Am J Clin Dermatol 2006; 7 (2): 71-84 1175-0561/06/0002-0071/$39.95/0

THERAPY IN PRACTICE

© 2006 Adis Data Information BV. All rights reserved.

Cutaneous Manifestations of Internal Malignancy Diagnosis And Management C Elise Kleyn, Joey E Lai-Cheong and Hazel K Bell Department of Dermatology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 1. Cutaneous Metastases of Internal Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 2. Direct Tumor Involvement of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 3. Paraneoplastic Cutaneous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 3.1 Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 3.2 Acrokeratosis Paraneoplastica (Bazex Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 3.3 Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.4 Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.5 Bullous Eruptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.5.1 Paraneoplastic Pemphigus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3.6 Annular Erythemas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.6.1 Erythema Gyratum Repens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.6.2 Necrolytic Migratory Erythema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.7 Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 3.8 Acquired Ichthyosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 3.9 Acquired Palmoplantar Keratoderma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 3.10 Acanthosis Nigricans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 3.11 Leser Trelat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 3.12 Humoral Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 3.12.1 Malignant Carcinoid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 4. Inherited Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.1 Muir-Torre Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.2 Neurofibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.2.1 Neurofibromatosis Type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 4.3 Tuberous Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.4 Multiple Hamartoma Syndrome (Cowden Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.5 Basal Cell Nevus Syndrome (Gorlin Syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.6 Familial Polyposis Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.6.1 Gardner Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 4.6.2 Peutz-Jeghers Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 4.7 Inherited Tylosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 5. General Cutaneous Manifestations of Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Abstract

An association between systemic malignancy and cutaneous manifestations has long been recognized. The cutaneous features that can occur are numerous and heterogeneous, and many different etiologic mechanisms are represented – from direct tumor invasion of skin or distant metastases to a wide variety of inflammatory dermatoses that may occur as paraneoplastic phenomena. In addition, there are a number of inherited syndromes that carry an increased risk of cutaneous as well as internal malignancies. While some of these inherited syndromes and paraneoplastic phenomena are exceedingly rare, all clinicians will be aware of the common cutaneous manifestations of advanced malignant disease such as generalized xerosis and pruritus.

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This review classifies these wide-ranging cutaneous manifestations of internal malignancy into five basic groups and provides practical advice regarding diagnosis and screening of patients who initially present with a cutaneous complaint. Also included is up-to-date information on two rapidly expanding and exciting areas of research that are likely to have far-reaching clinical implications: (i) clarification of underlying humoral mechanisms, for example, in the malignant carcinoid syndrome; and (ii) identification of an increasing number of specific genetic defects that confer a susceptibility to malignancy. Increased clinician awareness regarding the associations between these lesions and internal malignancy or inherited syndromes will facilitate screening and early diagnosis.

The skin may provide a useful insight into the presence of systemic disease. Internal malignancy may be associated with a wide variety of cutaneous manifestations, and cutaneous signs may be the presenting complaint. Cutaneous manifestations may also provide a useful indicator of disease activity and prognosis. An awareness of possible associations between internal malignancies and cutaneous manifestations is therefore important in the diagnosis and management of cancer. This review focuses on the following broad categories: cutaneous metastases; direct tumor involvement of the skin; paraneoplastic disorders, including humoral syndromes; inherited syndromes; and general cutaneous manifestations of malignant disease. Furthermore, the review includes practical advice regarding diagnosis and screening of patients who present with a cutaneous lesion associated with an inherited syndrome and/or suggestive of an internal malignancy.

Cutaneous metastases may commonly present as single or multiple nodules with a predilection for old surgical scars. These tumors are always firm and rubbery to stone-hard in consistency.[3] Metastases usually share histologic features with the primary tumor; >60% are adenocarcinomas, while approximately 15% are of squamous cell type.[4] Identification of the primary tumor is based on screening for tumors that more commonly metastasize to the skin. Primary tumors that tend to invade veins, such as kidney and lung carcinomas, are most likely to metastasize to the skin (figure 1).[6] Metastases from tumors that invade lymphatic vessels tend to appear later in the course of the disease and overlay the primary tumor.[6]

1. Cutaneous Metastases of Internal Malignancies Cutaneous metastases of internal malignancies are uncommon, with the reported prevalence varying from 0.7% to 10% of all patients with cancer.[1,2] In 1990, one large study reported a 5% frequency of cutaneous metastases in 7316 patients with internal carcinoma identified in a retrospective cancer registry.[1] A second study by the same authors, conducted in 1993, examined records of 4020 patients with metastatic disease and found that 10% had skin metastases.[3] Most cutaneous metastases are metachronous, developing months or years after the primary malignancy has been diagnosed.[4] Rarely, cutaneous metastases may be the first indication of an underlying neoplasm.[1,5] Lookingbill et al.[1] reported that local cutaneous metastatic disease was the presenting feature in 0.3% of cases, breast cancer being the most common primary tumor in this group, while distant cutaneous metastases were the presenting sign in 0.2%. The primary tumor was not identified in >70% of cases in the group with distant metastases. Cutaneous metastases from cancers of the lung, large intestine, and kidney are most commonly found in men; cancers of the breast and large intestine are the most likely primary tumors to metastasize to the skin in women.[5] © 2006 Adis Data Information BV. All rights reserved.

Fig. 1. Renal cell carcinoma metastasis to the upper lip. Am J Clin Dermatol 2006; 7 (2)

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3. Paraneoplastic Cutaneous Syndromes

Fig. 2. Abdominal wall metastasis in a patient with adenocarcinoma of the colon.

