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Malignant acanthosis nigricans with florid papillary oral lesions
Malignant acanthosis nigricans with florid papillary oral lesions Martin T. Tyler, BS, DDS, MEd, a Giuseppe Ficarra, MD, b Sol Silverman, Jr, MA, DDS, c Richard B. Odom, MD, d and Joseph A. Regezi, DDS, MS, e Montrral, Qurbec, Canada, San Francisco, Calif., and Florence, Italy MCGILL UNIVERSITY, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, AND UNIVERSITY OF FLORENCE
Acanthosis nigricans is a distinctive skin disease of importance, because it has served as an external marker for a variety of systemic disorders including endocrinopathies and malignant tumors of internal organs. It typically appears as hyperpigmented, roughened plaques of velvety consistency and infrequently as verruca-like papillations. The oral cavity and lips can be affected by florid papillary growths. Because of its rarity and nonspecific microscopic appearance, clinical recognition of acanthosis nigricans continues to be a challenge. A case of mucocutaneous "malignant" acanthosis nigricans is. presented in which pigmented skin lesions led to the discovery of a gastric adenocarcinoma, which in turn was followed by the appearance of massive oral papillomatosis. No effective treatment was found. (ORAL SURGORALMED ORALPATHOLORALRADIOLENDOD1996;81:445-9)
Acanthosis nigricans (AN) is a mucocutaneous condition o f undetermined cause. Early detection o f the characteristic pigmented skin lesions m a y be crucial to the prognosis. Oral lesions m a y also be a marker for this disorder. Although eight types o f A N have been described, one type, " m a l i g n a n t " acanthosis nigricans, has served as a marker o f internal malignancy. 1 W h e n cutaneous A N was first reported by Pollitzer 2 in 1890, a link was suspected with abdominal malignancy. By 1909 Pollitzer 3 had confirmed the association. To date numerous cases have been reported that support the original observations o f Pollitzer. K n o w l e d g e of the current classification o f the eight types is important because o f the occm-rence o f both benign and " m a l i g n a n t " types. NonmaligaAssistant Professor and Chair, Division of Oral Medicine and Radiology, Faculty of Dentistry, McGill University, Montreal, Qudbec, Canada. Currently Visiting Assistant Professor, University of California, San Francisco.
bAdjunct Professor of Oral Pathology and Medicine, Clinical Assistant, National Health System (USL/10D), Institute of Stomatology, University of Florence. Cprofessor and Chair, Division of Oral Medicine, School of Dentistry, University of California, San Francisco. dClinical Professor and Associate Chair, Department of Dermatology, University of California, San Francisco. ~Professor of Oral Pathology, School of Dentistry, Professor of Pathology, School of Medicine, University of California, San Francisco. Received for publication Feb. 6, 1995; returned for publication Apr. 23, 1995; accepted for publication June 19, 1995. Copyright 9 1996 by Mosby-Year Book, Inc. 1079-2104/96/$5.00 + 0 7/14/67432
nancy-associated A N (benign AN) is not activated by a tumor, tends to develop at an earlier age, and, like obesity-associated AN, which is usually weight-dependent and reversible, occurs more frequently than the malignant form. The prognosis of malignant A N is dependent on detection and treatment of the associated neoplasm. The underlying malignancy is usually gastric adenocarcinoma. 4 Other malignancies have been found in other regions of the gastrointestinal tract and in the ovaries, uterus, breast, testes, and lungs. 5 Cutaneous A N typically presents as hyperpigmented plaques that progressively thicken, resulting in a velvety texture. Although any area o f the skin m a y be involved, the most c o m m o n sites are the nape o f the neck, sides o f the neck, and axillae. Groin, antecubital, popliteal, and umbilical areas m a y be affected. The onset of the malignant form o f A N m a y appear with three other cutaneous signs: florid cutaneous (and occasionally oral) papillomatosis, especially o f the lips and eyelids, hyperkeratosis of the palms and soles (tylosis), and the sign o f Leser-Trrlat (the sudden appearance of numerous seborrheic keratoses). 1 These clinical markers m a y or m a y not appear before the hyperpigmented lesions of A N appear. This report presents a case o f this rare condition in which marked oral papillomatous lesions developed after multiple cutaneous lesions o f A N appeared and an abdominal malignancy was detected. CASE REPORT
A 57-year-old white man presented to the dermatologist with hyperpigmented velvety skin changes on the nape 445
446
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Fig. 1. Axillary pigmentation and verrucous eruption in patient with acanthosis nigricans.
