Cutaneous paraneoplastic disease: Sometimes prognosis remains poor

Q. Please review inappropriate urination/cystitis in cats.

A. Dr. Stephen D. White at the 2005 American College of Veterinary Internal Medicine Forum in Baltimore gave a lecture on cutaneous paraneoplastic syndromes. Some relevant points in this lecture are provided below.

Cat diseases

Feline paraneoplastic alopecia presents as a ventral alopecia in which the abdominal skin appears to glisten but is not fragile. This syndrome can have a secondary Malassezia infection and also can be associated with dry, fissured foot pads. Necropsy usually reveals an exocrine pancreatic adenocarcinoma and can metastasize to the liver and elsewhere. Histopathologic examination of the skin shows severe atrophy and miniaturization of the hair follicles. Temporary resolution of the skin disease can occur when the primary tumor is removed. Prognosis is poor.

Feline skin fragility syndrome is seen in older cats in association with hepatic neoplasia, hyperadrenocorticism or hepatic lipidosis. Serum concentrations of progesterone and testosterone are increased when compared with a group of normal cats, and the clinical signs of skin fragility are attributed to hyperprogesteronemia. Diagnosis of hyperadrenocorticism can be made either by ultrasonography of the adrenal glands or an ACTH stimulation test protocol of synthetic solution of 125 micrograms intravenously with collected post samples at one and two hours. Therapy has not been standardized — bilateral adrenalectomy, ketoconazole (10 to 15 mg/kg SID) and metyrapone (65 mg/kg BID) are all recommended.

Thymomas are associated with an exfoliative dermatitis in older, and often orange, cats. The causative mechanism is unknown, but an erythema multiforme-type reaction has been proposed. If detected, the tumor's removal usually will lead to resolution of signs. Recently, radiotherapy has been reported as a therapeutic option.

Paraneoplastic pemphigus appears to be a combination of pemphigus foliaceus (exfoliative dermatitis) and pemphigus vulgaris (ulcers, especially in the oral cavity). Thymic lymphoma and cutaneous lymphoma are among the neoplasms implicated. The auto-antibodies in paraneoplastic pemphigus target different proteins than those of pemphigus foliaceus or pemphigus vulgaris.

Metastatic pulmonary adenocarcinomas have been reported in cats. The lesions occur on the distal extremities, especially the front feet, and look more like inflammatory pododermatitis than a neoplastic process. Their presence can be observed before pulmonary signs are noted. The neoplasm may be either a bronchogenic or squamous cell carcinoma. Palliative treatment to reduce the discomfort may be attempted (topical or systemic corticosteroids to reduce edema or piroxicam). Finally, clinicians should remember that malignancies of all kinds may metastasize to the skin and even mimic inflammatory dermatoses.

Dog diseases

Nodular dermatofibrosis syndrome in German Shepherds and occasionally other breeds is associated with renal cystadenocarcinomas or cystadenomas. Intact females may have multiple uterine leiomyomas. Histopathologic study of the nodules reveals dense collagen fibrosis. These nodules are most often found on the distal extremities. Diagnosis of renal lesions is best done by ultrasound study. This should be repeated at six-month intervals if the disease is suspected but original ultrasound study is normal. While the prognosis is serious, some dogs with benign renal cysts have survived for five years or more after diagnosis. In German Shepherds, this syndrome might be caused by a mutation in a previously unidentified tumor suppressor gene.

