JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-T01

 

Signalment (JPC# 1757055):  A dog

 

HISTORY:  None provided

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin: There is a focally extensive area of epidermal and follicular hyperplasia characterized by acanthosis and moderate parakeratotic hyperkeratosis, as well as prominent intercellular bridging (spongiosis) and intracellular edema. Diffusely, the stratum granulosum of the epidermis and follicular epithelium is thin and lacks keratohyaline granules (hypogranulosis). Multifocally, there are intracorneal pustules that contain numerous degenerate neutrophils and necrotic debris. Follicles often lack hair shafts, are moderately ectatic, and are plugged by lamellations of parakeratotic keratin (comedones). There are numerous viable and degenerate neutrophils, plasma cells, lymphocytes, and fewer macrophages surrounding hair follicles (perifolliculitis), occasionally infiltrating the follicular walls and lumina (mural and luminal folliculitis), and occasionally effacing ruptured follicular walls (furunculosis).  

 

MORPHOLOGIC DIAGNOSIS:  Haired skin: Hyperkeratosis, parakeratotic, focally extensive, moderate, with epidermal and follicular epithelial hyperplasia, neutrophilic and lymphoplasmacytic folliculitis and dermatitis and intracorneal pustules, breed unspecified, canine.

 

ETIOLOGIC DIAGNOSIS:  Cutaneous thallotoxicosis

 

CAUSE:  Thallium toxicosis

 

GENERAL: 

• Potent heavy metal toxin; pharmacological actions similar to lead and mercury
• Extensively used as rodenticide and pesticide prior to 1963; use banned in US
• Toxicosis is now rare; primarily occurs in dogs, less often in cats, occasionally in sheep, cattle, and pigs
• Salts are odorless, colorless, tasteless, and water soluble

 

PATHOGENESIS: 

• LD50 in the dog = 10-15 mg/kg; cumulative toxin
• Absorbed from the gastrointestinal and respiratory tracts and skin readily > disseminates widely in the body > persists > excreted slowly in bile and urine
• Toxic to epithelial cells in many organs (especially in hair papillae) and neurons
• Mechanism of action unknown; two hypotheses prevail:

1. Thallium binds sulfhydryl groups in mitochondrial membranes > disrupts mitochondrial respiratory chain enzymes > inhibits oxidative phosphorylation
2. Thallium replaces potassium in many critical biochemical functions (e.g. Na-K ATPase, pyruvate kinase) > impaired membrane transport systems and protein synthesis > general cellular poison

• Pathogenesis of alopecia (poorly understood):  Thallium enters hair by binding to sulfhydryl groups in keratin > may interfere with metabolism of matrix cells of anagen follicles > necrosis of matrix cells (within 48 hours of exposure in rat experimental intoxication) > abnormal catagen phase > telogen without club attachment formation > rapid depilation > growth resumes if animal survives
• Other potentially important toxic mechanisms of thallium:
  • Interacts adversely with riboflavin derivatives
  • Depolarizes nerve cell membranes
  • Antagonizes effects of calcium on the heart

 

TYPICAL CLINICAL FINDINGS:

• Clinical effects are both dose- and rate-dependent
• Animals may survive acute thallotoxicosis and develop chronic syndrome, or develop only the chronic syndrome
• Acute thallotoxicosis (high-dose, 12 hours - 3 days PI):
  • Gastrointestinal and neurologic disease > death by respiratory failure
  • Vomiting, glossitis, stomatitis, hemorrhagic gastroenteritis 
  • Convulsions, tremors, salivation, weakness, and paralysis
  • Rhinitis, bronchitis; dyspnea often earliest sign
  • No cutaneous lesions
• Chronic syndrome (low-dose/cumulative exposure, 3-10 days PI):
  • Cutaneous, renal, and neurological signs > progressive debilitation > death
  • In mild cases, alopecia / ease of depilation may be the only clinical sign
  • Mild gastrointestinal signs
  • Characteristic pattern of cutaneous lesions (see gross/microscopic findings): Begin at lip commissures or nasal cleft (or sometimes ear margins) > expand over face and head > later involve interdigital skin, footpads, axillae, inguinal areas, perineum, lateral extensor surfaces

 

TYPICAL GROSS FINDINGS:

• Integument:
  • Erythema, scaling, alopecia, exudation, crusting +/- necrosis, sloughing
  • Paws:  Swollen; chronic cases may resemble "hard pad" disease
  • Mucous membranes:  Characteristically “brick-red” +/- ulcerated
• Other tissues:
  • Pulmonary edema and consolidation +/- secondary bronchopneumonia 
  • Myocardial and skeletal muscle necrosis
  • Hemorrhagic gastroenteritis (acute thallotoxicosis)
  • Esophageal paralysis with dilation and erosion/ulceration

 

TYPICAL MICROSCOPIC FINDINGS:

• Integument:
  • Marked epidermal and follicular parakeratotic hyperkeratosis
  • Intraepithelial pustules in follicles and epidermis
  • Follicular plugging, hypogranulosis, epidermal hyperplasia
  • Most follicles in catagen or telogen; degenerative changes in anagen follicles
  • Dermal edema, erythrocyte exocytosis, neutrophilic / mononuclear infiltrates
  • +/- partial or full thickness epithelial necrosis
  • +/- necrosis of apocrine and sebaceous glands
• Other tissues:
  • Lung: pulmonary edema +/- secondary bronchopneumonia (due to damage to ciliated epithelia > disturbed mucociliary clearance)
  • Heart, skeletal muscle: Necrosis
  • Gastrointestinal tract: 
    • Ulcerative esophagitis (due to neuronal damage > dilation) 
    • Hemorrhagic gastroenteritis (acute thallotoxicosis) 
    • +/- suppurative pancreatitis
  • Spleen, lymph nodes:  Histiocytic hyperplasia, lymphoid depletion 
  • Central nervous system:  Neuronal chromatolysis, neuronophagia, severe edema; little glial reaction
  • Peripheral nerves:  Myelin sheath distention, +/- swollen/fragmented axons

 

ADDITIONAL DIAGNOSTIC TESTS:  

For detection of thallium:

• Gabriel-Dubin colorimetric assay:  Urine
• Atomic absorption spectroscopy:  Urine, liver, kidneys, gastric contents, or suspected bait

 

DIFFERENTIAL DIAGNOSIS:

Gross:

• Canine distemper virus (morbillivirus) (I-V12):  Conjunctivitis, perioral crusting and ulceration, hard pad disease, neurological signs
• Autoimmune diseases:  
  • Pemphigus vulgaris (I-M25):  Acantholysis, suprabasilar clefts, and noninflammatory blisters which often coalesce and spread (bullous ulcers usually remain the same size)
  • Bullous pemphigoid (I-M27):  Subepidermal clefts and vesicles; no acantholysis
  • Systemic/discoid lupus erythematosus (I-M28): Lichenoid interface dermatitis (mononuclear cell infiltrate at dermoepidermal junction, lymphocytes predominate); basal cell hydropic degeneration that may involve follicles and pigmentary incontinence; Civatte bodies (basal cell apoptosis); cleft and bulla formation between epidermis and dermis with severe subepidermal vacuolization 
• Toxic epidermal necrolysis (I-M29):  Apoptotic epidermal cells at all levels of the epidermis; may progress to confluent or full thickness coagulation necrosis of epidermis and hair follicles
• Mucocutaneous candidiasis:  Immunosuppressed animals; ulcers and erosions coated with adherent, foul-smelling exudate
• Epitheliotropic lymphoma (I-N26):  Uncommon in dogs; rare in cats; oral lesions may resemble those seen with pemphigus vulgaris
• Generic dog food dermatosis:  Deficiency of multiple trace minerals, vitamins, and amino acids; rapid onset; systemic illness is common; bilateral scaling and crusting of the nose, pressure points, mucocutaneous junctions, extremities; perivascular dermatitis with parakeratotic hyperkeratosis, focal keratinocyte apoptosis, mixed dermal cellular infiltrate

 

Microscopic:  For parakeratosis:  lesions of thallium toxicosis, superficial necrolytic dermatitis, and zinc-responsive dermatosis are similar; confirmation requires additional diagnostics (see above):

• Superficial necrolytic dermatitis (hepatocutaneous syndrome)(I-M16):  Histologic lesions virtually pathognomonic [red (parakeratotic hyperkeratosis), white (superficial epidermal edema and acanthosis), and blue (basal cell hyperplasia)] 
• Zinc-responsive dermatosis (I-M18):  Two clinical syndromes [syndrome I = inherited (Alaskan malamutes and Siberian huskies); syndrome II = rapidly-growing, large breed dogs with relative dietary Zn deficiency] 
• Generic dog food dermatosis
• Lethal acrodermatitis of bull terriers (I-M18):  Autosomal recessive inheritance;  pathogenesis of low plasma Zn disease is unknown but copper deficiency may play a role; growth retardation, progressive dermatopathy, paronychia, diarrhea, bronchopneumonia, death by 18 months of age; thymic and lymph node hypoplasia and giant cell bronchopneumonia are important findings
• Vitamin A responsive dermatosis (D-M09):  Lesions primarily in chest and abdomen; marked follicular keratosis
• Sarcoptic mange (I-P06) and flea-hypersensitivity dermatitis may also have diffuse parakeratosis, but usually increased inflammatory infiltrate

 

COMPARATIVE PATHOLOGY:

 

REFERENCES:

1. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Vascular diseases of the Dermis. In: Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis, 2nd ed. Ames, IA: Blackwell Publishing Professional; 2005: 242.
2. Maudlin EA, Peters-Kennedy J. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals.  Vol 1. 6th ed. Philadelphia, PA: Elsevier Saunders; 2016:568-569.
3. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1129, 1158.

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