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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 Montreal, Quebec, 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 SURG ORAL MED ORAL PATHOL ORAL RADIOL ENDOD 1996;81:445-9)

Acanthosis nigricans (AN) is a mucocutaneous con­dition of undetermined cause. Early detection of the characteristic pigmented skin lesions may be crucial to the prognosis. Oral lesions may also be a marker for this disorder. Although eight types of AN have been described, one type, "malignant" acanthosis nigricans, has served as a marker of internal malig­nancy.1

When cutaneous AN was first reported by Pol­litzer2 in 1890, a link was suspected with abdominal malignancy. By 1909 Pollitzer3 had confirmed the association. To date numerous cases have been reported that support the original observations of Pollitzer. Knowledge of the current classification of the eight types is important because of the occurrence of both benign and "malignant" types. Nonmalig-

"Assistant Professor and Chair, Division of Oral Medicine and Radiology, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada. Currently Visiting Assistant Professor, Univer­sity of California, San Francisco. h Adjunct Professor of Oral Pathology and Medicine, Clinical As­sistant, National Health System (USUIOD), Institute of Stoma­tology, University of Florence. cprofessor and Chair, Division of Oral Medicine, School of Den­tistry, University of California, San Francisco. dCJinical Professor and Associate Chair, Department of Derma­tology, University of California, San Franci~co. cprofessor 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© 1996 by Mosby- Year Book, Inc. 1079-2104/96/$5.00 + 0 7/14/67432

nancy-associated AN (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 AN 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 AN typically presents as hyperpig­mented plaques that progressively thicken, resulting in a velvety texture. Although any area of the skin may be involved, the most common sites are the nape of the neck, sides of the neck, and axillae. Groin, an­tecubital, popliteal, and umbilical areas may be affected. The onset of the malignant form of AN may appear with three other cutaneous signs: florid cuta­neous (and occasionally oral) papillomatosis, espe­cially of the lips and eyelids, hyperkeratosis of the palms and soles (tylosis), and the sign ofLeser-Trelat (the sudden appearance of numerous seborrheic keratoses). 1 These clinical markers may or may not appear before the hyperpigmented lesions of AN ap­pear.

This report presents a case of this rare condition in which marked oral papillomatous lesions developed after multiple cutaneous lesions of AN 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 a/.

Fig. 1. Axillary pigmentation and verrucous eruption in patient with acanthosis nigricans.

Fig. 2 . Patient's eye showing hypopigmentation, papillo­matosis of lower eyelid, and conjunctivitis.

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

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY April 1996

Fig. 3. Extensive papillomatous enlargement and crust­ing of patient's lips.

Fig. 4 . Patient's palate showing marked papillomatosis, partially obscuring teeth.

included pigmented, velvety, raised, cutaneous lesions (Fig. I), 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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Tyler et al. 447

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 xlOO.)

thelia! 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 a/.

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 Recent work 1 suggests that when AN occurs with

an associated malignancy, the secretion of a variety of tumor products (e.g., melanin-stimulating hor­mone, epidermal growth factor, transforming growth factor-a) is likely to have a role in activating muco­cutaneous expression of AN through the stimulation of melanocytes, keratinocytes, and fibroblasts. For­tunately, AN occurs much more frequently without associated malignancy. When AN occurs alone or is induced by medication, it is a benign, mostly asymp­tomatic dermatosis requiring no treatment.

In this case the occurrence of cutaneous AN was followed by the detection of gastric adenocarcinoma and subsequently the development of oral and peri­oral papillomatosis. It has been reported that malig­nancies preceded AN in approximately 20% of cases, that AN preceded the neoplasm in approximately 20%, and that both AN and the malignancy developed simultaneously in approximately 60%.6 The charac­teristic pigmented skin lesions may be accompanied by oral, perioral, and periorbital papillomatosis. These latter lesions may be valuable clinical markers for AN and possibly for occult malignant tumors.

