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Case Report Oral Acanthosis Nigricans as a Marker of Internal Malignancy. A Case Report Francesco Cairo,* Ida Rubino,† Roberto Rotundo,* Giovanpaolo Pini Prato,* and Giuseppe Ficarra†
Background: Acanthosis nigricans (AN) is a rare mucocutaneous condition that can involve the oral tissues. There are 2 clinical forms of AN: benign and malignant. Benign AN is related to systemic diseases such as diabetes and obesity or can be induced by drugs such as systemic corticosteroids, nicotinic acid, estrogens, insulin, and fusidic acid. Malignant AN appears in association with tumors such as lung, ovarian, breast, and gastric carcinoma. Methods: A rare case of malignant AN that initially manifested in the oral cavity of a 73-year-old patient is reported. Results: A bladder and lung carcinoma were detected following the diagnosis of AN . Conclusions: The diagnostic importance of oral AN is emphasized because, in our patient, its recognition led to the detection of 2 occult malignant tumors. J Periodontol 2001;72:1271-1275. KEY WORDS Acanthosis nigricans; paraneoplastic syndromes; bladder neoplasms/diagnosis; lung neoplasms/ diagnosis; mouth neoplasms/diagnosis.
* School of Dental Medicine, University of Florence, Florence, Italy. † Section of Oral Pathology and Medicine, Department of Odontology and Stomatology.
J Periodontol • September 2001
Acanthosis nigricans (AN) is a mucocutaneous disorder of unclear origin characterized by the presence of hyperpigmented papillary lesions on the skin and papillomatous lesions in the oral cavity.1 This syndrome was first described in 1890 by Pollitzer,2 who discovered its association with an abdominal cancer. The characteristic feature of AN is a dark, velvety thickening of the skin in locations such as the axillae, neck, groin, umbilical area, antecubital and popliteal surface. The lesions initially appear as hyperpigmented areas that progressively transform into extensive cutaneous papillomatosis. The dark color is attributable to epithelial acanthosis rather than to an increased production of melanin or proliferation of melanocytes.1 A localized or generalized pruritus may be present, especially when AN is associated with malignant tumors. Although mucosal involvement is more frequent in the malignant form, it can also occur in benign AN.1,3 In ocular AN, the palpebral and bulbar conjunctivae display gross multiple papillations with involvement of the periorbital skin.1 Oral AN is characterized by extensive papillomatosis of the lips, palate, gingiva, and tongue. Hyperplasia of the interdental papilla and pseudopockets have been reported as well as hypertrophy of the filiform papillae and a deep fissuring of the tongue.4,5 Oral AN may extend to the nasal, pharyngeal, and esophageal mucous membranes.1,6 The multiple soft papillary lesions in the esophagus can be visualized by endoscopic or radiographic examination. Although AN is well known as a disease related to cancer, several studies have reported an association with systemic disorders and congenital syndromes.7-10 These conditions are quite complex and numerous as shown in Tables 1 and 2. Benign AN may be hereditary, drug-induced, or related to systemic diseases such as diabetes, obesity, Cushing’s syndrome, or Addison’s disease.1 AN has also been observed after the administration of drugs such as systemic corticosteroids, nicotinic acid, estrogens, insulin, and fusidic acid.1 Benign AN tends to develop at an earlier age and occurs more frequently than the
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Case Report Table 1.
Table 2.
