Haemolymphatic Oncology 2: Feline Lymphoma Myeloma ; Leukaemia in Cats and Dogs

Understand the common clinical presentations of cats with lymphoma, and differential diagnoses • Describe the diagnosis and staging of feline lymphoma • Understand and distinguish between treatment options for lymphoma • Understand the potential toxicities of treatment • Understand the clinical presentations of dogs and cats with leukaemia • Describe the diagnosis of leukaemia, and where treatment is possible

feline lymphoma:

• prevalance in cat tumour? is it common?

• age at presentation?

• breed predispose? wb anatomical preference

• any other environmental factor increasing risk?

• 25% of feline tumours

• Age varies with anatomical site

• No breed incidence

  • Cranial mediastinal in oriental breeds and feLV

• environmental tobacco smoke exposure

what are the anatomical forms of feline lymphoma

• alimentary

• renal

• CNS

• nasal

• mediastinal

• extraodal

• multicentric

Role of FeLV in feline lymphoma

• exposure but recovered: 5x increased risk

• persistent infection: 50-62x increased risk

• FeLV and FIV positive: 80X increased risk

• FIV positive: 5x increased risk

FeLV/FIV often associateed with cranial mediastinal tumour

• FeLV infection reduced in UK

  • shift to older cats

  • increased alimentary, reduced cranial mediastinal

Feline Lymphoma anatomic location: Multicentric

• is multicentric common in cats? are the lymphadenopathy symmetrical or not?

• age?

• in what situation would thei mass self resolve? what breed predispose?

• multicentric lymphoma + ymmetrical generalised lymphadenopathy rare in cats

  • Regional lymphadenopathy more common

• any age

• generalised lymphadenopathies mimicing lymphoma

  • Young cats, non-neoplastic origin, generally self-resolve

  • BSH in New Zealand

clinical signs of multicentric feline lymphoma

• name 1 identical to dog

• name 5 that is cat specific. give them a group name

• Non-painful lymph node enlargement

can be systemicallly unwell

• Hyporexia • Depression • Non-specific malaise • Pyrexia • (PU/PD)

genereal lymphanopathy is an important clinical sign. name ddx other than lymphoma (5)

• Retroviral, viral, bacterial, fungal, mycobacterial and (protozoal), infections

• Other haemopoietic malignancies

• Immune-mediated disease

• Idiopathic lympahdenopathy

• Metastatic disease (also for locoregional LN enlargement)

feline mass at Submandibular or Cervical: it could be lymphoma. what are the

1. clinical presentations?

2. give neoplasia ddx

3. what other structure can be involved

1. can be solitary or miltiple submandibular/ cervical swelling

2. • Lymphoma: High grade or Hodgkin’s like disease (more indolent)

   • metastatic disease

3. salivary gland, thyroid, vocal cord etc.

Submandibular or Cervical mass: other ddx

• Abscesses

• Reactive nodes

• Mycobacterial infection

• Salivary gland, thyroid and other masses

Feline Lymphoma: Cranial Mediastinal

• young/ old common?

• breed predisposition

• clinical presentation 5

• what may you notice at a physical exam? 2

• what other structures are at the site

Younger cats, oriental breed

• Respiratory distress

• Regurgitation/ dysphagia (due to mass compression)

• Weight loss

• Lethargy, exercise intolerance

  • Cough (rare)

physcial exam

• Palpable reduction in compressibility of chest

• Displaced apex beat— caudally

thymus!

non- neoplastic, Cranial Mediastinum mass in a cat.

• list common differentiatls 3

• list Other causes of pleural effusion 3/4

• Thymoma (main ddx in older cats)

• Other cranial mediastinal lymphadenopathy (see above)

• Other causes of pleural effusion

  • Congestive cardiac failure

  • Pyothorax

  • FIP

  • trauma induces Haemothorax

Feline lymphoma anatomical location: alimentary canal

• what form of lymphoma can they be?

• age— more common in?

• clinical presentation— they can be different depending on ______

  • clinical signs are non specific. name

can be Low-grade or high-grade (multiorgan involvement)

Older cats

presentation depends on whether infiltration is diffuse/ mass-like

• Hypo/anorexia – more common and severe in cats than dogs

  • —> Insidious weight loss

• Diarrhoea

• Malabsorption/PLE

• Occasionally vomiting (cat>dog)

  • mass gastric / SI involvement—> secondary gastritis

picture:

what are other alimentary ddx other than lymphome?

