 Treatment is similar to the nonparaneoplastic form, with oral prednisone and other drugs such as azathioprine and methotrexate, besides the use of sunscreens, topical steroids, and hydroxichloroquine.1 The frequency with which dermatomyositis is associated with malignant diseases averages 25% (range, 6%-60%), being more common in patients over 50 years of age.1,24 Its onset can precede, be concurrent, or occur after a diagnosis of cancer. Myositis can present with paraneoplastic behavior, following the evolution of the tumor or following its clinical course despite treatment of the cancer.24

References

Fig. 9 Dermatomyositis: poikiloderma (atrophy depigmentation and telangiectasia) in photo-exposed areas of sudden onset.

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Cutaneous paraneoplasia 4. Moore RL, Devere TS. Epidermal manifestations of internal malignancy. Dermatol Clin 2008;26:17-29. 5. Callen JP. Skin signs of internal malignancy. In: Callen JP, editor. Dermatological signs of internal disease. 3rd ed. Philadelphia: WB Saunders; 2003. p. 95-110. 6. Sabir S, James WD, Schuchter LM. Cutaneous manifestations of cancer. Curr Opin Oncol 1999;11:139-44. 7. Yeh JS, Munn SE, Plunkett TA, et al. Coexistence of acanthosis nigricans and the sign of Leser-Trélat in a patient with gastric adenocarcinoma: a case report and literature review. J Am Acad Dermatol 2000;42:357-62. 8. Gross G, Pfister H, Hellenthal B, Hagedorn M. Acanthosis nigricans maligna: clinical and virological investigations. Dermatologica 1984;168:265-72. 9. Pentenero M, Carrozzo M, Pagano M, Gandolfo S. Oral acanthosis nigricans, tripe palms and sign of Leser-Trélat in a patient with gastric adenocarcinoma. Int J Dermatol 2004;43:530-2. 10. Ozdemir M, Toy H, Mevlitoğlu I, Demirkesen C. Generalized idiopathic acanthosis nigricans treated with acitretin. J Dermatol Treat 2006;17:54-6. 11. Blobstein SH. Topical therapy with tretinoin and ammonium lactate for acanthosis nigricans associated with obesity. Cutis 2003;71:33-4. 12. Thiers BH, Sahn RE, Callen JP. Cutaneous manifestations of internal malignancy. CA Cancer J Clin 2009;59:73-98. 13. Heaphy Jr MR, Millns JL, Schroeter AL. The sign of Leser-Trélat in a case of adenocarcinoma of the lung. J Am Acad Dermatol 2000;43: 386-90.

547 14. Patel N, Spencer LA, English III JC, Zirwas MJ. Acquired ichthyosis. J Am Acad Dermatol 2006;55:647-56. 15. Pérez-Losada E, Pujol RM, Domingo P, et al. Hypertrichosis lanuginosa acquisita preceding extraskeletal Ewing's sarcoma. Clin Exp Dermatol 2001;26:182-3. 16. Grimalt R, Gelmetti C, Brusasco A, et al. Pityriasis rotunda: report of a familial occurrence and review of the literature. J Am Acad Dermatol 1994;31:866-71. 17. Hasson I, Shah P. Pityriasis rotunda. Indian J Dermatol Venereol Leprol 2003;69:50-1. 18. Stone SP, Buescher LS. Life-threatening paraneoplastic cutaneous syndromes. Clin Dermatol 2005;23:301-6. 19. Weenig RH, Mehrany K. Dermal and pannicular manifestations of internal malignancy. Dermatol Clin 2008;26:31-43. 20. Rodrigues AS, Goldemberg S. Mãos e pés. In: Ramos-e-Silva M, Castro MCR, editors. Fundamentos de dermatologia. 1st ed. Rio de Janeiro: Atheneu; 2009. p. 1789-816. 21. Ljubenovic MS, Ljubenovic DB, Binic II, et al. Acrokeratosis paraneoplastica (Bazex syndrome). Indian J Dermatol Venereol Leprol 2009;75:329. 22. Bazex A, Griffiths A. Acrokeratosis paraneoplastica—a new cutaneous marker of malignancy. Br J Dermatol 1980;103:301-6. 23. Louvel G, Vauléon E, Boucher E, Raoul JL. Acrokeratosis paraneoplastica (Bazex' syndrome) associated with metastatic squamous cell esophageal carcinoma. J Clin Oncol 2008;26:5128-9. 24. Callen JP, Wortmann RL. Dermatomyositis. Clin Dermatol 2006;24: 363-73.