Diseases Linked to Benign Form of AN
Tumors Linked to Malignant Form of AN
Endocrine Disorders Acromegaly Addison’s disease Cushing’s disease Hypothyroidism Type 2 diabetes mellitus Insulin resistance syndrome (type A, B, C) Obesity Polycystic ovarian syndrome and ovarian hyperthecosis Pinealoma Congenital Syndromes Ataxia teleangiectasia Bloom syndrome Crouzon’s disease Prader-Willi syndrome Leprechaunism Total lipodistrophy Drugs Estrogens Glucocorticoids Pituitary extracts Nicotinic acid Fusidic acid Modified from Rogers.10
malignant form.1 Stuart et al.11 reported that among 1,412 children, 7.1% were found to be affected by benign AN. The prevalence of benign AN was less than 1% among white non-Hispanics, while it was higher among Hispanics (5.5%) and blacks (13.3%). In particular, it was found that the prevalence among adolescents who weighed more than 200% of their ideal body weight was 66%.11 In an obese adult population, 74% of the patients were affected.12 The most frequent form of benign AN is generally associated with insulin-resistant diabetes and hyperinsulinemia. The pathogenesis of this condition is related to the unbound serum insulin that stimulates fibroblasts (via the insulin-like growth factor receptors) and keratinocytes, resulting in a growth-promoting effect on these cells.9,10 Malignant AN is considered part of the spectrum of paraneoplastic syndromes associated with malignant tumors, but it is not in itself malignant.1 Malignant AN is rarer than the benign form and is more frequent in middle-aged and elderly people.13 In analyzing the data of 12,000 cancer patients, Andreev6 observed only 2 cases of malignant AN.
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Squamous Cell Carcinomas Lung, uterine cervix, hyphopharynx Adenocarcinomas Esophagus, stomach, colon, hepatic ducts, pancreas, breast, uterus, ovaries, testes, lung Lymphomas Hodgkin’s disease, non-Hodgkin’s lymphomas Others Alveolar cell carcinoma, osteosarcoma, pinealoma, mycoses fungoides
This article reports on a patient with oral, esophageal, and cutaneous AN as well as malignant visceral tumors and presents a discussion of the pertinent literature. CASE REPORT A 73-year-old Caucasian man was referred to the Section of Oral Pathology and Medicine of the University of Florence for the evaluation of verrucous papules on the oral mucosa associated with a thickening and darkening of the skin. The patient’s medical history included hypertension, gastritis, mild depression, and heavy cigarette smoking. The patient used antidepressant and antihypertensive drugs. No other systemic diseases were reported. Clinical examination of the oral cavity revealed extensive papillomatosis of the vestibular mucosa, dorsum of the tongue, palate, and gingiva (Figs. 1 and 2). Reported oral symptoms were a burning sensation and pain accompanying the intake of hot food. Subtle changes in the skin were visible on the neck, axillae, and the internal surface of the thighs, with hyperpigmented and thickened areas. A clinical diagnosis of oral AN was made and a biopsy was taken from the palate and buccal mucosa and fixed in formalin. Microscopic examination of the tissue specimens showed marked papillary hyperplasia of the epithelial lamina with no cellular atypia or any signs of viral infection. The lamina propria was formed by loose, fibrous connective tissue with the presence of a mild aspecific inflammatory cell infiltrate (Figs. 3 and 4). The clinical and histological findings suggested a diagnosis of AN, and investigation for an occult visceral cancer was then begun. The patient underwent
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Figure1.
Figure 3.
Extensive papillomatosis of the edentulous gingiva.
Papillary hyperplasia of the epithelial lamina (hematoxylin & eosin, original magnification ×4).
the thorax, which revealed a mediastinal mass and opacity of the upper lobe of the left lung (Fig. 5). A bronchoscopy detected a neoplastic growth in the left lung which, after biopsy, was identified as squamous cell carcinoma. The extension of the malignancy made surgical treatment unfeasible, thus chemotherapy and radiotherapy were begun. During treatment of the lung cancer, the oral lesions remained stable, showing no response to the anticancer treatment. Two years after the initial diagnosis of oral malignant AN, the patient died of multiple organ failure and widespread metastatic lung carcinoma. Figure 2. Papillomatosis of the right vestibular mucosa.