Although there is a predilection of cutaneous metastases for certain areas of the body (for example, approximately 5% of metastases involve the scalp),[4,5] most cutaneous metastases tend to occur in the vicinity of the primary tumor. Therefore, breast and lung cancers tend to metastasize to the chest wall, and cancers of the bowel, ovary, and bladder tend to metastasize to the abdominal skin (figure 2). A well recognized example is the Sister Mary Joseph nodule, which presents in the umbilical area, the most common site of origin of the primary tumor being the stomach, followed by the ovary, large bowel, and pancreas.[6] Benign tumors of the umbilicus are uncommon and any lesion presenting in this area should be biopsied.[6] In one study, distant metastases remote from the primary site occurred in 39% of patients with cutaneous metastases, the most frequent primary tumors being melanoma, lung, and breast cancer, although other cancers also showed this potential.[1] Identification and treatment of the primary tumor is the priority in patients with cutaneous metastases of internal malignancies. Although cutaneous metastases usually reflect a poor prognosis, the skin may be the only site of secondary involvement, particularly in the case of local metastasis; therefore early recognition and treatment may prevent widespread disease.[7] Cutaneous metastases, particularly if symptomatic, are best managed by excision.

Paraneoplastic syndromes are a group of malignancy-associated disorders reflecting a pathologic communication between tumor cells and host cells at a site remote from the primary tumor and its metastases. Criteria that define a paraneoplastic cutaneous syndrome include: (i) development of a dermatosis only after the development of a malignant neoplasm; and (ii) both the dermatosis and the malignant neoplasm follow a parallel clinical course.[8] Thus the dermatosis may play an important role in both the diagnosis and management of the malignant neoplasm. A uniform etiology for paraneoplastic cutaneous syndromes is unlikely, given the diversity of paraneoplastic manifestations. Although the pathogenesis is poorly understood, several mechanisms are likely to be involved, including production of biologically active hormones, growth factors, and other unidentified mediators by the tumor, or tumor-induced antigen-antibody interactions.[6] Early recognition of the syndrome, which may present before the primary tumor, will facilitate early diagnosis and management of the associated malignancy, thereby prolonging life expectancy. 3.1 Dermatomyositis

The quoted frequency of an association between dermatomyositis and underlying malignancy in adults varies considerably from 15% to 50%.[9,10] Since this frequency increases with age, the possibility of an associated malignancy should be given particular consideration in patients in the >40-year age group with dermatomyositis.[11,12] Childhood dermatomyositis appears to be an autoimmune disease and is not usually associated with malignancy.[13] This suggests that the adult paraneoplastic form, which shares similar clinical features, is likely to be mediated by tumorinduced autoimmunity. The diagnostic features of dermatomyositis include a typical violaceous, photosensitive rash, proximal myopathy, elevated serum creatinine kinase levels, and/or an abnormal electromyelogram. A purplish-red heliotrope eruption occurring on the face (particularly involving periorbital skin), nail fold changes (figure 3), and small violaceous papules (Gottron papules; figure 4) and

2. Direct Tumor Involvement of the Skin Skin ulceration may be a sign of direct tumor invasion and is most commonly seen in breast carcinoma. Less common examples of localized inflammation, also seen in breast carcinoma, include carcinoma erysipeloides. Tumors of the oral cavity (usually squamous cell carcinoma) are the second most likely to directly invade skin.[1] Usually the site of the primary tumor is easily identified in this group and skin involvement can be treated along with the primary lesion. © 2006 Adis Data Information BV. All rights reserved.

Fig. 3. Nail fold telangiectasia and ragged cuticles. Am J Clin Dermatol 2006; 7 (2)

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plaques occurring over the knuckles are commonly observed cutaneous signs. In paraneoplastic dermatomyositis, the cutaneous features tend to predominate over the myositis, and there is a female preponderance. In cases where an underlying malignancy is suspected, surveillance is particularly important during the 3-year period following diagnosis of dermatomyositis. Underlying tumor types reflect tumor prevalence in the general population, with lung cancer and cancer of the gastrointestinal tract occurring most commonly in men, and breast and gynecologic tumors, particularly ovarian, most common in women.[14] Tumors associated with the patient’s age group, sex, or ethnicity should also be considered. A history of previous neoplasia or a poor therapeutic response to treatment of dermatomyositis should raise the index of suspicion of a coexistent neoplasm, either a recurrence or new tumor. In this setting, the possibility of occult tumors of the female genitourinary tract, in particular, should be considered.[15] Although the role of extensive screening is controversial, it is recommended that all adult patients undergo an annual routine malignancy screen for at least 3 years after diagnosis. This should include a thorough history and physical examination, standard laboratory investigations (biochemistry, liver function tests, full blood count with differential, urinalysis), chest x-ray, mammography and complete gynecologic examination in women, and any test directed toward abnormal symptoms or results.[16] Some authors also recommend abdominal-thoracic CT scans in men and pelvic-abdominal-thoracic CT scans in women.[17] Corticosteroids are the principal treatment, but subsequent adverse effects often prompt additional treatment. Oral prednisolone may be used in conjunction with an antimalarial such as hydroxychloroquine.[18] Other treatments include azathioprine, methotrexate, cyclosporine (ciclosporin), mycophenolate mofetil,[19] and intravenous immunoglobulin; however, the risk/benefit profile of each drug should be evaluated particularly in cases of coexistent or suspected malignancy.[20] Potent topical corticosteroids are a useful adjunct to systemic therapies. Patients should be counseled about photoprotection and the use of high-factor, broadband sunscreens. The cutaneous signs often regress following treatment of the primary tumor, but relapse of the rash can herald recurrence and always merits further investigation. 3.2 Acrokeratosis Paraneoplastica (Bazex Syndrome)

The typical cutaneous features of Bazex syndrome are psoriasiform plaques, which in most patients have a symmetrical distribution and favor acral areas such as the distal hands and feet, the helices of the ear, and the nose. An associated nail dystrophy has been noted in up to 77% of patients.[21] © 2006 Adis Data Information BV. All rights reserved.