• note that alimentary/GI signs are various and very nonspecific

  • name 1 specific disaese that could cause GI sign

• what are other causes of mesenteric lymphadenopathy (5)

• name 3 other types of intestinal mass

other causes of GI signs

• IBD

All other causes of mesenteric lymphadenopathy

• FIP

• Peritonitis of other aetiologies

• IBD

• Metastatic neoplasia

• Pancreatitis

• Mycobacterial infection

Other intestinal masses

• (carcinoma, leiomyoma, leiomyosarcoma)

what is common is cats with alimentary lymphoma?

low B12; hypocobalaminaemia

Feline lymphoma anatomical location: Extranodal

• give the most common extranodal sites (3)

• what are their respective clinical presenation?

CNS, Nasal/ retrobulbar, renal

• CNS : signs depend on site

• Nasal/ retrobulbar

  • nasal discharge. epistaxis, obstruction

  • exophthalmos— beyond nasal cavity common

• Renal (cat> dog)

  • malaise, anorexia

  • organomegaly (bilateral)

  • azotaemia (often severe @ time of dx)

Other findings: feline lymphoma

• consider common paraneoplastic syndrome? 3 what about in cats? 1

  • compared to lymphoma, hypercalcaemia is more common in1

• what else is often needed in cat lymphoma, especially alimentary locations?

• Paraneoplastic syndromes is rare in cats

  • Hypercalcaemia (more likely in myeloma)

  • Hypergammaglobulinaemia

  • Immune mediated disease

cobalamin supplpiment (B12) as hypocobalanimaemia common

list diagnosis approaches in feline lymphome

FNA cytology, biopsy, clin path

imaging?

using FNA cytology for feline lymphoma diagnosis

• often use with ____ and ____

• what is a challange in cytology in cats? is what area is lymphoma hard to diagnose

• then where is it easier to dx on FNA? what needs concurrent biopsy?

• what is often high grade?

  • can you use LN FNA in that location?

often have to use with histopath and cytology

multicentric/peripheral: often low-grade small cell or mixed lymphomas

• Difficult to differentiate from reactive hyperplasia , less diagnostic

Cranial mediastinal and extranodal—> higher grade

• Easier to diagnose on FNA

• Renal often require biopsy

GI often high-grade (can be low)

• LN FNA in GI rarely diagnostic

using cytology to diagnose feline lymphoma

• describe what you would see in cytology, high grade lymphoma 4

lymphoma on R,

high-grade lymphoma

• monomorphic population of large lymphoblasts (>50%).

• nuclei with clumped chromatin, multiple, pleomorphic

• basophillic cytoplasm than normal small lymphocyte

• Mitotic figure

using biopsy to diagnose feline lymphoma

• how and where would u do LN biopsy (1)

  • avoid what node 1

  • caution in tools 1

• describe extranodal lesion/ big node leision biopsy

• what if you also suspect mycobacterial or fungal?

• Excisional biopsy of node 23g needle: popliteal good

  • submandibular as often recctive for dental issue

  • avoid trucut except renal

• Wedge biopsy from extranodal lesion or enormous node

  • Impression smears

keep fres tissue if suspecct mycobacterial disease (or fungal)

• if granulomatous indication—>PCR

why can cat lymphoma diagnosis be tricky?

secific it to:

• low grade GI lymphoma 3

• CNS lymphoma 3

  • what else can you do

Low-grade alimentary vs IBD

• PARR (specific not sensitive)

• Negative unhelpful

CNS lymphoma

• PARR done on CSF + epidural

• Often no/few tumour cells in CSF

• Rarely solitary: may find other sites on staging

  • Bone marrow aspirate? rare

when do you clinical pathologgy in feline lymphoma cases?

• effectiveness of haem?

• how could haem suggest lymphoma

• how does biochem reflect lymphoma

• name 4 things to look out for

what else do you look out or in dogs with GI involvement

Haematology / biochemistry required before chemotherapy

Haematology non-specific in most cases

• 10-15% have abnormal cells in circulation

These suggest lymphoma

• Neutrophilia, thrombocytopenia, lymphopenia, eosinopenia

• Mild non-regen anaemia

• Abnormal lymphoid cells

Biochemistry may reflect organ involvement

• Hypoalbuminaemia (poor prognosis if multicentric)

• Azotaemia— renal

• Hepatic involvement

• paraneoplastic syndrome

Measure cobalamin (B12)

feline lymphoma and Bm involvement

• use in routine staging?

