Canine lymphoma

What is lymphoma?

• Diverse group of neoplasms that arise from the lymphoreticular cells (T or B cells).

• Normally arise from lymphoid tissue but can arise from virtually any tissue.

• Mostly haematopoietic malignancies

What is the aetiology of lymphoma?

Multifactorial & largely unknown

• Genetic & molecular factors

• IDs

• Toxins

• Immunological factors e.g. immune mediated conditions

What is the clinical presentation of lymphoma?

• Can virtually affect any dog

  • Middle age to old incr. risk

  • Oestrogen protective effect of intact F have reduced risk

  • Breed predisp & familiar traits —> boxers, bull mastiff, dog de bordeaux

• Clinical signs depend on location

What are the anatomical classifications of lymphoma?

• Multicentric

• Craniomediastinal

• GI

• Cutaneous

• Extra-nodal forms (CNS, renal, heart, bladder)

Many presentations overlap

What is the most common form of canine lymphoma?

Multicentric lymphoma

What are the clinical signs of multicentric lymphoma?

Generalized peripheral lymphadenopathy +/- other clinical signs.

• Mod to marked LN enlargement.

• Some dogs clinically well but deteriorate quite quickly if left

• Rapid deterioration.

• Non-specific signs (weight loss, inappetence/anorexia, lethargy, pyrexia).

• More specific signs (D+, V+, cough, ocular signs).

• Regional oedema if LN drainage impaired

What are the clinical signs of cranial mediastinal lymphoma?

Can occur as solitary lesion or part of multicentric form —> normally T cell form

• Tachypnoea, dyspnoea.

• Signs of hypercalcaemia of malignancy because T-cell form (PU/PD, V+ / D+, muscle tremors, anorexia, weight loss).

• Occasionally pre-caval syndrome (regional oedema from impaired venous return due to mass)

• Altered position of point of maximum intensity (PMI) for cardiac auscultation, displacement of apex beat (more cd)

What are the clinical signs of GI (alimentary) lymphoma?

• V+, D+, weight loss, anorexia, pan-hypoproteinaemia (hypoalbuminemia), evidence of malabsorption.

• Abdominal masses or diffuse.

• Lymphadenopathy (abdominal & less commonly peripheral).

• Tends to be aggressive in dogs

What are the different forms of cutaneous lymphoma and how do they differ?

Histopathological classifications:

Epitheliotrophic

• T cell

• Solitary / generalized

Non-epitheliotrophic

• More frequently B cell

• More likely to have lesions elsewhere

How do cutaneous lymphomas present?

Different appearances.

• Progression to raised, erythematous plaques/nodules.

• Variable pruritus.

• In general poorly responsive to chemotherapy

What are the forms of extranodal lymphoma and their features?

• Hepatosplenic

  • Just liver & spleen affected

  • Aggressive, no peripheral lymphadenopathy

  • T cell

• CNS

  • Mass lesion or diffuse, variable neuro deficits but commonly signs of multicentric / diffuse lesions

  • Commonly ocular involvement

  • Generally T cell

• Renal, urinary, bladder, heart, muscle etc.

What is paraneoplastic syndrome?

Set of signs and symptoms that it is a consequence of the tumour but it is not due to the presence of tumour cells in that location.

What paraneoplastic syndromes can lymphoma cause?

• Hypercalcaemia (caused by PTHrp i.e. PTH related protein produced by tumour cells —> tells body to produce more calcium)

  • T cell (35%)

  • Mediastinal and GI forms

• Immune mediated diseases

  • IMHA, immune mediated thrombcytopenia, and Pemphigus foliaceous

• Monoclonal gammopathies

  • B-cell

• Neuropathies

• Cachexia

How is lymphoma diagnosed?

• Cytological or histopathological

  • Ancillary tests:

    • PARR (PCR) —> clonality (B cell / T cell) & phenotype

    • Flow cytometry —> cell size, phenotype & expression of aberrant markers (needs fresh samples)

    • Immunohistochem / immunocytochem

• Biomarker tests

What are some histological features of lymphoma with clinical or prognostic implications?

