Unanswered Questions in the Management of Stage I-III Merkel Cell Carcinoma

Many unanswered questions remain about what constitutes appropriate guidelines for treatment of Merkel cell carcinoma (MCC). In this review, we address current uncertainty surrounding optimal management of MCC. These areas of uncertainty include early recognition features; clinical and histopathologic prognostic factors; optimum margins of excision of the primary tumor; indications for and value of surgical staging of the clinically negative regional nodes; optimum management of the patient with pathologically positive regional nodes; and indications for and value of radiation to the primary and regional nodes. Through identifying and elaborating on these areas of uncertainty, the authors hope to foster additional research and ultimately improve the evidence base for future iterations of the NCCN Clinical Practice Guidelines in Oncology in this rare but increasingly encountered cutaneous malignancy. The intent, however, is not to exhaustively identify all areas of controversy, but rather to highlight clinically relevant questions that further studies could address to improve the standard of care for MCC.

Abstract

Many unanswered questions remain about what constitutes appropriate guidelines for treatment of Merkel cell carcinoma (MCC). In this review, we address current uncertainty surrounding optimal management of MCC. These areas of uncertainty include early recognition features; clinical and histopathologic prognostic factors; optimum margins of excision of the primary tumor; indications for and value of surgical staging of the clinically negative regional nodes; optimum management of the patient with pathologically positive regional nodes; and indications for and value of radiation to the primary and regional nodes. Through identifying and elaborating on these areas of uncertainty, the authors hope to foster additional research and ultimately improve the evidence base for future iterations of the NCCN Clinical Practice Guidelines in Oncology in this rare but increasingly encountered cutaneous malignancy. The intent, however, is not to exhaustively identify all areas of controversy, but rather to highlight clinically relevant questions that further studies could address to improve the standard of care for MCC.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/41670; and 4) view/print certificate.

Release date: March 10, 2014; Expiration date: March 10, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Identify areas of uncertainty surrounding management of Merkel cell carcinoma

  • Summarize available data on radiation therapy in the treatment of Merkel cell carcinoma

  • Compare management options for patients with clinically positive or negative nodes

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) acknowledge the rarity of this tumor and the lack of prospective data, noting that “the panel relied on trends that are documented in smaller, individual studies, in meta-analyses, and in their own collective experiences.”1 Consequently, all recommendations are based on lower-level evidence and many unanswered questions remain. This article addresses areas of uncertainty surrounding optimal management of localized (stage I-III) MCC, with the intent to highlight areas for future research rather than provide definitive answers. In general, the authors have chosen to focus on the aspects they consider least well defined in the existing corpus of knowledge and in the current NCCN Guidelines (in this issue; to view subsequent updates to these guidelines, visit NCCN.org).

Evaluation of the Primary Tumor

In many ways, MCC is analogous to thick melanoma: most lesions are thick and deeply invasive, regional nodal metastases are commonly identified, and subclinical distant dissemination is present in many patients at diagnosis.2 Compared with melanoma, however, this disease entity has a critical lack of reliable recognition features for early diagnosis and a dearth of information about the most important clinicopathologic predictors of outcome.

What Criteria Can Be Used to Recognize Lesions Suspicious for Primary MCC?

NCCN Guidelines for MCC call for biopsy of “a suspicious lesion,” without defining the characteristics considered most likely to raise suspicion for this disease. In fact, the diagnosis of MCC is rarely made or even considered before biopsy,3 and delays in diagnosis are more the rule than the exception.4 In an effort to define early recognition features analogous to the “ABDC” criteria widely used in melanoma, Nghiem et al4 proposed the “AEIOU” acronym: MCC lesions (or patients) were frequently Asymptomatic, Expanding, Immunosuppressed, Older than 50 years, and located on an Ultraviolet-exposed site. In their study of 62 patients/tumors, 89% met 3 or more criteria, 52% met 4 or more, and 7% met all 5. This acronym has never been prospectively validated, and has been criticized because an enormous number of non-MCC lesions (benign and malignant) would share at least 3 of these features.5 Improved early recognition features that could serve as the basis of a broad-based educational campaign are clearly needed. Until then, good clinical judgment in the evaluation of any enlarging skin lesion remains essential, and the threshold for performing a biopsy should be low for patients at risk of MCC, especially those with immunosuppression.