• name BM asipiration site

Unknown how many cats have BM involvement; Haematology poor indicator.

• Rarely used in routine staging but may be useful in CNS disease

• occasional +ve for FeLV cat

proximal femur. humurus

Feline Lymphoma: FeLV Testing

• importance

• what does it test? what do you do if come back +ve?

FeLV +ve→ poorer response to chemo and prognosis

Detects viral core protein p27

• Single positive should be confirmed

• Care with “in house” tests

diasg img for feline lymphoma used fro staging

cxr, axr, us

Diagnostic Imaging: CXR in feline lymphoma

• list structures and their features of LN 4

• wb pulmonary whatd u see 1

• what else do u look for 2

CXR also used used for? 2

Lymph node enlargement

• cranial mediastinal

• suprasternal

• tracheobronchial nodes

• thymus

Pulmonary infiltration

• Little data on the appearance of round cell tumour infiltrates in cats

Pleural effusion + Concurrent disease

MONITORING REMISSION and Staging

Diagnostic Imaging: AXR in cat lymphoma

• if the owner cannot afford abdo us what do u do

• what would you look for, consistent with lymphoma 4

  • name the abdo lyph nodes

lots can be palpated

• Internal lymph node enlargement

  • sublumbar lymphadenopathy

  • mesenteric lymphadenopathy

• Hepato/splenomegaly

• Peritoneal effusion

• Concurrent disease

Diagnostic Imaging: Ultrasound in cat lymphoma

• US can be used to look for

• apprearance?

• name 2 other thing US is used for in lymphoma

• cranial mediastinal and abdominal masses

  • Appearance can be variable

also used for

• renal/ cranial mediatinal FNAs/tru-cut biopsies guide

• Monitoring of remission

Clinical Staging, Grading, Typing of feline lymphoma

• how to stage cats?

• 2e?

• Cats dont fit in the standard clinical staging boxes

• anatomical location: none useful

• histopathological: none establish

• immunophenotype none prognostic

feline Lymphoma: Prognostic Indicators +ve 2

• Achieving CR

• small volume, extranodal disease

feline Lymphoma: Prognostic Indicators -ve

• name 2

• name effect FeLV status have on remission

• Failure to achieve CR

• previous corticosteoird therpay

• FeLV +ve status

  • chance of remission, duration

Treatment of Lymphoma

• name 4

• one that we dont use

• what else is important

• None

• Corticosteroids

• COP regimes

• Doxorubicin-containing regimes – CHOP

• Non-continuous regimes – Poorly evaluated for cats

• (B12/cobalamin supplementation)

MST without therapy: feline lymphoma

4 wk

COP: feline lymphoma

• excellent protocol for cats

• High dose COP —75% CR

• 1 year survival 49%, 2 year survival 40%

doxorubicin containig CHOP: Feline lymphoma

3

• doxorubicin is controversial

• single agent poor response

• MST disappointing — 5-6 months

outcome

• goal? 3

• what would probably happen

  • what do you do then?

Goal is to induce complete remission

• no detectable tumour

• good QOL

Most cats develop drug resistance and relapse

• Rescue therapy: small % cured

describe high dose cop

10 week protocol

• pred per

cat specific consideration for COP

name alteranative to cyclophosphamis

Vincristine ? Mild transient inappetance

Cyclophosphamide GI effects tend to be hyporexia ?altered taste/subclinical stomatis, alopecia: whisker loss and coat changes, (Sterile haemorrhagic cystitis rare in cat)

Prednisolone Hyperadenocorticism Coat changes Malassezia, seborrhoea (smelly feet!)

