AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2019

I-N25

 

SLIDE A

Signalment (JPC# 2017869): Horse

 

HISTORY: This horse had a dermal mass

 

HISTOPATHOLOGIC DESCRIPTION (Slide A): Haired skin: Expanding and effacing the deep dermis, infiltrating the subcutis, elevating the epidermis, and extending to cut margins is an unencapsulated, well circumscribed, densely cellular neoplasm composed of sheets of round cells on a moderate pre-existing collagenous stroma. Neoplastic cells have indistinct cell borders, a scant amount of eosinophilic cytoplasm, and round to ovoid nuclei with finely stippled chromatin and 1-3 variably distinct nucleoli. The mitotic count averages 1 per 40X HPF. There is multifocal individual cell necrosis. Admixed with neoplastic cells are many small, reactive lymphocytes and large histiocytes up to 20 um in diameter. Histiocytes have a moderate amount of eosinophilic cytoplasm and occasionally contain intracytoplasmic, variably sized, up to 1 x 7 um, eosinophilic, acicular crystals.

 

MORPHOLOGIC DIAGNOSIS: Haired skin, site not specified: Lymphoma, nonepitheliotropic, breed not specified, equine.

 

SLIDE B

Signalment (JPC# 2604555): Cow

 

HISTORY: This cow had multiple, 1-3 cm diameter, cutaneous bumps

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Infiltrating the dermis, separating and surrounding adnexa and pre-existing collagen bundles, elevating the focally eroded epidermis, and occasionally infiltrating the epidermis and follicular epithelium is an unencapsulated, poorly circumscribed, densely cellular neoplasm composed of sheets of round cells. Neoplastic cells have indistinct cell borders and scant eosinophilic granular cytoplasm. Nuclei are round to ovoid with coarsely-stippled chromatin and 1-4 distinct nucleoli. The mitotic count is up to 4 per HPF. There is multifocal individual cell necrosis. Multifocally, neoplastic cells infiltrate the follicular epithelium and epidermis forming Pautrier’s microabscesses. Within the superficial dermis, there is multifocal moderate hemorrhage admixed with fibrin and edema. Overlying the epidermis and occasionally extending into follicular lumina is a 500 um thick serocellular crust composed of many degenerate neutrophils admixed with abundant serum, necrotic debris, and multifocal colonies of 1 um diameter cocci. Multifocal apocrine glands adjacent to the neoplasm are mildly ectatic.

 

MORPHOLOGIC DIAGNOSIS: Haired skin, site not specified: Lymphoma, epitheliotropic, breed not specified, bovine.

 

GENERAL DISCUSSION:

Overview:

·      Cutaneous lymphoma may be primary or part of multicentric neoplasia

·      Two main groups of cutaneous lymphoma:

·      Epitheliotropic (I-N26): Invades epidermis and/or adnexal epithelium

o   Mycosis fungoides: Older animals; chronic exfoliative dermatitis or plaques/nodules often involving mucocutaneous junctions; often ulcerated; neoplastic T-cells (80% express CD8) are diffuse, scattered, or aggregated within epidermis (“Pautrier’s microabscesses”)

o   Sezary syndrome: Mycosis fungoides (transformed) with a leukemic component; circulating neoplastic cells have characteristic cerebriform nuclear indentations

o   Pagetoid reticulosis (Woringer-Kolopp disease): Solitary plaque form; neoplastic lymphocytes confined to epidermis; dermal mixture of mature lymphocytes and macrophages

·      Nonepitheliotropic: Dermal/subcutaneous nodules; rarely ulcerated; separated from epidermis by a Grenz zone; usually B-cell origin (exceptions below):

o   T-cell-rich large B-cell lymphoma (TCRLBCL): Most common form of cutaneous lymphoma in the horse, quarter horse predisposed; neoplastic large B-cells on a background of smaller reactive T-cells that comprise 10-90% of the population

o   Angiocentric lymphoma (lymphomatoid granulomatosis): RARE w/ few case reports, usually a cutaneous manifestation of pulmonary lymphoma; angiodestructive neoplastic T-lymphocytes in dermis/subcutis with extravascular infiltrates; necrosis and infarction

o   Intravascular lymphoma (malignant angioendotheliomatosis): Intravascular neoplastic lymphocytes in the absence of a primary mass or circulating neoplastic cells; forms dermal/subcutaneous plaques and nodules; most cases in dogs are T-cell origin

EQUINE: Lymphoma is the most common malignant neoplasm of the horse; the quarter horse is the most common breed affected

