AFIP Wednesday Slide Conference - No. 26
April 7, 1999

Conference Moderator: Dr. Michael Goldschmidt, Diplomate, ACVP
Laboratory of Pathology, School of Veterinary Medicine
University of Pennsylvania
Philadelphia, PA 19104
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Case I - 512132 (AFIP 2633363)

Signalment: Approximately two-year-old, male, ACI/Seg Hsd, rat.
History: This male rat was a control animal in a carcinogenicity study. Approximately 2 weeks prior to the scheduled necropsy, an approximately 0.4 cm round dermal mass was palpated in the dorsal lumbar area. The animal survived to the scheduled study termination, when it was euthanatized and a necropsy performed.
Gross Pathology: At gross examination, the animal was noted to be thin and had an approximately 1 cm diameter, raised, skin nodule with a roughened and crusty surface.
Laboratory Results: None.
Contributor's Diagnosis and Comments: Skin: Neoplasia, squamous cell carcinoma; undifferentiated sarcoma.
This combination of adjacent neoplasms is consistent with a so-called "collision tumor", generally defined as two histologically distinct neoplasms simultaneously arising adjacent to each other in the same organ.1 On microscopic examination, both tumors generally have a sharp, delineated interface without evidence of interdigitating components. Specific case reports of collision tumors have been described in the human medical literature, specifically localized to skin2, stomach, esophagus, liver, lung, uterus, cervix, etc. There are also several recent descriptions specifically describing the collision of non-Hodgkin's lymphoma and Kaposi's sarcoma in immunosuppressed HIV-positive individuals.3,4 However, descriptions of collision tumors are rare in the comparative literature, with a single description in the mouse.1 This particular mouse was 55 weeks of age, had been treated with urethane at 5 weeks of age, and had a mammary carcinosarcoma in collision with a lymphosarcoma.
The pathogenesis of collision tumors is poorly understood, largely due to the sporadic nature of the tumors and lack of an animal model. The true incidence of such neoplasms may never be appreciated since gross features of these masses may not be indicative of such a formation.
AFIP Diagnoses: Haired skin: Squamous cell carcinoma and fibrosarcoma ("collision tumor"), ACI/Seg Hsd rat, rodent.
Conference Note: Participants generally agreed with the contributor, identifying abutting epithelial and mesenchymal neoplasms without an intervening transition zone. For the epithelial neoplasm, a strong resemblance to keratoacanthoma was noted, but infiltrative growth, high mitotic rate and nuclear atypia supported low grade malignancy. The spindle cell neoplasm was considered to be consistent with a fibrosarcoma.
In order to obtain opinions of those experienced in classification of rodent tumors, the histologic sections were studied in consultation with pathologists of Covance Laboratories Inc., Vienna, Virginia. They favored the contributor's diagnosis of squamous cell carcinoma (SSC) for the epithelial neoplasm, and suspected that it may have arisen within a keratoacanthoma. They considered the spindle cell neoplasm consistent with fibrosarcoma, but felt that immunohistochemical or ultrastructural studies were needed to conclusively determine whether or not this lesion represented a separate neoplasm (fibrosarcoma) or spindle cell differentiation of the SCC.
Immunohistochemistry performed at the AFIP revealed the epithelial cells to be keratin positive and vimentin negative, and the spindle cells to be vimentin positive and keratin negative. Further, a Masson's trichrome stain demonstrated thin, aniline blue-positive strands and wisps of material consistent with collagen separating the spindle cells. It was concluded that the lesion represents a "collision" between a fibrosarcoma and a squamous cell carcinoma that probably arose in a keratoacanthoma.
Contributor: Merck Research Laboratories, Department of Safety Assessment, West Point, PA 19486.
1. Maeda H, Ozaki K, Nakajima H, Narama I: Spontaneous combination (collision) tumor in an ICR mouse. Lab Anim Sci 41:632-634, 1991.
2. Pierand GE, Fazaa B, Henry F, Kamoun MR, Pierard-Franchimont C: Collision of primary malignant neoplasms in the skin: The connection between malignant melanoma and basal cell carcinoma. Dermatology 194:378-379, 1997.
3. Ko AH, Thomas DL, Gallant JE: 1995. Non-Hodgkin's lymphoma and Kaposi's sarcoma causing cavitary lung lesions in a patient with AIDS: An HIV-associated collision tumor. AIDS 9:1195-1197, 1995.
4. Tunc M, Simmons ML, Char DH, Herndier B: Non-Hodgkin lymphoma and Kaposi sarcoma in an eyelid of a patient with acquired immunodeficiency syndrome. Arch Ophthal 115:1464-1466, 1997.
5. Asano S, et al.: Morphological characterization of spindle cell tumors induced in transgenic mouse skin. Toxicol Pathol 26:512, 1998.
6. Hirose M: Squamous cell carcinoma, skin, rat. In: ILSI's Monographs on Pathology of Laboratory Animals: Integument and Mammary Glands, Jones TC, Mohr U, Hunt RD, eds., pp. 25-30, Springer-Verlag, New York, 1989.

