Michael S. Sabel
Presentation
A 69-year-old woman presents to her primary care physician when she notices a firm, nontender, red mass on her left forearm (Figure 1). She first noticed it a few weeks ago, and in the interval, it has grown rapidly. An excisional biopsy performed under local anesthesia demonstrates a Merkel cell carcinoma (MCC). She is referred to your office for further evaluation and treatment.
FIGURE 1 • Merkel cell carcinoma.
Differential Diagnosis
MCC is a rare but aggressive skin cancer, which is also called neuroendocrine carcinoma of the skin or small cell carcinoma of the skin. MCC is rare, with only approximately 500 new cases each year and an annual incidence of 0.6 per 100,000 (based on Surveillance, Epidemiology and End-Results [SEER] data). They are most common among older individuals, with an average age at diagnosis of 69 years and only 5% of patients below the age of 50. They typically present as an intracutaneous nodule or plaque that has grown rapidly over a few weeks to months. It can be flesh-colored, red, or purple. While it sometime ulcerates, the overlying skin is frequently intact. They are most common on sun-exposed areas, with approximately 50% on the face and neck, 40% on the extremities, and 10% on the trunk. The differential includes lipoma, keratoacanthoma, epidermal cysts, pyogenic granuloma, basal cell carcinoma, squamous cell carcinoma, amelanotic melanoma, lymphoma cutis, and metastatic carcinoma of the skin.
Workup
Approximately 70% of MCC patients present with localized disease, while 25% will have palpable regional lymphadenopathy at presentation and 5% present with distant metastases. As with any patient with a new cutaneous or subcutaneous lesion, a thorough history and physical examination including a complete skin and lymph node examination is warranted. However, MCC is rarely suspected clinically at the time of presentation. The diagnosis is made on excisional biopsy. Microscopically, MCC tumors arise in the dermis and frequently extend into the subcutaneous fat. The tumor is composed of small blue cells with round-to-oval, hyperchromatic nuclei and minimal cytoplasm. There are three variants: intermediate (the most common), small cell, and trabecular. The small cell variant is identical to other small cell carcinomas and must be distinguished from metastatic small cell carcinoma. This can be accomplished through immunohistochemistry. Merkel cell tumors express CAM 5.2 and cytokeratin (CK) 20. CK7 and thyroid transcription factor-1 (TTF-1), which is typically found on bronchial small cell carcinomas, are absent on MCC. The intermediate type can often be confused for melanoma or lymphoma. MCC is invariably negative for S-100 and leukocyte-common antigen, which distinguishes it from these.
MCC typically metastasizes to the regional lymph nodes, skin, lung, brain, bone, and liver. Patients with clinically involved lymph nodes or symptoms suggestive of distant metastases should have a computed tomography (CT) scan of the chest, abdomen, and pelvis. CT scan of the chest should also be considered in patients with the small cell variant to exclude the presence of a lung mass suspicious for small cell lung cancer. Otherwise, for patients who have clinically localized disease, a chest x-ray alone is reasonable. The use of routine imaging studies in asymptomatic patients with clinically localized MCC is associated with a low rate of detecting true disease and a high false-positive rate, generating additional tests or biopsies and increasing patient anxiety without impacting overall survival.
On history, the patient is otherwise asymptomatic and physical examination reveals no evidence of in-transit, regional, or distant metastases. There are no other suspicious skin lesions. Review of the biopsy results confirms MCC, measuring 3.5 cm. Chest x-ray shows no pulmonary lesions.
Diagnosis and Treatment
MCC is considered to be both radiosensitive and chemosensitive. Therefore, treatment of MCC should proceed in a multidisciplinary fashion. The initial treatment is usually surgical. Because of the high rate of local recurrence, margins of 2 to 3 cm have historically been recommended. However, low local recurrence rates have been reported after margin-negative excision with more narrow margins. For lesions <2 cm in greatest dimension, margins of 1 cm are typically adequate. For lesions >2 cm, a 2-cm margin is recommended when feasible. For patients with MCC in cosmetically sensitive areas, where even 1-cm margins would be difficult, Mohs micrographic surgery has been reported to have comparable local control rates.
All patients with clinically localized MCC should undergo sentinel lymph node biopsy (SLNB) in conjunction with wide excision. Approximately 20% to 30% of clinically node-negative MCC patients are SLNB positive, and the pathologic lymph node status is the most consistent predictor of survival. Because MCCs have a histologic appearance of a small cell, approximately the size of a lymphocyte, they can be extremely difficult to detect within the lymph nodes using standard hematoxylin and eosin (H&E) staining alone. Therefore, immunohistochemical analysis of the sentinel nodes, in particular with anti-CK-20, is essential. For patients having Mohs surgery, it may be preferable to perform the Mohs surgery after the patient has undergone SLNB.
