Round cell tumors in cats (Proceedings)

Lymphoma and retroviruses (non-alimentary)

Lymphoma is considered to be the most common cancer in the cat.  Lymphoma can affect cats of any age group and any breed.  There seems to be biphasic occurrence with a peak in young cats and then another peak in middle aged to slightly older cats.  Initially, reports indicated that DSH and DLHs were predisposed; however, more recently Siamese and Oriental pure bred cats were noted to be at higher risk of developing lymphoma.  This may be due to the higher incidence of FeLV in catteries.  Siamese are also predisposed to developing mediastinal lymphoma.  Male cats have predominated in several studies.  This is likely due to a greater propensity to roam and fight with other cats leading to an increased risk of viral infection.

Approximately 25% of all FeLV positive cats will develop lymphoma at some point in their lives.  Just because a cat is seronegative for FeLV doesn't mean that they are not infected.  Five percent of lymphomas in nonFeLV positive cats will have provirus in their tumors.  PCR and IHC have been developed to more accurately diagnose feline leukemia virus in those cats that are seronegative. 

FIV has been implicated in the development of lymphoma in cats, however, the true incidence is difficult to determine because it often occurs with FeLV. These cats tend to develop multicentric lymphomas as well as extranodal lymphomas.  According to one study, cats with FeLV are 60 times more likely to develop lymphoma, cats with FIV are 5 times more likely to develop lymphoma and cats with both viruses are 80 times more likely to develop lymphoma than non-infected cats.

Mediastinal lymphoma

In the 1980's it represented 20-40% of all feline lymphomas in the United States.  Recently it has been found to account for only 15% of feline lymphoma cases.  The median age for all cats affected is less than 5 years.  Siamese and oriental breeds appear to be at a higher risk for this form representing 30-90% of cats affected in various studies.  Young Siamese cats are at the highest risk for this form of lymphoma.  FeLV plays a role in the etiology of this disease.  It is estimated that about 75% of cats with this form of lymphoma are FeLV positive. 

Clinical signs/ physical exam

Dyspnea is the most common presenting sign associated with mediastinal lymphoma. Other clinical signs that have been reported include regurgitation, dysphagia, anorexia, weight loss, enlarged lymph nodes, cough and ptyalism.  The history of clinical signs is usually acute.  PE: Often reveals dull lung and heart sounds ventrally.  The chest may not have normal compressibility and occasionally a palpable mass is present at the thoracic inlet.  Peripheral lymph node enlargement may be present in 30-40% of cats.  Most commonly the lymph nodes of the head, axilla and neck are affected.  Pleural effusion is common with invasion of intrathoracic structures.  This can lead to exacerbation of dyspnea and can become life threatening. 

Diagnosis

Basic blood work including a CBC, biochemistry profile, urinalysis and FeLV/FIV test should be performed on every cat with a mediastinal mass.  Thoracic radiographs often demonstrate the mediastinal mass.  The mass may be obscured by pleural effusion.   Cytologic evaluation of pleural effusion is almost always diagnostic because large lymphoblasts exfoliate into the fluid.  Thoracic ultrasound is a good way to get a fine needle aspirate or tru-cut biopsy of the mass. The patient should be stabilized before performing this or any diagnostics.  The main differentials for a mediastinal mass in the cat include: lymphoma, thymoma, ectopic thyroid tissue and a branchial cyst.  Ultrasound guided fine needle aspirates or tru-cut biopsies can help you to differential all of these.  It can be difficult to differentiate a thymoma from lymphoma with a fine needle aspirate alone.  Therefore, a biopsy may be required. 

Staging

Approximately half of these cats will have evidence of lymphoma elsewhere.  Most commonly it is found in peripheral lymph nodes, intra-thoracic and intra-abdominal lymph nodes. Less commonly it can be found in other organs such as the spleen, liver, bone marrow or kidney.  Complete staging includes abdominal ultrasound and a bone marrow aspirate in addition to the tests mentioned previously.

