JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2022

I-N23

 

SLIDE A

Signalment (JPC # 2731574):  Age and breed unspecified dog

 

HISTORY:  Solitary dermal mass protruding from the lip

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, lip (per contributor): Expanding the dermis, compressing surrounding dermal collagen and adnexa, elevating the overlying minimally hyperplastic and hyperkeratotic epidermis, and extending to the deep border is an unencapsulated, well demarcated, densely cellular neoplasm which is separated from the overlying epidermis by a narrow zone of dermal collagen devoid of neoplastic cells (Grenz zone). The neoplasm is composed of round cells arranged in sheets and indistinct nests and packets on a preexisting collagenous stroma. Neoplastic cells have variably distinct cell borders and moderate amounts of eosinophilic, granular cytoplasm.  Occasional cells, often toward the periphery of the neoplasm, have a pale perinuclear hof (Golgi zone). Nuclei are irregular with finely stippled to dense chromatin with one variably prominent nucleolus. Anisocytosis and anisokaryosis is moderate. Mitotic figures average 1 per HPF. There are few scattered multinucleate neoplastic cells with up to 5 nuclei, occasional single cell necrosis, and few foci of hemorrhage, fibrin, and edema. Within the superficial dermis there is minimal pigmentary incontinence and few scattered lymphocytes. 

 

MORPHOLOGIC DIAGNOSIS:  Haired skin: Plasmacytoma, breed unspecified, canine

 

SLIDE B

Signalment (JPC #4076145): 12yo F/S Husky.

 

HISTORY: Mass, right mandible near lip

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin, lip (per contributor): Expanding the dermis, compressing adnexa, elevating the epidermis, and extending into the subcutis and to surgical margins is an unencapsulated, well-demarcated, poorly circumscribed, moderately cellular neoplasm composed of round cells arranged in sheets on a preexisting collagenous stroma, surrounded and separated by lakes of amorphous, smudgy, extracellular, eosinophilic hyaline material (amyloid). Neoplastic cells have distinct cell borders, a moderate amount of eosinophilic cytoplasm which often contains a pale perinuclear hof (Golgi zone), and a round to irregular nucleus with coarsely stippled chromatin and 1-3 variably prominent nucleoli. Anisocytosis and anisokaryosis are moderate; mitoses average 3 per 2.037mm². There are occasional multinucleated neoplastic cells with up to 3 nuclei, and rare intranuclear cytoplasmic invagination. Within the neoplasm are multifocal infiltrates of lymphocytes and areas of hemorrhage, fibrin, and edema and macrophages that contain granular brown intracytoplasmic pigment (hemosiderin). The neoplasm is separated from the epidermis by a broad, up to 200µm wide, dermal band devoid of neoplastic cells (Grenz zone). Within and surrounding the lakes of amyloid are infiltrates of epithelioid macrophages and multinucleated giant cells with up to 27 nuclei, both Langhans type with peripheral nuclei and foreign body type with central nuclei. 

 

Congo red: Lakes of eosinophilic, amorphous extracellular material are diffusely orange-red (congophilic), and exhibit apple-green birefringence under polarized light (amyloid). 

 

MUM1: Within the external control (canine lymph node) there is moderate, multifocal, intranuclear immunoreactivity of paracortical and medullary plasma cells. Within the section of interest, there are occasional non-neoplastic plasma cells within the dermis with moderate intranuclear immunoreactivity (internal control). Neoplastic cells demonstrate diffuse, strong intranuclear immunoreactivity.

 

MORPHOLOGIC DIAGNOSIS: Haired skin, lip: Plasmacytoma with amyloid, husky, canine.

 

SYNONYMS:  Cutaneous extramedullary plasmacytoma (EMP); Plasma cell tumor

 

GENERAL DISCUSSION:  

• Cutaneous extramedullary plasmactyomas occur commonly in the dermis of middle aged or older dogs, and are rare in cats 
• Originate from variably differentiated plasma cells
• Plasmacytic tumors:

• Extramedullary plasmacytomas (D-N10):  Solitary or rarely multiple tumors arising in soft tissues
• Solitary osseous plasmacytoma:  Single tumor arising in bone
• Multiple myeloma:  Involving bone marrow of multiple bones, plasma cells comprise over 30% of marrow, monoclonal gammopathy, Bence-Jones proteinuria, radiographic evidence of osteolysis