This case illustrates the value of being cognizant of the association of clinical markers; the recognition of AN and the level of suspicion that this finding pro­voked were responsible for the detection of the ma­lignancy. When the malignancy was confirmed by surgery, clinical diagnosis and correlation of newly appearing oral papillomatosis followed. All clinical findings, histopathologic findings, and the clinical course of this case were consistent with the findings of the reported cases of this rare syndrome of malig­nant AN.

The unesthetic appearance of the skin is usually of concern to the patient. In this case the chief complaint was sore mouth and lips that resulted in an inability to eat comfortably. In a review by Sedano and Gor­lin 7 of more than 200 cases of AN with a neoplastic association, up to 40% had the characteristic oral le­sions. The lips and tongue are most frequently involved, but the palatal mucosa and the gingival in­terdental papillae may be severely affected. The oral lesions rarely appear pigmented8; the dark color of the skin is due to acanthosis and not to an increase in melanin. Evaluating the skin for hyperpigmentation may be misleading, because atopic dermatitis and tinea corporis may also produce similar dark lesions.

ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY April/996

Papillomatous growths of the pharyngeal, laryngeal, esophageal, and anogenital areas have also been de­scribed.9

Improvement has been reported 10 in the oral mucosal lesions of a patient with simultaneous cuta­neous AN and a malignant tumor after treatment with anticancer drugs. In this case, although some reduc­tion in the size of the skin lesions followed partial surgical removal of the tumor, the effect was tempo­rary, and chemotherapy had no effect on the reduction of the mucocutaneous lesions.

The papillomatous lesions of AN have been suc­cessfully treated with oral retinoids. 11 · 13 The rationale for use of those agents is related to their effect on cellular growth-promoting factors and to their anti­keratinizing properties. In this case no measurable decrease in the signs or symptoms was noticed with prolonged retinoid therapy. Methotrexate was pre­scribed for its anti proliferative effects to halt the pro­gression of the oral lesions, but the patient died of complications associated with his malignancy before its value could be assessed.

Tumors associated with AN are usually aggressive adenocarcinomas; the average survival of the patient after diagnosis is less than 2 years. Because of the close link of AN with gastrointestinal malignancies, it has been suggested that if the original neoplasm is not an adenocarcinoma, a search should be conducted to rule out the possibility of a second malignancy of gastrointestinal origin. 1 This case supports the obser­vation that extensive oral papillomatosis may be a component of AN and an external sign of an occult internal malignancy.

REFERENCES

I . 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 di ~­eases. 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 . Curth HO, Hilberg A W, Machacek GF. The site and histol­ogy of the cancer associated with malignant acanthosis nig­ricans. 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, Gum port SL, Popkin GL, et al., editors. Cancer of the skin: biology--diagnosis- management. Philadelphia: WB Saun­ders, 1976: 1308-41.

7 . Sedano HO, Gorlin RJ . Acanthosis nigricans . ORAL SuRa ORAL MED ORAL PATHOL 1987;63:462-7.

8. Nomura J, Tagawa T. Acanthosis nigricans with oral lesions and a malignant visceral tumor: a case report. J Oral Maxil­lofac Surg 1992;50: 169-72.

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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.

II . Katz RA. Treatment of acanthosis nigricans with oral isotre­tinoin. Arch Dermatol 1980; I 16: I 10-1.

12. Darmstadt GL, Yokel BK, Hom TD, et al. Treatment of acanthosis nigricans with tretinoin. Arch Dermatol 1991; 127: 1139-40.

13. Baalbaki SA, Malak JA, Al-Khars MAA. Confluent andre-

AVAILABILITY OF JOURNAL BACK ISSUES

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ticulated papillomatosis: treatment with etretinate. Arch Der­matol 1993;129:96I-3.

Reprint requests: Martin T. Tyler, DDS Division of Oral Medicine and Radiology Faculty of Dentistry McGill University 1650 Cedar A venue, 83- 112 Montreal, Quebec, Canada H3G 1A4

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