·      Multicentric (most common form): TCRLBCL; masses in the abdomen and thoracic cavity; multiple organ involvement; typically NO lymphadenomegaly

·      SQ masses in the skin often the primary clinical presentation

·      Cutaneous: epitheliotropic cutaneous T-cell lymphoma (CTCL); similar to human/dog Mycosis fungoides and Sezary syndrome; rare, thoroughbreds predisposed

·      Alimentary: most commonly enteropathy-associated T-cell lymphomas of small cell type (EATL type 2)

BOVINE: Lymphoma is categorized by frequency of occurrence (sporadic or endemic/enzootic), age at onset, organ system(s) involved, and the etiologic agent:

·      Sporadic (non-BLV-associated): Most are T-cell morphology, but can be B-cell

·      Cutaneous form: Cutaneous lesions in cattle 2-3 years of age; epitheliotropic

·      Thymic or juvenile form: Cattle 6 months to 2 years of age; beef breeds, especially Hereford cattle, may be predisposed; most cases aleukemic

·      Multicentric or calf form: Develops within first 6-months of life (may be present at birth); symmetrical lymphadenomegaly and leukemia; myelophthisis and marrow infarction; kidneys +/- liver and spleen involved

·      Adult form/enzootic bovine leukosis (bovine leukemia virus, BLV): B-cell origin; most common form; involves multiple organ systems (lymph nodes, retrobulbar area, pharyngeal area, abomasum, uterus, spinal canal perineural fat, right atrium, liver, spleen, kidney) often causing compression issues, particularly in nervous system, eye and bone marrow; high incidence in dairy cattle

 

PATHOGENESIS:

Equine:

·      Unknown

·      In TCRBCL, it is speculated that neoplastic B cells produce cytokines that lead to infiltrates of non-neoplastic T cells and +/- other leukocytes

Bovine:

·      Sporadic cutaneous (non-BLV-associated): Unknown

·      BLV-associated (bovine enzootic lymphoma):

·      Infection of IgM-expressing B lymphocytes with BLV (oncogenic deltaretrovirus); regulatory protein Tax immortalizes CD5-positive IgM-positive B cells and stimulates their proliferation; new virus is released to infect naïve B-cells; suspect suppression of p53 in neoplastic transformation

·      Transmission of infected lymphocytes (i.e. cell-associated transmission) is horizontal; blood-sucking arthropods or other mechanical means principal mode of spread

 

TYPICAL CLINICAL FINDINGS:

Equine:

·      Nonepitheliotropic (TCRLBCL): Seen in adult to aged animals; most have concurrent systemic illness (e.g. depression, inappetence, weight loss, anemia, leukemia, peripheral lymphadenopathy); may have skin lesions for months to years before systemic involvement; may be immunosuppressed and develop IMHA or thrombocytopenia

·      Epitheliotropic:

·      Mycosis fungoides: Generalized exfoliative dermatitis +/- pruritus

·      Sezary syndrome: Pruritus, erythroderma, peripheral lymphadenopathy,

Bovine:

·      Sporadic cutaneous:

·      Affects 1-3 year-old cattle; lesions wax and wane over months with some regressing; may survive 12-18 months before deep organ involvement that can resemble enzootic type of bovine lymphoma

·      BLV-associated: Of infected cows, lymphocytosis occurs in ~30% and lymphoma in <5%; lymphoma develop in animals 4-8 years of age - multiple enlarged lymph nodes, GI obstruction, nervous symptoms (compression of nerves from enlarged nodes, and/or infiltration of epidural fat by neoplastic cells)

 

TYPICAL GROSS FINDINGS:

Equine:

·      Subcutaneous (TCRLBCL): Numerous 1-3 cm diameter subcutaneous masses (especially chest, thorax, flanks, perineum, face, neck, sparing the limbs); nodules are round and flattened and often appear to follow lymphatics.

·      Epitheliotropic (CTCL): Generalized exfoliative dermatitis (alopecia, scaling, crusting), +/- nodules, +/- ulceration (especially over pressure points)

Bovine:

·      Sporadic cutaneous: Plaque-like, round, raised 2-3 cm diameter lesions on head, sides, perineum; often ulcerate and have necrotic centers

·      BLV-associated: Classic lesions in abomasum but also in many other organ systems including skin (rare), multiple enlarged lymph nodes

 

TYPICAL LIGHT MICROSCOPIC FINDINGS

Equine:

·      Non-epitheliotropic (TCRLBCL): Mixed population of mostly small lymphocytes (T-cells), <10% larger neoplastic cells (B-cells) and variable numbers of histiocytic cells

