British Journal of Dermatology (1975) 93» 329.
Case Reports
Cowden disease REPORT OF TWO ADDITIONAL CASES JOSEPH W.BURNETT,RONALD GOLDNER AND GARY J.CALTON Division of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 2r2or, U.S.A. Accepted for publication 18 November 1974
SUMMARY
Two patients with Cowden disease, a syndrome consisting of cutaneous papules and nodules on the face, oral mucous membranes and dorsal aspects of the forearms and hands in association with tumours of the thyroid gland, breasts, gastro-intestinal tract, and female reproductive tract, are reported. This disease is important to the physician because recognition of these cutaneous lesions may allow early diagnosis of internal neoplasia.
Many genetic diseases either predispose the patient to cancer or include neoplasia as a late manifestation. Some of these disorders have early diagnosable cutaneous manifestations. Cowden disease is important to the physican because of its association with internal malignancy (Lloyd & Dennis, 1963; Weary et al., 1972; Gentry, Eskritt & Gorlin, 1974). In this disease, warty papules and nodules appear predominantly on the central face, the oral mucosa, the hands and the dorsal aspects of the forearms in early adult life. These cutaneous lesions often antedate neoplasia of the breasts, thyroid and female reproductive tract. CASE REPORTS
Case I A 50-year-old woman sought medical assistance because of multiple nodules and papules on the face, hands and feet (Figs 1-3). These warty lesions first appeared on her hands at the age of 28 and on her face at about 40. She has had extensive vitiligo since childhood. Radical mastectomies for intraductal and infiltrating mammary carcinomas (grade III) were performed when she was 39 (left breast) and 44 (right breast); no carcinoma was detected in any regional lymph nodes. Partial colectomy was performed at the age of Reprint requests to: J.W.Burnett, M.D., Division of Dermatology, University of Maryland School of Medicine, Baltimore, Md. 21201, U.S.A.
H
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J.W.Burnett, R.Goldner and G.J.Calton
FIGURE I . Case i : side view of face showing 'beak-like' appearance.
Cowden disease
FIGURE 2 . Case I: small papules and cobblestone appearance around the lips.
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J.W.Burnett, R.Goldner and G.J.Calton
1' 1 u u K l; 3 . Case i: multiple small, umbilicated papules.
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45 to remove an adenocarcinoma of the caecum, which had invaded the pericolic fat. At that time, a serous cyst of the right ovary and a neuroma of Auerbach's plexus were detected. Follicular adenomatous goitres of the thyroid were removed during the past lo years. Recently, papillomatahave developed on her vulval and perianal skin. Her maternal aunt and grandmother also had vitiligo. An older sister had numerous skin tags and fibrocystic breast disease; one younger sister had acne and another younger sister suffered with fits and mental retardation. The patient's father had rosacca and numerous seborrhoeic keratoses. He died of pulmonary carcinoma.
FIGURE 4. Case i: biopsy of cutaneous papule showing acanthosis, hyperkeratosis and dilated dermal capillaries ( x 430).
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J.W.Bumett, R.Goldner and G.J.Calton
^'m: FIG u R E 5 . Case i: Biopsy of second cutaneous papule showing acanthosis, dilatation of capillaries and a scattered dermal infiltrate of mononuclcar cells ( x 260).
