Nov 10, 2012 - The patient was treated with four cycles of fluorouracil ... Discussion. Acanthosis nigricans was first described in 18901 and is usually related to ...
VOLUME 30 䡠 NUMBER 32 䡠 NOVEMBER 10 2012
JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
O N C O L O G Y
gastrectomy with D2 lymphadenectomy and resection of the aortointercaval lymph node metastasis was performed in May 2011. The gastric cancer showed marked tumor regression, whereas the lymph node metastasis did not. Postoperative tumor stage was ypT2, ypN3 with 23 of 39 positive lymph nodes, and pM1 status as a result of the aortointercaval metastasis. The patient received four adjuvant cycles of fluorouracil, leukovorin, and docetaxel until July 2011. Computed tomography (CT) scans in September 2011 were without evidence of recurrence or residual disease. In October 2011, the patient presented with extensive generalized pruritus. To rule out a paraneoplastic cause, repeated CT scans were performed and did not show any evidence of recurrent disease. CA72-4 was slightly increased (23 U/mL), and carcinoembryonic antigen was normal. The patient was
Paraneoplastic Acanthosis Nigricans With Cutaneous and Mucosal Papillomatosis Preceding Recurrence of a Gastric Adenocarcinoma Case Report A 52-year old man was diagnosed with a human epidermal growth factor receptor 2–negative signet cell carcinoma of the stomach in February 2011. Staging examinations showed an uT3uN2cM1 stage with limited distant metastasis consisting of an isolated aortointercaval lymph node metastasis. The patient was treated with four cycles of fluorouracil, leukovorin, and docetaxel in a neoadjuvant intention. R0
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treated symptomatically with H2 blockers, systemic corticosteroids, and paroxetine, with some relief of his cutaneous symptoms. In January 2012, the patient was admitted to our hospital because of progressivedermal,mucosal,andperianallesions.Meanwhile,weightloss of 6 kg and fatigue occurred. Three weeks before admission, the patient had consulted a dermatologist who had raised the suspicion of human papillomavirus (HPV) -associated generalized verrucosis. Dermatologically, the patient presented with generalized brownish hyperpigmentation of the skin associated with extensive itching. The cutaneous alterations were especially present in the armpits, axillae, groin, and neck folds (Fig 1A). In addition, extensive verrucous papules and plaques were present on the eyelid conjunctivae, labial angles, palate (Fig 1B), tongue, aureola (Fig 1C), and perianal area (Fig 1D). A differential diagnosis of the cutaneous and mucosal lesions included generalized verrucosis associated with HPV infection and paraneoplastic acanthosis nigricans (PAN). Histopathologic analysis revealed a marked acanthosis, papillomatosis and hyperkeratosis as well as a slight dermal inflammatory infiltrate, but no additional signs of viral cytopathic effects (Fig 1E). Multiple biopsies were tested for ␣-HPVs, -HPVs, Merkel cell polyomavirus, and human polyomaviruses 6 to 9 and were completely negative, excluding an association with HPV or the previously mentioned human polyomaviruses. A CT scan revealed an enlarged infraclavicular lymph node and multiple abdominal lymph nodes up to 15 mm. An endoscopic ultrasound was performed with fine-needle aspiration of an enlarged periportal lymph node (Fig 1F). Cytology revealed metastasis of a signet-cell carcinoma. CA72-4 showed an additional increase (56 U/mL), and carcinoembryonic antigen remained normal. The patient received palliative chemotherapy with fluorouracil, leucovorin, and irinotecan and achieved a stable disease according to the CT scan after 8 weeks of treatment. However, CA72-4 was normalized (3.9 U/mL), fatigue was markedly decreased, and weight loss was stopped. Discussion Acanthosis nigricans was first described in 18901 and is usually related to benign conditions, especially endocrinopathies, obesity, and diabetes mellitus.2 Among the different forms of acanthosis nigricans, it is important to recognize PAN. Mucosal lesions are rare and always exclusively point toward PAN. PAN may precede the diagnosis of the tumor and generally has a sudden onset with rapid spreading. PAN is usually associated with abdominal malignancies (70% to 90%), particularly with gastric cancer (50% to 80%).3-6 However, several reports on PAN associated with extra-abdominal cancer including breast, gynecologic, lung, kidney, and thyroid cancers as well as sarcomas and hematologic malignancies.3-8 The current concept in the pathogenesis of PAN is the secretion of growth factors by the tumor. It has been shown that transforming growth factor ␣, insulin growth factor 1, and fibroblast growth factor play an important role in the pathogenesis of hyperplasia and hyperpigmentation observed in PAN. In particular, tumor-derived transforming growth factor ␣ binds to the EGFR, which is found on epidermal cells, particularly within the basal layer where it is involved in the growth and differentiation of keratinocytes.9-11 PAN may regress with tumor-specific therapy11,12 and usually worsens with cancer progression.3,13 In our patient, PAN was diagnosed and preceded the diagnosis of recurrence of the previously treated gastric cancer by several weeks.
