Feline Lymphoma and Leukemias
E. Gregory MacEwen
INCIDENCE AND RISK FACTORS
Lymphoma is a proliferative disease arising from lymphoid tissues involving any organ or tissue and accounts for 50 to 90% of all hematopoietic tumors in the cat.1,2 Since hematopoietic tumors (lymphoid and myeloid) account for approximately one-third of all feline tumors, it is estimated lymphoid neoplasia accounts for an incidence of 200 per 100,000 cats at risk.3 In one series of 400 cats with hematopoietic tumors, 61% had lymphoma, 39% had leukemias and myeloproliferative disorders, of which 21% were categorized as undifferential leukemias, which were most likely myeloid in origin.4
The mean age neoplastic development is reported to range from 2 to 6 years.5,6 In one study, males were at greater risk, and in another study females were reported to have a greater risk.7,8
The feline leukemia virus (FeLV) is the most common cause of hematopoietic tumors in the cat. The incidence of FeLV (positive), based on indirect immunofluorescent antibody (IFA) will range from 30 to 80%, depending on the location of the tumor and the age of the cat.5,9 Younger cats tend to be FeLV positive and have leukemia or mediastinal lymphoma. Older cats tend to be FeLV negative and alimentary lymphoma are usually FeLV negative.6
There is mounting evidence that feline immunodeficiency virus (FIV) infection will increase the incidence of lymphoma in cats.10,11 Shelton et al. determined that FIV infection alone in cats was associated with a fivefold increased risk for development of lymphomas.10 Coinfection with FeLV will further potentiate the development of lymphoproliferative disorders.10 Experimentally, cats infected with FIV have developed lymphoma in the kidney and liver of B-lymphocyte origin.12,13 It has been suggested that FIV infection may be associated with alimentary lymphoma of B-cell origin, and this may be related to chronic dysregulation of the immune system or the activation of oncogenic pathways.14,15
PATHOLOGY AND NATURAL BEHAVIOR
The classification of lymphoma and leukemias can be correlated with anatomic location and histologic criteria. Anatomic classification for lymphoma has been categorized as mediastinal, alimentary, multicentric, leukemic, and extranodal form.2 The frequency of anatomic form will vary with geographic distribution and may be related to FeLV strain as well as prevalence of FeLV vaccine use.Mediastinal Form
This form involves the thymus, mediastinal, and sternal lymph nodes. More commonly the disease involves the anterior and posterior lymph nodes in the mediastinum. Pleural effusion is common. Occasionally the tumor will extend out of the thoracic inlet and can be palpated in the ventral neck region. Hypercalcemia occurs frequently with mediastinal lymphoma in dogs and is very rare in cats.16,17 The majority of cats with mediastinal lymphoma are young and FeLV positive.2
Alimentary lymphoma usually consists of gastrointestinal, mesenteric lymph nodes and liver involvement. Some reports will limit the alimentary form to gastrointestinal involvement with or without extension to the liver. The low prevalence of FeLV infection in cats with gastrointestinal involvement is because most of these tumors are from B-lymphocytes in gutassociated lymphoid tissue.18 Although recent evidence suggests some FeLV-negative tumors may be derived from transformation of multipotent lymphoid or monocyte precursors19 or FIV transformed B-lymphocytes. 12,13 The most common site of involvement is the small intestines (50%), then the stomach (25%), followed by ileocecocolic junction and colon. The tumor can be solitary or diffuse throughout the intestines, muscle layers, and intestinal submucosa, resulting in annular thickening, leading to partial or completed intestinal obstruction. There is a report describing chronic lymphocytic-plasmacytic enteritis in cats progressing to overt lymphoma, following 6 to 18 months of conservative therapy.20
The multicentric form will usually involve peripheral lymph nodes with or without simultaneous abdominal (spleen/liver) involvement. Peripheral lymphadenopathy alone is very unusual. Cats with generalized peripheral lymphadenopathy due to lymphoma may have minimal signs of illness. As the lymphoma progresses, bone marrow infiltration with malignant cells and hepatosplenomegaly may develop.
There have been reports of nonneoplastic peripheral lymphadenopathy in cats, which clinically resembles lymphoma and histologically has features that may also resemble lymphoma.21-23 These lymph nodes may be two to three times normal size. In one report, this syndrome was termed distinctive peripheral lymph node hyperplasia (DPLH) of young cats.22 These cats tend to be young (2-4 years), many have had episodes of fever, previous viral infections, may have hypergammaglobulinemia (polyclonal gammopathy) and most are negative for FeLV.21 Histopathologically the nodal architecture is severely distorted with loss of subcapsular and medullary sinuses. The cell population shows an admixture of histiocytes, lymphocytes, plasma cells, and immunoblasts, and occasionally effaced lymphoid follicles. The lymph nodes will regress spontaneously in most of these cats.21 The histologic changes noted in these lymph nodes resemble the histologic features of AIDSrelated lymphadenopathy in humans.22
C. Feline Lymphoma and Leukemias
The most common extranodal sites for lymphoma include the kidneys, eyes, retrobulbar, central nervous system (CNS), nasal cavity, and skin. Renal lymphoma can be primary or associated with alimentary lymphoma. In a study of 28 cases of renal lymphoma the mean age was 7 years and 50% were FeLV positive.24 Metastasis to the CNS is a frequent sequela to renal lymphoma and occurs in 40 to 50% of treated cats.