Therapy

Surgery does not play a role in the treatment of mediastinal lymphoma.  Radiation therapy has been used to increase response rates or treat those cats that have become resistant to chemotherapy.  There is not a lot of information available on survival times for cats treated with radiation therapy. There is high risk of pulmonary damage associated with high doses of radiation therapy; however, lymphoma tends to be very radiation responsive.  Chemotherapy is the mainstay of therapy for mediastinal lymphoma.  This particular form of lymphoma has been reported to be one of the most chemotherapy responsive lymphomas in the cat.  CHOP chemotherapy (see appendix A) is the treatment of choice for these cats.  Multiple drug therapy has been shown to be more effective than single agent therapy, especially when doxorubicin has been added to the protocol.  Response rates have been reported to range from 50-90%. 

Prognosis

FeLV negative cats tend to have the longest survival times with remissions of greater than 1 year.  FeLV positive cats have reported median survival times of 2-3 months to 4-6 months.  Anecdotally, many oncologists feel that these cats enjoy longer survival times then what has been reported.  Some of these cats have been reported to have disease free intervals of years and often die of other causes related to their FeLV status.  Cats with a single mediastinal site that stage clean elsewhere tend to survive longer than cats with more diffuse disease. 

Multicentric lymphoma

Diagnosis and Staging

The extent of the disease should be determined in all cats with peripheral lymphadenopathy.  The minimum data base of a CBC, biochemistry profile, urinalysis and FeLV/FIV test should be performed.   In addition, thoracic radiographs, abdominal ultrasound and bone marrow aspirates should be performed.  A fine needle aspirates of the affected lymph node is often enough for diagnosis.  Therapy and Prognosis- Treatment for a single node lymphoma may be surgical excision after appropriate staging has been done. Some cats may experience recurrence at the primary site or at another site; these cats should be re-staged and possibly followed up with either another surgery for a single location, or chemotherapy for more disseminated recurrences.  For Hodgkin's like lymphomas the prognosis can be very good after surgical excision. For cats with more disseminated disease chemotherapy is warranted.  We use the CHOP protocol for these cats.  FeLV/FIV positive cats and cats that are sick on presentation carry a worse prognosis than those with single or regional node involvement. 

Nasal lymphoma

The clinical signs include nasal discharge, facial deformity, watering of the eyes, anorexia (due to inability to smell food) and weight loss.  Diagnosis is usually achieved with a nasal biopsy or fine needle aspirate through the face. Staging includes a minimum database previously discussed, thoracic radiographs, abdominal ultrasound, bone marrow aspirate and CT scan of the head for radiation planning.  Treatment options include radiation therapy and chemotherapy either alone or in combination. 

Intracranial lymphoma/CNS lymphoma

The overall incidence is unknown. Not all cats with brain involvement will have symptoms.  Intracranial lymphoma is more commonly associated with older FeLV negative cats, whereas spinal lymphoma is more commonly associated with young FeLV positive cats.  Clinical signs are associated with the location of the mass.  Diagnosis may be achieved about 50% of the time with a CSF tap.  CT or MRI is very good at demonstrating a mass in the brain.  CT images of cats with intracranial lymphoma revealed a solitary ring enhancing mass in 5 of 6 cats.  Staging should be done as previously discussed. Therapy options include radiation and chemotherapy.

Renal lymphoma

Affects middle aged (median age 7.5 years) male cats.  Most cats are domestic short and long hairs. 25% of cats are FeLV positive.  Clinical signs are typically related to acute renal insufficiency due to cortical infiltration by lymphoma cells.  Renal lymphoma is always bilateral and renomegaly is often easily found on abdominal palpation. Staging should be done as previously described.  Diagnosis is usually achieved with a fine needle aspirate of the kidney.  Therapy consists of combination chemotherapy such as the CHOP protocol. Median survival times are longer for FeLV negative cats.  The median survival time for all cats is 3-5 months. 

Mast Cell tumors

Mast cell tumors are the 2nd most common skin tumor in cats. Histiocytic tumors tend to occur in younger cats (mean age 2.4 yrs) and mastocytic MCTs are more likely to occur in older cats with a mean age of 10 years. Siamese cats are predisposed to both histologic forms of the disease. The etiology is unknown.