What Histopathologic Criteria and Workup Should Be Used for Optimal Diagnosis and Prognostication of Primary MCC?

NCCN Guidelines call for confirmatory immunostains to establish the diagnosis of MCC, preferably including cytokeratin-20 for confirmation and thyroid transcription factor-1 to exclude metastatic small cell lung carcinoma.1 Because this panel is less than 100% sensitive and specific, other markers, such as chromogranin A, synaptophysin, CD56, neurofilament, and neuron-specific enolase, may be used on equivocally staining lesions.6 When appropriate, other markers to exclude lesions in the differential diagnosis, such as S-100 and Melan-A for melanoma and cytokeratin 7 for other carcinomas with small cell morphology, may be considered, and a prescribed panel that maximizes sensitivity and specificity should be recommended.

Once diagnosed, current NCCN Guidelines acknowledge the uncertainty regarding histopathologic prognostic factors in MCC, but recommend reporting tumor diameter, margin status, lymphovascular invasion, and extracutaneous extension into bone, muscle, fascia, or cartilage. In addition, the NCCN Guidelines strongly encourage reporting of additional clinically relevant factors, such as tumor thickness, mitotic index, tumor growth pattern, and tumor-infiltrating lymphocytes, as well as the presence of a second malignancy, such as a concurrent squamous cell carcinoma. Of these, tumor thickness is infrequently part of the routine histopathologic evaluation of primary MCC, and is deemed optional by the College of American Pathologists.7 However, because of its indisputable value in melanoma and its greater reliability compared with measurements of tumor diameter, the authors believe thickness is critical to evaluate as a prognosticator for MCC, and strongly encourage the use of synoptic reporting to ensure all key features are described.2 Correlating sentinel lymph node biopsy (SLNB) status with thickness (nodal status has only poorly correlated with diameter8,9) may be particularly useful to elucidate the biologic significance of tumor thickness, because many patients with MCC ultimately die from comorbid conditions rather than from the disease. Furthermore, appropriate thickness cutoffs must be defined. Lim et al10 found particularly poor survival for patients with MCCs thicker than 10 mm, but perhaps 4 mm might be a better discriminator between MCCs with a poor and intermediate prognosis, as in melanoma. MCCs less than 1 mm in thickness are infrequently encountered, but the prognosis of this group also needs definition.2

Although measuring tumor diameter is considered less accurate and reproducible than micrometer thickness,11 MCC is often relatively spherical, meaning diameter and thickness may correlate more closely than in melanoma. Mitotic index is difficult and arduous to evaluate in MCC because it is almost always high, but defining and validating appropriate cutoffs may be helpful to best evaluate its ability to predict outcome. Lymphovascular invasion may correlate with sentinel node status and survival,12 and might predict local recurrence risk, but more data are needed because studies to date have yielded inconsistent results.9

Implications of Merkel Cell Polyomavirus for Prognostication and Treatment of MCC

Studies have also been inconsistent regarding the prognostic significance of detecting Merkel cell polyomavirus (MCPyV) DNA in the tumor or antibodies in the serum,13-15 but the potential preventive and therapeutic implications make further investigation of paramount importance. The relatively limited understanding of the significance of existing prognostic factors makes the independent contribution of virus-related markers difficult to ascertain, and therefore comprehensive and ideally prospective evaluations of old and new prognosticators are urgently needed. Current NCCN Guidelines do not include studies of MCPyV DNA or serologies, but the value of these assays in predicting prognosis and/or identifying tumor recurrence must be considered unanswered questions.

Should MCC Be Treated Differently in Immunosuppressed Patients Versus Nonimmunosuppressed Patients?

