Lymphoma (Malignant lymphoma, Lymphosarcoma, LSA)

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• Cats have a higher incidence of lymphoma than dogs (20-30% of all tumors in cats).
• Lymphoid neoplasia accounts for an incidence of 200 per 100,000 cats at risk and is 90% of all feline hemopoietic neoplasms.
• Lymphoma can originate in any organ or tissue containing lymphocytes:
  • Alimentary .
  • Multicentric.
  • Mediastinal .
  • CNS/Spinal .
  • Renal .
  • Other:
    • Nasal .
    • Cutaneous .
    • Ocular.
• Cause : Some forms associated with FeLV infection (only 25% of cases in a recent report).
• Signs: Depend on form, eg malaise, weight loss, respiratory distress, vomiting, diarrhea.
• Diagnosis: Cytology, histopathology.
• Treatment: Cytotoxic drugs, surgery if alimentary and obstructed; radiation therapy for nasal, surgery for ocular.
• Prognosis: Poor if no treatment.

• Dyspnea/cough/regurgitation (mediastinal lymphoma).
• Vomiting/diarrhea (alimentary lymphoma).

• Lymphadenopathy.
• Hepatosplenomegaly (multicentric lymphoma).

• Respiratory distress due to pleural effusion (mediastinal lymphoma).
• Intestinal obstruction (alimentary lymphoma).

• Young (2-3 years, FeLV positive cats or >4 months, mediastinal form).

• Older animals (mean 7-8 years for FeLV negative animals and gastrointestinal form).

• Siamese may be predisposed, particularly mediastinal form.

• Cytotoxic agents and need for close monitoring with regular CBCs.

• Related to FeLV infection .
• Possible development of alimentary (intestinal) lymphoma in cats with lymphocytic enteritis .
• Recent reports suggest that FIV infection may be implicated in some forms.

• FeLV for some forms (not alimentary)
  • Mediastinal 80% FeLV positive.
  • Alimentary <30% FeLV positive.
  • Multicentric 80% FeLV positive.
  • CNS 80% FeLV positive.
  • Cutaneous <10% FeLV positive.
  • Renal 50% FeLV positive.
  • Often occurs in households of FeLV infected cats.

• Relative incidence of different forms varies with geographical region (and therefore depends on study):
  • Alimentary: 30-50% Scotland (but 15% in New York).
  • Mediastinal: 25-38% England (but 18% Scotland).
  • Multicentric: 20-44%.
  • Renal: .
  • Spinal : rare (but most common spinal neoplasm in cat).

• Malignant proliferation of lymphoid cells arising in any area containing lymphoid tissue focal or diffuse masses in intestine, skin, thymus or lymph nodes progresses to extranodal sites, eg liver, spleen, bone marrow.
• Stage 1:
  • Single tumor.
• Stage 2:
  • Single tumor and regional lymph node involvement.
  • Two single tumors on same side of diaphragm.
  • Resectable gastrointestinal lesion.
• Stage 3:
  • Two single tumors on opposite sides of diaphragm.
  • Inoperable intra-abdominal mass.
  • Spinal neoplasia.
• Stage 4:
  • Stage 1-3 plus liver/spleen involvement.
• Stage 5:
  • Stage 2-4 plus CNS or bone marrow involvement (leukemic).

• Rapidly fatal (6-8 weeks) without treatment in most cases.
• Months (nasal, cutaneous forms).

• Lethargy
• Polyuria/polydipsia.
• Dyspnea.
• Vomiting .
• Diarrhea.

• Anorexia.
• Vomiting/diarrhea.
• Weight loss.

• Anorexia.
• Depression.
• Gross lymphadenopathy.
• Weight loss.

Mediastinal

• Anorexia.
• Weight loss.
• Regurgitation.
• Respiratory distress.

• May be asymptomatic apart from lymphadenopathy.

• Posterior paresis (spinal).
• Ocular signs (ocular).

• Pallor of mucous membranes.
• Pleural effusion or incompressible ribcage (mediastinal).
• Palpable abdominal mass or thickened "ropey" small intestines (alimentary).
• Bilateral (occasionally unilateral) renomegaly (renal).
• Neurological deficits (spinal).
• Nasal discharge or unilateral nasal obstruction (nasal).
• In mediastinal form, tumor may be palpated in ventral neck region.

• Gross enlargement of one or more lymph nodes (multicentric).

• Hepatosplenomegaly.