Fig. 4. Gottron papules.

The underlying malignancy most commonly associated (>90%) with Bazex syndrome is squamous cell carcinoma of the oropharynx, larynx, or esophagus.[22] Consequently, this disorder mainly affects males aged >40 years. Other associated malignancies include carcinoma of the bronchus and, rarely, the prostate, liver, uterus, vulva,[22] and breast,[23] as well as T-cell lymphoma, Hodgkin disease, metastatic neuroendocrine tumors, and cutaneous squamous cell carcinoma.[21] A skin biopsy should be performed in suspected cases of Bazex syndrome, although histologic features are not diagnostic. These features include hyperkeratosis, focal parakeratosis, and acanthosis. Variable epidermal changes such as spongiosis with associated exocytosis of lymphocytes, basal vacuolar change, and scattered degenerate keratinocytes have also been reported.[24] Late-onset psoriasis is the main differential diagnosis. Histologically, degenerate keratinocytes and basal vacuolar change are not consistent with psoriasis, and the possibility of Bazex syndrome should be considered when these features are observed. Other differential diagnoses include recalcitrant eczema, mycosis fungoides, drug-induced psoriasiform eruptions, and superficial fungal infections. Since psoriasis is a common skin disease with a prevalence of 2% in the general population, Bazex syndrome is a diagnosis that is easily missed; however, recognition of the syndrome is important since the psoriasiform lesions may precede the diagnosis of the associated malignancy in up to 67% of patients.[22] Patients with Bazex syndrome should undergo a routine malignancy screen including a thorough history and physical examination, standard laboratory investigations (biochemistry, liver function tests, full blood count with differential, urinalysis), chest xray, and mammography in women. Particular attention should be directed to the upper aerodigestive tract (laryngoscopy, endoscopy) and any abnormal symptoms and/or results. Am J Clin Dermatol 2006; 7 (2)

Cutaneous Manifestations of Internal Malignancy

3.3 Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

Sweet syndrome is characterized by fever, neutrophilia, and the eruption of multiple, asymmetric, erythematous, and indurated plaques, which show a dense dermal neutrophilic infiltrate histologically.[25] Intense plaque edema can give the appearance of pseudovesiculation. It is estimated that 10–40% of cases of Sweet syndrome have an associated underlying malignancy, particularly hematologic disorders such as acute myeloid leukemia.[26] Sweet syndrome may be the presenting feature of myelodysplasia (figure 5) or herald transformation to acute leukemia[27] and less commonly it has been described in association with solid tumors. Clinical and laboratory features that may distinguish malignancy-associated Sweet syndrome from classical Sweet syndrome include: (i) presentation in an elderly patient; (ii) involvement of the oral mucosa, which most commonly presents as ulcers in patients with associated hematologic disorders; (iii) anemia; and (iv) normal or low neutrophil count and/or an abnormal platelet count.[25] If associated with leukamia, bullous lesions may occur and the lesions may resemble pydoerma gangrenosum.[28] Consequently, a physical examination for lymphadenopathy and a full blood count, film, differential, and erythrocyte sedimentation rate (ESR) are the recommended baseline investigations. Abnormal signs or results should prompt a referral to a hematologist or physician. Improvement or resolution of lesions in patients with malignancy-associated Sweet syndrome may occur following successful treatment of the underlying cancer.[25] 3.4 Pyoderma Gangrenosum

Pyoderma gangrenosum is a destructive, non-infective ulceration of the skin. Although any area of the body may be involved, the legs are the most common site (80%).[29] The precise incidence of pyoderma gangrenosum is difficult to ascertain. In approximately 50% of adults, pyoderma gangre-

Fig. 5. An ulcerated nodule consistent with Sweet syndrome in a patient with myelodysplastic syndrome. © 2006 Adis Data Information BV. All rights reserved.

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nosum occurs in association with systemic disease,[29] most commonly arthritis (37%), inflammatory bowel disease, paraproteinemia, and hematologic malignancy. Similar diseases are associated with pyoderma gangrenosum in children, although ulcerative colitis (26.6%) followed by leukemia (17.7%) are more common.[29] Carcinoid tumors, as well cancer of the colon, prostate, breast and bronchus, have also been associated with pyoderma gangrenosum. The diagnosis of pyoderma gangrenosum is usually made on clinical grounds, since histopathology is not diagnostic. Atypical or bullous lesions are more frequently associated with underlying malignancy.[30] Pyoderma gangrenosum can be difficult to treat, particularly if the underlying disease is not controlled. Topical treatment alone is seldom successful, and systemic corticosteroids (prednisolone ≈1 mg/kg) are usually the treatment of choice in patients with an underlying malignancy; however, other systemic immunosuppressive agents used to treat pyoderma gangrenosum include cyclosporine, azathioprine, cyclophosphamide, tacrolimus, methotrexate, and mycophenolate mofetil.[31] Other possible treatments include sulphonamides such as dapsone and sulfapyridine. 3.5 Bullous Eruptions

A possible link between malignancy and the autoimmune bullous disorders, such as pemphigus and pemphigoid, has been the source of much debate for many years. Although bullous pemphigoid has been reported to be more resistant to treatment when it coexists with malignancy, the overall incidence of neoplasia in patients with bullous pemphigoid does not exceed that expected in an elderly population.[32,33] Mucous membrane pemphigoid (cicatricial pemphigoid) is not associated with malignancy except in patients with laminin 5 antibodies.[34] In contrast, paraneoplastic pemphigus, a distinctive form of pemphigus, is associated with an increased incidence of malignancy.[35] 3.5.1 Paraneoplastic Pemphigus

