Lymphoma

From Dog
Jump to: navigation, search
Multicentric lymphadenopathy, characteristic of multicentric lymphoma in a dog[1]
Lymphoma in a Doberman, presenting with submandibular lymphadenopathy[2]
MALT lymphoma in the tongue of a Boxer dog[4]
Necrotized scrotal ulcer secondary to lymphoma infiltration in a Bull Dog that responded to a therapy[5]
Spinal extradural lymphoma in a Bordeaux dog[6]

Canine malignant lymphoma (lymphosarcoma) are a round cell tumor classified as one of the most common, life-limiting neoplastic disease of dogs.

In dogs, lymphoma primarily affects lymphoid tissues of the bone marrow, thymus, lymph nodes, and spleen, but other organs can be affected, including skin, eye, kidneys, brain, testis, prostate and bone.

Two basic forms of lymphoma have been recognized: B-cell and T-cell lymphoma[7][8]. B-cell lymphomas have a good prognosis to treatment, whereas 50% of T-cell lymphomas are fatal.

Cause

The cause(s) of malignant clonal expansion of lymphoid cells associated with lymphoma remains poorly understood. Some hypotheses have been forwarded, including:

  • Genetic susceptibility
  • Toxins - including lawn care pesticides (phenoxy herbicides)[9], magnetic field exposure, chromosomal abnormalities (Monosomy X mutagenesis[10])
  • Dietary preservatives
  • Viral diseases
- Epstein-Barr virus[11]
- Heterobilharzia spp[12]
- Helicobacter pylori[13]
- Ehrlichia spp[14]
- Echinococcus spp[15]

Classification

The traditional classification of lymphomas as Hodgkin or non-Hodgkin lymphomas has recently been abandoned for more generalized nomenclature involving listing of individual types of lymphoma instead[16], including:

  • Multicentric B-cell or T-cell lymphoma[17] - may result in secondary leukemia
  • Alimentary lymphoma (from oral to rectal lymphoma)[18][19], including intestinal polyposis
  • Mediastinal lymphoma
  • Extranodal lymphoma
- Renal lymphoma[20]
- Pulmonary lymphoma
- Hepatosplenic and Hepatocytotropic T-Cell Lymphoma[21]
- Primary CNS lymphoma[22]
- Epitheliotropic T-cell lymphoma[23]
- Ocular and adnexal ocular lymphoma[24] (e.g. uveodermatologic lymphoma)[25]
- Waldenström's macroglobulinemia (lymphoplasmacytic lymphoma)
- Mucosa-associated lymphoid tissue lymphoma - MALT lymphoma[26]
- Prostatic lymphoma
- Polyostotic lymphoma[27]
- Intravascular lymphoma[28]
- Neurolymphomatosis[29] - invasion of regional nerves - often presents as local paralysis and metastases
- Indolent nodular lymphoma[30]

B-cell lymphomas, the less life-threatening of the two forms, have a clear hierarchy of progenitor cells responsible for initiation of neoplasia in dogs[31] as well as high telomerase activity[32] (which confers cell immortality) and resistance to adenovirus uptake, making in vivo gene delivery using capsid-modified vectors difficult to trial as chemotherapeutic agents[33].

Clinical signs

Affected dogs usually show early vague clinical symptoms such as vomiting, diarrhea, protein-losing enteropathy[34], dyspnea (due to pleural effusion, chylothorax or pyothorax), weight loss and in some cases palpable lymphadenopathy. In intracranial lymphoma, seizures are common.

Multicentric lymphoma is by far the most common form, accounting for ~80% of all diagnosed cases, followed by mediastinal and alimentary lymphoma. A significant proportion are indolent lymphomas (slow, insidiously developing)[35].

Diagnosis

Diagnosis of lymphoma is usually determined by biopsy obtained by fine needle aspirate or laparotomy. Other clinical symptoms may assist, such as lymphadenopathy in the case of multicentric lymphoma.