Pathologic and natural behavior

Visceral mast cell disease is more common in the cat than the dog.  Up to 50% of cats can have visceral involvement. Visceral tumors are more likely to spread than cutaneous forms. Metastatic rates for cutaneous tumors in cats are variable from 0-22% in different studies.  Diffuse tumors are thought to have higher metastatic rates than others.  The histiocytic types often regress on their own within 4-24 months.  In the feline visceral form the spread is most often to the liver first, then visceral lymph nodes, bone marrow, lung and intestine.  Cats are much more likely to develop mastocytosis than the dog.

The grading system and histology

The one used in dogs does not apply to cats. Histologically anaplastic mast cell tumors may be difficult to differentiate from other round cell tumors. The two different histologic types of tumors in cats are differentiated by certain characteristics.  The mastocytic tumors are more like those that occur in the dog.  There are two main types: well differentiated (compact) and anaplastic (diffuse).  Well differentiated tumors are the most common comprising 50-90% of feline MCTs. 

Cutaneous MCTS

Similar to dogs with small, solitary nodules that are frequently non-haired and ulcerated ~25% of the time.  Less frequently they may appear as plaque like masses or subcutaneous masses.  Multiple nodules occur in approximately 20% of cases. The histiocytic type tends to occur as multiples on the head and may be ulcerated, but often resolve on their own. Cutaneous MCTs in the cat often occur on the head and neck, then the trunk and limbs. 

Visceral MCTS

More common in cats than in dogs (up to 50%).  Splenic MCT is the most common splenic disease of cats. Often cats with visceral or disseminated forms will present with clinical signs of depression, anorexia, weight loss, vomiting, diarrhea and melena.  Most cats have been sick for several months. 

Intestinal MCTS

Intestinal MCTs are the 3rd most common intestinal tumor in cats behind LSA and adenocarcinoma and commonly affect the SI with only 15% affecting the colon. Diarrhea is a common sign associated with intestinal MCT.

Diagnosis and staging

Initial diagnosis is usually achieved with fine needle aspirates of the mass as well as any local lymph nodes that are accessible.  A CBC, biochemistry panel and urinalysis are needed even in the most benign appearing MCT. Approximately 50% of all cats with visceral MCT are anemic and many animals may have abnormalities concurrent with GI ulcers such as low protein, anemia and increased BUN.  Buffy coats are still warranted in the cat because they are more likely to have spread to their bone marrow with disseminated disease. Some cats with splenic MCTs have also been reported to have hyperglobulinemia.

Therapy and prognosis

Surgical excision of cutaneous lesions is usually curative.  Cats often do not have recurrence (0-24%) and if they do, they typically have it within 6 months.  Cats with histiocytic MCT can be identified on biopsy and then watched.  If they do not regress in several months, then they should be removed.  Splenic MCT in the cat may have spread elsewhere, but cats can improve clinically with a splenectomy.  Survival times post splenectomy has been reported to be 12-19 months even in the face of bone marrow and peripheral blood disease.  Intestinal MCT in the cat carry a worse prognosis.  They require large surgical margins (if focal) of 5-10 cm of bowel on either side.  They often have high spread rates and cats usually die or are euthanized soon afterwards. Chemotherapy in the cat is mostly untested, however, post splenectomy or with disseminated MCT people have tried vinblastine, vincristine, cyclophosphamide and methotrexate. Radiation therapy is not very useful in cats because they tend have more systemic disease. 

Plasma cell tumors:

Multiple myeloma (MM)

The true incidence in the cat is unknown, but it is much rarer in the cat than in the dog.  It is estimated to be 0.9% of all feline malignancies and 1.9% of all hematopoietic malignancies. Median age affected- 12-14 years. Most often in DSH. No sex predilection. MM has not been associated with retroviral infections in the cat.

Pathology and natural behavior

Feline MM is more likely to look anaplastic and poorly differentiated compared to canine MM. Hypergammaglobulinemia can result in many clinical signs (detailed below). Bone lesions can be solitary or diffuse. They occur in 50-65% of cats.  Bleeding diathesis can occur for many reasons.  Often the M components will interfere with platelet aggregation and clotting factors.  Hemorrhage occurs in ~25% of cats. Thrombocytopenia can also occur with myelophthisis. Hyperviscosity syndrome (HVS) occurs because of the large amount of protein in the blood leading to sludging in the small vessels, ineffective delivery of oxygen and nutrients, and coagulation abnormalities.  Renal disease occurs in up to 33% of cats with MM. 

