Canine lymphoma: The naive patient (Proceedings)

Incidence and signalment

Canine lymphoma (LSA) makes up approximately 18% of all malignancies in the dog, and 80% of all hematopoietic tumors in dogs are LSA. Middle-aged dogs are most commonly affected; but out of cancers affecting young dogs (as young as 6 months), LSA is common. No sex predisposition is consistently reported. Boxers, golden retrievers, basset hounds, St. Bernards, Scottish terriers, and mastiffs are breeds that are all overrepresented.

Etiology

No definitive etiology for canine lymphoma has been identified. Risk factors investigated include viral, genetic (shown only in a limited lineage in mastiffs, otterhounds, rottweilers, Scotties, and golden retrievers), environmental (herbicides such as 2,4-dichlorophenoxyacetic acid (2,4 D) - this study was found to be erroneous), and inflammatory bowel disease. No strong associations have been found.

History

In dogs, the multicentric form of lymphoma (multiple peripheral lymph nodes (LNs)) is the most common. Typically, dogs are asymptomatic and present because their owners have noticed enlarged LNs ("lumps under chin"), or the LNs are noted to be enlarged on a routine physical exam. Less commonly, dogs with multicentric LSA may present clinically ill (decreased appetite, lethargy). For forms of LSA other than multicentric, the signs are consistent with the organs affected: vomiting/weight loss for GI, altered mentation/seizures for CNS, etc.

Biologic behavior

LSA is a malignancy that usually arises in lymphoid tissues (LNs, liver, spleen, bone marrow); however, it can arise in or invade any tissue. As it is almost always a systemic disease, chemotherapy is the mainstay of therapy. Different anatomic sites (or FORMS) of lymphoma respond differently to therapy. Additionally, for multicentric LSA in dogs, many prognostic factors in regards to potential response to treatment are known. Negative factors include substage b (clinically ill), hypercalcemia, T cell immunophenotype, cranial mediastinal mass, leukemia, and >50% bone marrow involvement.

Diagnostic evaluation/staging

The diagnosis of LSA is easy to make via fine needle aspirate (FNA). LSA is almost always a systemic disease, thus staging to determine extent of disease is important for prognosis and monitoring response to therapy. Thorough staging of animals with LSA includes:

Fine needle aspirate (FNA)

Simple and almost always diagnostic. A needle aspirate of the typical untreated canine lymphoma consists of a monomorphic population of immature (large) lymphocytes (a homogenous population of round, mononuclear cells). These cells have a large size (> neutrophil), high nuclear to cytoplasmic ratio, open and coarse ('lacy') nuclear chromatin pattern with prominent nucleoli, and deep blue cytoplasm. A normal LN contains 75 to 95% small, mature lymphocytes, a reactive LN can have up to 50% lymphoblasts (and will also have plasma cells), and > 50% lymphoblasts is diagnostic for LSA.

Complete blood count

May be normal, or may reveal cytopenias or leukemia. Cytopenias may be due to the paraneoplastic syndromes of immune-mediated hemolytic anemia or thrombocytopenia or may be due to bone marrow infiltration by the tumor cells (see below).

Serum chemistry profile

May be normal, or may reveal abnormalities related to organ infiltration (e.g. elevated liver enzymes) or production of substances by the tumor cells. Hypoglycemia is rarely identified in dogs with LSA. Hypercalcemia is a paraneoplastic syndrome that occurs secondary to malignant cell production of one or more factors, one of which can be parathyroid hormone-related peptide (PTHrP). Hyperproteinemia is a rare finding and is secondary to antibody production by tumor cells.

Urinalysis

Important to assess prior to starting chemotherapy. Subclinical urinary tract infections can become a source for bacterial sepsis in an animal with chemotherapy-induced myelosuppression. Also, animals with LSA have decreased immune function due to their disease and can be predisposed to infections.

Thoracic radiographs

Evaluate for lung parenchymal involvement (diffuse interstitial pattern, almost never nodular) and perihilar, mediastinal or sternal lymph node enlargement.

Abdominal radiographs

Evaluate for organomegaly. Changes associated with GI lymphoma may be difficult to detect on plain films. Abdominal ultrasound is indicated in dogs where GI LSA is suspected.

