Lymphomas represent the third most prevalent tumour type diagnosed in dogs. They originate from lymphocytes (a type of white blood cell) and primarily appear in lymphoid tissue. Lymphoid tissue is present on many places throughout the body.

Lymphomas have many subtypes and forms. They can appear as a solitary tumour. When present at multiple places at once, it is called multicentric (which is the case for 84% of forms of lymphoma). Furthermore, lymphoma can appear in the digestive system (5%), in the space between both lungs (mediastinum) (5%), in the skin, independent from lymph nodes (eye, central nervous system, bone marrow, urinary bladder, heart, nasal cavity), in the spleen and kidneys and the blood vessels.

Behaviour

Some lymphoma variants grow very slowly and barely cause clinical symptoms, while other variants are very aggressive. There are many different kinds of lymphoma (called subtypes), varying from very benign (low-grade) to very malignant (high-grade) behaviour. Lymphoma is a catch-all term for approximately two dozen lymphocyte cancer subtypes.

Treatment response rates are high and often durable (over 6 months), but cures are rare (less than 10%) and it is ultimately a uniformly fatal disease. As most forms of lymphoma (80%) appear on multiple sites throughout the body (multicentric), a systemic (with an effect on the whole body) treatment such as chemo- and/or immune therapy is recommended.

Prevalence

Lymphomas represent one of the most common neoplasms in dogs, 7-24% of all tumours in dogs. They most commonly appear at the age of 6-9 years.

Breed predisposition

A higher risk to develop this tumour type has been reported for the Airedale Terrier, Boxer, Bulldog, Bull Mastiff, Basset Hound, German Shepherd, Golden and Labrador Retriever, Scottish Terrier, St-Bernard vs other breeds. It seems to appear less in Dachshunds and Pomeranians vs other breeds.

Symptoms

The symptoms vary and depend on the subtype, the extent and location of the lymphoma form. Especially in the early stages the dog can seem to be completely fine with no clinical symptoms at all, except for enlarged lymph nodes.

• Multicentric: mostly accompanied by a general painless enlargement of the lymph nodes. Non-specific symptoms are a lack of appetite, weight loss, vomiting, diarrhea, loss of subcutaneous fat and muscle, abdominal fluid, difficulties breathing, difficulties defecating, drinking and urinating a lot (especially in case of hypercalcemia (a high amount of calcium present in the blood)), fever. If the lymphoma takes up room within the bone marrow, this can lead to lowered production and therefore lack of red blood cells, blood platelets and/or neutrophils. These shortages can in turn lead to fever, bleeding and blood poisoning. A spread infiltration in the lungs occurs in 27-34% of cases with a form of multicentric lymphoma.
• Digestive system: entails thickening of the intestine wall and a narrowing of the passage, frequent ulcers on the mucosa. As a secondary effect, the liver and lymph nodes are often affected. Non-specific digestive anomalies consist of vomiting, diarrhea, weight loss, poor resorption of nutrients. The lymph nodes in the abdomen can be involved, as well as the spleen and liver.
• Mediastinal: involves the enlargement of lymph nodes in the mediastinum: the space taken up by this process can press on the surrounding structures resulting in breathing difficulties (when pressure is present on the trachea and lungs), regurgitating (when pressure is present on the esophagus), subcutaneous accumulation of fluids (edema) near the head, neck and front paws (when pressure on the vena cava is present), being easily tired.
• Extranodal: the symptoms depend on the organ involved.
• Skin: mostly generalised or multifocal. This can manifest itself in the nodules, plaques, ulcers, red/desquamating skin inflammation with a local underpigmentation and baldness.

  epitheliotropic form (=with a preference for the upper skin layer): the skin will at first exfoliate, followed by baldness and itching, which makes it difficult to distinguish from a regular skin infection. Afterwards, the skin reddens, the thickness increases, ulcers can appear as well as production of fluids. In an advanced stage, it is possible to distinguish spreading plaques and/or nodules with progressive ulceration.

  non-epitheliotropic form: single or multiple tissue masses in the dermis or subcutaneous. In this form, usually the lymph nodes and other organs are involved too, so this should be considered a late stage of a multicentric lymphoma.

• Spleen-liver: rare, no clearly swollen peripheral lymph nodes, no infiltration in the bone marrow. This location is associated with very aggressive behavior that poorly responds to treatment. The non-specific symptoms include lethargy, inappetence, and weakness and de mucosal membranes are often yellow.
• Intravascular: a lymphoma can be present in the blood vessel (wall) and the intravascular lymphoma is often situated in the nervous system.

Hypercalcemia (elevated calcium levels in the blood) occurs in 10-40% of dogs with lymphoma.

The veterinarian will perform a physical examination, a blood analysis (cell count, biochemical values and ideally also ionized calcium) and a urine analysis. It is essential to do an aspirate or take a tissue sample for the identification of the tumour type.