Examination demonstrated a beak-like deformity of the face, a high-arched palate and scoliosis of the dorsal spine with convexity to the left. Smooth, flesh-coloured papules 0-5-10 cm in diameter were present on the perineum, palms, tongue and oral mucosa. Slightly larger papules were located on the perioral skin and in the nasolabial folds. A verrucous papule was seen on the lateral periungual fold of the right index finger. There was diffuse vitiligo of the trunk and extremities. Pathological examination of a cutaneous papule showed hyperkeratosis with parakeratosis, acanthosis and telangiectasia of the dermal papilla (Figs 4 and 5). An oral mucous membrane lesion was found to be a fibroma. A complete blood count, urinalysis, and 12-channel serum chemical analysis were normal. General-
Cowden disease
335
ized osteoporosis, and fibrosis of the right apex were seen on chest X-ray. Round subhepatic calcifications, presumably gallstones, were visible on an abdominal film. Her serum alpha fetoprotein, chorioembryonic antigen and human choriogonadotrophin assays were normal. No abnormalities were detected in the chromosomes of her blood cell cultures analysed by the Giemsa banding technique. Numerous therapeutic measures including surgery, electrosurgery, liquid nitrogen cryotherapy and 40"/ salicylic acid ointment applied topically provided only temporary improvement. Topical 5fluorouracil cream and lotion have been most helpful in eliminating the cutaneous lesions. Case 2
A 30-year-oid white female had been receiving irregular ineffective therapy with tetracycline and abrasive scrubs over the past 15 years for 'acne and flat warts of the face.' Her past medical history included a large congenital A-V malformation of the right groin area, which was partially removed in 1970; and a total thyroidectomy was performed in 1972 to excise a follicular adenocarcinoma. Postoperative therapy included radioactive iodine and daily replacement thyroid. A lipoma was removed from her right thigh 15 years ago. Several breast fibroadenomas have also been excised since that time. Her family history revealed that six sisters and one brother are in good health. Her mother has diabetes and her father is being treated for hypertension. There is a paternal family history of cancer. Physical examination revealed a slightly obese female with scattered facial acneiform follicular papules and pustules. Many additional hyperkeratotic and soft ^-i cm verrucous papules were present on the cheeks, chin and nose. The gingival tissues had a cobblestone appearance and her tongue was normal. Papillomatous lesions were present on the mucosa at both lip corners and translucent papules on both palms. Scattered i cm firm nodules were noted in both breasts. A soft pulsatile mass was noted in the right inguinal area. DISCUSSION
In Cowden syndrome there appears to be a clear association between the cutaneous lesions and neoplasia of the breast, thyroid, bowel and female reproductive tract. The most characteristic cutaneous lesions are small (2-8 mm) papules or nodules clustered about the orifices of the face and on the dorsal surfaces of the arms and hands. Some of these lesions appear in a perleche fashion. Others may be verruciform, hyperkeratotic, or fiat. On the palm they are translucent. Often mucous membrane lesions of the same type may be cobblestone-like or digitate. These lesions are present in the nares, the oral cavity and the labial surfaces. Our patients did not have laryngeal lesions although they have been reported (Weary et al., 1972). The breast lesions usually are those of fibrocystic disease but carcinoma can occur (Lloyd & Dennis, 1963). The thyroid gland disorders include thyroiditis (Weary et al.., 1972; Gentry et ai, 1974), thyroglossal duct cyst (Weary et al.i 1973) and follicular cell carcinoma (Weary et al.^ 1973) as well as follicular adenomas. Polyps are the commonest bowel tumour but a caecal carcinoma was reported in our first case. Serous ovarian cysts were found in our first case in addition to one earlier patient (Weary et al, 1973). It is not possible to determine whether other changes such as vitiligo, kyphosis, cutaneous hpomas, fibromas and haemangiomas are also included in the syndrome. The beak-like facies reported in the original case (Lloyd & Dennis, 1963) and in our first case may not be seen in most instances. No characteristic laboratory tests have been reported. The chromosomal analysis in Case i was normal as were her serological assays which might be indicative of malignancy. No pathognomonic pathological changes were detected in the cutaneous lesions. The genetic transmission is tmknown. The disease has appeared in siblings and in successive
336
J.W.Burnett, R.Goldner and G.J.Calton
generations with an approximate i :i sex ratio, suggesting an autosomal dominant inheritance (Gentry et al, 1974). The differential diagnosis of the cutaneous lesions here would include warts, tuberous sclerosis, epithelioma adenoides cysticum and keratoses. Therapy of these lesions has been disappointing although two cases, including one of our own, have responded to topical 5-fluorouraciI (Weary et al., 1973). Since these cutaneous lesions are not lethal their primary importance resides in the fact that they serve as diagnostic signals for internal neoplasia. ACKNOWLEDGMENTS
The authors wish to acknowledge the aid and assistance of Drs Victor A.McKusick and Digamber S.Borgaonkar of The Johns Hopkins Hospital, who performed the chromosomal analysis and Dr Saro) Das ofthe National Cancer Institute Immunoglobulin Reference Center, Springfield, Virginia who completed the chorioembryonic antigen, alpha fetoprotein and human choriogonadotropin assays. REFERENCES LLOVD, K . M . & DENNIS, M . (1963) Cowden's disease: a possible new symptom complex with multiple system involvement. Annals of Inlernal Medicine, 58, 136. WEARY, P.E., GORLIN, R.J., GENTRY, W . C , JR., COMER, J.E. & GREER, K . E . (1972) The multiple hamarioma
syndrome (Cowden's disease). Archives of Dermatology, 106, 682. GENTRY, W.C, JR., ESKRITT, N . R . & GORLIN, R.J. (1974) Multiple hamartoma syndromes (Cowden disease). Archives cf Dermatology •, 109, 521.
