JPC SYSTEMIC PATHOLOGY
Signalment (JPC #21474-25): Adult dog
HISTORY: Plaque-like lesion from the dorsum of the neck of a dog with bilaterally symmetrical alopecia of the trunk.
HISTOPATHOLOGIC DESCRIPTION: Haired skin: Diffusely, deep dermal collagen fibers are hypereosinophilic, fragmented, disrupted, or effaced by deposits of deeply basophilic, angular material (mineral), which extends into the subcutis and is surrounded by variable amounts of fibrin, necrotic debris, moderate numbers of macrophages, lymphocytes, plasma cells, and few foreign-body type multinucleated giant cells. Follicular infundibula and other regions of outer root sheath are moderately dilated and expanded with lamellated keratin and keratin debris (comedones), frequently containing fragmented hair shafts and lined by thin, attenuated epithelium. There is an absence of hair follicles in anagen phase; most appear to be in telogen with prominent tricholemmal keratin, inconspicuous dermal papillae and termination in the superficial dermis (physiologic atrophy/hair growth cycle arrest). Hair follicles are markedly smaller than normal, reduced to a small aggregate of hair bulb cells (true follicular atrophy) and surrounded by fibrosis. There is an overall paucity of arrector pili muscles and sebaceous glands; when present, they appear smaller than normal. Apocrine glands are moderately ectatic. There is diffuse, mild orthokeratotic hyperkeratosis with rare intracorneal pustules and multifocal epidermal thinning to as few as one to two cells.
MORPHOLOGIC DIAGNOSIS: Haired skin: Dermal mineralization (calcinosis cutis), diffuse, moderate, with granulomatous dermatitis, epidermal and follicular atrophy, hair growth cycle arrest, and comedones, breed not specified, canine.
ETIOLOGIC DIAGNOSIS: Endocrine dermatopathy
SYNONYMS: Cushing’s syndrome or disease; hyperglucocorticoidism
- Canine hyperadrenocorticism is a common disorder caused by excessive endogenous or exogenous glucocorticoids and may be pituitary-dependent adrenal-dependent, or iatrogenic
- Spontaneous hyperadrenocorticism in dogs
- 80-90% of cases are pituitary-dependent and most often caused by a functional corticotroph (ACTH-secreting) adenoma of the pituitary gland (pars distalis or pars intermedia)
- 10-20% are adrenal dependent; caused by functional adrenocortical tumors
- Dachshunds, Boston terriers, boxers, and poodles are predisposed
- Hyperadrenocorticism is the second most common endocrine skin disorder in the dog; hypothyroidism is the most common endocrine skin disorder.
- Most common mechanism: Functional corticotroph (ACTH-secreting) adenoma of the pituitary (pars distalis or pars intermedia) that causes bilateral adrenal cortical hypertrophy and hyperplasia primarily of the zona fasciculata
- Corticotropin-releasing hormone (CRH) from hypothalamus stimulates secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which stimulates glucocorticoid secretion from the adrenal cortex (zona fasciculata and zona reticularis)
- Feedback regulation: Cortisol secretion inhibits release of CRH, which suppresses secretion of ACTH
- Anti-inflammatory effects of corticosteroids are due to down-regulation of expression of target genes (i.e. those encoding COX-2, phospholipase A2, and nitric oxide synthase) and up-regulation of genes that encode anti-inflammatory proteins (i.e., lipocortin 1, which inhibits release of arachidonic acid from membrane phospholipids)
- Promote gluconeogenesis, inhibit uptake of glucose by cells, and induce lipolysis
- Induce protein catabolism resulting in collagen loss, thin skin, and poor wound healing
- Cause selective atrophy of fast-twitch (type 2) myofibers resulting in decreased muscle mass and muscle weakness
TYPICAL CLINICAL FINDINGS:
- Middle-aged dogs; no sex predilection
- Polyuria, polydipsia, polyphagia
- Muscle weakness and atrophy
- Pot-bellied, pendulous abdomen secondary to muscle atrophy and hepatomegaly
- Secondary bacterial infections especially in the skin, urinary tract, lung, and conjunctiva
- Neurological signs
- Clinical Pathology:
- Stress Leukogram: Neutrophilia, lymphopenia and eosinopenia
- Monocytosis (dogs)
- High serum alkaline phosphatase (both hepatic isoenzyme and steroid-induced isoenzyme)
- Lipemia and hypercholesterolemia
- Hypercoaguable state (i.e. canine hyperadrenorticism has been associated with thromboembolic disease)
TYPICAL GROSS FINDINGS:
- Bilaterally symmetrical truncal alopecia or hypertrichosis
- Thin, inelastic skin that tears easily and is transparent with prominent subcutaneous blood vessels
- Hyperpigmentation, depigmentation, or changes in coat color
- Bruising easily and delayed wound healing
- Secondary seborrheic skin diseases (comedone formation, bacterial pyoderma)
- Calcinosis cutis: Deposition of calcium and phosphate ions in the dermis, epidermis, and subcutis; often see mineralization of individual collagen bundles; commonly occurs in the axilla, groin, or dorsal neck region
- Cutaneous phlebectasia is a vascular lesion that is macular to papular, erythematous, and most common over the ventrum and medial thighs
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Varying degrees of epidermal and follicular infundibular epithelial atrophy (1-3 cell layers), inflammation (+/-)
- Dystrophic mineralization of collagen fibers and basement membrane of epidermis and hair follicles (calcinosis cutis; which can result in osseous metaplasia, is virtually pathognomonic for hyperadrenocorticism ); when present, epidermis is frequently hyperplastic and can be ulcerated