Physical examination

All lymph nodes that can be examined are palpated to localize possible swellings, and a rectal examination is done to determine the presence of possible changes. The veterinarian checks whether the mucous membranes have an appropriate colour (pale/yellow are abnormal), the presence of a speckled haemorrhage and/or ulcers. This indicates a possible shortage of red blood cells or blood platelets. When palpating the abdomen, the veterinarian can check whether some organs are larger than normal, whether the intestines have a thickened wall and whether enlarged lymph nodes are palpable. With a stethoscope, he can auscultate the heart and lungs. Dampening or crackles can be an indication of the presence of a mass in the mediastinum or fluid (in case of pleural effusion). However, especially in large dogs the exam may be normal even if changes are present and further diagnostics like radiography and ultrasound may be necessary to identify all the changes.

Blood analysis

Cell count

Anomalies in red and white blood cell count can be an indication of the presence of a lymphoma and possible bone marrow involvement.

Biochemical levels

The location of the lymphoma may have an impact on certain biochemical values. If the lymphoma is situated in the intestines, a too low protein level may be apparent in the blood. Infiltration of the liver or kidneys can lead to increased liver or kidney values respectively. Increased kidney values can also be the consequence of calcium deposits in the kidneys as a result of high blood levels of ionized calcium (hypercalcemia). Hypercalcemia is a manifestation of a paraneoplastic syndrome.

Urine analysis

A urine analysis allows the evaluation of the kidney function and urinary tract.

Cytology and histology of the lymph nodes

Although a cytologic examination can provide an indication about the tumour type, a histologic examination gives the most accurate information about the tumour grade and cell type present in the lymphoma. For accurate histology, it is advised to remove the whole lymph node. However, a short general anaesthesia is necessary for lymph node removal. An alternative, that has become widely available recently, is flowcytometry (FCM) and/or the PCR test PARR. A cytology sample is sufficient for these exams and can be taken without anaesthesia. Histology however remains the gold standard, as FCM and PARR cannot answer all the questions (yet). Through ultrasound, aspirates or fine needle biopsies can be obtained which depict the possible involvement of the liver, spleen and abdominal lymph nodes.

Cytology and histology of other lymphoid tissue

The method to obtain tissue samples will depend on the location of the suspicious tissue mass: surgically in case of intestinal biopsies, aspirates in case of chest or spine fluid, a punch biopsy in case of the skin.

Multiple diagnostic tests can be done on these tissue samples to better understand the tumour properties:

• cell population: a uniform cell population is indicative of tumoral tissue, whereas a mixed cell population of healthy tissue (in this regard lymphoma differs from most other tumour types!)
• cell type: one can determine the cell type (B or T cell) through immunohistochemistry/immunocytochemistry/flow cytometry. This is important information, as it will indicate how well the tumour will respond to standard treatments (the B cell lymphomas respond generally better to chemotherapy than T cell lymphomas).

Staging

Phase I: only 1 lymph node or lymphoid tissue in 1 organ is affected

Phase II: multiple lymph nodes are regionally involved

Phase III: general involvement of lymph nodes

Phase IV: liver and/or spleen are involved on top of phase III

Phase V: blood or bone marrow and/or other organs are involved (on top of phase I-IV)

Substage a: no general symptoms, i.e. the dog is feeling well and behaving normally Substage b: with general symptoms, i.e. the dog is ill and not feeling well

More than 80% of lymphoma are in an advanced stage at the moment of diagnosis (stage III or IV). To identify all the lesions and affected organs, the veterinarian may use imaging and/or perform a bone marrow punction. This is especially useful when we don’t know whether one or multiple organs/lymph nodes are involved. If only one tissue mass consisting of lymphoma cells is present, a local surgical excision may be sufficient. If there are multiple, it’s better to opt for a systemic treatment such as chemotherapy. For multicentric forms of lymphoma, anomalies situated in the chest are present in 60-75% of dogs (can be lung infiltrates or swollen lymph nodes), anomalies in the abdominal lymph nodes, spleen and/or liver in 50% of dogs.

Imaging

Evaluation of chest and abdominal radiographs may be important in determining the extent of internal involvement. Approximately 60-75% of dogs with multicentric lymphoma have abnormalities on chest radiographs. Abdominal radiographs can show involvement of various lymph nodes, spleen or liver in approximately 50% of cases. Abdominal ultrasound can be important to obtain ultrasound-guided intra-abdominal samples (if more peripheral lesions are not evident) for diagnosis or if complete clinical staging is necessary.

Histology

The classification of lymphoma is based on the anatomical location, the histological and immunophenotypical properties.

