Complementary role of positron emission tomography in Merkel cell carcinoma.

Abstract: Merkel cell carcinoma is a rare type of neuroendocrine tumor of the skin with approximately 470 documented new cases annually in the United States. These tumors have high metastatic and recurrence rates, making them aggressive and difficult to treat. Diagnostic workup usually includes computed tomography, magnetic resonance imaging, and scintigraphy methods such as octreotide scans. More recently, positron emission tomographic scanning has been used to evaluate Merkel cell carcinomas. A case of Merkel cell carcinoma, in which positron emission tomography imaging with fluorodeoxyglucose played an important role in staging, re-staging, and identifying previously unknown distant metastatic disease, is presented in this article.

Key Words: magnetic resonance imaging, Merkel cell carcinoma, positron emission tomography

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The first report of Merkel cell carcinoma (MCC) was published by Toker in 1972 under the title, "Trabecular Carcinoma of the Skin." At the time, Toker believed the cell of origin to be a sweat gland cell. (1-5) However, 6 years later, Tang and Toker found ultramicroscopic features in MCC tumors that were more suggestive of a neuroendocrine origin rather than sweat gland cell origin. Specifically, the tumors contained cells that resembled Merkel cells, a type of neuroendocrine cells that were first described in 1875 by German anatomist and pathologist Friedrich Sigmund Merkel. The first published use of the term "Merkel cell carcinoma" was by De Wolf-Peters et al (6) in 1980. Other terms that have been applied to this tumor include cutaneous Apudoma, neuroendocrine carcinoma of the skin, primary small cell carcinoma of the skin, and murky cell carcinoma. (7,8)

Case Report

A 56-year-old male presented with generalized fatigue, gait disturbances, and weakness of the lower extremities. This was soon followed by the appearance of a left inguinal mass. Initial biopsy revealed an undifferentiated or poorly differentiated neuroendocrine tumor. The final pathologic diagnosis was Merkel cell carcinoma. Further workup failed to identify a primary site or any suspicious skin lesions. After the diagnosis was confirmed, the patient was treated with cisplatin and etoposide. The patient initially showed improvement after two cycles of cisplatin and etoposide, with minimal decrease in the size of the inguinal mass. However, after two additional cycles, the tumor increased in size and was no longer responsive to the chemotherapy regime. A positron emission tomography (PET) scan performed in March 2003 showed a hypermetabolic lesion in the left inguinal region (Fig. 1A) that correlated with a 2.3 X 2.3-cm left inguinal lymph node identified on a computed tomographic (CT) scan performed at approximately the same time (Fig. 1B). No evidence of other metastatic lesion was identified at this time on either the PET or CT scan. The left inguinal lymph node was surgically removed, and localized radiotherapy to the left inguinal region was performed.

Six months after treatment, the patient presented with new symptoms of left lower extremity swelling, low back pain, and pelvic pain. CT evaluation revealed a new, large pelvic mass measuring 5.5 X 9.0 cm that obliterated the external iliac vein and caused deep venous thrombosis and lymphedema (Fig. 2D). A second PET scan showed hypermetabolic lesions in the left pelvis, left periaortic region, and left supraclavicular region (Fig. 2A), consistent with recurrence. Left inguinal lesion was not identified. On retrospective review of CT performed before the PET scan, the left supraclavicular (Fig. 2B) as well as the left periaortic lymph nodes (Fig. 2C) were identified, but these CT findings were less obvious compared with PET. The new findings led to palliative radiotherapy and chemotherapy with carboplatin and taxol.

[FIGURE 1 OMITTED]

Discussion

Merkel cell tumors typically present as painless, nonulcerated areas of skin thickening or plaque. Sun-exposed regions of the body, particularly the head and neck, are at highest risk. (9) Size usually ranges from a quarter inch to 2 inches. Tumors are generally found in the older population (mean age, 69 years) but have been identified at any age. (1,10) Merkel cells, for which the tumors are named, are located in the epidermis and are believed to function as type I mechanoreceptors. Histologic diagnosis is based on confirmation with immunocytochemical staining and electron microscopy of the lesion. The immunocytochemical profile typically includes CAM 5.2, S100, and cytokeratin (CK) 7 and 20. (11)