Glucagonoma syndrome is a less common cause of superficial necrolytic dermatitis; the more common cause is the hepatocutaneous syndrome. This disease has been reported in a small number of dogs. The cutaneous lesions include crusting, erythema, exudation and alopecia periorally and periocularly, around the genitals, and the distal extremities, as well as hyperkeratosis and ulceration of the footpads. The skin disease may precede the onset of the signs of the internal disease. Histopathologic findings include superficial perivascular-to-lichenoid dermatitis, with marked diffuse parakeratotic hyperkeratosis and striking intercellular and intracellular edema limited to the upper half of the epidermis (red, white and blue sign). Diagnosis may be problematic; typical physical and histopathologic findings in the absence of a hepatic ultrasound findings of both hyperechoic and hypoechoic areas in the liver (Swiss-cheese or honey-comb pattern) should prompt suspicion. Ultrasonography may show a tumor in the pancreas region. Dogs are often hyperglycemic or diabetic and have hypoaminoacidemia. Serum glucagon may be measured but is not always elevated; there are concerns that there might be different forms of glucagon, not all of which are detectable with current tests. Special immunohistopathologic stains for glucagons secreting cells may be done on tumors found in the pancreas. These tumors often, but not always, metastasize. These dogs also commonly have secondary skin infections (bacterial and/or yeast); appropriate treatment can make the dog more comfortable.

Multicentric squamous cell carcinoma in-situ (Bowen's disease) presents as single, but more commonly multicentric, eroded crusted papules and plaques on the head, neck, shoulders or forelegs of older cats (older than 10 years). These lesions are not associated with solar exposure of non-pigmented skin. There is a long clinical course with minimal progression. Some cats may have concurrent Demodex cati infestation of the lesions. As this disease is likely due to localized loss of immune competence complete evaluation of health status, including FeLV and FIV testing is indicated. Histopathological examination shows epidermal dysplasia without disruption of the basement membrane. Surgical (laser) excision is the treatment of choice. Radiation, cryosurgery and synthetic retinoid therapy have been suggested as appropriate adjunctive treatments. Recent work with topical 5-percent imiquimod cream (Aldara®, 3M Pharmaceuticals), a local immunological response modifier is promising; cats may develop reversible leukopenia following ingesting (via grooming) imiquimod cream that was placed on their lesions.

Cutaneous lymphosarcoma occurs in older dogs with no sex predilection but with a predilection for Boxers, Cocker Spaniels, Beagles, German Shepherds, Golden Retrievers and Scottish Terriers. It is uncommon in cats. Cutaneous lymphosarcoma is usually generalized or multifocal and can present as nodules, plaques, ulcers, erythroderma and/or exfoliative dermatitis. It can occur with or without other systemic involvement. Pruritus is very common. Histopathologically, cutaneous lymphosarcoma in the dog can be divided into epitheliotropic and non-epitheliotropic types. Epitheliotropic (following or hugging the epidermis histologically) forms of cutaneous lymphosarcoma have been shown in the dog to usually be of T-lymphocyte origin while non-epitheliotropic forms are usually of B-lymphocyte origin. Non-epitheliotropic lymphosarcomas are characterized by diffuse dermal and subcutaneous infiltration by malignant lymphocytes. The epitheliotropic form is often termed mycosis fungoides. It often begins as a generalized pruritic exfoliative dermatitis or erythroderma, and progresses over a variable length of time (weeks to months) to nodules and plaques, ultimate systemic involvement and death. Canine mycosis fungoides also may have a primarily mucocutaneous distribution. Clinical management of cutaneous lymphosarcoma, with or without concurrent systemic involvement, is difficult. Response to standard chemotherapeutic protocols used in lymphosarcoma of other organ systems are disappointing; 40 percent to 50 percent success rate may be seen using isotretinoin (Accutane®: Roche US Pharmaceuticals; AmnesteemTM: Bertek Pharmaceuticals), 3-4 mg/kg daily. Prednisone (1 mg/kg daily) may alleviate some of the pruritus. Lomustine (CCNU), an alkylating agent, has been effective in the treatment of dogs with cutaneous lymphoma at a dose of 50 mg/m2 every 21-30 days. Remission lasts from two to 15 months. Neutropenia may be seen and is most likely to occur one to two weeks after treatment, although this has usually been noted with higher doses. While generally a safe drug, irreversible hepatic toxicity (again, generally at higher doses) has been reported.

Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200, or e-mail: jdhoskins@mindspring.com