Results AFIP Wednesday Slide Conference - No. 25 12 April 1995 Conference Moderator: Dr. Michael H. Goldschmidt Diplomate, ACVP Laboratory of Pathology School of Veterinary Medicine University of Pennsylvania Philadelphia, PA 10104 Case I - 94-9456 (AF IP 2461135) Signalment. The skin sections are from a 9-month-old female mouse (Mus musculus) of the C3H/HeJ inbred strain. History. This mouse is from a research colony used to study the genetics of inherited hair loss in aging mice. Gross Pathology. The mouse submitted had multiple foci of alopecia on the dorsal and ventral skin. White foci were observed on the heart during necropsy (epicardial mineralization or cardiac calcinosis). Laboratory Results. None done. All previous surveillance studies and specific microbiological studies in other affected mice in this colony failed to identify known mouse pathogens. Preliminary Western blots suggest that these mice have autoantibodies to hair follicle proteins. Contributor's Diagnosis and Comments. Alopecia areata. Etiology: This appears to be an autoimmune disease. Although genetic studies are not conclusive, this appears to be an autosomal dominant trait with incomplete penetrance. This disease occurs sporadically in colonies of C3H/HeJ mice, but not in other related strains. It is a disease of adult onset, usually seen at 6 months or older in females and 12 months or older in males. Onset is associated with loss of fecundity. Inflammatory cells, predominantly CD8+ lymphocytes, infiltrate into the hair follicle root sheaths causing destruction of the hair shaft that is being formed at the time. This results in focal defects in the hair shaft as it emerges. Hairs subsequently break off at the weak spot, creating the appearance of alopecia or a fine fuzz. This mouse disease closely resembles the human disease known as alopecia areata. The DUNDEE Experimental Bald Rat (DEBR rat) is a second mutation in another species that resembles this human disease. Similar case reports suggest that alopecia areata occurs in many domestic species as well, although none are characterized to any degree. AFIP Diagnosis. Haired skin: Perifolliculitis and mural folliculitis, lymphoplasmacytic, diffuse, moderate, with follicular loss, C3H/HeJ mouse, rodent. Conference Note. Several conference participants diagnosed alopecia areata; others suspected dermatophytosis, parasitism, or a psychogenic cause. This case was reviewed by the Department of Dermatopathology of the AFIP. Changes consistent with alopecia areata in humans include: depigmentation and hair shaft dystrophy, edema and degenerative changes in the matrix of some follicles, and peribulbar lymphocytic infiltrates around some follicles. Dr. Goldschmidt and two human dermatopathology consultants with whom he reviewed this case believe that the presented lesion more closely resembles graft-versus-host disease or lupus erythematosus (without superficial epidermal involvement). Unlike this case, in which the infiltrate is primarily isthmic, alopecia areata in humans is characterized by infiltration around hair bulbs only. Alopecia areata is also very rarely reported in dogs, cats, horses, cattle, and nonhuman primates. In the majority of animal cases, the cellular infiltrate is not confined to hair bulbs as in human alopecia areata patients, but is confined to the lower two-thirds of the follicle. The pathogenesis of alopecia areata is poorly understood. It is thought to be an autoimmune disease, possibly with immunoreactivity against melanin-containing cells. Selective loss of pigmented hairs may cause sudden accentuation of graying in humans, and occasionally, the disease is restricted to hair of one coat color in dogs. Alopecia is permanent if hair follicle progenitor cells are destroyed. Affected animals have focal or multifocal areas of well-circumscribed alopecia without visible inflammatory changes in the exposed skin. Successive waves of peripheral follicular damage may gradually expand the alopecic areas. In dogs, the head and neck are most frequently involved. The differential diagnosis includes diseases with clinically noninflammatory alopecia, such as occurs in some cases of demodicosis, dermatophytosis, and early epitheliotrophic lymphoma. Skin scrapings, fungal culture, and histopathology are needed to differentiate these. Alopecia areata may also appear grossly similar to post-rabies vaccination alopecia, cicatricial alopecia, canine traction alopecia, acquired pattern alopecia, and canine follicular dysplasia. An accurate clinical history and histopathology are needed. Contributor. The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609- 1500. References. 1. Sundberg JP, Cordy WR, King Jr. LE: Alopecia areata in aging C3H/HeJ mice. J Invest Dermatol 102:847-856, 1994. 2. Sundberg UP, Vallee CM, King Jr. LE: Alopecia areata in aging C3H/HeJ mice. IN: Handbook of mouse mutations with skin and hair abnormalities: animal models and biomedical tools. Sundberg JP (ed.), CRC Press, Boca Raton, pp. 499-505, 1994. 