JPC SYSTEMIC PATHOLOGY

HEMATOLYMPHATIC SYSTEM

February 2024

H-N01

 

Signalment (JPC #3165081): 9-year-old female Shih Tzu dog

 

HISTORY: Tissue from a mediastinal mass. 

 

HISTOPATHOLOGIC DESCRIPTION: Thymus: Disrupting and expanding the thymus and extending to all borders is a densely cellular neoplasm composed of polygonal cells arranged in small nests and trabeculae on fine fibrovascular stroma. Neoplastic cells have variably distinct cell borders and a moderate amount of granular eosinophilic cytoplasm, a round to oval nucleus with fine chromatin and one variably distinct nucleolus. Anisocytosis and anisokaryosis are moderate and the mitotic count is < 1 per 2.37mm^2. Multifocally, neoplastic cells form eosinophilic, keratinizing, concentrically lamellated bodies (Hassall’s corpuscles). Separating, surrounding, and obscuring neoplastic cells are abundant small lymphocytes, with scant cytoplasm and round nuclei containing coarsely clumped chromatin. There are multifocal variably sized cystic areas throughout the neoplasm that contain pale eosinophilic fluid and/or eosinophilic granular debris. 

 

MORPHOLOGIC DIAGNOSIS:  Thymus: Thymoma, type B1 (mixed type), Shih Tzu dog, canine.

 

GENERAL DISCUSSION: 

• Thymus has both lymphoid and epithelial components, so neoplasms can arise from either; thymomas arise from the epithelial component, usually benign
• Occurs in dogs and cats of 10-12 years of age; common in adult female goats
• In dogs, generally localized to one lobe, or may leave a remnant of benign thymus compressed to the periphery of the thymic capsule
• In cats, may be ectopic mass in cervical area, often focally cystic
• In goats, contained within thoracic cavity
• They tend to have benign biologic behavior; less than one third are locally invasive or metastasize
• Older dogs and dogs with lymphocyte predominant thymomas tend to have a longer survival time
• Historically classified based on cellular composition and the type and degree of atypia of the epithelium: Lymphocytic, epithelial, or mixed
• More accurate classification system includes 3 types according to histologic phenotypes
  1. Type A = composed of spindle shaped cells
     • 10% of canine thymomas
     • Micronodular thymoma = exceedingly rare variant of type A 
  2. Type B = epithelioid cells
     • 70% of canine thymomas; B1 & B2 being most common
     • Also frequent in cattle, sheep, goat; rare in horse
     • Further subdivided into B1, B2, B3 thymomas, with relative ratio of epithelioid cell population to non-neoplastic lymphocytes as the major distinguishing feature; B1 most closely resembles normal thymus and most dense lymphocyte population
  3. Type AB = admixture of both type A & B; mostly in goat & sheep as space occupying mass
• The epithelial reticular cells of the thymus arise from the third pharyngeal pouches
• Prognosis for goats following excision of ventral cervical thymomas was favorable, whereas goats with mediastinal thymomas appeared more likely to have severe clinical signs and a guarded prognosis

 

TYPICAL CLINICAL FINDINGS:

• In ruminants, especially goats and sheep, thymomas are usually incidental
• Dog, cat, and horse typically have signs consistent with a space occupying mass in the thoracic cavity (respiratory signs/cardiovascular impairment)
• Edema of the head and neck and rarely the forelimbs
• Paraneoplastic syndromes:

• Myasthenia gravis – Up to 40% of dogs with thymomas have this as a paraneoplastic syndrome often presenting as megaesophagus; the source of antibodies produced against the acetylcholine (Ach) receptor at the neuromuscular junction remains unknown; involves functional reduction in acetylcholine receptors and neuromuscular junctions

• Antibody reaction developed against thymic myoid cells (associated with Hassall’s corpuscles) that express Ach receptors

• Paraneoplastic exfoliative dermatosis associated with thymoma in rabbits
• Paraneoplastic eosinophilia in dogs
• Other paraneoplastic syndromes reported in dogs and cats with thymomas include hypercalcemia of malignancy, polymyositis, pure red cell aplasia, T-cell lymphocytosis, and immune mediated skin diseases

 

TYPICAL GROSS FINDINGS:

• Cranial mediastinal mass
• May extend from the neck to the posterior mediastinum
• Nodular, firm, grey-white, expansile, and encapsulated
• There is loss of the normal cortical/medullary architecture
• Macro and microscopic protein filled cysts are common
• There are foci of necrosis and hemorrhage

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Note percentage of each component
• Type A (10%) = Composed of spindle shaped cells

1. Cells arranged in storiform, fascicular, or pericytomatous pattern
2. Uniform elongated nuclei, with dense chromatin and inconspicuous nuclei
3. Rare signet ring cells and pseudorosettes 

• Type B (70%) = Epithelioid cells; subdivided into B1-B3 based on the population of non-neoplastic small lymphocytes; most common in dogs

1. Type B1 = Lobulated mass, resembling exaggerated normal thymic structure

• Dense small lymphocyte population, easily mistaken for lymphoid neoplasm; most characteristic is random foci of pale-staining medullary differentiation

