Clinical Pathology in the Oncologic Patient
World Small Animal Veterinary Association World Congress Proceedings, 2014
Fred Reyers, BVSc (Hons), MMedVet(KLD), MRCVS, Registered Pathologist (Clinical Pathology)
IDEXX, South Africa

Introduction

This presentation takes the approach of looking at the panel of blood tests used by the average veterinarian to identify which parameter may become abnormal in cancer and, if so, whether it is a reliable marker for a particular tumour. In addition, this review will tend to focus on those tumours that are common.

The tests that constitute the average profile are selected to reveal organ damage or dysfunction, not specifically neoplasia. Neoplasia may produce very little damage, at any moment in time, and often only compromises organ function late in the disease.

Blood Chemistry

Serum Proteins

It is the globulin fraction and its subfractions that constitute a marker for some tumours. If the A:G ratio is low and hypoalbuminaemia is not the only obvious reason, then it is worth requesting serum protein electrophoresis (SPE).

Gammopathies

There are three gammopathies (abnormalities in the gamma fraction - invariably implies high levels), associated with neoplasia.

Monoclonal gammopathy (a single, narrow-based peak) is strongly associated with multiple myeloma. Consequently, a monoclonal gammopathy is a sensitive and a very specific marker for multiple myeloma in all reported species. Rarely such a gammopathy relates to massive non-neoplastic plasma cell activity as in chronic ehrlichiosis, but in the writer's opinion, this is a misclassification - it is a pseudo-monoclonal gammopathy (see below).

Oligoclonal gammopathy. More than one narrow-based spike in the gamma zone. These represent the proliferation of two distinct clones of plasma cells representing a multiple myeloma and another plasma cell tumour.

Pseudo-monoclonal gammopathy. A single, relatively narrow, but not obviously a polyclonal gammopathy, seen in some functional B-cell tumours. The finding is not very sensitive nor specific.

Bence-Jones Proteins

Immunoglobulin light chains, produced in multiple myeloma and some other conditions. Identifying the presence of these in urine constitutes a highly sensitive diagnostic marker. The modern approach of immunofixation is very reliable but requires species-specific reagents that are seldom available in the average laboratory. Cross-reactivity with human reagents is extremely poor and these cannot be used reliably.

Alpha globulins (Acute Phase Proteins [APP])

Alpha globulins largely represent APP. Some tumours consistently cause alpha globulin elevations, but the finding is neither very sensitive nor specific. The tumour most commonly associated with an increase in APP is the mast cell tumour. Also lymphomas, certain sarcomas, and mammary tumours.

Serum Enzyme Activities

Alanine Transaminase (ALT) and Alkaline Phosphatase (ALP)

Cushing's syndrome (hyperadrenocorticism - HAC) in the dog

Hyperadrenocorticism is due to neoplasia of the adrenal or pituitary leading to persistently high cortisol. This induces production and release of ALP. Serum ALT is also usually raised but seldom to the same degree as ALP. Thus, the presence of a markedly elevated ratio of the increase of ALP to ALT is a fairly sensitive marker for HAC. However, it is not specific as ALP production is also induced by pathology of the bile duct system and in such cases ALT is also often increased.

Feline hyperthyroidism (FHT)

In many cases of FHT (adenoma of the thyroid gland) serum ALT and/or ALP are increased. The finding is a reasonably sensitive marker for FHT in cats but poorly specific as hepatobiliary pathology (not uncommon in cats) can also elevate the enzymes. However, as serum ALP has a very short half life in cats, the finding of an elevated serum ALP in an elderly cat points to ruling in/out of FHT.

Serum Gamma Glutamyl Transferase (GGT) Activity

Renal tubular epithelial cells are rich in GGT. The enzyme is usually lost in the renal filtrate when renal pathology occurs. In some cases of renal neoplasia (esp. with metastasis), it is possible to find markedly elevated serum GGT. The marker is not sensitive nor specific for renal neoplasia.

Serum Lactate Dehydrogenase (LD) Activity

Most tissues are relatively rich in LD. Highly active cells such as leukocytes tend to have more of this enzyme (esp. lymphocytes). Elevation of serum LD is a fairly sensitive marker for lymphoid cell neoplastic proliferation but definitely not specific. Damage to any tissue (esp. liver and muscle) can cause marked serum elevations. Based on the same principle, serum LD should be a reasonably sensitive marker for tumours that have a high cell turnover rate.

Serum Amylase (AMS) and Lipase (LIP) Activity

Serum AMS and LIP are usually reserved for the confirmation of suspected acute pancreatitis. In pancreatic neoplasia, however, these enzymes are often raised and classically tend to remain elevated for a longer time.

Blood/Plasma Glucose

Blood glucose elevation is usually associated with the diagnosis of diabetes mellitus. Low values are often ignored but play a significant role in the diagnosis of insulinoma. In a patient with unexplained seizures or coma, a persistently/markedly low blood glucose (< 2.3 mmol/l), despite normal food intake, is fairly sensitive and specific for this tumour.

