12 | companion

HOW TO
MANAGE THE SYSTEMICALLY
UNWELL, SUBSTAGE b, CASE
OF CANINE LYMPHOMA
HOW TO
Gerry Polton of North
Downs Specialist Referrals
discusses the management
of those more difficult
canine lymphoma cases
I
t has long been recognised that prognosis
in cases of canine lymphoma is
significantly affected by the apparent state
of systemic health at the time of diagnosis.
This reflects more than the simple fact that
moribund cases are fewer steps from
mortality. The management of these cases
is not something that receives attention in
the veterinary literature. The purpose of
this article is to help clinicians to consider
the management of those cases systemically
unwell at presentation, so called substage b.
While some cases of substage b lymphoma
sadly do show little or no response to the
management offered, others achieve
complete remission and a full quality of life
for prolonged periods.
Presentation
Affected cases can be divided into two
groups, those with obvious multicentric
lymphoma and those without. The
importance of this distinction is that the
former are usually diagnosed promptly, and
speed may be of the essence in regaining
control of the disease.
The aetiology of the substage b status
is varied (see Table 1). Efforts should be
made to understand the pathophysiology
of the patients ill health in order to
optimise management. Pathogenesis is
often multifactorial.
It has long been recognised in human
haemato-oncology that lymphoma
represents a broad umbrella classification of
lymphoproliferative disease. Refinements in
diagnostic capacity have led to the
development of a classification system that
incorporates clinical, histomorphological,
cytomorphological, flow cytometric and
cytogenetic characteristics to define
subtypes of disease. This extensive
classification effort is rewarded by more
accurate prediction of biological behaviour
and responses to therapy. Similar efforts
have been made in veterinary oncology with
a landmark study by Frdrique Ponce and
others (2004) demonstrating significant
survival implications for six different canine
lymphoma subtypes.
Substage b patients may present without peripheral lymphadenopathy
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HOW TO
Pathogenesis Notes
Metabolic
derangements
Hypercalcaemia Varied causes, including PTHrP, IL-6, OAF
Hypoglycaemia Consumption by tumour
Uncoupling of energy
transduction pathways
Due to aberrant cytokine elaboration
Organ
dysfunction due
to infiltration
Renal insufficiency Chemotherapy doses may require
adjustment
Hepatic insufficiency Chemotherapy doses may require
adjustment
CNS involvement Neurological signs may be generalised or
focal
Respiratory compromise Widespread pulmonary infiltration is
unusual
Bone marrow See haematological aberrations
Haematological
aberrations
Neutropenia
Thrombocytopenia
Anaemia
Failure of production or immune-
mediated destruction of blood cells
Mass effect Partial airway obstruction
Vascular occlusion
Typically only in advanced cases without
other systemic compromise
Table 1: Causes of failure of systemic health seen in substage b lymphoma
PTHrP: parathyroid hormone related peptide, IL-6: interleukin 6, OAF: osteoclast
activating factor
Diagnostic considerations:
definitive diagnosis
Cytology
Cases of suspected lymphoma should
undergo appropriate diagnostic testing to
make a definitive diagnosis. For patients
with generalised lymphadenopathy, fine
needle aspiration and cytology can yield a
robust diagnosis and spare the need for
chemical restraint for biopsy. Further
refinements of the diagnosis can be
obtained by immuno cytochemistry or
flow cytometry. These should be discussed
with your laboratory prior to sampling, in
case specific sample-handling practices
must be observed.
Across a population of cases,
histological evaluation of an entire lymph
node remains a more reliable means of
diagnosis of lymphoma. However, in
addition to issues of anaesthetic safety,
both time and cost factors merit
consideration. A competent cytologist
could make a diagnosis of lymphoma in
minutes; the author advises that
practitioners interested in managing
lymphoma cases obtain lymph node
aspirates and perform in house cytological
evaluations regularly to gain confidence
with the techniques. While a diagnosis of
lymphoma may be best made by an
experienced cytologist, practitioners can do
both themselves and their cases a
tremendous service by confidently defining
that sample quality is adequate for diagnosis
and that the appropriate target has been
sampled prior to submission.
Lymphoid cells are easily disrupted by
forceful aspiration or smearing. The author
advises that samples are obtained without
suction and that only the weight of the
spreading slide is used to disperse cells in
the expelled sample.