Paraneoplastic pemphigus, first described by Anhalt[36] in 1990, affects adults as well as children and has well-defined clinical, histologic, and immunopathologic criteria. Clinical features of this multisystem disorder include painful mucosal lesions (oral in 100% of cases and conjunctival in approximately 60%),[37,38] polymorphic vesicular and lichenoid skin eruptions, and pulmonary involvement. In keeping with the polymorphic cutaneous signs, skin biopsy shows variable features, which include keratinocyte necrosis, vacuolar interface dermatitis, and suprabasal clefting with acantholysis.[39] A neoplasm is identified prior to the cutaneous eruption in approximately two-thirds of cases.[38] Most cases (84%) of paraneoplastic pemphigus have been associated with hematologic malignancies, mainly non-Hodgkin lymphoma, chronic lymphocytic Am J Clin Dermatol 2006; 7 (2)

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leukemia, and Castleman disease.[38] The latter is particularly associated with paraneoplastic pemphigus in children. Other neoplasms include thymoma, Waldenstr¨om macroglobulinemia, adenocarcinoma of the lung, follicular lymphoma, and retroperitoneal sarcomas.[38] Circulating antiplakin antibodies to desmosomal proteins, including desmoplakin I and desmoglein l, have been identified in patients with paraneoplastic pemphigus, although it is suspected that there is a wider spectrum of target antigens.[37] In approximately one-third of cases, the neoplasm is detected after the onset of mucocutaneous disease. Therefore a routine malignancy screen should be performed in patients with recalcitrant, erosive, mucocutaneous lesions. Paraneoplastic pemphigus is typically refractory to treatment, including high-dose oral corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, dapsone, and plasmapheresis.[37] The combination of prednisolone (1–2 mg/kg/day) with cyclosporine (5 mg/kg/day) and pulse therapy with cyclophosphamide has been reported to be the most effective treatment.[38] Paraneoplastic pemphigus associated with malignancy has a poor prognosis. Complications of immunosuppressive therapy plus progression of the malignancy usually result in death within 2 years.[38] The prognosis is more favorable when it is associated with low-grade neoplasia. 3.6 Annular Erythemas

The annular erythemas are a group of cutaneous conditions characterized by the presence of migrating, well-demarcated, annular erythematous lesions and a dermal perivascular mononuclear cell infiltrate. There are variants associated with specific diagnoses, such as erythema chronicum migrans in Lyme disease and erythema marginatum in rheumatic fever, and idiopathic variants including erythema annulare centrifugum and erythema gyratum repens. Both erythema annulare centrifugum and erythema gyratum repens have been described in association with malignancy, although the link is much stronger for erythema gyratum repens. A study of 113 patients with erythema annulare centrifugum, published in 1969, found no increased incidence of underlying neoplasia.[40] 3.6.1 Erythema Gyratum Repens

Erythema gyratum repens is a rare pruritic eruption that tends to occur on the trunk and is characterized by regular waves of erythema that may migrate up to 1 cm/day to produce a woodgrain appearance. There is a clear association with systemic malignancy, particularly of the breast, esophagus, and lung. In a review of 21 reported cases, all were associated with underlying malignancy, with bronchial neoplasia being the most frequent association, occurring in 40% of cases. In 60% of cases, the erythema gyratum repens preceded the diagnosis of malignant disease.[41] However, there may have been a reporting bias, and there have © 2006 Adis Data Information BV. All rights reserved.

been reported cases of erythema gyratum repens occurring in the absence of malignancy, even after many months of follow-up.[42,43] The prevalence of internal malignancy in patients with erythema gyratum repens is currently estimated to be between 77% and 82%.[44,45] An immunologic mechanism is likely to be involved in the pathogenesis of erythema gyratum repens. When the condition is associated with bronchial carcinoma, the tumor may alter components of the pulmonary basement membrane zone, with subsequent induction of antibodies to exposed antigens. These antibodies may cross-react with similar antigens found in the basement membrane zone of the skin.[46,47] Histopathologic features of erythema gyratum repens include mild spongiosis with focal parakeratosis and mild to moderate acanthosis. A lymphohistiocytic infiltrate is present around vessels in the superficial plexus, often associated with mild edema of the papillary dermis. Direct immunofluorescence often reveals granular deposits of IgG and/or C3 along the basement membrane zone, usually in a less regular pattern than occurs in bullous pemphigoid.[48] Patients with erythema gyratum repens should undergo a routine malignancy screen and there should be a low threshold for bronchoscopy in at-risk individuals. Treatment of the underlying disease generally results in improvement or resolution of both the rash and pruritus. 3.6.2 Necrolytic Migratory Erythema

Necrolytic migratory erythema is typically associated with glucagon-secreting islet-cell tumors of the pancreas.[49] The eruption, which waxes and wanes in intensity, begins with erythematous macules that evolve centrifugally into circinate and polycyclic lesions. There may be associated bullae, which are easily ruptured. Other typical features include painful glossitis, angular cheilitis, anemia, and weight loss. This eruption is associated with several histologic patterns depending on which stage of the rash is biopsied. The most distinctive pattern described is the process termed ‘necrolysis’, which manifests as pale, vacuolated keratinocytes in the upper epidermis, leading to focal or confluent necrosis. The least common histologic pattern is psoriasiform hyperplasia of the epidermis with overlying confluent parakeratosis. A mild to moderate perivascular infiltrate of lymphocytes in the upper dermis is common to all patterns.[50] Cutaneous features improve markedly with treatment of the underlying tumor, which includes surgical resection, chemotherapy, and long-acting somatostatin.[51] 3.7 Vasculitis

In contrast to erythema gyratum repens and necrolytic migratory erythema, cutaneous vasculitis is common and usually idiopathAm J Clin Dermatol 2006; 7 (2)