Primary CNS lymphoma (PCNSL) is most commonly seen extradural in the spinal canal and most cats are FeLV (positive) (80%).(25,26) Following meningioma, lymphoma is reported to be the second most common tumor involving the CNS in cats. The mean age is 3 to 4 years with some suggestion of a male predilection.25-27 Most cats present with paresis of the hindlegs and thoracolumbar spine and epidural space are most commonly involved. The predilection for thoracolumbar spine in cats is unknown. Feline PCNSL may be primary or secondary to multicentric involvement (especially renal or bone marrow).28 Bone involvement is rarely seen radiographically.29 In necropsy findings, renal involvement and bone marrow are the common sites in cats presenting with spinal lymphoma.25,26
Cutaneous lymphoma is usually primary but can rarely be seen secondary to multicentric involvement. It is commonly seen in older cats (5-14 years) with an average age of 10 to 12 years.30-34 No sex or breed predominance has been found. Uniformly, cats with cutaneous lymphoma test FeLV negative. However, one recent case report using polymerase chain reaction (PCR) technology found evidence of FeLV provirus in tumor DNA.34 Cutaneous lymphoma can be solitary or generalized. Two forms of cutaneous lymphoma have been distinguished histologically and immunohistochemically.30-34 The epitheliotrophic form, also called mycosis fungoides, is associated with T-lymphocytes. Non epitheliotrophic form is usually composed of B-lymphocytes. Neoplastic T-lymphocytes are characterized as large with abundant cytoplasm and convoluted nuclei (mycosis cells). These cells usually form intraepidermal nests of 5 to 10 cells, separated from surrounding keratinocytes by a clear space (Pautrier's microabscesses). The B-cell lymphomas show lymphocytes deep in the epidermis, with sparing of the papillary dermis and epidermis. Confirmation, using immunohistophenotyping of B-cell lymphoma in cats with cutaneous lymphoma is lacking.
Recently, a cat with cutaneous T-cell lymphoma with circulating atypical lymphocytes was diagnosed.33 The circulating cells were lymphocytes with large, hyperchromatic, grooved nuclei. In humans, cutaneous T-cell lymphoma with circulating malignant cells is called Sezary syndrome.35 This syndrome has also been reported in dogs.36-38
Histologic Classification of Lymphomas
A number of histopathologic staging systems have been developed and used to classify human non-Hodgkin's lymphoma. Recently, the morphologic criteria of the NIH Working Formulation was used to classify more than 600 cases of feline lymphoma.39 Low-grade lymphoma was found in 8.6%, intermediategrade in 35.1%, and high-grade in 55.2% of the cases. The remaining 1.1% were plasmacytomas. More than one-third of the tumors were of the immunoblastic type. Lymphoblastic lymphoma, a subtype of the high-grade tumor, constituted less than 3%. There was considerable variation in age of the animals with various subtypes, but in general, low-grade tumors tended to develop in older cats (>10 years) and high-grade tumors developed in younger cats (<6 years).
The majority of lymphomas in the cats are composed of T-cells transformed by FeLV.40-41 Lymphomas arising from the gastrointestinal tract are usually Blymphocytes and most of these test FeLV negative.25
A rare reported form of alimentary lymphoma is classified as large granular lymphoma.42,43 Large granular lymphocytes are characterized by abundant cytoplasm with prominent azurophilic granules. This population of cells includes natural killer cells and cytotoxic T-cells. These tumors commonly originate in the small intestine, especially the jejunum or mesenteric lymph nodes. All cats reported with this type of tumor have been FeLV negative. Large granular lymphocytes must be differentiated from several other granular cell types that may be found in the small intestine, including globule leukocytes, enterochromaffin cells, mast cells, and eosinophils.
The classification of leukemias in cats is difficult because of the similarity of clinical and pathological features and the transition, overlap, or -mixture of cell types involved.44-51
Leukemia is defined as a neoplastic proliferation of hematopoietic cells originating within the
Table 28-16 Anatomic Forms of Feline Lymphomas
Frequency (%) Age Average FeLV + %
20-50% 15-45% 20-40% 25-30%
5-10% < 5
80% 30% 80% 80%
3-4 years 80%
8-10 years< 10%