Canine Malignant Histiocytosis (Canine Disseminated Histiocytic Sarcoma): An Overview

Elizabeth Lamp, DVM, Bruce E. LeRoy, DVM, PhD, Kenneth S. Latimer, DVM, PhD, Holly Moore, DVM

Class of 2005 (Lamp) and Department of Pathology (LeRoy, Latimer, Moore), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

Canine histiocytic disorders include a wide spectrum of diseases ranging from benign cutaneous histiocytoma to malignant histiocytosis (disseminated histiocytic sarcoma).¹ Benign canine histiocytic proliferative diseases include cutaneous histiocytoma, cutaneous histiocytosis, and systemic histiocytosis. Malignant diseases include localized and disseminated histiocytic sarcoma.

Canine cutaneous histiocytoma is a benign epitheliotropic neoplasm composed of intraepidermal, dendritic, antigen-presenting cells. Most canine cutaneous histiocytomas spontaneously regress.¹ Systemic histiocytosis is a non-neoplastic proliferative disorder of histiocytes characterized by remissions and relapses. In this disease, histiocytic infiltrates are found in the skin and lymph nodes, but the infiltrating mononuclear cells closely resemble normal marcrophages and do not demonstrate criteria of malignancy.⁹ In contrast, localized histiocytic sarcomas develop from a single site. They are locally invasive and metastasize to draining lymph nodes.^1,3,9

Malignant histiocytosis / disseminated histiocytic sarcoma (MH/DHS) is distinct from the other histiocytic diseases. This is an aggressive, multisystemic disease characterized by the presence of multiple tumor masses in several organs systems.¹ MH/DHS cells are atypical round cells that no longer resemble normal macrophages and display multiple criteria of malignancy. This disease most commonly affects middle-aged (median = 7 years) dogs. Bernese Mountain Dogs, Rottweilers, and Golden/Labrador retrievers are over-represented (79%) in larger studies.^1,2 Organs that are often infiltrated by the neoplastic cells include the lungs, liver, spleen, bone marrow, and lymph nodes, with the spleen most commonly affected.^1,3

Medical History and Physical Findings

Historical findings in patients affected with MH/DHS are non-specific but may include anorexia, weight loss, fever, and lethargy. Additional clinical signs, such as dyspnea, lameness, and neurological deficits, are variable and depend upon the organ system involved.¹ Clinical laboratory findings may be quite variable among dogs affected with MH/DHS, and may include anemia, thromobocytopenia, hyperbilirubinemia, and rarely hyperferritinemia.⁴

Imaging

Radiographic evaluation of 15 dogs with MH/DHS revealed abnormalities in all patients. The most common radiographic abnormality observed was the presence of a mediastinal mass (11 dogs), followed by pulmonary nodules or consolidation (10 dogs), hepatomegaly (6 dogs), pleural effusion (3 dogs), and splenomegaly (2 dogs).⁵

Ultrasonographic evaluation of 16 dogs with MH/DHS also revealed abnormalities in all patients. These included hypoechoic nodules in the spleen (12 dogs) and variable hepatic lesions (10 dogs). Other ultrasonographic abnormalities include mesenteric and medial iliac lymphadenopathy (11 dogs) as well as hypoechoic lesions in the kidneys (1 dog).⁶ Typical hypoechoic splenic nodules of a dog affected with malignant histiocytosis are illustrated in Figure 1. Hepatic nodular foci of hypoechogenicity surrounded by areas of hyperechogenicity in a dog with malignant histiocytosis are shown in Figure 2.

Figure 1: Ultrasonographic appearance of a hypoechoic nodule in the spleen of a dog with malignant histiocytosis.	Figure 2: Ultrasonographic appearance of liver metastasis of malignant histiocytosis. Note the characteristic hyperechogenic appearance surrounding a discrete area of hypoechogenicity.

Cytologic Evaluation

Cytologically, cells from lesions of MH/DHS are consistently described as neoplastic, with multinucleated giant cells presenting as either large round cells or bizarre stellate cells with long cytoplasmic processes.^1,4,7 In a study of 13 cytologic samples obtained from Bernese Mountain Dogs with MH, mononuclear cells measuring 15-50 µm in diameter predominated. Marked anisokaryosis was present. Nuclei appeared hyperchromatic and ovoid, indented, or folded. The cytoplasm of individual cells was abundant, eosinophilic, and granular. The plasma membrane was distinct but irregular and cytoplasmic vacuoles were frequently observed.^4,7 Multinucleated giant cells ranging from 30 to 100 µm in diameter were also noted. Phagocytosis of erythrocytes, neutrophils, and other tumor cells by both mononuclear and multinucleated tumor cells was also observed.⁴

