Clinical evaluation of etretinate for the treatment of canine solar-induced squamous cell carcinoma and preneoplastic lesions

Clinical and laboratory studies Clinical evaluation of etretinate for the treatment of canine solar-induced squamous cell carcinoma and preneoplastic lesions Stanley Leon Marks, BVSc,a Mitchell Darius Song, DVM,a Anthony Albert Stannard, DVM, PhD,b and Helen Trevor Power, DVMa

Davis, California Background: Tumors of the skin and subcutaneous tissue account for 30% of all canine neoplasms. Canine solar-induced squamous cell carcinoma (SCC) is the most frequently reported canine cutaneous neoplasm. Objective: The purpose of this study was to provide preliminary observations on the safety and efficacy of etretinate for the treatment of solar-induced SCC and associated preneopIastic lesions in dogs. Methods: Etretinate was administered to 10 dogs at 1 mg/kg twice daily for a minimum of 90 days. Results: Clinically, two dogs showed complete resolution of their preneoplastic lesions, three dogs had partial responses, two dogs maintained stable disease, and three dogs showed progression of lesions after 90 days of etretinate administration. Three dogs showed histologic improvement, four dogs showed no changes, and three dogs showed evidence of progressing SCC. Treatment-related biochemical abnormalities included reversiblehypertriglyceridemia and transient serum liver enzyme elevations in three dogs. Conclusion: These preliminary findings suggest that etretinate, at the dosage administered, may provide therapeutic efficacy for solar-induced preneoplastic lesions in the dog, particularly for those multifocallesions not easily managed by local methods of therapy. (1 AM ACAD DERMATOL 1992;27:11-6.)

Tumors of the skin and subcutaneous tissue are the most common tumors of dogs, and account for 30% of all canine neoplasms. 1 Squamous cell carcinoma (SeC) is the most frequently reported malignant epithelial neoplasm in the dog. 2 Long-term exposure to sunlight has been shown to contribute to the development of these tumors in lightly pigmented dogs. 2-5 Current treatments of canine solarinduced sec include surgical excision, external beam radiation therapy, or both. I, 6 Small superfi· cial tumors can be treated with cryosurgery or hyperthermia, but recurrences, new tumors, or both are common. I, 6 In addition, local forms of therapy From the Veterinary Medical Teaching Hospital,· and the Department of Medicine,b University of California, Davis. Supported in part by a grant from the Companion Animal Laboratory, University of California, Davis. Accepted for publication Jan. 14, [992. Reprint requests: Stanley L. Marks, BVSc, University of California, Davis, VMTH, Davis, CA 95616

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have limited value because of the multifocal distribution of sunlight-associated lesions in the dog. eisplatin7 and 5-fiuorouraci16 have been administered intralesionally and systemically; however, administration of these drugs has had limited therapeutic benefit, and both drugs have potential side effects. Etretinate, a synthetic retinoid, has been shown to be of benefit in human patients for the treatment of preneoplastic conditions such as xeroderma pigmentosum8 and cutaneous neoplasms such as mycosis fungoides, basal cell carcinoma, and see.9-!1 The purpose of this study was to determine the therapeutic benefit of etretinate in canine solar-induced sec and preneoplastic lesions and to identify any drug-related toxicities.

MATERIAL AND METHODS Ten dogs with a histologic diagnosis of solar-induced

sec and/or associated preneoplastic lesions were evaluated. Dogs selected for study had no other significant medical problems, normal renal and hepaticfunction, and normal serum triglyceride levels. Pregnant or intact

11

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12 Marks et al.

ratory tests were repeated monthly during the trial. Pretrial and posttrial skin biopsy specimens were examined and graded in a blinded fashion by a veterinary dermatopathologist (A. A. S). The histologic response was assessed according to the following categories: (1) Epidermal hyperplasia: acanthosis of the epidermis with hypergranulosis; (2) epidermal dysplasia: disordered appearance ofthe keratinocytes in the epidermis without atypia; (3) carcinoma in-situ: disorganization of epidermal maturation and cellular atypia, but no evidence ofdermal invasion; (4) see level 1:dermal invasion to the level ofthe sebaceous glands; (5) sec level 2: dermal invasion to the level of the apocrine sweat glands; (6) see level 3: invasion through the dermis to the subcutaneous adipose tissue. RESULTS

