Lymph node involvement appears to be important in staging and prognosis. The use of immunostains on sentinel lymph nodes may improve detection of occult disease [26]. Some authors report 19–40% of sentinel lymph nodes sampled are positive [12, 27]. Sentinal lymph node evaluation is best performed prior to wide local excision to preserve draining patterns of the primary tumor. SLN biopsy is less reliable on the head/ neck because of the complex draining pattern which increases the likelihood of false negative results [20].

The National Comprehensive Cancer Network (NCCN) also recently published guidelines for evaluation and management of patients with MCC based on lower-level evidence and panel consensus. Patients are stratified into three groups at the outset: those with no clinical nodal involvement, those with clinical nodal involvement, and those with metastatic disease. These guidelines can be used in conjunction with the AJCC recommendations for staging in determining prognosis and management strategies in patients with MCC [20].

24.3.1.1 No Clinical Nodal Involvement

The following are recommendations based on clinical nodal involvement:

•If a patient has already undergone wide local excision, options are to observe or consider radiation therapy to the primary tumor site, in transit lymphatics, and draining nodal basins.

combination of surgery, radiation, and chemotherapy. More common sites of distant metastatic disease include liver, bone, brain, lung, and skin [11, 18].

24.3.2 Treatment

Appropriate treatment of MCC depends on accurate diagnosis and staging. The treatment of choice for localized disease is surgical [10]. Different surgical approaches have been described in the literature. Some support wide local excision with 1–2-cm margins down to fascia, but most studies agree that wide local excision with 2.5–3-cm margins has lower rates of recurrence [10, 16, 18, 20]. Additional approaches include Mohs surgery or a modified Mohs technique where an additional final layer is sent for permanent sectioning after tumor extirpation [20].

Merkel cell carcinoma is a very radiosensitive tumor, but the indications for radiation are unclear given the lack of prospective studies. Multiple retrospective studies show a decreased local recurrence rate with adjuvant radiation [28–32]. A larger retrospective analysis of 1,254 patients showed statistically significant reduction in local and regional recurrence in patients who received adjuvant radiation, but no reduction in rate of metastatic disease or survival benefit [30].

Systemic chemotherapy has also been used in meta-

tains (especially CK-20 and pancytokeratins AE1/ AE3) followed by observation or radiation as above. Note that sentinel lymph node (SLN) biopsy is less reliable on the head and neck because of a less predictable draining pattern.

agree there is no survival advantage [10, 15]. Regardless of the stage at diagnosis, patients with a

history of MCC need close follow-up to detect recurrence. Patients should be followed regularly with history and physical, complete skin exam, lymph node exam and

24.3.1.2 Clinical Nodal Involvement

The panel recommends fine needle aspiration (FNA) of the clinically involved lymph node. If FNA is positive, image to assess for distant metastases. If FNA is negative, do an open biopsy. If the open biopsy is negative, refer to guidelines listed above for node-negative patients.

24.3.1.3 Metastatic Disease

If widespread disease is found on imaging, consider consultation with a tumor board and treatment with a

24.3.3 Prognosis

Merkel cell carcinoma is an aggressive tumor with a high propensity for local recurrence (25–30%), regional lymph node involvement and distant metastasis. Regional lymph node involvement is present in 52–66%, and is usually noted within 2 years of diagnosis. Distant metastatic disease is noted in 34–36% or patients who almost always have preceding or concurrent nodal disease. Five-year survival rates range from

30% to 64%, depending on lymph node or systemic involvement [20, 21, 30].

A recent study published by Lemos et al. addressed staging and survival in 5,823 patients from the National Cancer Data Base with MCC. They note an overall 5-year survival rate of 40% and relative survival of 54% (when patients were compared with age and sexmatched controls). Patients with localized disease and pathologically negative lymph nodes had the best overall survival (76% at 5 years) [25].

Factors associated with a poor prognosis include: tumor size greater than 2 cm, metastatic disease at presentation, vascular or lymphatic invasion noted on pathology, small cell histologic pattern, greater than 10 mitoses per high-power field [18]. Other studies note poor prognosis if the primary tumor is on located on the head and neck. This may be secondary to incomplete excision as highest recurrence rates are on the head and neck [18]. Lymph node status is particularly important in prognostication and correlates with survival. Lack of lymph node involvement improves survival rate [21].

Summary: Mohs Micrographic Surgery

and Merkel Cell Carcinoma

•Mohs micrographic surgery is an alternative to wide local excision in the treatment of primary Merkel cell carcinoma.

•Mohs micrographic surgery offers the advantage of circumferential complete margin assessment with sparing of normal tissue.

24.4Mohs Micrographic Surgery and Merkel Cell Carcinoma

Mohs micrographic surgery (MMS) is an effective alternative to wide local excision for local control of disease [33]. The Mohs technique is commonly used in the treatment of non-melanoma skin cancers, but its use is increasing in rare tumors such as MCC. Two major advantages of MMS include circumferential margin assessment (including the deep margin) and sparing of uninvolved tissue. In areas where excess tissue is lacking (i.e., the head and neck), the Mohs technique is especially useful. For example, one patient developed a MCC on the left upper eyelid margin requiring three stages for clear margins, and

the patient is without recurrence or metastasis 2 years later [34]. Merkel cell carcinoma has an extensive vertical growth phase, and complete evaluation of the deep margin is imperative because of the high risk of recurrence with incomplete excision [12]. In general, MMS is associated with higher success rates because of the extent of margin assessment, and the high rate of complete tumor extirpation minimizes the risk of local recurrence [35]. Disadvantages of MMS include length of the procedure and interpretation of frozen sections rather than permanent sections (the surgeon needs excellent slide quality from the technician/lab).