Case II - W7826 (AFIP 2642327)

one 2x2 gross color photo transparency
Signalment: Two-year-old, male, white-tailed deer (Odocoileus virginianus).
History: A hunter-killed, 4-point, white-tailed deer was presented to Mississippi Department of Wildlife and Fisheries because of an abnormal hair coat.
Gross Pathology: The deer was submitted in field-dressed condition. Internal organs were submitted separately. Nutritional condition was good. The overall skin coloration was darker than normal and had irregular dark gray on tan mottling. There was a severe alopecia over the trunk and proximal limbs with relative sparing of the tailhead, distal limb, and sternal areas. A 3 cm x 3 cm, X-shaped laceration extended through the left dorsal trunk, the left diaphragmatic lung lobe, the diaphragm, and the liver. This caused moderate local hemorrhage, pulmonary hemorrhage, and extensive abdominal hemorrhage. Scattered, multifocal areas of consolidation were found along the caudal borders of the diaphragmatic lung lobes. A focal area of catarrhal rhinitis was found over the right ventral turbinate. The liver had a moderately accentuated lobular pattern and was slightly tough. All endocrine organs were within normal limits.
Laboratory Results: Analysis of the liver yielded the following results:

Se: 0.072 ppm (normal: 0.25-0.46); Mo: 0.310 ppm (cattle normal: 0.14-1.4); Cu: 108 ppm (cattle normal: 25-100); Zn: 15.3 ppm (cattle normal: 25-100); Pb: 0.049 ppm (cattle normal: <0.5); and As: 0.015 ppm (cattle normal: <0.4).
Contributor's Diagnosis and Comments: Follicular dystrophy.

Syndrome: Toothpaste hair disease of white-tailed deer.
The skin has a distinct abnormality of hair formation. Initial hair formation in the inferior portion of the hair follicle and the hair bulb is apparently normal. However, there is failure of additional keratinization as the hair progresses up the follicle. The medullary cavity tends to collapse and become compact, eosinophilic, and hyaline. This results in a markedly attenuated hairshaft, which tends to break off shortly after emergence. In other follicles, this malformed hairshaft coils within the infundibular follicle and does not emerge from the surface. Mild to moderate hyperkeratosis is seen in the superficial epidermis. Some sections have a mild dermatitis. Otherwise, all other dermal structures are within normal limits.
This represents one of the few congenital follicular dystrophies recognized in veterinary medicine. Other examples include nude mice, Chinese crested dogs, Rhino mice, and murine pelis defluvium. It qualifies as a follicular dystrophy because of the abnormal hair development despite a morphologically normal hair follicle. This contrasts with the more common follicular dysplasias (eg. color-mutant alopecia), in which cellular abnormalities in the hair follicles are associated with abnormal hairs. This condition in deer has not been reported in the literature and has only been mentioned briefly in presentations.1 It has been seen in both Mississippi and Great Lakes area deer so it is likely widespread, though uncommon, throughout the white-tailed deer population. The underlying defect is not known. As is common in Mississippi animals, this deer was deficient in selenium. Selenium toxicosis can cause hair abnormalities, but deficiencies have not been associated with hair changes. This deer is also marginally deficient in zinc based on our normal values for cattle. However, the abnormalities seen in this deer are not compatible with zinc deficiency.
AFIP Diagnosis: Haired skin: Follicular dystrophy, diffuse, white-tailed deer (Odocoileus virginianus), cervid.
Note: Some sections contain a focal plant foreign body granuloma.
Conference Note: Participants identified histomorphological changes affecting hair shafts similar to those noted by the contributor. Coiled and fragmented hair shafts are found within hair follicles. Follicles are thickened, misshapen, and sometimes "S"-shaped, as they conform to the deformed hair shafts. The keratin that forms the cortex of the hair shaft appears somewhat thinner than normal. Within the superficial dermis, there is scattered lymphoplasmacytic inflammation. Participants identified vacuolated hair shafts near the base of follicles and interpreted this finding as a normal histologic feature when compared to sections of "normal" deer skin.
This case was also studied in consultation with the Department of Dermatopathology. They noted several similar follicular dystrophies in humans, including deficiency disorders, some of which are inherited, and acquired disorders of the hair shaft. Among the deficiency disorders mentioned were Menke's kinky hair syndrome, an inherited copper deficiency syndrome; trichothiodystrophy, a deficiency of sulfur; and various amino acid deficiencies, including trichorrhexis invaginata seen in Netherton's syndrome. Other human syndromes cited were acquired progressive kinking of the hair, most likely an androgen associated disorder, and "wooly hair nevus", a focal hair shaft deformity affecting the scalp.
Contributor: Mississippi State University, College of Veterinary Medicine, PO Box 9825, Mississippi State, MS 39762.