·      Non-neoplastic small round lymphocytes (T-cells) have a basophilic granular nucleus and little cytoplasm

·      Larger neoplastic cells (B-cells) are round to stellate with a moderate amount of eosinophilic cytoplasm, pale vesiculate nucleus; high mitotic rate in B-cells; atypical mitotic figures

·      Usually contain variable numbers of macrophages, epithelioid macrophages, and occasionally multinucleated giant cells, eosinophils

·      Histiocytic cells may contain elongated needle shaped eosinophilic crystals in the cytoplasm

·      Epitheliotropic CTCL: Most commonly CD3+ T-cells with strong tropism for epidermis and adnexal structures

·      Intermediate size with round, hyperchromatic, convoluted nucleus, indistinct nucleoli, water-clear cytoplasm

·      Pautrier’s microabscesses in epidermis

 

Bovine:

·      Sporadic cutaneous: Dense infiltration by malignant lymphocytes in the papillary dermis; neoplastic cells are of moderate size with narrow rim of cytoplasm and cerebriform convolutions of nuclear membrane

·      BLV-associated: Large B-cell type

 

ULTRASTRUCTURAL FINDINGS:

·      In the equine, histiocytic cells have large nuclear and cytoplasmic volumes with numerous intermediate filaments, vacuoles, and mitochondria with large lamellar crystalline protein inclusions

 

ADDITIONAL DIAGNOSTIC TESTS:

·      Immunohistochemistry:

·      CD79a/CD20/Pax5: Stains cytoplasm/membrane of B-cells

·      CD3: Stains cytoplasm of T-cells

·      80% of epitheliotropic lymphomas in domestic animals express CD8 and the γδ T-cell receptor

·      Cytology:

·      Epitheliotropic: lymphocytes vary in morphology from small to large with round, indented, or convoluted nuclei; variably distinct nucleoli

·      Sezary Syndrome: possibly see Sezary cells (neoplastic T-cells can have a folded/indented nucleus) in peripheral blood; rare (Raskin, Canine and Feline Cytology 2016)

·      Clonality testing of T-cell and B-cell populations by PARR (PCR for antigen receptor rearrangement)

 

DIFFERENTIAL DIAGNOSIS:

Gross:

Equine cutaneous lymphoma:

·      Urticaria; drug eruptions; multiple collagenolytic granulomas; multiple hypodermal lesions; cutaneous amyloidosis; cutaneous pseudolymphoma

Bovine cutaneous lymphoma:

·      Urticaria; drug eruptions; multiple hypodermal lesions; cutaneous pseudolymphoma

Microscopic:

·      Inflammation: Differentiation between benign inflammatory lesions and early cutaneous lymphoma can be extremely difficult

·      Cutaneous pseudolymphomas: Benign reactive proliferations of lymphocytes that mimic cutaneous lymphomas histologically and clinically

 

COMPARATIVE PATHOLOGY:

·      Canine/feline epitheliotropic lymphoma (I-N26): Neoplastic lymphocytes in the epidermal or adnexal epithelium (Pautrier’s microabscesses); highly convoluted nuclei; T-cell origin (CD3+, CD8+, CD4- in dogs); less common in cat (CD3+, CD4-, CD8-)

·      Canine/feline nonepitheliotropic cutaneous T-cell lymphoma (NETCL, less common): Sheets or nodules of homogenous lymphocytes in the dermis and subcutis; T-cell origin; reactive eosinophils common, occasionally infiltrated with non-neoplastic lymphocytes

·      Subcutaneous pannicultitis-like T-cell lymphoma (SPTCL): a recognized sub-type of NETCL in humans; recently proposed as a distinct entity in dogs; proliferation of CD3+ cells that infiltrate the subcutis and rim adipocytes; tend to be more aggressive in dogs than in humans; further characterization needed (Noland, Vet Pathol. 2018)

·      Canine intravascular lymphoma: Intravascular neoplastic lymphocytes in vessels of skin and other organs in the absence of a primary mass or circulating lymphocytes; skin lesions appear as plaques and nodules; majority of cases in the dog T-cell origin

·      Cutaneous lymphoma at injection sites (CLIS) in cats: Typically large B-cell lymphoma (65%); characterized by necrosis (not a feature of feline primary cutaneous lymphoma), angiocentricity, angioinvasion, angiodestruction, and lack of epitheliotropism; speculated that persistent inflammation induced by injection and reactivation of FeLV expression may contribute to CLIS