NCCN Guidelines are also silent on whether the presence of therapeutic or pathologic immunosuppression should lead to alterations in the management of patients with MCC, such as SLNB, postoperative radiation, and cytotoxic chemotherapy with one important exception. A revision to the NCCN Guidelines introduced in 2014 states that observation without postoperative radiation “should be limited to patients with small primary lesions that have been widely excised and present with no adverse risk factors such as lymphovascular invasion or immunosuppression.”1 However, the impact of immunosuppression on local recurrence after surgery alone has never been clearly defined. After diagnosis of MCC, it stands to reason that immunosuppressive drugs should be reduced to the smallest possible dose required to manage the patient’s condition, but whether certain drugs or regimens should be particularly avoided is currently unknown. Given the association between MCC and immunosuppression16 and the etiologic role of MCPyV,17 this question needs to be addressed in future studies. Furthermore, reproducible definitions and categorization of the types/degrees of immunosuppression that may relate to tumor development and prognosis would help identify the strength of any associations.

Management of the Primary Tumor in MCC

Although widespread consensus exists that excision is the gold standard, the evidence base for recommendations concerning the extent of surgery and the role of radiation in the management of primary MCC is remarkably thin.

What is the Proper Excision Margin for MCC?

No consensus exists on whether to use prespecified excision margins or how wide those margins should be. NCCN Guidelines indicate that the goal of excision is to obtain a histologically negative margin, and recommend 1- to 2-cm margins down to fascia or pericranium when feasible.1 Some have recommended 2- to 3-cm margins, whereas a retrospective literature review found that margins less than 1 cm had similar recurrence rates compared with margins of 1 cm or greater (9% vs 10%, respectively).3 Confounding the discussion of excision margins is the widespread use of postoperative radiation, especially after narrow-margin excisions. Although an R0 resection is a desirable minimum goal for any excision, if a slightly wider excision margin could routinely replace the need for postoperative radiation, the risk/benefit ratio would clearly support a recommendation for wider surgery.

When Should Postoperative Radiation to the Primary Site Be Used After Complete Excision?

MCC is clearly a very radiosensitive tumor, and postoperative radiation of the primary site is included in the NCCN Guidelines for MCC.1 The evidence base regarding postoperative radiation is large compared with that available for other aspects of MCC treatment, yet there is substantial reason to question its routine use. The use of adjuvant radiation did not significantly lower the risk of local recurrence in one recent relatively large single-institution series: 1.7% of patients experienced recurrence after receiving postoperative radiation versus 3.8% for patients not selected for adjuvant radiation (P=.77).18 Another study reviewed 104 patients treated with wide excision over a 30-year period, of whom 78 (75%) received adjuvant radiation.19 Local/regional recurrence rates analyzed by stage did not show a significant benefit for radiation: 27% for surgery alone versus 32% for surgery plus radiation for stage I (P=.765), and 60% for surgery alone versus 39% for surgery plus radiation for stage II (P=.433).19 These 2 series graphically illustrate the problems inherent in retrospective MCC studies: cases were accumulated over decades, making inherent treatment and selection biases impossible to adequately define; end points were assessed retrospectively and reported inconsistently (note the difference between the local recurrence rate in the first series and the local/regional recurrence rate in the second); and the power to detect large and potentially clinically important differences (eg, 39% vs 60% local/regional failure rates) is minimal.

Attempts have been made to address the deficiencies in single-institution reviews through performing meta-analyses. Although these have generally represented literature summations rather than true meta-analyses of individual patient data, the aggregate results of multiple series support postoperative radiation significantly reducing local recurrence: of 441 patients included, the local recurrence rate was 10.5% after radiation versus 52.6% without radiation (P<.00001).20

Two studies analyzing the SEER database yielded conflicting results. In one, postoperative radiation was not associated with improved disease-specific survival.21 In another, median survival was significantly improved in patients receiving radiation (63 vs 49 months; P<.012).22 Many patients with MCC are older and often have substantive comorbidities, and it is reasonable to expect that patients with a shorter life expectancy would be less likely to undergo adjuvant radiation. Hence, the survival impact of postoperative radiation must be considered an unanswered question requiring a prospective randomized trial to address.

Ideally, radiation might be used selectively in patients at highest risk of local recurrence, and omitted in patients at low risk of local recurrence, and perhaps in those at prohibitive risk of distant failure. One report addressed the possible role of lymphovascular invasion in predicting local recurrence. Among patients without lymphovascular invasion, only 2 of 132 (<2%) developed a local recurrence, compared with 83 of 162 patients (51%) with lymphovascular invasion.18 This dramatic impact of lymphovascular invasion on local recurrence has not been seen by other authors, but merits further study. Also worth studying is the possibility that thicker MCC primaries should be selected for postoperative radiation, analogous to recent findings in desmoplastic melanoma.23

When, if Ever, Should Mohs Micrographic Surgery Be Used?

