Lymphosarcoma In Cats
Mary Ann Vonderhaar and Wallace B. Morrison
Lymphosarcoma is a neoplasm of malignant lymphocytes in solid organs such as lymph nodes, bone marrow, or visceral organs such as the liver and spleen. Lymphosarcoma is usually amenable to chemotherapy protocols that are within the capabilities of most veterinary practices.
LYMPHOSARCOMA IN CATS
Hematopoietic tumors are the most frequently occurring tumors in domestic cats, and they account for about 33% of all feline tumors. Lymphosarcoma accounts for up to 90% of the hematopoietic tumors in cats, with an estimated incidence of 200 cases/100,000 cats at risk. No increased prevalence has been reported for any sex or breed of cat. The usual age of cats at diagnosis is between 2 and 6 years. In many cases, lymphosarcoma in cats follows infection with the feline leukemia virus (FeLV). FeLV is a very immunosuppressive retrovirus that has been linked to the development of lymphosarcoma in both FeLV test-positive and FeLV test-negative cats. Depending on tumor location and age at diagnosis, the rate of FeLV infection (positive test by IFA) ranges from 30%-80%. Young cats with multicentric, mediastinal, spinal, extranodal, or leukemic lymphosarcoma tend to be FeLV test positive. Older cats and those with alimentary lymphosarcoma tend to be FeLV test negative. It appears that the difference in FeLV-test status in cats with lymphosarcoma is not because of differences in exposure to FeLV. Epidemiological studies have shown that FeLV test negative cats with lymphosarcoma have the same exposure to the virus as FeLV test positive cats. Also, tumor cells from both FeLV test-positive and test-negative cats express tumor specific cell membrane antigens on their surface known as feline oncornavirus-associated cell membrane antigens (FOCMA), indicating that both have been exposed to FeLV.
Feline immunodeficiency virus (FIV) is a T-cell lymphocytotrophic lentivirus that causes an immunodeficiency-like syndrome in cats. There is considerable evidence suggesting that FIV infection contributes to the development of lymphosarcoma in some cats. The relative risk of developing lymphosarcoma or leukemia is approximately 6 times greater in cats persistently infected with FIV, 62 times greater when persistently infected with FeLV, and 77 times greater in cats persistently infected with both FeLV and FIV when compared with noninfected cats. Coinfection with FIV and FeLV increases the potential of developing lymphoproliferative diseases. Possible effects of the FIV infection that can lead to lymphosarcoma include activation of ß lymphocytes with the eventual emergence of malignant cells from the proliferating ß-cell pool, chronic dysregulation of the immune system, or activation of oncogene pathways that facilitate the malignant transformation of normal cells.
In one report, chromosomal aberrations were present in 8/9 leukemic cats that tested positive for FeLV. This abnormality was absent in cells from healthy, FeLV test negative cats. The most common abnormalities were numerical tetrasomy, trisomy, and monosomy. Chromosomal changes were observed in aleukemic, FeLV test positive cats. It is unknown if these cases represent early neoplastic transformation or preneoplastic damage. At the present time, there is no known association between these chromosomal abnormalities and the genes that control lymphoid differentiation.
Lymphosarcoma in cats can arise from ß cells, T cells, null cells, lymphoblasts, immunoblasts, or plasma cells. Lymphosarcoma occurs primarily in visceral organs (GI tract, liver, spleen), bone marrow, or lymph nodes. Histologically, either nodular aggregates of malignant lymphocytes or complete effacement of the architecture by malignant cells can be seen. In similar fashion to dogs, lymphosarcoma in cats canbe categorized by the anatomic location of the primary site of involvement and by histologic grade.
The anatomic forms of lymphosarcoma in cats are mediastinal, alimentary, multicentric, and extranodal. Unlike dogs, in which the multicentric form is overwhelmingly the most common presentation (up to 84%), the most common form occurring in cats is inconsistently reported. Early studies reported that the multicentric form was the most common, occurring in 44% of cats with lymphosarcoma, followed by the mediastinal form in 38% of cases, and the alimentary form in 15% of cases. A later cytologic and histologic review reported that alimentary was the most common form (30%), and extranodal was the second most common type.
In 1994, Rojko and Hardy compared several feline lymphosarcoma studies from different parts of the world and noted the differences in the reported primary anatomic site of involvement among cats from different geographic locations. Surveys from New York indicate that multicentric lymphosarcoma is the most common type, followed by mediastinal, alimentary, and extranodal. Surveys from Boston indicate that lymphocytic leukemia is more common than mediastinal, extranodal, multicentric, or alimentary lymphosarcoma. A California study reported almost equal numbers of cats diagnosed with alimentary and mediastinal forms, whereas in Japan and Scotland the mediastinal form was reported to be most common. It is unclear why these apparent regional differences exist. Until recently, feline lymphosarcoma was histologically classified using the Rappaport classification scheme. Unfortunately, classification by this scheme does not provide any prognostic information for cats with lymphosarcoma.
