Acrokeratosis Paraneoplastica

Acrokeratosis paraneoplastica is a rare acral psoriasiform dermatosis associated with internal malignancy, most frequently squamous cell carcinoma (SCC) of the upper aerodigestive tract.[1] The syndrome of acrokeratosis paraneoplastica typically precedes the diagnosis of malignancy. Acrokeratosis paraneoplastica evolves through 3 stages, which are discussed more under in History. Note the images below.

Acrokeratosis paraneoplastica. A 67-year-old woman presented with scaly plaques of the hands, feet, ears, and nose associated with esophageal squamous cell carcinoma. The eruption resolved with resection of the cancer. Image courtesy of Ronald Grimwood, MD.

Acrokeratosis paraneoplastica. A 67-year-old woman presented with scaly plaques of the hands, feet, ears, and nose associated with esophageal squamous cell carcinoma. The eruption resolved with resection of the cancer. Image courtesy of Ronald Grimwood, MD.

The term Bazex syndrome describes 2 different entities, both described by Bazex and colleagues: (1) acrokeratosis paraneoplastica and (2) the genetic syndrome of basal cell carcinomas, follicular atrophoderma, hypotrichosis, and disorders of sweating. Note the images below.

Bazex syndrome. Acquired palmar keratoderma in a woman with a history of breast cancer and recent primary lung cancer. Courtesy of Jeffrey J. Meffert, MD.

Bazex syndrome. Violaceous psoriasiform dermatitis on the ankles. Lung cancer appeared to be in remission; both keratoderma and psoriasiform plaques resolved quickly with clobetasol ointment. Courtesy of Jeffrey J. Meffert, MD.

The pathophysiology of acrokeratosis paraneoplastica is not understood. Proposed mechanisms include cross-reactivity between skin and tumor antigens, the action of tumor-produced growth factors, and even zinc deficiency.[2, 3]

Most acrokeratosis paraneoplastica cases are associated with squamous cell carcinoma (SCC) of the upper one third of the respiratory or GI tracts (ie, oropharynx/larynx, lungs, esophagus).

Case reports also describe SCC of the thymus, vulva, cervix,[4] and skin[5] (including SCC in situ).[6] Reports have also described acrokeratosis paraneoplastica associated with SCC with an unknown primary tumor.

Other reported associated tumors include poorly differentiated carcinoma (not otherwise specified), small cell carcinoma of the lung, lymphoma, ductal carcinoma of the breast, carcinoid, multiple myeloma, transitional cell carcinoma of the bladder, cholangiocarcinoma,[7] liposarcoma,[8] well-differentiated thymic carcinoma,[9] and adenocarcinoma of multiple primary sites including tonsils and pancreas.[10, 11]

Frequency

Approximately 140 cases of acrokeratosis paraneoplastica have been reported in the literature.[7]

Sex

In one review, only 12 of 140 cases of acrokeratosis paraneoplastica were in women.[7]

Age

In one review, the mean age of onset for acrokeratosis paraneoplastica was 61 years.[12]

In most reported cases of acrokeratosis paraneoplastica, cervical lymph node metastases are present at the time of diagnosis, usually indicating a poor prognosis.[12]  Morbidity and mortality in acrokeratosis paraneoplastica are related directly to the underlying neoplasm. The skin lesions of acrokeratosis paraneoplastica rarely improve without successful treatment of the underlying malignancy.[12]

A diagnostic algorithm for acrokeratosis paraneoplastica has been proposed by Valdivielso, et al. At first suspicion of acrokeratosis paraneoplastica, a detailed history should be taken.[13]

The physician should inquire regarding risk factors for malignancy, including smoking habit, alcohol consumption, and family history. Upon further questioning, patients with suspected acrokeratosis paraneoplastica may admit to mild constitutional symptoms, weight loss, and other nonspecific findings of internal malignancy.

In one review of acrokeratosis paraneoplastica, when skin findings preceded the diagnosis of malignancy, they were present for an average of 1 year.[12] The interval between acrokeratosis paraneoplastica skin manifestations and tumor diagnosis has been reported to be as long as 3 years in some cases.[14] Signs of acrokeratosis paraneoplastica precede the detection of the primary malignancy in 65-70% of instances. Of acrokeratosis paraneoplastica patients, 10-15% have lesion appearance after the diagnosis of malignancy. In the remaining 15-25% of acrokeratosis paraneoplastica cases, both occur simultaneously.[15]

A complete physical examination should be performed in all patients suspected of having acrokeratosis paraneoplastica. This should include a thorough head and neck examination, including endoscopic examination, and pelvic examination in women.[12, 13]

Cutaneous manifestations of acrokeratosis paraneoplastica include the following:

• Symmetrical, acral, scaly, red-to-violaceous plaques or patches

• Acrally distributed, hyperpigmented patches possible in persons with darker skin types

• Involvement of the fingers, distal hands, feet, nose, and helices of the ears: Isolated involvement of the helices is particularly suggestive of acrokeratosis paraneoplastica.[16]

• Involvement of the cheeks, trunk, elbows, knees, palms, and soles in advanced disease

• Nail dystrophy, horizontal and vertical ridging (75%), subungual hyperkeratosis, nail plate atrophy, tender periungual erythema, and cuticle loss[17]

• Swelling of the digits with a blue-to-violet discoloration

• Bullae of the hands and feet

There have been case reports of more unusual presentations, including oral ulcerations[18] and generalized erythroderma.[19]

Three stages of lesion evolution have been described for acrokeratosis paraneoplastica. After performing the physical examination, the patient can be staged as follows[20] :

• Stage 1: Characterized by poorly defined psoriasiform plaques involving the ears, nose, nails, fingers, and toes; nail folds become dystrophic at this stage

• Stage 2: Characterized by involvement of larger and more proximal regions; violaceous keratoderma with central clearing is seen over the cheeks, palms, and/or soles

• Stage 3: Characterized by involvement of the legs, knees, thighs, and arms

Attention should also be paid to signs of other paraneoplastic syndromes, because patients may present with more than one.[21] Other physical examination findings suggesting the possibility of neoplasia are as follows:

• Ichthyosis

• Pruritus

• Sign of Leser-Trélat

• Clubbing

• Dermatomyositis

Skin biopsy and potassium hydroxide (KOH) examination should be performed, as should a CBC count and liver function profile.

