Multicentric lymphoma and disseminated coccidioidomycosis in a dog

Abstract

An 11-year-old, spayed female Alaskan malamute with a history of coccidioidal osteomyelitis was evaluated for inappetance and lethargy. Findings included generalized lymphadenopathy, pale mucous membranes, tachycardia, and labored breathing. Laboratory findings and radiographic imaging were consistent with generalized lymphoma and disseminated coccidioidomycosis. Treatment consisted of antibiotics, chemotherapeutic agents, and antifungals.

An 11-year-old, 26 kg, spayed female Alaskan malamute dog presented with a 1-week history of inappetance and lethargy. Three years earlier, the dog had received itraconazole (Sporanox; Janssen-Ortho Inc., Toronto, Ontario) for coccidioidal osteomyelitis of the distal part of the left tibia. Physical examination revealed cachexia and pale mucous membranes. A complete blood cell (CBC) count showed a regenerative anemia and mature leukocytosis (Table 1, day 1). Treatment consisted of IV fluids and ampicillin (Novo-Ampicillin; Novopharm, Toronto, Ontario) 575 mg, IV, q8h for 24 h, and then amoxicillin/clavulanic acid (Clavamox; Pfizer Canada, London, Ontario), 375 mg, PO, q12h for 7 d. Physical examination on day 7 revealed a generalized lymphadenomegaly. A CBC count showed a regenerative anemia (Table 1, day 8). A biopsy of the right popliteal lymph node was submitted for histopathologic examination. Prednisone (Apo-prednisone; Apotex, Toronto, Ontario) was prescribed at 15 mg, PO, q12h, for 7 d. Three days later, an edematous vulva was observed on physical examination.

Table 1.

Light microscopy revealed total effacement of the lymph node architecture caused by populations of large immunoblastic cells (1,2). Thick-walled fungal spherules (50 to 60 microns) containing endospores were present and surrounded by reactive macrophages. These changes are consistent with the diagnosis of lymphosarcoma (1,2) and a mild granulomatous lymphadenitis. The fungal spherules match previous descriptions of coccidioidomycosis (3,4). Referral to the oncology service at Colorado State University (CSU) Veterinary Teaching Hospital followed.

Findings on physical examination at the CSU were consistent with those of the referring veterinarian. Thoracic and abdominal radiographs revealed marked enlargement of hilar, sternal, and sublumbar lymph nodes. Uultrasonography of the abdomen to further evaluate the liver, spleen, and lymph nodes was declined. A CBC count and serum biochemical panels revealed leukocytosis, mature neutrophilia, and regenerative anemia (Table 1, day 12). Cytologic examination of aspirates from the popliteal lymph nodes was consistent with previously described light microscopic findings, with the exception of no fungal spherules being seen. Initial treatment for lymphoma consisted of IV fluids; prednisone, 30 mg, PO, q12h; and L-asparaginase (Kidrolase; Aventis Pharma, Laval, Quebec), 8800 IU, IM.

Cimetidine (Tagamet; SmithKline Beechham, Oakville, Ontario), 150 mg, IV, q8h, was administered and the dosage of prednisone was decreased to 20 mg, PO, q24 h on the following morning, because the dog had vomited blood. Treatment of lymphoma was continued with 0.44 mg of vincristine (Oncovin; Novopharm), IV. Ampicillin (Novo-Ampicillin; Novopharm), 585 mg, IV, q8h, and enrofloxacin (Baytril; Bayer, Etobicoke, Ontario), 67 mg, IV, q12h, were administered after the dog developed hyperthermia (40.7°C) and a packed cell volume (PCV) of 0.18 L/L.