Diagnostic considerations:
supporting data
Haematological evaluation
Haematological aberrations can arise for
numerous reasons. Cytopenias arise due
to bone marrow infiltration, immune-
mediated destruction of mature cells or
precursors, anaemia of chronic disease
(lymphoma or chemotherapy for
lymphoma) and significant haemorrhage.
Significant neutropenia predisposes patients
to sepsis, so broad spectrum antibiotic
therapy is indicated. Thrombocytopenia can
result in spontaneous haemorrhage that is
really only responsive to prophylaxis by
transfusion of fresh whole blood. Clinicians
must be aware that administration of
chemotherapy in these instances may
precipitate a lethal complication.
Anaemia due to haemorrhage is best
managed by diagnosis and treatment of the
inciting cause, and whole blood transfusion
Cranial vena caval syndrome as a
consequence of lymphadenopathy
Photo courtesy of Mark Goodfellow, UoB
if indicated. Anaemia of chronic disease is
usually mild to moderate and is typically not
addressed. In cases with other significant
signs of ill health, anaemia with a PCV of
20% or greater does not warrant
intervention. If PCV is less than 20% and
the patient is symptomatic, transfusion
should be considered as a short-term
measure while other health parameters are
given a chance to improve.
14 | companion
HOW TO
MANAGE THE SYSTEMICALLY UNWELL,
SUBSTAGE b, CASE OF CANINE LYMPHOMA
Biochemical evaluation
Hypercalcaemia and indicators of renal and
hepatic compromise are readily identified
on serum biochemical profiles.
Hypercalcaemia frequently responds
promptly to the administration of
lymphocytolytic therapy, such as
corticosteroids. It is critical that diagnostic
quality samples are obtained prior to
steroid administration, however, as the
chances of harvesting diagnostic samples
subsequently are reduced. Hypercalcaemia
induces cardiovascular and neuromuscular
compromise, and uncontrolled
hypercalcaemia precipitates renal failure.
This effect is exacerbated by reduced renal
perfusion, for example under anaesthesia.
Renal compromise may be due to
pre-renal effects, such as hypovolaemia due
to hypercalcaemia, or it may reflect renal
disease. Renal lymphoma can be diagnosed
on renal aspirate biopsy. If a diagnosis is
already made, ultrasonographic changes
consistent with lymphoma are adequate.
Hepatic compromise has far-reaching
implications. Frequently these cases are
anorectic, hypoproteinaemic, icteric and
vomiting. Dramatic weight loss can be seen.
Both renal and hepatic disease can lead to
marked alterations in metabolism of
chemotherapeutic agents. Usually this
results in increased plasma drug
concentrations due to failure of elimination,
and dose reductions are critical. Patients
with hepatic compromise can need
aggressive support in order to give them a
chance of recovery.
Imaging studies
Thoracic radiography is indicated to identify
the presence of intrathoracic masses.
Hypercalcaemia is more common among
cases with cranial mediastinal lymphoma
and there may be no evidence of lymphoma
affecting other sites. Massive intrathoracic
lesions can compromise respiratory
function. A single lateral thoracic projection
is often adequate to define presence or
absence of mediastinal disease.
Abdominal radiography is rarely helpful.
Significant lymphadenopathy can be missed
whereas hepatomegaly and renomegaly may
be recognised. Ultrasonography yields more
valuable information and, if a diagnosis
remains in doubt, aids biopsy of abnormal
structures. Clinicians must be aware of the
potential for biopsy-induced haemorrhage,
which is of greater concern in hepatic or
renal compromise.
Bone marrow sampling
Lymphoma can reside solely in the bone
marrow, so the diagnosis should not be
ruled out on the basis of absence of
evidence of disease in other body systems.
If haematological parameters indicate bone
marrow involvement and a diagnosis has
already been made, there are few
indications for marrow sampling. If the
diagnosis remains in doubt, however, or if
immune-mediated destruction of blood cell
precursors is suspected, sampling can be of
benefit for subsequent management.