1. Dunstan RW: An opinionated approach to diseases of the hair follicle. Proceedings 45th Annual Meeting American College Veterinary Pathologists: pp. 187-198, 1994.
2. Whiting DA: Structural abnormalities of the hairshaft. J Amer Acad Dermatol 16:1-25, 1987.

Case III - 10570 (AFIP 2640143)

one 2x2 gross color photo transparency
Signalment: Seven-year-old, castrated male, Dandie Dinmont Terrier dog.
History: There was acute onset of bilaterally symmetrical skin lesions following three days of inappetence. The dog's environment had not changed, and he had not been exposed to any type of drug. The skin lesions have remained static for a month (to date), and other than the initial three day period of inappetence, the dog has otherwise been normal.
Gross Pathology: The skin lesions were erythematous, vesiculopapular with crusts, and roughly annular. Sites affected included mucocutaneous junctions of eyes, mouth and anus, inner pinnae, axillae, chest, groin, forearms and back.
Laboratory Results: Complete blood cell count revealed a normal total leukocyte count of 4.7 x 109 cells/L with a left shift of 0.235 x 109 cells/L (RR <0.200 x 109 cells/L). Serum biochemistries and urinalysis were normal.

Contributor's Diagnosis and Comments: Erythema multiforme of unknown etiology.
Histological findings of lymphocytic interface dermatitis, lymphocyte satellitosis around dying keratinocytes, and single keratinocyte necrosis in all layers of the epidermis is virtually diagnostic of erythema multiforme, especially when there is a history of acute and symmetrical, cutaneous eruptions. Skin lesions are variable (as the term multiforme implies), including erythematous macules and papules that spread peripherally and clear centrally forming annular to arciform patterns, urticarial plaques, vesicles and bullae, or any combination thereof. Mucocutaneous junctions, footpads, nose and ventrum (especially the groin) are typically affected. Animals are not usually systemically ill.
Erythema multiforme is an uncommon, acute, usually self-limiting, skin eruption. Most cases of documented erythema multiforme in small animals are the result of a drug eruption; concurrent infection, neoplasia, connective tissue diseases and unknown causes are other initiators. Recovery is expected within 2-16 weeks of onset of lesions if the initiating drug is removed or the underlying infection is treated. Lesions may progress if the underlying cause cannot be identified and removed. The pathogenesis of this disease is not well understood.
AFIP Diagnosis: Haired skin: Dermatitis, interface, chronic-active and eosinophilic, focally extensive, moderate, with transepidermal apoptotic keratinocytes, lymphocytic satellitosis, orthokeratotic hyperkeratosis, and epidermal hyperplasia, Dandie Dinmont Terrier, canine.
