JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2022

I-N22

 

Signalment (JPC #3071368):  Castrated male cocker spaniel

 

HISTORY:   This dog had a solitary, dome‑shaped, and rapidly growing dermal mass on the outer ear.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin, pinna:  Expanding the dermis, elevating and multifocally infiltrating the hyperplastic and ulcerated epidermis, and tracking hair follicles, is a 1 x 2 cm, unencapsulated, well-circumscribed, densely-cellular, dome-shaped neoplasm composed of sheets of round cells that separate and surround pre-existing dermal collagen bundles.  Neoplastic cells have distinct cell borders, a moderate amounts of eosinophilic, finely granular cytoplasm, a round to oval or reniform nucleus, with finely-stippled chromatin and one distinct nucleolus. Mitoses average 17 per 2.37 mm² and there is mild anisocytosis and anisokaryosis, scattered individual cell necrosis, and focally extensive areas of hemorrhage, fibrin, and edema.  Multifocally at the base of the neoplasm are aggregates of lymphocytes and plasma cells. The overlying epidermis is hyperplastic with narrow, elongate rete ridges and is multifocally ulcerated and replaced by a serocellular crust containing abundant hemorrhage, fibrin, edema, lymphocytes, and degenerate neutrophils.  

 

MORPHOLOGIC DIAGNOSIS:  Haired skin, pinna:  Histiocytoma, cocker spaniel, canine.

 

SYNONYMS:  Button tumor

 

GENERAL DISCUSSION:  

• Benign common skin disease of young dogs <3 years old, but can occur in dogs of all ages; appears as a single, focal bulging, “dome shaped”, button tumor
• Seen most often in the brachycephalic breeds, such as Boxers, Dachshunds, Doberman Pinschers, and Cocker Spaniels 
• In young dogs lesions will usually involute spontaneously and spontaneous regression is a major characteristic CCH; they are more persistent in old dogs 
• Surgical excision is generally curative and recurrence or development of additional masses is rare; when dogs develop multiple lesions they are considered a form of Langerhans cell histiocytosis (LCH)
  1. Shar Peis are predisposed to developing multiple lesions
• Cutaneous histiocytomas may arise from CD14+ dermal precursors to Langerhans cells; Langerhans cells lack Birbeck granules in dogs

 

PATHOGENESIS:

• Pathogenesis of spontaneous regression is poorly understood; the leading theory is that lysis of histiocytic cells is mediated by infiltrating lymphocytes, especially CD8+; another theory is that the tumor cells could facilitate their destruction by functioning as antigen-presenting cells
• Cutaneous histiocytomas may arise from CD14+ dermal precursors to Langerhans cells; lack Birbeck granules in dogs
• Spread through lymph nodes is rare and may represent cases of LCH

 

TYPICAL CLINICAL FINDINGS:

• +/- irritation, ulceration
• Grows rapidly, undergoes spontaneous immune-mediated regression, and rarely metastasizes

 

TYPICAL GROSS FINDINGS:  

• 1-2 cm dome-shaped, skin protrusion; hairless; often located on the head, ears, and limbs
• +/- abrasion or ulceration
• Flat thickened plaque is a less common presentation

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Lesions are seen in the superficial dermis and neoplastic cells line up below the basement membrane; dome shaped and “top heavy”; cells are dense in the deep dermis and loosely arranged closer to the epidermis; cells can extend from the dermoepidermal junction to the deep dermis and panniculus 
• Neoplastic cells may penetrate the surface epithelium (epitheliotropism)
• Neoplasm surrounds dermal vessels and displaces, but does not destroy, adnexal structures
• Histiocytic cells have a highly variable morphology
  1. Nuclei: vesicular nuclei; ~1.5-2 times the diameter of erythrocytes; round to oval, reniform, or convoluted shapes are common; multinucleated cells occur; mitotic rate is variable, but can be very high
     • Marked anisokaryosis or megalokaryosis are not features
  2. Cytoplasm: Abundant and lightly eosinophilic; same density from nucleus to cell margin; cell boundaries distinct near skin surface
• Regressing lesions: deep infiltration of small lymphocytes that progress throughout the nodule; lymphocytes are predominantly CD3+, CD8+ cytotoxic T cells; necrosis of histiocytes is concurrent with lymphocyte infiltration
  1. +/- neutrophilia with ulceration

 

ADDITIONAL DIAGNOSTIC TESTS:

 

Immunohistochemistry: 

 

 

• Acquire a mature phenotype (CD206+) with regression (Belluco Vet Pathol 2020)
• Can exhibit  nuclear +/-cytoplasmic immunoreactivity to MUM1/IRF4 (Stillwell Vet Pathol 2018)
• It may be impossible to detect E-cadherin in heavily ulcerated or regressing tumors 

 

Cytology:

• Discrete cells, round to irregular/amoeboid (later stages of regression), 12-30 μm in diameter, with variably distinct borders; abundant clear to lightly basophilic granular cytoplasm; nuclei are round, oval, or indented with fine chromatin and indistinct nucleoli; minimal anisocytosis and anisokaryosis 
• There may be a variable number of small, well-differentiated lymphocytes more common in regressing lesions and can become the dominant cell type late in regression

 

DIFFERENTIAL DIAGNOSIS:  

For histologic findings:

• Mast cell tumor (I-N21):  Usually have a Grenz zone (tumor-free zone between neoplasm and overlying epidermis); cells separated by compressed or lytic collagen fibers; fewer mitotic figures; no cleaved nuclei; eosinophils; metachromatic granules (toluidine blue, Giemsa, Luna mast stains) 
• Non-epitheliotropic lymphoma: Late stage of regressing CCH may be mistaken for a non-epitheliotropic lymphoma because there are only a few recognizable histiocytes remaining; analysis of clonality of the T-cell receptor γ will not help differentiate these two entities
• Epitheliotropic lymphoma (mycosis fungoides, I-N25):  Ulcerative plaques; sheets of round cells; Pautrier's microabscesses and epidermal invasion; usually multicentric; differentiate from CCH with CD3 and CD18
  • PCR for antigen receptor rearrangement (PARR) may not be useful to differentiate regressing histiocytoma from epitheliotropic lymphoma because the T-cell response to histiocytoma has been documented to be clonal in 30% of cases
• Plasma cell tumor (I-N23):  Prominent Grenz zone; cells may packet, have round, eccentric nuclei with a “clock face” chromatin pattern; variation in chromatin pattern; perinuclear clearing 
• Arthropod-induced focal lymphocytic dermatitis: Can be similar to regressing histiocytoma but lacks neoplastic histiocytes with reniform nuclei

 

Other Histiocytic Proliferative Disorders:

• Canine cutaneous Langerhans cell histiocytosis (LCH): Dogs have multiple (up to hundreds) raised, red nodules that histologically resemble CCH but may invade deeper tissues and have more atypia; may involve oral cavity; may metastasize to local lymph nodes; may have delayed regression
• Reactive histiocytosis (I-M10): Inflammatory disease; proliferation of activated interstitial dendritic cells positive for CD1, CD11c, MCH II, CD4, Thy-1 (CD90):
  • Cutaneous reactive histiocytosis: Collies, Shetland sheepdogs; young dogs; long, waxing and waning course; single or multiple dermal nodules; cells do not approach the epidermis; perivascular histiocytic infiltrate; large macrophages with mild atypia and a high mitotic rate
  • Systemic reactive histiocytosis: Bernese Mountain dogs; young-middle aged males; often in the skin and draining lymph nodes; histopathology similar to cutaneous form, but not limited to the skin and involves internal organs
• Histiocytic sarcoma (non-hemophagocytic)(I-N27, H-N03, P-N05A): Neoplasm of myeloid / interstitial dendritic cells (in locations throughout body including skin), positive for CD18, CD204, CD11c, MHC II, lysozyme, MAC-2, ICAM-1:
  • Localized histiocytic sarcoma (LHS): rapidly growing dermal or subcutaneous nodules; often near and crossing a joint; composed of bundles and whorls of spindle cells, sheets of large round cells; multinucleated giant cells 
  • Disseminated histiocytic sarcoma (old name: malignant histiocytosis): fatal, familial disease of older Bernese mountain dogs, Rottweilers, golden retrievers and flat coated retrievers; primary neoplasm in spleen, lung, bone marrow; +/- dissemination to liver, lymph nodes, rarely skin; pleomorphic histiocytes; numerous multinucleated giant cells
• Hemophagocytic histiocytic sarcoma: neoplasm of macrophages resident in splenic red pulp and bone marrow; positive for CD11d (beta 2-integrin), MHC II, rarely CD11c/CD18, CD1c; primary neoplasm of spleen, bone marrow; also lesions in liver, lung; erythrophagocytosis; clinical pathology includes responsive anemia, thrombocytopenia, hypoalbuminemia, and hypocholesterolemia

 

COMPARATIVE PATHOLOGY:  

• Cats:  

• Langerhans cell disorders do not occur in feline skin but there is a lung condition referred to as feline pulmonary Langerhans cell histiocytosis (P-N05B)
• Feline progressive histiocytosis: Origin is interstitial dendritic cells of the skin; occurs in middle aged to older cats; solitary or multiple nodules or plaques

• Goat: Cutaneous histiocytomas occur in goats; generally less than 4 years old; in one study when surgically excised they did not recur within 24 months of surgical removal; histiocytomas were positive for Iba1, but not CD117/KIT (Oneill Vet Pathol 2021)

 

References:

1. Belluco S, Sammarco A, Sapin P, et al. FOXP3, CD208, and CD206 Expression in Canine Cutaneous Histiocytoma. Vet Pathol. 2020; 57(5):599-607.
2. DeNicola, DB. Round Cells. In Cowell RL, Valenciano AC eds. Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. St. Louis, MO: Elsevier; 2014:74-75.
3. 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 Inc. 2016:728-730.
4. Miller WH, Griffin CE, Campbell KL. In: Muller & Kirk’s Small Animal Dermatology. 7th ed. St Louis, MO: Elsevier, Inc; 2013: 817-821.
5. O’Neill TW, Lohr CV. Mast cell tumors and histiocytomas in domestic goats and diagnostic utility of CD117/c-Kit and Iba1 Immunohistochemistry. Vet Pathol. 2021; 58(3):508-515.
6. Raskin RE, Conrado FO. Integumentary System. In: Raskin RE, Meyer DJ, Boes KM eds. Canine and Feline Cytology. 4th ed. St. Louis, MO: Elsevier; 2023: 98-100. 
7. Stilwell JM, Rissi DR. Immunohistochemical labeling of multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF-4) in canine cutaneous histiocytoma. Vet Pathol. 2018; 55(4):517-520.
8. 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 Inc. 2016:243-255.
9. Welle MM, Linder KE. The Integument. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022: 1213.

 

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