Fig. 3. Extensive papillomatous enlargement and crusting of patient's lips.
Fig. 2. Patient's eye showing hypopigmentation, papillomatosis of lower eyelid, and conjunctivitis.
Fig. 4. Patient's palate showing marked papillomatosis, partially obscuring teeth.
and sides of the neck, the axillae, the nipple, and the groin area. The patient had no other symptoms. A diagnosis of AN was made, and a diagnostic workup was started for the detection of an associated internal malignancy. Examination with computed tomography and magnetic resonance imaging detected an abdominal mass. A laparotomy revealed an unresectable gastric adenocarcinoma with regional lymph node metastasis. Treatment with fluorouracil and leucovorin was started, but the gastric tumor progressed. One year after the initial diagnosis was made, the patient underwent surgical reduction of the tumor, and 1 month after the debulking operation was performed, the skin lesions showed some reduction in size. Two months later oral lesions developed, and the patient was referred to the oral medicine clinic at the University of California, San Francisco, for evaluation. At the time of the oral examination the patient's chief oral complaint was "blistered lips and a tender mouth," and his major medical problem was residual adenocarcinoma that was being treated with chemotherapeutic drugs. Significant cutaneous physical findings
included pigmented, velvety, raised, cutaneous lesions (Fig. 1), periorbital hypopigmentation, conjunctivitis, and mild papillomatosis of the lower eyelid. The patient had recently seen an ophthalmologist with the chief complaint of "blocked tear ducts and watery eyes." Hyperplasia of the lacrimal caruncle and epiphora from occlusion of the lacrimal canaliculi by the papillomatous proliferations were seen (Fig. 2). Oral examination revealed extensive papillomatosis of the lips (Fig. 3) and palatal mucosa (Fig. 4). Involvement of the upper lip was more pronounced than in the lower lip. Lesions appeared as yellow, encrusted, papillomatous growths, giving the lips a swollen appearance. The lesions on the hard palate were generalized with a papillated architecture. The interdental papillae of the palatal gingiva were enlarged and partially obscured the palatal surfaces of the teeth. Biopsy specimens from the upper lip and palate exhibited similar histopathologic changes. These consisted of papillary projections composed of parakeratotic and hyperplastic epithelium supported by slightly inflamed edematous vascular cores (Figs. 5 and 6). No evidence of epi-
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Fig. 5. Photomicrograph of palatal biopsy showing papillary architecture. (Hematoxylin-eosin stain; original magnification x45.)
Fig. 6. Higher power photomicrograph of palatal biopsy showing bland papillary hyperplasia with slight inflammatory infiltrate. (Hematoxylin-eosin stain; original magnification xl00.)
thelial dysplasia or viral inclusions was seen. The microscopic features, although nonspecific, were consistent with the papillary expression of oral acanthosis nigricans. Immunohistochemical stain for human papillomavirus common antigen was negative. An attempt was made to reduce the severity of the oral lesions with isotretinoin at a daily dosage of 40 mg for 6
weeks. Isotretinoin was then supplemented with etretinate (25 mg/day) for 2 weeks. At the end of 6 weeks the skin lesions were less severe, but the oral lesions had increased in severity. A total weekly dose of 10 mg methotrexate was administered two times weekly in an attempt to control the oral lesions. The therapeutic regimen for the oral lesions had very little effect; no significant side effects of the
448
Tyler et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
April 1996 medication were noted. Twenty-three months after the initial diagnosis of malignant AN was made, the patient died of multiple organ failure and widespread metastatic adenocarcinoma. DISCUSSION R e c e n t w o r k 1 suggests that w h e n A N occurs with an a s s o c i a t e d m a l i g n a n c y , the secretion o f a variety o f rumor p r o d u c t s (e.g., m e l a n i n - s t i m u l a t i n g hormone, e p i d e r m a l g r o w t h factor, transforming g r o w t h factor-tx) is l i k e l y to h a v e a role in activating m u c o cutaneous e x p r e s s i o n o f A N through the stimulation o f m e l a n o c y t e s , keratinocytes, and fibroblasts. F o r tunately, A N occurs m u c h m o r e frequently w i t h o u t a s s o c i a t e d m a l i g n a n c y . W h e