Conference Note: Erythema multiforme (EM) is a cutaneous reaction seen uncommonly in the dog and rarely in cats. The disease appears to be a hypersensitivity response and has been associated with certain drugs, infections, and neoplasia. As noted by the contributor, the condition in animals is most commonly associated with the administration of drugs, including sulfonamides, cephalosporins, levamisole, and topical insecticidal rinses.4 EM has also been associated with staphylococcal infections. Other cases are idiopathic.
Differential diagnosis for the gross lesions includes demodicosis, bacterial folliculitis, dermatophytosis, urticaria, bullous autoimmune diseases, and other pustular disorders. When severe, EM may also grossly resemble systemic lupus erythematosus, burns, and vasculitis. Toxic epidermal necrolysis is closely related to and may be part of the spectrum of EM. Histopathological examination usually allows differentiation of these entities.
Contributor: Western College of Veterinary Medicine, 52 Campus Drive, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4.
1. Gross TL, Ihrke PJ, Walder EJ: Necrotizing diseases of the epidermis. In: Veterinary Dermatopathology: A Macroscopic and Microscopic Evaluation of Canine and Feline Skin Disease, Gross TL, Ihrke PJ, Walder EJ, eds., pp. 41-42, Mosby Year Book, Saint Louis, MO, 1992.
2. Yager JA, Wilcock BP: Lymphoplasmacytic interface dermatitis. In: Color Atlas and Text of Surgical Pathology of the Dog and Cat: Dermatopathology and Skin Tumors, Yager JA, Wilcock BP, eds., vol. I, pp. 93-94, Mosby-Year Book Europe Limited, London, England, 1994.
3. Scott DW, Miller WH, Griffin CE: Immunologic skin diseases. In: Muller & Kirk's Small Animal Dermatology, Scott DW, Miller WH, Griffin CE, eds., 5th ed., pp. 595-596, WB Saunders Company, Philadelphia, PA, 1995.
4. Lewis DT: Life-threatening dermatoses. Comp Contin Med Ed Small Anim Pract 20:271-282, 1998.

Case IV - 96-9002 (AFIP 2641857)

96-9002: BALB/cJ X CAST/Ei F2 - ichq/ichq, male, 8 days of age.
96-9002: BALB/cJ X CAST/Ei F2 - ichq/ichq, male, 6 days of age.
History: Both mice submitted were F2 generation from a cross between the inbred strains BALB/cJ (carrying the ichq mutant gene in a heterozygous state) and CAST/EiJ +/+. This cross was set up as part of a gene mapping strategy. Although the mice could easily be phenotyped by gross observations, we routinely collect the primary organ involved, in this mutation the skin, and evaluate it by histology. This provides verification if there are any concerns with the genotyping, but also permits identification of minor phenotype variations that potentially permit concurrent mapping of background modifier genes.
Gross Pathology: Both mutant mice (ichq/ichq) were runted compared to their litter mate controls (+/? Or +/ichq). Mutant mice had thickened skin that was sticky to the touch. Various degrees of white scales were present on the surface that tended to crack and form fissures over joints.

Laboratory Results: Mice were genotyped by PCR by simple sequence length polymorphisms (SSLP) analyses using MIT microsatellite markers. Genowide scans revealed linkage on the proximal end of mouse Chromosome18.
Contributor's Diagnosis and Comments: Skin, type II harlequin ichthyosis.

