JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M16

Signalment (JPC #2678477):  13-year-old neutered female mixed breed dog

 

HISTORY:  This dog had a long history of pododermatitis, migratory erythema, truncal alopecia, and weight loss.  Serum alkaline phosphatase and alanine aminotransferase were elevated.

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin, adjacent to foot pad:  Diffusely, the epidermis is markedly thickened (acanthosis) up to 5mm, characterized by a superficial hypereosinophilic layer of marked parakeratotic hyperkeratosis; an intermediate layer of pallor with superficial keratinocytes expanded by intracellular edema (vacuolar degeneration) and intercellular edema with prominent intercellular bridges (spongiosis); and a deep layer of increased basophilia composed of a markedly hyperplastic stratum basale with prominent rete ridges in which basal cells are characterized by an increased N:C ratio and increased cytoplasmic basophilia.  The stratum corneum is composed of lamellations of keratin occasionally admixed with degenerate neutrophils, necrotic debris, and colonies of basophilic 2 µm cocci (intracorneal pustules).  The superficial dermis is multifocally mildly expanded by increased clear space and dilated lymphatics (edema), few plasma cells, lymphocytes, neutrophils, and scattered free melanin and melanin laden macrophages (pigmentary incontinence). 

 

Liver:  Approximately 50% of the section is composed of anastomosing branching bands of hepatocytes expanded up to 20 µm by either microvacuolated lacy cytoplasm with a centrally placed nucleus (vacuolar change, glycogen-type) or expanded by a large, clear, intracytoplasmic vacuole that peripheralizes the nucleus (vacuolar change, lipid type). There are areas of hepatocellular loss with parenchymal collapse characterized by close apposition of portal triads and central veins. Affected areas are infiltrated moderate numbers of neutrophils, lymphocytes, plasma cells, and macrophages which often contain golden brown cytoplasmic material (hemosiderin and/or bile) or are in aggregates with pale brown microvacuolated cytoplasm (lipid, lipogranuloma).  Portal areas are surrounded by mildly increased mature collagen and fibroblasts (periportal fibrosis), with increased small bile duct profiles (ductular reaction).  Occasionally, the tunica media of arterioles is thickened by eosinophilic hyaline material. Separating areas of vacuolar change are multiple regenerative nodules of hepatocytes exhibiting mild anisocytosis, anisokaryosis, and increased basophilia, arranged in tortuous sinusoidal patterns without a distinct central vein, and frequently forming hepatic cords two cell layers thick.

 

MORPHOLOGIC DIAGNOSIS:  1.  Haired skin, adjacent to foot pad:  Hyperkeratosis, parakeratotic, diffuse, severe, with acanthosis, spongiosis, and basal cell hyperplasia, mixed breed, Canis familiaris, canine.

2. Liver: Hepatocellular vacuolar degeneration and loss, multifocal to coalescing, severe, with parenchymal collapse, multinodular regeneration, and biliary ductular reaction.

 

CONDITION:  Superficial necrolytic dermatitis (SND)

 

SYNONYMS:  Hepatocutaneous syndrome, metabolic epidermal necrosis, necrolytic migratory erythema, diabetic dermatopathy

 

GENERAL DISCUSSION:

• SND is an uncommon skin disorder associated with underlying systemic disease, occurs primarily in dogs; rare in cats
• In dogs, SND is primarily associated with liver disease (>90%); also reports of association with pancreatic glucagon-secreting tumors, hyperglucagonemia, diabetes mellitus, and chronic phenobarbital administration
• Prognosis usually poor due to underlying systemic disorder
• Canines rarely have pancreatic glucagonomas; surgical excision of pancreatic glucagonoma can result in resolution of skin lesions

 

PATHOGENESIS:

• Pathogenesis is unknown; hepatic dysfunction and metabolic derangements (i.e. glucose and amino acid metabolism) implicated
• Metabolic hepatopathy à increased hepatic catabolism of amino acids à (hypoaminoacidemia) (+/- acids and/or zinc) à insufficient epidermal proteins à epidermal necrosis

 

TYPICAL CLINICAL FINDINGS:

• Hypoaminoacidemia and decreased serum essential fatty acid levels are consistent findings
• Systemic clinical signs are consistent with underlying metabolic disease
• Pruritus and pain +/- secondary bacterial, yeast, or dermatophyte infections

 

TYPICAL GROSS FINDINGS:

• Bilateral and symmetric erythematous, scaling, crusty, hyperkeratotic dermatitis with erosion or ulceration on feet, pressure points (elbows and hocks), flank, perineal area, muzzle, facial mucocutaneous junctions, and/or oral cavity
• Footpad lesions are not seen in cats
• Liver: Most common gross lesion is a nodular liver with a firm, collapsed parenchyma

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Classic “red, white, and blue” epidermis is essentially pathognomonic when all of components are present
• "Red" - Diffuse, severe parakeratotic hyperkeratosis with crusting
• "White" - Superficial keratinocyte vacuolar degeneration (intracellular edema) and spongiosis (intercellular edema) with acanthosis
• "Blue" - Hyperplastic basal cell layer
• Perivascular and superficial cellular infiltrate in dermis consisting of neutrophils, macrophages, lymphocytes, and plasma cells
• Liver: Lipid-type vacuolar change of hepatocytes with parenchymal collapse, and nodular regeneration with minimal inflammation, necrosis, and fibrosis

 

ADDITIONAL DIAGNOSTIC TESTS:

• Lipid-type vacuolar change of hepatocytes: lipid stains with oil red O in frozen sections
• Serology and further diagnostic tests to identify any underlying internal disease

 

DIFFERENTIAL DIAGNOSIS:

• Parakeratotic hyperkeratosis:
• Zinc responsive dermatosis (I-M18): Crust, scale and alopecia around eyes, mouth, chin, and ears; microscopically, perivascular dermatitis and follicular parakeratotic hyperkeratosis (usually no intra/intercellular edema); husky, malamute
• Thallium toxicosis (I-T01): Very rare; alopecia and erythema of frictional areas, followed by ulceration; can progress to involve face, ventrum, perineum, feet, and mucocutaneous junctions
• Lethal acrodermatitis of bull terriers: Autosomal recessive; similar to zinc responsive dermatosis but does not respond to zinc
• Erythema multiforme(I-M29): Both entities may have random individualized necrotic epidermal keratinocytes; satellitosis of necrotic keratinocytes is not a feature of superficial necrolytic dermatitis

                                                                                                     

COMPARATIVE PATHOLOGY:

• Cats: Rare; typically associated with hepatopathy; rare cases of pancreatic carcinoma (suspected endocrine origin) and glucagon-producing hepatic neuroendocrine carcinoma
• Horses: Similar syndrome reported with erosive, ulcerative coronitis and concurrent hepatopathy; similar dermal microscopic lesions, including sloughing of hoof wall
• Captive black rhinoceros (Diceros bicornis): Relatively common and any age may be affected; lesions typically bilateral and most commonly affect lateral body surfaces, coronary bands, tail tip, and ear margins; similar gross and histologic features
• Humans: Resembles necrolytic migratory erythema; paraneoplastic syndrome associated with pancreatic alpha cell neoplasms

 

REFERENCES:

1. Cullen JM, Stalker MJ. Liver and biliary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier; 2016: 295, 329.
2. Duncan, M. Perissodactyls. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018:440.
3. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science; 2006:86-91.
4. Hargis AM, Ginn PE. The integument. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier; 2012: 1141-1142.
5. 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: 586-587.
6. Van Wettere AJ, Brown DL. Hepatobiliary system and exocrine pancreas. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:504.
7. Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1131.

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