gastrointestinal and chest x-rays, a complete blood count, a serum profile, and urinalysis, all of which were normal. Multiple papillary lesions in the esophagus were detected by endoscopic examination. An abdominal ultrasound examination did not show any gastrointestinal masses but revealed a vegetative plaque of the bladder and prostatic hypertrophy. A biopsy of the bladder lesion was taken, which revealed the presence of a grade 3 transitional carcinoma. The bladder tumor was then resected endoscopically. Nevertheless, the patient’s general condition began to deteriorate with the appearance of hemoptysis and dysfonia and the progression of oral, esophageal, and cutaneous lesions. About 12 months after the initial diagnosis of AN, the patient underwent a CT scan of
J Periodontol • September 2001
DISCUSSION The cause of malignant AN is related to the secretion of a variety of tumor products such as epidermal growth factor, transforming growth factor-alpha, melanin-stimulating hormones, and other hormones that have the ability to stimulate the growth of melanocytes, keratinocytes, and fibroblasts.14 These tumor products may have autocrine, paracrine, or endocrine actions, which explains why they may affect distant host tissues. Regression of AN after removal of the associated malignant tumors further supports the hypothesis that certain tumor products play a role in the pathogenesis of AN.1 In this paper, a patient with oral, esophageal, and cutaneous AN is described. The clinical manifestations were extensive papillomatosis of the oral mucosa associated with esophageal involvement and cutaneous pigmented lesions confined to the neck,
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Figure 5. CT scan showing a mediastinal neoplasia.
Figure 4. Higher magnification of Figure 3: papillary hyperplasia, acanthosis, and slight inflammatory infiltrate in the lamina propria (H&E, original magnification ×20).
axillae, and thighs. These findings, plus the histopathologic aspects and the clinical course of this case, were consistent with previously reported cases of malignant AN.1,4,15-17 The discovery of these findings in an aged individual, with no family history of AN, endocrinopathies, or use of drugs inducing AN, led to the suspicion of a possible association with an internal malignancy. After a full clinical investigation, a grade 3 transitional carcinoma of the bladder and a squamous carcinoma of the lung were found. The first tumor discovered was the bladder carcinoma; this was followed (12 months after the initial diagnosis of AN) by the squamous cell carcinoma of the left lung. It is reasonable to state that in this patient, both tumors were linked to a common etiological factor
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due to heavy smoking. The bladder cancer was very limited in size, thus surgical treatment led to its definitive cure. On the other hand, the lung carcinoma was already in an advanced stage when discovered, preventing the possibility of radical surgery. Despite aggressive treatment with radiotherapy and chemotherapy, the lung tumor progressed and the patient died of metastatic disease 2 years after the initial diagnosis of mucocutaneous AN. Malignant AN is a paraneoplastic disorder of the skin and oral mucosa that is associated with an underlying neoplasm. From previous studies it appears that, although rarely, malignant AN may precede the clinical symptoms of cancer in 17% to 20% of cases.8 Most malignant tumors in AN are abdominal tumors such as gastric, gallbladder, pancreatic, and ovarian carcinoma. Other carcinomas, such as those in the esophagus, testes, breast, uterus, lungs, and bladder have been reported with less frequency. A case of AN showing cutaneous and mucosal signs linked to a lung tumor has been described in a recent report.18 In the case of our patient, it seems reasonable to hypothesize that the occurrence of malignant AN was linked more to lung carcinoma than to bladder carcinoma, as the latter was at an early stage, confined to the superficial bladder epithelium. Additional evidence may be the fact that AN progressed despite the surgical eradication of the bladder tumor. Involvement of the oral mucosa is more common in malignant AN than in benign forms.4,15,16,19 In a recent review of more than 200 cases of malignant AN, up to 40% showed oral lesions.15 There has been only one case report describing malignant AN limited
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Case Report to the buccal mucosa.5 AN may involve any part of the oral mucosa and extend to pharyngeal and esophageal mucous membranes. Oral AN, unlike skin lesions, is rarely pigmented.1 Histologically, both benign and malignant AN show marked epithelial hyperplasia with acanthosis and prominent parakeratosis of the epithelial lamina.1 This morphological similarity means that the histological features are not distinctive of either the benign or the malignant form.17 Therefore, the diagnosis of malignant AN cannot be based solely on histopathology but is made according to clinical findings such as the patient’s age, the exclusion of any familial history of AN, systemic diseases or use of drugs, and the confirmation of the presence of an internal malignancy. The histologic differential diagnosis of AN should include human papilloma virus-related oral lesions, leucoedema, benign hereditary intraepithelial dyskeratosis, and white sponge nevus.4,17 In conclusion, this case report stresses the importance of the diagnosis of oral AN. The dentist may be the clinician who discovers this lesion during routine clinical practice. The presence of oral AN may be the first clinical sign of an undiagnosed internal cancer.
