JPC SYSTEMIC PATHOLOGY

Hemolymphatic System

February 2024

H-N05

 

SLIDE A (JPC Accession #4048572): 

 

SIGNALMENT: 9-year-old castrated male beagle dog, Canis familiaris.

 

HISTORY: Patient was referred to a veterinary surgeon for evaluation of a possible splenic mass. An abdominal ultrasound showed a 2 inch mass in the cranial aspect of the spleen, which was confirmed at surgery for splenectomy. 

 

HISTOPATHOLOGIC DESCRIPTION: Spleen: Affecting 70% of the section, expanding the white pulp marginal zone, surrounding fading follicles, and compressing the adjacent red pulp is a densely cellular, unencapsulated, poorly demarcated neoplasm composed of homogenous lymphocytes in multifocal to coalescing nodules on a pre-existing fibrovascular stroma. Neoplastic lymphocytes have distinct cell borders, a moderate amount of granular eosinophilic cytoplasm, and a round central nucleus that is approximately 1.5x larger than a red blood cell (intermediate size) with finely stippled chromatin and 1-2 prominent nucleoli. Anisocytosis and anisokaryosis are moderate and there are 10 mitoses per 2.37mm². The marginal sinuses and tingible body macrophages are often not visible within neoplastic nodules, and splenic trabeculae are inapparent. The red pulp is compressed and multifocally lacks peripheral blood or has large blood-filled dilations of the red pulp vascular spaces that are up to 4.2mm in diameter. 

 

MORPHOLOGIC DIAGNOSIS: Spleen, white pulp: Lymphoma, intermediate size, low grade, consistent with marginal zone lymphoma, canine.  

 

SLIDE B (JPC Accession #4048571):

 

SIGNALMENT: 10-year-old castrated male golden retriever, Canis familiaris.

 

HISTORY: This patient was previously diagnosed with T-cell lymphoma based on PARR only. CHOP-based chemotherapy protocol for 6-month duration elicited a minimal response and one month after cessation of therapy, lymph nodes enlarged further. A nodal biopsy and fine needle aspirate was performed on the left mandibular lymph node. 

 

HISTOPATHOLOGIC DESCRIPTION: Lymph node: Affecting 90% of the section, expanding the paracortex and medullary cords, compressing medullary, cortical, and subcapsular sinuses, and peripheralizing and compressing fading follicles in the outer cortex is an unencapsulated, poorly demarcated, densely cellular neoplasm composed of round cells arranged in sheets and vague nodules on a pre-existing fibrovascular stroma. Neoplastic cells have distinct cell borders, moderate amounts of eosinophilic, granular cytoplasm, and a round central nucleus that is approximately 1.5x larger than a red blood cell (intermediate size) with finely stippled chromatin and one variably prominent nucleolus. Anisocytosis and anisokaryosis are mild and there are 2 mitotic figures per 2.37mm². There is rare single cell necrosis. Remaining sinuses are ectatic and filled with neoplastic lymphocytes. 

 

MORPHOLOGIC DIAGNOSIS: Lymph node: T-zone lymphoma, canine.

 

CONDITION: Indolent lymphoma; non-viral lymphoma 

 

GENERAL: 

• Lymphoma encompasses a diverse group of neoplasms that arise in lymphoid tissues outside of the bone marrow
• Characterization on histology uses the morphologic features of pattern (diffuse or nodular), nuclear size (nuclei compared to red blood cell), and mitotic rate
• Subtypes are based on the World Health Organization system and are based on the assumption of a normal cell counterpart to each different subtype
• “Indolent lymphoma” encompasses a heterogenous group of lymphoma subtypes, including T cell-rich large B cell lymphoma, marginal zone lymphoma, and T zone lymphoma
• Most likely origin:
  • Marginal zone lymphoma = Post-germinal center marginal zone B cells
  • T-zone lymphoma = Activated mature paracortical T cells

 

PATHOGENESIS:

• Neoplastic proliferation of subpopulations of lymphocytes
• “Indolent” terminology indicates the slowly progressive character of these subtypes of lymphoma; extremely long survival times

 

TYPICAL CLINICAL FINDINGS:

• Marginal zone lymphoma
  • Usually a nodular tumor in the spleen
  • Three subtypes in dogs and cats: Splenic MZL, nodal MZL, and extranodal MZL (BALT and GALT) 
  • Otherwise clinically healthy
  • Can progress to diffuse large B cell lymphoma with subsequent poor prognosis (Shiga, Vet Pathol 2020)
• T-zone lymphoma (about 10% of canine nodal lymphomas)
  • Mild lymphocytosis
  • Otherwise good health  
  • One or more nodes affected
  • Characterized in dogs (especially golden retrievers and shih tzus) and rarely horses