• Lymph node: Fine-needle aspirate is cheap, quick, simple.
• Monomorphic population of large neoplastic lymphoblasts with prominent and multiple nucleoli .
• Lymph node biopsy more accurate in some cases.
   Excisional biopsy recommended because wedge/ Tru-Cut biopsies may be extremely misleading.
• Can also biopsy/aspirate any mass identified or intestine in intestinal disease.
• Demonstration of malignant lymphoid cells by the cytological or histological examination of affected tissues.

Hematology

• Essential as some cats may become anemic particularly in multicentric form to detect bone marrow involvement (leukemia ).
• Approximately 25% of cats with lymphoma will have leukemic blood picture and many animals become leukemic terminally.
• May see circulating lymphoblasts .
   Provides values for assessing possible cytopenic effects of therapeutic drugs.

Biochemistry

• Monitor indicators of renal although often normal in renal lymphoma.
• Also check hepatic involvement .
• Rarely gammopathies have been reported.
• Hypercalcemia (very rare) .

Radiography

• Mediastinal: Large anterior mediastinal mass or masses elevating trachea and often displacing cardiac silhouette .
• Masses may also be present in posterior mediastinum.
• Pleural effusion may be present concurrently and obscure mediastinal masses .
• Intestinal mass (alimentary).
• Enlargement of intra-abdominal lymph nodes .
• Opacification of nasal chamber (nasal) .

Contrast radiography

• Barium meal may be necessary to show intestinal involvement .

• Bone marrow aspirate indicated if hematological abnormalities identified or if suspect spinal lymphoma (~70% have bone marrow infiltration).

• May show enlarged mediastinal or abdominal lymph nodes or thickened GI loops.
• Diffuse hepatic or splenic infiltration will show as mixed echogenicity.
• Useful guide for fine-needle aspiration.

• Radiography.

• Histopathology.

• Gross lymphadenopathy involving one or more nodes.
• +/- hepatosplenomegaly with pale yellow discoloration.
• Infiltration may be nodular or diffuse.

Mediastinal form

• Pale mediastinal mass surrounding pericardium, base of heart, trachea.
• May infiltrate into thoracic muscle.
• +/- amber or chylous pleural effusion.

Alimentary form

• Discrete mass or diffuse intestinal thickening.
• Often segmental thickening of jejunum/ileum with thickening of intestinal wall and dilated lumen .
• Local lymph node enlargement.
• Ulceration of mucosa.

Renal

• Nodular or diffuse infiltration mainly affecting cortex .
• Changes may be subtle so always compare with contralateral kidney , although disease usually bilateral.

• Variable sized lymphocytes or lymphoblasts infiltrating or replacing normal tissue.

• Traditionally classified according to the Rappaport scheme:
  • Lymphocytic, well differentiated.
  • Lymphocytic, poorly differentiated.
  • Histiocytic, undifferentiated.
  • Mixed (lymphocytic).

• Gastrointestinal obstruction .
• Malabsorption .
• Inflammatory bowel disease .

Mediastinal form

• Causes of dyspnea.
• Pleural effusion .

• Leukemia .
• Generalized peripheral lymphadenopathy.

• Different regimes documented - cyclophosphamide, vincristine and prednisolone often employed.
• Induction protocol for 8 weeks:
  All Of Cyclophosphamide (300 mg/m2 PO every 3 weeks) - best given early morning.
  And Vincristine (0.75 mg/m2 IV every 7 days for 4 weeks then every 3 weeks).
   Use catheter to avoid perivascular irritation.
  And Prednisolone (2 mg/kg PO daily).
• Alternative protocol to be given for 6-8 weeks until in remission and then on alternate weeks
  All Of Cyclophosphamide 300 mg/m2 PO every 14 days.
  And Vincristine 0.5-0.75 mg/m2 IV every week.
  And Prednisolone 40 mg/m2 daily for 1 week then 20 mg/m2 every other day.
  And Protocols that include doxorubicin have increased remission rates and survival times.

Surgery

• Excize discrete alimentary mass if obstructed, followed by chemotherapy.

• Corticosteroids : use alone useful short-term regression if chemotherapy not appropriate.
   If hoping to initiate chemotherapeutic protocol at later date, significantly lower response rates and survival times if corticosteroids used previously.

• Hematology with every chemotherapy treatment - then as necessary: to monitor cytopenic effects of drugs (reduce dose of cyclophosphamide and give prophylactic antibiotics if neutrophil count < 1000 cells/ml).
• Cyclophosphamide may cause myelosuppression 7 days after dose - (rarely causes sterile hemorrhagic cystitis).
• Vincristine may cause anorexia and vomiting - if so delay subsequent dose by 7 days and reduce dose to 0.5 mg/m2 .