Insidious lymphomas may be difficult to confirm without ancillary tests (e.g. ultrasonographic or radiographic studies[36]) as historical evidence is often vague. Ultrasonography affords high predictive value for hepatic and splenic lymphomas[37].

Laparotomy is usually conducted to visualize visceral lymphomas[38].

Primary or secondary cerebral lymphomas usually require CT or MRI imaging to accurately assess morphology[39].

Many types of B-cell lymphomas are now readily assayed with PCR tests[40], amplifying the rearranged immunoglobulin heavy chain gene of neoplastic B-cells[41]. These tests can be used both as diagnostic tests as well as assessing chemotherapeutic effects.

Lymphomas are often stage histologically:

- Stage I: one lymph node affected
- Stage II: two lymph nodes (on the same side of the diaphragm) affected
- Stage III: multiple lymph nodes affected
- Stage IV: the liver and spleen are affected
- Stage V: the bone marrow is affected (lymphoma and leukemia)

Variations exists between pathologist's interpretations[42] and staging is primarily a predictor of response to therapy. Regardless of staging or classification, the overall response rate of dogs with B-cell lymphoma approaches 100% when using drugs such as doxorubicin, compared with a response rate of 50% in dogs with T-cell lymphoma[43].

Staging of lymphomas can also be performed with the use of radio-labeled isotope uptake[44] and thymidine kinase 1 assays[45].

Treatment

Regardless of the classification of lymphoma, most veterinary treatment revolves around palliative care and a choice of one or more chemotherapeutic drugs. Palliative care cannot be over-emphasized, particularly in young or geriatric patients.

Predictors of long-term survival in dogs with high-grade multicentric lymphoma include a body weight ≥ 10 kg, a PCV ≥ 35%, absence of ionized hypercalcemia, monocyte chemotactic protein-1[46], centroblastic lymphoma, immunophenotype B, absence of bone marrow involvement, and not previously treated with corticosteroids[47].

A number of protocols are available, depending on the client's needs and the veterinarian's skills. Generally speaking, dogs treated with multi-agent chemotherapy protocols have longer survival times.

Treatment can be based on Kamofsky's performance criteria, which uses criteria of well-being as a determinant for assessing suitability of canine patients to chemotherapy regimens.

Types of treatments for lymphoma include:

- Doxorubicin - a total of 5 treatments of doxorubicin at 3-week intervals. The average survival time with this approach is 10-11 months.
- Dacarbazine - single-agent therapy for relapsed lymphoma[54]
- Prednisolone - often used as a palliative drug in non-compliant patients or financially challenged cases. Survival time limited to 2 - 3 months.
- Lansoprazole - rescue protocol in dogs in dogs with adverse side-effects associated with chemotherapy

Masitinib has also shown benefit as an adjuvant in doxorubicin treatment of lymphoma[58].

Actinomycin-D[59] and carmustine[60] are also effective for rescue chemotherapy of dogs with relapsed or resistant lymphoma.

Alternative drugs such as acemannan have also been trialed with variable responses[61].

Prognosis

Without treatment, most dogs will die within 1 - 2 months from organ failure. For Stage III lymphoma, 80 - 90% of dogs undergo clinical remission (absence of clinical or ultrasonogrpahic evidence of neoplasia). Stage IV lymphomas have a cure rate of 60 - 80% and Stage V about 50%. If a dog does go into remission, then a first remission of 9 - 14 months is most common. Second remissions can be obtained, but they are harder to obtain and do not last as long as the first.

In most cases of lymphoma, the dose of chemotherapy cocktails (e.g. COP protocol) does not necessarily correlate with patient outcomes[62] and must be re-evaluated in light of quality of life factors.

Many forms of lymphoma cases achieve complete clinical remission following chemotherapy, but relapse due to drug resistance[63].

In dogs with B-cell lymphoma, response to therapy can be predicted based Class II MHC expression, cell size, chemotherapy treatment and age[64]. B-cell lymphoma, which, if treated with multi-agent chemotherapy, has a survival time of approximately 12 months[65].

