Mr.Billfold
12-23-2007, 08:45 PM
Lymphoma, Lymphosarcoma, Lymphocytic leukemia)
Canine malignant lymphoma is a progressive, fatal disease characterized by neoplastic transformation and proliferation of lymphoid cells, usually originating in solid lymphoid organs (lymphosarcoma) or bone marrow (lymphocytic leukemia). The variable signs depend on which organs are involved. No viral etiology has been established in dogs, in contrast to most other domestic species. The disease is histologically and immunologically heterogeneous, and different morphologic subtypes may behave differently. It is the most common hematopoietic neoplasm of dogs (reported incidence 24:100,000). All breeds and both sexes are affected, although the incidence is higher in Boxers, Golden Retrievers, and Old English Sheepdogs.
Clinical Findings:
The most common early clinical sign is a painless, peripheral lymphadenopathy, often first noticed in lymph nodes about the throat and neck. Subsequently, nonspecific signs, including anorexia, weight loss, anemia, and inactivity develop gradually as neoplastic cells progressively infiltrate visceral organs. In the alimentary form, signs are associated with GI obstruction or malabsorption; 80% of affected dogs may have diarrhea and weight loss. Other less common types include an anterior mediastinal form with primary involvement of the area of the thymus, an epitheliotropic form (mycosis fungoides), and extranodal (atypical) forms that involve a single organ such as the kidney.
Hypercalcemia may be seen in 10-40% of dogs with malignant lymphoma. There are two general mechanisms: one is local elaboration of an osteolytic factor that induces resorption of bone and mobilization of calcium when the bone marrow is infiltrated by tumor cells; the other, probably more common, is humoral hypercalcemia in which neoplastic cells produce a substance that acts at a distance (see also hypercalcemia of malignancy, Hypercalcemia of Malignancy (http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/40404.htm) ). In both cases, it appears that a bone-resorbing substance is produced that is immunologically distinct from parathyroid hormone, prostaglandin E2, and 1,25-dihydroxycholecalciferol. Dogs with hypercalcemia have polyuria and polydipsia or renal failure. Urinary excretion of calcium, phosphorus, and hydroxyproline is increased if there is hypercalcemia.
Untreated dogs usually die within 1-2 mo of diagnosis.
Lesions:
Commonly, all superficial and various internal lymph nodes are 3-10 times normal size (multicentric form). Affected nodes are freely movable, firm, and gray-tan; they bulge on cut surface and have no cortical-medullary demarcation. Frequently, there is hepatosplenomegaly with either diffuse enlargement or multiple, pale nodules of variable size disseminated in the parenchyma. Involvement of the bone marrow, GI tract, kidney, heart, tonsils, pancreas, and eyes can occur but is less common. In the alimentary form, the second most common form of the disease, any part of the GI tract or mesenteric lymph nodes may be affected, but superficial lymph nodes and the spleen are rarely involved.
Diagnosis: True lymphocytic leukemia, which is characterized by a normal to increased WBC count with a predominance of lymphoid cells in peripheral blood and bone marrow is rare and must be differentiated from lymphosarcoma because of the different prognosis and response to therapy. Poorly differentiated, acute lymphoblastic leukemia is an aggressive disease with a poor prognosis, whereas well-differentiated, chronic lymphocytic leukemia is slowly progressive and responds relatively well to therapy. Frequently, there is a diffuse splenomegaly. Most dogs with lymphosarcoma have a normal hematologic profile. In the later stages, an absolute neutrophilia may develop.
Most canine lymphomas are high-grade (blast cell), diffuse lymphosarcomas, although ~20% are low-grade (well-differentiated). Dogs with high-grade tumors respond better to chemotherapy and have longer remission and survival times than those with low-grade lymphomas, which may have a more indolent course and do not respond as well to chemotherapy.