The National Cancer Institute-Working Formulation (NCI-WF) uses mitotic and clinical features to group tumors in low, intermediate, and high grades. Valli et al. classified more than 600 cases of feline lymphosarcoma using the NCI-WF. Only 2% of the cats in this large study had lymphoblastic lymphosarcoma compared with >15% in dogs. There were more low-grade tumors (diffuse, small lymphocytic lymphosarcoma) in the cats with alimentary lymphosarcoma and more high-grade tumors (small, noncleaved cell lymphosarcoma) in cats with mediastinal lymphosarcoma. There was a wide range of ages reported among affected individuals, but generally the older cats (>10 years) developed low-grade alimentary and skin tumors, and the young cats (<6 years) developed high-grade mediastinal, central nervous system (CNS), and multicentric tumors. No association of classification type with prognosis was determined from this study.
Multicentric lymphosarcoma in cats is characterized by the involvement of multiple peripheral lymph nodes with or without hepatic and/or splenic involvement. Cats with lymphosarcoma can present with painless, recently noticed, lymphadenomegaly of one or more peripheral lymph nodes. Finding only peripheral lymph nodes affected in a cat is unusual. Hepatosplenomegaly and bone marrow involvement tend to be secondary and occur late in the disease process. Cats with primary bone marrow involvement are considered to have leukemia. Extranodal involvement is common, so routine examination of the eyes, kidneys, and CNS is recommended. Multicentric lymphosarcoma, especially because it occurs more often in younger cats, needs to be distinguished from lymph node hyperplasia. Nonspecific clinical signs such as lethargy, fever, anorexia, and weight loss are common. Most cats with multicentric lymphosarcoma test positive for FeLV. In these cats, pale mucous membranes from anemia is a common finding. Unlike dogs, hypercalcemia is very rare.Patients with the alimentary lymphosarcoma can have a solitary or multifocal mass or have diffuse gastrointestinal infiltration, with or without mesenteric lymph node, spleen, or liver involvement. Cats with alimentary lymphosarcoma tend to be older (>7 years), FeLU test negative (70%), and not anemic. The low occurrence of FeLU infection is thought to be secondary to these tumors arising from B cells in the gut-associated lymphoid tissue (GALT). The most common sites of alimentary involvement in decreasing frequency are small intestines (50%), stomach (25%), ileocecocolic junction, and colon. The cats with alimenary lymphosarcoma usually present with gastrointestinal signs (many owing to malabsorption and protein losing enteropathy from an infiltrated bowel) that can include weight loss, vomiting, diarrhea, anorexia, and melena. Clinical signs have frequently been present for several weeks; however, acute signs can result from obstruction or perforation of the tumor. A distinct subpopulation of cats with lymphosarcoma has been described in which the tumors are composed of large granular lymphocytes (LGL). These large granular lymphocytes are a morphologically distinct population of lymphocytes characterized by abundant cytoplasm and prominent azurophilic granules. Natural killer cells and cytotoxic T lymphocytes are examples of LGLs. The majority of these tumors originate in the GI tract, especially the jejunum and mesenteric lymph nodes, and an abdominal mass is usually easily palpated. Clinical presentation includes anorexia, lethargy, vomiting, and/or diarrhea. Laboratory abnormalities can include leukocytosis, hypoalbuminemia, hypocalcemia, increased AST activity, and increased concentrations of serum bilirubin. In one study, all cats with this type of lymphosarcoma were FeLV test negative. Cats with mediastinal lymphosarcoma tend to be between 2 and 3 years of age and test positive for FeLV. Mediastinal lymphosarcoma in cats usually involves the cranial and caudal mediastinal lymph nodes, rather than the thymus gland. Pleural effusion secondary to mediastinal lymphosarcoma is common and contributes to the clinical signs of dyspnea, coughing, exercise intolerance, regurgitation, dysphagia, and anorexia. The thorax may be noncompressible on physical examination. While hypercalcemia is more commonly associated with mediastinal lymphosarcoma in the dog, hypercalcemia is rare in any cat with lymphosarcoma. Clinical signs of extranodal lymphosarcoma can be nonspecific (lethargy, anorexia, weight loss, polyuria, polydipsia) or associated with a specific organ system. Regional lymph nodes may or may not be involved. Cutaneous and subcutaneous lymphosarcoma in the cat is rare and tends to occur in older cats (8-10 years) with most testing negative for FeLV The lesions of cats with cutaneous lymphosarcoma can be generalized, multifocal or solitary, and occur as nodules, plaques, ulcers, erythroderma, or exfoliative dermatitis. Pruritis, crusting, and alopecia may be present. The skin may be the primary tumor site or be disseminated from other anatomical areas. Lymphosarcoma can affect the central and peripheral nervous systems, but CNS involvement is more common. Cats with CNS lymphosarcoma tend to be young (3-4 years) and FeLV test positive (80%). One study of CNS tumors in cats reported that lymphosarcoma is the second most common tumor (32%) type affecting the CNS. Central nervous system lymphosarcoma may be primary or occur as part of a multicentric presentation. Development of CNS lymphosarcoma is a common occurrence (40%-50%) in cats with primary renal lymphosarcoma. Spinal lymphosarcoma can occur in the epidural space, the subdural space (leptomeningeal), or within the parenchyma of the spinal cord. Epidural and spinal lymphosarcoma are often thoracolumbar in location (between T2 and L4). Many cats with spinal lymphosarcoma are brought for veterinary care with paresis or paralysis of the hind legs secondary to compression of the spinal cord. Bone marrow evaluation should be performed in cats with spinal lymphosarcoma because up to 69% of these cats will have bone marrow infiltration with malignant lymphocytes. Clinical signs of lymphosarcoma of the nasal and/or paranasal sinuses include dyspnea, nasal discharge, facial distortion, and anorexia. One study concluded that FeLV test positive cats with nasal/paranasal sinus lymphosarcoma were more likely to develop systemic disease and recommended systemic chemotherapy instead of local therapy such as radiation therapy.