Alternatives to Cyclophosphamide

Chlorambucil (only if in remission) 20mg/m 2 q21days in high dose COP 5-6mg/m 2 every other day (equivalent) or 2mg every other day or 20mg/m2 q 14-21 days for low grade alimentary

Melphalan 20mg/m 2 q21 days Care re cumulative myelosuppression

use of doxi/epirubicin in cat

• CHOP still used in some centre. reword

• Poor response to dox as single agent

• Fewer than 30% CR– Poor response as rescue agent

CHOP – Reasonable remission and survival times in some multidrug studies – Small numbers, only CRs achieved survival comparable to COP

Patient Monitoring

Remission – Check achieves and maintains remission – Often requires imaging $

Toxicity

• Myelosuppressive agents • check haem prior to every bolus dose • on low dose chlorambucil, check at appropriate intervals

• intermittently check urine —> for UTI—> pyrlonephritits, kidney problem

Treatment: Solitary Lymphomas feline

Surgical excision – e.g. intestinal mass • Radiotherapy – e.g. nasal lymphoma • Very few lymphomas are solitary – esp true of cats – e.g. 75% of cats presenting with CNS lymphoma have lymphoma in other sites • Adjunctive chemo or chemo as sole therapy

cat Alimentary Lymphoma: tx

Surgical excision of solitary mass lesion – Must biopsy nodes • ? Follow up chemotherapy • Extensive infiltration – Staggered induction to reduce risk of perforation • Adequate supportive therapy (b12, food, appetitie stimulent, antiemetic

• Gastric lymphoma very difficult to treat • Low grade may respond very well to chlorambucil and prednisolone only (mostly hihg grade)

feline Renal Lymphoma- azotemia as prog fator?

response rate?

involcement?

Degree of azotaemia is not prognostic • Overall low response rate and poor survival time • High incidence of CNS involvement in cats with renal lymphoma – few agents cross the blood brain barrier – add cytosine arabinoside in induction ? • Possible association with nasal/retrobulbar lymphoma

feline Cutaneous Lymphoma tx

Generally non-epitheliotrophic in cats • Generally not very responsive to chemotherapy – Possible role for lomustine • ?Role of retinoids – in amelioration of clinical signs • (? Other agents e.g. interferon) • Possible indolent form affecting head and neck • NB subcutaneous leisionusually aggressive

felien lymphoma rescue therapy

Second remissions are generally shorter than first – Cats more difficult to rescue than dogs – Low response rates, median progression free intervals 14-166 days • Usually alter regime completely – Anthracycline (doxorubicin/epirubicin) • 22% response rate, less than 10% CR – Lomustine • PFI 180d for gastrointestinal, 26 days for other – Lomustine, methotrexate, cytosine (LMC) • 46% response rate – MOPP (mechlorethamine, vincristine, prednisolone, procarbazine) and variants • 10/23 CR (mainly alimentary)

solitary mediatinal : radiation 9(CNS?)

Multiple Myeloma/Myeloma Related Disorder

how to dx

Functional B cell (plasma cell) tumour : Variable presentation

• Hypergammaglobulinaemia • Hyperviscosity signs – ocular, neuro, GI, PU/PD, malaise – Hypercalcaemia • GI, PU/PD, malaise – Bone lesions

Lameness • Mild -cytopenias

dx wtih BM aspiration and SPE to confirm

MRD diagnosis: mathopneumpnic

BM aspirate: plasma cell

PCR

MRD tx

h melphalan and prednisolone • Median survival times are 12m or more • Add other agents if response is poor or at relapse • Negative prognostic indicators – Proteinuria – Hypercalcaemia/azotaemia (common) – Extensive bone lesions

Leukaemia occurs when vs

lymphoma occurs when

leukemia: neoplastic transformation occurs in the BONE MARROW

lymphoma: neoplastic transformation occurs in the peripheral lymphoid tissue

– Cells in acute lymphoblastic leukaemia and high grade lymphoma look similar • Leukaemia is CD34+ve because arises from stem cells • Lymphoma is CD34-ve because arises from lymphoid cells

• fudamentally difference diseaes

lymphoid/ Lymphoid or myeloid – Depends on cell of origin • More precise determination of lineage will help identify treatment – Presentation is essentially the same • Acute or chronic – Reflects clinical presentation – Correlates with stage at which neoplastic transformation has occurred

acute leukemia

Transformation of stem cell results in failure to differentiate – Stem cells/committed blasts (usually CD34+ve) • Rapid proliferation • Arrested/defective maturation • Marrow rapidly becomes overcrowded – Normal cell production fails – -cytopenias • Clinical signs are severe, course is rapid