·      T-cell-rich, B-cell lymphoma also reported in cat, pig, & dog

·      Rabbits: Adult European pet rabbits predisposed to develop nonepitheliotropic diffuse large B cell lymphomas (centroblastic and T cell-rich-B cell subtypes); no underlying viral infection has been identified

·      Rare cases of epitheliotropic T cell lymphoma reported in ferrets, guinea pigs, Syrian hamsters, llamas

·      T-cell rich B-cell lymphoma: Also reported in cats, pigs, and dogs

·      Chickens: Marek’s Disease (I-V13) more common in skin than Avian Leukosis Virus

 

REFERENCES:

1.    Aboellail TA. Pathologic and immunophenotypic characterization of 26 camelid malignant round cell tumors. J Vet Diagn Invest. 2013;25(1):168-172.

2.    Dettwiler M, Croci M, Vaughan L, Guscetti F. Immunohistochemical expression study of proapoptotic BH3-only protein Bad in canine nonneoplastic tissues and canine lymphomas. Vet Pathol. 2013;50(5):789-796.

3.    Durham AC, Pillitteri CA, San Myint M, Valli VE. Two hundred three cases of equine lymphoma classified according to the World Health Organization (WHO) classification criteria. Vet Pathol. 2013;50(1):86-93.

4.    Fry MM, McGavin MD. Bone marrow, blood cells, and lymphatic system. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Mosby Elsevier; 2012: 767, 770.

5.    Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat Clinical and Histopathologic Diagnosis. Ames, IA: Blackwell Publishing Professional; 2005: 866-889.

6.    Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017: 1108f, 1119.e6t-1119.e12t.

7.    Koebrich S, Grest P, Favrot C, Wilhelm S. Epitheliotropic T-cell lymphoma in a guinea pig. Vet Dermatol. 2011;22(2):215-219.

8.    Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier; 2016: 733-735.

9.    Miller CA, Durham AC, Schaffer PA, Ehrhart EJ, Powers BE, Duncan CG. Classification and clinical features in 88 cases of equine cutaneous lymphoma. J Vet Diagn Invest. 2015;27(1):86-91.

10. Miller WH, Griffin CE, Campbell KL. Muller & Kirk’s Small Animal Dermatology, 7th ed. St. Louis, MO: Elsevier Mosby; 2013: 810-816.

11. Moore PF, Affolter VK, Keller SM. Canine inflamed nonepitheliotropic cutaneous lymphoma: a diagnostic conundrum. Vet Dermatol. 2013;24:204-211.

12. Noland EL, Keller SM, Kiupel M. Subcutaneous panniculitis-like T-cell lymphoma in dogs: morphologic and immunohistochemical classification. Vet Pathol. 2018;55(6):802-808.

13. Ojkic D, Brash ML, Jackwood MW, Shivaprasad HL. Viral diseases. In: Boulianne M, ed. Avian Disease Manual, 7th ed. Jacksonville, FL: AAAP, Inc.; 2013: 30-38.

14. Raskin RE. Skin and Subcutaneous tissues: Cutaneous Lymphoma. In: Raskin RE and Meyer DJ, eds. Canine and Feline Cytology. 3rd ed. St. Louis, MO: Elsevier Inc.; 2016:82-84.

15. Ritter JM, von Bomhard W, Wise AG, Maes RK, Kiupel M. Cutaneous lymphomas in European pet rabbits (Oryctolagus cuniculus). Vet Pathol. 2012;49(5):846-851.

16. Roccabianca P, et al. Cutaneous lymphoma at injection sites: pathologic, immunophenotypical, and molecular characterization in 17 cats. Vet Pathol. 2016;53(4):823-32.

17. Schaffer PA, Wobeser B, Martin LE, Dennis MM, Duncan CG. Cutaneous neoplastic lesions of equids in the central United States and Canada: 3,351 biopsy specimens from 3,272 equids (2000-2010). J Am Vet Med Assoc. 2013;242(1):99-104.

18. Schweizer G, Hilbe M, Braun U. Clinical, haematological, immunohistochemical and pathological findings in 10 cattle with cutaneous lymphoma. Vet Rec. 2003;153(17):525-528.

19. Scott DW. Large Animal Dermatology. Philadelphia,PA: WB Saunders Company; 1988: 446-448.

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21. Valli VE, Jacobs RM, Parodi AL, Vernau W, Moore PF. WHO Histological Classification of Hematopoietic Tumors of Domestic Animals, Vol VIII, Second Series. Washington, DC: Armed Forces Institute of Pathology; 2001: 35-38.

22. 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: 232-242.


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