 

TYPICAL GROSS FINDINGS:

• Marginal zone lymphoma
  • Single splenic nodule or enlarged lymph node
  • Multiple nodes or sites affected later in disease
• T-zone lymphoma
  • One or more enlarged lymph nodes
  • Rarely generalized lymphadenopathy can occur
  • Rare cases of epitheliotropic T-cell proliferations have been reported in late-stage disease 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Ideally, use cytology and histology together to diagnose lymphomas
• Marginal zone lymphoma
  • Marginal zone proliferation of neoplastic B cells surrounds fading germinal centers
  • Marginal zone lymphocytes are intermediate size with large central nucleolus and abundant pale cytoplasm
  • Difficult to diagnose on cytology; medium lymphocytes with a single prominent nucleolus, may have PAS(+) cytoplasmic inclusions
• T-zone lymphoma (TZL)     
  • Paracortical proliferation of neoplastic T cells causing compression, peripheralization, and fading of cortical germinal centers
  • Cells are often small to intermediate size
  • Mitotic count is 0-10 per 2.37mm^2
  • On cytology: Homogenous population of small lymphocytes with sharp, shallow nuclear indentations, indistinct nucleoli, and a moderate volume of pale or clear cytoplasm often with a single cytoplasmic extension (uropod)

 

ADDITIONAL DIAGNOSTIC TESTS:

• PCR for antigen receptor rearrangements (PARR) can help establish clonality; should never be used independent of histologic features, IHC, and clinical findings; clonality does not equal immunophenotype due to cross-lineage rearrangements (10% frequency in lymphomas)
  • TZL usually has a T-cell receptor (TCR) gene rearrangement
• Flow cytometry – Distinguishes immunophenotype on fluid specimens
• IHC:
  • MZL should be CD79a(+) and CD20(+)
  • TZL should be CD3(+), CD45(-), low Ki67 index, CD8(+), FOXP3(-)

 

DIFFERENTIAL DIAGNOSIS:

• Marginal zone lymphoma: Intermediate size B cells with abundant pale cytoplasm; usually MUM-1(+), may be MCL-1(+), CD79a(+), CD20(+)
  • Marginal zone hyperplasia: Discontinuous cuffs of marginal zone lymphocytes that are mixed with smaller mantle cell and centroblast lymphocytes
  • Mantle cell lymphoma (MCL): Intermediate size B cells with scant cytoplasm and hyperchromatic nuclei; usually MUM-1(-), MCL-1(-) (Stein, Vet Pathol, 2019)
• T-zone lymphoma: Clonal CD8(+), CD45(-) T cells with TCR gene rearrangement; potentially naïve cytotoxic T cell origin
  • T-zone hyperplasia: Heterogenous population of small T lymphocytes, macrophages, and dendritic cells; immunophenotypically heterogenous CD45(+), FOXP3(+) T cells (Kazuhiro et al., Vet Pathol, 2022), 

 

COMPARATIVE PATHOLOGY: 

 

REFERENCES:

1. Blauvelt M, Messick JB. The Lymph Nodes. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:181. 
2. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:868, 886, 887.
3. Hughes KL, et. al. Diffuse small B-cell lymphoma: a high grade malignancy. Vet Pathol. 2021;1-11. 
4. Kojima K, Chambers JK, Mizuno T, Uchida K. Nodal T-zone lymphoma and T-zone hyperplasia in dogs. Vet Pathol. 2022;59(5):733-739.
5. Raskin RE. Chapter 4: Hemolymphatic System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:140, 142, 163.
6. Sabattini S, et. al. Canine splenic nodular lymphoid lesions: immunophenotyping, proliferative activity, and clonality assessment. Vet Pathol. 2018;55(5):645-653. 
7. Schaefer DMW, Corn SC. Special Tests: Flow Cytometry. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:523, 525-528.
8. Shiga T, et al. Long-term observation of the progression from nodal marginal zone lymphoma to diffuse large B-cell lymphoma in a dog. Vet Pathol. 2020;57(4):520-524. 
9. Stein L, et. al. Immunophenotypic characterization of canine splenic follicular-derived B-cell lymphoma. Vet Pathol. 2019;56(3):350-357. 
10. Stein L, Bacmeister C, Kiupel M. Immunophenotypic Characterization of Canine Nodal T-Zone Lymphoma. Vet Pathol. 2021;58(2):288-292.
11. Valli VEO, Kiupel M, Bienzle D. Hemopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:190, 214-218; 222-226; 229-230.
12. Wolfesberger B, et al. World Health Organisation classification of lymphoid tumours in veterinary and human medicine: a comparative evaluation of gastrointestinal lymphomas of 61 cats. J Comp Pathol. 2018;159:1-10. 

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