NCCN Guidelines mention consideration of Mohs micrographic surgery when tissue-sparing is of critical importance,1 but the evidence supporting Mohs seems particularly scanty, and its implications on the ability to perform SLNB are not addressed. If Mohs is used, NCCN Guidelines advocate sending the central tumor for permanent pathologic analysis. The available literature describing Mohs for primary MCC are limited by their small size, retrospective design, and limited long-term follow-up.24,25 Overall, the reported local recurrence rates after Mohs resection seem to be comparable to those after wide excision,26 but this neither supports nor refutes its use. The number of unanswered questions about Mohs for MCC is sufficient to call into question its inclusion in the current NCCN Guidelines, and the authors do not use this technique in their patients.

What is the Role of Radiation Before or Instead of Surgery for Primary MCC?

Definitive radiation of MCC (ie, without prior or subsequent removal of the primary) has been reported. The largest series described 43 patients deemed unresectable or inoperable because of severe comorbidities. The infield control rate was 75%; recurrence developed in 60% of patients, with most recurrences outside the treatment field.27 Given the limited alternatives, the available data strongly support the use of radiation to treat primary MCC in patients with severe comorbidities precluding surgery, but the optimum role of preoperative radiation without or with systemic chemotherapy for large “unresectable” tumors remains in question.

Management of the Clinically Node-Negative Lymph Node Basin in MCC

Another controversial area is the management of the clinically node-negative regional nodal basin in MCC. The indications for SLNB and regional nodal basin radiation remain inadequately defined.

What is the Prognostic and Therapeutic Value of SLNB for MCC?

NCCN Guidelines recommend that SLNB be performed in patients at the time of wide excision, and considered selectively if wide excision has been performed previously (because of concerns that the accuracy of results may be compromised).1 SLNB in patients with MCC has the same theoretical advantages as in those with melanoma. It helps identify clinically occult nodal metastasis, enabling patients with negative nodes to be spared further treatment and those with positive nodes to receive further treatment before they experience clinical recurrence. Numerous retrospective and pooled-data studies have concluded that SLNB improves prognostication and identifies a group of patients with node-negative disease with excellent long-term survival, whereas other studies found no differences in rates of recurrence or death from MCC between SLNB-positive and -negative patients.28,29 A review of the National Cancer Data Base concluded that patients with microscopic nodal involvement (stage IIIA) had significantly better adjusted survival than those with clinically detected nodal involvement (stage IIIB).30 For now, although SLNB seems to be well justified overall and should be considered in all patients with clinically node-negative MCC,3 some questions remain.

Which Patients With MCC Should Not Undergo an SLNB?

Patients with very small MCCs may be able to safely avoid an SLNB without experiencing an increased risk of regional nodal recurrence.31 However, using tumor size of 1 cm or less in diameter as a criterion for “small” MCC, the data are conflicting but still insufficient to justify omitting SLNB in this group, with one study showing a 42% incidence of positive sentinel nodes.8 However, other criteria, including tumor thickness, should be studied as possible selection factors.

What is the Role of Ultrasound in Nodal Basins in MCC?

Ultrasound evaluation of regional nodal basins is used in melanoma and breast cancer preoperatively and in surveillance in patients who did not undergo an SLNB.32,33 Although useful in selected patients with these malignancies, SLNB is more sensitive for detecting small nodal metastases.34 There is little reason to believe that ultrasound detection of MCC nodal metastases will differ from that of melanoma metastases, and therefore the use of ultrasound is logical in selected cases pending specific studies.35 In particular, it is worthwhile to evaluate how often routine preoperative nodal ultrasound could identify patients with sufficient nodal tumor burden to allow ultrasound-guided biopsy and obviate the need for SLNB.

What is the Role of Radiation Treatment of the Regional Basin in the Absence of Biopsy Proof of Nodal Metastasis From MCC?