Other tests are guided by findings from a complete history and physical examination[13] and may include the following:

• Serum tumor markers (ie, prostate-specific antigen, carcinoembryonic antigen)

• Serum and urine protein electrophoresis

• Creatinine, BUN, and electrolyte values

• Urinalysis

• Erythrocyte sedimentation rate (ESR)

• Stool guaiac

Chest radiography should be performed in all patients suspected of having acrokeratosis paraneoplastica.[13] Other radiological examinations to be considered based on the history and physical examination findings include the following:

• CT scanning of the head/neck, chest, and abdomen

• MRI of the head/neck, chest, and abdomen

• Abdominal or pelvic ultrasonography

• Mammography

• Positron emission tomography scanning

Other tests should be guided by the history, physical examination, imaging, and laboratory findings. These may include the following[13] :

• Upper GI endoscopy

• Bronchoscopy

• Lymph node biopsy

• Bone marrow biopsy

• Cystoscopy

• Colonoscopy

Skin biopsy specimens in acrokeratosis paraneoplastica often reveal nonspecific findings. In one review of 80 acrokeratosis paraneoplastica skin biopsy specimens, the most common histologic findings were hyperkeratosis, acanthosis, parakeratosis, and a perivascular infiltrate of lymphocytes and histiocytes. Dyskeratotic keratinocytes, vacuolar degeneration, and pigment incontinence were also occasionally seen. Other reported findings in acrokeratosis paraneoplastica lesions include spongiosis, exocytosis, lichenoid inflammation, and telangiectasias.[12, 22]  Note the images below.

At this power, a patchy lichenoid infiltrate of predominantly lymphocytes can be seen underneath an epidermis with psoriasiform hyperplasia and serum crust in the parakeratotic cornified layer (hematoxylin and eosin, 100X).

Focal vacuolar interface change is seen with associated pigment incontinence and exocytosis of lymphocytes (hematoxylin and eosin, 200X).

In acrokeratosis paraneoplastica cases in which immunofluorescence is performed, localized deposits of immunoglobulins, C3, or fibrin may be seen within the basement membrane.[23]

Treatment of acrokeratosis paraneoplastica depends on the type and stage of the underlying neoplasm. Successful treatment of the underlying malignancy typically improves the acrokeratosis paraneoplastica skin lesions.

Recurrence of acrokeratosis paraneoplastica skin lesions in a successfully treated patient implies a recurrence of the malignancy.[24, 25]

If the malignancy is untreatable or does not respond to treatment, acrokeratosis paraneoplastica skin-directed therapy may improve the eruption; however, the response to treatment is variable and often unsatisfactory.[12]

Improvement has been reported with the use of topical and systemic retinoids, topical and oral corticosteroids, salicylic acid, topical vitamin D analogues, and psoralen plus UVA (PUVA).[13]

One report suggests a role for zinc supplementation in patients with acrokeratosis paraneoplastica.[2]

Consultation with an internal medicine specialist for a malignancy workup is appropriate with an acrokeratosis paraneoplastica diagnosis.

Consultation with a hematologist, oncologist, otolaryngologist, pulmonologist, and/or gastroenterologist also can assist with focused evaluations related to acrokeratosis paraneoplastica.

The goal of pharmacotherapy in acrokeratosis paraneoplastica is to improve scaly lesions, reduce morbidity, and prevent complications.

Acitretin (Soriatane)

Acitretin is a metabolite of etretinate and related to both retinoic acid and retinol (vitamin A). Its mechanism of action is unknown. However, it is thought to exert its therapeutic effect by modulating keratinocyte differentiation, keratinocyte hyperproliferation, and tissue infiltration by inflammatory cells.

Salicylic acid topical

By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin while not affecting structure of viable epidermis.

Hydrate the skin and enhance the effects of the medication by soaking the affected area in warm water for 5 minutes prior to use. Remove any loose tissue with a brush, wash cloth, or emery board and dry thoroughly. Improvement should generally occur in 1-2 weeks.

Calcipotriene (Dovonex)

Calcipotriene is a synthetic vitamin D-3 analog that regulates skin cell production and development. It inhibits epidermal proliferation, promotes keratinocyte differentiation, and has immunosuppressive effects on lymphoid cells. It is used in the treatment of moderate plaque psoriasis. Use 0.005% cream, ointment, or solution.

Cholecalciferol (Delta-D, Vitamin D-3)

Cholecalciferol stimulates the absorption of calcium and phosphate from the small intestine and promotes the release of calcium from bone into blood. It has antiproliferative and anti-inflammatory effects on skin.

Betamethasone topical (Diprolene, Betatrex)

Betamethasone topical is for inflammatory dermatoses responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

Zinc

Zinc is a cofactor for more than 70 types of enzymes. It plays a role in many metabolic processes. A higher requirement may be indicated in pregnancy.

Use the sulfate or gluconate zinc salts. Zinc sulfate 4.4 mg = 1 mg of elemental zinc. Zinc gluconate 7.1 mg = 1 mg of elemental zinc.