n A N occurs alone or is i n d u c e d b y m e d i c a t i o n , it is a benign, m o s t l y a s y m p tomatic d e r m a t o s i s requiring no treatment. In this case the o c c u r r e n c e o f cutaneous A N was f o l l o w e d b y the detection o f gastric a d e n o c a r c i n o m a and s u b s e q u e n t l y the d e v e l o p m e n t o f oral and perioral p a p i l l o m a t o s i s . It has been r e p o r t e d that m a l i g nancies p r e c e d e d A N in a p p r o x i m a t e l y 20% o f cases, that A N p r e c e d e d the n e o p l a s m in a p p r o x i m a t e l y 20%, and that both A N and the m a l i g n a n c y d e v e l o p e d s i m u l t a n e o u s l y in a p p r o x i m a t e l y 60%. 6 T h e characteristic p i g m e n t e d skin lesions m a y be a c c o m p a n i e d b y oral, perioral, and periorbital p a p i l l o m a t o s i s . T h e s e latter lesions m a y be v a l u a b l e clinical m a r k e r s for A N and p o s s i b l y for occult m a l i g n a n t tumors. This case illustrates the value o f being c o g n i z a n t o f the association o f clinical markers; the r e c o g n i t i o n o f A N and the level o f suspicion that this finding prov o k e d were r e s p o n s i b l e for the detection o f the m a lignancy. W h e n the m a l i g n a n c y was c o n f i r m e d b y surgery, clinical d i a g n o s i s and colTelation o f n e w l y a p p e a r i n g oral p a p i l l o m a t o s i s followed. A l l clinical findings, h i s t o p a t h o l o g i c findings, and the clinical course o f this case were consistent with the findings o f the r e p o r t e d cases o f this rare s y n d r o m e o f m a l i g nant A N . The unesthetic a p p e a r a n c e o f the skin is usually o f concern to the patient. In this case the c h i e f c o m p l a i n t was sore m o u t h and lips that resulted in an inability to eat c o m f o r t a b l y . In a r e v i e w b y S e d a n o and Gorlin 7 o f m o r e than 200 cases o f A N with a n e o p l a s t i c association, up to 4 0 % h a d the characteristic oral lesions. T h e lips and tongue are m o s t frequently involved, but the palatal m u c o s a and the g i n g i v a l interdental p a p i l l a e m a y b e s e v e r e l y affected. T h e oral lesions rarely a p p e a r p i g m e n t e d 8; the dark c o l o r o f the skin is due to acanthosis and not to an increase in melanin. E v a l u a t i n g the skin for h y p e r p i g m e n t a t i o n m a y b e m i s l e a d i n g , b e c a u s e atopic dermatitis and tinea corporis m a y also p r o d u c e similar d a r k lesions.
P a p i l l o m a t o u s g r o w t h s o f the p h a r y n g e a l , laryngeal, e s o p h a g e a l , and a n o g e n i t a l areas have also been describe& 9 I m p r o v e m e n t has been r e p o r t e d 1~ in the oral m u c o s a l lesions o f a patient with simultaneous c u t a neous A N and a m a l i g n a n t t u m o r after treatment with anticancer drugs. In this case, although s o m e reduction in the size o f the skin lesions f o l l o w e d partial surgical r e m o v a l o f the tumor, the effect was t e m p o rary, and c h e m o t h e r a p y h a d no effect on the reduction o f the m u c o c u t a n e o u s lesions. The p a p i l l o m a t o u s lesions o f A N have been successfully treated with oral retinoids. 11-13 The rationale for use o f those agents is related to their effect on cellular g r o w t h - p r o m o t i n g factors and to their antikeratinizing properties. In this case no m e a s u r a b l e d e c r e a s e in the signs or s y m p t o m s was noticed with p r o l o n g e d retinoid therapy. M e t h o t r e x a t e was prescribed for its antiproliferative effects to halt the progression o f the oral lesions, but the patient d i e d o f c o m p l i c a t i o n s a s s o c i a t e d with his m a l i g n a n c y before its v a l u e could be assessed. T u m o r s associated with A N are u s u a l l y aggressive a d e n o c a r c i n o m a s ; the a v e r a g e survival o f the patient after d i a g n o s i s is less than 2 years. B e c a u s e o f the close link o f A N with gastrointestinal malignancies, it has b e e n suggested that if the original n e o p l a s m is not an a d e n o c a r c i n o m a , a search should be conducted to rule out the p o s s i b i l i t y o f a second m a l i g n a n c y o f gastrointestinal origin.1 This case supports the observation that extensive oral p a p i l l o m a t o s i s m a y be a c o m p o n e n t o f A N and an external sign o f an occult internal m a l i g n a n c y .
