Xanthomatous Keratitis, Disseminated Xanthomatosis, and ...

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Xanthomatous Keratitis, Disseminated Xanthomatosis, and Atherosclerosis in Cuban Tree Frogs 

J. L. Carpenter, A. Bachrach, Jr., D. M. Albert, S. J. Vainisi and M. A. Goldstein 

Vet Pathol 1986 23: 337 

DOI: 10.1177/030098588602300320 

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Vet. Pathol. 23:337-339 (1986) 

Xanthomatous Keratitis, Disseminated Xanthomatosis, and 

Atherosclerosis in Cuban Tree Frogs 

J. L. CARPENTER, A. BACHRACH JR., D. M. ALBERT, 

S. J. VAINISI, AND M. A. GOLDSTEIN 

Xanthomas are white or yellow non-neoplastic papules, 

nodules, or plaques that contain excess lipids and often cholesterol 

esters. Microscopically they are characterized by aggregates 

of lipid-laden macrophages with abundant foamy 

cytoplasm or by cholesterol granulomas. Veterinary literature 

contains reports of xanthomas in mammals, birds, and 

a reptile.3.5.6,8,1L-15 Lipid keratopathy characterized by lipid, 

cholesterol, and cholesterol ester deposits in one or both eyes 

occurs in adult dogs4 

Cuban three frogs inhabit the West Indies, and from Cuba 

they spread to southern Florida on ships carrying vegetables. 

One frog in this report was a vagabond that traveled to Boston 

in a lettuce crate shipped from Florida and upon discovery 

was given to the Museum of Science. These nocturnal frogs 

have toe suction disc and a body length up to 12 cm. Their 

skin secretion when in contact with human mucous membranes 

will elicit pain. In southern Florida, they have been 

found in the Everglades, lakes, ponds, cisterns, and in other 

moist, shady areas. Their natural diet consists of insects, 

spiders, and other smaller tree frogs. 

An adult female Cuban tree frog residing at the Museum 

of Science in Boston, Massachusetts, and fed on day-old mice 

developed an apparently painless, white, stromal infiltrate in 

the cornea adjacent to the right temporal limbus. No corneal 

or conjunctival exudate accompanied the lesion, and the left 

eye was normal. Over a 2-month period, the corneal lesion 

developed into an elevated mass that involved the temporal 

third of the cornea and extended into and thickened the 

adjacent sclera. Therapy with a topical broad-spectrum antibiotic 

was unsuccessful, and the eye was enucleated. 

About 2 months later, similar lesions were seen at the nasal 

and temporal areas of the left cornea. A parenteral injection 

of 20 units of vitamin A as well as daily oral administration 

of multiple vitamins failed to halt the progression of the 

lesions. Within 1 month, all but the central cornea was involved. 

Cultures of cornea scrapings isolated Aeromonas hydrophila, 

Pseudomonas aeruginosa, and acid-fast bacilli, but 

were negative for fungi. Lethargy and decreased mobility 

prompted another general examination. Subcutaneous nodules 

were evident over the extensor surfaces of the stifles and 

hocks. Joint movement was not noticeably restricted therefore 

it was concluded that decreased motor activity was due 

to blindness or to systemic disease. The frog was humanely 

killed and necropsied. 

At the Lincoln Park Zoo in Chicago, Illinois, two Cuban 

tree frogs that were fed crickets and meal worms had bilateral 

corneal dystrophies diagnosed by biomicroscopic examination 

as cholesterosis. Blood and eyes were collected at euthanasia 

for lipid and cholesterol analyses. Necropsies were 

performed to determine if they too had disseminated xanthomas. 

Disseminated xanthomas were found only in the frog from 

the Museum of Science, Boston. They occurred in the cornea 

and sclera, penarticular soft tissues over extensor surfaces 

(Fig. l), digital pads, brachial, lumbar, and femoral nerves 

(Fig. 2), ovaries, lung, gastric submucosa, brain, and pituitary. 

Distinct xanthomas, as well as diffuse regions of xanthomatous 

inflammation, contained numerous cholesterol 

crystals seen by polarization of frozen sections and as lenticular 

clefts seen in paraplast-embedded sections. Neutral 

lipids were abundant, occumng as large globules and as distinctly 

intracytoplasmic droplets with oil-red-0 stains. In 

addition, there were many foamy macrophages; occasional 

multinucleated giant cells, melanocytes/melanophores, mast 

cells; and a few penvenular lymphocytic infiltrates. Fibrosis 

was prominent with abundant intercellular matrix that failed 

to stain with PAS and stained very lightly with alcian blue. 

Mineralization within the xanthomas was infrequent. Acidfast 

bacilli, hemosiderin, and products of phagocytized elastic 

fibers sometimes present in foamy macrophages were absent. 