Failure of response to primary or secondary course of chemotherapy must be weighed up against quality of life, which must be the priority for continuing further treatment[66].

In cases which are already advanced at the time of diagnosis due to neglect or financially-constrained owners, palliative care followed by euthanasia a few weeks or months later may be an only option.

References

  1. RVC
  2. Tufts University
  3. Wikipedia
  4. Veterinary Dentistry
  5. Spugnini EP et al (2011) Lansoprazole as a rescue agent in chemoresistant tumors: a phase I/II study in companion animals with spontaneously occurring tumors. J Transl Med 9:221
  6. Veraa S et al (2010) Comparative imaging of spinal extradural lymphoma in a Bordeaux dog. Can Vet J 51(5):519-521
  7. Sapierzyński R et al (2012) High agreement of routine cytopathology and immunocytochemistry in canine lymphomas. Pol J Vet Sci 15(2):247-252
  8. Sato M et al (2012) The prognostic significance of minimal residual disease in the early phases of chemotherapy in dogs with high-grade B-cell lymphoma. Vet J Aug 18
  9. Takashima-Uebelhoer BB et al (2012) Household chemical exposures and the risk of canine malignant lymphoma, a model for human non-Hodgkin's lymphoma. Environ Res 112:171-176
  10. Reimann-Berg N et al (2011) Cytogenetic analysis of CpG-oligonucleotide DSP30 plus Interleukin-2-Stimulated canine B-Cell lymphoma cells reveals the loss of one X Chromosome as the sole abnormality. Cytogenet Genome Res 135(1):79-82
  11. Huang SH et al (2012) Evidence of an oncogenic gammaherpesvirus in domestic dogs. Virology 427(2):107-117
  12. Stone RH et al (2011) Lymphosarcoma associated with Heterobilharzia americana infection in a dog. J Vet Diagn Invest 23(5):1065-1070
  13. Asano N et al (2012) Eradication Therapy Is Effective for Helicobacter pylori-Negative Gastric Mucosa-Associated Lymphoid Tissue Lymphoma. Tohoku J Exp Med 228(3):223-227
  14. Brunker JD & Hoover JP (2007) B-cell lymphoma in a dog with ehrlichiosis (Ehrlichia canis) and systemic histoplasmosis (Histoplasma capsulatum). Can Vet J 48(3):292-295
  15. van Riel A et al (2007) A dog with alveolar echinococcosis: the larval stage of the fox tapeworm. Tijdschr Diergeneeskd 132(21):828-831
  16. Swerdlow, SH et al (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Oxford Univ Pr. ISBN:978-92-832-2431-0
  17. Joetzke AE et al (2012) Flow cytometric evaluation of peripheral blood and bone marrow and fine-needle aspirate samples from multiple sites in dogs with multicentric lymphoma. Am J Vet Res 73(6):884-893
  18. Berlato D et al (2012) Radiotherapy in the management of localized mucocutaneous oral lymphoma in dogs: 14 cases. Vet Comp Oncol 10(1):16-23
  19. Van den Steen N et al (2012) Rectal lymphoma in 11 dogs - a retrospective study. J Small Anim Pract 53(10):586-591
  20. Durno AS et al (2011) Polycythemia and inappropriate erythropoietin concentrations in two dogs with renal T-cell lymphoma. J Am Anim Hosp Assoc 47(2):122-128
  21. Keller SM et al (2012) Hepatosplenic and Hepatocytotropic T-Cell Lymphoma: Two Distinct Types of T-Cell Lymphoma in Dogs. Vet Pathol Jun 18
  22. Palus V et al (2012) MRI features of CNS lymphoma in dogs and cats. Vet Radiol Ultrasound 53(1):44-49
  23. Nemec A et al (2012) Erythema multiforme and epitheliotropic T-cell lymphoma in the oral cavity of dogs: 1989 to 2009. J Small Anim Pract 53(8):445-452