Radiotherapy

• See radiotherapy for more details.
• Lymphomas are very radiosensitive and this treatment can achieve temporary remission in localized cases, eg nasal.
• Mediastinal form, where severe respiratory distress requires fast induction of remission.

• If disease in full remission: continue induction protocol treatment but on alternate week basis for further 4 months.Then 1 week in 3. Then 1 week in 4.
• Switch to doxorubicin for maintenance.

Rescue protocol

• Majority of cases relapse due to drug resistance development by tumor - rescue treatment includes:
• Change treatment entirely - probably most effective option is doxorubicin (1 mg/kg or 20 mg/m2  IV every 3 weeks).
• Side-effects include anorexia and myelosuppression at 7-10 days (if develops reduce dose of doxorubicin to 1 mg/kg.
• Cardiomyopathy is much less likely to develop than in dogs.
   Has been reported to cause renal failure therefore check function.
• Severe slough if perivascular administration.

• Blood cell counts.
• Renal function.
• For presence of infection and start antibiotics if neutropenia develops.

• Complete remission achieved in 50-75% cases.
• Median survival time 5-7 months with approximately 25-30% survival at 1 year.
• Affected by :
• FeLV status :
  • FeLV positive median survival 4.2 months.
  • FeLV negative median survival 9.1 months.
• Stage:
  • Stage 1-2 median survival 7.6 months.
  • Stage 3 median survival 3.2 months.
  • Stage 4-5 median survival 2.6 months.
   Cats with stage 1-2 disease and FeLV negative have best prognosis (median survival 17 months).
   Most cats with alimentary form respond poorly to chemotherapy. One third respond with a median survival of 1 year.

• Clinical remission:
  • a) Apparent disappearance of tumor is termed complete response. Affected by stage of tumor.
  • b) Partial response is a reduction in the tumor of 50% or more. May occur within days of therapy initiated - relapse usually occurs within months.

• Drug resistance of neoplastic cells.
• Cytotoxic side-effects and secondary infections.
• Blastic crisis.

• Louwerens M, London C A, Pedersen N C & Lyons L A (2005) Feline lymphoma in the post-feline leukemia virus era. J Vet Intern Med 19, 329-335  PubMed. 
• Brown M R, Rogers K S, Mansell K J, Barton C (2003) Primary intratracheal lymphosarcoma in four cats. J Am Anim Hosp Assoc. 39(5), 468-472. PubMed
• Teske E et al (2002) Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol. JVIM 16 (2), 179-186. 
• Kristal O, Lana S E et al (2000) Single agent chemotherapy with doxorubicin for feline lymphoma - a retrospective study of 19 cases (1994-1997). JVIM 15, 125-130.
• Parnell N K et al (1999) Hypoadrenocorticism as the primary manifestation of lymphoma in two cats. JAVMA 214 (8), 1208-1211, 1200.
• Gabor L J, Malik R, Canfield P J (1998) Clinical and anatomical features of lymphosarcoma in 118 cats. Aust Vet J 76 (11), 725-732.
• Court E A, Watson A D & Peaston A E (1997) Retrospective study of 60 cases of feline lymphosarcoma. Aust Vet J 75, 424-427.
• Maleo K A (1997) The role of radiotherapy in the treatment of lymphoma and thymoma. Vet Clinics NA SAP. 27, 115-129.
• Moore A S, Cotter S M, Frimberger A E, Wood C A, Rand W M and L'Heureux D A (1996). A comparison of doxorubicin and COP for maintenance of remisssion in cats with lymphoma. JVIM. 10, 372-375.
• Mahoney D M, Moore A S, Cotter S M, Engler S J, Brown D & Penninck D G (1995). Alimentary lymphoma in cats 28 cases (1988-1993). JAVMA 207, 1593-1598.
• Mooney S, Hayes A, Matus R et al (1987) Renal lymphoma in cats 28 cases (1977-1984). JAVMA 191, 1473-1477.
• Mooney S, Hayes A, McEwan E et al (1989) Treatment and prognostic factors in lymphoma in cats 103 cases (1977-1981). JAVMA. 194, 696-700.

• Laura Garrett DVM DipACVIM, School of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506-5606, USA.
• Irene Rochlitz BVSc MSc PhD MRCVS, Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.

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