Renal lymphosarcoma is the most common neoplasm affecting the kidneys in cats. It can occur as the primary tumor or in association with an alimentary or multicentric distribution. Mooney reported that the mean age of 28 cats with renal lymphosarcoma was 7 years and that 50% of the cats tested positive for FeLV. Presenting signs are nonspecific (anorexia, lethargic, vomiting) and are owing to renal dysfunction or significant tumor size. Abdominal palpation reveals unilateral or bilaterai renomegaly, often with irregular surface contours. Many cats are also anemic. A biochemistry profile can help detect azotemia and hyperphosphatemia. Urine specific gravity may be isosthenuric. Central nervous system metastasis was reported in 40% of the cats with renal lymphosarcoma.
Primary or secondary ocular lymphosarcoma occurs in about 10% of cases. Lymphosarcoma behind the eye can create buphthalmous. The third eyelid and palpebral conjunctiva may be infiltrated and bulge through the palpebral fissure. Intraocular involvement is relatively common, and anterior uveal and chorioretinal changes are common. Since ocular and orbital lymphosarcoma can occur secondary to FeLV infection, the FeLV status of cats with ocular inflammation with or without obvious tumor formation should be determined. Anemia is a common finding in cats with lymphosarcoma, especially in those that test positive for FeLV. Hardy reported that 68% of FeLV test positive cats with lymphosarcoma have anemia, while <10% of the FeLV test negative lymphosarcoma cats are anemic. The anemia is most often normochromic, normocytic, or nonregenerative anemia of chronic disease, in which a clear cause of the anemia is not found. This type of anemia may be caused by chronic inflammation associated with the disease, decreased RBC lifespan, abnormal iron metabolism, decreased bone marrow response, or decreased iron stores. FeLV infection may also affect the bone marrow more directly and cause myelodysplastic diseases and red cell aplasia. Immune-mediated hemolytic anemia, with or without thrombocytopenia, can also be present.Thrombocytopenia is less commonly observed in cats with lymphoproliferative disease than in dogs. Decreased platelet numbers may occur secondary to decreased platelet production from direct invasion of bone marrow by malignant lymphocytes (myelophthisis). Other mechanisms causing platelet numbers to decline include sequestration, immune-mediated destruction, and increased consumption secondary to disseminated intravascular coagulation. In a report of 41 cats with thrombocytopenia, 12% had lymphoproliferativemalignancies. Leukocytosis, especially with lymphocytosis, should lead to critical evaluation of peripheral blood smears by the clinician and a clinical pathologist. Circulating abnormal lymphoid cells indicate bone marrow involvement that in one study suggested a poorer prognosis for remission. Bone marrow aspirates should be performed as part of staging, especially in cats with lymphosarcoma affecting the spinal cord. In a report of 16 cats with spinal lymphosarcoma that had bone marrow aspirates performed, 11 cats (69%) had lymphoblasts in the bone marrow.
While hypercalcemia is a relatively common paraneoplastic syndrome associated with canine lymphosarcoma, it is a rare occurrence in cat. Most cases of hypercalcemia reported in cats have been associated with lymphoproliferative diseases. The most common clinical signs associated with hypercalcemia in cats include anorexia, vomiting, weight loss, and dehydration. Hypercalcemia does not seem to cause polydipsia and polyuria in cats.
Monoclonal gammopathy has been described in cats with lymphosarcoma and is primarily because of the increased production of IgG from a clone of immunoglobulin producing cells. Clinical signs are primarily associated with hyperviscosity resulting in ophthalmic, neurologic, hematologic, and renal abnormalities. Clinical signs in cats with monoclonal gammopathy are nonspecific and include anorexia and lethargy Protein electrophoresis and immunoelectrophoresis help establish a diagnosis after the recognition of an abnormally elevated total serum protein concentration. Differentials for a monoclonal gammopathy in a cat include multiple myeloma, amyloidosis, and benign hyperglobulinemia.
Most cats should be evaluated and staged according to the World Health Organization scheme in a similar fashion to dogs Some authors feel that the WHO groups too many of the varying anatomic presentations into too few staging categories. The result is that some have created novel grading schemes that add little to our practical communication and decision making. In most respects, the diagnosis and clinical staging of lymphosarcoma in cats are identical to diagnosis and staging of lymphosarcoma in dogs. Cats also need tests for FeLV and FIV infection to help establish a prognosis and help guide decisions regarding other cats in the affected household.
