JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2025

I-N26A

SLIDE A

Signalment (JPC# 2776270): A dog

HISTORY: None

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Effacing the dermis, elevating the epidermis, infiltrating the epidermal and adnexal epithelium, and extending into the subcutis is an unencapsulated, infiltrative, poorly demarcated, densely cellular neoplasm composed of round cells arranged in sheets on a preexisting fibrovascular stroma. Neoplastic cells have variably distinct cell borders, a moderate amount of eosinophilic cytoplasm, and an irregularly round nucleus with finely stippled chromatin and one distinct nucleolus. The nucleus of neoplastic cells is ~1.5-2x the size of a RBC (intermediate to large lymphocyte). Anisocytosis and anisokaryosis are moderate. There are 5 mitotic figures per HPF. Within the epidermis are clusters of intraepithelial neoplastic lymphocytes surrounded by clear space (Pautrier’s microabscesses). Diffusely within the superficial dermis there is abundant edema, hemorrhage, scant fibrin, and degenerate and non-degenerate neutrophils. The epidermis is multifocally hyperplastic with parakeratotic and orthokeratotic hyperkeratosis and/or acanthosis, multifocal intracorneal pustules, intracellular edema, and spongiosis.

MORPHOLOGIC DIAGNOSIS: Haired skin: Epitheliotropic lymphoma, breed unspecified, canine.

SLIDE B

Signalment (JPC# 4089041): 4-year-old neutered male shepherd mix

HISTORY: 1x1x1cm, cutaneous, superficial, freely moveable mass on digit 4 of the left pelvic limb

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis, raising the overlying epidermis, infiltrating the epidermal and adnexal epithelium, and surrounding and widely separating adnexa is an unencapsulated, poorly demarcated, infiltrative, moderately cellular neoplasm composed of round cells arranged in sheets on a preexisting dense fibrous stroma. Neoplastic cells have variably distinct cell borders, scant eosinophilic cytoplasm, and an irregularly round nucleus with finely stippled chromatin and one distinct nucleolus. The nucleus of neoplastic cells is ~1-1.5x the size of a RBC (intermediate lymphocyte). Anisocytosis and anisokaryosis are moderate. There are 3 mitotic figures per HPF. Within the epidermis are occasional small clusters of neoplastic lymphocytes surrounded by a clear space (Pautrier’s microabscesses). Within the superficial dermis there is free pigment and occasional melanin-laden macrophages (pigmentary incontinence). Diffusely within the dermis are low to moderate numbers of neutrophils, plasma cells, and fewer macrophages. The epidermis has diffuse, mild compact orthokeratotic hyperkeratosis and multifocally there are clear vacuoles within keratinocytes (intracellular edema).

SLIDE C

CD3: Haired skin: There is diffuse, strong, membranous immunoreactivity of the neoplastic T lymphocytes within epidermal and follicular epithelium and dermis.

MORPHOLOGIC DIAGNOSIS: Haired skin: Epitheliotropic T-cell lymphoma, shepherd mix, canine.

SYNONYMS: Mycosis fungoides, cutaneous epitheliotropic T-cell lymphoma (CTCL)

GENERAL DISCUSSION:

• Uncommon (more common in dogs than cats), progressive T-cell lymphoma that affects the skin and mucous membranes
• Primarily a disease of older animals; reported in dog, cat, horse, rabbit, cattle
• Poor prognosis due to rapid progression
• Lesions are usually restricted to the skin, but may be found in multiple tissues
• Epitheliotropic cutaneous lymphoma divided into:
  • Classic mycosis fungoides (MF)
    • Most common form – strong tropism of neoplastic T cells for epidermis and adnexal structures
  • Sézary syndrome
    • Is considered the generalized form of MF with lymphadenopathy and neoplastic cells in the peripheral blood
  • Pagetoid reticulosis (Woringer-Kolopp disease)
    • More epitheliotropic variant of MF
    • Localized solitary plaque, neoplastic cells confined to the epidermis/epithelium
    • May represent early CTCL

PATHOGENESIS:

• Pathogenesis unknown
• In domestic animals:
  • Epitheliotropic lymphomas express T-cell surface antigens (eg. CD3)
  • >80% express CD8 and the γδ T-cell receptor (in contrast to human disease)
• Humoral hypercalcemia of malignancy
  • Neoplastic T-cells can secrete PTHrP, which is the most consistent factor responsible for hypercalcemia in dogs with lymphoma; neoplastic T-cells also product TNFα and receptor activator of NFκB ligand (RANKL)
    • Increased PTHrP 🡪 bind to and activating PTH1 receptors in bone and kidney 🡪 hypercalcemia and hypophosphatemia via:
    • Increased osteoclastic bone resorption
    • Increased calcium reabsorption in the renal tubules
    • Decreased phosphorous reabsorption in the renal tubules
    • Activated vitamin D precursors, increasing intestinal absorption of calcium

TYPICAL CLINICAL FINDINGS:

• Early lesions can resemble inflammatory skin disease and erythema is the most common clinical sign
• Ranges from erythematous, exfoliative dermatitis to plaques and nodules, to mucous membrane depigmentation
• +/- humoral hypercalcemia of malignancy
• Gammopathy is rare
• Poor prognosis associated with extensive infiltration of the panniculus, mitotic count >/=7/HPF, cell diameter >/=10um, and nuclear diameter >/=8.3um (Dettwiler, 2023)

TYPICAL GROSS FINDINGS:

• Pagetoid reticulosis (Woringer-Kolopp disease)
  • Exfoliative erythroderma, scale formation, alopecia, and erosions or ulcerations without the presence of distinct masses
  • Usually solitary, localized lesion
• Classic MF/Sézary syndrome
  • Patch/plaque progresses to tumor stage
  • Common sites are the head, mucocutaneous junctions, feet, and ventral abdomen
  • Metastasis, especially to local lymph nodes, occurs late in the disease

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• The most characteristic lesion, common to all forms of canine epitheliotropic T-cell lymphoma is the tropism of neoplastic cells for epithelium, especially follicular epithelium and apocrine sweat glands
• Neoplastic T cells are:
  • Small to intermediate size with a round, hyperchromatic, and convoluted nucleus with occasional sharp, shallow indentations and large nucleoli that are variably distinct
  • Cytoplasm is generally minimal
  • Mitotic figures are rare, can be moderate numbers
  • Can have spindle shape (Carpenter, 2024)
• Mycosis Fungoides
  • Epidermis: Intraepidermal vesicles contain clusters of pleomorphic lymphoid cells (Pautrier’s microabscesses); or solitary cells surrounded by a clear halo
  • Pleomorphic infiltrate: Composed of histiocytes, plasma cells, eosinophils and non-neoplastic lymphocytes, combined with neoplastic lymphocytes
  • Neoplastic cells have convoluted to cerebriform hyperchromatic nuclei
  • Neoplastic lymphocytes may have a histiocytic appearance
• Sézary syndrome
  • Sézary cells (cerebriform nuclei) are also present in peripheral blood
• Pagetoid reticulosis
  • Neoplastic lymphocytes confined to epidermis and adnexa; no dermal involvement
  • Neoplastic cells are either small with hyperchromatic nuclei or may be larger with more cytoplasm

ULTRASTRUCTURAL FINDINGS:

• Neoplastic cells have a high nuclear to cytoplasmic ratio, deep invaginations of the nuclear membrane (cerebriform pattern), a wide rim of peripheral chromatin, a paucity of organelles, and peripheral cytoplasmic villi or projections

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: Sézary cells on blood smear in Sézary syndrome
• All T-cells are CD3 positive, CD4 negative
  • 80% are also CD8 positive
  • Remaining 20% are CD4 negative and CD8 negative
  • Approximately half are γδ-TCR positive and half are αβ-TCR positive
  • Pagetoid reticulosis – all cases are γδ-TCR positive

DIFFERENTIAL DIAGNOSIS:

• Nodular cutaneous lesions:
  • Inflammatory interface dermatitis: Clinical follow up and subsequent biopsies
  • Nonepitheliotropic cutaneous T-cell lymphoma: do not involve epidermis
    • Indolent cutaneous T-cell lymphoma: band of monomorphic lymphocytes in the superficial and mid dermis
    • Inflamed nonepitheliotropic T-cell lymphoma: difficult to differentiate from cutaneous reactive histocytosis. Form bottom heavy nodules in dermis/subcutis with atypical lymphocytes and often have a Grenz zone admixed with small lymphocytes, plasma cells, histiocytes, and neutrophils
    • Subcutaneous panniculitis-like T-cell lymphoma: proliferation of T cells that infilitrate the subcutis and are frequently rimmed by adipocytes, no epitheliotropism
    • Disseminated T-cell lymphoma with cutaneous involvement reported in a cat: nonepitheliotropic (Robveille, 2023)
  • Hypersensitivity reaction: More severe spongiosis, epidermal hyperplasia, and migration of lymphocytes through the entire epidermis (neoplastic cells usually accumulate in the lower half of the epidermis)
  • Erythema multiforme (I-M29): Fewer lymphocytes in the epidermis which are usually associated with apoptotic keratinocytes
  • Histiocytic proliferation or neoplasm (I-M10, I-N22, I-N27A): CD3 negative
  • Melanoma (I-N24): CD3 negative
• Oral lesions:
  • Pemphigus vulgaris (I-M26): Suprabasilar pustules and acantholysis
  • Inflammatory stomatitis: CD3 negative
• Facial disease (symmetrical with depigmentation)
  • Discoid lupus (I-M28): Lymphoplasmacytic interface dermatitis restricted to face
  • Systemic lupus erythematosus (I-M28): Lymphoplasmacytic interface dermatitis
  • Uveodermatologic syndrome (S-M07): Uveitis, rare basal cell degeneration

COMPARATIVE PATHOLOGY:

• Cattle: Mycosis fungoides with microscopic features similar to dogs that may progress to systemic disease; usually occurs in 2-year-old bovine leukemia negative cattle
• Cats: Very rare
  • Microscopic lesions similar to MF in dogs
  • Clinical signs: Well-circumscribed exfoliative erythroderma, alopecia, and crusting primarily of head and neck; often misdiagnosed as dermatophytosis or demodicosis
• Reported in two bonteboks within the forestomachs (Imanse, 2021)
• Reported in the oral cavity of a bearded dragon; PAX5+ and CD3+ (Rooney, 2022)
• Other animals identified with mycosis fungoides: Rat, hamster, rabbit

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4^th ed. Ames, IA: John Wiley & Sons, Inc.; 2016:170, 205.
2. Carpenter A, Aeschlimann K, Kuroki K. Spindle cell cutaneous epitheliotropic T-cell lymphoma in an American Bulldog. J Comp Pathol. 2024;210:1-4.
3. Dettwiler M, Mauldin EA, Jastrebski S, Gillette D, Stefanovski D, Durham AC. Prognostic clinical and histopathological features of canine cutaneous epitheliotropic T-cell lymphoma. Vet Pathol. 2023;60(2):162-171.
4. 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: 87-88.
5. Imanse SM, Monahan CF, Thompson KA, Marrow JC, Corner SM. Epitheliotropic T-cell lymphoma in 2 half-sibling bontebok. J Vet Diagn Invest. 2021;33(2):370-374
6. 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.
7. Raskin RE, Conrado FO. Chapter 3: Integumentary 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; 2022:109-113.
8. Robveille C, Kim MW, Stayt J, Sharp CR, Langner KFA. Disseminated T-cell lymphoma with non-epitheliotropic cutaneous involvement in a cat with erythematous patches and regenerative anemia. J Vet Diagn Invest. 2023;35(1):42-46.
9. T, Ford AK, Plattner BL, Highland MA, Eshar D. Pax5 and CD3 immunophenotyping of lymphoma in 2 central bearded dragons. J Vet Diagn Invest. 2022;34(2):258-262.
10. Rosol TJ, Gröne A. Endocrine Glands. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:306,309.
11. Valli VEO, Kuipel 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; 2016:232-4.
12. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1214.

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