The following day, the PCV was 0.154/L; after blood typing, 1 unit of A+ packed red blood cells was given. Following the transfusion, the dog was normothermic, appeared less depressed, and the PCV was 0.21 L/L. Treatment of the coccidiodomycosis was initiated with amphotericin B (AmBisome; Fugisawa, Markham, Ontario), 13.5 mg, IV. The dog was discharged the next day with a PCV of 0.20 L/L. The owners were instructed to give amoxicillin (Moxilean; Bimeda-MTC Animal Health, Cambridge, Ontario), 400 mg, PO, q12h for 7 d, and famotidine (Pepcid AC; McNiel Laboratories, Guelph, Ontario), 20 mg, PO, q12h.

Four days later, a physical examination revealed that all peripheral lymph nodes had decreased dramatically in size. A CBC count revealed anemia with a strong regenerative response (Table 1, day 19). The single agent doxorubicin (Adriamycin; Pharmacia & Upjohn, Mississauga, Ontario) protocol was selected for long-term treatment of the lymphoma. An echocardiogram prior to commencing treatment was declined. The first dose of doxorubicin (19.1 mg, IV, administered slowly) was decreased by 25% of the normal dose (30 mg/m²), because the dog was still anemic and lethargic. Treatment of the coccidioidomycosis was continued at the referring veterinary clinic (0.5–0.8 mg/kg BW of liposomal amphotericin B, mixed in 0.45% saline and 2.5% dextrose up to a total volume of 500 mL, given SC, twice weekly, to a cumulative dose of 12 mg/kg BW) (9).

At the time of writing, the dog has received her 3rd doxorubicin treatment and 200 mg of the total 320 mg liposomal amphotericin B. Lymph nodes have remained a normal size, and the CBC count serial evaluation has been unremarkable.

Lymphoma (malignant lymphoma, lymphosarcoma) is one of the most common neoplasms seen in the dog (1,5,6,7), with middle-aged to older dogs (median age of 6 to 9 y) being primarily affected (1,6,7). The recognized classifications of lymphoma in order of decreasing prevalence are multicentric, alimentary, mediastinal (thymic), cutaneous, and extranodal (renal, central nervous system, eye, bone, testis) (1,5). As in this case, 80% of dogs with lymphoma present with the multicentric form, distinguished by the presence of superficial lymphadenomegaly. In addition, hepatomegaly, splenomealy, and bone marrow involvement commonly occur. Most animals are asymptomatic at the time of presentation; however, some will have a history of weight loss, lethargy, anorexia, and febrile episodes (1,5). Differential diagnoses that must be considered in a dog with peripheral lymphadenomegaly are neoplastic causes, infectious causes, immune-mediated disorders, and inflammatory causes.

Aspiration cytology is frequently successful in making a definitive diagnosis; however, a biopsy is usually required to differentiate between low, intermediate, and high grade lymphomas (1). A lymphoma work-up should include a CBC count and a serum biochemical profile. Thoracic and abdominal radiographs, as well as abdominal ultrasonographs, are important in determining the extent of internal organ involvement. Bone marrow aspirates, which are important in staging the disease, were not performed in this case, as sedation or anesthesia was considered to be too risky. Once a diagnosis of multicentric lymphoma has been made, the disease should be staged according to the World Health Organization's clinical staging system (Table 2) (1).

Table 2.

The prognosis for lymphoma is variable and it has been suggested that many factors may influence survival (1,5). The most consistent prognostic factors are clinical stage and substage of the disease. Dogs with stage I or II disease have a more favorable prognosis than those in more advanced stages (1). In addition, dogs that are clinically ill (substage “b”) when they are presented do poorly when compared with dogs that are not ill when their disease is diagnosed (1,8). This dog presented with stage III to IV (b) disease, which would suggest a poor prognosis.

Without treatment, most dogs die of their disease within 4 to 6 wk. Many different chemotherapeutic protocols for lymphoma have been described. In this case, doxorubicin was chosen for long-term treatment (30 mg/m², IV, q21d for 5 treatments) (1,8). The expected remission rate with this drug is 50% to 75%, with an anticipated median survival time of 6 to 8 mo (1).