REFERENCES
]. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1-19. 2. Pollitzer S. Acanthosis nigricans. In: Unna PG, Morris M, Besnier E, et al., editors. International atlas of rare skin diseases. London: HK Lewis & Co, 1890: 1-3. Cited in: Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1 19. 3. Pollitzer S. Acanthosis nigricans: a symptom of a disorder of the abdominal sympathetic. JAMA 1909;53:1369-73. 4. Curtb HO, Hilberg AW, Macbacek GF. The site and histology of the cancer associated with malignant acanthosis nig ricans. Cancer 1962; 15:364-82. 5. Rogers DL. Acanthosis nigricans. Sem Dermatol 1991;10: 160-3. 6. Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, et al., editors. Cancer of the skin: biology~iagnosis--management. Philadelphia: WB Saunders, 1976:1308-41. 7. Sedano HO, Gorlin RJ. Acanthosis nigricans. ORAL SURe ORAL MED ORALPATHOL1987;63:462-7. 8. Nomura J, Tagawa T. Acanthosis nigricans with oral lesions and a malignant visceral tumor: a case report. J Oral Maxil lofac Surg 1992;50:169-72.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 81, Number 4 9. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;114:1803-6. 10. Kazuhiko N, Masatoma M. Improvement of oral lesions associated with malignant acanthosis nigricans after treatment of lung cancer. ORAL SURG ORAL MED ORAL PATHOL 1989; 68:74-9. 11. Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980;116:110-1. 12. Darmstadt GL, Yokel BK, Horn TD, et al. Treatment of ac anthosis nigricans with tretinoin. Arch Dermatol 1991; 127: 1139-40. 13. Baalbaki SA, Malak JA, A1-Khars M A A . Confluent and re-
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ticulated papillomatosis: treatment with etretinate. Arch Dermatol 1993;129:961-3.
Reprint requests: Martin T. Tyler, DDS Division of Oral Medicine and Radiology Faculty of Dentistry McGill University 1650 Cedar Avenue, B3-112 Montr6al, Queb6c, Canada H3G 1A4
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Acanthosis nigricans is a distinctive skin disease of importance, because it has served as an external marker for a variety of systemic disorders including endocrinopathies and malignant tumors of internal organs. It typically appears as hyperpigmented, roughened plaques of velvety consistency and infrequently as verruca-like papillations. The oral cavity and lips can be affected by florid papillary growths. Because of its rarity and nonspecific microscopic appearance, clinical recognition of acanthosis nigricans continues to be a challenge. A case of mucocutaneous "malignant" acanthosis nigricans is. presented in which pigmented skin lesions led to the discovery of a gastric adenocarcinoma, which in turn was followed by the appearance of massive oral papillomatosis. No effective treatment was found. (ORAL SURGORALMED ORALPATHOLORALRADIOLENDOD1996;81:445-9)
Acanthosis nigricans (AN) is a mucocutaneous condition o f undetermined cause. Early detection o f the characteristic pigmented skin lesions m a y be crucial to the prognosis. Oral lesions m a y also be a marker for this disorder. Although eight types o f A N have been described, one type, " m a l i g n a n t " acanthosis nigricans, has served as a marker o f internal malignancy. 1 W h e n cutaneous A N was first reported by Pollitzer 2 in 1890, a link was suspected with abdominal malignancy. By 1909 Pollitzer 3 had confirmed the association. To date numerous cases have been reported that support the original observations o f Pollitzer. K n o w l e d g e of the current classification o f the eight types is important because o f the occm-rence o f both benign and " m a l i g n a n t " types. NonmaligaAssistant Professor and Chair, Division of Oral Medicine and Radiology, Faculty of Dentistry, McGill University, Montreal, Qudbec, Canada. Currently Visiting Assistant Professor, University of California, San Francisco.