1. Type B2 = Prominent lobulation; similar structure as B1 with abundant small lymphocytes but with more easily recognizable epithelial cells compared to B1; lymphoid follicles may be present
2. B3 = Lobules of round or polygonal epithelial cells with no or mild atypia; mixed with fewer non-neoplastic T-cell which result in sheet-like growth of neoplastic epithelial cells

• Type AB (15%) = Composed of lymphocyte-poor type A and lymphocyte-rich type B 

1. A mix of each component with percentage of each subtype varying among and within neoplasms
2. Predominance of each component will vary
3. Most common in goats and sheep
4. May have marked encapsulation and septation
5. Type A component may have cystic spaces but not type B component
6. Hassall’s corpuscles may not be seen in type B component

• Neoplastic epithelial cells are cytokeratin positive
• Clear cell thymoma: An unusual variant that has large round cells with abundant clear cytoplasm and distinct cell margins
• Hassall’s corpuscles are usually present
• Myoid cells, which are large round cells with abundant finely granular, eosinophilic cytoplasm containing cross-striations, some with fine fibrils concentrically arranged, may be present, often around Hassall’s corpuscles, in goats, small mammals, birds, and reptiles; may be involved in the development of myasthenia gravis
• Cystic spaces are branchial duct remnants and are lined by ciliated columnar to squamous epithelium and are frequently filled with eosinophilic material (sometimes resembling thyroid follicles and colloid)

 

ADDITIONAL DIAGNOSTIC TESTS:

Cytology:

• Cranial mediastinal mass with thoracic effusion containing large number of lymphocytes and mast cells is suggestive of thymoma
• Epithelial cells generally don’t exfoliate
• Lymphocyte coexpression of CD4 and CD8 (characteristic of thymocytes) is suggestive of thymoma

 

DIFFERENTIAL DIAGNOSIS:

• Thymic Lymphoma: Cats and young cattle, less common in dogs

• Lymphoid tumors of the cranial mediastinum in cats and cattle are majority precursor T cell lymphoblastic lymphoma and rarely in dogs may be a large B cell lymphoma

• Thymic lymphoma in cattle occurs in yearlings, beef breeds and is not associated with Bovine leukemia virus; tumors may extend from rami of mandibles to base of heart; compression of lungs by tumor and excess pleural fluid; high grade, largely Burkitt-like (small noncleaved type) and high number of lymphoblasts, all are T-cell type and CD3 positive 
• Difficult to distinguish from lymphocytic thymoma- thymoma will have epithelioid component; on cytology, small and large lymphocytes mixed with epithelial cells with pale nuclei and abundant cytoplasm
• Lymphoma there is homogenicity of cell type even if an occasional epithelial cell is present in the population
• Thymic lymphoma maybe differentiated from thymoma using Flow Cytometry which would identify lymphocytes coexpressing CD4 and CD8, typical of thymic lymphocytes, whereas coexpression of these markers would be considered very uncommon in lymphoma

• Thymic hyperplasia is a rarely reported lesion, which may be difficult to distinguish from thymoma

• Normal separation of the cortex and medulla persists resulting in large and small lymphocytes being clustered separately
• Characteristic cuffing of small veins by reticular epithelial cells

• Thymic carcinoma: Malignant thymoma; subdivided based on features not found in normal thymus such as squamous cell carcinoma (most common), clear cell carcinoma and lymphoepithelioma-like carcinoma

• Lobulated with ample stroma, and have pleomorphic, vesicular nuclei with many mitotic figures; may have desmoplasia and varying degrees of keratinization; highly invasive and must be differentiated from pulmonary squamous cell carcinoma that invades the mediastinum 

• Thymic cyst: Cystic changes may be prominent in a thymoma
• Thymoma with anaplasia (Type X):   Uncommon group of thymomas that do not fit into either thymoma or thymic carcinoma category based on histo features
• Primary germ cell tumor, resemble seminomas, occur in thymus glands of males in the absence of primary tumor in the testicle (rare)
• PARR may be used to differentiate canine thymoma from canine lymphoma in certain instances

 

COMPARATIVE PATHOLOGY:

