JEADV (2005) 19, 340– 344 DOI: 10.1111/j.1468-3083.2005.01083.x
CASE REPOR T
Acrokeratosis paraneoplastica (Bazex syndrome) Blackwell Publishing, Ltd.
M Valdivielso,*† I Longo,† R Suárez,† M Huerta,† P Lázaro† †Hospital Gregorio Marañón, C/ Doctor Esquerdo, 46, 28007 Madrid, Spain. *Corresponding author, Marta Valdivielso Ramos, Servicio de Dermatología. Hospital Gregorio Marañón, C/ Doctor Esquerdo, 46, 28007 Madrid, Spain, tel. +915866680; fax +915868018; E-mail:
[email protected]
ABSTRAC T Bazex syndrome is a paraneoplastic dermatosis characterized by acral psoriasiform lesions associated with an underlying neoplasm. We present the case of a 64-year-old patient that was diagnosed with squamous cell lung carcinoma after being evaluated for lesions compatible with paraneoplastic acrokeratosis. With a high frequency Bazex syndrome is the earliest marker of an underlying subclinical neoplasm. An early suspicion is of the outmost importance in order to perform a prompt diagnosis of an underlying malignancy. We propose a diagnostic algorithm upon suspicion of acrokeratosis paraneoplastica and review the pathogenesis of this entity. Key words: acrokeratosis paraneoplastica, Bazex, paraneoplastic syndrome. Received 30 January 2004; accepted 4 March 2004
Introduction
Case report
The first description of this entity was performed by Bazex1 in 1965, under the name of ‘paraneoplastic syndrome with hyperkeratosis of the extremities’ in a patient with a pyriform sinus cancer and cervical metastases whose cutaneous lesions resolved after the tumour was treated. Since this first report all patients with Bazex syndrome published in the literature have had an underlying neoplasm.2,3 The most common associated neoplasms are squamous cell carcinoma of the upper aerodigestive tract and other tumours with cervical or mediastinal lymph node metastases.4,5 Other associated neoplasms described include gastric adenocarcinoma,6 colon adenocarcinoma,7 small cell lung carcinoma,8 lung adenocarcinoma,9 Hodgkin’s disease,5 T-cell lymphoma,10 multiple myeloma,11 hepatocarcinoma,2 thymoma,2 cutaneous squamous cell carcinoma,12 prostate adenocarcinoma,13,14 vulvar,8 uterine15 and bladder carcinoma.4 The recognition of characteristic cutaneous lesions is very important to allow an early diagnosis of a malignant process. Bolognia2 found that in 67% of the patients with Bazex syndrome, cutaneous lesions preceded the diagnosis of an underlying malignancy while in 15% of the cases the lesions developed after the neoplasm was discovered. We present the case of a 64-year-old patient that was diagnosed of squamous cell lung carcinoma after being evaluated for lesions consistent with acrokeratosis paraneoplastica.
A 64-year-old male was referred for evaluation of a 2-month history of intense pruritus that began on his hands and feet, which he associated with exposure to industrial gasoline. Afterwards he noticed the appearance of lesions on the hands, feet, nose and ears as well as fatigue, anorexia and weight loss of 10 kg in 2 months. He was an ex-smoker (two packs of cigarettes per day during 30 years) and had hepatic alcoholic cirrhosis (A grade). His medications included spironolactone. A general physical exam revealed a cachectic patient with hepatomegaly, and without palpable lymph nodes. The cutaneous physical exam showed symmetrical involvement of the dorsum of the fingers of both hands and feet by red violaceous plaques with ‘honeycomb’ appearance. The nail plate was affected in both hands and feet with longitudinal streaks, subungual hyperkeratosis, and a striking onychomadesis (fig. 1). We also noticed thickening of the distal phalanges and the presence of hyperkeratotic plaques on the palms and soles, predominantly at pressure points (fig. 2). On the nasal dorsum and the helices of both ears the plaques were hyperpigmented and slightly scaly (fig. 3). A biopsy was obtained from one finger. The histological study showed an orthokeratotic hyperkeratosis, slight acanthosis, irregular enlargement of the rete ridges and a superficial perivascular inflammatory infiltrate (fig. 4). The direct immunofluorescence was negative.
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fig. 1 Typical distribution of lesions, mainly with acral, bilateral and symmetric involvement. Nail involvement and fissuring of fingertips.
fig. 3 Hyperpigmentation and hyperkeratosis on the tip of the nose. fig. 2 Plantar hyperkeratosis mainly in pressure points.
Complementary exams showed a normocytic normochromic anaemia, leucocytosis (13 400 cells / L with 90% neutrophils), hypoalbuminaemia 2.8 g/ dL (normal: 3.5 – 5), ferropenia 18 µg / dL (normal: 59 –158), and increased erythrocyte sedimentation rate 91 mm / h, fibrinogen 583 mg/ dL (normal: 150 – 450), CA125 171 U/mL (normal: 5–35), immunoglobulin G 1650 mg/ dL (normal: 751–1560), immunoglobulin A 766 mg/ dL (normal: 82 –453), C-reactive protein 24 mg/ dL (normal: 0–0.8). The otolaryngological examination showed no abnormalities. Chest X-rays showed a lesion on the right lower lobe. A thoracoabdominal scan confirmed the presence of this lesion in the posterolateral segment of the right lower lobe associated with subcarinal and ipsilateral bronchial adenopathies. A biopsy specimen taken by fibrebronchoscopy showed a well-differentiated squamous cell carcinoma. After a thorough work-up study the patient was diagnosed with stage IIIA ( T2 N2 M0) squamous cell carcinoma of the lung. Given that the tumour was not amenable to surgical treatment the patient was started on chemotherapy with carboplatin and paclitaxel. After six cycles the chemotherapy was withdrawn due to haematological toxicity. For treatment consolidation the patient received radiotherapy up to a total dose of 55 Gy.
fig. 4 Photomicrograph showing orthokeratotic hyperkeratosis, acanthosis and enlargement of rete ridges. Superficial inflammatory infiltrate (haematoxylin and eosin, original magnification × 200).