The corneal xanthomas of both eyes were similar grossly 

and microscopically (Figs. 3, 4). Extracellular cholesterosis, 

together with lipid accumulation that stained with oil-red-0, 

and the ensuing granulomatous reaction produced the white 

opaque lesions of the cornea and sclera that extended into 

the ciliary body. The ins, choroid, retina, vitreous, and lens 

were normal. 

The brain was largely replaced by a xanthoma that apparently 

developed in the region of the third ventricle, and 

a smaller xanthoma in the hypothalamus extended into the 

neuropil and pituitary (Fig. 5). The liver and spleen were 

devoid of xanthomas, but both contained abundant fat that 

stained with oil-red-0. Neutral fat in the hepatocytes accounted 

for about half of the liver mass. Mononuclear phagocytes 

of the splenic red pulp contained fat, hemosiderin, and 

melanin. 

Atherosclerosis involved both the aorta and femoral arteries 

(Fig. 2). Skeletal muscles of the limbs exhibited motor 

unit atrophy and small xanthomas associated with nerves as 

well as foci of interstitial penvascular lymphocytes. The epithelial 

cells of the renal proximal convoluted tubules contained 

an abundance of ferric iron. 

No lesions were found in the ears, skin, nose, tongue, intestines, 

thyroid, pancreas, adrenals, oviduct, vertebrae, or 

spinal cord. 

The two frogs from the Lincoln Park Zoo had corneal 

lesions similar to those in the frog from the Museum of 

Science, but no xanthomas or atherosclerosis were found. 

One frog also had a small cholesterol granuloma (cholesteatoma) 

of the choroid plexus of the fourth ventricle. Both 

frogs had geologic stones in the stomach and gastrointestinal 

nematodes. Serum cholesterol and lipid values were essentially 

the same for the two frogs (cholesterol = 196 and 20 1 

mg/dl, triglycerides = 84 and 94 mg/dl, high-density lipo- 


338 Brief Communications 

Fig. 1. Periarticular xanthomas over extensor surfaces of the knee (right center) and hock with skin removed. Cuban 

tree frog. 

Fig. 2. Xanthomatous and granulomatous sciatic neuritis with many cholesterol clefts. Atherosclerosis of adjacent 

femoral artery (bottom). HE. 

Fig. 3. Xanthomatous keratitis and scleritis involving three-fourths of the right eye of a Cuban tree frog. (Courtesy of 

Dr. Gustavo Aguirre.) 

Fig. 4. Cornea. Numerous cholesterol clefts, large foamy macrophages, and blood vessels obscure the substantia propria. 

HE. 

proteins = 22 and 25, and low-density lipoproteins = 62 and 

65 mg/dl). 

In humans, xanthomas may occur in acquired disorders 

such as hypercholesterolemia of liver disease and lipemia of 

diabetes mellitus and pancreatitis as well as in familial dysbetalipoproteinemia, 

hypercholesterolemia, and lipoprotein 

lipase deficiency.' Xanthomas also accompany some malignancies, 

especially myeloproliferative diseases and lympho- 

sarcoma.Io Skin diseases of infants and adults that have a 

primary histiocytic phase before granuloma or xanthoma 

forms include juvenile xanthogranuloma and xanthoma disseminatum.I6 

Xanthoma disseminatum of man, a rare, non-familial disorder 

of unknown etiology, is often characterized by a triad 

of diabetes insipidus, widespread xanthomas, and xanthomatous 

involvement of the upper respiratory tract.9 Lesions 


Brief Communications 339 

of crickets and earth worms. Future study of the Cuban tree 

frog as a potential animal model for xanthomatosis, xanthomatous 

keratitis, or atherosclerosis requires nutrition and 

genetic investigation, and analysis of serum cholesterol, lipid, 

and lipoprotein of normal and affected frogs. 

Fig. 5. Mid-longitudinal section through cranium, brain, 

and pituitary (arrow) of a Cuban tree frog. Half of the brain 

is replaced by a multinodular xanthoma (center); a smaller 

xanthoma in the hypothalamus extends posteriorly into the 

pituitary. PAS. 

occur as papules, nodules, or plaques in mucous membranes, 

sclera, brain, pituitary, and flexor surfaces of the extremities.2 

Histiologic features are a secondary accumulation of lipids 

and cholesterol within those histiocytes in patients with norm~lipemia.~ 

The etiology of the generalized xanthomas and of the xanthomatous 

keratitis in the Cuban tree frogs is not determined. 