• Grade: most forms of lymphoma are intermediate to high-grade, only 5.3 to 29% are low-grade. High-grade tumours often respond better to chemotherapy than low-grade, but dogs with low-grade lymphomas tend to live longer without aggressive treatment.
• Immunophenotype: a lymphoma can develop out of B cells or T cells. These 2 cell types are called lymphocytes and both have a different function within the immune system. In general, forms of lymphoma consisting of T cells are less responsive to chemotherapy than those consisting of B cells. This leads to a shorter period of remission and survival for T cell lymphomas. Luckily, most lymphomas are B cell lymphomas (60-80%). The distinction between both is made through tissue sampling. Antibodies that specifically bind B or T cells will reveal the tumour’s identity.

Most forms of lymphoma are multicentric and therefore demand a systemic approach. This is why chemotherapy is the preferred treatment option for most forms of lymphoma, as chemotherapeutics reach cancer cells via the bloodstream. Chemotherapy is very well tolerated by companion animals. If the lymphoma is restricted to one location, local removal via surgery or radiotherapy is the preferred treatment option.

Chemotherapy

Combination chemotherapy is most frequently used for the treatment of a malignant form of lymphoma. Combination chemotherapy consists of different kinds of chemotherapeutics that are sequentially administered during the course of the treatment. The treatment duration and which chemotherapeutics are exactly used, depends on the (sub)stage of the lymphoma, the presence or absence of paraneoplastic disease, the general state of the dog, the balance between the dog’s wellbeing and treatment response, side effects of the treatment and of course the time and budget the owners can invest (some protocols take up to 24 weeks with weekly treatments, others 15 weeks with treatment every 3 weeks). Combination chemotherapy is generally preferred over chemotherapy with only one kind of cytostatic drug, as the effect is better and lasts longer.

Remission (the disappearance of the tumour) occurs in 80 to 90% of dogs after combination chemotherapy. The median survival time is 10 to 12 months. After 2 years, 20-25% of dogs treated with combination chemotherapy are still alive when treated for multicentric B cell lymphoma.

The cost of combination chemotherapy depends on the chemotherapeutic used, the size of the animal, the frequency of administration and (lab) monitoring. Before each chemotherapeutic treatment, a blood examination should be done to evaluate whether the levels of certain blood cells are sufficiently high. If the levels are too low, treatment should be withheld and the blood should be checked again after 3 to 7 days. If there’s lymphoma present in the bone marrow, the blood levels are more difficult to interpret.

Although the lymphoma will initially disappear in many dogs, most will relapse (generally within 1 year). This is generally due to the fact that in most cases not all tumour cells can be killed by chemotherapy, the number can only be decreased up to a certain point. After that it's up to the body's own immune system whether it is able to eliminate the residual tumour cells or not. A non-response or early relapse can be due to an initial treatment with prednisolone, administration of lower doses of cytostatic drugs (in line with the dog’s wellbeing), insufficiently high penetration of the chemotherapeutic drug into the tumour, or because the cancer cells became resistant to the chemotherapeutics. Although the lymphoma will initially disappear in many dogs, most will relapse (generally within 1 year). This is generally due to the fact that in most cases not all tumour cells can be killed by chemotherapy, the number can only be decreased up to a certain point. After that it's up to the body's own immune system whether it is able to eliminate the residual tumour cells or not. A non-response or early relapse can be due to an initial treatment with prednisolone, administration of lower doses of cytostatic drugs (in line with the dog’s wellbeing), insufficiently high penetration of the chemotherapeutic drug into the tumour, or because the cancer cells became resistant to the chemotherapeutics.

When a dog relapses, it’s necessary to repeat the treatment or to start up another treatment protocol with substances the dog has not received before (rescue protocol). In case of a high-grade form of lymphoma, a single chemotherapeutic drug will typically not lead to a durable remission compared to the standard combination protocols. Of note, for certain types of low-grade lymphoma, the use of metronomic oral cytostatic drugs with low levels of side effects - possibly combined with prednisolone- can lead to a long survival time. These subtypes are called “indolent lymphoma”. They make up about 5-10% of all lymphomas.

Enzyme therapy

Enzyme therapy such as PEG asparaginase (Oncaspar®) offers an alternative to those who do not want to start with chemotherapy for the treatment of malignant lymphoma forms or leukaemia. It is also used in conjunction with chemotherapy. This enzyme breaks down nutrients (the amino acid asparagine) for the cancer cell, preventing it from multiplying. This therapy does not achieve a cure, but rather suppresses the disease. The drug is quite safe for the dog and the waste products from PEG asparaginase are less harmful than those from chemotherapy. As a result, owners do not have to take precautions with faeces / urine / saliva. This option is often recommended (as opposed to chemotherapy) when pets are part of a family with children or live with pregnant women. There is no need for intravenous administration and bone marrow suppression rarely occurs. The main side effect is 1-2 days of diarrhoea and sometimes poor appetite, but this usually only occurs when the lymph nodes respond very well to the administered treatment and shrink very quickly. Hypersensitivity reactions are rare and can manifest as itching, redness, bumps, scabs or muscle pain.