• NHPs: Thymomas associated with obstruction of vena cava, with cranial edema and swelling, and respiratory signs
• Avian: Thymomas may form anywhere in the subcutis of neck from mandible to thoracic inlet; may be cystic or hemorrhagic; often metastasize by the time the primary mass is recognized; described in birds as young as 2 months
• Rat thymic neoplasms with medullary differentiation are common lesions that may be difficult to differentiate from thymic hyperplasia, which can be induced by hypertensive vascular disease and nephrosis
• Rabbit – Occur between 1 to 4 years old & usually incidental at necropsy; often associated with exfoliative dermatosis; may present with dyspnea due to an anterior mediastinal mass; +/- metastatic; +/-; paraneoplastic syndrome: Hypercalcemia, exfoliative dermatosis, periodic exophthalmos; Type A thymoma reported in a pet rabbit (Robson, J Vet Diagn Invest 2022)
• Dog – Thymoma and small cell (thymic) lymphoma: Both associated with a mediastinal mass and persistent peripheral small-cell lymphocytosis; thymomas have been diagnosed where mediastinal masses contained ≥ 10% of double positive CD4 and CD8 small-cell lymphocytes and < 10% were suggestive of lymphoma 
  1. This case: Thymoma-associated lymphocytosis lack the classic CD4+CD8+ immunophenotype
  2. Suggest there may be more diversity in the thymoma-associated lymphocyte immunophenotype 
  3. Cytologic and/or histologic evaluation, immunophenotyping, clonality assessment should be utilized to circumvent misdiagnosing (Wikander, J Vet. Diagn Invest 2020)
• Dogs – Polymyositis can be seen in dogs with thymoma
• Reported in backyard chickens (Blakey, J Vet Diagn Invest 2021)
• Thymoma-associated exfoliative dermatitis reported in a goat
  1. Should be considered a clinical differential in goats with dermatologic disease (Byas, J Vet Diagn Invest 2019)
• Lagomorphs – Thymoma associated paraneoplastic syndromes 
• Thymoma reported in the elephant shrews
• Thymoma reported in the Nilgai
• Malignant thymoma reported in the mongoose lemur
• Reported in a degu (Okumura, J Vet Diagn Invest 2022)

 

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Rabbit. In: Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016:309,322. 
2. Bertram CA, Bertram B, Bartel A, Ewringmann A, Fragoso-Garcia MA, Erickson NA, Müller K, Klopfleisch R. Neoplasia and Tumor-Like Lesions in Pet Rabbits (Oryctolagus cuniculus): A Retrospective Analysis of Cases Between 1995 and 2019. Vet Pathol. 2021;58(5):901-911.
3. Blakey J, Jerry C, da Silva A, Stoute S. Thymoma in an aged backyard Leghorn chicken, with reviews of a database and literature. J Vet Diagn Invest. 2021;1-4.
4. 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; 2022:173-179.
5. Byas AD, Applegate TJ, Stuart A, Byers S, Frank CB. Thymoma-associated exfoliative dermatitis in a goat: case report and brief literature review. J Vet Diagn Invest. 2019;31(6):905-908.
6. Delaney MA, Treuting PM, Rothenburger JL. Lagomorpha. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals.  Cambridge, MA: Elsevier Inc. 2018:486.
7. 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; 2022:880.
8. Hargis AM, Myers S. The Integument.  In: Zachary JF, ed. Pathologic Basis of Veterinary Medicine. 6^th ed. Philadelphia, PA: Elsevier; 2017:949, 1146
9. Jacobs RM, Messick JB, Valli VE. Tumors of the Hemolymphatic system.  In: Meuten DJ, eds. Tumors in Domestic Animals. 4th ed. Ames, Iowa: Iowa State University Press; 2002:165-168.
10. Jones MEB, Nemeth NM, Ryser-Degiorgis MP. Bovidae, Antilocapridae, Giraffidae, Tragulidae, Hippopotamidae. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals.  Cambridge, MA: Elsevier Inc. 2018:141.e8.
11. Lowenstein LJ, Osborn KG. Strait K, Else JG, Eberhard ML. Respiratory System Diseases of Nonhuman Primates. In: Abee CR, Mansfield K, Tardif S, Morris T. Nonhuman Primates in Biomedical Research: Volume 2: Diseases. 2^nd ed. San Diego, CA: Elsevier; 2012: 444.
12. McAloose D, Stalis IH. Prosimians. In: Terio KA, McAloose D, St. Leger J ed. Pathology of Wildlife and Zoo Animals.  Cambridge, MA: Elsevier Inc. 2018:339.e8.
13. Okumura N, Kondo H, Suzuki S, Shibuya H. Thymoma originating from the cervical component of the thymus in a degu. J Vet Diagn Invest. 2022;34(1):126-129.
14. Robson HR, Yanez RA, Magestro LM, French SJ, Kiupel M. Type A thymoma in a pet rabbit. J Vet Diagn Invest. 2022;34(2):327-330.
15. Schmidt R, Reavill DR, Phalen DN. Lymphatic and Hematopoietic System. In: Pathology of Pet and Aviary Birds. 2nd ed. Ames, IA: John Wiley & Sons, Inc.; 2015:181-182
16. Stockham SL, Scott MA. Leukocytes. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 88.
17. Valenciano AC, Rizzi TE. Abdominal, Thoracic, and Pericardial Effusions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:244-245.
18. Vali VEO, Kiepul M, Bienzle D, The hematopoietic system.  In: Maxie MG, ed. Jubb, Kennedy and Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:151-158. 
19. Wikander YM, Knights K, Coffee C, Vernau W, Biller DS, Higginbotham ML, Springer NL. CD4 and CD8 double-negative immunophenotype of thymoma-associated lymphocytes in a dog. J Vet. Diagn Invest. 2020;32(6):918-922.

 

 

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