Keratoacanthoma

Abstract

Merkel cell carcinoma (MCC) has been shown to have a higher incidence in many etiologically distinct immunosuppressed populations. We report a case of aggressive MCC diagnosed in a man with autoimmune hepatitis who was treated with immunosuppressive therapy for more than 30 years.

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Introduction

In the settings of both exogenous and endogenous immunosuppression, Merkel cell carcinoma (MCC) has a higher incidence as well as an earlier, more aggressive presentation when compared with the general population. Although there have been many case reports and cohort studies of MCC occurring in transplant patients (1-5) as well as those with Chronic Lymphocytic Leukemia (CLL) (6-11) and HIV/AIDS, (12-15) there are a limited number of reported cases of MCC arising in patients on chronic immunosuppressive treatment for autoimmune conditions. We report the case of a patient with autoimmune hepatitis who was treated with azathioprine and prednisone for more than 30 years before presenting with an advanced stage of MCC. We report this case to raise awareness that such patients may be at a higher risk of developing aggressive cutaneous malignancies such as MCC.

Case Report

A 65-year-old man with autoimmune hepatitis that had been treated with prednisone and azathioprine for 33 years presented with a firm, reddish brown, dome-shaped, indurated nodule approximately 2 cm in diameter on the left posterior lower leg. The lesion had gradually enlarged over a period of 6 weeks.

On presentation, the nodular lesion on the leg was further investigated with two 3 mm punch biopsies, which demonstrated deep dermal columns of large cells with fine chromatin, scant cytoplasm, small nucleoli, and numerous mitoses (Figure 1). These cells were positive for CK20 in a dot pattern and were negative for thyroid transcriptase factor-1 (Figure 2). This histological presentation was consistent with undifferentiated carcinoma and favored a primary neuroendocrine tumor designation. The patient underwent several wide excisions that removed skin from approximately two-thirds of the circumference of his lower leg, all of which resulted in continued positive margins. Following this procedure, the patient underwent a sentinel lymph node biopsy, which showed inguinal lymph node micrometastasis, and a PET scan that indicated increased uptake in his left forearm. There were no significant physical exam findings on the forearm. A subsequent CT scan did not find signs of metastasis. Due to the positive margins in the lower leg and positive sentinel node in the inguinal region, post-operative radiation was performed. Five months after the initial biopsy from the posterior lower leg, a second punch biopsy was obtained from the left anterior lower leg, just below the knee. This showed metastatic carcinoma consistent with Merkel cell carcinoma. The patient was treated with an above the knee amputation and the specimen revealed tumor invading through the dermis and into the subcutaneous tissue. There was also involvement of the intima/lumen of an adjacent vein. Analysis of the bone marrow did not find tumor. The patient has recently been started on chemotherapy with vincristine, cyclophosphamide and doxorubicin.

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Discussion

Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm that was first described by Toker in 1972. (16) It may appear flesh-colored, red, or blue and is typically a firm, non-tender, cutaneous mass that grows rapidly over a few weeks to a few months. (17) Specific etiological factors include increased sun exposure (18) and chronic arsenicism. (19) There is also an increased incidence as well as an earlier, more aggressive presentation in immunosuppressed populations.

In transplant populations, an overall increase in the incidence of MCC has been suggested by case reports (1-3) and cohort studies. (3,4) Other immunosuppressed populations are similarly affected--there is an increased incidence of MCC in the setting of HIV/AIDS, (12-15) as well as CLL. (6-11) In light of the well-established increased incidence of MCC in these etiologically distinct immunosuppressed populations, it is surprising that there are few published reports of MCC occurring in patients treated with chronic immunosuppressive therapy for autoimmune disorders. The only published report in English is by Gooptu et al, who described a 68-year-old woman with rheumatoid arthritis treated with azathioprine for 20 years before developing stage II MCC. (20) Although causality is only presumed, both our patient and the one described by Gooptu et al have many similarities in their presentation of MCC that not only differ from what is seen in the general population, but also from transplant patients and those with HIV/AIDS or CLL.

The most striking differences are seen in the age at presentation and the duration of immunosuppression prior to diagnosis. In transplant patients, 29% (4) to 49% (5) of cases of MCC were found in patients less than 50 years of age with the tumors typically appearing at a mean time of 6.9 (5) to 7.2 (4) years after transplantation. Similar findings are seen in patients with HIV/AIDS. (12,13) At ages 65 and 68, our patient and the patient described by Gooptu et al did present at a slightly younger age than most patients in the general population, (21) but they were still significantly older at presentation than other immunosuppressed populations. Furthermore, both patients were immunosuppressed for a much longer duration of time. Despite these differences, however, both patients had a similar advanced stage of MCC at diagnosis consistent with other immunosuppressed populations, where up to 75% of patients present with stage II or III disease. (5)

Many patients treated for autoimmune diseases such as rheumatoid arthritis, autoimmune hepatitis, or inflammatory bowel disease are on azathioprine and corticosteroids for long periods of time due to the frequency of relapses when treatment is withdrawn. (22) Consequently, such patients may be at a higher risk for developing aggressive cutaneous malignancies such as MCC. This case report suggests that patients treated for autoimmune diseases with long durations of immunosuppressants may present at the advanced stages of MCC as seen in transplant, HIV/AIDS, or CLL patients. It is important, therefore, that patients on long-term immunosuppressive therapy continue to receive thorough routine skin surveillance and aggressive intervention if any new lesions appear.

References

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16. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105:107-10.

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18. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev. 1999;8:153-8.

19. Lien HC, et al. Merkel cell carcinoma and chronic arsenicism. J Am Acad Dermatol. 1999;41:641-3.

20. Gooptu C, et al. Merkel cell carcinoma arising after therapeutic immunosuppression. Br J Dermatol. 1997;137:637-41.

21. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;29:832-41

22. Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med. 1995;333:958-63.

Joseph Lillis BA, (a) Roger I. Ceilley MD, (b) Paula Nelson RN

a. Georgetown University School of Medicine, Washington, DC

b. University of Iowa Department of Dermatology, Iowa City, IA

Address for Correspondence

Roger I. Ceilley MD

6000 University Ave

West Des Moines, IA 50266-8203

Phone: 515-241-2000

Email: Ricakb@aol.com

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