Hypercalcemia can occur in up to 25% of cats with MM. These cats are immunologically crippled by their disease and very susceptible to secondary infections. Cardiac disease occurs as a result of increased work load on the heart and myocardial hypoxia secondary to HVS.  Up to 50% of cats with MM will have a murmur.  Infiltration of the heart by tumor cells can also occur.

History and clinical signs

Most common clinical signs seen in cats with MM in order: Weakness and lethargy, Anorexia, Pallor, PU/PD, Vomiting/ diarrhea, Dehydration, Organomegaly, Lameness, Heart murmur, Hind limb paresis/paralysis, Bleeding diathesis, CNS dementia, Lymphadenopathy, Concurrent cutaneous plasma cell tumor.

Diagnosis and staging

Cats can be harder to diagnose than the dog because of their lack of bone marrow involvement in many cases. Differential diagnoses for cats with Monoclonal gammopathies: Lymphoma, EMP- extramedullary plasmacytoma, Chronic and acute lymphocytic leukemias, Ehrlichiosis, Leishmaniasis, FIP- feline infectious peritonitis, MGUS.

The diagnosis is usually made using a combination of CBC, Chemistry, UA, serum or urine protein electrophoresis and a bone marrow aspirate. In cats a 10% infiltrate with plasma cells that appear atypical is adequate for a diagnosis. Chest films are recommended in all cats. An abdominal ultrasound should be performed in all cats.  Most will have splenomegaly (with or without nodules), hepatomegaly (with or without nodules) and many may have renomegaly and lymphadenopathy as well.  Fine needle aspirates should be performed on abnormal organs for diagnostic support.  Survey skeletal films can be done if bone lesions are suspected. 

Treatment

Because response to therapy can be quite remarkable initially it is important to make sure that all diagnostics are completed before initiating therapy.  Cats do not respond to therapy as well as dogs, unfortunately.  Approximately 50% of cats will respond to therapy and of those that do the responses are often short lived.  However, long term responses have been reported and it may that cats do better than initially thought. Melphalan (Alkeran®) is the drug of choice for MM in both the cat and the dog.  This drug is more myelosuppressive in the cat than in the dog.  It can also lead to myelofibrosis with long term use and therefore, must be used with care in the cat.  The dose schedule in the cat is 0.1mg/kg (or approximately 0.5 mg- ¼ of a 2 mg tablet) given once daily for 10-14 days, then every other day until clinical improvement or leucopenia. 

Prognosis

50-60% of cats will respond initially to melphalan therapy. However, most responses are partial and not durable.  Most cats live an average of 3-4 months.  Occasional cats will live over 1 year, and anecdotally, some oncologists feel that cats can do better than previously thought because are better at diagnosing it. 

Solitary and Extramedullary Plasmacytomas

Less common in cats than in dogs, and often in middle aged to older cats (8.5 yrs). The skin is the most common site, but other sites that can be affected include the oral cavity, eye, GI tract, liver, subcutaneous tissue, and brain.

Clinical signs

They are typically small, pink, non-haired smooth appearing cutaneous masses.  Oral tumors are often solitary, usually located on the palate and often very red.  Oral bleeding, appetence, dropping of food and ptyalism can be seen in association with these tumors. Gastrointestinal tumors often have non-specific GI signs of vomiting, anorexia, and weight loss.  Colorectal tumors may lead to frank blood in the stool, tenesmus and rectal prolapses.

Diagnosis

A diagnosis can typically be made using a fine needle aspirate; however, occasionally a biopsy is necessary.

Treatment

If there is no evidence of systemic disease surgery is the treatment of choice whenever possible.  Complete surgical excision can often result in long term survival and even cures.  This is generally true for cutaneous and oral lesions.  However, gastrointestinal tumors are often not cured with surgery alone.  For nonresectable oral lesions, radiation therapy has been very successful in the dog.  If the surgery is complete and there is no evidence of systemic disease, no systemic therapy is initiated.  If systemic disease is found then therapy is initiated as indicated for MM.

Prognosis

Not known. Local disease that is controlled with surgery and possibly chemotherapy can result in long term survival. 