• Extramedullary plasmactyoma, especially in the oral cavity and the skin, tend to be benign; whereas, osseous lesions tend to progress to systemic multiple myeloma
• Extramedullary plasmactyoma of the esophagus, stomach, intestine, and rectal area tend to be more aggressive lesions that metastasize to regional lymph nodes
• Rarely, cutaneous plasmacytomas may precede or be present simultaneously with multiple myeloma
• Attempts have been made to develop grading systems, but are of little prognostic value

 

PATHOGENESIS:  

• Unknown
• Amyloid is a pathogenic proteinaceous substance composed of polypeptides arranged in beta-pleated sheets; amyloid associated with plasma cell tumors is AL, amyloid light chain; derived from plasma cells; contains immunoglobulin light chains (either λ light chains or κ light chains)

 

TYPICAL CLINICAL FINDINGS:

• Average age of dogs is 10 years with no sex predilection; Cocker Spaniels may be predisposed
• Commonly present on digits, around the mouth (lips and chin), and ears
• Solitary; may be polypoid when associated with the ear canal; rarely multiple
• Tumors of digits are often ulcerated and hemorrhagic
• Surgical excision is curative; local recurrence and metastases are rare
• Bence-Jones proteinuria with multiple myeloma
• Hyperviscosity syndrome with high [Ig]
• Monoclonal gammopathy (narrow globulin spike on serum protein electrophoresis)

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Round cells arranged in sheets 
• Cells are either well differentiated or atypical and pleomorphic
• Some cells may retain a Golgi zone or perinuclear hof
• Nuclei are round or crescentic (helmet cells), often eccentrically placed and vesiculate, with coarse chromatin forming a “clockface” pattern or finely stippled/hyperchromatic
• Approximately 10% may contain amyloid, more frequently found in feline EMP, which is often accompanied by granulomatous inflammation; occasionally, multifocal chondrous metaplasia can develop in the deposited amyloid
• Intravascular neoplastic cells have been reported in a small subset of cases, but are not indicative of biological behavior (Ehrensing; J Vet Diagn Invest; 2018)
• Occasionally can take on a “pseudoglandular” appearance (McHale; J Vet Diagn Invest; 2018)

 

ULTRASTRUCTURAL FINDINGS:

• Oval to round, eccentric nucleus with marginated chromatin described as “cartwheel” or “clockface”
• Ample cytoplasm with abundant rough endoplasmic reticulum and a well developed perinuclear Golgi apparatus 

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Cytology: Aspirates tend to be moderately to highly cellular with discrete round cells that have abundant blue cytoplasm that may have a perinuclear clearing (golgi zone), a large, round nucleus, which is typically eccentric, chromatin is coarsely reticulated to stippled, and indistinct nucleoli; moderate anisocytosis and anisokaryosis, binucleate and multinucleate cells are typically found; may have an extracellular pink fibrillar material (amyloid); rarely rod-shaped to spiculated granules in the tumor cells
• Immunohistochemistry:  Plasma cells are immunoreactive for: vimentin, CD79a, CD20, CD18, IHC or CISH for lambda/kappa light chains, MUM1/IRF4

• Histiocytomas can also be immunoreactive for MUM1/IRF4; a recent study showed strong nuclear immunoreactivity in all 20 tested canine cutaneous histiocytomas (Stilwell; Vet Pathol; 2018)
• Most normal and neoplastic plasma cells are lambda light chain positive (9:1 lambda to kappa)
• CISH for lambda/kappa light chains can be absent in a subset of tumors and concurrent IHC markers needed for diagnosis (Foiani; J Vet Diagn Invest; 2020)

• Histochemistry:

• Amyloid stains with Congo red (congophilic)
• Most amyloid stains with thioflavine-T, a fluorescent dye
• Methyl green pyronine stains cytoplasmic ribonucleic acid magenta

 

DIFFERENTIAL DIAGNOSIS:

• Gross: Similar to canine cutaneous histiocytoma (I-N22)
• Microscopic:

• Amelanotic epithelioid melanoma (I-N24):  Finely granular, pale cytoplasm; prominent nucleoli; junctional activity; and positive Fontana-Masson, Melan-A, and/or S-100 stains
• Histiocytoma (I-N22):  Cords of cells perpendicular to skin surface, lymphocytic infiltrates, no tumor giant cells
• Mast cell tumor (I-N21):  Granular cytoplasm, stromal collagen, positive toluidine blue and Giemsa, granules stain orange-brown with methyl green pyronine
• Cutaneous lymphoma (I-N25, I-N26):  Rare, most often multiple, recur after surgical excision

 

COMPARATIVE PATHOLOGY:  