If SLNB is not performed or is unsuccessful, NCCN Guidelines recommend irradiation of nodal beds for subclinical disease be considered,1 but no prospective data support this recommendation. Radiating clinically node-negative basins exposes patients without lymph node metastases to unnecessary treatment, and in areas of ambiguous lymphatic drainage could result in treating basins not at risk of metastasis. Radiation after negative SLNB has been advocated because of concerns about false-negative SLNB results,36 but when clinical factors such as patient age and tumor location are taken into account, little evidence suggests that patients with MCC are at such high risk of nodal recurrence after negative SLNB that routine radiation is justified.37 Further investigation may be warranted, but consideration of radiation in these situations does not seem justified.

Management of the Patients With Clinically Node-Positive MCC

NCCN Guidelines for patients with clinically node-positive MCC, confirmed through fine-needle aspiration or core biopsy, were updated in 2014 but remain remarkably nonprescriptive and afford considerable latitude in treatment. The guidelines recommend multidisciplinary tumor board discussion, with node dissection and/or radiation as the definitive treatment. Adjuvant chemotherapy is no longer recommended for consideration as part of the treatment of clinically node-positive disease, although it could be used “on a case-by-case basis if clinical judgment dictates.”1 The evidence base to support or refute use of adjuvant chemotherapy has not changed recently, so this appears to represent a change in emphasis rather than a change in the available data. What remains surprising is how few good data exist on outcomes of the management of these patients with single-modality or multimodality therapy. Until better data are available, particularly regarding regional relapse and distant metastasis rates for node-positive MCC treated with surgery, radiation, or both, optimum management strategies cannot be defined. Similarly, data are woefully lacking regarding adjuvant systemic chemotherapy, especially considering that substantial selection bias exists when decisions are made outside the context of a clinical trial. One specific area the current NCCN Guidelines are silent on is node-positive MCC with an unknown primary site (MCCUP).

Should Patients With MCCUP Metastatic to Regional Nodes Be Managed Differently From Those With a Known Primary Site?

The incidence of nodal MCCUP in the literature ranges from 2% to 19% of all cases of MCC. The largest series reported to date identified 27 of 195 (14%) and 38 of 321 (12%) patients who presented with nodal MCCUP.4,38 The origin of MCCUP is unknown, but likely involves spontaneous regression of a primary MCC lesion. Available data support treating MCCUP using the same guidelines as those for clinically node-positive MCC, because long-term survival is possible with an aggressive multimodality treatment approach, but further data on treatment and outcome should be accumulated.

Management of MCC in the Future

In summary, the body of knowledge concerning MCC, a tumor that was only recognized and characterized in the past 40 years, continues to increase. Recent discoveries of a viral association and the development of techniques such as SLNB have taken their place alongside the mainstays of treatment, such as excision and radiation. Although the relative rarity of the tumor confounds efforts to prospectively determine key elements of prognostication and treatment, future research focusing on creating large databases similar to the AJCC melanoma database39 and conducting large, controlled, and likely multi-institutional studies should be actively supported. Through understanding and addressing the unanswered questions of today, the development of improved methods of diagnosing, reporting on, and treating localized and metastatic MCC will enhance patient outcomes in the future.

Dr. Zager has acted as a consultant and member of the scientific advisory board and received a grant from Delcath Systems Inc., has acted as a consultant and member of the scientific advisory board for IGEA and Amgen, and has acted as a consultant and member of the advisory board and received a grant from LifeCell. Dr. Messina has acted as a consultant for GlaxoSmithKline. Dr. Glass has a paid leadership position in Aurora Diagnostics LLC. Dr. Sondak has acted as a consultant and member of the advisory board for Merck & Co., Inc., Navidea Biopharmaceuticals, and Provectus Pharmaceuticals, Inc., and as a consultant for GlaxoSmithKline and Bristol-Myers Squibb.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants

Ms. Moonan has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education & Grants

Ms. Gianola has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations

Ms. Gregory has disclosed that she has no relevant financial relationships.

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Correspondence: Vernon K. Sondak, MD, Department of Cutaneous Surgery, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. E-mail: vernon.sondak@moffitt.org

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