Clinical features

Fig. 1. Multifocal erythematous and ulcerated nodules and tumors representing sec on ventral abdomen ofdog. female dogs were excluded from the trial because of the teratogenic effects of etretinate.9, 12-14 Etretinate was given orally at 1 mg/kg twice daily for a minimum of 90 days after surgical excision of gross tumor(s). This dose was extrapolated from the human dose for etretinate of approximately 1 mg/kg administered once daily.9, 12-14 The dose of etretinate was reduced to I mg/kg given once daily in those dogs with toxicity to the drug. Etretinate was discontinued temporarily in those dogs with a marked elevation (> 1000 mg/dl) in the serum triglyceride level. At entry and at monthly intervals after onset of therapy, all lesions were evaluated by counting and bidimensional measurement and by color photography. The lesions were also evaluated for degree of erythema, amount ofscale, and degree ofinduration. In addition, the change in severity of superficial pyoderma, ifpresent, was assessed. Response to etretinate was defined as complete when physical examination revealed no evidence of any lesion for at least 4 weeks. A partial response was defined as a decrease of more than ~O% in the largest cross-sectional area of a single lesion or in the sum of the cross-sectional areas for all lesions for at least 4 weeks. A response was classified as stable when the decrease in lesion size was less than 50% of the baseline measurement. Disease progression was defined as an unequivocal increase in the size of any lesion during therapy or the appearance of a new lesion(s). Pretrial laboratory evaluations included excisional or punch biopsy of a representative lesion, a complete blood cell count, serum chemistry profile, serum triglyceride evaluation, urinalysis, and Schirmer tear test. The labo-

Ten dogs representing five different breeds were evaluated for a minimum of 90 days. Their ages ranged from 3 to 13 years (median 9 years). The duration of clinical signs before presentation ranged from 2 to 36 months (median 7.5 months). Seven dogs had undergone previous surgical excision(s) of SCC and preneoplastic lesions, ranging from one to eight surgeries per dog. All dogs were outdoor pets and each had areas of nonpigmented, glabrous skin in which the sunlight-associated lesions developed. The sites of involvement were the axilla (6 dogs), inguinal region (10 dogs), flank (4 dogs), and ventral abdomen (10 dogs). One dog had extensive involvement of the inner thighs in addition to the aforementioned sites. All dogs had diffuse erythematous areas of solar-damaged skin of the ventral abdomen predominantly. Within these areas were multiple erythematous, ulcerated plaques, nodules, and tumors, measuring 0.2 to 15 cm at the greatest diameter (Fig. 1). Several papular and nodular eruptions were crusted and ulcerated. Two dogs had complete resolution of their preneoplastic lesions (Figs. 2 and 3), and three dogs showed partial responses after 90 days of etretinate therapy. Preneoplastic lesions remained stable in two dogs, whereas three dogs had disease progression. One dog developed diffuse erythema of the nonlesional skin and two dogs showed increased scaling, crusting and increased induration of the solar-damaged skin. Three of 10 dogs with concurrent folliculitis and furunculosis had marked improvement. All 10 dogs tolerated etretinate therapy well. Clinical side effects included ventral abdominal

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Etretinate for canine solar-induced see and preneoplasms 13

Fig. 2. Case 1. Solar-induced SCC of ventral abdomen before etretinate therapy. Fig. 3. Case 1. Resolution of solar-induced SCC after 90 days of etretinate therapy.

erythema (1 of 10 dogs) and joint stiffness (1 of 10 dogs). Biochemical abnormalities included elevated alanine aminotransferase (ALT) (l of 10 dogs), elevated alkaline phosphatase activity (ALP) (3 of 10 dogs), hypercholesterolemia (2 of 10 dogs), and hypertriglyceridemia (3 of 10 dogs). Marked hypertriglyceridernia in one dog was reversed after cessation of drug therapy for 5 weeks.

vesicular nuclei with a mitotic index of 0 to 3 per high-power field. Many nests were centered in large keratin pearls. The surrounding epidermis in these dogs was irregularly acanthotic and mildly dysplastic. Three of six dogs with invasive sec showed no histologic benefit from etretinate. There was histologic resolution of level 1 in one dog (Figs. 4, 5, and 6).