3. Gross TL, Ihrke PJ, Walder EJ: Veterinary Dermatopathology. Mosby Year Book. pp. 161, 288, 289, and 291-294, 1992. 4. Yager JA, Scott DW: Chapter 5, The Skin and Appendages. In: Jubb KVF, Kennedy PC, Palmer N: Pathology of Domestic Animals, 4th Edition. Academic Press, Vol. 1, p. 628, 1994. International Veterinary Pathology Slide Bank Laser disc frame # None. Case II - 94-3422 (AFIP 2458522) Signalment. 11-year-old poodle (male) History. Alopecic macule, 4 cm in diameter, at the site of a rabies vaccination, three months earlier. Contributor's Diagnosis and Comments. Post-rabies vaccination alopecia. There is a mild orthokeratotic hyperkeratosis of the epidermis. Several hair follicles are severely atrophic (telogen phase). In the deep dermis there are diffuse or nodular inflammatory infiltrates composed of lymphocytes and plasma cells. There is also a focal granulomatous lesion. These histological findings combined with the clinical history are highly suggestive of post-rabies vaccination alopecia. This lesion has been reported more frequently in toy or small-breed dogs, particularly poodles. AFIP Diagnosis. Skin: Dermatitis and panniculitis, lymphoplasmacytic and histiocytic, multifocal, moderate, with periadnexal fibrosis, follicular atrophy and loss, and pigmentary incontinence, Poodle, canine. Conference Note. Post rabies vaccination dermatitis was considered the most likely cause of the lesion by most conference participants. Other possible causes considered by some included lymphomatoid granulomatosis, lupus, canine familial dermatomyositis, alopecia areata, and immune-mediated vasculitis. All breeds of dogs may develop rabies vaccine-induced vasculitis and associated alopecia, but poodles comprise the majority of reported cases. The condition is believed to be an idiosyncratic hypersensitivity reaction. Immunofluorescent studies have demonstrated rabies-specific antigens in the walls of dermal blood vessels and the follicular epithelium of these lesions. Similar reactions have occurred following subcutaneous injection of other vaccines. Follicular changes are secondary to ischemia induced by the vasculitis. Lesions typically develop 2 to 3 months after vaccination and range from 2 to 10 cm in diameter. They are asymptomatic, with minimal to no erythema, and may become hyperpigmented. A similar gross lesion can develop subsequent to prolonged topical application or injection of corticosteroids. Microscopic findings usually include normal epidermis, possibly with dermal edema and a mild lymphohistiocytic infiltrate that is loosely scattered or surrounds residual hair follicles. There is severe hair follicle atrophy, and the outer root sheath and overlying basilar epidermis may exhibit mild vacuolar degeneration. The panniculus exhibits mild to moderate inflammation that is typically nodular and perivascular. Advanced lesions may have only mild inflammation. Contributor. Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Univ. of Montreal, P.O. Box 5000, St. Hyacinthe, Quebec, Canada J2S 7C6. Reference. 1. Gross TL, Ihrke PJ, Walder EJ: Veterinary Dermatopathology. Mosby Year Book. pp. 287-289, 1992. 2. Yager JA, Scott DW: Chapter 5, The Skin and Appendages. In: Jubb KVF, Kennedy PC, Palmer N: Pathology of Domestic Animals, 4th Edition. Academic Press, Vol. 1, pp. 626-627, 1993. International Veterinary Pathology Slide Bank. Laser disc frame # None. Case III - 94N391 (AFIP 2460107) Signalment. 10-year-old, male blue Doberman Pinscher History. The dog had chronic skin problems. The dog presented with multiple, occasionally ulcerated, cutaneous nodules over all of the body surface. The owner refused further diagnostic work-up and the dog was euthanized. Gross Pathology. There are patchy areas of hypotrichosis with poor coat quality or alopecia over all of the body surface. Numerous, 0.5 to 1.5 cm, occasionally ulcerated, nodules are also present over all of the body surface. The nodules consist of a dilated cystic space filled with inspissated tan-yellowish material. Approximately 15 heartworms are present in the right ventricle. The liver has an accentuated lobular pattern. Contributor's Diagnosis and Comments. Follicular dysplasia and atrophy with marked clumping of melanin, follicular keratosis, and epidermal melanin clumping, consistent with color-dilution alopecia. Follicular (infundibular) cysts. Folliculitis and furunculosis are present in some areas. The gross and microscopic findings are consistent with a diagnosis of color-dilution alopecia (CDA). CDA is an hereditary dysplastic disease which occurs in the hair follicles of dogs with blue coats or other color-diluted mutations. CDA is seen most frequently in the blue Doberman Pinscher, but also is seen in other breeds such as the Dachshund, Great Dane, Whippet, Italian Greyhound, Chow Chow, Standard Poodle, Yorkshire Terrier, Miniature Pinscher, Chihuahua, Burnese Mountain Dog, Shetland Sheepdog and