Gingival overgrowth in a dog that received long-term cyclosporine for immune-mediated hemolytic anemia

Abstract

Gingival mass lesions developed when cyclosporine was administered for 600 days to a female, 7-year-old, longhaired dachshund diagnosed with intractable immune-mediated hemolytic anemia (IMHA). Histopathology indicated hyperplastic suppurative gingivitis. As the anemia improved, the dosage of cyclosporine A (CsA) was markedly decreased, and the mass lesions decreased in size and disappeared, thus suggesting that the mass lesions were an adverse reaction to CsA.

A 7-year-old intact female, longhaired dachshund weighing 4.0 kg was brought to Azabu University Veterinary Hospital in October 2006. Two months before the initial visit, the dog had become lethargic and had reduced appetite. The referring veterinarian had determined that the packed cell volume (PCV) was low. Prednisolone and a protein anabolic hormone were administered. However, because there were no signs of improvement and the PCV had decreased to 6% 3 d before the visit, the dog was given a blood transfusion.

Case description

Figure 1 shows the course of the cyclosporine dosage (CsA, Neoral; Novartis Pharma, Tokyo, Japan) and the PCV after the initial visit. At the initial visit, the dog was not active, but physical and neurological tests showed no abnormality, and since the blood test was conducted after the transfusion, there was no marked anemia (PCV 36%). Spherocytes were observed in the blood smear. Blood chemistry, chest and abdominal X-rays, and abdominal ultrasound revealed no abnormal findings. From the medical history and examination, bleeding, infectious disease and toxicity were not considered to be causes of the anemia. A bone marrow biopsy was conducted because the dog had received treatment over a long period and the anemia was progressive and non-regenerative (reticulocytes 0.4%). The results showed no abnormal findings such as tumor cells or hypoplasia. The dog was diagnosed with aplastic immune-mediated hemolytic anemia caused by hemolysis at the blast level.

Figure 1.

Changes in packed cell volume (PCV) and cyclosporine dosage in the dog affected with immune-mediated hemolytic anemia. 1 — transfusion; 2 — hIVIG administration; 3 — mass detection; 4 — mastectomy; and 5 — mass disappearance.

For therapy, 1.8 mg/kg of prednisolone (Prednisolon; Sanwa Kagaku Kenkyusyo Co, Aichi, Japan) and 12.2 mg/kg body weight (BW) of CsA (Neoral; Novartis Pharma K.K.) were administered orally once a day. Because the anemia did not improve and hemolysis increased, in order to prevent disseminated intravascular coagulation, 2.5 g of human intravenous immunoglobulin (hIVIG, Gammagard; Baxter, Tokyo, Japan) were administered with an infusion of low-molecular-weight heparin in physiological saline (75 U/kg BW per day). A whole blood transfusion was also given (after having confirmed no aggregation by crossmatch), and 200 U/kg BW of heparin and 2 mg/kg BW of prednisolone were administered. The PCV improved by 27% immediately after the transfusion. On day 118 of the illness, the PCV improved to 41%, and the course appeared favorable. The dose of prednisolone was gradually reduced. However, the anemia recurred starting on day 196 of the illness; azathioprine (AZA, imuran; GlaxoSmithKline, Tokyo, Japan) was administered at 2.1 mg/kg BW, PO, q48h starting on day 218 of the illness, and whole blood transfusions were given on days 241 and 339 of the illness.

The progression of the anemia gradually slowed, and the dog began to recover its strength starting on day 399 of the illness. The CsA blood level on day 328 of the illness was 220 ng/mL (within the acceptable range of 200 to 500 ng/mL) and on day 497 of the illness it was 230 ng/mL. The PCV was low at 26% but stable and because of signs of iatrogenic Cushing’s syndrome, such as a bloated abdomen and frequent thirst and urination, prednisolone administration (0.4 mg/kg BW q48h) was terminated on day 567 of the illness, so that only CsA was being administered.

The anemia began to improve, but on day 619 of the illness the owner observed oral masses which grew in subsequent days. On day 623 of the illness, gingival swelling was seen around the left and right upper 1st and 2nd incisors (Figure 2), and masses of about 1 cm diameter were seen around the right 4th mammary gland and the left 5th nipple. The mammary gland lesions, uterus, and ovary were removed under general anesthesia, and a part of the gingival mass lesion was ligated and excised using surgical suture and examined pathologically. The results showed that the mammary masses were mammary carcinoma (left) and mammary hyperplasia (right). The gingival swelling was hyperplastic gingivitis with suppuration, for which the antibiotic cephalexin (Larixin; Toyama Chemical Co, Tokyo, Japan; 30 mg/kg BW, PO, BID) was given for 7 d, but the swelling did not decrease.

Figure 2.

Oral mass lesions on day 623. Note the mandibular mass lesion (A) and gingival swelling around the left and right upper first and second incisors (B).

On day 668 of the illness, the PCV increased to 34%, the dosage of CsA was halved, and azathioprine was discontinued. On day 745 of the illness the mandibular mass lesion and the mass lesion around the incisors decreased in size, and on day 840 of the illness (Figure 3), the mandibular mass lesion and the mass lesion around the incisors had disappeared, with some residual swelling in the medial hard palate of the upper incisors. The CSA blood level after halving the dosage was 120 ng/mL.

Figure 3.

Oral mass lesions on day 840 following reduction in the dose of cyclosporine A. The mandibular mass lesion disappeared (A), and the mass lesion around the incisors disappeared, with some residual swelling in the medial hard palate of the upper incisors (B).

Discussion

Canine IMHA is a disease in which hemolysis occurs when autologous red blood cells bind to complement. Red blood cells are opsonized when autoantibody binds to protein components, such as glycophorin on red blood cell membranes. Red cells binding to autoantibodies are phagocytosed by the mononuclear phagocyte system, such as the spleen (1–5). As a result, immunosuppressants, such as prednisolone, azathioprine, cyclophosphamide, and CsA are administered, and hIVIG is used to block the macrophage Fc receptor (6), thus markedly improving the early therapy of IMHA. However, IMHA often recurs, and when hematopoiesis is insufficient, immunosuppressants must be administered for a long period of time to maintain a favorable quality of life.

Although CsA is useful for canine immune-mediated diseases (2,7), adverse events such as gingival hyperplasia, hypertrichosis, excessive shedding, and papillomatosis have been documented (7), and gingival hyperplasia was documented in 3 of 4 dogs with blood concentrations resulting in immunosuppression that were maintained for 20 to 24 wk (8).

Because cyclosporine was continuously administered for 600 d, the mass lesions in the dog in this case were suspected to be gingival hyperplasia. However, according to the WHO (9), oral tumors are the most common form of head and neck tumors, and 59.6% of canine head and neck tumors are malignant (10). Oral and cervical tumors include oral melanoma, squamous cell carcinoma, and fibrosarcoma; all these diseases progress quickly. Early diagnosis makes it possible to perform surgical resection or radiation therapy, and even a benign tumor needs to be resected if it increases in size (11,12). Although differentials for the clinical appearance of these masses included a wait-and-see approach and cytological diagnosis, a histopathological test was conducted, and since it became clear that the gingival mass lesions were hyperplastic, they were monitored without being resected. When continuously administering CsA for a long period of time, it is necessary to explain to pet owners that gingival hyperplasia can occur, and if it arises, a histological test is necessary to rule out other mass lesions. CVJ