Cyclosporine treatment of perianal gland adenoma concurrent with benign prostatic hyperplasia in a dog

Abstract

A 13-year-old, intact male, mixed-breed dog was evaluated for multiple intradermal nodules around the anus. The nodules were diagnosed as perianal gland adenoma based on histopathologic examination. After therapy with cyclosporin A for 5 wk, the perianal masses were moderately shrunken. The dog’s condition has remained stable over 6 mo.

Cyclosporin A is a cyclic oligopeptide macrolide that is extensively employed in organ transplantation, auto-immune disorders, and dermatology of human and veterinary medicine due to its immunosuppressive properties (1). It also has a potential for the treatment of perianal fistulae and epitheliotropic lymphoma in dogs (2,3).

Three types of glandular tumors, namely perianal gland (or circumanal or hepatoid) tumor, apocrine gland tumor of the anal sac, and apocrine gland tumor commonly occur in the perianal area of the dog (4). The biological behavior of each type varies considerably (5). Most perianal gland swellings are focal hyperplasia and the benign proliferative form (adenoma), while their malignant counterparts (adenocarcinoma) are uncommon.

As a therapeutic approach, castration and tumor removal with surgery or cryosurgery is effective for most adenomas (6). Estrogens have been used in the past to reduce tumor volume but carry a significant risk of bone marrow suppression (7). No other pharmacological treatments have been used for hepatoid gland adenoma in dogs. There is only 1 report describing the inhibitory effects of cyclosporin A on proliferation and secretion but in another type of adenoma (pancreatic adenoma) under in vitro conditions (8).

The purpose of this case report is to determine whether administration of cyclosporin A systemically can reduce the proliferative activity of perianal gland tumors in a dog.

Case description

A 13-year-old, intact male, mixed-breed dog was evaluated because of multiple, 0.5 to 1.5 cm in diameter, round, intra-dermal nodules around the anus. There was a history of intermittent hematochezia and perianal nodules causing perianal pain and colorectal obstruction with tenesmus. On physical examination, the lesions of the perianal area were ulcerated and rectal mucous membrane was mildly protruded through the anus (Figure 1A). Hemorrhagic and keratinaceous material from the nodules was extruded with local pressure. Radiography showed prostatomegaly with a mildly compressed rectum (Figure 2). Ultrasonographic examination revealed a diffuse, symmetrically enlarged prostate gland. A punch biopsy (4 mm in diameter) using local anesthesia with lidocaine (Lidocaine HCl Inj. 0.5%; KunWha Pharma, Seoul, Korea) was taken on the right margin of the mass below the anus in the 4 o’clock direction. A perianal gland adenoma was diagnosed based on histopathological examination, which revealed hepatoid epithelial cells with round nuclei with 1 or 2 prominent nucleoli, and moderately dense light eosinophilic granular cytoplasm (Figure 3). The perianal gland adenoma was surrounded by a thin fibrous capsule and a well-developed stroma was noted. According to histopathologic, radiographic and ultrasonographic findings, this case was diagnosed as perianal gland adenoma concurrent with benign prostatic hyperplasia. This patient underwent medical control with cyclosporine (Implanta; Hanmi Pharm, Seoul, Korea), 5 mg/kg, BID, PO, for 5 wk. One week after therapy with cyclosporin A, clinical signs including swelling and exudation had progressively improved without any side effects. After 2 weeks of therapy with cyclosporin A the perianal lesions had partially regressed (0.35 to 1.1 cm in diameter) (Figure 1B). At the completion of the treatment all clinical signs including pain and tenesmus had disappeared. The size of the mass around the anus had remained moderately decreased (0.2 to 0.8 cm in diameter) (Figure 1C) and the prostate seemed to remain mildly shrunken on rectal palpation. Since then the dog has been normal without any side effects or relapses.

Figure 1.

A — These lesions were ulcerated and the rectal mucous membrane was mildly protruded (arrowhead) due to the masses (arrows). B — Two weeks after cyclosporine therapy. Shrinkage of the lesion and mild exudation are apparent (arrowhead). C — Moderate remission of the perianal lesion 5 wk after cyclosporine therapy. Exudation and protrusion of the rectal mucous membrane have disappeared.

Figure 2.

A — Lateral abdominal radiograph of the dog showing prostatomegaly. B — Retrograde urethrocystography reveals reflux of contrast media into the prostate gland.

Figure 3.

Histopathologically, perianal gland adenoma was clearly observed. In addition, the well-developed stroma surrounding the lobules and hepatoid cells was noted (×100, hematoxylin & eosin).

Discussion

Cyclosporin A is an immunomodulatory/immunosuppressive drug that inhibits T-helper cell activity. Since T-cells orchestrate most chronic immune responses, cyclosporine has broad anti-inflammatory effects (9). Its systemic indications currently include many autoimmune disorders. Recently, cyclosporin A as a calcineurin-inhibitor has been applied successfully to control atopic dermatitis (AD) in dogs (10–13).