Schipperke. It has been speculated that defects in melanosome transfer to the hair matrix cell may result in disruption of hair matrix keratinocytes and cause malformed hair shafts and eventual senescence. Therefore, melanin clumping within the follicular keratin, hair shafts, and hair bulbs, as well as in perifollicular melanophages is quite diagnostic for CDA. However, some special feature of the dilution gene or other unknown defects may be involved in weakening of the hairs and hair loss. CDA should be a preventable disorder if restrictive breeding is followed. AFIP Diagnosis. Haired skin: Dysplasia, follicular, with ectasia, hyperkeratosis, melanin clumping, and pigmentary incontinence, Doberman Pinscher, canine. Conference Note. Most conference participants considered color-dilution alopecia and black-hair follicular dysplasia to be the most likely diagnoses. The histopathologic features of color-dilution alopecia and black-hair follicular dysplasia are virtually identical and must be distinguished clinically. Black-hair follicular dysplasia likely represents focal expression of color-dilution alopecia. Although melanin clumping can occur perifollicularly in a variety of inflammatory conditions, clumped melanin within the follicle indicates color dilution. Hypothyroidism and hyperadrenocorticism were discussed but not favored. These endocrinopathies may appear grossly similar to color-dilution alopecia but have distinguishing clinicopathologic and histopathologic features not present in this case. Canine color-dilution alopecia is also reported in the red Doberman Pinscher, as well as in the fawn Irish Setter and Doberman Pinscher. Affected animals develop the syndrome between 4 months and 6 years of age. Initially, the hair coat is dry and brittle. Hair shaft fragmentation and poor regrowth result in progressive alopecia that may become complete on the trunk. Seborrhea sicca, comedones, follicular cysts, and folliculitis may also develop. Black-hair follicular dysplasia is a rare hereditary skin disease reported in mongrel and purebred dogs with black spots, and in the cow and horse. Only black areas of the coat and underlying skin are affected. Contributor. Department of Pathology, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803. References. 1. Gross TL, Ihrke PJ: Dystrophic diseases of the hair follicle. In: Gross TL, Ihrke PJ, Walder EJ: Veterinary Dermatopathology, Mosby Year Book, St. Louis, MO, pp. 298- 310, 1992. 2. Miller WH: Color dilution alopecia in Doberman Pinschers with blue or fawn coat colors: a study on the incidence and histopathology of this disorder. Vet Dermatol 1:113-122, 1990. 3. Miller WH: Alopecia associated with coat color dilution in two Yorkshire Terriers, one Saluki, and one mix-breed dog. J Am Anim Hosp Assoc 27:39-43, 1991. 4. Brignac MM, et al: Microscopy of color mutant alopecia. Proceedings of American Academy of Vet Dermatology and American College of Vet Dermatology, Washington, DC, 4:14-15, 1988. 5. Yager JA, Scott DW: Chapter 5, The Skin and Appendages. In: Jubb KVF, Kennedy PC, Palmer N (eds.): Pathology of Domestic Animals, 4th Edition, pp. 559-560, 1993. International Veterinary Pathology Slide Bank Laser disc frame # 11787, 11856, 11857, 13849-13851. Case IV - E79/94 (AFIP 2465439), photo Signalment. 9-year-old, female, Poodle-cross, dog History. The owner reported that a nodule had been present on the hind leg of this dog for 8 weeks. The consulted veterinarian removed a solitary nodule from the medial aspect of the left hind leg, just above the tarsus. The nodule, which was about 2 cm in diameter, was localized in the subcutis. It was encapsulated. Involvement of lymph nodes was not observed. Gross Pathology. The submitted tissue consisted of skin and a subcutaneous, firm, white nodule which measured 1 cm x 1 cm x 2 cm. Contributor's Diagnosis and Comments. Granular basal cell tumor (trichoblastoma). Histological examination reveals lobules of tumor cells in the dermis and subcutis. The overlying epidermis is unaltered and there is no connection between the tumor and epidermis. Lobules of tumor cells are separated by scant to moderate amounts of connective tissue and surrounded by a thin layer of connective tissue. Two types of tumor cells can be distinguished. Most lobules consist of basaloid cells with a palisading, ribbon-like, or medusoid arrangement. There are moderate numbers of mitotic figures. Other lobules consist of solid sheets of large cells with abundant cytoplasm containing small eosinophilic granules. They have small, hyperchromatic, eccentric nuclei. Foci of granular cells are interspersed between the basaloid cells with a continuous transition between these cell types. Formalin-fixed tissues of the tumor were examined by electron microscopy. Ultrastructural examination of granular cells revealed numerous pleomorphic, coalescing, partly membrane-bound granules. Granules contained amorphous and granular material of various electron density. Nuclei