Signalment:  

12-year 10-month-old, castrated male, Cocker Spaniel, canine (Canis familiars).This was a mass on the left front digit present for four months. The mass had not changed since first noticed. The left prescapular lymph node was enlarged and there were multiple other pedunculated skin masses. A mass was removed from the right front paw one year prior but not biopsied. The dog had chronic severe dental disease, severe chronic bilateral ear infections, keratoconjunctivitis sicca bilaterally, and hyperpigmentation and lichenification of the groin. The dog had been on long-term metronidazole, rimadyl, tacrolimis, and clindamycin.

Gross Description:  

The mass markedly enlarged the digit but did not grossly invade the bone.

Histopathologic Description:

Haired skin, left front foot (per contributor): The deep dermis contains an unencapsulated, poorly demarcated, highly cellular, invasive neoplastic mass which effaces and surrounds the adnexal structures. The mass is composed of cuboidal epithelial cells arranged in tubules and acini that are often palisading and are supported by a small to large amount of collagenous stroma (desmoplasia) that multifocally contains many plasma cells and lymphocytes. The epithelial cells have a small amount of pale eosinophilic cytoplasm with distinct cell borders. The central or basally located nuclei are large and round, with finely stippled chromatin and 1 small nucleolus. Anisocytosis and anisokaryosis are marked. Mitotic figures range from 0-15 per 400x field, with an average of 5 per 400x field. Multifocally the neoplastic cells demonstrate piling upon one another, with occasional protrusion and blebbing into the acinar or tubular lumina, some of which also contain few sloughed or necrotic cells, proteinaceous material, or mild hemorrhage. Many follicles and glands are surrounded by numerous lymphocytes and plasma cells, fewer macrophages, and rare mast cells. Multiple follicles are mildly dilated, filled with laminated keratin, and contain 0-12 cross and/or tangential sections of arthropods that are up to 50 microns in diameter and 300 microns long. The arthropods have a thin eosinophilic chitinous exoskeleton, blunt jointed appendages, skeletal muscle, and digestive and/or reproductive tracts. The overlying epidermis is minimally hyperplastic with orthokeratotic hyperkeratosis. There is moderate pigmentary incontinence as well as scattered macrophages that contain a pale grey-tan pigment consistent with lipofuscin.

Morphologic Diagnosis:  

1. Adenocarcinoma, apocrine or eccrine origin, left front paw.
2. Intrafollicular mites (Demodex spp.)

Condition:  

Apocrine adenocarcinoma; Demodex canis

Contributor Comment:  

Sweat glands are divided into two types: apocrine and merocrine (eccrine).(11) Apocrine gland secretion consists of release of a large secretory granule that is surrounded by a small amount of cytoplasm and cell membrane, and is microscopically apparent as apical blabbing.(3) In merocrine secretion, the contents of the secretory granules is released by fusion of the granule with the cell membrane.(3) Apocrine glands are the most abundant in domestic animals, and consists of saccular tubular glands with a coiled secretory portion and a straight duct that is lined by two layers of epithelium and typically opens into the hair follicle.11 Merocrine glands are limited to the non-haired areas of the footpad of dogs and cats, the frog of ungulates, planum rostrale and the carpal glands of pigs, and the planum nasolabiale of cows.(11) Myoepithelial cells are specialized smooth muscle cells that aid in emptying both apocrine and merocrine glands of secretion.(3,11)

Apocrine gland carcinomas include solid, cystic, and tubular types.(5,6,7) The tubular type is the most common and typically has marked desmoplasia.(5,7) Apocrine carcinomas are locally aggressive, extending through the dermis, subcutis, and underlying skeletal muscle. Lymphatic invasion and spread to the regional lymph nodes and lungs is common.(5,6) Apocrine carcinomas also occur as ductal, compound, and mixed types, similar to mammary gland tumors.(5,7)

Tumors of eccrine glands are extremely rare but do occur as adenomas or carcinomas of the footpad of dogs and cats.(5,6,8,10) Eccrine carcinomas are morphologically similar to apocrine gland carcinomas and are very difficult to differentiate by light microscopy.(5,10) There is no reliable immunohistochemical antibodies that can separate eccrine carcinoma from apocrine carcinoma.(10) Differentiation is based on proving that the tumor arises from the footpad, rather than the adjacent haired skin,(6,10) or by observing the apical blebbing that occurs when apocrine glands are in their secretory state.(3,6) Both tumors types stain positively with antibody to carcinoembryonic antigen, which can help differentiate them from other tumor types.(5,8)

Demodex mites are obligate parasites that are normal inhabitants of the hair follicles and sebaceous glands of dogs and most other domestic animals and humans. The exception is Demodex cati, which is found in the superficial stratum corneum.(4) Disruption of the host-parasite equilibrium can result in overgrowth of the mites and lesions of demodecosis. Demodex has been found in association with several dermatologic conditions in humans(1) and animals.(4,9)