The importance of routinely performing bone marrow aspirates and core biopsies has not been as clearly defined in cats as it has been for dogs. There is good evidence to justify the practice of evaluating peripheral blood smears, bone marrow cytology smears, and bone marrow core biopsies in dogs prior to chemotherapy. It is logical to assume that cats would also benefit from the evaluation of bone marrow cytology and core biopsies. A bone marrow that is heavily infiltrated by malignant lymphocytes that comes from a patient with a significant thrombocytopenia and/or neutropenia may change the clinician's approach to chemotherapy.
Cytologic evaluation of thoracocentesis fluid of cats with mediastinal lymphosarcoma frequently reveals the presence of serosanguinous fluid containing numerous vacuolated, neoplastic lymphoid cells. Chylothorax may be present secondary to obstruction or rupture of the thoracic duct. If no malignant lymphocytes are identified in the pleural fluid, serum and fluid cholesterol and triglyceride concentrations should be measured. Chylous effusions contain higher triglyceride concentrations than serum, although anorexic cats may have lower than expected pleural triglyceride concentrations. Care should be taken in evaluating chylous fluid, because it will contain numerous small mature lymphocytes, which could be (but should not be) confused with lymphosarcoma. Chylous fluid associated with lymphosarcoma contains predominantly malignant lymphocytes.
While cytologic evaluation of pleural fluid or a fine-needle aspiration cytology of affected tissue can provide a diagnosis, a tissue biopsy of affected tissue is needed in order to properly grade the tumor. Histologic examination is especially important when evaluating lymph nodes. Examination of a whole lymph node is of more value to the pathologist and the clinician than a needle core biopsy because it allows analysis of the architecture and capsular invasion. It also makes it easier for the pathologist to differentiate lymphosarcoma from lymphoid hyperplasia that arises secondary to a number of causes.
"Idiopathic lymphadenopathy" is a non-neoplastic peripheral lymphadenomegaly reported in young cats (usually 1-2 years of age). Clinical signs of fever and generalized lymphadenomegaly (nodes 2-3 times normal) are similar to lymphosarcoma. Affected cats test negative for FeLV, but some have neutralizing antibody titers and FOCMA titers, suggesting previous transient infection. Histologically, lymph nodes from affected cats resembled lymphosarcoma by loss of normal architecture, increased numbers of uniform lymphoid cells in the paracortical area, capsular and perinodal infiltrating lymphoid cells, and large follicular structures without germinal centers and mantle. These lymph nodes also have features that do not indicate neoplasia such as abundant nodal vascularity, primary and secondary follicles with active germinal centers, a heterogeneous cell population, and lack of high-grade anaplastic changes and high rate of mitotic activity. In a report of six cats with this syndrome, the lymphadenomegaly resolved in all cases within 6 months without any treatment. Subsequent biopsies were similar to prior biopsies or became normal.
Endoscopy can be helpful in identifying the presence of masses in the stomach and proximal gastrointestinal tract, but it does not allow the abdominal lymph nodes and organs to be evaluated for staging. Pinch biopsies taken through an endoscope may not get deep enough into the submucosa, and an underlying lymphosarcoma can be missed, since early lymphosarcomatous lesions are usually submucosal and surrounded by areas of lymphoplasmacytic inflammation. Pinch biopsies of gastric and intestinal mucosa with a diagnosis of lymphocytec-plasmacytic enteritis must be interpreted cautiously. Deep or full thickness biopsies may be required for a acccurate diagnosis of lymphosarcoma affecting the alimentary tract. Surgery should be performed with caution, because the combination of neoplastic invasion and low serum albumin can increase the risk of slow healing or dehiscence.
PRETREATMENT PROGNOSTIC FACTORS
Few clinical reports have adequately defined reliable prognostic factors for cats with lymphosarcoma. Lymphosarcoma involving different anatomic sites variably affect prognosis. While Cotter reported that 11 of 12 cats with mediastinal lymphosarcoma had a complete response to chemotherapy and a median duration of remission of 6 months when treated with a combination protocol of cyclophosphamide, vincristine, and prednisone (COP), Jeglum et al. reported that 14 of 31 cats with mediastinal lymphosarcoma had a complete remission and an overall median duration of remission of 1.5 months for cats treated with COP plus methotrexate. However, both studies showed that the multicentric lymphosarcoma without hepatosplenomegaly had a better prognosis and that most cats achieved a complete remission with median duration of remission greater than 1.5-2 years. Four of eight cats with alimentary lymphosarcoma that responded to chemotherapy in Jeglum's study had a median survival of 9.6 months. In the same report, the median survival of six cats with renal lymphosarcoma that were treated with chemotherapy was 5 months.The effects of clinical staging on treatment response and survival were evaluated in 103 cats with lymphosarcoma. In this study, the lower the clinical stage, the more likely the patient was to have a complete remission in response to treatment. In this study, 93% (13/14) of cats with stage I lymphosarcoma, 83% (20/ 24) of cats with stage II lymphosarcoma, 48% (13/27) of cats with stage III lymphosarcoma, 42% (11/26) of cats with stage IV lymphosarcoma, and 58% (7/12) of cats with stage V lymphosarcoma had a complete remission. In addition, the lower the clinical stage, the longer the survival was. Cats with clinical stage I and 11 lymphosarcoma had a median survival of 243 days, while cats with stage III lymphosarcoma had a median survival of 92 days, and cats with stages IV and V lymphosarcoma had a median survival of 76 days. Cats with a positive FeLV test status had a shorter survival (median survival=122 days) than did cats with a negative FeLV test status (median survival = 547 days). In this and other studies, cats with positive FeLV test had a shorter survival but did not seem to have a blunted initial response to chemotherapy or radiation therapy.