Disseminated coccidioidomycosis was also diagnosed in this dog upon observing Coccidioides immitis spherules on light microscopic examination of a lymph node biopsy. Coccidioides immitis is a soil saprophyte that is endemic to parts of California, Arizona, Texas, New Mexico, southwest Texas, Nevada, and Utah (3,4,9). Coccidioidomycosis is a systemic fungal infection that typically infects the lungs initially and may disseminate to other areas of the body. An adequate cell-mediated immune response, which occurs in most dogs, will result in subclinical or mild respiratory disease that resolves spontaneously. A poor immune response (common in immunocompromised animals) may result in hematogenous and lymphatic spread leading to disseminated disease. Dissemination can be to any organ system. The most common clinical sign is a chronic cough; however, nonspecific clinical signs, such as depression, anorexia, and a waxing and waning fever, are common (3). Occasionally lameness and painful bone swelling caused by osteomyelitis are reported. Regional or localized lymphadenomegaly may be seen, but generalized lymphadenopathy is extremely uncommon (3,9).

A definitive diagnosis of coccidioidomycosis can only be made by visualization of the C. immitis spherules containing endospores via cytologic or histopathologic examination. Aspiration of affected tissues is often unsuccessful due to low numbers of spherules, especially in bone. Microscopic examination is more likely to demonstrate organisms, but multiple biopsies should be taken to increase the likelihood of finding them (3). Serology can also be used to make a presumptive diagnosis (9). A complete work up includes a CBC count, serum biochemical profile, and thoracic radiographs to assess for pulmonary involvement and hilar lymph node enlargement. Limbs on which the animal is lame should be radiographed for evidence of fungal osteomyelitis.

There are a few options for treatment of disseminated coccidioidomycosis. Amphotericin B is the drug of choice for treatment of coccidioidomycosis in humans; however, the toxicities and difficulties associated with the administration of this drug make it less favorable. A liposomal formulation of amphotericin B that is less toxic is now available and SC protocols have been reported; unfortunately, they have not been clinically tested in animals (9). The azoles (ketaconazole, itraconazole) are reported to be less toxic; however, they are fungistatic and, therefore, relapses are common (9).

Prognosis for dogs with localized respiratory coccidioidomycosis that is not treated is good. Dogs with disseminated disease that are not treated will usually die or have to be euthanized after the disease is discovered. With treatment of disseminated disease, complete recovery rates vary with the severity and extent of the disease. As mentioned earlier, relapses are common, especially when medications are discontinued.

Diagnosis was a challenge in this case. If only a fine needle aspirate, rather than a biopsy of the lymph node had been taken, the dog would probably have been diagnosed with only lymphoma, and treated accordingly, because coccidial spherules are rarely aspirated from tissues infected with Coccidioides. The immunosuppression caused by the lymphoma likely resulted in a relapse of coccidiomycosis. Treatment for lymphoma would have immunosuppressed the animal even more, and most likely resulted in an overwhelming disseminated coccidioidal infection. Fortunately, light microscopy revealed C. immitis. It was then a question of whether or not coccidioidomycosis on its own could result in such a marked and generalized lymphadenopathy and cause total effacement of a lymph node, making it look neoplastic. The dog was eventually diagnosed with both multicentric lymphoma and disseminated coccidioidomycosis, because the pathologists identified both neoplastic lymphocytes and coccidioidal spherules within the same lymph node, and the dog's clinical signs could not be explained by only one of these disease processes.

Treatment of neoplastic disease in combination with an infectious disease is difficult, because the treatment of neoplastic disease results in compromise of the immune system. Theoretically, treatment of lymphoma would allow a coccidioidal infection to thrive and disseminate even further. However, treatment of the lymphoma was mandatory, as it was felt to be causing the majority of this dog's clinical signs. The other challenge associated with treatment is the combination of drugs with many toxic side effects. Initially the dog was not treated for both diseases simultaneously, because she was systemically ill. Once stabilized, she was started on a chemotherapeutic protocol to treat both of the diseases.

Currently, no documented cases of a dog having both disseminated coccidioidomycosis and concurrent multicentric lymphoma have been documented.