  24. Olbertz L et al (2012) Supposed primary conjunctival lymphoma in a dog. Vet Ophthalmol Apr 23
  25. Escanilla N et al (2012) Uveodermatologic lymphoma in two young related Portuguese water dogs. Vet Ophthalmol 15(5):345-350
  26. Hong IH et al (2011) Mucosa-associated lymphoid tissue lymphoma of the third eyelid conjunctiva in a dog. Vet Ophthalmol 14(1):61-65
  27. Vascellari M et al (2007) Vertebral polyostotic lymphoma in a young dog. J Vet Diagn Invest 19(2):205-208
  28. Lane LV et al (2012) Canine intravascular lymphoma with overt leukemia. Vet Clin Pathol 41(1):84-91
  29. Schaffer PA et al (2012) Neurolymphomatosis in a dog with B-cell lymphoma. Vet Pathol 49(5):771-774
  30. Valli VE et al (2006) Canine indolent nodular lymphoma. Vet Pathol 43(3):241-256
  31. Ito D et al (2011) A tumor-related lymphoid progenitor population supports hierarchical tumor organization in canine B-cell lymphoma. J Vet Intern Med 25(4):890-896
  32. Peruzzi D et al (2010) A vaccine targeting telomerase enhances survival of dogs affected by B-cell lymphoma. Mol Ther 18(8):1559-1567
  33. O'Neill AM et al (2011) Resistance of canine lymphoma cells to adenoviral infection due to reduced cell surface RGD binding integrins. Cancer Biol Ther 11(7):651-658
  34. Dossin O & Lavoué R (2011) Protein-losing enteropathies in dogs. Vet Clin North Am Small Anim Pract 41(2):399-418
  35. Flood-Knapik KE et al (2012) Clinical, histopathological and immunohistochemical characterization of canine indolent lymphoma. Vet Comp Oncol Feb 2
  36. De Swarte M et al (2011) Comparison of sonographic features of benign and neoplastic deep lymph nodes in dogs. Vet Radiol Ultrasound 52(4):451-456
  37. Crabtree AC et al (2010) Diagnostic accuracy of gray-scale ultrasonography for the detection of hepatic and splenic lymphoma in dogs. Vet Radiol Ultrasound 51(6):661-664
  38. Gieger T et al (2011) Alimentary lymphoma in cats and dogs. Vet Clin North Am Small Anim Pract 41(2):419-432
  39. Thomovsky SA et al (2011) Imaging diagnosis-magnetic resonance imaging features of metastatic cerebral lymphoma in a dog. Vet Radiol Ultrasound 52(2):192-195
  40. Pate DO et al (2011) Diagnosis of intraocular lymphosarcoma in a dog by use of a polymerase chain reaction assay for antigen receptor rearrangement. J Am Vet Med Assoc 238(5):625-630
  41. Sato M et al (2011) Increase in minimal residual disease in peripheral blood before clinical relapse in dogs with lymphoma that achieved complete remission after chemotherapy. J Vet Intern Med 25(2):292-296
  42. Valli VE et al (2011) Classification of canine malignant lymphomas according to the World Health Organization criteria. Vet Pathol 48(1):198-211
  43. Beaver LM et al (2010) Response rate after administration of a single dose of doxorubicin in dogs with B-cell or T-cell lymphoma: 41 cases (2006-2008). J Am Vet Med Assoc 237(9):1052-1055
  44. Statham-Ringen KA et al (2012) Evaluation of a B-cell leukemia-lymphoma 2-specific radio-labeled peptide nucleic acid-peptide conjugate for scintigraphic detection of neoplastic lymphocytes in dogs with B-cell lymphoma. Am J Vet Res 73(5):681-688
  45. Sharif H et al (2012) A sensitive and kinetically defined radiochemical assay for canine and human serum thymidine kinase 1 (TK1) to monitor canine malignant lymphoma. Vet J Apr 17
  46. Perry JA et al (2011) Increased monocyte chemotactic protein-1 concentration and monocyte count independently associate with a poor prognosis in dogs with lymphoma. Vet Comp Oncol 9(1):55-64