The cell of origin is either the B- or T-cell lymphocyte, although some are of undetermined origin. Two separate studies have found that >75% of canine lymphomas are of B-cell origin, and 10-20% are of T-cell origin. B-cell neoplasms are associated with better response and longer remission and survival times than T-cell neoplasms. There is a strong correlation between some T-cell neoplasms and hypercalcemia (especially with T-cell lymphomas involving the thymus and bone marrow), and these tumors are associated with poorer response rates and shorter survival and remission times.
Microscopical examination of lymphoid tissue is required for positive diagnosis because lymphadenopathy may be caused by non-neoplastic diseases. Examination of peripheral blood or bone marrow usually is not diagnostic except in terminal stages of the disease or in lymphocytic leukemia. Although cytology of lymph node aspirates or smears of biopsy specimens may provide a diagnosis, histopathologic examination of an involved peripheral lymph node is desirable and usually provides a definitive diagnosis. Because the submandibular nodes are often hyperplastic, they are more difficult to evaluate and should be avoided if other nodes are enlarged.
Treatment:
Cyclic combination chemotherapy can achieve long-term remission. Response rates to chemotherapy of 70-80% and median survival times of 10-14 mo after diagnosis may be expected; 25% may survive ≥2 yr. Most treatment regimens use a combination of cyclophosphamide, vincristine, and prednisone. The addition of asparaginase or adriamycin has improved response rates and survival times.
Periodic clinical and laboratory examinations are imperative during the course of all chemotherapeutic regimens because the drugs are toxic. Adverse reactions include bone marrow suppression, increased susceptibility to infection, and hemorrhagic cystitis from cyclophosphamide. Use of antibiotics in an attempt to prevent these occurrences is controversial. Transfusions may be necessary.
Chemotherapy is generally divided into an induction phase, in which a combination of drugs is administered intensively over a short period of time, and a maintenance phase. The following protocol has proved effective:
Induction:
Week 1—vincristine (0.7 mg/m2, IV), asparaginase (400 IU/kg, IP), prednisone (30 mg/m2 , PO). Week 2—cyclophosphamide (200 mg/m2, IV), prednisone (20 mg/m2, PO). Week 3—doxorubicin (30 mg/m2, IV), prednisone (10 mg/m2, PO). Week 4-6—as above for weeks 1-3, but asparaginase and prednisone are discontinued. (See Table: Weight to Body Surface Area Conversiona (http://javascript%3cb%3e%3c/b%3E:TableWin('tref09.htm')) , for weight to body surface areas [in m2] conversion.)
Maintenance:
Cyclic administration of the drugs should be continued as in weeks 4-6, but the treatment interval should be extended to every 2 wk for two treatment cycles, then every 3 wk for two further treatment cycles. If relapse occurs within this time period (expected in ~50% of cases), reinduction using asparaginase and prednisone may achieve a second remission. Asparaginase is given IM or SC to reduce risk of inducing anaphylaxis. Continuous chemotherapy is then reinstituted every 2 wk, sequentially administering cyclophosphamide, vincristine, and methotrexate (0.5 mg/kg, IV) in combination with prednisone (1 mg/kg, PO, every other day). Due to delayed cardiac toxicity, the maximal cumulative dose of doxorubicin should be 150-200 mg/m2. Chlorambucil (1.4 mg/kg, PO, divided into two doses) also can be substituted for cyclophosphamide after remission is achieved. Many other protocols have been reported for the treatment of canine lymphoma; these include adriamycin as the sole agent; cytoxin, oncovin, and prednisone (COP protocol); and cytoxin, oncovin, methotrexate, and prednisone (COMP protocol). Additionally, many newer chemotherapeutic agents and immunotherapies are currently being evaluated.
The diffuse alimentary form of lymphosarcoma often responds poorly to chemotherapy. However, if the lesion is localized to a segment of the intestine, surgical resection followed by chemotherapy should be performed. In this case, the prognosis is guarded to fair for long-term response.
Well-differentiated lymphocytic leukemia can be treated with chlorambucil at 0.2 mg/kg, PO, for 7-10 days, followed by a reduced daily dose of 0.1 mg/kg. Remissions of 1-2 yr can be expected. Treatment of lymphoblastic leukemia has been less successful, with a median survival time of <6 mo and a complete response rate of ~30%.
