Merkel Cell Carcinoma: An Uncommon Tumor Without a Definitive Treatment Protocol

Mark R. Levine, MD · Amarpreet Singh, MD · Marc R. Criden, MD

Introduction

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine malignancy of epidermal origin with a natural history of local recurrence, lymph node metastasis, and distant dissemination.^1,2 MCC is an uncommon skin neoplasm, and approximately 600 patients are diagnosed with MCC in the United States every 8 years.³ MCC usually affects the head, neck, and periorbital areas and the upper eyelid and canthal regions.⁴ MCC occurs most commonly in Caucasian patients between 66 and 73 years old. Most patients have MCC on sun-exposed areas. Men and women have an equal chance of having MCC. MCC also occurs commonly in patients who are immunocompromised or have received methoxsalen and ultraviolet A for psoriasis. The 5-year survival rate is approximately 38% to 90%.^2,5

Clinical Findings

Normal Merkel cells are mechanoreceptors found in the basal layer of the epidermis that are associated with the sense of touch.^1,5 MCC presents as a rapidly growing and painless dermal nodule that may be mildly erythematous or deeply violaceous in color (Slide 1).²

Slide 1

Overlying telangiectases (Slide 2) are characteristic of MCC but not always present. Eyelashes remain unaffected, and skin rarely ulcerates (Slide 3, Slide 4).⁴ Patients usually present to their physican with MCC within 6 months of the onset of symptoms. Patients with other common eyelid lesions such as basal cell carcinoma, squamous cell carcinoma, or sebaceous cell carcinoma may have clinical signs or symptoms for 1 year or more before initial presentation.⁵ MCC may grow a little more quickly than basal or squamous cell and it may look more red.

Slide 2

Slide 3

Slide 4

Patients with MCC sometimes receive a delayed diagnosis because the tumor in MCC is rare and is similar to other benign lesions such as chalazion (Slide 5) and keratoacanthoma.⁴ However, chalazion is less common than MCC in older patients. If chalazion is detected in an older patient, then an alternate etiology should be suggested. Although a biopsy is required to diagnose MCC, biopsies can yield misleading results because the tumor in MCC is similar to other small cell tumors such as those found in lymphoma and metastatic small-cell lung cancer. MCC is aggressive when malignant transformation occurs. Regional lymph nodes are frequently involved at the time of presentation, and 50% to 75% of regional lymph nodes develop regional lymph node metastases. Up to 70% of patients develop distant metastases. The most common sites of metastases are the lymph nodes, liver, bone, brain, and skin.²

Slide 5

Diagnostic Features and Histopathology

MCC invades the subcutaneous tissues and lacks a capsule. It has been stratified into three distinct histologic subtypes: trabecular, intermediate, and small cell. Trabecular MCC is the least common type of MCC and is composed of compact polygonal to round cells with abundant cytoplasm (Slide 6). These cells are arranged in clusters and trabeculae and may also demonstrate ribbons. Few to moderate mitoses are also found. Trabecular MCC is usually located adjacent to adnexal structures such as hair follicles. The cells in intermediate MCC are less compactly arranged and demonstrate a more solid and diffuse growth pattern than the cells in trabecular MCC. Less abundant cytoplasm and mitoses are present in intermediate MCC than in trabecular MCC, and areas of focal necrosis are common (Slide 7). Intermediate MCC is the most common type of MCC. Like trabecular MCC, it is adjacent to adnexal structures. However, intermediate MCC may invade the dermis and behave in a more aggressive manner than trabecular MCC. Small cell MCC occurs as solid sheets or clusters of cells within the dermis. Frequent areas of necrosis and crush artifact are present in small cell MCC. Small cell MCC and intermediate MCC are equally aggressive.³

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Slide 7

Diagnosing MCC is dependent on histologic analysis, specifically electron microscopy (EM) or immunohistochemistry. Patients who present with equivocal results must undergo further immunohistologic analysis.⁵ A characteristic profile of immunologic markers demonstrates co-expression of cytokeratin and neurofilament, as well as positivity for neuron-specific enolase and negativity for the S100 protein and leukocyte common antigen.^1,6 EM diagnosis is demonstrated by cytoplasmic neurosecretory granules averaging 80 nm to 120 nm (Slide 8). Other common EM findings include paranuclear aggregates of intermediate filaments, polyribosomes, and a prominent golgi apparatus.

