Lymphoma

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Mesenteric lymphoma in a 13-year-old domestic longhair which presented with acute inappetance and vomiting. Post-mortem revealed a large central mesenteric mass. The kidneys were small, irregular-shaped and the liver shrunken and fibrotic. Courtesy Dr Jim Euclid
Ventral view of the brain of the 10-year-old domestic shorthair. It shows the marked enlargement of both trigeminal nerves, which was caused by an infiltrating lymphoma. Courtesy of Prof A. de Lahunta
Radiograph of a pulmonary lymphoma in a cat
Radiograph from a cat with mediastinal lymphosarcoma. Note the mass effect in the cranial mediastinum and the associated thoracic effusion
Postmortem examination of above cat with lymphoma affecting kidneys.
Fine needle aspirate from a cat with generalized peripheral lymphadenopathy due to lymph node hyperplasia that can be confused with lymphoma
Fine needle aspirate from a cat with alimentary lymphoma. Small arrow denotes a small mitotic figure and large arrow a small lymphocyte
Fine needle aspirate from a cat with large granular lymphoma

Lymphoma is the most commonly diagnosed neoplasm in cats and accounts for approximately 30% of all diagnosed tumors[1][2][3][4].

Feline lymphoma is a loose generic term for any feline tumour affecting lymph cells or lymph nodes[5].

Lymphomas are irregular (neoplastic) growth of lymphoid tissue as tumors, which can affect a single organ (e.g. kidney, mesenteric or mediastinal lymph node, spleen or liver). Whereas lymphoma have been classically defined as neoplastic cells found in fluid exudates (such as ascitic fluid), lymphosarcoma usually refers to solid tumours within organs, but such classification is academic and from a clinical perspective. However, since treatment regimens are pragmatically identical, we have adopted the generic term lymphoma to refer to any neoplastic change of lymphocytes that does not involve leukemia.

Lymphomas may occur within a lymph node (nodal) or outside lymph node tissue (extra-nodal) and are classified as either B-cell lymphoma or T-cell lymphoma. Regardless of classification, feline lymphoma invariably receive the same veterinary treatment[6].

Feline lymphomas differ from canine lymphomas. Most canine lymphomas are composed of large lymphocytes, with only a low incidence of well-differentiated small cell lymphomas[7]. Feline lymphoma is most often an intermediate or large cell type, but small cell lymphomas are much more common in cats than in dogs. Small cell lymphomas are often seen in older cats, most commonly in the alimentary tract or liver, whereas large cell lymphomas are seen more frequently in younger cats (<6 years of age). Feline lymphoma is often more challenging to diagnose than canine lymphoma because small cell lymphomas are difficult to differentiate cy­tologically from a lymphoid inflammatory in­filtrate or reactive hyperplasia. Definitive diagnosis of small cell lymphoma often requires histopathology, and the practicing cytologist must be aware of the cytologic appearance of feline lymphoma to accurately interpret cytologic findings and determine the necessity of surgical biopsy[8].

Classifications of feline lymphoma

The classifications of feline lymphoma are loosely based on anatomical site involvement.

Causes

  • Inflammatory processes - no definitive proof exists as yet to conclude that chronic inflammation leads to formation of feline lymphoma, but inflammation-associated neoplasia is well-established[12]. An association between chronic inflammatory bowel disease and development of feline T-cell lymphoma has been suggested[13]. Concurrent lymphocytic-plasmacytic IBD has been identified in other regions of the alimentary tract in up to 20% of cats with LGAL[14].
  • Environmental - a variety of chemicals such as aromatic benzenes, organophosphates and dioxins (DDT and 2,4,5-T) are implicated in human lymphoma[15], and cannot be excluded as possible causes of feline lymphoma.
  • Nutritional - the proven relationship between nutrition and neoplasia in humans suggests a plausible link between nutrition and lymphoma in cats, although more work is needed in this area[16][17].
  • Bacterial - Spirochetes have been observed in a feline epitheliotropic T- cell gastrointestinal tract lymphoma and a natural killer-like T cell lymphoma. There were Helicobacter spp-like organisms and Spirochetes in a cougar affected with gastroduodenal adenocarcinoma and rectal adenoma[18]. Unlike in human lymphomas associated with Helicobacter pylori or Borrelia burgdorferi, the etiologic significance of spiral-shaped bacteria is not clear in feline lymphoid neoplasms. Records of bacteria belonging to the genus Helicobacter, such as Flexispira suggests a possible synergistic role of bacteria in the etiopathogenesis of feline lymphoma.
  • Genetic - breed predisposition (e.g. Maine coon) and familial susceptibility have been implicated anecdotally but no evidence to prove such hypotheses has surfaced.
  • Viral
- in some cases, FeLV-associated lymphoma follows infection with the feline leukemia virus (FeLV). FeLV has a strong association with development of mediastinal and muticentric lymphoma in cats (60 fold increased risk)[19].
- FIV also increases the risk of lymphoma formation in cats, but less so, compared with FeLV (5 fold increased risk)[20][21][22][23]. An indirect role is favoured for FIV in the development of extranodal B-cell neoplasms in cats[24]. Possible effects of the FIV infection that can lead to lymphosarcoma include activation of ß lymphocytes with the eventual emergence of malignant cells from the proliferating ß-cell pool, chronic dysregulation of the immune system, or activation of oncogene pathways that facilitate the malignant transformation of normal cells.