The epidemiology of perianal gland neoplasms and their relationship with endogenous sex hormones was described in 472 dogs (4). Neoplasms of the perianal gland are usually slow-growing and adenomas are diagnosed about 4.5 times more often than carcinomas (14). These tumors occur primarily in male dogs and the maintenance of androgen receptors in adenomas of the perianal gland throughout cancer progression provides evidence for the hormone dependency of these tumors (15). Surgical resection including castration in male dogs has most commonly been used to treat perianal gland adenomas; however, fecal incontinence is a common complication following surgical intervention because anal sphincter muscle contiguous to the perianal gland can be damaged during surgery. In the present case, the clients declined to castrate the dog to take further opportunity for breeding; therefore, we decided to provide only medical treatment with cyclosporin A, for its anti-proliferative effects. Previous studies demonstrated that cyclosporin A inhibits testosterone biosynthesis in vivo (16) and in vitro (17). Sikka et al (18) reported that oral administration of cyclosporin A impaired testosterone synthesis mainly by inhibiting the hypothalamopituitary axis function. A decline in testosterone biosynthesis in a dose-dependent manner is attributable to blocking the signal transduction pathway (17). We suggest that testosterone biosynthesis was probably suppressed in this case after using cyclosporin A. A decrease in size of the prostate gland in this dog may be due to the suppression of testosterone, which can regress benign prostatic hyperplasia (BPH). Thus, clinical signs of BPH (tenesmus, persistent or intermittent hematuria, and bleeding) can be improved by reducing the level of testosterone. But there was no change in sexual behavior in this dog. In addition, it is thought that perianal gland adenoma concurrent with rectal compression by BPH caused hematochezia in this dog.

Sjöholm (18) described the inhibitory property of cyclosporin A on rat insulinoma cell proliferation, polyamine content, and insulin secretion. The mechanism of this anti-proliferative effect is suggested to be due to cytotoxicity of cyclosporin A. Cyclosporine induces apoptosis in related cell types by a mechanism similar to inhibition of calcineurin/nuclear factor signaling of activated T-cells (19,20). Mathews and Sukhiani (21) showed that cyclosporin A was effective in dogs with perianal fistulas, which is suggested to be involved with an abnormality in immune function but the exact mechanism is unknown (2,21,22). Hernández et al (23) revealed that cyclosporin A inhibits migration of primary endothelial cells and angiogenesis induced by vascular endothelial growth factor (VEGF), which contributes to tumor neovascularization and is increased in nearly every type of cancer. This growth factor belongs to a family including the placenta growth factor (PGF), VEGF-B, VEGF-C, and VEGF-D, each of which interacts with a different tyrosine kinase receptor. Signaling through these receptors is blocked by cyclosporin A, which results in inhibition of tumor growth (24).

In our case, there was no evidence of inflammation in the peripheral region of the adenoma. At its early presentation the lesion was ulcerated probably as a consequence of the pressure produced by the space-occupying mass. The biopsy sample was taken from a non-ulcerated area of the mass and inflammatory cells were not detected. The presence of an inflammatory component, however, cannot be ruled out since not all of the mass was excised. Cyclosporine may contribute to resolution of the inflammation not only by anti-inflammatory action but also by decrease of the mass probably by apoptosis, but the actual mechanism is not understood.

Although dogs are less susceptible to the side effects of cyclosporin A than other animals based on toxicity studies in rats, mice, rabbits, and dogs (25), dogs may uncommonly experience gingival hyperplasia and papillomatosis, vomiting, diarrhea, bacteriuria, bacterial skin infections, anorexia, hirsuitism, involuntary shaking, nephropathy, bone marrow suppression, and lymphoplasmatoid dermatosis at daily doses of 20 to 30 mg/kg (26).

Potential side effects in animals due to cyclosporin A therapy can be expected at the level of various side effects reported in humans. Hypertrichosis occurs in 50% to 80% of human transplant recipients taking cyclosporine (27). Acute bone pain, joint swelling, and limb paraesthesia have been reported in humans taking cyclosporine after renal transplantation or for immune-mediated diseases (28). Patricelli et al (29) reported that lameness in dogs receiving cyclosporine has been associated with septic arthritis and possibly the recurrence of panosteitis. Neuropsychological effects, including tremor, headaches, depression, anxiety, confusion, and somnolence, have been reported in humans receiving cyclosporine (30).

Because there have never been studies on cyclosporine effects on perianal gland adenoma in animals, the authors were guided by dosage and duration reported in research on perianal fistula in dogs. The optimal dosage and therapy period for perianal adenoma, therefore, should be further studied. However, we may consider various therapeutic dosing plans of cyclosporine based on previous studies. First, cyclosporin A is most commonly administered orally at a daily dose of 5 mg/kg to treat atopic dermatitis in dogs (31,32). Despite the beneficial effect of cyclosporin A, the high cost of cyclosporin A prohibits its use in many cases requiring long-term management. Application of low dose cyclosporin A combined with ketoconazole has been studied in dogs with anal fistula (33). Ketoconazole is reported to extend the half-life of cyclosporin A in a dose-dependent manner by reducing the dose of cyclosporin A required to maintain therapeutic serum concentrations by 56% to 90% (34).

Estrogen can be considered as a medical treatment for suppressing testosterone in perianal gland adenoma when the owners refuse castration. However, bone marrow suppression and fatal anaplastic anemia are serious side effects of estrogen therapy. Recently, zinc gluconate/arginine, has become available for chemical castration of 3- to 10-month-old male puppies. Zinc causes testicular atrophy and decreases spermatogenesis with concurrent reduction of androgen concentration when injected in the testicular parenchyma (35).

Cyclosporin A was administered for 5 wk in the present case. This dog showed moderately improved perianal lesion and complete remission of concurrent clinical signs. The absence of clinical signs remained stable for 6 mo, possibly due to the anti-proliferative effects and anti-inflammatory action of cyclosporin A as described above. Information on mechanism and action of cyclosporine on perianal gland adenoma and other forms of canine tumors is required in large scale studies.

In conclusion, this is the first report which describes management and prognosis of perianal gland adenoma with long-term administration of cyclosporin A without radiation therapy and surgical resection. The purpose of this study was to determine if the administration of cyclosporine systemically could reduce the proliferative activity of perianal gland adenoma in a dog. CVJ