A different retrospective analysis of 132 cats with lymphosarcoma also found substage and FeLV status to be related to response to therapy and survival. Cats that were not clinically sick (substage A) and tested negative for FeLV responded to treatment better and had longer survival times than those cats that were FeLV test positive and/or clinically ill (substage B).
Histologic classification, nucleic size, size of nucleoli, and numbers of nucleoli were associated with survival in cats with nasal lymphosarcoma that were treated with chemotherapy, radiation therapy, or a combination of both. Median survival times for immunoblastic lymphosarcoma was 308 days, compared with 47 days for cats with tumors classified as small lymphocytic, and 96 days for cats with tumors classified as mixed.
TREATMENT AND PROGNOSISThe use of chemotherapy to treat cats with lymphosarcoma is effective, as illustrated by first remission duration and survival length data in Table . In the early days of chemotherapy for lymphosarcoma in cats, many of the drugs were given alone. However, results of treatment with single agents such as prednisone and cyclophosphamide were disappointing. Subsequently, combination protocols were developed that dramatically improved remission rates, duration of remission, and overall survival data.
Most cats tolerate the side effects of the common chemotherapy protocols intended for cats with minimal toxicity. When they occur, toxicities seem to be more associated with induction (especially when the cats are clinically ill at presentation) and with the use of cyclophosphamide, methotrexate, or doxorubicin. It is important to evaluate a CBC and platelet count prior to each therapy. Significant myelosuppression may occur, especially after a few weeks of therapy, that could necessitate dose reduction and/or delay in therapy.
Myelosuppression may lead to fever, anorexia, and sepsis. If side effects are severe enough, supportive care may be needed. Gastrointestinal toxicities may occur (vomiting, anorexia with weight loss) that may necessitate delay of therapy, reduction of dose, or a change to alternate drugs. Subcutaneous or intravenous fluids, appetite stimulants, colony-stimulating factors, or antibiotics may be helpful. Chemotherapy drugs used to treat feline lymphosarcoma include prednisone, cyclophosphamide, vincristine, chlorambucil, L-asparaginase, mitoxantrone, cytosine arabinoside, idarubicir, and doxorubicin. Prednisone, cyclophosphamide, and chlorambucil have been evaluated as single-agent therapy for feline lymphosarcoma. Treatment with prednisone or cyclophosphamide resulted in survival ranging from 1 to 14 months. No response was seen to chlorambucil when used alone, and survival time averaged 3 months. Vincristine alone has also resulted in longterm remissions, even when the cat was resistant to other drugs. L-asparaginase alone has also been used to induce a complete remission in cats. Mitoxantrone was unsatisfactory in inducing or maintaining a remission in cats with lymphosarcoma. Only 11%, (2/17) of cats treated with mitoxantrone had any response (partial).
Idarubicin is a member of the anthracycline drug family that has high bioavailability after oral administration. When given alone at a dose of 2 mg/day for 3 consecutive days every 21 days in a pilot study, two cats achieved a complete remission. Additional studies with this drug showed that idarubicir, as a single agent, was able to maintain a complete remission (median duration = 183 days) in 53% (18/34) of the cats induced with a COP protocol The most common toxicities reported with idarubicir were leukopenia, vomiting, and anorexia.
Doxorubicin can be used alone or in combination with other drugs to treat lymphosarcoma in cats. The most common doxorubicin dose for cats when usec as a single agent or in combination chemotherapy protocols is 20-25 mg/m2 or 1 mg/kg every 21 days. Doxorubicin is administered as an intravenous bolus with 5% dextrose in water, with care given to avoid extravasation.
In a study in which 18/38 (47%) cats were success fully induced into a remission with COP, maintenance therapy was divided into two groups. Doxoru bicin was used as the maintenance drug in 7 cats witt a median duration of remission of 281 days. This was significantly longer than the remission times for the remaining 11 cats given COP as maintenance therapy that had a median remission of only 83 days.Side effects of doxorubicin therapy that are com mon in dogs (vomiting, diarrhea, urticaria) are uncommon in cats. The most common side effects reported by owners of cats receiving doxorubicin are anorexia and nausea. These symptoms car be profound, but they are usually reversible. One study reported cats had significant weigh loss owing to profound anorexia after receiving 15( mg /M2 total dose of doxorubicin when given as 30 week 1 of induction in 103 cats with lymphosarcoma, median survival was 210 days with a 62% (64/103) complete remission rate, for which complete remission was defined as >75% reduction in volume of tumor. Cats with FeLV positive test had shorter survival times but still responded to therapy well. Of the cats that achieved a complete response as defined in this study, 30% were alive at 1 year.
In a different study of 28 cats with renal lymphosarcoma treated with a similar protocol, 17 cats (61%) achieved a complete remission, with median remission length of 127 days. Ten of the 28 cats with renal lymphosarcoma had cytosine arabinoside added to their maintenance protocol and none developed CNS relapse, while 40% of the remaining cats not treated with cytosine arabinoside developed CNS lymphosarcoma.