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ic, although it can be associated with infection, drugs, connective tissue diseases and, rarely, malignancy.[52] The clinical presentation is heterogeneous and depends on the depth and size of the blood vessel affected, ranging from livedo reticularis (due to involvement of the superficial cutaneous plexus) to necrosis and ulceration if the deeper and larger blood vessels are involved.[53] Papules, nodules, and urticaria may also be present.[54] Cutaneous vasculitis is recognized to be an uncommon marker of malignancy and is more likely to be associated with hematologic cancers.[55] An underlying malignancy is found in <5% of patients, and vasculitis may present with the primary tumor or precede or follow it by months or even years.[56] The clinical course is unpredictable;[57] however, the presence of cutaneous vasculitis does not necessarily indicate a poor prognosis, and cutaneous lesions usually improve with treatment of the primary tumor. Urticarial vasculitis has been described in association with multiple myeloma,[58] metastatic adenocarcinoma of the colon,[59] metastatic malignant teratoma of the testes,[60] non-Hodgkin lymphoma,[61] and renal carcinoma.[62] Paraneoplastic cutaneous leukocytoclastic syndrome has been reported in association with hematologic malignancies and, more rarely, solid neoplasms,[63,64] including squamous carcinoma of the lung.[65] Since cutaneous vasculitis is rarely associated with an underlying malignancy, a thorough history, physical examination, and routine laboratory investigations (biochemistry, full blood count with differential and ESR) should be sufficient for screening. As noted above, cutaneous vasculitis lesions usually improve with treatment of the primary tumor. 3.8 Acquired Ichthyosis

Acquired ichthyosis is an extremely rare, nonhereditary, cutaneous keratinization disorder. It usually occurs in adulthood and is clinically and histologically indistinct from the hereditary forms.[66] Acquired ichthyosis is a cutaneous pointer to internal disease, mainly malignancy.[67] It has been suggested that transforming growth factor α, secreted from the tumor cells, may be implicated in the pathogenesis.[68] Acquired ichthyosis usually manifests after detection of the cancer, unlike erythema gyratum repens, which usually precedes the diagnosis. Interestingly, erythema gyratum repens and acquired ichthyosis have been described concurrently in a patient with transitional cell carcinoma of the kidney.[68] Associated malignancies include Hodgkin disease,[67] non-Hodgkin lymphoma (including mycosis fungoides), multiple myeloma, Kaposi sarcoma, leiomyosarcoma, and breast, ovarian, lung, and cervical carcinomas.[69,70] Acquired ichthyosis has also been described in association with endocrine, autoimmune, infectious, nutritional, and renal disorders.[71] © 2006 Adis Data Information BV. All rights reserved.

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Acquired ichthyosis improves with treatment of the underlying malignancy. Liberal use of emollients may be helpful to alleviate symptoms. 3.9 Acquired Palmoplantar Keratoderma

Acquired palmoplantar keratoderma is another cutaneous marker of internal malignancy, in this case characterized by abnormal thickening of the skin on the palms and soles which may be punctuate, focal or diffuse.[72] Development of palmoplantar keratoderma in association with malignancy heralds a poor prognosis. The most common associations are pulmonary and esophageal cancers, although the condition has rarely been reported with myeloma[73] and breast cancer. 3.10 Acanthosis Nigricans

Acanthosis nigricans is a velvety thickening and hyperpigmentation of the skin, mainly affecting the axillae and flexural sites. Acanthosis nigricans associated with benign conditions (insulin resistance secondary to obesity being the most common association) is much more frequently encountered than malignancy-associated acanthosis nigricans, which is more likely to have a rapid onset and to spread beyond the typical flexural sites.[74] Malignancies most commonly involve the gastrointestinal tract (90%), particularly adenocarcinoma of the stomach.[75] Adult onset in the absence of a predisposing cause such as a positive family history, obesity, endocrinopathies, or drugs (nicotinic acid, glucocorticoids) is particularly associated with malignancy-associated acanthosis nigricans.[14] A thorough history and physical examination facilitates the identification of the underlying cause. If malignancy-associated acanthosis nigricans is suspected, the initial screen may include routine laboratory investigations, urinalysis, chest x-ray, and gastrointestinal assessment, including endoscopy.[75,76] Treatment of the underlying cause may lead to resolution of clinical signs but the prognosis of malignant acanthosis nigricans is generally poor.[77] 3.11 Leser Trelat

Internal malignancy associated with sudden development of numerous, eruptive seborrheic keratoses (figure 6), with or without pruritus, is generally accepted as the definition of the sign of Leser Trelat, which has been credited to two European surgeons, Edmund Leser and Ulysse Trelat.[78] However, multiple seborrheic keratoses are a common occurrence in the elderly, who are also more prone to malignancies, and therefore this diagnosis should be made with caution. Moreover, such lesions have also been recognized in association with primary dermatoses such as eczema, contributing further to the unreliability of this sign as a marker of underlying malignancy.[79] Am J Clin Dermatol 2006; 7 (2)

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interesting questions regarding the role of circulating vasodilators in the development of vascular ectasia. Flushing is usually responsive to treatment of the primary tumor by excision or embolization and can also be controlled medically by administration of subcutaneous octreotide.[84]

Fig. 6. The sign of Leser Trelat: multiple, eruptive, pruritic, seborrheic keratoses – the presenting feature of gastric carcinoma.

