JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-P07

 

Slide A

Signalment (JPC# 1368758):  3-year-old German shepherd dog

 

HISTORY:  Euthanized because of generalized chronic dermatitis

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin: There is multifocal perifolliculitis centered predominantly on the follicular isthmus and extending to the infundibulum composed of moderate numbers of lymphocytes, plasma cells, macrophages, and fewer neutrophils admixed with moderate numbers of melanin laden macrophages (pigmentary incontinence). Inflammatory cells occasionally infiltrate follicular epithelium and there is hydropic degeneration and single-cell necrosis of follicular epithelial cells (interface mural folliculitis). Filling and expanding ectatic follicles are multiple cross and tangential sections of arthropods up to 40µm in diameter and 200µm in length with a thin, eosinophilic, chitinous exoskeleton; short, jointed appendages; a hemocoel; striated muscle; and digestive and reproductive tracts. Diffusely, there is moderate follicular and epidermal hyperplasia with orthokeratotic hyperkeratosis. There is mild superficial, often perivascular, lymphoplasmacytic and histiocytic dermatitis. Apocrine glands are mildly ectatic, occasionally hyperplastic, and filled with varying amounts of necrotic debris.

 

Tongue:  No significant lesions.

 

MORPHOLOGIC DIAGNOSIS:  Haired skin: Perifolliculitis and interface mural folliculitis, lymphoplasmacytic and histiocytic, multifocal, moderate, chronic with epidermal and follicular hyperplasia, and intrafollicular mites, German shepherd dog, canine.

 

CAUSE:  Demodex canis

 

Slide B

Signalment (JPC# 1051577):  A pig

 

HISTORY:  None

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin and subcutis: Diffusely, hair follicles are markedly ectatic, dilated up to 2‑3 mm in diameter, and lined by swollen, vacuolated epithelial cells (degeneration). These follicles are expanded and filled with numerous elongated mites that are 40µm wide and 150-200µm long with a thin, eosinophilic, chitinous exoskeleton; short jointed appendages; a hemocoel; striated muscle; and digestive and reproductive tracts. Multifocally there are few lymphocytes, plasma cells, macrophages, and eosinophils that surround hair follicles, sebaceous glands, and dermal blood vessels. Multifocally, apocrine glands are mildly ectatic and filled with numerous neutrophils. Diffusely, the epidermis and hair shafts are absent (due to slaughter scalding and processing).

 

MORPHOLOGIC DIAGNOSIS:  Haired skin and subcutis: Follicular ectasia, multifocal, marked, with mild periadnexal and perifollicular lymphoplasmacytic and eosinophilic dermatitis, moderate neutrophilic hidradenitis, and numerous intrafollicular mites, breed not specified, porcine.

 

CAUSE:  Demodex phylloides

 

ETIOLOGIC DIAGNOSIS:  Follicular demodicosis

 

CONDITION:  Demodectic mange 

 

CONDITION SYNONYMS:  Red mange; follicular mange

 

GENERAL DISCUSSION:  

• Common skin parasites of numerous mammalian species; tend to be host specific; more than 140 species have been identified in hair follicles, sebaceous glands, Meibomian glands, and ceruminous glands; Demodex gatoi in cats lives within the stratum corneum rather than in follicles.
• Demodex spp. are normal inhabitants of hair follicles and sebaceous glands of humans and dogs and probably most mammals
• Significance of infection is variable depending on host‑parasite relationships
• Canine demodicosis
  • Two forms based on age affected):
    • Young animals: (two forms based on distribution of lesions):
      • Localized demodicosis: one to several small lesions, usually resolves spontaneously
      • Generalized demodicosis: usual onset between 3 and 18 months of age; often severe, linked to immunosuppression; either many localized lesions, involvement of an entire body region (e.g. face), or complete involvement of two or more feet
      • Adult-onset generalized demodicosis: onset at 4 years of age or older, associated with underlying disease (e.g. hypothyroidism, hyperglucocorticism, leishmaniasis, malignant neoplasia, immunosuppressive therapy); underlying disease is often diagnosed after demodicosis diagnosis (weeks to months)
      • Two species of canine demodex mites:  D. canis is the most common, and D. injai.  (D. cornei, the short-tailed mite, has been determined to be a morphologic variant of D. canis)
      • D. injai breed predilection: West Highland white terrier, shih tzu, and wirehaired fox terrier; typically middle aged and older, generalized demodicosis, and prior history of allergic dermatitis, immunosuppression, or immunomodulatory therapy; one case report of otitis externa
      • In a retrospective study of 431 dogs with demodicosis from 2000-2016 in California (Bowden Vet Dermatol. 2018), allergic dermatoses were strongly associated with higher odds of demodicosis, with a stronger association with adult-onset demodicosis