Histologic features

DISCUSSION

All preneoplastic and neoplastic lesions were placed into six categories: epidermal hyperplasia, epidermal dysplasia, carcinoma in situ, and invasive see (levels 1-3). A few lesions exhibited changes similar to those seen in seborrheic keratosis and inverted follicular keratosis of humans (Figs. 4 and 5). On the basis of the degree of epidermal disorganization, cellular atypia, and relative lack of a basaloid cell component, all lesions were believed to represent sees and not the aforementioned entities. A summary of the pretrial and day 90 histologic changes is given (Table I). Invasive see (level 3) was the most common histologic grade at presentation (4 of 10 dogs). The lesion was characterized by a pleomorphic population of squamous epithelial cells with distinct cell borders separated by prominent intercellular bridges. Cells contained abundant amphophilic to eosinophilic cytoplasm and large oval

These results suggest therapeutic benefit for etretinate in dogs with solar-induced sec and preneo-plastic lesions. Two dogs with noninvasive sce and one dog with early invasive sec (level 1) had a partial response clinically after 90 days of etretinate therapy. However, two dogs with advanced histologic lesions (SeC level 3) showed rapid clinical progression of sec despite drug therapy. There are several possible reasons for the lack of therapeutic response in these dogs. Because the pharmacokinetics of etretinate have not been examined in the dog, the drug dosage or the duration of treatment may have been insufficient. Furthermore, because of the lack of sunlight avoidance in several of these dogs, the erythema (sunburn) possibly persisted despite any beneficial effects of the drug. Dog 2 showed clinical progression of disease despite histologic improvement (See level 3 to level 1). This discrepancy

see

14 Marks et aZ.

Journal of the American Academy of Dermatology

Fig. 4. Case 1. Early invasive sec at day O. (Hematoxylin-eosin stain; XlOO.) Fig. 5. Portion of biopsy specimen illustrated in Fig. 4 shows complete disorder of epidermal keratinocytes with cellular atypia and nuclear hyperchromasia. (Hematoxylin-eosin stain; X250.) Fig. 6. Case 1. Normal epidermis at day 90. (Hematoxylin-eosin stain; X250.)

occurred because the most advanced grade of tumor at day 0 and day 90 was used for comparison. This dog had a large, ulcerated, deeply invasive see (level 3) in the inguinal region that had been surgically excised. Progressive multifocal disease developed despite etretinate therapy. At the time of repeat biopsy, the tumors were only slightly invasive (level 1). Thus the histologic grades in dog 2 indicated improvement (SeC level 3 to level I), although the dog had clinically progressive disease. Similarly, etretinate therapy in dogs 8 and 9 resulted in a marked decrease in ventral abdominal erythema, crusting, and lichenification, despite histologic progression of the initial lesions. Although a statistical statement cannot be made regarding the relation of dosage to both response and duration of remission, we observed a greater objec-

tive response in the dogs with preneoplastic lesions. This may be associated with the effects of vitamin A and its derivatives on cellular differentiation that produces a greater effect on preneoplastic lesions. 12, 14, 15 Aside from actinic keratosis, the solitary keratoacanthomas, and approximately 10% of basal cell carcinomas, the synthetic retinoids usually do not cure cutaneous tumors but produce variable degrees of partial regression when given at high doses. 16 The side effects of etretinate were minimal, and all adverse reactions were reversed by extending the dose to 1 mg/kg (1 of 10 dogs) or temporarily discontinuing the medication for 5 weeks (1 of 10 dogs). The percentage of dogs with triglyceride and liver enzyme elevation was similar to that reported in human trials. 14 In one dog diffuse erythema developed

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Etretinate for canine solar-induced sec and preneoplasms 15

Table I. Histologic and clinical features of squamous cell carcinoma (SCC) and preneoplastic lesions in 10 dogs before and after etretinate therapy Histologic features Dog

Day 0

6 7

sec 1 sec 3 sec 1 sec 3 see 3 Hyperplasia sec 3

9

eIS

I 2 3 4 5 8

10

I

Hyperplasia Hyperplasia

Day 90

Normal

sec 1

SCC 1 SCC 2 SCC 3 Dysplasia SCC 3 SCC2 SCC 1 Hyperplasia

Clinical outcome

Complete response Progression Partial response Stable Progression Partial response Progression Stable Partial response Complete response

CIS, Carcinoma in situ.

in nonlesional skin, a finding reported in some human patients. 14 Erythroderma caused by etretinate has also been reported. 17 Three dogs with concurrent superficial pyodermas showed a marked improvement with etretinate. This effect may be meliorated by the influence of etretinate on the immune response. The retinoids have been shown to enhance cell-mediated cytotoxicity in vitro as well as in vivo by enhanced action of T-helper cells and increased interleukin 2 production.18, 19 The retinoids inhibit the migration and motility of neutrophils and eosinophils into the epidermis, which may play an antiinflammatory role. 20, 21 see and preneoplastic lesions developed in all dogs in our study at sites of sunlight exposure after long periods of skin irritation. Tumors developed in non pigmented or lightly pigmented glabrous skin, often immediately adjacent to normal pigmented skin in nine dogs. All tumors were locally invasive and appeared to behave in a similar manner to see in human patients. 22 Canine solar-induced sec appears to be a useful animal model system for the study of novel therapeutic approaches to solarinduced disease in human beings because the pathophysiologic changes in the canine skin appear to parallel those of human photocarcinogenesis. 23 The results of the present study suggest that etretinate, at the dosage and duration of administration used, provides therapeutic efficacy for the treatment of preneoplastic lesions in the dog. Etretinate had little effect on invasive sec lesions and surgical excision is indicated for such lesions. How-