Other considerations
Nutrition
Inappetence or anorexia, vomiting,
infiltrative intestinal disease and
hepatopathy will all contribute to a negative
energy balance. The metabolic demands of
Pretreatment lateral thoracic radiograph revealing mediastinal
lymphadenopathy in a severely hypercalcaemic Boxer
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HOW TO
advanced lymphoma are great; adequate and
balanced nutrition can make the difference
between success and failure in these cases.
Risk of sepsis
Neutropenia due to bone marrow
infiltration and/or chemotherapy, exposes
patients to risk of bacteraemia and sepsis.
Extra attention to infection control
measures is warranted. In addition,
lymphoma can induce vasculitis, with
consequential systemic inflammatory
response syndrome (SIRS), mimicking
changes associated with septicaemia. Sepsis
promotes inappropriate cycles of coagulation
and thrombolysis; concurrent
thrombocytopenia exacerbates risk of
disseminated intravascular coagulation (DIC).
Water and electrolyte turnover
Substage b patients typically fail to consume
adequate water to compensate for
insensible losses. An attempt should be
made to quantify losses so that appropriate
replacement therapy can be provided.
Medications to limit losses through vomiting
and diarrhoea are advised.
Most patients are significantly
hypokalaemic. Plasma potassium
concentration may not accurately reflect
total body potassium depletion, as
potassium is primarily an intracellular cation.
Hypomagnesaemia is also recognised.
Potassium and magnesium deficiencies can
result in inappetence or anorexia.
Hypercalcaemia can be managed by
saline diuresis. Excessive volume
replacement should be avoided as cases
with significant renal insufficiency are unable
to excrete significant water loads; cerebral
oedema may result.
Case management
When a diagnosis of substage b lymphoma
has been made, priority must be given to:
1. Supporting the patient
2. Controlling the disease process
In order to support the patient, basic
nutrition, warmth, fluid and electrolyte
needs must be attended to. Inappetent or
anorexic patients should not be supported
on intravenous fluids alone. Assisted feeding
is mandatory; this can be greatly aided by
the placement of an appropriate feeding
tube. Investigations should be undertaken
to obtain supporting data, as presented
earlier, so that potential problems can be
anticipated and prevented or managed.
Control of the disease requires the
judicious use of chemotherapy.
Hypoalbuminaemia, hepatopathy and renal
insufficiency can all lead to apparent
overdose of chemotherapy due to reduced
plasma protein drug binding or relative
deficiencies of excretory metabolism.
Biochemical and haematological
parameters must be known prior to
chemotherapy so that appropriate dose
adjustments can be made.
Clinicians are strongly advised not to
embark upon unfamiliar chemotherapy
protocols when presented with a case of
lymphoma that is complicated by systemic
illness. Good decision-making in these
cases requires confident and timely
identification of progressive changes,
whether those changes represent
improvement or deterioration.
Prognosis
At the current time, knowledge of the
behaviour of distinct canine lymphoma
subtypes is rudimentary. Historically, B or
T cell immunophenotype has been
regarded to be predictive of outcome but
this is an oversimplification. In fact, in the
Ponce study (2004), the group of cases
exhibiting the best survival outcome were a
subgroup of T cell immunophenotype
whilst the cases exhibiting the poorest
prognosis were a subgroup of B cell
immunophenotype. Such a pattern would
not be predicted by the traditional
interpretation of effect of
immunophenotype on prognosis. This is a
rapidly developing field of veterinary
oncology; an experienced veterinary
haemato-oncologist should be consulted to
offer insight into the prognostic
information provided by flow cytometry
and detailed cytomorphological evaluations.
Conclusion
As a group, cases of substage b lymphoma
carry a poor prognosis. While in part this is
simply a reflection of their ill health, it is
unclear whether their prognosis would
remain poorer than comparable substage a
cases if complete remission were achieved.
Initial management of these cases can be
intensive and, with no guarantee of a
successful outcome, not all owners would
choose to pursue such an approach. It is the
authors experience, however, that many of
these cases can enjoy a normal-for-
lymphoma quality and length of life if
appropriate management is implemented at
an early stage. n
Ponce F, Magnol J-P, Ledieu D et al. (2004)
Prognostic significance of morphological
subtypes in canine malignant lymphomas during
chemotherapy. The Veterinary Journal 167,
158166
Dramatic clinical improvement
following treatment and resolution
of hypercalcaemia same dog as
in radiograph