Few retrospective studies and no prospective studies evaluate the use of MMS in the treatment of MCC. Gollard et al. performed a retrospective analysis of 22 patients with MCC, and 8 patients were treated with MMS (with permanent sections). Tumor size ranged from 0.7 to 1.9 cm (average 1.2 cm). An average of 1.4 layers was needed to get a clear margin. Average margin for clearance was 1.5 cm (1.2 cm on face, 1.9 cm on extremities). Five of the eight patients treated with MMS also got radiation (three local to the tumor bed, two to lymph node basin as well). Average follow-up was 37 months, and none of the patients treated with MMS had a local recurrence. However, two patients developed distant metastatic disease 8 and 10 months after surgery [10].

O’Conner et al. retrospectively evaluated 86 patients with MCC to determine rates of local recurrence and development of metastatic disease after surgical treatment. A total of 41 patients with clinically localized disease were treated with wide local excision (WLE), and 13 patients were treated with MMS (only 12 of which were included in analysis because the tumor persisted in the 13th case). In patients treated with wide local excision: mean preoperative size was 1.57 cm, no adjuvant radiation was used, local recurrence rate was 32%, regional metastatic rate was 49%, and 26% of patients MMS: mean preoperative size was 2.98 cm (notably larger than those in the WLE group), 4 patients were also treated with radiation, local recurrence rate was 8.3%, regional metastatic rate was 33%, and no patients died of metastatic disease [16].

Boyer et al. performed a retrospective analysis to determine the effect of adjuvant radiation when combined with MMS. Forty-five patients with Stage I disease were treated with MMS, and 20 also received adjuvant postoperative radiation (to primary

site ± regional lymph node basin). In the MMS alone group, mean preoperative size was 14 mm, with a 13.7 mm mean margin post-Mohs. Local (marginal) recurrence was 4%. Regional recurrence (defined as marginal + in transit lesions) was 16%. Lymph node metastatic rate was 16%, and distant metastatic rate was 8%. In the MMS + radiation group, the mean preoperative size was 18.4 mm, with a 20.6 mm mean margin. Local recurrence was 0%. Lymph node metastatic rate was 15%, and distant metastatic rate was 5%. There was no significant difference in local recurrence or metastatic pattern between the two groups. Five year survival rate was 79% in MMS alone and 80% in the MMS + radiation group. The authors conclude MMS is an effective alternative to WLE, and the most important step in managing MCC is complete removal of the primary tumor. The higher marginal recurrence rate seen with WLE may be secondary to inadequate excision of primary tumor (infiltrating border not clinically evident, narrow margin) or incomplete evaluation of pathologic margin [17]. Notably, no difference in recurrence or survival was observed with tumor bed/draining lymph node basin radiation [17].

Another retrospective study looked at MCC of the extremities. Thirty-two patients were treated with WLE and six patients were treated with MMS with primary endpoints of overall survival and recurrence. No difference was observed in local recurrence rates. Lymph node status was noted to be important in the risk of regional recurrence, which is in agreement with other studies. Radiation reduced local recurrence rate but had no overall survival benefit [12].

Not all case reviews have shown a favorable outcome when MMS is used as a treatment modality for MCC. Hanke et al. treated four patients with MMS. Three developed local recurrence, one had regional metastasis to lymph nodes, and two patients had distant metastases. No data was available regarding stage at presentation [3]. Similarly, a chart review of 22 patients with MCC revealed the best survival in patients who underwent wide local excision (with 2–3 cm margins) and elective/ prophylactic dissection of the lymphatic drainage basin [15]. It is this author’s opinion that the risk/ benefit ratio and morbidity associated with complete lymph node dissection may be unfavorable, especially with the availability of sentinel lymph node biopsy.

Wide local excision with 2–3-cm margins is the standard of care for primary MCC, but local recurrence rates reported in literature range from 27% to 32% [16–18]. In those studies looking at MMS for the treatment of MCC, margins after Mohs surgery ranged from 1.2 to 3.3 cm, sparing centimeters of normal skin in the majority of cases [10, 16, 17]. Overall, MMS compares favorably with WLE and usually is tissue-sparing, but may have less effect when in transit and nodal metastasis present. Postoperative radiation may be considered in patients with large or recurrent tumors, or in patients where excision is incomplete or impossible [17].

Summary: Conclusion

•Merkel cell carcinoma is a rare tumor with a high likelihood of regional involvement and metastatic spread.

•Sentinal lymph node biopsy is important in prognosis and management.

•Complete surgical excision with margin control is the mainstay of management for primary Merkel cell carcinoma.

24.5Conclusion

Merkel cell carcinoma is a rare tumor with a propensity for local recurrence, regional, and distant metastatic spread. Staging is based on the tumor size and involvement of lymph nodes and/or distant organs. Lymph node involvement is an important prognostic indicator and predictor of survival. The mainstay of management for primary Merkel cell carcinoma is complete excision with clear surgical margins. Mohs micrographic surgery is an effective alternative to wide local excision. Mohs surgery has the advantage of circumferential margin assessment and sparing of uninvolved tissue. The role of adjuvant radiation to the postoperative tumor bed and/ or draining lymph node basin is unclear. Radiation may lower the rate of local recurrence, although no survival benefit has been noted. Patients with a history of Merkel cell carcinoma need close follow up to detect recurrence.

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