Chronic Leukaemia

Transformation occurs in the stem cell but differentiation is not blocked – Cells may look morphologically mature and normal – May function abnormally • Proliferation not controlled but slower than acute • Effects on normal haemopoiesis less devastating • Clinical signs less severe • Course insidious

What causes clinical signs in leukemia px

DISRUPTION OF NORMAL HAEMOPOIESIS – Effects of -cytopenias

Hyperviscosity if there are vastly elevated circulating cell numbers

Paraneoplastic syndromes — clincial sign, infiltration of liver, spleen and other organ

Organ infiltration resulting in functional compromise

presentation of Acute Leukaemia

History of malaise, hyporexia, PU/PD

Clinical signs – Lethargy – Pyrexia – Hepatosplenomegaly – Mild lymphadenopathy – Pallor – Sepsis – Haemorrhage – Hyperviscosity

leukemia: neutropenia as indication of disruption of normla haemapoiesis

e first manifestation of failure of haemopoiesis – Use storage pool to replenish circulating pool • Runs out after about 5 days

• Reduced host defence against pathogens

• Malaise • Pyrexia • Sepsis, septic shock – Often from Gram -ve organisms in the GIT • Septic shock • Reduced inflammatory response – Difficulty identifying foci of infection

thrombocypopoaeamiaas indication of disruption of normla haemapoiesis

Thrombocytopenia with or before neutropenia – Impairment of primary coagulation • Petechial and ecchymotic haemorrhages • Bleeding from mucous membranes – Epistaxis – Melaena • Ooze from small wounds • (Significant or ongoing haemorrhage may contribute to anaemia) • (?immune mediated destruction)

Anaemia generally mild – Normocytic, normochromic – Non-regenerative • (?

Secondary immune mediated haemolytic anaemia) – ? Esp lymphoid leukaemias

Cats with AL often have moderate or severe anaemias – Marrow infiltration – Immune mediated destruction – FeLV infection blocking erythropoiesis – Secondary myelofibrosis

Leukocytosis big nastl blacst

In most cases abnormal cells are released into the circulation • May not be an absolute increase in white cell count in all cases • Leukaemia without circulating blasts – Aleukaemic leukaemia – More common in cats • Very large numbers of cells can lead to hyperviscosity – Capillary sludging – Poor perfusion of end vessels • CNS signs • Ocular signs • Renal compromise

Biochemical Abnormalities in leukaemia

Azotaemia • Monoclonal gammopathy • Hypoproteinaemia • Hypercalcaemia • Raised liver enzymes • (Hyperkalaemia) • (Hypoglycaemia)

— check Blood smear and haem

Acute leukaemias: diagnosis

Circulating abnormal cells – Usually in high numbers • Pancytopenia • Difficult to determine morphologically if atypical blasts are lymphoid or myeloid – Flow cytometry – Also useful to differentiate stage V lymphoma from ALL: CD34 specific

Acute leukaemias: treatment

Prognosis poor – Requirement for supportive care – Dose intensity required • ALL – CHOP based protocols – Median survival times 16-120 days •acute myeloid leukemia – Many protocols – Doxorubicin/cytarabine – MST 15-60 days

Chronic Leukaemia: presentation

Chronic myeloid leukaemias rare – Differentiate from other causes of extreme neutrophilia • Mostly chronic lymphocytic leukaemia – CLL • Older dogs

Mild clinical signs – Insidious onset – Lethargy – Mild splenomegaly – Mild lymphadenopathy – Anaemia

May be incidental finding

Chronic Leukaemia: CLL

Not all need treated

Respond well to chlorambucil and prednisolone – 70% have normalisation of count •

Median survival times 1 to 3 years – T CLL better than B CLL

No blast crises in dogs but B CLL patients may develop a high grade lymphoma – Richter’s syndrome— resistant to ???

Polycythaemia/Primary Erythrocytosis

Rare – uncontrolled erythroid proliferation – hyperviscosity

Differentiate Polycythaemia/Primary Erythrocytosis from other causes of erythrocytosis

Relative • hypovolaemia – Secondary to hypoxia • respiratory disease, cardiac disease with left to right shunts – Inappropriate EPO production • renal disease (esp neoplasia), other tumours

Polycythaemia/Primary Erythrocytosis tx

Treat with hydroxyurea/hydroxycarbamate – antimetabolite • Phlebotomy in emergency