Acanthosis Nigricans with Endometrial Carcinoma: Case Report and Review of the Literature

Acanthosis Nigricans with Endometrial Carcinoma: Case Report and Review of the Literature

Gynecologic Oncology 84, 332–334 (2002) doi:10.1006/gyno.2001.6472, available online at http://www.idealibrary.com on CASE REPORT Acanthosis Nigrican...

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Gynecologic Oncology 84, 332–334 (2002) doi:10.1006/gyno.2001.6472, available online at http://www.idealibrary.com on

CASE REPORT Acanthosis Nigricans with Endometrial Carcinoma: Case Report and Review of the Literature Tarek M. Mekhail, M.D., 1 and Maurie Markman, M.D. Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Received April 6, 2001; published online December 13, 2001

Background. Acanthosis nigricans is classified into benign and malignant forms on the basis of clinical associations. The main interest in acanthosis nigricans has been based on its association with malignancy because of the dramatic clinical appearance of the skin lesions and the usually rapidly fatal nature of the underlying disease. “Tripe palms” is a descriptive term of acanthosis nigricans of the palms. It more often is associated with internal malignancy. Most importantly, it often precedes the diagnosis of a new or recurrent tumor. Malignant acanthosis nigricans is most commonly associated with intra-abdominal malignancies. There are very few reports in the literature of malignant acanthosis nigricans associated with gynecological malignancies. Only five cases of endometrial carcinoma associated with acanthosis nigricans and/or tripe palms have been reported in the literature. Case. A 69-year-old African-American female presented with skin changes consistent with the diagnosis of acanthosis nigricans and tripe palms. More than 14 months later she was found to have endometrial carcinoma. She subsequently underwent total abdominal hysterectomy and salpingo-oophorectomy followed by chemotherapy with paclitaxel and carboplatin. During treatment of the underlying malignancy the skin condition dramatically improved. Conclusion. Tripe palms can be associated with endometrial carcinoma and may be the first sign of malignancy. Malignant acanthosis nigricans may improve with treatment of the underlying malignancy. Patients who present with tripe palms may need to undergo workup to search for underlying malignancy. © 2001 Elsevier Science

Key Words: endometrial carcinoma; acanthosis nigricans; paraneoplastic syndromes.

CASE REPORT A 69-year-old African-American female presented to the dermatology clinic at our institution in May of 1997 with generalized painless nonitchy thickening and discoloration of 1

To whom correspondence and reprint requests should be addressed at Department of Hematology and Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. Fax: 1 216 444 9464. E-mail: [email protected] 0090-8258/01 $35.00 © 2001 Elsevier Science All rights reserved.

the skin of the palms, face, neck, axillae, groin, and the skin under the breasts. She had no other symptoms. At that time, the patient was 10 years postmenopausal. She had a history of hypothyroidism, but no history of diabetes mellitus and no other significant medical disorders. The patient had been receiving hormone- and thyroid-replacement therapy for several years. She had a brother who had prostate cancer. The family history was otherwise unremarkable for malignancies. Evaluation at the dermatology clinic was descriptive of black velvety lichenified skin plaques consistent with the diagnosis of acanthosis nigricans. The skin of the palms was described as “tripe palms.” Skin biopsy was consistent with the diagnosis of acanthosis nigricans. Evaluation thereafter focused on the search for an underlying internal malignancy. Examination revealed a moderately obese female. General examination was otherwise within normal limits. Complete blood count and basic labs were all within normal limits. The patient was referred for endocrine, gynecologic, and oncology consultations. Clinical and laboratory data showed the patient to be euthyroid. Gynecologic examination, Pap smear, upper gastrointestinal endoscopy, colonoscopy, chest X ray, mammography, and CT scans of the abdomen, pelvis, and chest revealed no abnormal findings. The workup was repeated 6 months later and remained negative for underlying malignancies. In July of 1999, in response to a transient periumbilical pain, abdominal ultrasound and CT scan of the pelvis were performed, which showed a right adnexal cystic structure consistent with the appearance of hydrosalpinx. The CA 125 was within normal limits. Secondary to the benign appearance of the adnexal mass and to the disappearance of the pain, it was elected to follow up with the patient in 2 months. Repeat CT scan of the abdomen at that time revealed an increase in the size of the adnexal mass with a more complex structure. Transvaginal ultrasound showed a 9.7 ⫻ 4.5 ⫻ 6.3 cm cystic structure with internal echogenicity with some vascular signals. The uterus appeared normal except for a small leiomyoma. The CA 125 remained within normal limits.