The authors recommend a standard COP protocol for cats with most forms of lymphosarcoma. Cats tolerate the drugs well, side effects are minimal, and the remission times are good. Side effects, if seen at all, usually occur during the induction phase. Since most drugs in this COP protocol are given orally, dosage or schedule adjustments are easily made.
Supportive care is not usually needed. While the authors have not personally used doxorubicin as maintenance for lymphosarcoma, one report of COP followed by doxorubicin showed dramatically better remission times and bears consideration. If the total tumor burden is large and needs to be decreased in size quickly, L-asparaginase may be added into the COP protocol at the beginning of the therapy (day 1) for 1-2 treatments.
Radiation therapy is primarily used in cases of localized lymphosarcoma (spinal, mediastinal, nasal, retrobulbar). A complete remission was achieved in 8 of 10 cats with localized lymphosarcoma that were treated with radiation therapy. The overall median remission length was 798 days. Total radiation dose ranged from 6-40 Gy. Radiation therapy can be useful for those cats with solitary lesions that are small and/or cutaneous. Since malignant lymphocytes are so responsive to radiation therapy, it is also potentially a good treatment modality for cats that present with large or obstructive masses, in mediastinal, laryngeal, or spinal locations.Klein et al. reported on cats with nasal lymphosarcoma treated with chemotherapy, radiation therapy, or a combination of radiation and chemotherapy. Of 33 cats with complete enough data for evaluation, 19 were treated with chemotherapy (unspecified) alone and 53% (10/19) had a complete response. Of the 6 cats treated with radiation alone, 83% (5/6) had a complete response. Of the 8 cats treated with chemotherapy plus radiation therapy, 75% (6/8) had a complete response. Median survival times for the chemotherapy treated group was 151 days, 593 days for the radiation therapy treated group, and 178 days for the group treated with chemotherapy plus radiation. Survival times in this study also varied with histologic classification. Cats with tumors classified as immunoblastic had a median survival of 308 days. Cats with tumors classified as mixed had a median survival of 96 days, and cats with tumors classified as small lymphocytic had a median survival of 47 days.
Survival data for lymphosarcoma in cats are difficult to evaluate for the same reasons that they are difficult to evaluate in dogs. When a patient fails the first remission, there is not always a consistent protocol used to induce a second remission (rescue). No matter what the initial protocol used, it is likely that a number of different protocols using different drugs and dosages are used for rescue, and the results are reported in a way that gives the impression that the survival and remission data are associated only with the initial protocol. Other factors that influence survival times are concurrent illnesses (especially if a cat is FeLV test positive), and the owner's willingness to continue chemotherapy. The median survival times for cats with lymphosarcoma treated with combination chemotherapy is reported to range from 49-210 days. Survival is shortened by the presence of FeLV associated diseases.
CUTANEOUS LYMPHOSARCOMA IN DOGS AND CATS
Cutaneous lymphosarcoma accounts for 3% to 8% of all lymphosarcoma reported in dogs. Cutaneous lymphosarcoma is more common in dogs than cats. It tends to occur in older animals with the mean age of onset in dogs of 9.5 years and 11 years in cats. In several studies, all cats tested for FeLV were negative. One retrospective study of 260 dogs with Cuaneous lymphosarcoma reported briards, English cocker spaniels, Bulldogs, Scottish terriers, and golden retrievers as breeds having an increased risk. In a separate study, Weimaraners were reported to have an increased risk and airedale terriers to have a decreased risk. Cutaneous lymphosarcoma is usually categorized as either epitheliotropic (epidermotropic), which tends to be of T-cell origin, or nonepitheliotropic, which tends to be of ß-cell, or sometimes null cell, origin. The T cells present in canine and human mycosis fungoides are thought to be memory T cells and in dogs are CD8+.
Epitheliotropic cutaneous lymphosarcoma can be categorized as three forms: mycosis fungoides, Sezary syndrome, or pagetoid reticulosis. Of these, mycosis fungoides is the most common type of epitheliotropic lymphosarcoma diagnosed in dogs and cats.
Mycosis fungoides is a nonleukemic variant of cutaneous lymphosarcoma that occurs occasionally in dogs but rarely in cats. It is characterized histologically by epitheliotropic atypical lymphocytes, minimal spongiosis, and Pautrier's microabcesses (a discrete accumulation of neoplastic cells in the epidermis), which are characteristic histologic features of mycosis fungoides.
Sezary syndrome or Sezary-like disease has been reported in both dogs and cats. It is characterized by the presence of cutaneous lymphosarcoma (generalized, exfoliative erythroderma, and lymphadenopmegaly) plus a leukemia. Pruritis is common. Histologic evaluation of skin lesions is consistent with that of mycosis fungoides, and the circulating neoplastic lymphocytes are large cells with convoluted, hyperchromatic nuclei and a high nuclear:cytoplasmic ratio that are known as Sezary cells.
