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: There are multifocal to coalescing areas in which deep dermal collagen fibers are hypereosinophilic, fragmented, disrupted, or effaced by deposits of deeply basophilic, angular material (mineral). These foci extend into the subcutis and are surrounded by variable amounts of fibrin, necrotic debris, and moderate numbers of macrophages, lymphocytes, plasma cells, and few foreign-body type multinucleated giant cells. Hair follicles are moderately dilated and lumina are filled with lamellated keratin, keratin debris (comedones), and fragmented hair shafts, and are lined by thin, attenuated epithelium (follicular epithelial atrophy). Hair follicles are in telogen phase characterized by prominent tricholemmal keratin, inconspicuous dermal papillae, and termination in the superficial dermis, with an absence of anagen phase follicles (physiologic atrophy/hair growth cycle arrest). Hair follicles are often markedly small/attenuated, 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 are small/atrophic. Apocrine glands are moderately ectatic. There is diffuse, mild orthokeratotic hyperkeratosis with rare intracorneal pustules and the epidermis is multifocally attenuated to as few as one to two cells (epidermal atrophy).
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 (E-N01), adrenal-dependent (E-N09), or iatrogenic (E-M04)
· Spontaneous hyperadrenocorticism in dogs:
· 80-85% 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)
· 15-20% are adrenal dependent; caused by functional adrenocortical tumors
· One case report of hyperadrenocorticism in a Chihuahua caused by a ganglioglioma in the pituitary region (Ishino, Vet Pathol 2019)
· Hyperadrenocorticism is the second most common endocrine skin disorder in the dog; hypothyroidism is the most common endocrine skin disorder.
· Most common mechanism (pituitary-dependent hyperadrenocorticism): Functional corticotroph (ACTH-secreting) adenoma of the pituitary (pars distalis or pars intermedia) à bilateral adrenal cortical hypertrophy and hyperplasia primarily of the zona fasciculata
· Normal hypothalamic-pituitary-adrenal axis function:
· 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 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 to older dogs; no sex predilection; Dachshunds, Boston terriers, boxers, and poodles are predisposed
· 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 hypotrichosis
· 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/or subcutis commonly occurs in the axilla, groin, or dorsal neck
· Cutaneous telangiectasia: A macular to papular, erythematous vascular lesion 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, thin dermis, absence of arrector pili muscles, sebaceous gland atrophy
· Calcinosis cutis (virtually pathognomonic for hyperadrenocorticism): dystrophic mineralization of collagen fibers (often of individual collagen bundles) and basement membrane of epidermis and hair follicles; mineral deposition may occur in the dermis, epidermis, and/or subcutis; can result in osseous metaplasia; if calcinosis cutis is present, epidermis is frequently hyperplastic and can be ulcerated
· Hair follicles
· Growth cycle arrest (physiologic atrophy): May be in telogen or catagen phase (telogen phase usually predominates)
· True follicular atrophy (follicles smaller than normal)
· Comedo formation (dilated, keratin-filled follicles)
· Cutaneous telangiectasia:
· 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: 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: Screening test for hyperadrenocorticism
· Normal dogs: Appropriate suppression of 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: Appropriate suppression of cortisol concentration (i.e. 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 (I-M22), canine Sertoli cell tumor-associated skin disease, alopecia X, female hyperestrogenism (I-M24)
· 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; clinical signs are due to hypothalamic compression rather than direct hormone production
· 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, +/- 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); can be iatrogenic due to removal of gonads causing a negative GnRH and LH feedback loop; 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); rare hypercortisolism and no atrophy of the contralateral cortex
· Adrenal cortical carcinomas with myxoid differentiation are 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
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