 

LIFE CYCLE:  

• Similar for all Demodex species, approximately 20-35 days
• Mites are obligate parasites with entire life cycle spent on the host, usually in hair follicles or rarely in sebaceous glands
  • Stratum corneum for D. gatoi in cats
• Females lay fusiform eggs that hatch into six-legged larvae; there are three instar/nymph stages (eight legs) before adulthood (eight legs)
• Transmission is by direct contact from mother to offspring during nursing

 

PATHOGENESIS:  

• Normal immune response hypothesis: Toll-like receptor 2 (TLR2) membrane proteins of keratinocytes recognize mite chitin à innate immune response that inhibits mite proliferation without inducing an inflammatory response
• Disease is due to Type IV hypersensitivity: Perifollicular and peri-mite aggregates of T-helper cells, and perifolicular and mural cytotoxic T-lymphocytes (CD3+/CD8+) in generalized demodicosis; there is no appreciable humoral immune response
• Diseased state is multifactorial and not completely understood;  
  • Associated with diverse pathologic conditions (neoplasia, endocrine, and metabolic disorders)  
  • Factors predisposing dogs to generalized demodicosis include immune status, breed and lineage, age, length of hair coat, nutritional status, stage in estrus cycle, parturition, stress, endoparasitism, and debilitating disease
    • Thought to be partially genetically mediated, because 1) it shows breed predilection (American Staffordshire terrier, Staffordshire bull terrier, and shar pei), and 2) one study showed association between generalized juvenile demodicosis and certain DNA microsatellite markers;  there are likely multiple genes involved
    • Associated with several immunological abnormalities, especially decreased T-cell function but NOT decreased numbers (termed T-cell exhaustion); T-cell exhaustion is usually characterized by low production of supportive/stimulatory cytokines (e.g. IL-2 and IL-21), high levels of suppressive cytokines (IL-10 and TGF-β), and low numbers of circulating CD4+ lymphocytes (this also helps explain the lack of relapse after treatment)
• Recurring demodicosis is associated with increased IL-10 à inhibits Th1 cell secretion of proinflammatory cytokines (IL-1, IFN-g, and TNF-β), has anti-inflammatory and suppressive effects on most hematopoietic cells, and inhibits antigen presentation by APCs
• More severe immune suppression is associated with secondary bacterial pyoderma, leading to suppurative folliculitis and furunculosis

 

TYPICAL CLINICAL FINDINGS:  

• Localized lesions: focally extensive, scaly, alopecic, erythematous or pustular rashes; lesions may wax and wane over several months
• Generalized lesions: more common in juveniles (3-18 months)
• Demodectic pododermatitis: disease is confined to the paws, may be complicated by secondary bacterial infection; there may be a history of generalized demodicosis that healed except for foot lesions
• Cytology: non-staining outline of mite may be seen surrounded by degenerating neutrophils and cell debris, most often on unstained aspirates

 

TYPICAL GROSS FINDINGS:

Localized form:

• Alopecia and erythema; may be covered with fine, silvery scales
• Periocular; oral commissures; forelegs; more rarely, trunk or rear leg lesions
• Bilateral pruritic ceruminous otitis externa

Generalized form:

• Numerous lesions on the head, legs, and trunk; progressively worsening into deep folliculitis and furunculosis with thick exudative crusts, especially with secondary Staphyloccus intermedius infection (also Pseudomonas aeruginosa and Proteus mirabilis)
• Marked peripheral lymphadenopathy
• May progress to chronic pyogenic demodectic pododermatitis

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:  

• Mites:
  • Adult arthropods: elongate, 40 x 250-300 um (shorter and longer forms exist), have a thin, chitinous exoskeleton, short jointed appendages, striated muscle, a body cavity (hemocoel), and intestinal and reproductive tracts
  • Adults and nymphs have 4 pairs of legs, larvae have 3 pairs of legs
  • Eggs are elongated and ovoid
• Mite-induced lesions: Variable depending on the stage of the disease and presence of secondary bacterial infection, and variable numbers of mites (few to countless; numerous mites may suggest poor immune response)

• Early uncomplicated lesions: predominantly lymphocytic mural interface folliculitis; lymphocytic infiltration of the isthmus and infundibulum with varying degrees of vacuolar degeneration and apoptosis of keratinocytes of the outer root sheath; follicular melanosis or pigment clumping in the outer rooth sheath; perifollicular pigmentary incontinence; perifolliculitis with infiltrates of plasma cells, macrophages, and lymphocytes with fewer mast cells and eosinophils; mural folliculitis may be present
  • Mural infiltrating lymphocytes are CD8+ cytotoxic T-cells whereas perifollicular infiltrates are mixed CD4+ and CD8+ T-lymphocytes
• Complicated lesions:  follicles with large numbers of mites, build-up of mite products, and marked follicular hyperkeratosis à follicular plugging à follicular rupture with release of mites, bacteria, sebum, keratin, and other irritants into the dermis à pyogranulomatous furunculosis
• Epidermal changes include hyperplasia, orthokeratotic and parakeratotic hyperkeratosis, variable spongiosis, neutrophilic exocytosis, ulceration, crusting
• Later stages: Mural folliculitis consistently present; perifollicular mid to deep dermal and occasionally subcuticular granulomas that sometimes contain mite remnants; marked dermal fibrosis often with adnexal obliteration; mites or fragments of mites may be seen in subcapsular sinus of regional lymph nodes
• D. injai: Marked sebaceous gland hyperplasia, lymphoplasmacytic periadnexal dermatitis; very few if any mites seen
• In the absence of mites in sections, pigmentary incontinence at the follicular isthmus and hyperpigmentation of the outer root sheath at the same location and/or perifollicular granulomas strongly suggest demodicosis

• Bacteria (Staphylococcus spp.) may induce suppurative luminal folliculitis

 

DIFFERENTIAL DIAGNOSIS:

For gross lesions:

• Generalized pyoderma: may be associated with generalized demodicosis
• Other causes of dermatitis: dermatophytosis; pustular dermatitis; acne; allergic contact dermatitis; pemphigus; epidermolysis bullosa simplex; incidental abrasions; localized seborrheic dermatitis 

 

For histologic lesions (if mites are not present):

 

COMPARATIVE PATHOLOGY:

• Dog – D. canis (300µm), D. injai (“long-bodied mite,” 334-368µm)
• Cat – D. cati (182-291µm, follicular involvement, similar presentation as D. canis, associated with diabetes mellitus, feline immunodeficiency virus, and squamous cell carcinoma), D. gatoi (shorter 91-108µm, stratum corneum involvement, pruritic, contagious), third unnamed species (139 +/- 4.5µm)
• Ox – D. bovis; D. ghanensis; D. tauri:  Nodular demodicosis with few to several hundred cutaneous papules or nodules; uncommon, worldwide; only D. bovis is known to cause clinical disease, assumed underlying immunocompromise (e.g. concurrent disease, poor nutrition, stress, genetic predisposition); economic consideration due to hide damage
• Goat – D. caprae:  Nodular demodicosis; common; similar to cattle
• Sheep – D. ovis; D. aries:  Nodular demodicosis; relatively rare; D. ovis in medium- to coarse-wooled sheep in Meibomian glands and sebaceous glands; has been associated with matted fleece/”stringy wool”;  D. aries infests large sebaceous glands of vulva, prepuce, and nostrils
• Horse – D. caballi; D. equi:  Commonly found in Meibomian glands, but disease is very rare; associated with glucocorticoid administration and pituitary pars intermedia disfunction (PPID); D. caballi in pilosebaceous units of eyelid and muzzle, D. equi over body
• Pig – D. phylloides: Nodular demodicosis; uncommon, relatively unimportant compared to sarcoptic mange; in pilosebaceous units; economic loss (hide); small red macules develop into cutaneous nodules covered by surface scale
• Alpaca, llama – Rare
• Guinea pig – D. caviae
• Hamster – D. criceti; D. aurati
• Mouse – D. flagellurus (preputial/clitoral gland); D. lacrimalis (Meibomian gland); D. musculi: Rare, possibly underrecoginzed; D. musculi infection reported in transgenic SCID mice (mites in the superficial dermis and follicular ostia without inflammation)  
• Wild cervids:  Likely due to environmental stressors and concurrent disease; white-tailed deer over 2 years of age more likely to develop disease than younger individuals, most cases occur during the rut, gross lesions include emaciation and patchy to generalized alopecia, hyperemia, hyperpigmentation, lichenification (nodules uncommon)
• Primates:  Documented Demodex spp. in wild Senegal Bushbabies, captive Goeldi’s monkeys (suspected ultraviolet light induced) and Red-Handed Tamarins, and Demodex-like mites likely in all apes
• Reports of demodicosis also in black bears, raccoons, ferrets, and Armenian hamster

 

References:  

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits, 4th ed. Ames, IA: Blackwell Publishing; 2016: 87, 154, 191, 205, 238, 238.
2. Bowden, DG, Outerbridge, CA, et al. Canine demodicosis:  a retrospective study of a veterinary hospital population in California, USA (2000-2016). Vet Dermatol. 2018:29:19-24.
3. Churgin, SM, Lee, FK, et al. Successful treatment of generalized demodicosis in Red-Handed Tamarins (Saguinus midas) using a single administration of oral fluralaner. J Zoo Wildl Med. 2018:49(2):470-474.
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: 83-84. 
5. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin diseases of the dog and cat. 2nd ed. Oxford, UK:Blackwell Science; 2005:222-225, 442-449.
6. Gruber-Dujardin, E, Ludwig, C. et al. Cutaneous demodicosis and UV-induced skin neoplasia in two Goeldi’s monkeys (Callimico goeldii). J Zoo Wildl Med. 2019:50(2):470-473.
7. Howerth, EW, Nemeth, NM, Ryser-Degiorgis, MP. Cervidae. In:  Terio, KA, McAloose, D, St. Leger, J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press Elsevier; 2018:174.
8. Lowenstine, LJ, McManamon, R, Terio, KA. Apes. In:  Terio, KA, McAloose, D, St. Leger, J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Academic Press Elsevier; 2018:174.
9. McAloose D, Stalis IH. Ch. 13 Prosimians. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:339-402.
10. Maudlin EA, Peters-Kennedy J.  Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016: 678-682.   
11. 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: 59-60. 
12. Strait K, Else JG, Eberhard ML. Parasitic Diseases of Nonhuman Primates. In: Bennett BT, Abee CR, and Henrickson R. Nonhuman Primates in Biomedical Research: Diseases. 2nd ed. London, UK: Academic Press; 2012: 266.
13. Walsh KA, DeHeer HL, Patel R. The external ear canal. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and hematology of the dog and cat. 5th ed. St. Louis, MO: Elsevier; 2020: 165-167.
14. Welle MM, Linder KE. The integument.  In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed., St. Louis, MO; Elsevier; 2022:1179-1181.

Click the slide to view.

---