A follow-up scan showed a decrease in adenopathies and lung infiltrates that correlated with clinical improvement of cutaneous lesions on the nose and ears. The patient remained in a stable condition for 5 months. Currently the patient is receiving chemotherapy due to increased tumour burden and the cutaneous lesions have notably worsened, especially those present on the hands.
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Table 1 Diagnostic algorithm after clinical suspicion of Bazex syndrome
Discussion Bazex syndrome is a specific marker of an underlying neoplasm, and mainly affects middle-aged white males.2,3,16,17 Clinical manifestations include red, violaceous psoriasiform plaques with ill-defined margins and a characteristic symmetric, bilateral and acral distribution, affecting mainly the hands, feet, ears, nose, and, to a lesser extent, elbows and knees. Hyperpigmentation predominates in dark-skinned individuals.2 The skin may be thickened mainly in the fingers and the helices of the ears. Palmoplantar keratoderma is characteristically described in pressure points.3,18 Nail involvement occurs early and appears in more than three-quarters of the cases with subungual hyperkeratosis, onycholysis, longitudinal streaks and yellow pigmentation. The onychomadesis finding in our patient is rarely described in the literature.2,17,18 A violet discoloration and bulbous enlargement of the distal phalanges is characteristic. Associated features include bullous lesions and carpal tunnel syndrome.19,20 The simultaneous occurrence with paraneoplastic acquired ichthyosis has also been described.5 Histological findings are unspecific with hyperkeratosis and foci of parakeratosis, acanthosis, isolated necrosis of keratinocytes, and a perivascular lymphohistiocytic inflammatory infiltrate. The immunofluorescence studies of lesional skin from patients with acrokeratosis paraneoplastica usually give negative results, as was noted in our case.3,21 A differential diagnosis should be made with psoriasis, treatment-resistant eczema and superficial fungal infections.2 In psoriasis the entire ear is usually affected, and the palms and soles are more frequently involved than the dorsum, with thick plaques without a ‘honeycomb’ appearance. In Bazex syndrome, the bulbous enlargement of the distal phalanges, and the isolated involvement of the helices are characteristic. On the other hand, we have to consider Bazex syndrome in an acral dermatosis that has failed to respond to an appropriate therapy. The pathogenesis of Bazex syndrome is unknown. Some authors have implicated an immunological mechanism based on the findings of immunoglobulins (IgG, IgA, IgM) and complement (C3) along the basal membrane in involved and healthy skin.19,22,23 Other authors have observed in two patients that serum levels of squamous cell carcinoma antigen (SCC-Ag) parallel the severity of cutaneous lesions, also suggesting an immunological mechanism.12,22 The association of Bazex syndrome with other autoimmune diseases such as alopecia areata and vitiligo has prompted the hypothesis of an autoimmune mechanism.12 Ellis et al.24 found increased expression of the epidermal growth factor receptor, which is the common receptor for epidermal growth factor and transforming growth factor α, along the epidermis in a patient with melanoma, acanthosis nigricans, Leser-Trélat sign and multiple skin tags. The increased expression of this receptor decreased following excision of the melanoma. These findings suggest that secreted factors by tumour cells
might play an important part in the pathogenesis of cutaneous hyperproliferative paraneoplastic disorders.5,24,25 As we have stated previously the most significant aspect related to this entity is that, in a high number of cases, it is the earliest marker of an underlying subclinical neoplasia. Its discovery compels the clinician to perform a work-up study of the patient. Bolognia et al.25 studied the primary sites of malignancies in 113 patients with Bazex syndrome with the following results: oropharynx and larynx (55 patients; 48.6%), lung (20; 17.7%), unknown location (18; 16%), oesophagus (12; 10.6%, one of them with an associated pyriform sinus carcinoma), prostate (two; 1.7%), and isolated cases in the liver, stomach, thymus, uterus, vulva, and bone marrow. With these results in mind, we propose a diagnostic algorithm based on the most commonly associated tumours ( Table 1). Upon suspicion of Bazex syndrome the first step of the evaluation, and perhaps the most important, consists of a detailed anamnesis and physical examination, to orientate further complementary exams. A basic work-up study should include a complete otolaryngological examination, chest X-rays, a complete blood cell count, an erythrocyte sedimentation rate, a biochemistry profile (including an iron study), tumour markers, and a test for occult blood
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in stool. If the ear, nose and throat exam and the chest X-rays appear unrevealing, further studies should include an upper gastrointestinal endoscopy. In the presence of anaemia or occult blood in stool, a colonoscopy should be performed. Based on clinical history and physical findings a chest, abdominal or pelvic scan may be required. If the clinical suspicion is very high and we do not find any neoplasm the patient should be followed every 3 months with periodic repetition of, at least, history, physical examination, otolaryngological exam and basic laboratory tests. As with other paraneoplastic dermatoses the only effective therapy is to treat the primary tumour. The skin lesions significantly improve when the underlying neoplasm is treated, or they remain unchanged in the setting of persistent disease. Nail involvement usually persists long after the tumour has been successfully treated. Residual hyperpigmentation has also been described.2 Occasionally, the reappearance of the skin lesions signals tumour recurrence. There are several reports of patients being treated with topical and systemic steroids, etretinate, salicylic acid, topical vitamin D analogues and psoralen + ultraviolet A with variable results. The spontaneous remission of cutaneous lesions without treatment of the underlying neoplasm has rarely been described in the literature.26–29
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