Juvenile-onset demodecosis is often familial, and is thought to be due to a genetic cell-mediated immunity disorder.(4,9) In adult-onset demodecosis, the overgrowth of the mites is often associated with hyperadrenocorticism, corticosteroid administration, hypothyroidism, chemotherapy, or other serious diseases.(4) Demodex is not typically associated with tumors in animals, but a significant increase in the prevalence and density of Demodex has been found in eyelid basal cell carcinomas in people, and is postulated to be a triggering factor for carcinogenesis due to chronic irritation.(2) Demodecosis lesions in dogs are often generalized but are more severe on the face and paws, and in some may be confined to the paws.(4,9) In this case, the patient had congestive heart failure, chronic severely infected gums, hypothyroidism, and had indications of pituitary-dependent hyperadrenocorticism in addition to a locally aggressive neoplasm in the area of mite overgrowth. The dog had hyperpigmentation and lichenification, which can be found in chronic cases of both generalized demodicosis(9) and hyperadrenocorticism. 

Histologically, demodecosis can range from early lesions of lymphocytic mural interface dermatitis, perifollicular pigmentary incontinence, and follicular hyperkeratosis, to suppurative folliculitis and pyogranulomatous furunculosis due to development of secondary bacterial infections.(4) Rupture of the follicles results in release of mites into the dermis, and fragments of mites have occasionally been found in the draining lymph nodes.(4)

JPC Diagnosis:  

1. Haired skin and subcutis: Apocrine adenocarcinoma.
2. Haired skin: Follicular ectasia, hyperkeratosis and hyperplasia, focally extensive, mild with histiocytic and lymphoplasmacytic dermatitis, pigmentary incontinence, and intrafollicular arthropod parasites (Demodex spp.)
3. Haired skin, subcutis, vessels: Smooth muscle hypertrophy and hyperplasia, multifocal, with occasional luminal occlusion.

Conference Comment:  

Participants agreed with the diagnosis of adenocarcinoma, with most favoring apocrine origin based on the observation of occasional decapitation-type secretion (apical blebbing), location of the tumor in haired skin, and the extreme rarity of eccrine carcinoma in veterinary species. Another unique feature of apocrine adenocarcinomas noted by the moderator, and not found with eccrine carcinoma, is extension of neoplastic cells into the overlying epidermis with associated epidermal ulceration. 

Participants also discussed the various histologic variants of apocrine adenocarcinoma mentioned above by the contributor. Several raised the possibility of apocrine ductal carcinoma; the moderator pointed out that there should be foci of squamous differentiation in addition to a double-layer of neoplastic epithelial cells, both of which are lacking in this specimen. In dogs and cats, eccrine carcinomas occur in the footpads, whereas apocrine adenocarcinomas and apocrine ductal carcinomas generally arise on the legs of dogs and on the head, legs and abdomen of cats. 

Participants discussed the significance of finding Demodex spp. in this, as well as other, biopsy specimens. The finding of demodecosis must be communicated to the submitting clinician, regardless of the severity or apparent insignificance since treatment with steroids will worsen the condition. The moderator commented that follicular epithelial hyperplasia, melanin within basal cells, and perivascular lymphoplasmacytic dermatitis is highly suggestive of demodecosis and should prompt the reviewing pathologist to thoroughly search hair follicles for the presence of Demodex spp.

References:

1. Dhingra KK, Saroha V, Gupta P, Khurana N. Demodex-associated dermatologic conditions-a coincidende or an etiological correlate. Review with a report of a rare case of sebaceous adenoma. Pathol Res Pract. 2009;205:423-426.

2. Erbagci Z, Erbagci I, Erkilic S. High incidence of demodicidosis in eyelid basal cell carcinomas. Int J Dermatol. 2003;42:567-571.

3. Frappier BL. Epithelium. In: Dellman HD, Eurell J, eds. Textbook of Veterinary Histology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1998:31.

4. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol. 1, 5th ed. Philadelphia, PA: Elsevier Ltd; 2007:724-726.

5. Ginn PE, Mansell JEKL, Rakich PM. Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. Vol. 1, 5th ed. Philadelphia, PA: Elsevier Ltd; 2007:758.

6. Goldschmidt MH, Dunstan RW, Stannard AA, von Tscharner C, Walder EJ, Yager JA. Histological Classification of Epithelial and Melanocytic Tumors of the Skin of Domestic Animals. 2nd Series. Vol III. Washington, D.C.: The Armed Forces Institute of Pathology, American Registry of Pathology; 1998:29-32.

7. Goldschmidt MH, Hendrick MJ. Tumors of the skin and soft tissues. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002:72-73. 

8. Goldschmidt MH, Hendrick MJ. Tumors of the skin and soft tissues. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002:76.

9. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Pustular and nodular diseases with adnexal destruction. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science Ltd; 2005:442-446.

10. Gross TL, Ihrke PJ, Walder EJ, Affolter VK. Sweat gland tumors. In: Skin Diseases of the Dog and Cat. 2nd ed. Ames, IA: Blackwell Science Ltd; 2005:677-691. 

11. Monteiro-Riviere NA. Integument. In: Dellman HD, Eurell J, eds. Textbook of Veterinary Histology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1998:316-318.

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