ever, it may reduce the need for surgery by reversing or at least preventing the progression of preneoplastic lesions to carcinoma in situ and SCc. Etretinate was supplied through the courtesy of Hoffmann-LaRoche, Inc., Nutley, N.J. REFERENCES 1. Susaneck SJ, Withrow SJ. Tumors of the skin and subcutaneous tissues. In: Withrow SJ, MacEwen EG. Clinical veterinaryoncology. Philadelphia: JB Lippincott, 1989: 13944. 2. Priester W A. Skin tumors in domestic animals: data from 12 United States and Canadian Colleges of Veterinary Medicine. J Nat! Cancer Inst 1973;50:457-66. 3. Hargis AM, Thomassen RW, Phernister RD. Chronic dermatosis and cutaneous squamous cell carcinoma in the beagle dog. Vet Pathol 1977;14:218-28. 4. Madewell BR, Conroy JD, Hodgkins EM. Sunlight-skin cancer association in the dog: a report of three cases. J Cutan PathoI1981;8:434-43. 5. Rothwell TLW, Howlett CR, Middleton DJ, et al. Skin neoplasms of dogs in Sydney. Austr Vet J 1987;64:161-4. 6. Madewell BR, Theilen GH. Tumors and tumor-like conditions of epithelial origin. In: Theilen GH, Madewell BR, eds. Veterinary cancer medicine. Philadelphia: Lea & Febiger, 1987:240-325. 7. Himsel CA, Richardson RC, Craig lA. Cisplatin chemotherapy for metastatic squamous cell carcinoma in two dogs. J Am Vet Moo Assoc 1986;189:1575-8. 8. Berth Jones J, Graham-Brown RAC. Xeroderma pigmentosum variant: response to etretinate. Br J Dennato1 1990;122:559-61. 9. Boyd AS. An overview of the retinoids. Am J Med 1989; 86:568-74. 10. Hughes BR, Marks R, Pearse AD, et al. Clinical response and tissue effects of etretinate treatment of patients with solar keratoses and basal cel! carcinoma. J AM ACAD DERMATOL 1988;18:522-9. 11. Claudy AL, Rouchouse B, Boucheron S, et at. Treatment

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12. 13. 14. 15. 16. 17. 18.

of cutaneous lymphoma with etretinate. Br J Dennato1 1983;109:49-56. Dicken CH. Retinoids: a review. J AM ACAD DERMATOL 1984;11:541-52. Olsen JA. Adverse effects oflarge doses of vitamin A and retinoids. Semin Onoo11983;1O:290-3. Ellis CN, Voorhees JJ. Etretinate therapy. J AM ACAD DERMATOL 1987;16:267-9l. Halter SA. Vitamin A: its role in the chemoprevention and chemotherapy of cancer. Hum PathoI1989;20:205-9. Peck GL. Retinoids and cancer [Editorial]. J Invest DermatoI1985;85:87-8. Levin J, Almeyda J. Erythroderma due to etretinate [Letter]. Br J Dennatol 1985;112:373. Lotan R. Effects of vitamin A and its analogues (retinoids) on normal and neoplastic cells. Biochem Biophys Acta 1980;605: 33-91.

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19. Dennert G. Retinoids and the immune system: immunostimulation by vitamin A. In: Sporn MB, Roberts AB, Goodman DS, eds. The retinoids. New Yark: Academic Press, 1984:373-90. 20. Orfanos CE, Bauer R. Evidence for anti-inflammatory activities oforal synthetic retinoids: experimental findings and clinical experience. Br J Dermatol 1983;109:55-60. 21. Dubertret L, Lebeton C, Touraine R. Inhibition of neutro-phil migration by etretinate and its main metabolite. Br J DermatoI1982;107:681-5. 22. Khansur T, Kennedy A. Cisplatin and 5-fluorouracil·for advanced locoregional and metastatic squamous cell carcinoma of the skin. Cancer 1991;67:2030-2. 23. Kripke ML. Immunology and photocarcinogenesis. J AM ACAD DERMATOL 1986;14:149-55.

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