Canine malignant lymphoma is a progressive, fatal disease characterized by neoplastic transformation and proliferation of lymphoid cells, usually originating in solid lymphoid organs (lymphosarcoma) or bone marrow (lymphocytic leukemia). The variable signs depend on which organs are involved. No viral etiology has been established in dogs, in contrast to most other domestic species. The disease is histologically and immunologically heterogeneous, and different morphologic subtypes may behave differently. It is the most common hematopoietic neoplasm of dogs (reported incidence 24:100,000). All breeds and both sexes are affected, although the incidence is higher in Boxers, Golden Retrievers, and Old English Sheepdogs.
Clinical Findings:
The most common early clinical sign is a painless, peripheral lymphadenopathy, often first noticed in lymph nodes about the throat and neck. Subsequently, nonspecific signs, including anorexia, weight loss, anemia, and inactivity develop gradually as neoplastic cells progressively infiltrate visceral organs. In the alimentary form, signs are associated with GI obstruction or malabsorption; 80% of affected dogs may have diarrhea and weight loss. Other less common types include an anterior mediastinal form with primary involvement of the area of the thymus, an epitheliotropic form (mycosis fungoides), and extranodal (atypical) forms that involve a single organ such as the kidney.
Hypercalcemia may be seen in 10-40% of dogs with malignant lymphoma. There are two general mechanisms: one is local elaboration of an osteolytic factor that induces resorption of bone and mobilization of calcium when the bone marrow is infiltrated by tumor cells; the other, probably more common, is humoral hypercalcemia in which neoplastic cells produce a substance that acts at a distance (see also hypercalcemia of malignancy, Hypercalcemia of Malignancy (http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/40404.htm) ). In both cases, it appears that a bone-resorbing substance is produced that is immunologically distinct from parathyroid hormone, prostaglandin E2, and 1,25-dihydroxycholecalciferol. Dogs with hypercalcemia have polyuria and polydipsia or renal failure. Urinary excretion of calcium, phosphorus, and hydroxyproline is increased if there is hypercalcemia.
Untreated dogs usually die within 1-2 mo of diagnosis.
Lesions:
Commonly, all superficial and various internal lymph nodes are 3-10 times normal size (multicentric form). Affected nodes are freely movable, firm, and gray-tan; they bulge on cut surface and have no cortical-medullary demarcation. Frequently, there is hepatosplenomegaly with either diffuse enlargement or multiple, pale nodules of variable size disseminated in the parenchyma. Involvement of the bone marrow, GI tract, kidney, heart, tonsils, pancreas, and eyes can occur but is less common. In the alimentary form, the second most common form of the disease, any part of the GI tract or mesenteric lymph nodes may be affected, but superficial lymph nodes and the spleen are rarely involved.
Diagnosis: True lymphocytic leukemia, which is characterized by a normal to increased WBC count with a predominance of lymphoid cells in peripheral blood and bone marrow is rare and must be differentiated from lymphosarcoma because of the different prognosis and response to therapy. Poorly differentiated, acute lymphoblastic leukemia is an aggressive disease with a poor prognosis, whereas well-differentiated, chronic lymphocytic leukemia is slowly progressive and responds relatively well to therapy. Frequently, there is a diffuse splenomegaly. Most dogs with lymphosarcoma have a normal hematologic profile. In the later stages, an absolute neutrophilia may develop.
Most canine lymphomas are high-grade (blast cell), diffuse lymphosarcomas, although ~20% are low-grade (well-differentiated). Dogs with high-grade tumors respond better to chemotherapy and have longer remission and survival times than those with low-grade lymphomas, which may have a more indolent course and do not respond as well to chemotherapy.
The cell of origin is either the B- or T-cell lymphocyte, although some are of undetermined origin. Two separate studies have found that >75% of canine lymphomas are of B-cell origin, and 10-20% are of T-cell origin. B-cell neoplasms are associated with better response and longer remission and survival times than T-cell neoplasms. There is a strong correlation between some T-cell neoplasms and hypercalcemia (especially with T-cell lymphomas involving the thymus and bone marrow), and these tumors are associated with poorer response rates and shorter survival and remission times.