Bone marrow aspirate

Due to its invasive nature and the fact that significant marrow involvement is very rare and when present is usually suspected by CBC changes, this procedure is not often performed. Greater than 50% infiltration of LSA within the marrow is a poor prognostic factor. Very severe infiltration may cause myelophthisis (crowding out of normal marrow elements by malignant cells) and cause peripheral cytopenias. "Aleukemic leukemia" is when the marrow is heavily infiltrated with lymphoblasts yet no malignant cells are circulating.

Tissue biopsy

RARELY needed! Tru-cut biopsies are not much better than FNAs. Excisional biopsy of an entire LN may be necessary to diagnose small cell, or low grade, LSA. The small cell variant is uncommon in dogs; nodal architecture/sinus spaces/etc. need to be evaluated to determine that the small cells are malignant. (i.e., on FNA a uniform population of small cells is seen. Malignancy is proven by seeing these cells ablating normal nodal architecture and invading the subcapsular sinus).

While clinical substage is highly prognostic for treatment response and survival time, the stage itself does NOT predict response and survival in direct correlation to the stage number. For example, stage IV LSA (liver and or splenic involvement with peripheral lymphadenopathy) does NO WORSE than stage III LSA (only peripheral lymphadenopathy). Pulmonary involvement is not a negative factor, yet makes dogs a stage V (non-hematopoietic organ), while mediastinal lymphadenopathy IS worse, yet is still a stage III. Noting the previously mentioned prognostic factors is more important than the specific stage number.

Treatment

Lymphoma can be an extremely gratifying tumor to treat. As it is almost always a systemic disease, the treatment must be systemic (chemotherapy). There are many different protocols for lymphoma. The response rate for multicentric lymphoma ranges from 65 to 90%, with a complete remission (CR) occurring within the first few weeks of chemotherapy. Although the majority of animals experience complete clinical remission, a cure is rarely obtained. Most protocols result in a disease free interval of 6 to 10 months. Doxorubicin-based combination chemotherapy protocols are associated with the longest disease free intervals. Survival time varies, depending upon whether or not the owner elects to attempt a second round of chemotherapy. On average, a dog with multicentric LSA will survive 12 months following diagnosis if treated with a multidrug chemotherapy protocol. Dogs with poor prognostic factors do worse.

Maintenance therapy

In the past 5-10 years, a shift has occurred away from protocols with an extended maintenance phase in which treatments are given at progressively longer intervals to protocols that are more intensified early on and last for a shorted duration (e.g. 4-6 months vs years). Recent studies have shown that shorter protocols result in similar disease free and survival times when compared to protocols with prolonged maintenance. The author's preferred protocol (modified UW Madison) entails 8 weekly treatments, then 8 treatments every other week for a total treatment duration of 6 months.

Rescue therapy

Rescue treatment is given when an animal comes out of remission or fails to respond to the initial chemotherapy protocol chosen. Depending upon the length of time the animal was in remission and if they have been able to be off of drugs, the original induction protocol or other drugs will be recommended. Anywhere from 50-100% of animals (depending on the protocol) experience a 2nd complete remission, which usually will be shorter than the first. Whether to try to obtain a 2nd, 3rd, 4th, etc remission is a decision each owner needs to make, once presented with the costs/side effects/likely response to the protocol.

Chemotherapy resistance

Eventually, tumor cells become resistant to chemotherapy. The most common mechanism of resistance is through induction of p-glycoprotein. This membrane-bound protein is an energy-utilizing pump that removes toxins from the cell's cytoplasm. It confers resistance to many of the commonly used chemotherapy drugs and is the ultimate cause of failure of therapy in many LSA patients. Many agents have been evaluated as potential inhibitors of this pump; however, nothing to date has been clinically successful.

New treatments on the horizon

Dogs with LSA respond well to chemotherapy and have a good quality of life throughout most of their treatments; however, a wall has been hit in regards to improving survival time by tweaking chemotherapy protocols. Bone marrow transplantation in combination with high dose chemotherapy for pet dogs with LSA has recently been used at NC State University; while still in the early phases of patient accrual, initial responses have been encouraging. At the author's institution (U of Illlinois), several variants of a targeted therapy for inducing apoptosis are currently under investigation. Hopefully new options will be shown to increase survival times for this common cancer.