bAdjunct Professor of Oral Pathology and Medicine, Clinical Assistant, National Health System (USL/10D), Institute of Stomatology, University of Florence. Cprofessor and Chair, Division of Oral Medicine, School of Dentistry, University of California, San Francisco. dClinical Professor and Associate Chair, Department of Dermatology, University of California, San Francisco. ~Professor of Oral Pathology, School of Dentistry, Professor of Pathology, School of Medicine, University of California, San Francisco. Received for publication Feb. 6, 1995; returned for publication Apr. 23, 1995; accepted for publication June 19, 1995. Copyright 9 1996 by Mosby-Year Book, Inc. 1079-2104/96/$5.00 + 0 7/14/67432
nancy-associated A N (benign AN) is not activated by a tumor, tends to develop at an earlier age, and, like obesity-associated AN, which is usually weight-dependent and reversible, occurs more frequently than the malignant form. The prognosis of malignant A N is dependent on detection and treatment of the associated neoplasm. The underlying malignancy is usually gastric adenocarcinoma. 4 Other malignancies have been found in other regions of the gastrointestinal tract and in the ovaries, uterus, breast, testes, and lungs. 5 Cutaneous A N typically presents as hyperpigmented plaques that progressively thicken, resulting in a velvety texture. Although any area o f the skin m a y be involved, the most c o m m o n sites are the nape o f the neck, sides o f the neck, and axillae. Groin, antecubital, popliteal, and umbilical areas m a y be affected. The onset of the malignant form o f A N m a y appear with three other cutaneous signs: florid cutaneous (and occasionally oral) papillomatosis, especially o f the lips and eyelids, hyperkeratosis of the palms and soles (tylosis), and the sign o f Leser-Trrlat (the sudden appearance of numerous seborrheic keratoses). 1 These clinical markers m a y or m a y not appear before the hyperpigmented lesions of A N appear. This report presents a case o f this rare condition in which marked oral papillomatous lesions developed after multiple cutaneous lesions o f A N appeared and an abdominal malignancy was detected. CASE REPORT
A 57-year-old white man presented to the dermatologist with hyperpigmented velvety skin changes on the nape 445
446
Tyler et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
April 1996
Fig. 1. Axillary pigmentation and verrucous eruption in patient with acanthosis nigricans.
Fig. 3. Extensive papillomatous enlargement and crusting of patient's lips.
Fig. 2. Patient's eye showing hypopigmentation, papillomatosis of lower eyelid, and conjunctivitis.
Fig. 4. Patient's palate showing marked papillomatosis, partially obscuring teeth.
and sides of the neck, the axillae, the nipple, and the groin area. The patient had no other symptoms. A diagnosis of AN was made, and a diagnostic workup was started for the detection of an associated internal malignancy. Examination with computed tomography and magnetic resonance imaging detected an abdominal mass. A laparotomy revealed an unresectable gastric adenocarcinoma with regional lymph node metastasis. Treatment with fluorouracil and leucovorin was started, but the gastric tumor progressed. One year after the initial diagnosis was made, the patient underwent surgical reduction of the tumor, and 1 month after the debulking operation was performed, the skin lesions showed some reduction in size. Two months later oral lesions developed, and the patient was referred to the oral medicine clinic at the University of California, San Francisco, for evaluation. At the time of the oral examination the patient's chief oral complaint was "blistered lips and a tender mouth," and his major medical problem was residual adenocarcinoma that was being treated with chemotherapeutic drugs. Significant cutaneous physical findings
included pigmented, velvety, raised, cutaneous lesions (Fig. 1), periorbital hypopigmentation, conjunctivitis, and mild papillomatosis of the lower eyelid. The patient had recently seen an ophthalmologist with the chief complaint of "blocked tear ducts and watery eyes." Hyperplasia of the lacrimal caruncle and epiphora from occlusion of the lacrimal canaliculi by the papillomatous proliferations were seen (Fig. 2). Oral examination revealed extensive papillomatosis of the lips (Fig. 3) and palatal mucosa (Fig. 4). Involvement of the upper lip was more pronounced than in the lower lip. Lesions appeared as yellow, encrusted, papillomatous growths, giving the lips a swollen appearance. The lesions on the hard palate were generalized with a papillated architecture. The interdental papillae of the palatal gingiva were enlarged and partially obscured the palatal surfaces of the teeth. Biopsy specimens from the upper lip and palate exhibited similar histopathologic changes. These consisted of papillary projections composed of parakeratotic and hyperplastic epithelium supported by slightly inflamed edematous vascular cores (Figs. 5 and 6). No evidence of epi-
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Fig. 5. Photomicrograph of palatal biopsy showing papillary architecture. (Hematoxylin-eosin stain; original magnification x45.)