• Grade (low, intermediate, high)

• Immunophenotype (B cell tend to be better, T cell = terrible or null phenotype)

How can you stage lymphoma based on involvement?

extranodal forms (CNS & renal) = stage V = poorer prog

bone marrow involvement = poor prognostic indicator

What can be tested for when deciding staging on lymphoma?

• Haematology:

  • thrombocytopenia

  • neutrophilia

  • lymphocytosis

  • abnormal cells on smear

• Biochem:

  • hypercalcaemia

  • check for signs of organ dysfunction

• Aspirate / biopsy of other LNs / organs

• Thoracic rads

• Abdo U/S

• Bone marrow biopsy if suspected involvement

What are the tx options for lymphoma?

• No tx

  • Median survival time 3-6wks for asymp dogs

  • reccommend euthanasia for symptomatic

• Prednisolone alone as palliative tx

  • median response duration 1-2months

    • NB: Resistance to chemo develops —> won’t respond as well or for as long to chemo

• Gold standard is multidrug chemo

  • survival times vary depending on protocol & individual response

  • doesn’t tend to be curative because of low dose but less side effects

What chemo protocols can you use for lymphoma?

High dose COP (preferred over low dose version)

• Prednisolone, Vincristine & Cyclophosphamide

  • Haematology & urine sample prior to each tx

  • median survival time 6-9 months

Discontinuous CHOP/CEOP

• COP drug + Doxorubiciin (=CHOP) / Epirubicin (=CEOP)

  • median survival time 10-12 months

  • better response rate than COP

  • no advantage to cont. tx (stop @ 25wks)

What are the side effects of chemo?

• GI tox —> V+, D+, nausea.

• Myelosupression —> Neutropenia, thrombocytopenia & anaemia.

• Drug specific toxicities

  • sterile haemorrhagic cystitis due to Cyclophosphamide

  • cardiotoxicity due to Doxorubicin & Epirubicin

  • hepatotox due to lomustine —> monitor ALT & liver protectors

How is sterile haemorrhagic cystitis due to cyclophosamide managed?

Give furosemide to encourage urination

When may local txs be useful in lymphoma?

(Rarely indicated)

Radiation

• Stage I dx

• Palliation of local dx

• Mass lesion on CNS

Surgery

• Considered for rare Hodgkin's lymphoma & poss extranodal and early stage I

(^^^ Adjuvants of chemo, not substitutes)

What consideration do we need to make about drugs for CNS lymphoma? Which can we use?

Many drugs do not penetrate the BBB

Can use:

• Cytarabine

• Lomustine (CCNU)

• Steroids

• L-asparaginase

How is epitheliotrophic lymphoma treated?

• COP or lomustine + prednisolone

  • No proven extension of lifespan, maybe improvement of quality of life

• Retinoids (for control of clin signs such as pruritis) —> improve quality of life

• Radiation therapy useful for localised mucocutaneous dx

How do you assess the response of lymphoma to treatment?

• Palpation of LNs / other lesions prior to every tx.

• Resolution of clinical signs.

• Repeating imaging (restaging) for internal lesions.

• Monitoring blood parameters (Ca, ALT etc.)

Achieving a complete response @ end of discontinuous protocol is good prognostic indicator (if do not achieved —> suggests resistant population of tumour cells → will rapidly become dom population )

Give some examples of rescue protocols (for dogs that have stopped responding to a current protocol) that can be used with lymphoma?

• DMAC (Dexamethasone, Melphalan, Actinomycin-D, Citarabine)

• LPP (Lomustine, procarbazine, prednisolone)

• Single agent anthracyclines i.e. doxorubicin / epirubicin (if not already used)

short-lived resonses but occassional long term survivors

What is the average relapse time of a complete response patient?

4 months

• (follow up monthly for at least first 6 months, then every 2-3 months)

When would you restage a lymphoma?

• When there are no sentinel LNs to follow.

• When patient not doing as well as expected or all clinical signs do not resolve.

• @ end of induction phase.

• @ end of a discontinuous protocol