Slide 8

Treatment

No accepted staging paradigm for treatment of patients with MCC exists because MCC is rare, and no randomized, controlled treatment trials are performed. However, clinical presentation is used to stage the MCC tumor according to Yiengpruksawen⁷ and Tai.⁸

Stage Ia: Primary tumor ≤2 cm without evidence of lymphatic or distant spread
Stage Ib: Primary tumor >2 cm without evidence of lymphatic or distant spread
Stage II: Regional node involvement without distant metastases
Stage III: Systemic metastases beyond regional lymph nodes

Because the MCC tumor is rare and patients are frequency misdiagnosed with MCC, patients with rapidly growing, violaceous lid lesions or recurrent chalazia should have biopsies.^4,5 A wide local excision with 2.5-cm to 3-cm margins is standard treatment for patients with MCC.^3,9,10 Peters and colleagues² recently reported the effectiveness of a 5-mm margin with tumor-free margins for local control. However, the size of the surgical margin does not correlate with a decreased recurrence rate, and recurrences have been reported even after wide excision with negative margins.^2,4 Moh's surgery also compares well to wide excision and may be better suited to eyelid lesions because it spares more tissue.⁵

Adjuvant radiation therapy to the primary site has also been advocated as treatment for patients with MCC. A study by Meeuwissen and colleagues¹¹ reports a 100% recurrence rate of the tumor following surgical excision alone and a 10% recurrence rate of the tumor following excision combined with radiotherapy. Because radiation can cause scarring and functional impairment, some patients reserve adjuvant radiation therapy in case they develop recurring MCC or lymph node spread. Radiation alone has been used in patients with large tumors, patients with lymphatic invasion, and patients with locally unresectable tumors.⁴ Treatment options for patients with recurring MCC are limited. Regional lymph node dissection with adjuvant radiation is an option if the regional draining nodes have not been previously irradiated. Elective lymph node dissection has been associated with improved local control, but no improvement in the survival rate exists.^2,3,11 However, in patients with a positive sentinel node biopsy, which is strongly predictive of a high risk of recurrence, subsequent lymph node dissection reduces the short-term risk of recurrence.^2,5

Chemotherapy has been used in patients with unresectable recurrent tumors, systemic metastatic disease, positive lymph nodes, stage III MCC, or in patients who have reached the maximum tolerated radiation dose. The chemotherapeutic regimens used in patients with MCC parallel the chemotherapeutic regimens used in patients with small cell lung cancer, namely cyclophosphamide, doxyrubicin, and vincristine.^5,10 Although patients with MCC often respond well to chemotherapy, their tumors have a strong tendency to recur after chemotherapy has ended.¹ Approximately one half of patients with MCC demonstrate a complete response to chemotherapy. However, no effect on subsequent metastasis or mortality exists.^5,7,10

Because MCC is rare, no universally accepted treatment protocols or randomized clinical treatment trials exist. Nevertheless, most physicians seem to support aggressive initial treatment. Aggressive initial treatment includes a wide excision with 5-mm margins with, but not limited to, local radiation. According to Meeuwissen, the combination of a wide excision and local radiation decreases recurrence from 100% (with excision alone) to 10%.¹¹ If sentinel node biopsy is positive, then therapeutic lymph node dissection should be considered to decrease the risk of short-term recurrence.

References

1. Hamilton J, Levine MR, Lash R, Koenigsberg A. Merkel cell carcinoma of the eyelid. Ophthalmic Surg. 1993;24:764-769.
2. Peters GB, Meyer DR, Shields JA, et al. Management and prognosis of Merkel cell carcinoma of the eyelid. Ophthalmology. 2001;108:1575-1579.
3. Haag ML, Glass LF, Fenske NA. Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg. 1995;21:669-683.
4. Kivela, T. Periocular Merkel cell carcinoma. In: Fraunfelder FT, Roy H, eds. Current Ocular Therapy. 5th ed. Philadelphia, Pa: W. B. Saunders Company; 2000:260-261.
5. Nicoletti AG, Matayoshi S, Santo RM, Ferreira VR. Eyelid Merkel cell carcinoma: Report of three cases. Ophthal Plastic Reconstr Surg. 2004;20:117-121.
6. Lamping K, Fischer MJ, Vareska G, Levine MR, Aikawa M, Albert DM. A Merkel cell tumor of the eyelid. Ophthalmology. 1983;90:1339-1402.
7. Yiengpruksawan A, Coit DG, Thaler HT, Urmacher C, Knapper WK. Merkel cell carcinoma. Prognosis and management. Arch Surg. 1991;126:1514-1519.
8. Tai PT, Yu E, Tonita J, Gilchrist J. Merkel cell carcinoma of the skin. J Cutan Med Surg. 2000;4:186-195.
9. O'Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma. Comparison of Moh's micrographic surgery and wide excision in eighty-six patients. Dermatol Surg. 1997;23:929-933.
10. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg. 1999;134:388-393.
11. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Biol Phys. 1995;31:325-331.