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The patient underwent laparascopy and subsequently total abdominal hysterectomy, salpingo-oophorectomy, and periaortic lymph node sampling. Pathological examination revealed a large parametrial mass. The tumor invaded into the serosa of the uterus but not into the myometrium or underlying endometrium. Both ovaries were negative for neoplasm. The histopathologic features of the tumor showed greater than 75% tubular formation but a high nuclear grade in focal areas. Four of five periaortic lymph nodes contained metastatic adenocarcinoma. Immunohistochemical studies of the tumor revealed that the tumor cells were diffusely strongly positive for cytokeratin 7 and negative for cytokeratin 20. These findings were consistent with an adenocarcinoma of mu¨llerian origin and argued against a metastatic carcinoma from the gastrointestinal tract. Overall, the diagnosis was consistent with endometrioid adenocarcinoma with a high nuclear grade. Through this period the patient’s acanthosis nigricans was worsening clinically. Due to the high-grade histology and the involvement of the periaortic lymph nodes, in June 2000 she was started on chemotherapy with paclitaxel and carboplatin every 3 weeks. After two cycles of chemotherapy the patient noticed significant improvement of the skin, especially that of the palms. This was confirmed by examination by a dermatologist. The patient completed six cycles of chemotherapy by October 2000 and had no evidence of disease recurrence at that time. In February 2001 she had a brief flare of the acanthosis nigricans. The patient had no clinical or radiological evidence of disease recurrence when she was last seen in August of 2001. DISCUSSION Acanthosis nigricans, first described simultaneously by Pollitzer [1] and Janovsky in 1890 [2], is a symmetric eruption characterized by a hyperpigmented, velvety cutaneous thickening that can occur on any part of the body, but characteristically affects the axillae, nape and sides of the neck, the groin, antecubital and popliteal surfaces, and umbilical areas. Histologic examination typically reveals hyperkeratosis and papillomatosis with slight, irregular acanthosis and usually no hyperpigmentation [3]. Acanthosis nigricans can be classified into benign and malignant forms on the basis of clinical associations. Benign acanthosis nigricans may be familial, drug induced, or related to a variety of endocrinological disorders, in particular the syndrome of insulin resistance and obesity [4, 5]. Acanthosis nigricans prevalence is different among races with a prevalence of 13.3% of blacks, 5.5% of Hispanics, and fewer than 1% of white non-Hispanics [6]. The main interest in acanthosis nigricans has been based on its association with malignancy because of the dramatic clinical appearance of the skin lesions and the usually rapidly fatal nature of the underlying disease. Acanthosis nigricans became identified as the foremost cutaneous marker of internal malignancy [7]. Malig-