Surgical Approach
Preoperative planning is critical to determine whether the patient will be able to be closed primarily. If not, then reconstruction with either a split-thickness skin graft or a rotational flap should be considered. The likelihood of postoperative radiation to the primary site should be taken into account when deciding the optimal method for reconstruction.
Prior to being taken to the operating room, the patient should undergo a perilesional injection of technetium sulfur colloid and lymphoscintigram. In the operating room, blue dye (either Lymphazurin or Methylene Blue) is injected intradermally around the lesion. In cases where shine-through may impact the ability to find the sentinel lymph node, the wide excision should be performed first. One- to two-centimeter margins, depending on the size of the primary tumor, are measured around the tumor (or scar from the prior biopsy). If primary closure is feasible, an ellipse is drawn around the lesion with a 3.5 to 1 ratio of length to width. After excision, the skin flaps are elevated to allow primary wound closure. If primary closure is not likely, then either a rotational flap is marked out preoperatively or a donor site for a split-thickness skin graft is prepped out. After changing gowns, gloves, and instruments, the SLNB is performed.
If there is any concern regarding the margin status, it may be preferable to place a temporary graft, such as Integra, until the final pathology results are known. The patient can then return to the operating room for a skin graft or rotational flap once it is known that negative margins have been attained (Table 1).
TABLE 1. Key Technical Steps and Potential Pitfalls in Wide Excision and SLNB for MCC
The patient undergoes wide resection without the need for a skin graft. Two axillary sentinel lymph nodes are identified. The final pathology report reveals no residual MCC in the primary specimen and two of two lymph nodes are positive for metastatic disease, evident on both H&E and immunohistochemical staining.
For patients who have clinically involved lymph nodes and no evidence of distant metastasis, complete lymph node dissection (CLND) should be performed at the time of wide resection. For clinically node-negative patients who undergo SLN biopsy and are found to harbor metastases, CT scan may be considered to rule out distant disease. If negative, CLND is typically considered. As MCC is a radiosensitive tumor, radiation therapy to the regional basin alone can be considered in cases where CLND may be excessively morbid or for patients with minimal tumor burden in the SLN. Failure to treat the lymph node basin after a positive SLN has been associated with high recurrence rates, although the impact on overall survival is unknown. Presentation to a multidisciplinary tumor board on a case-by-case basis is recommended.
Case Conclusion
The patient returns to the operating room for a completion node dissection. None of the 24 lymph nodes contain metastatic MCC.
Postoperative Management
MCC is radiosensitive and radiation therapy is often part of the treatment algorithm. Adjuvant radiation is critical if surgical margins are positive or relatively narrow. Adjuvant radiation may be omitted for small primary tumors (<2 cm) if clear margins are obtained. For primary tumors ≥ 2 cm, even with negative margins, adjuvant radiation should be strongly considered.
Radiation can also be used for the regional basin. As stated above, radiation may be considered as an alternative to completion node dissection for patients with minimal tumor burden within a positive SLN; however, CLND is typically considered first-line treatment. Adjuvant radiation after CLND is not necessary for patients with microscopic disease within the SLN. This combination may be considered for patients with extensive lymph node disease or extracapsular extension. However, the benefits of reducing regional recurrence must be weighed against the increased morbidity of surgery and radiation, the most significant of which is lymphedema.
Although MCC is generally considered a chemosensitive tumor, adjuvant chemotherapy is the least studied treatment modality for MCC and currently has no established role in the treatment of local or regional disease.
TAKE HOME POINTS
· MCC is a relatively rare, but highly aggressive, cutaneous malignancy that is more common among the elderly.
· Workup, including immunohistochemical staining of the biopsy, is needed to differentiate from amelanotic melanoma, lymphoma cutis, metastatic carcinoid, and metastatic small cell lung cancer.
· MCC can be treated with surgery, radiation, and in some cases chemotherapy, so a multidisciplinary approach is strongly recommended.
· Local disease is treated by wide excision with clear margins and often followed by adjuvant radiation.
· Clinically node-negative patients should undergo SLNB in addition to wide excision. Patients with a positive SLN typically undergo CLND, although radiation to the involved basin may also be considered.
· CLND followed by radiation should be considered for patients with extensive lymph node involvement or extracapsular extension.