AFIP Wednesday Slide Conference - No. 26
April 7, 1999
- Conference Moderator: Dr. Michael Goldschmidt, Diplomate,
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
- 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,
- 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,
- 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
- 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
- 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
- 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
- AFIP Diagnosis: Haired skin: Follicular dystrophy,
diffuse, white-tailed deer (Odocoileus virginianus), cervid.
Note: Some sections contain a focal plant foreign body
- 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"
- 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
- Contributor: Mississippi State University, College
of Veterinary Medicine, PO Box 9825, Mississippi State, MS
- 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
- 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
- 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,
- 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
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
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,
- 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
- 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,
- 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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