Small Animal Oncology- Feline Lymphoma

What type of tumour is feline lymphoma?

Malignant

Feline Lymphoma

Lymphoma is a lymphoid malignancy

• originates from solid organs e.g. lymph nodes, liver and spleen

Lymphoma most commonly diagnosed neoplasm in cats

• ~30% of all feline tumours

Origin of lymphocytes

Pluripotent stem cell divides into more specialised progenitor cells that give rise to lymphoid, myeloid and erythroid linages

Lymphoid linage

Lymphoid progenitors → B cells, T cells and NK cells

Activation (by infection) B cells → plasma cells and T wells → effector cells

Lymphocytes- origin

Lymphoid cells are predominantly found in lymphoid tissues

• primary (sites of T and B cell maturation): bone marrow and thymus

• secondary (sites where mature lymphocytes can be stimulated to respond to pathogens): e.g. lymph nodes, spleen and mucosal surface or respiratory, gastrointestinal and urogenital tract

Types of Lymphocytes

Natural Killer (NK) cells

B lymphocytes (B cells)

T lymphocytes (T cells)

Function of NK cells

Kill virus-infected cells and secrete cytokines to inhibit viral replication

Part of innate immune response

Function of B cells

Express cell surface immunoglobulins

Can be activated to become plasma cells- secrete immunoglobulins

Part of the adaptive immune response

Function of T cells

Express cell surface T cell receptors

Part of the adaptive immune response

Subdivided into 2 types of cytotoxic T cells (kill infected cells) and B cells (secrete cytokines)

Feline Lymphoma

Recent shift in presence and signalment in the developed world due to FeLV vaccination

Biomodal age of presentation

• 2 peaks, the first at ~2 years old (often FeLV positive) and the second 10-12 years old (FeLV negative)

Interaction between Lymphoma and FeLV?

FeLV (feline leukaemia virus) infection increases the risk of lymphoma 60-fold

What is FeLV?

FeLV is a gammaretrovirus that infects Felidae

FeLV transmission

Transmission is via prolonged intimate contact such as biting, licking, grooming and shared bowls

Types of FeLV infection

Progressive infection

Latent infection

Regressive infection

FeLV progressive infection

1/3 develop progressive infections

High viral loads

Excrete virus in saliva

Succumb to FeLV related disorders

• anaemia, immunosuppression

FeLV latent infection

Viral antigens detectable

Can become progressive or regressive

FeLV Regressive infection

Neutralising antibodies

Pose minimal transmission risk

1-10% of infected cats

Reactivation possible

What tissue does FeLV target?

• lymphoid tissue

• intestine

• bone marrow

What type is FeLV?

Single-stranded RNA genome

Provirus- DNA copy of genome integrated into the host genome

Provirus template for new iron production

FeLV- Cellular transformation

LTRs

• flank the viral genes

• contain promotor and enhancer

• control viral gene transcription

Oncogenes

Most cellular proto-oncogenes are normal components of growth factor signalling pathways

But… increased activity leads to increased cell growth

This can occur due to mutations in cellular proto oncogene (cellular oncogene- c-onc)

Viral transduction can result in overproduction of protein homologous to cellular oncogene (v-onc)

Viral insertion can also up regulate production of a cellular oncogene

FeLV- cellular transformation

Interplay between viral variants and cellular genes

Gained survival advantage- step towards transformation

Insertational Activation

Transduction 1

Infection of a new cell by virus which already carries a transducer cellular oncogene

Transduction 2

Infection of a new cell by a recombinant retrovirus carrying a transduced cellular onc gene (v-onc)

Insertion vs transduction

Insertion

• virus is replication competent

• process of oncogenesis slower

• main mechanism of oncogenesis for feline leukaemia

Transduction

• in most cases acquiring a cellular oncogene results in loss of essential retroviral genes- therefore virus is “defective” and requires “help” in order to replicate

• such defective viruses are generally not transmitted to a new host - i.e. they arise de novo in each infection

Mechanisms of retroviral oncogenesis

1. Oncogene capture and transduction

2. Insertional activation

3. Insertion leading to truncation

4. Insertion leading to gene inactivation

5. Other mechanisms

• viral proteins can disregulate normal cellular metabolism and lead to tumour formation

Impact of the FeLV Vaccine

Introduction of FeLV vaccine

• decline if FeLV infection incidence

• increased incidence of feline lymphoma

Increased incidence of gastrointestinal lymphoma

Change in age of presentation

• previously underreported

• other factors

FeLV diagnosis

History

• anorexia, weight loss, lethargy, polyuria/ polydipsia

Clinical exam

Viral status

Cytological/ histological

Blood counts/ bone marrow aspirates

Common complications of lymphoma

Anaemia

Thrombocytopenia (platelet deficiency)

White blood cell abnormalities

Hypergammaglobulinaemia

Cytology

Presence of lymphoid cells (50-100% of nucleated cells)

Cell size and mitotic activity

Staging

Offers little prognostic information for an individual but is a way or recording the disease

Prognostic factors

No markers that predict lymphoma occurrence or recurrence in cats

Factors indicating a favourable prognosis in cats:

• Early presentation

• Complete initial response to treatment

• Clinically well patient (substage a)

Treatment modalities

Lymphoma is a systemic disease

Chemotherapy

Surgery and radiotherapy can be considered in some cases

Chemotherapy multi-modal vs single agent

COP

• Cyclophosphamide (alkylating agent)

• Vincristine (vinca alkaloid)

• Prednsiolone (corticosteriod)

CHOP

• plus doxorubicin (anthracycline)

Single agent

• Doxorubicin

Advantages of chemotherapy

Treats systemic disease (radiation and surgery can be used in absence of systemic disease)

Cats suffer with less side effects (gastrointestinal toxicity)

Disadvantage of chemotherapy

Cats are less responsive than dogs and other species

Multi-drug resistance (failure at first treatment and failure of subsequent treatments)