were located at the margin of the cells and indented by granules. Basal cell and appendage tumors are an important group of skin tumors in dogs and cats. Basal cell tumors are distinct undifferentiated epithelial cell tumors of the skin. In dogs, they appear frequently as solitary, firm, alopecic, dome-shaped or polypoid nodules. On average they are 1 to 2 cm in diameter. Predilection sites are the head and neck. The average age of affected animals is 6 to 9 years. They occur with increased frequency in Poodles, Cocker Spaniels, and mixed-breed dogs. The characteristic cell is the basaloid cell, a primitive, pluripotent cell which lacks intercellular bridges. Walder and Gross (1992) reclassify most of the basal cell tumors in dogs as trichoblastomas. Trichoblastomas have been defined in humans as benign hair germ tumors derived from trichoblastic epithelium. Trichoblastomas have no contiguity with the epidermis. Basal cell tumors and trichoblastomas are further classified based upon their predominant histologic pattern. In dogs, solid, garland or ribbon-like, sinusoidal, adenoid, cystic, and basosquamous growth patterns have been described. In 1982, a granular basal cell tumor was reported as a new subtype of basal cell tumors in dogs. In a survey of 150 basal cell tumors, Seiler (1982) found 3 cases of the granular subtype. Ultrastructural investigations revealed that the granules were lysosomes containing numerous intact and fragmented vesicles of undetermined origin. Similar observations have been made in granular cell Schwannomas, granular cell ameloblastomas (only in humans), and granular cell basal carcinomas (only in humans). AFIP Diagnosis. Haired skin: Granular basal cell tumor, Poodle-cross, canine. Conference Note. All conference participants diagnosed the presented mass as a granular basal cell tumor. Basal cell tumors are common in dogs and cats and are rare in other domestic animals. Primitive hair germinal cells are the cell of origin and give rise to cords and nests of neoplastic cells without significant follicular or sebaceous differentiation. Common sites of occurrence are the head and neck of dogs and head of cats. In the dog, basal cell tumors are almost universally benign, but basal cell carcinomas have been described in cats; reported features of malignancy include lymphatic invasion and metastasis. In cats, basal cell tumors are often cystic or solid, may be multiple, and are sometimes pigmented due to dendritic melanocytes scattered throughout the mass and melanin within neoplastic cells. Granulated cells of granular basal cell tumors typically have cellular borders that are more distinct than those of the common variants. In dogs, the cytoplasmic granules are reported to be PAS-positive and diastase resistant(1). The presented mass contains moderate numbers of PAS-positive cytoplasmic granules that are diastase sensitive. Granular basal cell tumors have not been reported in cats. Basal cell tumors can be induced in rats by a number of carcinogenic compounds, but spontaneous basal cell tumors are rare. Granular basal cell tumors have been reported in two rats. A recently reported palpebral granular basal cell tumor in a F344 rat had small numbers of PAS-positive, diastase sensitive, cytoplasmic granules(6). Contributor. Institut fur Pathologie, Tierarztliche Hochschule Hannover, Bunteweg 17, 30559 Hannover, Germany. References. 1. Seiler RJ: Granular basal cell tumors in the skin of three dogs: A distinct histopathologic entity. Vet Pathol 19:23-29, 1982. 2. Stannard AA, and Pulley LT: Basal cell and appendage tumors, pp 58-61. In: Moulton JE (ed): Tumors in Domestic Animals, 3rd ed. University of California Press, Berkeley-Los Angeles-London, 1990. 3. Walder EJ, and Gross TL: Neoplastic Diseases of the Skin - Trichoblastoma, p. 367-371. In: Gross, TL, Ihrke PJ, and Walder EJ (eds): Veterinary Dermatopathology: A Macroscopic and Microscopic Evaluation of Canine and Feline Skin Disease. Mosby-Year Book, Inc., St. Louis 1992. 4. Weib E, and Frese K: Tumors of the skin. In: International Histological Classification of Tumors of Domestic Animals. Bull. WHO 50:79-100, 1974. 5. Yager JA, Scott DW: Chapter 5, The Skin and Appendages. In: Jubb KVF, Kennedy PC, Palmer N (eds.): Pathology of Domestic Animals, 4th Edition. Academic Press, Vol. 1., pp. 713-715, 1993. 6. Yoshitomi K, and Boorman GA: Granular cell basal cell tumor of the eyelid in an F344 rat. Vet Pathol 31:106-108, 1994. International Veterinary Pathology Slide Bank Laser disc frame # 01210, 11801. Duane A. Belote Captain, VC, USA Registry of Veterinary Pathology* Department of Veterinary Pathology Armed Forces Institute of Pathology (202)782-2615; DSN: 662-2615 Internet: Belote@email.afip.osd.mil * The American Veterinary Medical Association and the American College of Veterinary Pathologists are co-sponsors of the Registry of Veterinary Pathology. The C.L. Davis Foundation also provides substantial support for the Registry.