The distribution of the disseminated xanthomas, except that 

extensor surfaces are involved rather than flexor surfaces, 

resembles that of xanthoma disseminatum in man. Also similar 

is the lack of spontaneous resolution of the lesions. Microscopically 

the xanthomas in the frogs are dissimilar from 

human xanthoma disseminatum and can be distinguished 

by prominent fibrosis, including both collagen and elastic 

fibers, and by lack of multinucleated foam cells of Touton 

type.' The multinucleated cells in the frog lesions appear to 

be a response to cholesterol crystals. Autophagocytosis of 

iron and elastin, reported in some human patients with xanthoma 

disseminatum, was also absent in the frog lesions. 

Although not substantiated, the xanthomas of the hypothalamus 

and pituitary, like those in human xanthoma disseminatum, 

may have caused diabetes insipidus in the frog. 

Blood cholesterol and lipid values did not indicate lipemia 

nor was there morphologic evidence in the pancreas, liver, 

thyroid or kidneys of primary causes of lipemia in the frogs. 

Iron deposits in the renal proximal tubular epithelium appeared 

to be unrelated to the pathogenesis of the xanthomatous 

lesions. 

The xanthomas as well as the atherosclerosis in one frog 

were likely caused by some common factor(s) concerning 

nutrition. The diet consisted solely ofday-old mice. The milk 

contained within the stomachs of those mice should also be 

considered as part of that frog's diet. None of the eight female 

Cuban tree frogs, ranging from 1 to 52 months of age, that 

were necropsied at the Philadelphia Zoo had xanthomatous 

lesions (personal communication). Their daily diet consisted 

Addendum 

Two Cuban tree frogs photographed by Dr. Gustavo Aguirre 

at the Philadelphia Zoo had ocular lesions grossly similar to 

those in the three frogs reported here. This evidence suggests 

that xanthomatous keratitis of the Cuban tree frog is most 

likely not a rare disease. 

References 

1 Ackerman AB: Histologic Diagnosis of Inflammatory 

Skin Diseases, p. 469. Lea & Febiger, Philadelphia, 1978 

2 Allen AC: Skin. In: Pathology, ed. Anderson, 6th ed., 

p. 1643. The CV Mosby Company, St. Louis, 1971 

3 Chastain CB, Grahan CL: Xanthomatosis secondary to 

diabetes mellitus in a dog. J Am Vet Med Assoc 172: 

1209, 1978 

4 Dice PF The canine cornea. In: Veterinary Ophthalmology, 

ed. Gelatt, p. 365. Lea & Febiger, Philadelphia, 

1981 

5 Fawcett J, Dermmaray SY, Altman N: Multiple xanthomas 

in a cat. Feline Pract 7(3):31, 1977 

6 Haley PJ, Norrdin RW: Periarticular xanthomatosis in 

an American Kestrel. J Am Vet Med Assoc 181: 1394, 

1982 

7 Have1 R J: Disorders of lipid metabolism. In: Cecil Textbook 

of Medicine, ed. Wyngaarden and Smith, 16th ed., 

p. 1084. WB Saunders, Philadelphia, 1982 

8 Jones TC, Hunt RD: Veterinary Pathology, 5th ed., p. 

1682. Lea & Febiger, Philadelphia, 1983 

9 Kumakiri M, Sudoh M, Wivra Y: Xanthoma disseminatum, 

report of a case with histological and ultrastructural 

studies of skin lesions. J Am Acad Dermatol4:29 1, 

1981 

10 Murphy GF, Kwan TH, Mihm MC Jr: The skin. In: 

Pathologic Basis of Disease, ed. Robbins, Cotran, and 

Kumar, 3rd ed., p. 1270. WB Saunders, Philadelphia, 

1984 

11 Peckham MC: Xanthomatosis in chickens. Am J Vet 

Res 16:580, 1955 

12 Petrak ML, Gilmore CE: Neoplasms. In: Diseases of 

Cage and Aviary Birds, ed. Petrak, 2nd ed., p. 6 10. Lea 

& Febiger, Philadelphia, 1982 

13 Ryan M J, Whitney GD: Xanthoma in a gopher snake. 

VMISAC 75503, 1980 

14 Ridgway RL: Oral xanthoma in a budgerigar, Melopsittacus 

undulatus (a case report). VM/SAC 72:266, 1977 

15 Sanger VL, Lagace A: Avian xanthomatosis. Etiology 

and pathogenesis. Avian Dis 10:103, 1966 

16 Winkelmann RK, Kossard S, Fraga S: Eruptive histiocytoma 

of childhood. Arch Dermatol 116:565, 1980 

Request reprints from Dr. J. L. Carpenter, Department of 

Pathology, Angel1 Memorial Animal Hospital, 350 S. Huntington 

Ave., Boston, MA 02 130 (USA).

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