Clinical signs

The most common clinical signs are weight loss, inappetence, vomiting and/ or diarrhea, lethargy, and polyphagia. Vomiting and/or diarrhea are considered common signs and 20% of all cats biopsied with chronic intermittent vomiting and diarrhoea have been shown to caused by diffuse intestinal lymphoma[25]. Abdominal palpation is usually abnormal, with nodules and tumors often palpable in mesenteric lymph nodes. Regional lymph nodes may also be involved, including mandibular, popliteal and superficial cervical (prescapular) nodes. The most common ultrasonographic finding are increased intestinal wall thickness with preservation of layering.

Feline lymphoma has several different forms. In all forms, the tumors consist of abnormal proliferations of lymphoid tissue. Because lymphocytes and lymph tissue are found throughout the body, lymphoma can appear almost anywhere and affect a wide number of organs. Lymphoma more commonly appears, though, in three parts of the body. The location is often associated with the cause of the lymphoma and influences the clinical signs, treatment, and prognosis.

In all forms, the treatment outcome is more guarded if the cat is positive for Feline leukemia virus (FeLV).

Diagnosis

Diagnosis of lymphoma in cats is based on a series of observations and tests. A physical exam may revealing swellings in the lymph nodes or GI tract. Radiographs, ultrasounds or physical examinations may show tumors or swellings in other internal organs.Testing for FeLV and FIV may reveal that a cat is positive for one of these diseases, which increases the likelihood that she could develop feline lymphoma. A chemistry panel and complete blood count (CBC) may reveal particular organ involvement or an anemia, particularly in the multicentric form or in the FeLV positive cat. Fine needle aspirate or biopsies are often diagnostic for feline lymphoma. When a trained pathologist examines a fine needle aspirate or a biopsy, he or she is looking for a uniform population of immature lymphoid cells, which confirms feline lymphoma.

Hematological changes include mild anaemia, monocytosis and/or neutrophilic leucocytosis (Lingard, et al, 2009). Hypoalbuminaemia appears to be a relatively constant sign, depending primarily on the grade of lymphoma, with high-grade cases showing greater extents of hypoalbuminaemia[26].

Other causes of gastrointestinal disease with signs of vomiting, weight loss and/or diarrhoea include irritable bowel disease, gastritis, FIP, bacterial gastroenteritis, parasites, and obstructive causes (e.g. pyloric stenosis, foreign body, Intussusception, intestinal polyps.

Differential diagnoses of non-lymphoma neoplasia associated with lymphoid tissues include Feline Hodgkin's-like disease, B-cell lymphoma, Follicular lymphoma, and DPLH - distinctive peripheral lymph node hyperplasia


Table. 1. Histological classification of lymphoproliferative diseases in cats[27]


Low grade Chronic lymphocytic leukemia CLL
Small lymphocytic lymphoma SLL
Small lymphocytic intermediate lymphoma SLLI
Small lymphocytic plasmacytoid/plasmacytoma SLLP
Follicular small cleaved-cell lymphoma FSC
Follicular mixed-cell lymphoma FM
Intermediate grade Follicular large-cell lymphoma FL
Small cleaved-cell lymphoma SCC
Mixed-cell lymphoma MC
Large-cell lymphoma LC
Large cleaved-cell lymphoma LCC
High grade Acute lymphocytic leukemia ALL
Immunoblastic lymphoma IB
Immunoblastic small-cell lymphoma IBS
Immunoblastic polymorphous lymphoma IBP
Small noncleaved-cell lymphoma SNC
Lymphoblastic lymphoma LB
Lymphoblastic convoluted-cell lymphoma LBC

Treatment

The remission and survival rates of cats with lymphoma vary depending on the cat's FeLV status, the location of the tumor(s) and how quickly the tumor is diagnosed and treated. In general, about 70% of cats will respond to the chemotherapy treatment. On average, these cats will live an additional 4 to 16 months. However, about 30% - 40% of the cats that respond will go into a more complete remission that can last for 2 years or longer. This potential response is encouraging and is the reason that treatment for lymphoma in cats is so highly recommended. Cats that are not treated have an average survival time of only 4 to 6 weeks once the diagnosis has been made. Cats that are infected with FeLV or FIV have a lower rate of response to therapy as well as a shorter average survival time when treated[28].