Etiology: Autosomal recessive mutation on mouse Chr. 18.
This mouse mutation has many similarities to human harlequin ichthyosis and is most similar to the type II form. On the BALB/cJ inbred background, the mice are clinically indistinguishable at birth until 5 days of age when the phenotype becomes evident. This corresponds to the developmental point when hair shafts emerge from follicles. The homologous point in development in humans is about 20-24 weeks of gestation, the earliest point of detection of harlequin ichthyosis in humans. On the BALB/cJ background, most mice are dead by 10-12 days of age. Human neonates die shortly after birth as well.
In both species the epidermis is thickened. A prominent cuff of cornified cells surrounds emerging dystrophic follicles, a feature best assessed by scanning electron microscopy where three-dimensional visualization is best. Changes in keratin gene expression and other terminal differentiation proteins of the epidermis mimic the human type II disease. At the ultrastructural level, there are also many similarities. However, the lamellar granules in the stratum corneum are defective to various degrees in the mouse, but not to the degree that they are in humans.
Unlike the human disease and other forms of ichthyosis in domestic animals, stable colonies are available of tested breeders, and mice can be obtained for research purposes from The Jackson Laboratory through the Mutant Mouse Resource.
AFIP Diagnoses:
1. Haired skin: Hyperplasia, infundibular and epidermal, diffuse, moderate, with compact orthokeratotic hyperkeratosis and acanthosis, BALB/cJ X CAST/Ei F2 - ichq/ichq mouse, rodent.
2. Haired skin: Dermatitis, superficial, subacute and neutrophilic, diffuse, moderate.
Conference Note: Ichthyosis represents a group of inherited disorders that are expressed clinically as excessive keratin accumulation (hyperkeratosis) and results in fish-like scales on the surface of the skin. Four primary types occur in humans: ichthyosis vulgaris (autosomal dominant or acquired disease), lamellar ichthyosis (autosomal recessive), congenital ichthyosiform erythroderma (autosomal recessive), and X-linked ichthyosis. With the exception of ichthyosis vulgaris, which may begin in early childhood, disease is present at or near birth. The disease in domestic animals bears closest resemblance to lamellar ichthyosis in humans and is inherited as an autosomal recessive trait. Harlequin ichthyosis in humans is considered to be the most severe form of nonbullous, congenital ichthyosiform erythroderma/lamellar ichthyosis.
Congenital ichthyosis-like disease has been reported in several domestic animal species, including cattle, llamas, and dogs. A form of ichthyosis with autosomal recessive inheritance has been described in chickens (not harlequin ichthyosis). Abnormalities in keratinocyte adhesion in the stratum corneum are thought to be responsible for the defective mechanisms in desquamation that result in retention of abnormally formed scales on the skin in humans and animals. In X-linked ichthyosis of humans, there is a deficiency of steroid sulfatase, an enzyme that serves to remove proadhesive cholesterol sulfate secreted in the intercellular spaces of keratinocytes. Accumulation of nondegraded cholesterol sulfate causes persistent cell to cell adhesion in the stratum corneum, hindrance of desquamation, and retention of scales.
The dermatitis identified in the submitted section of skin was interpreted as a secondary change to primary congenital ichthyosis.
Contributor: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609.
1. Sundberg JP, Boggess D, Hogan ME, Sundberg BA, Rourk MH, Harris B, Johnson K, Dunstan RW, Davisson MT: Harlequin ichthyosis (ichq): A juvenile lethal mouse mutation with ichthyosiform dermatitis. Am J Pathol 151:293-310, 1997.
2. Scott DW: Congenital and hereditary diseases. In: Large Animal Dermatology, Scott DW, ed., page 339, WB Saunders, Philadelphia, PA, 1988.
3. Cotran RS, Kumar V, Collins T: The skin. In: Robbins Pathologic Basis of Disease, Cotran RS, Kumar V, Collins T, eds., 6th edition, page 1193, WB Saunders, Philadelphia, PA, 1999.
4. Scott DW, Miller WH, Griffin CE: Congenital and hereditary defects. In: Muller & Kirk's Small Animal Dermatology, Scott DW, Miller WH, Griffin CE, eds., 5th edition, pp. 745-747, WB Saunders Company, Philadelphia, PA, 1995.
5. Gross TL, Ihrke PJ, Walder EJ: Hyperkeratotic diseases of the epidermis. In: Veterinary Dermatopathology: A Macroscopic and Microscopic Evaluation of Canine and Feline Skin Disease, Gross TL, Ihrke PJ, Walder EJ, eds., pp. 98-100, Mosby Year Book, Saint Louis, MO, 1992.
WSC Coordinator:
Ed Stevens, DVM
Captain, United States Army
Registry of Veterinary Pathology*
Department of Veterinary Pathology
Armed Forces Institute of Pathology
(202)782-2615; DSN: 662-2615
* 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.
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