Microscopical examination of lymphoid tissue is required for positive diagnosis because lymphadenopathy may be caused by non-neoplastic diseases. Examination of peripheral blood or bone marrow usually is not diagnostic except in terminal stages of the disease or in lymphocytic leukemia. Although cytology of lymph node aspirates or smears of biopsy specimens may provide a diagnosis, histopathologic examination of an involved peripheral lymph node is desirable and usually provides a definitive diagnosis. Because the submandibular nodes are often hyperplastic, they are more difficult to evaluate and should be avoided if other nodes are enlarged.
Treatment:
Cyclic combination chemotherapy can achieve long-term remission. Response rates to chemotherapy of 70-80% and median survival times of 10-14 mo after diagnosis may be expected; 25% may survive ≥2 yr. Most treatment regimens use a combination of cyclophosphamide, vincristine, and prednisone. The addition of asparaginase or adriamycin has improved response rates and survival times.
Periodic clinical and laboratory examinations are imperative during the course of all chemotherapeutic regimens because the drugs are toxic. Adverse reactions include bone marrow suppression, increased susceptibility to infection, and hemorrhagic cystitis from cyclophosphamide. Use of antibiotics in an attempt to prevent these occurrences is controversial. Transfusions may be necessary.
Chemotherapy is generally divided into an induction phase, in which a combination of drugs is administered intensively over a short period of time, and a maintenance phase. The following protocol has proved effective:
Induction:
Week 1—vincristine (0.7 mg/m2, IV), asparaginase (400 IU/kg, IP), prednisone (30 mg/m2 , PO). Week 2—cyclophosphamide (200 mg/m2, IV), prednisone (20 mg/m2, PO). Week 3—doxorubicin (30 mg/m2, IV), prednisone (10 mg/m2, PO). Week 4-6—as above for weeks 1-3, but asparaginase and prednisone are discontinued. (See Table: Weight to Body Surface Area Conversiona (http://javascript%3cb%3e%3c/b%3E:TableWin('tref09.htm')) , for weight to body surface areas [in m2] conversion.)
Maintenance:
Cyclic administration of the drugs should be continued as in weeks 4-6, but the treatment interval should be extended to every 2 wk for two treatment cycles, then every 3 wk for two further treatment cycles. If relapse occurs within this time period (expected in ~50% of cases), reinduction using asparaginase and prednisone may achieve a second remission. Asparaginase is given IM or SC to reduce risk of inducing anaphylaxis. Continuous chemotherapy is then reinstituted every 2 wk, sequentially administering cyclophosphamide, vincristine, and methotrexate (0.5 mg/kg, IV) in combination with prednisone (1 mg/kg, PO, every other day). Due to delayed cardiac toxicity, the maximal cumulative dose of doxorubicin should be 150-200 mg/m2. Chlorambucil (1.4 mg/kg, PO, divided into two doses) also can be substituted for cyclophosphamide after remission is achieved. Many other protocols have been reported for the treatment of canine lymphoma; these include adriamycin as the sole agent; cytoxin, oncovin, and prednisone (COP protocol); and cytoxin, oncovin, methotrexate, and prednisone (COMP protocol). Additionally, many newer chemotherapeutic agents and immunotherapies are currently being evaluated.
The diffuse alimentary form of lymphosarcoma often responds poorly to chemotherapy. However, if the lesion is localized to a segment of the intestine, surgical resection followed by chemotherapy should be performed. In this case, the prognosis is guarded to fair for long-term response.
Well-differentiated lymphocytic leukemia can be treated with chlorambucil at 0.2 mg/kg, PO, for 7-10 days, followed by a reduced daily dose of 0.1 mg/kg. Remissions of 1-2 yr can be expected. Treatment of lymphoblastic leukemia has been less successful, with a median survival time of <6 mo and a complete response rate of ~30%.