10. Rogers DL. Acanthosis nigricans. Semin Dermatol 1991;10:160-163. 11. Stuart CA, Pate CJ, Peters EJ. Prevalence of acanthosis nigricans in an unselected population. Am J Med 1989;87:269-272. 12. Hud JA Jr., Cohen JB, Wagner JM, Cruz PD. Prevalence and significance of acanthosis nigricans in an adult obese population. Arch Dermatol 1992;128:941944. 13. Kierland RR. Acanthosis nigricans: An analysis of data in twenty-two cases and a study of its frequency in necropsy material. J Invest Dermatol 1947;9:299-305. 14. Hall TC. Paraneoplastic syndromes: Mechanisms. Semin Oncol 1997;24:269-276. 15. Sedano HO, Gorlin RJ. Acanthosis nigricans. Oral Surg Oral Med Oral Pathol 1987;63:462-467. 16. Ramirez-Amador V, Esquivel-Pedraza L, CaballeroMendoza E, Berumen-Campos J, Orozco-Topete R, Angeles-Angeles A. Oral manifestations as a hallmark of malignant acanthosis nigricans. J Oral Pathol Med 1999;28:278-281. 17. Hall JM, Moreland A, Cox GJ, Wade TR. Oral acanthosis nigricans: Report of a case and comparison of oral and cutaneous pathology. Am J Dermophatol 1988;10:68-73. 18. Bottoni U, Dianzani C, Pranteda G, et al. Florid cutaneous and mucosal papillomatosis with acanthosis nigricans revealing a primary lung cancer. J Eur Acad Dermatol Venereol 2000;14:205-208. 19. Curth HO. Malignant acanthosis nigricans. Arch Dermatol 1970;102:479-481.
REFERENCES 1. 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., eds. International Atlas of Rare Skin Disease. London: HK Lewis & Company; 1890:1-3. 3. Pindborg JJ, Gorlin RJ. Oral changes in acanthosis nigricans (juvenile type): Survey of the literature and report of a case. Acta Derm Venereol 1962;42:63-71. 4. Tyler MT, Ficarra G, Silverman S, Odom RB, Regezi GA. Malignant acanthosis nigricans with florid papillary oral lesions. Oral Surg Oral Med Oral Pathol 1996; 81:445-449. 5. Andreev VC, Raichev RD, Stojanov A. Acanthosis nigricans of oral mucosa. Dermatologica 1963;126:25-29. 6. Andreev VC. Malignant acanthosis nigricans. Semin Dermatol 1984;3:265-272. 7. Curth HO. Cancer associated with acanthosis nigricans: Review of literature and report of a case of acanthosis nigricans with cancer of the breast. Arch Surg 1943;47:517-552. 8. Curth HO. Classification of acanthosis nigricans. Int J Dermatol 1976;15:592-593. 9. Rendon MI, Cruz PD, Sontheimer RD, Bergstresser PR. Acanthosis nigricans: A cutaneous marker of tissue resistance to insulin. J Am Acad Dermatol 1989;21: 461-469.
J Periodontol • September 2001
Send reprint requests to: Prof. Giovanpaolo Pini Prato, Viale Matteotti 11, 55100 Firenze, Italy. Fax: 39 055572881; e-mail:
[email protected] Accepted for publication March 16, 2001.
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