• Although rare, they have been reported in aged cats; occur in the skin, gastrointestinal tract, retroperitoneal space, upper lip, gingival, orbit, respiratory tract, and cerebrum (Sykes; J Comp Pathol; 2017)
• Feline myeloma-related disorders (8): including cutaneous extramedullary plasmacytoma, multiple myeloma, noncutaneous extramedullary plasmacytoma, solitary plasmacytoma of bone, IgM macroglobulinemia, immunoglobulin-secreting lymphoma, immunoglobulin-secreting leukemia, and plasma cell leukemia
  1. Periarticular plasma cell tumors in cats can have low cellularity, abundant amyloid, and more aggressive behavior (Craig; Vet Pathol; 2022)
• Psittacine birds get round cell tumors, of 38 studied cases: B-cell lymphoma 50%, T-cell lymphoma 16%, Plasma cell tumor 8%, B-and T- cell IHC markers 8% (Gibson, Vet Pathol 2021)
• Plasma cell leukemia with  plasmablastic morphology in a dog (Dagher; J Vet Diagn Invest; 2019)
• Rarely erythrophagocytic multiple myeloma reported in dogs (Romanelli; J Vet Diagn Invest; 2022)
• Plasmacytomas reported in Chinook salmon, collared peccary (extramedullary plasmacytoma), suids. 
• Inducible tumor of mice with pristane injection, retrovirus infection, or in BALB/c and NZB strains of mice.
• Hamsters get ascites plasmacytomas. 
• Rhesus macaque plasmacytomas accompany anemia. 

 

REFERENCES:  

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell; 2016: 110, 186.
2. Craig LE, Lieske DE. Periarticular plasma cell tumors in cats. Vet Pathol. 2022;59(2):264-268.
3. Dagher E, Soetart N, Chocteau F, et al. Plasma cell leukemia with plasmablastic morphology in a dog. J Vet Diagn Invest. 2019;31(6):868-874.
4. 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; 2022:842-843, 869.
5. Ehrensing G, Craig LE. Intravascular neoplastic cells in canine cutaneous plasmacytomas. J Vet Diagn Invest. 2018;30(2):329-332. 
6. Fisher DJ. Cutaneous and subcutaneous lesions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 90-91. 
7. Foiani G, Zanardello C, Carminato A, et al. Chromogenic in situ hybridization for the detection of lambda and kappa immunoglobulin light chains as a potential auxiliary diagnostic technique in canine plasmacytomas. J Vet Diagn Invest. 2020;32(5):675-682.
8. Gibson DJ, Nemeth NM, Beaufrère H, Varga C, Garner MM, Susta L. Lymphoma in Psittacine Birds: A Histological and Immunohistochemical Assessment. Vet Pathol. 2021;58(4):663-673.
9. Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Philadelphia, PA: Elsevier Saunders; 2015:256-262.
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11. McHale B, Blas-Machado U, Oliveira FN, Rissi Dr. A divergent pseudoglandular configuration of cutaneous plasmacytoma in dogs. J Vet Diagn Invest. 2018;30(2):260-262. 
12. Raskin RE, Conrado FO. Integumentary system. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2023: 108-112. 
13. Romanelli P, Recordati C, Rigamonti P, Bertazzolo W. Erythrophagocytic multiple myeloma in a dog. J Vet Diagn Invest. 2022;34(4):718-722.
14. Stilwell JM and Rissi DR. Immunohistochemical labeling of multiple myeloma oncogene I/interferon regulatory factor 4 (MUMI/IRF-4) in canine cutaneous histiocytoma. Vet Pathol. 2018;55(4):517-520.
15. Stockham SL, Scott MA. Fundamentals of Veterinary Clinical Pathology. 2nd ed. Hoboken, NJ: Wiley; 2013: 383-385.
16. Sykes SE, Byfield V, Sullivan L, Bender SJ, Moore PF, Sanchez MD. Feline respiratory extramedullary plasmacytoma with lymph node metastasis and intrahistiocytic amyloid. J Comp Pathol. 2017;156(2-3):173-177. 
17. Terio KA, Mcaloose D, Leger JS, et al. Suidae and Tayassuidae. In: Pathology of Wildlife and Zoo Animals. Saint Louis: Elsevier Science & Technology; 2018:209, 226. 
18. Terio K, Mcaloose D, Leger J, et al. Osteichthyes. In: Pathology of Wildlife and Zoo Animals. Saint Louis, MO: Elsevier Science & Technology; 2018:965.
19. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 2. 6^th ed. St. Louis, MO: Elsevier; 2016:27-28. 
20. Valli VEO, Kiupel M, Bienzle D. Hematopoietic system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016: 226-228.

 

 

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