Serum Cholesterol

Though often elevated in HAC, an elevated serum cholesterol is an insensitive and poorly specific marker.

Serum Bilirubin (Total or Conjugated)

Bile duct neoplasia may cause obstruction of the bile duct or branches thereof and leads to increases in total and conjugated serum bilirubin. Consequently, it is reasonable to assume that this could constitute a useful marker for this type of neoplasia. However, it is both an insensitive as well as poorly specific marker.

Serum Calcium (> 3.1 mmol/L)

High levels of parathormone (PTH) or compounds functionally resembling PTH (PTH-rP), can cause very significant elevations of serum calcium levels. The relatively rare primary hyperparathyroidism (neoplasia of the parathyroid), but more importantly, the more common pseudo-hyperparathyroidism (caused by various tumours including lymphoid, adenocarcinomas [especially anal sac carcinoma], and occasionally sarcomas) have significant hypercalcaemia. The finding of marked hypercalcaemia is not very sensitive but fairly specific for PTH- or PTH-rP-producing tumours.

Haematology

Erythroid Cells

Although neoplasia of the red cell series is expected to produce "polycythaemia vera," a polycythaemic state is uncommon. Rare in dogs, but more common in cats (possibly FeLV associated) acute myeloid leukaemia-(erythroid) [AML-M6] is seen from occasionally. The most diagnostic finding is a marked, often unexpected increase in and aggregation of clusters of normoblasts. Early erythroid precursors are often present in significant numbers (but are usually misclassified as lymphoid blast cells by haematology technicians and machines).

Lymphoid Cells

Lymphoid tumours, in dogs and cats, are considered to be among the most common form of neoplasia.

Acute Lymphoblastic Leukaemia (ALL)

Relatively common tumours and, at presentation, usually have a substantially elevated lymphoid cell count and are easy to diagnose. Most competent haematology technicians will identify the abnormal population of blast cells and if not, the slide is usually referred to a pathologist who is unlikely to miss that feature. Thus the findings are generally both sensitive and specific.

Chronic Lymphocytic Leukaemia (CLL)

In CLL the lymphoid cells may appear normal. Only good haematology technicians are able to identify the more subtle abnormalities such as cell fragility, nuclear shape atypia, and cell aggregation. Unless the count is substantially elevated, the slide is unlikely to be referred to a pathologist. This means that the blood smear findings are poorly sensitive but (in good hands) reasonably specific. Useful guidelines that will increase the likelihood of the slide being referred are the facts that most dogs that are clinically ill should have low lymphocyte counts (stress induced) and that there is a decreasing trend in lymphocyte numbers with age. A technician aware of these would be more likely to refer a slide to a pathologist even when count is still below the "universally accepted" value of 4.8 x 109/L.

Stage V Lymphoid Lymphoma

Before the tumour has reached stage V, the probability of diagnosis by haematology is very low.

Here, as with ALL, if the cells present in blood are blasts, the slide is likely to be referred to a pathologist but the presence of a few blast lymphoid cells is by no means a specific finding as this is seen commonly in young animals and in those exposed to strong antigenic stimulation. Atypia is an important diagnostic feature but that requires a fairly experienced technician.

In the case of lymphocytic lymphoma the probability of the diagnosis being made is very low, unless the lymphocyte count is substantially elevated.

Myeloid Cells

Acute Myeloid Leukaemia - (AML-1 and AML-2)

These two categories represent myeloid leukaemia with no, or very little, differentiation into neutrophils (AML-M1) and those with significant differentiation (AML-M2). The diagnostic sensitivity and specificity is strongly dependent on the person doing the first screening of the slide. Very few haematology technicians, though able to identify the myeloid blast cells, are able to make the finite diagnosis. Even referral to a pathologist may still leave an open diagnosis. It requires bone marrow biopsy to be on a more secure diagnostic footing.

Acute Myelomonocytic Leukaemia (AML-M4)

This is a diagnosis that is difficult to make but also very difficult to be certain that it is not AML-M1. Bone marrow biopsy is the preferred approach in suspected cases.

Acute Monocytic Leukaemia (AML-M5)

This tumour is easy to miss. The cells look like normal, albeit slightly "odd," monocytes.

Non-neoplastic monocytosis is not an unusual finding - even with substantially raised counts. Consequently, blood smear examination is poorly sensitive and poorly specific for the diagnosis.

Acute Myeloid Leukaemia with Eosinophils (AML-M1/2-eos)

Generally the AML-M2 version of this tumour, though relatively rare (more common in cats), is very difficult (almost impossible) to distinguish from hypereosinophilic syndrome, considered to be a pre-leukaemic phenomenon.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Fred Reyers, BVSc (Hons), MMedVet(KLD), MRCVS, Registered Pathologist (Clinical Pathology)
IDEXX
South Africa


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