Fig. 6. Higher power photomicrograph of palatal biopsy showing bland papillary hyperplasia with slight inflammatory infiltrate. (Hematoxylin-eosin stain; original magnification xl00.)
thelial dysplasia or viral inclusions was seen. The microscopic features, although nonspecific, were consistent with the papillary expression of oral acanthosis nigricans. Immunohistochemical stain for human papillomavirus common antigen was negative. An attempt was made to reduce the severity of the oral lesions with isotretinoin at a daily dosage of 40 mg for 6
weeks. Isotretinoin was then supplemented with etretinate (25 mg/day) for 2 weeks. At the end of 6 weeks the skin lesions were less severe, but the oral lesions had increased in severity. A total weekly dose of 10 mg methotrexate was administered two times weekly in an attempt to control the oral lesions. The therapeutic regimen for the oral lesions had very little effect; no significant side effects of the
448
Tyler et al.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
April 1996 medication were noted. Twenty-three months after the initial diagnosis of malignant AN was made, the patient died of multiple organ failure and widespread metastatic adenocarcinoma. DISCUSSION R e c e n t w o r k 1 suggests that w h e n A N occurs with an a s s o c i a t e d m a l i g n a n c y , the secretion o f a variety o f rumor p r o d u c t s (e.g., m e l a n i n - s t i m u l a t i n g hormone, e p i d e r m a l g r o w t h factor, transforming g r o w t h factor-tx) is l i k e l y to h a v e a role in activating m u c o cutaneous e x p r e s s i o n o f A N through the stimulation o f m e l a n o c y t e s , keratinocytes, and fibroblasts. F o r tunately, A N occurs m u c h m o r e frequently w i t h o u t a s s o c i a t e d m a l i g n a n c y . W h e n A N occurs alone or is i n d u c e d b y m e d i c a t i o n , it is a benign, m o s t l y a s y m p tomatic d e r m a t o s i s requiring no treatment. In this case the o c c u r r e n c e o f cutaneous A N was f o l l o w e d b y the detection o f gastric a d e n o c a r c i n o m a and s u b s e q u e n t l y the d e v e l o p m e n t o f oral and perioral p a p i l l o m a t o s i s . It has been r e p o r t e d that m a l i g nancies p r e c e d e d A N in a p p r o x i m a t e l y 20% o f cases, that A N p r e c e d e d the n e o p l a s m in a p p r o x i m a t e l y 20%, and that both A N and the m a l i g n a n c y d e v e l o p e d s i m u l t a n e o u s l y in a p p r o x i m a t e l y 60%. 6 T h e characteristic p i g m e n t e d skin lesions m a y be a c c o m p a n i e d b y oral, perioral, and periorbital p a p i l l o m a t o s i s . T h e s e latter lesions m a y be v a l u a b l e clinical m a r k e r s for A N and p o s s i b l y for occult m a l i g n a n t tumors. This case illustrates the value o f being c o g n i z a n t o f the association o f clinical markers; the r e c o g n i t i o n o f A N and the level o f suspicion that this finding prov o k e d were r e s p o n s i b l e for the detection o f the m a lignancy. W h e n the m a l i g n a n c y was c o n f i r m e d b y surgery, clinical d i a g n o s i s and colTelation o f n e w l y a p p e a r i n g oral p a p i l l o m a t o s i s followed. A l l clinical findings, h i s t o p a t h o l o g i c findings, and the clinical course o f this case were consistent with the findings o f the r e p o r t e d cases o f this rare s y n d r o m e o f m a l i g nant A N . The unesthetic a p p e a r a n c e o f the skin is usually o f concern to the patient. In this case the c h i e f c o m p l a i n t was sore m o u t h and lips that resulted in an inability to eat c o m f o r t a b l y . In a r e v i e w b y S e d a n o and Gorlin 7 o f m o r e than 200 cases o f A N with a n e o p l a s t i c association, up to 4 0 % h a d the characteristic oral lesions. T h e lips and tongue are m o s t frequently involved, but the palatal m u c o s a and the g i n g i v a l interdental p a p i l l a e m a y b e s e v e r e l y affected. T h e oral lesions rarely a p p e a r p i g m e n t e d 8; the dark c o l o r o f the skin is due to acanthosis and not to an increase in melanin. E v a l u a t i n g the skin for h y p e r p i g m e n t a t i o n m a y b e m i s l e a d i n g , b e c a u s e atopic dermatitis and tinea corporis m a y also p r o d u c e similar d a r k lesions.