Case Reports
Cowden disease REPORT OF TWO ADDITIONAL CASES JOSEPH W.BURNETT,RONALD GOLDNER AND GARY J.CALTON Division of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland 2r2or, U.S.A. Accepted for publication 18 November 1974
SUMMARY
Two patients with Cowden disease, a syndrome consisting of cutaneous papules and nodules on the face, oral mucous membranes and dorsal aspects of the forearms and hands in association with tumours of the thyroid gland, breasts, gastro-intestinal tract, and female reproductive tract, are reported. This disease is important to the physician because recognition of these cutaneous lesions may allow early diagnosis of internal neoplasia.
Many genetic diseases either predispose the patient to cancer or include neoplasia as a late manifestation. Some of these disorders have early diagnosable cutaneous manifestations. Cowden disease is important to the physican because of its association with internal malignancy (Lloyd & Dennis, 1963; Weary et al., 1972; Gentry, Eskritt & Gorlin, 1974). In this disease, warty papules and nodules appear predominantly on the central face, the oral mucosa, the hands and the dorsal aspects of the forearms in early adult life. These cutaneous lesions often antedate neoplasia of the breasts, thyroid and female reproductive tract. CASE REPORTS
Case I A 50-year-old woman sought medical assistance because of multiple nodules and papules on the face, hands and feet (Figs 1-3). These warty lesions first appeared on her hands at the age of 28 and on her face at about 40. She has had extensive vitiligo since childhood. Radical mastectomies for intraductal and infiltrating mammary carcinomas (grade III) were performed when she was 39 (left breast) and 44 (right breast); no carcinoma was detected in any regional lymph nodes. Partial colectomy was performed at the age of Reprint requests to: J.W.Burnett, M.D., Division of Dermatology, University of Maryland School of Medicine, Baltimore, Md. 21201, U.S.A.
H
329
330
J.W.Burnett, R.Goldner and G.J.Calton
FIGURE I . Case i : side view of face showing 'beak-like' appearance.
Cowden disease
FIGURE 2 . Case I: small papules and cobblestone appearance around the lips.
331
332
J.W.Burnett, R.Goldner and G.J.Calton
1' 1 u u K l; 3 . Case i: multiple small, umbilicated papules.
Cowden disease
333
45 to remove an adenocarcinoma of the caecum, which had invaded the pericolic fat. At that time, a serous cyst of the right ovary and a neuroma of Auerbach's plexus were detected. Follicular adenomatous goitres of the thyroid were removed during the past lo years. Recently, papillomatahave developed on her vulval and perianal skin. Her maternal aunt and grandmother also had vitiligo. An older sister had numerous skin tags and fibrocystic breast disease; one younger sister had acne and another younger sister suffered with fits and mental retardation. The patient's father had rosacca and numerous seborrhoeic keratoses. He died of pulmonary carcinoma.
FIGURE 4. Case i: biopsy of cutaneous papule showing acanthosis, hyperkeratosis and dilated dermal capillaries ( x 430).
334
J.W.Bumett, R.Goldner and G.J.Calton
^'m: FIG u R E 5 . Case i: Biopsy of second cutaneous papule showing acanthosis, dilatation of capillaries and a scattered dermal infiltrate of mononuclcar cells ( x 260).