ExclusionofHPV-associatedpapillomatosiswascrucialbecausechemotherapy-induced immunosuppression can deteriorate the dermal and mucosal lesions in case of viral infection. In contrast, PAN requires additional tumor-specific treatment. In conclusion, florid cutaneous and mucosal papillomatosis with acanthosis nigricans is always exclusively associated with malignancy and should lead to the investigation of malignancy with special attention to gastric cancer and other abdominal tumors.
Karsten Schulmann, Katharina Strate, and Christian P. Pox Knappschaftskrankenhaus, Ruhr University Bochum, Bochum, Germany
Ulrike Wieland University Ko¨ln, Ko¨ln, Germany
Alexander Kreuter Ruhr University Bochum, Bochum, Germany
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Karsten Schulmann, Merck-Serono, Astra-Zeneca, Amgen, Falk Research Funding: None Expert Testimony: None Other Remuneration: Karsten Schulmann, Roche, Pfizer, Merck-Serono, Novartis REFERENCES 1. Janowsky V: Acanthosis nigricans, in Unna PG, Morris M, Besnier E, et al (eds): Internationaler Atlas seltener Hautkrankeiten [International Atlas of Rare Skin Diseases], Band 11, Leipzig, Germany, Voss 1890 2. Schwartz RA: Acanthosis nigricans. J Am Acad Dermatol 31:1-19; quiz 20-22, 1994 3. Gross G, Pfister H, Hellenthal B, et al: Acanthosis nigricans maligna: Clinical and virological investigation. Dermatologica 168:265-272, 1984 4. 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 47:517-552, 1943, doi: 10.1001/archsurg.1943.01220180003001, 1943 5. Gheeraert P, Goens J, Schwartz RA, et al: Florid cutaneous papillomatosis, malignant acanthosis nigricans, and pulmonary squamous cell carcinoma. Int J Dermatol 30:193-197, 1991 6. Rigel DS, Jacobs MI: Malignant acantosis nigricans: A review. J Dermatol Surg Oncol 6:923-927, 1980 7. Garrott TC: Malignant acanthosis nigricans associated with osteogenic sarcoma. Arch Dermatol 106:384-385, 1972 8. Ackerman AB, Lantis LR: Acanthosis nigricans associated with Hodgkin’s disease. Concurrent remission and exacerbation. Arch Dermatol 95:202-205, 1967 9. Koyama S, Ikeda K, Sato M, et al: Transforming growth factor-alpha (TGF alpha)-producing gastric carcinoma with acanthosis nigricans: An endocrine effect of TGF alpha in the pathogenesis of cutaneous paraneoplastic syndrome and epithelial hyperplasia of the esophagus. J Gastroenterol 32:71-77, 1997 10. Lenzner U, Ramsauer J, Petzoldt W, et al: Acanthosis nigricans maligna. Case report and review of the literature (in German). Hautarzt 49:41-47, 1998 11. Anderson SH, Hudson-Peacock M, Muller AF: Malignant acanthosis nigricans: Potential role of chemotherapy. Br J Dermatol 141:714-716, 1999 12. Schwartz RA, Burgess GH: Florid cutaneous papillomatosis. Arch Dermatol 114:1803-1806, 1978 13. White H: Acanthosis nigricans and wart-like lesions associated with metastatic carcinoma of the stomach. Cutis 17:931-933, 1976
DOI: 10.1200/JCO.2012.42.5454; published online ahead of print at www.jco.org on September 24, 2012
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