P a p i l l o m a t o u s g r o w t h s o f the p h a r y n g e a l , laryngeal, e s o p h a g e a l , and a n o g e n i t a l areas have also been describe& 9 I m p r o v e m e n t has been r e p o r t e d 1~ in the oral m u c o s a l lesions o f a patient with simultaneous c u t a neous A N and a m a l i g n a n t t u m o r after treatment with anticancer drugs. In this case, although s o m e reduction in the size o f the skin lesions f o l l o w e d partial surgical r e m o v a l o f the tumor, the effect was t e m p o rary, and c h e m o t h e r a p y h a d no effect on the reduction o f the m u c o c u t a n e o u s lesions. The p a p i l l o m a t o u s lesions o f A N have been successfully treated with oral retinoids. 11-13 The rationale for use o f those agents is related to their effect on cellular g r o w t h - p r o m o t i n g factors and to their antikeratinizing properties. In this case no m e a s u r a b l e d e c r e a s e in the signs or s y m p t o m s was noticed with p r o l o n g e d retinoid therapy. M e t h o t r e x a t e was prescribed for its antiproliferative effects to halt the progression o f the oral lesions, but the patient d i e d o f c o m p l i c a t i o n s a s s o c i a t e d with his m a l i g n a n c y before its v a l u e could be assessed. T u m o r s associated with A N are u s u a l l y aggressive a d e n o c a r c i n o m a s ; the a v e r a g e survival o f the patient after d i a g n o s i s is less than 2 years. B e c a u s e o f the close link o f A N with gastrointestinal malignancies, it has b e e n suggested that if the original n e o p l a s m is not an a d e n o c a r c i n o m a , a search should be conducted to rule out the p o s s i b i l i t y o f a second m a l i g n a n c y o f gastrointestinal origin.1 This case supports the observation that extensive oral p a p i l l o m a t o s i s m a y be a c o m p o n e n t o f A N and an external sign o f an occult internal m a l i g n a n c y .
REFERENCES
]. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1-19. 2. Pollitzer S. Acanthosis nigricans. In: Unna PG, Morris M, Besnier E, et al., editors. International atlas of rare skin diseases. London: HK Lewis & Co, 1890: 1-3. Cited in: Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1 19. 3. Pollitzer S. Acanthosis nigricans: a symptom of a disorder of the abdominal sympathetic. JAMA 1909;53:1369-73. 4. Curtb HO, Hilberg AW, Macbacek GF. The site and histology of the cancer associated with malignant acanthosis nig ricans. Cancer 1962; 15:364-82. 5. Rogers DL. Acanthosis nigricans. Sem Dermatol 1991;10: 160-3. 6. Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, et al., editors. Cancer of the skin: biology~iagnosis--management. Philadelphia: WB Saunders, 1976:1308-41. 7. Sedano HO, Gorlin RJ. Acanthosis nigricans. ORAL SURe ORAL MED ORALPATHOL1987;63:462-7. 8. Nomura J, Tagawa T. Acanthosis nigricans with oral lesions and a malignant visceral tumor: a case report. J Oral Maxil lofac Surg 1992;50:169-72.
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 81, Number 4 9. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;114:1803-6. 10. Kazuhiko N, Masatoma M. Improvement of oral lesions associated with malignant acanthosis nigricans after treatment of lung cancer. ORAL SURG ORAL MED ORAL PATHOL 1989; 68:74-9. 11. Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980;116:110-1. 12. Darmstadt GL, Yokel BK, Horn TD, et al. Treatment of ac anthosis nigricans with tretinoin. Arch Dermatol 1991; 127: 1139-40. 13. Baalbaki SA, Malak JA, A1-Khars M A A . Confluent and re-
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ticulated papillomatosis: treatment with etretinate. Arch Dermatol 1993;129:961-3.
Reprint requests: Martin T. Tyler, DDS Division of Oral Medicine and Radiology Faculty of Dentistry McGill University 1650 Cedar Avenue, B3-112 Montr6al, Queb6c, Canada H3G 1A4
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