A thorough history, physical examination, and routine laboratory investigations (as previously outlined) should suffice unless there are suspicious symptoms or signs that warrant further investigation. Treatment of the underlying tumor is purported to reduce the associated pruritus. 3.12 Humoral Syndromes 3.12.1 Malignant Carcinoid Syndrome

The prevalence of carcinoid tumors is approximately 1.5 per 100 000 of population. These tumors are derived from enterochromaffin cells, which are capable of producing a wide range of neuroendocrine mediators, the most recognized of these being serotonin or 5-hydroxytryptamine. The malignant carcinoid syndrome occurs in <10% of patients and is due to escape of the mediators, which are normally metabolized by the liver, into the systemic circulation. This occurs in the presence of hepatic metastases, extra-gastrointestinal tumors, or very large tumors producing sufficient quantities of mediators to overload the hepatic metabolism. This syndrome provides a useful model of a paraneoplastic process. Cutaneous manifestations of the malignant carcinoid syndrome can be divided into four main categories: flushing and rosacea, those related to niacin deficiency or pellagra, those related to a specific variant of scleroderma, and a miscellaneous group that includes cutaneous metastases. Flushing is almost universal in the syndrome and is usually confined to the face, neck, and upper trunk. The character of the flush is site-dependent. Tumors originating in the embryologic foregut produce a characteristic bright salmon-pink to red flush,[80] which has been demonstrated to be due to the release of histamine, whereas midgut tumors produce a cyanotic flush regarded as the classical carcinoid flush. The mechanism of this flush is more complicated, and studies have demonstrated the involvement of multiple mediators including serotonin,[80] tachykinins such as the vasodilating peptide bradykinin,[81] and prostaglandins.[82] After years of flushing, features of rosacea may develop,[83] which raises © 2006 Adis Data Information BV. All rights reserved.

Pellagra dermatitis and dependent edema may develop as a result of secondary niacin deficiency and hypoproteinemia, which occur as a result of excess consumption of dietary tryptophan by the serotonin-producing tumor.[85] Pellagra can be treated with improved overall nutrition and administration of oral nicotinamide. The association of scleroderma with the carcinoid syndrome was first described in 1958.[86] The absence of Raynaud phenomenon and the usual acral distribution of lesions, as well as involvement of the lower limbs prior to the upper limbs, distinguishes carcinoid-associated scleroderma from idiopathic forms of the disease.[87] Apart from carcinoid heart disease caused by endocardial fibrosis, internal organ involvement has not been described. There is substantial evidence linking serotonin to the pathogenesis of carcinoid-associated scleroderma. Serotonin has induced dermal fibrosis in rats and can stimulate DNA synthesis in fibroblasts in vitro.[88] Recently, serotonin has been shown to induce proliferation of cardiac valvular subendocardial cells in vitro,[89] suggesting that the fibrotic process affecting skin and cardiac tissue may have a shared mechanism. However, serotonin is secreted by the majority of carcinoid tumors, yet carcinoid-related scleroderma is unusual, suggesting that other factors must play a role. Substance P and neurokinin A are both secreted exclusively by carcinoid tumors arising in the gut and, so far, scleroderma has been exclusively associated with gut carcinoids. Both of these mediators are also capable of inducing DNA synthesis and proliferation of human dermal fibroblasts in vitro, and grossly elevated levels of both have been demonstrated in one patient with carcinoid-related scleroderma.[90] Development of scleroderma has been suggested to be a poor prognostic indicator.[90] While there are anecdotal reports of improvement of scleroderma with octreotide treatment,[91] in the majority of cases the scleroderma is irreversible. A diagnosis of carcinoid syndrome should be considered in any patient with persistent flushing of the face, neck, and upper trunk. It is usually distinguishable from other causes of flushing by its severity and associated systemic symptoms such as diarrhea, breathlessness, and wheeze. Initially, a full gut hormone profile should be performed, including 24-hour urinary 5-hydroxy indole acetic acid concentrations. Because the latter (which used to be the gold standard for diagnosis of carcinoid syndrome) can be unreliable, with fluctuating levels being influenced by other factors such as diet and drugs, chromogranin A is now regarded as a more reliable marker. Elevated levels should prompt specialized imagAm J Clin Dermatol 2006; 7 (2)

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ing including radiolabeled octreotide and iodine-131-metaiodobenzylguanidine scans. 4. Inherited Syndromes A number of inherited syndromes with cutaneous manifestations and an increased risk of internal malignancy have been described. Obtaining a detailed family history and recognizing typical cutaneous signs will facilitate screening and early diagnosis of associated malignancy in such cases. The treatment of each syndrome should be tailored according to the clinical symptoms and signs of each patient. 4.1 Muir-Torre Syndrome

Muir-Torre syndrome is a rare autosomal-dominant condition with variable penetrance, with approximately 200 cases having been described in the world literature.[92] The commonest age at presentation is the sixth decade, and men are slightly more affected than women (3 : 2). Muir-Torre syndrome may be part of the cancer family syndrome, which includes hereditary nonpolyposis colorectal cancer type II, also known as Lynch syndrome.[93,94] Mutations in DNA mismatch repair genes and microsatellite instability are implicated in both syndromes. Alterations of mismatch repair genes have been found in both the cutaneous sebaceous neoplasms and visceral tumors in the Muir-Torre syndrome and may provide a useful diagnostic tool in the future.[95] The clinical features of Muir-Torre syndrome include sebaceous neoplasms of the skin, including adenomas (figure 7), epitheliomas, carcinomas, and at least one internal malignancy.[96] Colorectal, breast, or urogenital malignancies occur in approximately 90% of cases. Hematologic, head and neck, and small intestinal malignancies have also been associated with Muir-Torre syndrome.[97] Approximately 50% of patients diagnosed with Muir-Torre syndrome present with an internal malignancy before

Fig. 7. Sebaceous adenomas on the face in Muir-Torre syndrome. © 2006 Adis Data Information BV. All rights reserved.

