JPC SYSTEMIC PATHOLOGY
Signalment (JPC #2776270): A dog
HISTOPATHOLOGIC DESCRIPTION: Haired skin: Effacing dermal collagen and adnexa, elevating the epidermis, infiltrating the epidermal and follicular epithelium, and extending into the subcutis and panniculus carnosus is an unencapsulated, infiltrative, poorly demarcated, densely cellular neoplasm composed of round cells arranged in sheets on a preexisting fibrovascular stroma. Neoplastic cells have indistinct cell borders, a moderate amount of eosinophilic cytoplasm, and irregularly round nuclei, with finely stippled chromatin, and one generally distinct nucleolus. The mitotic rate averages 2 per 40X HPF. Anisocytosis and anisokaryosis are marked. 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 and degenerate and non-degenerate neutrophils. The epidermis is focally ulcerated and replaced with a serocellular crust and has diffuse parakeratotic hyperkeratosis, multifocal intracorneal pustules, and epidermal hyperplasia (acanthosis).
MORPHOLOGIC DIAGNOSIS: Haired skin: Epitheliotropic lymphoma, breed unspecified, canine.
SYNONYMS: Mycosis fungoides, epitheliotropic T-cell lymphoma
- Cutaneous epitheliotropic lymphoma is an uncommon to rare unrelentingly progressive T-cell lymphoma with insidious onset, which primarily affects the skin and mucous membranes
- Neoplastic T-cells of canine epitheliotropic T-cell lymphoma are "skin homing" memory T-cells
- There is no breed or sex predilection
- Primarily a disease of older animals in dogs and cats (mean age of 10-years in both species)
- Less common in cats than dogs
- Predominantly develops in areas commonly affected with allergic conditions; may have an association with atopic dermatitis (unproven)
- Prognosis is grave, with survival time from onset of skin lesions until death (usually due to euthanasia) of a few months up to 2-year
- Does not respond well to chemotherapy
- Lesions are usually restricted to the skin, but may become systemic and have been reported in the lymph nodes, spleen, liver, heart, lungs, eyes, and kidneys
- Single report in a dog of metastatic lymphocytes also displaying epitheliotropism
- Epitheliotropic cutaneous lymphoma encompasses a spectrum of disease:
- Mycosis fungoides (MF), which has four clinical presentations (described below):
- Exfoliative erythroderma (category 1)
- Mucocutaneous localization (category 2)
- Solitary or multiple cutaneous plaques or nodules (category 3)
- Ulcerative disease of the oral mucosa (category 4)
- Sezary syndrome, a variant of MF
- Rare in dogs and cats
- Characterized by the simultaneous presence of cutaneous epitheliotropic lymphoma, peripheral lymphadenopathy, and circulating tumor cells (with characteristic cerebriform nuclei) in the peripheral blood
- Pagetoid reticulosis, a variant of MF
- Rare in dogs and cats
- Occurs in two clinical forms with neoplastic lymphocytes confined primarily to the epidermis
- Localized lesions (Woringer-Kolopp form) with a benign clinical course
- Generalized lesions (Ketron-Goodman form) with a progressive clinical course
- Mycosis fungoides (MF), which has four clinical presentations (described below):
- Pathogenesis unknown
- Chronic antigenic stimulation may be an initiator of a clonal neoplastic T-cell population in the skin
- Langerhans cell abnormalities may act as a stimulus for chronic T-cell activation and proliferation
- Dogs with mucosis fungoides had lower transcription levels of chemokine receptors associated with skin homing (CCR4), epitheliotropism (CXCR3), lymph node homing (CCR7), a type-1 cytokine (LT-a) and cytotoxic markers (perforin and granzyme B) in the circulation than healthy dogs; may be due to the sequestration of cytotoxic T cells in the skin lesions
TYPICAL CLINICAL FINDINGS:
- Mycosis fungoides is highly pleomorphic and it is useful clinically to divide it into four categories:
- Exfoliative erythroderma (category 1): Characterized by generalized erythema, scaling, loss of pigmentation and alopecia; closely mimics other inflammatory exfoliative skin diseases; over time, patches, plaques and nodules develop; the trunk and head are commonly affected but lesions may develop in any location; pruritis is variable
- Mucocutaneous localization (category 2): Characterized by erythema, depigmentation, alopecia, irregular infiltration, erosion, and ulceration; depigmentation is a common and clinically striking feature; the facial mucocutaneous junctions of the mouth, planum nasale, and eyelids are affected most frequently; localized involvement restricted to the lips is a common feature; marked bilateral symmetry can be noted on the lips and philtrum; the planum nasale also may be affected, as may the anorectal junction, vulva, and prepuce
- Solitary or multiple cutaneous plaques or nodules (category 3): Characterized by solitary or multiple plaques or nodules that usually are erythematous and scaly or crusted; larger lesions erode and ulcerate; grouped lesions gradually coalesce; in rare cases, individual lesions may regress as other lesions develop and expand; neoplastic lymphadenopathy is noted in more advance disease