Table 2. The University of Pennsylvania feline weekly sequential lymphoma protocol (2009)


Treatment week Drug, dosage and route
1 L-asparaginase (Leunase) 400 IU/kg SQ weekly
2 Chlorambucil (Leukeran) 0.5 mg/m2, IV
3 Cyclophosphamide 50mg PO (25mg PO day 1 and 25mg PO on day 3)
4 Vincristine 0.5mg/m2, IV
5 Methotrexate 2.5 mg PO
6-9 Repeat week 2-5

References

  1. Ettinger SN (2003) Principles of treatment for feline lymphoma. Clin Tech Small Anim Pract 18(2):98-102
  2. Carreras JK, Goldschmidt M, Lamb M, et al (2003) Feline epitheliotropic intestinal malignant lymphoma: 10 cases (1997-2000). J Vet Intern Med 17(3):326-331
  3. Vail DM, Moore AS, Ogilvie GK, et al (1998) Feline lymphoma (145 cases): Proliferation indices, cluster of differentiation 3 immunoreactivity, and their association with prognosis in 90 cats. J Vet Intern Med 12(5):349-354
  4. Podell M, DiBartola SP, Rosol TJ (1992) Polycystic kidney disease and renal lymphoma in a cat. JAVMA 201(6):906-909
  5. Mooney SC, Patnaik AK, Hayes AA, MacEwen EG (1987) Generalized lymphadenopathy resembling lymphoma in cats: six cases (1972–1976). J Am Vet Med Assoc 190:897-900
  6. August, J.R. (2006). Consultations in feline internal medicine. Elsevier Saunders, Missouri
  7. Dhaliwal RS, Kitchell BE, Messick JB (2003) Canine lymphosarcoma: Clinical features. Compend Contin Educ Pract Vet 25(8):572-581
  8. Cowell RL, Dorsey KE, Meinkoth JH (2003) Lymph node cytology. Vet Clin North Am Small Anim Pract '33:47-67
  9. Steele KE, Saunders GK, Coleman GD (1997) T-cell-rich B-cell lymphoma in a cat. Vet Pathol 34:47-49
  10. Lingard AE, Briscoe K, Beatty JA, et al (2009) Low-grade alimentary lymphoma: clinicopathological findings and response to treatment in 17 cases. J Feline Med Surg 11: 692-700
  11. Brockley LK et al (2012) Polyostotic lymphoma with multiple pathological fractures in a six-month-old cat. J Feline Med Surg 14(4):285-291
  12. Schafer, M & Werner, S (2008) Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 9:628
  13. Valli, VE ((2007) Enteropathy-type T-cell lymphoma. In Valli, VE (Ed): Veterinary comparative haematopathology. Blackwell Publishing, Oxford. pp:318
  14. Lingard, AE et al (2009) Low-grade alimentary lymphoma: clinicopathological findings and response to treatment in 17 cases. JFMS 11(8):692-700
  15. Lymphomainfo.net
  16. Grace PB, Taylor JI, Low Y, Luben RN, Mulligan AA, Botting NP, et al (2004) Phytoestrogen concentrations in serum and spot urine as biomarkers for dietary phytoestrogen intake and their relation to breast cancer risk in European prospective investigation of cancer and nutrition — Norfolk. Cancer Epidemiol Biomarkers and Prev 13:698-708
  17. Setchell KD, Briwb NM, Lydeking-Olsen E (2002) The clinical importance of the metabolite equol: a clue to the effectiveness of soy and its isoflavones. J Nutr 132:3577-3584
  18. Ezura, K et al (2007) Immunoblastic lymphoma of germinal center origin in a cat. Can Vet J 48(2):211–213
  19. Shelton, GH et al (1990) Feline immunodeficiency virus and feline leukaemia virus infections and their relationships to lymphoid malignancies in cats: a retrospective study (1968-1988). J Acquir Immune Defic Syndr 3623
  20. Podell M, DiBartola SP, Rosol TJ (1992) Polycystic kidney disease and renal lymphoma in a cat. JAVMA 201(6):906-909
  21. Hutson CA, Rideout BA, Pedersen NC (1991) Neoplasia associated with feline immunodeficiency virus infection in cats of southern California. JAVMA 199(10):1357-1362
  22. Poli A, Abramo F, Baldinotti F, et al (1994) Malignant lymphoma associated with experimentally induced feline immunodeficiency virus infection. J Comp Pathol 110(4):319-328
  23. Gabor LJ, Love DN, Malik R, et al (2001) Feline immunodeficiency virus status of Australian cats with lymphosarcoma. Aust Vet J 79(8):540-545
  24. Beatty, JA et al (1998) Feline immunodeficiency virus (FIV)-associated lymphoma: apotential role for immune dysfunction in tumorigenesis. Vet Immunol Immunopathol 65:309
  25. Kleinschmidt S, et al (2010) Chronic inflammatory and non-inflammatory diseases of the gastrointestinal tract in cats: diagnostic advantages of full-thickness intestinal and extraintestinal biopsies. J Feline Med Surg 12:97
  26. Gabor, LJ, Malik, R & Canfield, PJ (1998) Clinical and anatomical features of lymphosarcoma in 118 cats. Aust Vet J 76:725
  27. Barrs, VR & Beatty, JA (2010) In August, JR (Ed): COnsultations in feline internal medicine. Vol 6. Elsevier Saunders, Philadelphia. pp: 187
  28. Day MJ, Kyaw-Tanner M, Silkstone MA, Lucke VM, Robinson WF (1999) T-cell-rich B-cell lymphoma in the cat. J Comp Pathol 120:155-167
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