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nant acanthosis nigricans is more rare than acanthosis nigricans not induced by cancer, although the exact incidence is unknown. In one study, only 2 of 12,000 cancer patients in 10 years were noted to have acanthosis nigricans [8]. Malignant acanthosis nigricans often coexists with three other cutaneous markers of internal malignancy: the sign of Leser–Tre´lat [9 –11], florid cutaneous papillomatosis [10, 12], and hyperkeratosis of the palms and soles (tylosis) [12–15]. Tripe palms is a descriptive term of acanthosis nigricans of the palms. This term was first introduced by Clarke [16] and later popularized by Breathnach and Wells [13]. Although tripe palms has been reported without associated malignancy, it more often is associated with internal malignancy [14]. Most importantly, it often precedes the diagnosis of a new or recurrent tumor [14]. In a review of the literature by Cohen and colleagues of 77 patients with tripe palms, an association with malignancy was documented in 90% of these individuals (69 patients) and was suspected, although not proven, in an additional 4% (3 patients) [14]. Tripe palms were reported to precede the discovery of cancer by as long as 15 months [17]. Malignant acanthosis nigricans is reported to be most commonly associated with intra-abdominal malignancies. In a review by Curth of 191 patients with malignant nigricans, 177 (92%) had an abdominal cancer, 69% of which were gastric. Only 14 patients had extra-abdominal malignancies [18]. Mukai [19] described 94 probable cases of malignant acanthosis nigricans, of which 58 (61%) were associated with stomach cancer. In a more recent review by Cohen and colleagues on the association of tripe palms and malignancies, gastric carcinoma accounted for 30% of 74 patients. Intra-abdominal malignancy accounted for the majority (60%) of cases [15]. Acanthosis nigricans associated malignancies tend to be very aggressive; the average survival after their discovery is less than 2 years [20]. There are very few reports in the literature of malignant acanthosis nigricans associated with gynecological malignancies. To our knowledge only five cases of endometrial carcinoma associated with acanthosis nigricans and/or tripe palms have been reported in the literature [18, 21–23]. There are also very few reports of association with squamous cell carcinoma of the cervix [24] and with ovarian carcinoma [25]. Our patient, a moderately obese African-American, presented with skin manifestations consistent with acanthosis nigricans. She had no symptoms or signs at the time of presentation that suggested an internal malignancy. As previously noted, acanthosis nigricans appears to be more frequent in blacks and is associated with obesity. The presentation with involvement of the palms, tripe palms, raised the suspicion of malignant acanthosis nigricans. And indeed it was the first sign of a malignancy that was discovered 14 months later. In the five cases previously reported in the literature, acanthosis nigricans in one patient and tripe palms in another patient preceded the discovery of endometrial cancer by 4 and 3 years, respectively [22, 26]. In the other three cases

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acanthosis nigricans was concurrent with the diagnosis of malignancy [18, 21, 23]. Another interesting point of our patient’s course was the response to treatment. She noted significant improvement of skin of the palm after surgery and two courses of chemotherapy. This further enforces the correlation of the malignant process and the skin changes in our patient. This finding is consistent with other cases reported in the literature where skin changes regressed or disappeared following initial cancer treatment and reappeared with the recurrence of malignancy [14, 26]. In two of the five cases with endometrial carcinoma associated acanthosis nigricans, skin changes improved in response to anti-neoplastic therapy [18, 21–23]. The mechanism of this correlation and indeed the mechanism of malignancy induced acanthosis nigricans is not clear. It has been suggested that malignant acanthosis nigricans is probably caused by a tumor product(s) that stimulates keratinocytes and dermal fibroblasts at the cell receptor level [27]. For decades Curth insisted that the cancer associated with malignant acanthosis nigricans is an adenocarcinoma and questioned reports associating malignant acanthosis nigricans with nonadencarcinomatous cancer [21, 22, 27]. An adencarcinoma, presumably secreting a polypeptide producing acanthosis nigricans, is an attractive hypothesis. Nevertheless, there are many reports of squamous cell carcinoma, sarcomas, and hematologic malignancies with associated malignant acanthosis nigricans [10, 28, 29]. The mechanism of this association would be more difficult to speculate about. In summary, our case demonstrates a rare association between endometrial carcinoma and acanthosis nigricans, a major improvement of the dermatological condition in response to treatment of the underlying malignancy, and illustrates Curth’s admonition, “ If an adenocarcinoma is present, a diagnosis of acanthosis nigricans is not difficult to make, but one must have the courage to diagnose malignant acanthosis nigricans even in those cases in which no cancer seems to be present” [30]. REFERENCES 1. Pollitzer S. Acanthosis nigricans. In: Unna PG, Morris M, Besnier E, et al., editors. International atlas of rare skin diseases. London: Lewis, 1890: (Chap 10) 1–3. 2. Janovsky V. Acanthosis nigricans. In: Unna PG, Morris M, Besnier E, et al., editors. International atlas of rare skin diseases. London: Lewis, 1890: (Chap 11) 4 –5. 3. Lever WF, Schaumberg-Lever G. Histopathology of the skin, 7th ed. Philadelphia: Lippincott, 1990: 477. 4. Kahn CR, Flier JS, Bar RS, Arecher JA, Gordon P, Martin MM, Roth J. The syndromes of insulin resistance and acanthosis nigricans: insulinreceptor disorder in man. N Engl J Med 1976;294:739 – 45. 5. Moller DE, Flier JS. Insulin resistance-mechanisms, syndromes, and implications. N Engl J Med 1991;325:938 – 48. 6. Stuart CA, Pate CJ, Peters EJ. Prevalence of acanthosis nigricans in an unselected population. Am J Med 1989;87:269 –72.