The hemophagocytic variant of MH is characterized by large numbers of phagocytic tumor cells, resulting in systemic leukopenia, anemia, and thrombocytopenia. Cytologic evaluation of these neoplasms commonly reveals a high mitotic index with bizarre mitoses.^1,7 Cytologically and histologically, these neoplasms resemble localized histiocytic sarcomas.⁸ The characteristic cytologic features of MH/DHS are illustrated in Figure 3, which is a liver aspirate from a dog with MH. The aspirates are composed of large numbers of highly anaplastic round cells that exhibit marked anisocytosis and anisokaryosis and contain abundant, lightly to deeply basophilic cytoplasm as well as a round to oval to multilobulated nucleus. Numerous bizarre mitoses and multinucleated cells are also present. Similar cytologic features were present in samples from the patient’s primary mass, spleen, and bone marrow. The histologic features of this case are seen in Figure 4.

Figure 3: Cytologic appearance of malignant histiocytosis. There are numerous anaplastic round cells surrounding a markedly abnormal giant cell with a bizarre, hyperlobulated nuclear membrane.	Figure 4: Histologic appearance of malignant histiocytosis. Note the highly pleomorphic multinucleated giant cells (arrows).

Immunohistochemistry

Immunohistochemical staining is useful to determine the lineage of the highly anaplastic round cells seen with canine MH/DHS. In a study of 39 dogs with localized and disseminated histiocytic sarcoma, the histiocytes consistently (n=39) expressed CD18 reactivity.¹ CD1+, CD4-, CD11c+, CD11d-, MHCII+, ICAM-, and Thy-1+/- antigens also were consistently expressed in all snap-frozen samples (n=31). Expression of these antigens confirms that canine malignant histiocytes are of myeloid dendritic origin.¹ Immunoreactivity of canine MH/DHS for CD18 antigen is illustrated in Figure 5.

Figure 5: CD18 immunoreactivity (granular, dark brown intracytoplasmic staining) indicating leukocyte origin of malignant histiocytosis cells.

Treatment

Clinical outcome in dogs with MH/DHS reflects the aggressive behavior and poor prognosis of the neoplasm. Of 20 dogs presented for evaluation and treatment of canine malignant histiocytosis, 7 dogs failed to respond to cyclophosphamide, vincristince, and prednisolone. Another 7 dogs were euthanized following diagnosis, and clinical follow-up was not available for 6 dogs.^1,7 It has been suggested in the human literature that chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisolone may result in survival times ranging from several months to 6 years.⁷ It has also been reported that treatment with the human major histocompatibility complex, nonrestricted, cytotoxic T-cell line TALL-104 induced complete remission in four dogs with advanced disseminated histiosarcoma for time periods ranging from 9 to 22 months.¹⁰

References

1. Efforter VK, Moore PF: Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs. Vet Pathol 39:74-83, 2002

2. Withrow SJ, MacEwen EG: Small Animal Clinical Oncology, 2nd ed. W B Saunders Co., Philadelphia. p. 279, 1996.

3. Scott DW, Miller WH, Griffin CE: Muller and Kirk’s Small Animal Dermatology, 5th ed. W B Saunders Co, Philadelphia, PA. pp. 1080-1081, 1995.

4. Moore PF, Rosin A: Malignant histiocytosis of Bernese Mountain Dogs. Vet Pathol 23:1-10, 1986.

5. Schmidt ML, Rutteman GR, van Niel MHF, Wolvekamp PTC: Clinical and radiographic manifestations of canine malignant histiocytosis. Vet Quarterly 14:117-120, 1993.

6. Ramirez S, Douglass JR, Robertson ID: Ultrasonographic features of canine abdominal malignant histiocytosis. Vet Radiol Ultrasound 43:167-170, 2002.

7. Wellman SL, Davenport DJ, Morton D, Jacobs RM: Malignant histiocytosis in four dogs. J Am Vet Med Assoc 187:919-921, 1985.

8. Jacobs RM, Messick JB, Valli VE: Histiocytic proliferative diseases. In: Meuten DJ (ed): Tumors in Domestic Animals, 4th ed. Iowa State Press, Ames. pp. 170-173, 2002.

9. Rosin A, Moore P, Dubielzig R: Malignant histiocytosis in Bernese Mountain Dogs. J Am Vet Med Assoc 188:1041-1045, 1986.

10. Visonneau S, Cesano A, Tran T, Jeglum KA, Santoli D: Successful treatment of canine malignant histiocytosis with the human major histocompatibility complex nonrestricted cytotoxic T-cell line TALL-104. Clin Cancer Res 3:1789-1797, 1997.

Acknowledgment

Image of "Canine Color Plate From Kamerad Hund of Bernese Mountain Dog 2" is from the Encore Editions website and is used with permission.

^  Top of page