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developing sebaceous lesions. About 50% of cases have two or more internal malignancies, which are often low-grade with high potential for long-term survival.[98] Other associated cutaneous lesions include sebaceous hyperplasia, basal cell carcinomas, keratoacanthomas, and squamous cell carcinomas. Keratoacanthomas are found in up to 20% of patients and often show sebaceous gland differentiation[99] which, if identified in either keratoacanthomas or basal cell carcinomas, is virtually pathognomonic and should prompt investigation for internal malignancies. Screening of asymptomatic family members and lifelong surveillance of affected individuals are indicated.[96] Annual laboratory studies, chest x-rays, mammography in women, and 3- to 5-yearly colonoscopy or barium enemas and endometrial biopsy are recommended.[100] Some authorities also suggest regular CT scanning of the abdomen and pelvis every 3–5 years.[96] Although screening is recommended before the age of 30 years,[101] the yield is expected to be small in asymptomatic patients before that age. 4.2 Neurofibromatosis

Neurofibromatosis is a neurocutaneous syndrome with two clinically distinct types.[102] A feature common to both disorders is the presence of benign and malignant tumors of the CNS. However, as type 2 rarely exhibits skin manifestations, only type 1 (also known as von Recklinghausen disease) will be discussed. Neurofibromatosis type 1 (NF1) is an important example of a genetic syndrome in which identification of cutaneous features is frequently the key to early screening for internal malignancy. The long-recognized association between the syndrome and malignancy has been substantiated now at a molecular level by genetic studies. 4.2.1 Neurofibromatosis Type 1

NF1 is the commonest neurocutaneous syndrome, with an autosomal dominant inheritance and a prevalence of 1 in 4000.[102] Its characteristic cutaneous features are axillary or inguinal freckling, caf´e-au-lait macules measuring >5mm in diameter before puberty and >15mm subsequently, neurofibromas, and plexiform neuromas. In 50% of cases, there is a spontaneous mutation in the NF1 gene found on chromosome 17,[103] leading to abnormal expression of the protein neurofibromin.[104] The latter is involved in tumor suppression. Recently, mutations in DNA mismatch repair genes usually involved in hereditary nonpolyposis colorectal cancer have been implicated in the development of de novo NF1.[105] Associated malignant neoplasms include Wilms’ tumor, rhabdomyosarcoma, retinoblastoma,[106] melanoma[107] (including choroidal melanoma[108]), intestinal leiomyosarcoma,[109] medulloblastomas,[110] and leukemia.[111] Also associated are pheochromocytomas, which are benign in 90% of cases. The characteristic cutaneous neurofibromas can themselves undergo maligAm J Clin Dermatol 2006; 7 (2)

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nant change, and gliomas of other neural tissues such as the optic pathway and brainstem may develop.[112] There is an association between neurofibromatosis and familial gynecologic and breast malignancies. Genetic studies have shown that a common haplotype involving the NF1 and breast cancer (BRCA)-1 loci, both located on chromosome 17, is shared in those affected by NF1 and carcinomas that develop at a young age.[113] Individuals with NF1 are recommended to undergo annual clinical reviews, including measurement of blood pressure. Routine brain imaging is of debatable value and should be performed only in children with macrocephaly or focal neurologic symptoms.[102] There are currently no established cancer screening protocols for NF1. Symptomatic cutaneous neurofibromas may be surgically excised. 4.3 Tuberous Sclerosis

The preferred name for tuberous sclerosis is tuberous sclerosis complex (TSC), as this terminology highlights the multisystem involvement of skin, brain, heart, lungs, kidneys, and other organs associated with this condition. TSC is an autosomal dominant condition with an incidence of 1 in 100 000. There is an equal male : female ratio, and sporadic cases account for >50%.[114] The genes involved, TSC 1 and TSC 2, are located on chromosomes 9[115] and 16,[116] respectively, and can be commercially tested for, with a detection rate of approximately 80%.[117] Both genes are important in tumor suppression. The main clinical findings in TSC are cutaneous lesions, epilepsy, and mental retardation.[118] The cutaneous features, which may be the only clue to diagnosis, include connective tissue nevi known as shagreen patches, ash-leaf macules, periungual fibromas, and facial angiofibromas. Associated benign tumors include cardiac rhabdomyomas,[119] renal angiomyolipomas,[120] and hamartomatous colonic polyps.[121] Malignant tumors most commonly develop in the brain and kidneys and include astrocytomas (found in 70% of affected patients), which are pathognomonic of the complex,[122] and renal clear cell carcinoma (detected in 4%).[123] The recommendations for diagnostic evaluation of this complex include cranial magnetic resonance imaging, cardiac investigations (ECG and echocardiogram), and renal ultrasound at diagnosis and every 1–3 years. CT scanning of the chest is indicated for pulmonary symptoms to rule out the possibility of pulmonary lymphangiomyomatosis.[122] The prognosis for patients diagnosed with TSC is poor, usually death in the third and fourth decades resulting from progressive neurologic deterioration.[118] Symptomatic cutaneous features may be treated, for example, with laser surgery.[124] © 2006 Adis Data Information BV. All rights reserved.

4.4 Multiple Hamartoma Syndrome (Cowden Disease)

Cowden disease is an uncommon autosomal dominant condition with variable expressivity. It is estimated to affect 1 in 300 000 individuals, mainly with a female preponderance.[125] Mutations such as N48K[126] in the tumor suppressor gene PTEN (phosphatase and tensin homolog), found on chromosome 10, have been identified.[127] A viral etiology may be implicated, as the majority of cutaneous lesions harbor human papillomavirus DNA, as revealed by polymerase chain reaction.[128] The characteristic mucocutaneous lesions present in 99–100% of patients with Cowden disease include facial papules, oral papillomatosis, and acral keratoses.[129] Importantly, cutaneous features may precede the development of breast, endometrial, gastrointestinal, and thyroid tumors by many years. Heightened cancer surveillance is imperative. Asymptomatic family members may be identified by genetic testing for the PTEN mutation. Recommended clinical tests include regular mammography and gynecologic examination in females and thyroid function tests.[130] 4.5 Basal Cell Nevus Syndrome (Gorlin Syndrome)

