JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-M24 (NP)

Signalment (JPC# 21474-27): Male dog, breed unspecified

HISTORY: This dog had gynecomastia, alopecia, hyperpigmentation, and hyperkeratosis.

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin and mammary gland: Diffusely, there is mild epidermal and follicular epithelial hyperplasia with orthokeratotic hyperkeratosis. There is adnexal atrophy characterized by decreased size and number of sebaceous glands and a paucity of hair follicles. Hair follicle lumina are often expanded by abundant lamellations of keratin (follicular keratosis) and often lack hair shafts. Hair follicles are confined to the superficial dermis at the level of the sebaceous glands (hairless telogen phase, AKA kenogen). There is increased dermal collagen. Within the superficial dermis, there are few melanin-laden macrophages and free melanin granules (pigmentary incontinence). Apocrine glands are often mildly ectatic. Multifocally, the underlying mammary tissue is composed of variably ectatic ducts that are expanded up to 8 mm in diameter and lined by epithelium with rare apical blebbing that is either cuboidal, attenuated, or hyperplastic, occasionally piling up to 3-4 cells deep and forming arborizing papillary projections supported by fine fibrovascular stroma. The ectatic ducts contain variable amounts of eosinophilic, finely granular material (secretory product), rarely few macrophages and red blood cells. Multifocally, the stroma of the mammary gland contains few lymphocytes, plasma cells, and rare macrophages. 

 

MORPHOLOGIC DIAGNOSIS:

1. Haired skin: Atrophy, follicular, multifocal, moderate, with dermal fibrosis, telogenization, follicular ectasia, epidermal hyperplasia, and orthokeratotic hyperkeratosis, breed unspecified, canine.
2. Mammary gland: Hyperplasia, intraductular and papillary, diffuse, moderate.

 

CAUSE:  Hyperestrogenism secondary to Sertoli cell tumor

 

CONDITION:  Gynecomastia

 

GENERAL DISCUSSION: 

• Ovarian follicles, adrenocortical zona reticularis, testicular Sertoli and interstitial cells produce estrogen
• Normal hypothalamic-pituitary-gonad axis:
  • Gonadotropin releasing hormone (GnRH) from the hypothalamus stimulates follicle stimulating hormone (FSH) release from the pituitary gland
  • FSH stimulates ovarian follicular growth and spermatogenesis
  • Estrogen inhibits GnRH release
  • Inhibin from ovarian follicles and Sertoli cells inhibits FSH release
• Male mammary tissue is composed of only ductal elements and lacks fully developed terminal duct lobular units even under the influence of hyperestrogenism
• Hyperestrogenism in dogs:
  • In middle-aged to older intact dogs, it is associated with functional Sertoli cell tumors, which are usually associated with cryptorchidism; also rarely associated with testicular interstitial cell tumors and seminomas
  • In middle-aged to older intact females, may be secondary to cystic ovaries or functional granulosa-theca cell neoplasms
  • Rarely, secondary to administration of estrogen (e.g. treatment of incontinence of female dogs) or contact with human topical estradiol compounds
  • Occurs most commonly in Boxers, Shetland Sheepdogs, Pekingese, Weimaraners, Cairn Terriers and Miniature Schnauzers
  • Middle aged or older dogs most commonly affected

 

PATHOGENESIS: 

• Estrogen’s epidermal effects:
  • Stimulates epidermal mitosis
  • Increases both free skin melanin and intramelanocytic melanin
  • Reduces sebaceous gland size and sebum production
  • Suppresses initiation of anagen
• Cutaneous estrogen levels may be more than those in the blood (cutaneous hyperestrogenism)

 

TYPICAL CLINICAL FINDINGS:

• Hyperestrogenism may cause bone marrow suppression which can result in pancytopenia; initial neutrophilia followed by neutropenia, thrombocytopenia, and severe non-regenerative anemia
• Attraction to other male dogs

 

TYPICAL GROSS FINDINGS: 

• Bilaterally symmetrical alopecia beginning in the perineal and genital region and progressing to the abdomen, chest, flanks, and neck
• Chronically - hyperpigmentation and lichenification
• Dull, easily epilated hair coat that often fails to regrow after clipping
• Nipple hypertrophy and gynecomastia
• Pendulous prepuce or vulvar enlargement
• Variable seborrheic disease
• Linear preputial erythema (aka linear preputial dermatosis) and hyperpigmentation on ventral prepuce is a characteristic lesion of Sertoli cell tumors

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Orthokeratotic hyperkeratosis
• Follicular hyperkeratosis, dilation, or atrophy
• Hair follicles in catagen or telogen phase
• Excess trichilemmal keratinization (flame follicles): specific histopathological indicator of endocrine skin disease, but not a specific endocrinopathy
• Epidermal melanosis: Deposition of pigment in all viable levels of the epidermis (hyperpigmentation)
• Sebaceous gland atrophy
• Variable dermal inflammation with lymphocytes, macrophages, plasma cells, and neutrophils; may extend around adnexa and may reflect the presence of secondary pyoderma
• Squamous metaplasia within prostate gland and prostatic urethra

 

ADDITIONAL DIAGNOSTIC TESTS: 

• Radioimmunoassay for estrogens in plasma or serum

 

DIFFERENTIAL DIAGNOSIS: 

• Cutaneous lesions
  • Endocrine alopecias: definitive diagnosis based on clinical data (clinical signs, endocrine assays, sexual status)
    • Hypothyroidism
    • Hyperadrenocorticism
    • Growth hormone/castration-responsive dermatosis
  • Alopecia X

 

COMPARATIVE PATHOLOGY: 

• Ferret Hyperestrogenism:
  • Estrogen-Induced Anemia
    • Prolonged estrus due to lack of stimulus for ovulation (induced ovulators) may result in fatal aplastic anemia and alopecia
    • Gross findings: Progressive symmetrical alopecia (tail, flank, dorsum, abdomen), melena, hemorrhages throughout the body
  • Adrenal-associated endocrinopathy (AAE)
    • Sex hormone (estradiol, 17a-HPG, androstenedione, and DHEAS)-secreting adrenal cortical tumor (excess cortisol rarely occurs in ferret adrenocortical tumors)
    • Clinical/gross/microscopic findings: Alopecia, vulvar enlargement, attraction to males; mammary hyperplasia; squamous metaplasia of prostate gland that can result in urinary obstruction secondary to development of prostatic cysts
    • Hemorrhages do not typically occur with AAE

 

REFERENCES:

1. Fox JG, Marini RP. Biology and diseases of the Ferret. 3^rd Ames, IA: Wiley Blackwell; 2014:377-386.
2. 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: 589.
3. Stockham SL, Scott MA. Erythrocytes. In: Fundamentals of Veterinary Clinical Pathology. 2nd ed. Blackwell Publishing; 2008: 166.
4. Williams BH, Burek Huntington KA, Miller MA. Mustelids. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. Cambridge, MA: Elsevier; 2018: 288-289.
5. Welle MM and Linder KE. The integument. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Mosby Elsevier; 2022:1252.

 

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