The most common staging system is that described by Yiengpruksawa et al. (12) Stage I disease represents local disease, with no spread to lymph nodes or other parts of the body. Stage II disease includes lymphatic extension with spread to nearby lymph nodes. Stage III encompasses distant metastatic disease. Stage I, II, and III disease have 70 to 80%, 10 to 30%, and 1 to 4% patient distribution at the time of initial presentation, respectively. (1) Traditionally, stage I disease is treated with surgical resection with wide margins. Stage II disease usually involves complete lymph node dissection with postoperative irradiation of the primary and regional nodal disease sites. (13-15) Treatment options for stage III include chemotherapy, palliative radiation, and surgical debulking of metastases. Overall, 5-year survival rate is poor, estimated at 30 to 64%. (16)

[FIGURE 2 OMITTED]

Initial workup includes sentinel node imaging with technetium-99m-filtered sulfur colloid to assess the lymphatic drainage of the primary tumor. Currently, CT, MRI, and octreotide scans are performed to stage and evaluate the spread of known Merkel cell tumors. (2) The sensitivity and specificity of such scans range from 70 to 80%, with some studies showing slightly greater sensitivity/specificity with octreotide scans versus CT or MRI. (2) PET imaging for MCC is a more recent development that may yield additional foci of metastatic disease not visualized by other techniques. (3,4) One case study reported a metastatic MCC lesion that was identified on PET scanning but not visualized on more traditional CT/MRI/octreotide scans. (17)

Conclusion

PET imaging was useful in detecting a recurrent MCC tumor that was not easily demonstrated on CT. Based on our case and a limited number of previously published case reports, it appears that PET may play a complementary role in more accurate staging and identification of recurrent Merkel cell carcinoma.

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Accepted June 4, 2004.

References

1. Goesling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002;20:588-598.

2. Durani BK, Klein A, Henze M, et al. Somatostatin analogue scintigraphy in Merkel cell tumour. Br J Derm 2003;148:1135-1140.

3. Lampreave JL, Bernard F, Alavi A, et al. PET evaluation of therapeutic limb perfusion in Merkel's cell carcinoma. J Nuc Med 1998;39:2087-2090.

4. Nguyen BD. Positron emission tomographic imaging of Merkel cell carcinoma. Clin Nuc Med 2002;27:922-923.

5. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105:107.

6. De Wolf-Peters C, Marien K, Mebis J, et al. A cutaneous APUDoma or Merkel cell tumor? A morphologically recognizable tumor with a biological and histological malignant aspect in contrast with its clinical behavior. Cancer 1980;46:1810-1816.

7. Nguyen BD, McCullough AE. Imaging of Merkel cell carcinoma. Radiographics 2002;22:367-376.

8. Shea CR, Prieto VG. Merkel cell carcinoma. E-medicine Online 2003.

9. Grgic M, Grgic MP, Zurak, K, et al. Merkel cell carcinoma of the face: two case reports and literature review. Acta Clin Croat 2003;42:251-256.

10. Agelli M, Limin X. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832-841.

11. Skelton HG, Smith KJ, Hitchcock CL, et al. Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 1997;37:734-739.

12. Yiengpruksawan A, Coit DG, Thaler HT, et al. Merkel cell carcinoma: prognosis and management. Arch Surg 1991;126:1514-1519.

13. Tai PTH, Yu E, Winquist E, et al. Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 2000;18:2493-2499.

14. Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol 2000 43:755-767.

15. Savage P, Constenla D, Fisher C, et al. The natural history and management of Merkel cell carcinoma of the skin: a review of 22 patients treated at the Royal Marsden Hospital. Clin Oncol (R Coll Radiol) 1997;9:164-167.

16. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 1995;21:669-683.

17. Wong CO, Pham AN, Dworkin HJ. F-18 accumulation in an octreotide negative Merkel cell tumor. Clin Positron Imaging 2000;3:71.

RELATED ARTICLE: Key Points

* Positron emission tomography imaging may be useful for detecting recurrent Merkel cell carcinoma (MCC) that may not be easily demonstrated on computed tomography.

* MCC is rare but difficult to manage because of staging limitations with conventional healing.

* Positron emission tomography imaging using radiolabeled glucose may help in accurate staging and management of MCC.

Oscar Lin, MD, Aju Thomas, MD, Amolak Singh, MD, and Ben Greenspan, MD

From the University of Missouri, Columbia, MO.

Reprint requests to Amolak Singh, MD, Division of Nuclear Medicine and PET, University of Missouri Health Care, One Hospital Drive, DC069.10, Columbia, MO 65212. Email: [e-mail]