  47. Marconato L et al (2011) Predictors of long-term survival in dogs with high-grade multicentric lymphoma. J Am Vet Med Assoc 238(4):480-485
  48. Vail DM et al (2012) Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma. J Vet Intern Med 26(3):608-613
  49. Elliott JW et al (2012) Epirubicin as part of a mufti-agent chemotherapy protocol for canine lymphoma. Vet Comp Oncol Feb 28
  50. Fahey CE et al (2011) Evaluation of the University of Florida lomustine, vincristine, procarbazine, and prednisone chemotherapy protocol for the treatment of relapsed lymphoma in dogs: 33 cases (2003-2009). J Am Vet Med Assoc 239(2):209-215
  51. Rebhun RB et al (2011) CHOP chemotherapy for the treatment of canine multicentric T-cell lymphoma. Vet Comp Oncol 9(1):38-44
  52. 52.0 52.1 Hosoya K et al (2007) Comparison of COAP and UW-19 protocols for dogs with multicentric lymphoma. J Vet Intern Med 21(6):1355-1363
  53. Alvarez FJ et al (2006) Dexamethasone, melphalan, actinomycin D, cytosine arabinoside (DMAC) protocol for dogs with relapsed lymphoma. J Vet Intern Med 20(5):1178-1183
  54. Griessmayr PC et al (2009) Dacarbazine as single-agent therapy for relapsed lymphoma in dogs. J Vet Intern Med 23(6):1227-1231
  55. Escobar C et al (2012) Hematologic changes after total body irradiation and autologous transplantation of hematopoietic peripheral blood progenitor cells in dogs with lymphoma. Vet Pathol 49(2):341-343
  56. Lane AE et al (2012) Use of recombinant human granulocyte colony-stimulating factor prior to autologous bone marrow transplantation in dogs with lymphoma. Am J Vet Res 73(6):894-899
  57. Henson MS et al (2011) Immunotherapy with autologous tumour antigen-coated microbeads (large multivalent immunogen), IL-2 and GM-CSF in dogs with spontaneous B-cell lymphoma. Vet Comp Oncol 9(2):95-105
  58. Zandvliet M et al (2013) Masitinib reverses doxorubicin resistance in canine lymphoid cells by inhibiting the function of P-glycoprotein. J Vet Pharmacol Ther Jan 31
  59. Bannink EO et al (2008) Actinomycin D as rescue therapy in dogs with relapsed or resistant lymphoma: 49 cases (1999--2006). J Am Vet Med Assoc 233(3):446-451
  60. Ricci Lucas SR et al (2004) Carmustine, vincristine, and prednisone in the treatment of canine lymphosarcoma. J Am Anim Hosp Assoc 40(4):292-299
  61. Kruth SA (1998) Biological response modifiers: interferons, interleukins, recombinant products, liposomal products. Vet Clin North Am Small Anim Pract 28(2):269-295
  62. Burton JH et al (2012) Evaluation of a 15-week CHOP protocol for the treatment of canine multicentric lymphoma. Vet Comp Oncol May 2
  63. Sorenmo KU et al (2011) CD40-activated B cell cancer vaccine improves second clinical remission and survival in privately owned dogs with non-Hodgkin's lymphoma. PLoS One 6(8):e24167
  64. Rao S et al (2011) Class II major histocompatibility complex expression and cell size independently predict survival in canine B-cell lymphoma. J Vet Intern Med 25(5):1097-1105
  65. Bienzle D & Vernau W (2011) The diagnostic assessment of canine lymphoma: implications for treatment. Clin Lab Med 31(1):21-39
  66. Bergmann M et al (2011) Dog's quality and prospects of life during chemotherapy for canine lymphoma. An owner survey. Tierarztl Prax Ausg K Kleintiere Heimtiere 39(4):229-236
Personal tools
Namespaces

Variants
Actions
Navigation
Chapters
Toolbox