- Ulcerative disease of the oral mucosa (category 4): Characterized by ulceration which can occur in palpably infiltrated areas or seemingly occurs in normal-appearing oral mucosa; the gingiva, palate, or tongue may be involved
- Sezary syndrome: Characterized by generalized pruritis, exfoliative erythroderma, multiple skin plaques and nodules, and lymphocytic leukemia; presence of Sezary cells (neoplastic lymphocytes with hyperchromatic, folded and grooved nuclei) in the cutaneous infiltrate and in the peripheral blood
- Canine pagetoid reticulosis: Characterized by erythematous papules, plaques, erosions, and ulcers are seen on the mucocutaneous junctions, oral cavity, footpads, and abdomen; most canine and feline cases involve multiple areas of the body
TYPICAL GROSS FINDINGS:
- Erythematous plaques that are scaly, alopecic and ulcerated
- Early lesions resemble inflammatory skin disease and are often misdiagnosed
- Lesions wax and wane, and progress with time to leukemic phase
- Metastasis, especially to local lymph nodes, occurs late in the disease
- In dogs, footpads may be hyperkeratotic, ulcerated, or depigmented; rarely lesions are confined to the lips, nasal planum, nasal philtrum, tongue, gingival, buccal and palatine mucosa or anus
- In cats, there are well-circumscribed annular areas of alopecia, erythema and scaling; feline lesions most frequently affect the face, eyelids, mucocutaneous junctions, elbow, and trunk
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
- The epidermis may be mildly acanthotic, but marked epidermal hyperplasia is not a feature of epitheliotropic lymphoma
- Hyperkeratosis is mild to moderate
- Spongiosis is absent or mild
- Mycosis Fungoides
- Epidermis: 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
- Sezary syndrome
- Rare in dogs and cats
- Sezary cells (cerebriform nuclei) are also present in lymph nodes and peripheral blood
- Pagetoid reticulosis
- Rare in dogs NOT seen in cats
- Exhibits early, almost exclusive invasion of epidermis and adnexa by neoplastic lymphocytes
- Variable numbers of apoptotic keratinocytes
- Neoplastic cells are either small with hyperchromatic nuclei or may be larger with more cytoplasm
- Superficial dermis contains a mild to moderate pleocellular infiltrate composed of reactive lymphocytes, plasma cells, histiocytes, and occasional granulocytes
- As the disease progresses, the dermis is infiltrated by neoplastic lymphocytes
- 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:
- All T-cells are CD3 positive, COX 2 neg
- 80% are also CD8 positive and express the gamma/delta TCR
- Remaining 20% are CD4 negative, CD8 negative (double negative) and alpha/beta TCR
- Pagetoid reticulosis has noli TCR gamma/delta
- Protein Gene Product 9.5 (PGP 9.5): 8 out of 14 cases of MF in one study were positive for PGP 9.5, with reactivity mainly in the cytoplasm and less commonly in the nucleus
- In the case of one cat with epitheliotropic T-cell lymphoma, perforin expression was demonstrated, implying a cytotoxic tumor cell phenotype
- Para-nuclear E-cadherin staining distinguishes canine epitheliotropic lymphoma from other round cell tumors.
- Early nodular disease
- Inflammatory interface dermatitis: Clinical follow up and subsequent biopsies
- Nonepitheliotropic cutaneous T-cell lymphoma
- 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: Fewer lymphocytes in the epidermis which are usually associated with apoptotic keratinocytes
- Histiocytic proliferation or neoplasm: CD3 negative
- Melanoma: CD3 negative
- Mycosis fungoides with bullous lesions
- Bullous pemphigoid, epidermolysis bullosa acquisita, and toxic epidermal necrolysis: Lack epitheliotropic neoplastic cells
- Oral lesions:
- Pemphigus vulgaris: Suprabasilar cleft
- Inflammatory stomatitis: CD3 negative
- Facial disease (symmetrical with depigmentation)
- Discoid lupus: Lymphoplasmacytic interface dermatitis restricted to face
- Lupus erythematosis: Lymphoplasmacytic interface dermatitis
- Vogt-Koyanagi-Harada-like syndrome: Uveitis, rare basal cell degeneration
- 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: Rare
- Mycosis fungoides with microscopic lesions similar to dogs
- All affected cats are serologically negative for FeLV, but sometimes positive by PCR
- Clinical signs: Well-circumscribed exfoliative erythroderma, alopecia, and crusting primarily of head and neck; often misdiagnosed as dermatophytosis or demodicosis
- Other animals identified with mycosis fungoides:
- Sprague Dawley rat
- Syrian hamster
- Horse – thoroughbreds have increased frequency
- Guinea pig
- African hedgehog
- Mice (laboratory): Pagetoid reticulosis (Woringer- Kolopp) like condition with lymphoid infiltrate almost entirely confined to the epidermis
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