Pagetoid reticulosis can resemble mycosis fungoides and Sezary syndrome histologically, because a monomorphous population of neoplastic lymphoid cells infiltrates the epidermis. Clinically, it appears to take a relatively benign course as a solitary plaque of chronic duration. Histologic examination of the ß-cell nonepitheliotropic form of cutaneous lymphosarcoma reveals lymphocytes located deeper in the dermis, with sparing of the papillary dermis and epidermis. The malignant lymphocytes are characterized as well-differentiated, poorly differentiated, undifferentiated, or large cell. Since T-cell lymphosarcoma can also appear as a nonepitheliotropic form, the lack of epidermal infiltration by lymphocytes is not by itself a useful criterion in defining ß-cell or T-cell forms of this disorder. Immunohistochemistry plus routine histologic assessment can be used to distinguish B-cell from T-cell lymphosarcoma. Clinical lesions are usually discrete solitary or multifocal nodules, sometimes with acute onset and rapid progression.
CLINICAL FEATURES OF CUTANEOUS LYMPHOSARCOMA
Cutaneous lymphosarcoma is characterized by infiltration of any area of the skin by neoplastic lymphocytes. It can occur as the primary form of lymphosarcoma, or it may be disseminated from or to other areas. It may occur as single or multifocal lesions on the skin. Cutaneous lymphosarcoma can affect any skin surface, but it often will exhibit mucocutaneous and oral cavity involvement. Cutaneous lesions can progress through three stages (exfoliative erythroderma, plaque, and nodule) or present as nodular disease from the onset.
It is easy to misdiagnose cutaneous lymphosarcoma because of its variable clinical presentation, and it may mimic many other skin diseases. Animals may present for a second opinion after many months of therapy in which antibiotics, dips, and steroids were not successful in eradicating a misdiagnosed problem. In one study of cutaneous lymphosarcoma, 64% (14/22) of dogs presented with a history of chronic skin conditions. The various manifestations of cutaneous lymphosarcoma have been misdiagnosed as endocrine alopecia, seborrhea, atopic dermatitis, pododermatitis, or pyoderma. In cats, differential diagnosis should also include dermatophytosis, allergic dermatitis, eosinophilic plaque, autoimmune disease, drug eruptions, and external parasites (especially Cheyletiella).
General clinical signs include nodules, plaques, pustules, ulcers, erythroderma, depigmentation, or exfoliative dermatitis. The size of involved areas ranges from small (few millimeters) to large nodules or plaques (centimeters in diameter). Small animals initially may present with lesions of coalescing, erythematous patches with alopecia and scale on the head and face, that progress to the trunk. This form then progresses to circular then irregular erythemic plaques, some with central ulceration and dry crusts on mucocutaneous junctions. The plaque form is more common in cats than in dogs. Pruritis is variable with the patch and plaque forms, but cats tend to be more pruritic than dogs and may show more self-trauma and ulceration. Both the patch and plaque forms can regress and reappear at a later date or progress rapidly to a more aggressive form.
Variably sized, painless nodules (solitary or multiple) can appear as firm, elevated, dark red, shiny, scaly, or ulcerated lesions with serous exudate oozing onto the skin surface. This exudate tends to trap keratin and form a crust on top of the nodule. If the crust is removed, the skin underneath may be hemorrhagic and hyperemic. The combination of ulcerative skin and crust can lead to areas of matted hair with a foul odor. Less pruritis is usually seen with this stage than with previous stages, although secondary bacterial infection' can cause pruritis. Progression to lymph nodes or other organs can occur.
Beale and Bolon reported that 80% of 26 dogs with the epitheliotropic cutaneous lymphosarcoma had erythema at presentation, with nodules in 57% of dogs and plaques and scales in 62% of dogs. Mucosal lesions were present in more than one-third of the dogs. There was a trend for those dogs with epitheliotropic cutaneous lymphosarcoma to survive longer after diagnosis than dogs with nonepitheliotropic lymphosarcoma. Of the dogs with epitheliotropic cutaneous lymphosarcoma, those that received treatment lived 334 days, while those without treatment lived 79 days. Of the dogs with nonepitheliotrophic cutaneous lymphosarcoma, those that received treatment lived 173 days, and those without treatment lived 40 days.
In a retrospective study of nine cats with cutaneous lymphosarcoma, five had solitary masses, four had multiple or diffuse lesions, and one was classified as mycosis fungoides. In one study of 72 dogs, only 8 of the dogs had solitary involvement, and 14 dogs had diffuse involvement. Overall, the progression of disease in cats appears similar to that in dogs (patch, plaque, then nodular). However, unlike in dogs, standard chemotherapy may not as readily alter the progression of the disease.
Hematologic changes associated with cutaneous lymphosarcoma are varied and include anemia, lymphopenia, lymphocytosis, neutrophilia and leukemia. Hepatic and renal changes may be noted. Hypercalcemia is rare but tends to occur when only the skin is affected (no lymph node or solid organ metastasis). A monoclonal gammopathy (IgG) was reported in one dog with cutaneous lymphosarcoma.
DIAGNOSIS AND STAGING
The diagnosis of cutaneous lymphosarcoma is dependent on biopsy. Although a diagnosis of cutaneous lymphosarcoma may be established with a fineneedle aspiration cytology, histopathology is advised in order to fully characterize the nature of the tumor. With the availability and use of immunohistochemis try for cell markers, every effort should be made to identify the tumor as T or B cell origin. Staging for cutaneous lymphosarcoma is the same as for other forms of lymphosarcoma.