A few words about histiocytic diseases in cats

Very rare in the cat. A few cases have been reported, however. Usually cats present with multifocal or disseminated disease.  Reported organs of involvement include: Spleen, liver, CNS, lymph nodes, lung, mediastinum, kidney, bladder and bone marrow. Anemia (either regenerative or non-regenerative) is seen often and is often severe. Thrombocytopenia is also seen often and is also often severe. Bone marrow involvement seems to be a common occurrence (in the 4 cases I know of). The clinical course if often aggressive and no reports of response to treatment have been seen.   I recommend trying CCNU in these cats at 50-60 mg/m2 every 3-6 weeks.

Appendix

CHOP Protocol

Week 1:   Vincristine 0.5-0.7 mg/m2 IV

                     L-Asparaginase 400 U/kg SQ

                 Prednisone 2 mg/kg PO SID

Week 2:    Cytoxan 250 mg/m2  IV or 60 mg/m2 orally once daily for 4 days.

                 Prednisone 1.5 mg/kg PO SID

Week 3:   Vincristine 0.5-0.7 mg/m2  IV

                 Prednisone 1 mg/kg PO SID

Week 4:  Adriamycin 25 mg/m2  IV

                   Prednisone 1 mg/kg PO SID

Week 6: Vincristine 0.5-0.7 mg/m2  IV

                   Prednisone 1 mg/kg EOD

Week 7:  Cytoxan 250 mg/m2  IV or 60 mg/m2 orally once daily for 4 days.

               Prednisone 1 mg/kg EOD

Week 8: Vincristine 0.5-0.7 mg/m2  IV

               Prednisone 1 mg/kg EOD

Week 9: Adriamycin 25 mg/m2  IV

               Prednisone 1 mg/kg EOD

Week 11:   Vincristine 0.5-0.7 mg/m2 IV

                 Prednisone 2 mg/kg PO EOD

Week 13:    Cytoxan 250 mg/m2  IV or 60 mg/m2 orally once daily for 4 days.

                 Prednisone 1.5 mg/kg PO EOD

Week 15:   Vincristine 0.5-0.7 mg/m2  IV

                 Prednisone 1 mg/kg PO EOD

Week 17:  Adriamycin 25 mg/m2  IV

                   Prednisone 1 mg/kg PO EOD

Week 19: Vincristine 0.5-0.7 mg/m2  IV

                   Prednisone 1 mg/kg EOD

Week 21:  Cytoxan 250 mg/m2  IV or 60 mg/m2 orally once daily for 4 days.

               Prednisone 1 mg/kg EOD

Week 23: Vincristine 0.5-0.7 mg/m2  IV

               Prednisone 1 mg/kg EOD

Week 25: Adriamycin 25 mg/m2  IV

                   Prednisone 1 mg/kg EOD

Vinblastine Protocol

Week 1: Vinblastine 2 mg/m2  IV

                   Prednisone 2 mg/kg PO SID

Week 2: Vinblastine 2 mg/m2  IV

                   Prednisone 1.5 mg/kg PO SID

Week 3: Vinblastine 2 mg/m2  IV

                   Prednisone 1 mg/kg PO SID

Week 4: Vinblastine 2 mg/m2  IV

                   Prednisone 1 mg/kg PO SID

Week 6: Vinblastine 2 mg/m2  IV

                   Prednisone 1 mg/kg PO SID

Week 8: Vinblastine 2 mg/m2  IV

                   Prednisone 1 mg/kg PO SID

Week 10: Vinblastine 2 mg/m2  IV

                    Prednisone 1 mg/kg PO SID

Week 12: Vinblastine 2 mg/m2  IV

                    Prednisone 1 mg/kg PO SID

CCNU

CCNU (lomustine, CeeNU) 50-60 mg/m2  PO q 3-6 weeks for 5 total cycles (microscopic disease).

* Exceptions include partial remissions or palliative settings where you would continue CCNU past 5 cycles.  Technically you would give this drug in a gross disease setting until you have 2 doses past a complete remission or until the side effects require discontinuation.

** Cats can have prolonged nadirs to this drug that may take up to 6 weeks to reach full fruition.  Please monitor all cats carefully to make sure that their CBC values are adequate.