Gorlin syndrome is an autosomal-dominant condition with complete penetrance and variable expressivity. It is characterized by multiple basal cell carcinomas, jaw cysts, plantar or palmar pits (found in 60%),[131] ectopic calcification, and congenital skeletal abnormalities. Multiple basal cell carcinomas present early between puberty and the fourth decade, especially on the head and neck. Invasion and metastatic spread have been reported.[132] Internal malignancies such as medulloblastoma, oligodendroglioma, ovarian fibrosarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma[133] have been reported in association with this syndrome. The genetic defect has been mapped to chromosome 9[134] involving the patched (PTCH) gene.[135] Management of Gorlin syndrome includes excision of suspicious skin lesions and removal of jaw cysts, which have a high propensity for recurrence. Surveillance of patients with Gorlin syndrome who have a history of previous basal cell carcinomas may be useful for the identification and treatment of new lesions. There is currently no screening protocol for neoplasms associated with this condition.[136] 4.6 Familial Polyposis Syndromes 4.6.1 Gardner Syndrome

Gardner syndrome is an autosomal dominant syndrome characterized by the presence of intestinal polyposis and extraintestinal features involving skin, eye, bone, and thyroid. Virtually all paAm J Clin Dermatol 2006; 7 (2)

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tients with Gardner syndrome will develop adenocarcinoma of the colon.[137] The cutaneous features of Gardner syndrome include epidermoid cysts, fibromas, lipomas, and neurofibromas. The epidermoid cysts are clinically unremarkable but histologically show distinguishing features such as pilomatricoma-like changes and trichilemmal keratinization.[138] The presence of fibromas may indicate a predisposition to desmoid tumors and mesenteric and retroperitoneal fibrosis. Aggressive fibromatosis may simulate breast carcinoma.[139] Frequent endoscopic examinations, genetic testing, and surveillance for extracolonic manifestations are the mainstay of diagnosis of Gardner syndrome.[140] Genetic testing involves screening for the adenomatous polyposis coli (APC) gene by direct sequencing. Annual screening colonoscopy should start from the age of 10 years.[141] There are no clear guidelines for upper gastrointestinal endoscopy, which is, however, warranted for the screening of duodenal polyps. 4.6.2 Peutz-Jeghers Syndrome

Peutz-Jeghers is another rare gastrointestinal polyposis syndrome with autosomal dominant inheritance. Mutations involving serine threonine kinase, a tumor suppressor gene[142] on chromosome 19, are found in approximately 60% of cases. The characteristic features of Peutz-Jeghers syndrome are melanocytic mucocutaneous pigmentation and intestinal hamartomatous polyps, which are associated with a relative risk of cancer of up to 18 times.[143] Extraintestinal tumors involving the cervix, breasts, and testes are found more frequently.[144] Given the susceptibility to several cancers, vigorous screening protocols should be followed in patients with Peutz-Jeghers syndrome. Both the upper and lower gastrointestinal tracts should be endoscoped in any patient suspected of having the condition. The pancreas, breasts, testes, and uterus should also be investigated yearly from a young age.[144]

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5. General Cutaneous Manifestations of Malignancy Patients with advanced malignancy commonly exhibit nonspecific cutaneous signs such as xerosis and pruritus. Generalized xerosis, which is distinctive from acquired ichthyosis, is attributable to many causes in a patient with an underlying malignancy, including malnutrition, dehydration, and cachexia. The pathogenesis of itch in malignancy is complex. Both central and peripheral mechanisms are involved and, in certain tumors, the production of pruritogenic mediators such as histamine and serotonin may be implicated. Reticuloendothelial tumors such as polycythemia rubra vera, lymphoma, and Hodgkin disease are particularly associated with pruritis. Rarely, localized pruritus may be associated with an underlying tumor. For example, the onset of nasal pruritus in association with a brain tumor is usually a poor prognostic sign.[147] In the palliative care setting, pruritus may be a significant cause of morbidity and is likely to be more prevalent than the quoted figure of between 5%[148] and 27%.[149] Treatable causes such as cholestasis, xerosis, and use of opioids should be identified. 6. Conclusion The skin is a readily accessible organ, which should never be ignored. In cases of internal malignancy, cutaneous lesions may represent the tip of the iceberg. Increased clinician awareness and education regarding the associations between these lesions and internal malignancy will facilitate screening and early diagnosis. Cutaneous lesions may also be useful for monitoring the activity and response to treatment of malignant disease. In the future, identification of the specific defect in inherited syndromes may create opportunities for gene therapy, and treatments targeted at circulating humoral agents may provide symptomatic relief in some of the paraneoplastic syndromes. Acknowledgements

4.7 Inherited Tylosis

In the 1950s, two families were identified with autosomal dominantly-inherited focal palmoplantar keratoderma predominantly affecting the pressure points of the sole, with associated variable oral leukokeratosis.[145] Thirty-seven percent of affected family members developed esophageal cancer 30–40 years later.[146] The distribution and clinical appearance of the lesions were consistent with a keratin gene mutation, but none was identified; instead, the genetic abnormality was mapped to a locus on chromosome 17q23, now labeled the TOCG (tylosis with esophageal cancer) locus. Subsequently, another family was identified, with a 38-fold increased risk of esophageal cancer. Affected family members require annual endoscopic screening.[146] © 2006 Adis Data Information BV. All rights reserved.

The authors would like to thank Dr Davin Lim of Clatterbridge Hospital (Wirrall, UK) and Dr Jonathan Sowden of Wrexham Hospital (Wrexham, UK) for generously contributing clinical photographs. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of the review.

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