Examination demonstrated a beak-like deformity of the face, a high-arched palate and scoliosis of the dorsal spine with convexity to the left. Smooth, flesh-coloured papules 0-5-10 cm in diameter were present on the perineum, palms, tongue and oral mucosa. Slightly larger papules were located on the perioral skin and in the nasolabial folds. A verrucous papule was seen on the lateral periungual fold of the right index finger. There was diffuse vitiligo of the trunk and extremities. Pathological examination of a cutaneous papule showed hyperkeratosis with parakeratosis, acanthosis and telangiectasia of the dermal papilla (Figs 4 and 5). An oral mucous membrane lesion was found to be a fibroma. A complete blood count, urinalysis, and 12-channel serum chemical analysis were normal. General-
Cowden disease
335
ized osteoporosis, and fibrosis of the right apex were seen on chest X-ray. Round subhepatic calcifications, presumably gallstones, were visible on an abdominal film. Her serum alpha fetoprotein, chorioembryonic antigen and human choriogonadotrophin assays were normal. No abnormalities were detected in the chromosomes of her blood cell cultures analysed by the Giemsa banding technique. Numerous therapeutic measures including surgery, electrosurgery, liquid nitrogen cryotherapy and 40"/ salicylic acid ointment applied topically provided only temporary improvement. Topical 5fluorouracil cream and lotion have been most helpful in eliminating the cutaneous lesions. Case 2
A 30-year-oid white female had been receiving irregular ineffective therapy with tetracycline and abrasive scrubs over the past 15 years for 'acne and flat warts of the face.' Her past medical history included a large congenital A-V malformation of the right groin area, which was partially removed in 1970; and a total thyroidectomy was performed in 1972 to excise a follicular adenocarcinoma. Postoperative therapy included radioactive iodine and daily replacement thyroid. A lipoma was removed from her right thigh 15 years ago. Several breast fibroadenomas have also been excised since that time. Her family history revealed that six sisters and one brother are in good health. Her mother has diabetes and her father is being treated for hypertension. There is a paternal family history of cancer. Physical examination revealed a slightly obese female with scattered facial acneiform follicular papules and pustules. Many additional hyperkeratotic and soft ^-i cm verrucous papules were present on the cheeks, chin and nose. The gingival tissues had a cobblestone appearance and her tongue was normal. Papillomatous lesions were present on the mucosa at both lip corners and translucent papules on both palms. Scattered i cm firm nodules were noted in both breasts. A soft pulsatile mass was noted in the right inguinal area. DISCUSSION
In Cowden syndrome there appears to be a clear association between the cutaneous lesions and neoplasia of the breast, thyroid, bowel and female reproductive tract. The most characteristic cutaneous lesions are small (2-8 mm) papules or nodules clustered about the orifices of the face and on the dorsal surfaces of the arms and hands. Some of these lesions appear in a perleche fashion. Others may be verruciform, hyperkeratotic, or fiat. On the palm they are translucent. Often mucous membrane lesions of the same type may be cobblestone-like or digitate. These lesions are present in the nares, the oral cavity and the labial surfaces. Our patients did not have laryngeal lesions although they have been reported (Weary et al., 1972). The breast lesions usually are those of fibrocystic disease but carcinoma can occur (Lloyd & Dennis, 1963). The thyroid gland disorders include thyroiditis (Weary et al.., 1972; Gentry et ai, 1974), thyroglossal duct cyst (Weary et al.i 1973) and follicular cell carcinoma (Weary et al.^ 1973) as well as follicular adenomas. Polyps are the commonest bowel tumour but a caecal carcinoma was reported in our first case. Serous ovarian cysts were found in our first case in addition to one earlier patient (Weary et al, 1973). It is not possible to determine whether other changes such as vitiligo, kyphosis, cutaneous hpomas, fibromas and haemangiomas are also included in the syndrome. The beak-like facies reported in the original case (Lloyd & Dennis, 1963) and in our first case may not be seen in most instances. No characteristic laboratory tests have been reported. The chromosomal analysis in Case i was normal as were her serological assays which might be indicative of malignancy. No pathognomonic pathological changes were detected in the cutaneous lesions. The genetic transmission is tmknown. The disease has appeared in siblings and in successive
336
J.W.Burnett, R.Goldner and G.J.Calton
generations with an approximate i :i sex ratio, suggesting an autosomal dominant inheritance (Gentry et al, 1974). The differential diagnosis of the cutaneous lesions here would include warts, tuberous sclerosis, epithelioma adenoides cysticum and keratoses. Therapy of these lesions has been disappointing although two cases, including one of our own, have responded to topical 5-fluorouraciI (Weary et al., 1973). Since these cutaneous lesions are not lethal their primary importance resides in the fact that they serve as diagnostic signals for internal neoplasia. ACKNOWLEDGMENTS
The authors wish to acknowledge the aid and assistance of Drs Victor A.McKusick and Digamber S.Borgaonkar of The Johns Hopkins Hospital, who performed the chromosomal analysis and Dr Saro) Das ofthe National Cancer Institute Immunoglobulin Reference Center, Springfield, Virginia who completed the chorioembryonic antigen, alpha fetoprotein and human choriogonadotropin assays. REFERENCES LLOVD, K . M . & DENNIS, M . (1963) Cowden's disease: a possible new symptom complex with multiple system involvement. Annals of Inlernal Medicine, 58, 136. WEARY, P.E., GORLIN, R.J., GENTRY, W . C , JR., COMER, J.E. & GREER, K . E . (1972) The multiple hamarioma
syndrome (Cowden's disease). Archives of Dermatology, 106, 682. GENTRY, W.C, JR., ESKRITT, N . R . & GORLIN, R.J. (1974) Multiple hamartoma syndromes (Cowden disease). Archives cf Dermatology •, 109, 521.