7. Curth HO. Skin lesions and internal carcinoma. In: Andrae R, Gumport SL, Popkin GL, et al., editors. Cancer of the skin: biology-diagnosis management. Philadelphia: Saunders, 1976:1308 – 41. 8. Andre´a VC. Malignant acanthosis Nigricans. Semin Dermatol 1984;3: 265–72. 9. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;114:1803– 6. 10. Gheeraert P, Goens J, Schwartz RA, Lambert WC, Schroeder F, Debusscher L. Florid cutaneous paplillomatosis, malignant acanthosis nigricans, and pulmonary squamous cell carcinoma. Int J Dermatol 1991;30: 193–7. 11. Schwartz RA. Sign of Leser–Tre´lat. In: Demis DJ, editor. Clinical dermatology, 14th ed. Philadelphia: Lippincott, 1987: (unit 12-26A) 1– 4. 12. Schwartz RA. Acanthosis nigricans, florid cutaneous paplillomatosis and the sign of Leser–Tre´lat. Cutis 1981;28:319 –25. 13. Breathnach SM, Wells GC. Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy. Clin Exp Dermatol 1980;5:181–9. 14. Cohen PR, Grossman ME, Almeida L, Kurzrock R. Tripe palms and malignancy. J Clin Oncol 1989;7(5):669 –78. 15. Cohen PR, Grossman ME, Silver DN, Kurzrock R. Tripe palms and cancer. Clin Dermatol 1993;11:165–73. 16. Clarke J. Malignant acanthosis nigricans. Clin Exp Dermatol 1977;2:167– 70. 17. Ellenbogen BK. Acanthosis nigricans associated with bronchial carcinoma. Report of two cases. Br J Dermatol 1949;61:251– 4. 18. Curth HO. Cancer associated acanthosis nigricans: review of the literature and report of a case of acanthosis nigricans with cancer of the breast. Arch Surg 1943;47:517–52. 19. Mukai T. Acanthosis nigricans. Acta Derm (Kyoto) 1929;14:447– 60. 20. Sedano HO, Gorlin RJ. Acanthosis nigricans. Oral Surg 1987;63:462–7. 21. Curth HO, Tovell HM, Janovski N. Malignant acanthosis nigricans associated with endometrial adenocarcinoma. Bull Sloane Hosp Wom NY 1962;8:141– 6. 22. Gorisek B, Krajnc I, Rems D, Kuheli J. Malignant acanthosis nigricans and tripe palms in a patient with endometrial adenocarcinoma—a case report and review of the literature. Gynecol Oncol 1997;65:539 – 42. 23. Mikhail GR, Fachnie DM, Drukker BH, Farah R, Allen HM. Generalized malignant acanthosis nigricans. Arch Dermatol 1979;115(2):201–2. 24. Gross G, Pfister B, Hellenthal B, Hagedorn M. Acanthosis nigricans maligna. Dermatologica 1984;168:265–72. 25. Curth HO, Hilberg AW, Machacek GF. The site and histology of the cancer associated with acanthosis nigricans. Cancer 1962;15:364 – 82. 26. Crovoto F, Parodi A, Rebora A. Pachydermatoglyphie maligne isole´e. Ann Dermatol Venereol 1986;133:469 –70. 27. Dawe CJ, Banfield, WG, Morgan WD. Growth in continuous culture, and in hamsters, of cells from a neoplasm associated with acanthosis nigricans. J Natl Cancer Inst 1964;33:441–56. 28. Ellis DL, Kafka SP, Chow JC, Nannep LB, Inman WH, Mc Cadden ME, King LE Jr. Melanoma, growth factors, acanthosis nigricas, the sign of Leser–Tre´lat, and multiple acrochordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med 1987;317:1582–7. 29. Garrott TC. Malignant acanthosis nigricans associated with osteogenic sarcoma. Arch Dermatol 1972;106:384 –5. 30. Curth HO. Skin manifestations of internal malignant tumors. Md State Med J 1972;21(12):52– 6.