- Thin dermis; absence of arrector pili muscles
- Hair follicles in growth cycle arrest (physiologic atrophy): May be in telogen or catagen phase (telogen phase usually predominates)
- True follicular atrophy (follicles smaller than normal)
- Sebaceous gland atrophy
- May have comedo formation- dilated keratin filled hair follicle
- Cutaneous phlebectasia:
- Macular phase: Marked dilation and congestion of superficial dermal capillaries lined by a single layer of flattened endothelium
- Papular phase: Lobular proliferation of normal-appearing superficial dermal capillaries sometimes encased by an epidermal collarette
- Other non-specific lesions of dermal endocrinopathy include orthokeratotic hyperkeratosis, and hyperpigmentation
ADDITIONAL DIAGNOSTIC TESTS:
- Urine cortisol/creatinine ratio (screening test)
- Increased ratio with naturally occurring hyperadrenocorticism
- Stress can falsely elevate the ratio
- ACTH stimulation test is the test of choice for diagnosis of iatrogenic hyperadrenocorticism
- Normal dogs: Cortisol concentration increases two- to three-fold
- Iatrogenic: Little or no change in cortisol concentration
- Low-dose dexamethasone suppression test: Screen animals for hyperadrenocorticism
- Normal dogs: Suppressed cortisol concentrations
- Dogs with either pituitary- or adrenal-dependent will not adequately suppress cortisol concentration
- High-dose dexamethasone suppression test: Differentiate pituitary-dependent from adrenal-dependent hyperadrenocorticism
- Normal dogs and most dogs with pituitary-dependent hyperadrenocorticism: Cortisol concentration equal to or less than one-half of the baseline sample
- Dogs with adrenal-dependent hyperadrenocorticism (and 25% dogs with pituitary-dependent): Inadequate suppression of cortisol concentration
- Other endocrine dermatoses: Hypothyroidism, canine Sertoli cell tumor-associated skin disease, alopecia X, female hyperestrogenism
- Telogen effluvium: Uncommon, characterized by telogen arrest; true follicular atrophy is absent
- Acquired pattern alopecia
- Follicular dysplasia
- Other endocrine dermatoses
- Aged horses; no breed or sex predilection
- Associated with functional pituitary neoplasms; most commonly adenoma of the pars intermedia
- In the pars intermedia, high molecular weight ACTH forms alpha–MSH and CLIP (corticotrophin-like intermediate peptide; horses with pars intermedia dysfunction have marked increase in MSH, CLIP, and beta endorphins
- Clinical signs include hirsutism, episodic hyperhidrosis, weight loss, abnormal shedding, secondary skin infections (e.g. dermatophilosis), poor wound healing, and decreased muscle tone
- Rare; like dogs, more commonly pituitary dependent than adrenal dependent or iatrogenic
- Clinical presentation is similar to the dog; additionally, there is often concurrent diabetes mellitus
- Alopecia, thin, fragile skin and lacerated skin (“feline fragility syndrome”); most consistent histological change is marked reduction of dermal collagen
- Calcinosis cutis has not been reported
- Adrenal hyperplasia and carcinomas are common (adenomas less so); result in hyperestrogenism (vulvar enlargement, bilaterally symmetric alopecia, PU/PD, anemia, thrombocytopenia, pyometra, endometrial hyperplasia, squamous metaplasia of prostatic ductular epithelium, and cystic prostatic disease); no hypercortisolism and no atrophy of the contralateral cortex
- Adrenal cortical carcinomas with myxoid differentiation associated with increased invasiveness; transcription factor GATA-4 is a marker of anaplasia in ferret adrenocortical tumors (adenomas and carcinomas); there is no GATA-4 expression in normal or hyperplastic adrenocortical cells, or spindle cell population in adrenocortical tumors
- Baktavatchalu V, Muthapalani S, et al. Endocrinopathy and Aging in Ferrets. Vet Pathol. 2016; 53(2):349-365.
- Ferguson DC, Hoenig M. Endocrine system. In: Latimer, KS, ed. Duncan and Prasse’s Veterinary Laboratory Medicine Clinical Pathology. 5th ed. Hoboken, NJ: Wiley-Blackwell; 2011:317-323.
- Gross TL, Ihrke PJ, Walder EJ, et. al. Atrophic diseases of the adnexa. In: Gross TL, Ihrke PJ, Walder EJ, Affolter VK, eds. Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science Ltd; 2005:484-490.
- Gross TL, Ihrke PJ, Walder EJ, et. al. Degenerative, dysplastic and depositional diseases of dermal connective tissue. In: Gross TL, Ihrke PJ, Walder EJ, Affolter VK, eds. Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science Ltd; 2005:373-377.
- Hargis AM, Ginn, PE. The integument. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier Mosby; 2012:1060-1061.
- La Perle KMD. Endocrine system. In: Zachary JF, McGavin MD, eds. Pathologic Basis of Veterinary Disease. 5th ed. St. Louis, MO: Elsevier Mosby; 2012:672-675.
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- Mauldin 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: Saunders Elsevier; 2016: 588-589.
- Park FM, Blois LS, Abrams-Ogg ACG, et. al. Hypercoagulability and ACTH-Dependent hyperadrenocorticism in dogs. J Vet Intern Med. 2013;27(5):1136-1142.
- Rosenthal KL, Wyre NR. Endocrine diseases. In: Quesenberry KE, Carpenter JW, eds. Ferrets, Rabbits, and Rodents Clinical Medicine and Surgery. 3rd ed. St. Louis, MO: Elsevier Saunders; 2012:86-91.
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