TREATMENT OF CUTANEOUS LYMPHOSARCOMA AND PROGNOSIS
Treatment of cutaneous lymphosarcoma is often frustrating. Many treatments must be considered palliative, but some relief from clinical signs can be be offered. For example, regular bathing with sulfur-based shampoos may increase patient comfort and appearance, but has no effect on the primary disease. Prednisone can be used to successfully control persistent pruritis (doses ranging from 0.15-1.8 mg/kg every 24-48 hrs), but may have no appreciable effect on survival.
Radiation therapy has been used for solitary or multifocal lesions. One dog with mycosis fungoides was reported responsive to orthovoltage radiation. Palliative radiation therapy of dogs with mycosis fungoides can be rewarding, and ulcerated lesions may heal and regress.
Surgery has been effective as primary therapy in some dogs. In a report of 22 dogs with cutaneous lymphosarcoma, 8 dogs had solitary lesions and 7 of these were treated by surgical excision. Of these dogs treated by surgery, 4 were considered cured.
Caciolo, et al, however, reported a different outcome in a case study of nine cats. Five of the cats had solitary masses, and four had local excision. One cat was lost to follow up, but three had local reccurrence of lymphosarcoma within 1 month of surgery.
Numerous drugs and combinations of drugs (cyclosporine; mechlorethamine; cyclophosphamide and vincristine; doxorubicin, vincristine and prednisone; and chlorambucil and prednisone) have been used to treat cutaneous lymphosarcoma in small animals with varying success. The use of topical nitrogen mustard (mechlorethamine) was reported effective in some dogs, but it has a high incidence of allergic and irritant contact sensitization (dermatitis) in people exposed to it. Cats treated with nitrogen mustard tend to have significant bone marrow suppression and GI upset. Treatment of epitheliotropic cutaneous lymphosarcoma with chemotherapy usually results in slowing the progression or minimal regression of disease. However, one dog treated with Dacarbazine (DTIC) at a dose of 1000 mg/m2 intravenously over 2 hours every 3 weeks for 3 total treatments had a complete remission without significant side effects. Prior to the third chemotherapy, surgical removal of two resistant dermal nodules was performed, and the dog remained disease free for >1 year.
The best survival times for cutaneous lymphosarcoma are usually the result of treatment with combination chemotherapy protocols, especially if doxorubicin is a part of the protocol. Remission of 46 days was reported in one dog with epitheliotropic cutaneous lymphosarcoma treated with chlorambucil and prednisone, while a remission of 304 days was reported for another dog treated with doxorubicin, vincristine, and prednisone.
Retinoids have also recently been added to the choices available to veterinarians for treating cutaneous lymphosarcoma. The exact method of action of retinoids on neoplastic cells is unknown. Since retinoids are a vitamin A analog and vitamin A helps to regulate growth and differentiation of cells, retinoids may act by regulating epithelial differentiation and reversing malignant differentiation. White, et al, used retinoids to treat 14 dogs with cutaneous lymphosarcoma. Clinical remission, defined as >50% reduction of erythema, scaling and/or pruritis for at least 4 months after therapy initiation, was observed in 43% of the dogs treated with retinoids. Twelve dogs were treated with isotretinoin and 2 with etretinate. Of the 12 dogs with epitheliotropic lymphosarcoma treated with isotretinoin, 4 responded for between 152 and 395 days. One of the dogs responded to etretinate for 456 days, while one dog with nonepitheliotropic disease responded to isotretinoin for 535 days. For all dogs with epitheliotropic lymphosarcoma, the mean remission/ survival was 328 days. The study authors recommended a dose of 3 to 4 mg/kg of isotretinoin daily for treatment of cutaneous lymphosarcoma.
Side effects in dogs treated with isotretinoin included panting and salivation, mild dry cough, corneal lipid deposits, and high serum triglyceride value. Side effects in dogs treated with etretinate included abdominal alopecia. Adverse effects did not correlate with the dose given and occurred sporadically. Most abnormalities were transient and reversible upon cessation of therapy. Other infrequent, adverse side effects reported for retinoids include keratoconjunctivitis sicca, swollen tongue, polydipsia, signs of joint pain, pruritis, hyperlipidemia, hyperactivity, ear pruritis, erythema of the feet and mucocutaneous junctions, lethargy or anorexia with vomiting, and teratogenesis.
Of three cats with epitheliotropic lymphosarcoma treated with isotretinoin (10 mg daily), all had a good clinical response and showed a reduction of erythema and scaling, and there was abundant new hair growth. Complete remission was not achieved, but good quality of life was maintained for 182 to 547 days. In a separate study of three cats with epitheliotropic lymphosarcoma treated with 1 mg/ kg of isotretinoin every 12 to 24 hours, some improvement of clinical signs was seen (increased hair, less scale and erythema). All of the cats "felt" better, but no complete responses were seen. Survival ranged from 182 to 547 days. Diarrhea was noted in one of three cats treated with isotretinoin. Other side effects noted in cats given isotretinoin include periocular edema, periocular crusting, epiphora, and blepharospasm. Like in dogs, side effects in cats are sporadic.
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