The therapy consists of 1 injection into the muscles (or an intravenous infusion) every 2-3 weeks and if successful, the interval can be extended.

However, Oncaspar® is a very expensive medicine with a limited shelf life.

Immunotherapy

Much research is done on immunotherapeutic alternatives for dogs with a systemic form of lymphoma.

The antibody Rituximab is used in humans but has no effect on canine lymphoma. Multiple studies have been performed on vaccines against lymphoma. The APAVAC® vaccine for lymphoma has resulted in a significant increase of survival rates in some patients and thus seems to be a promising novel treatment. It is always used in conjunction with a polychemotherapy protocol. However, further studies and more patients are required to confirm these results.

Prednisolone

Administration of prednisolone can be considered a palliative treatment option. The use of steroids prior the chemotherapy can negatively affect the effect of the chemotherapy.

Surgery

Surgery can be appropriate when it entails a single lymph node (stage I) or when it’s a single tumour not localized in the lymph nodes. E.g. in case lymphoma is present in the eye or a solitary tumour in the digestive system, complete surgical removal has led to encouraging results.

Radiotherapy

Radiation therapy, although of limited routine use in the treatment of lymphoma, may be useful in selected cases. Potential indications are as follows:

• Curative intent for stage I and solitary extranodal disease (e.g. nasal, cutaneous, spinal lymphoma)
• Palliation for local disease (e.g. localized bone involvement, rectal lymphoma, mandibular lymphoma). For lymphoma located in the central nervous system generally the response rate is low and of short duration (a few weeks to months).
• Total body radiation combined with bone marrow or stem cell reconstitution. Bone marrow transplants as described in humans, is not a standard treatment option for companion animals in Europe. After consultation with a radiotherapist and oncologist, it can be decided to irradiate the entire body of the dog, it depends on the case.
• Half-body radiotherapy after chemotherapy-induced remissions or in between chemotherapy cycles.

The prognosis is very variable and depends on many factors (the subtype of the form of lymphoma, the clinical stage, a pretreatment with steroids, the location of origin, hypercalcemia, a shortage of red blood cells etc.). Without treatment, most dogs die within 4-8 weeks of the diagnosis (although there is a strong variability). Lymphomas are rarely completely curable (less than 10% of cases). The treatment is more likely to cause a temporary disappearance of the tumour (during months). However, during and after treatment, the dog experiences a good quality of life. If the dog is treated with combination chemotherapy, a median survival of 12 months can be expected for the most common form of lymphoma (multicentric), and after 2 years, 20-25% of dogs are still alive.

A study in 1992 examining the effects of PEG asparaginase treatment in dogs with lymphoma, showed that in 81% of treated dogs the tumour reduced in size or disappeared after the first 2 weeks of treatment. Furthermore, with the addition of other chemotherapeutic drugs, the number of responding dogs increased even further to 94%. The study also showed a median time to relapse of 217 days for dogs treated with PEG asparaginase combined with chemotherapy. The survival time for dogs treated with PEG asparaginase combined with chemotherapy ranged from 19 to 1030 days and the overall median survival time was 351 days. Other studies have shown that comparable results were obtained with chemotherapy only.

The prognosis is worse if:

• The dog has been treated with corticosteroids (for several weeks) before initiation of chemotherapy
• The dog is clinically sick (substage b)
• When the tumour consists of T cells
• When the tumour consists of B cells, but with a low expression of B5 and/or MHC receptors (on histology)
• When it’s a high-grade tumour
• When the tumour spreads in the skin or in the digestive system
• When the tumour is (only) in the spleen or liver
• When the tumour is in the central nervous system
• When blood calcium levels are elevated
• When there are multiple lesions

The prognosis is better if:

• The dog develops neutropenia after administration of chemotherapeutic drugs
• The drug administration interval has to be lengthened due to side effects
• The dog is clinically well
• For certain subtypes of lymphoma called 'indolent lymphomas'. Usually, histology and immunohistology are necessary for accurate diagnosis
• For low-grade (or small cell) lymphomas

General statements with regards to lymphoma:

• Treatment with prednisolone alone: average survival time of 2 months.
• Treatment with a single type of chemotherapy: less than one year survival (very variable in response and duration and depends on the form of lymphoma).
• Treatment with combination chemotherapy: average survival time one year, with a range of a few months to 4 years. It is possible that in the future longer survival times can be obtained by combining regular treatments with immunotherapy.

It is possible that in the future longer survival times can be obtained by combining regular treatments with immunotherapy.

Current level of knowledge: