Clinical Recognition, Diagnosis, and Staging of Merkel Cell Carcinoma, and the Role of the Multidisciplinary Management Team

Merkel cell carcinoma is a rare malignancy of the skin, with an estimated annual incidence in the United States of 3 per million.¹ The reported incidence of this disease has more than tripled in the past 2 decades.² It is clinically aggressive due to a relatively high local, regional, and metastatic recurrence potential. It is estimated that the overall 2-year disease-specific mortality rate for all patients with Merkel cell carcinoma is 28%, rendering it more lethal than melanoma.³ The rarity and lethality of this disease present unique challenges to the clinician charged with treating these patients. This chapter will review the clinical recognition of Merkel cell carcinoma, its diagnosis and staging, as well as the important role of a multidisciplinary management team.

Clinical Recognition

Merkel cell carcinoma typically presents as a rapidly growing, solitary nodule of the skin. The lesions are typically non-tender and can be reddish-pink, violaceous, or skin-colored and tend to arise in ultraviolet-damaged skin. The primary tumor typically retains the overlying epidermis or may be rarely ulcerated. The most common site of involvement is the head and neck (29%), closely followed by lower extremity (24%), upper extremity (21%), and less commonly the trunk (8%), buttock (5%), and vulva (0.5%).⁴ The differential diagnosis, listed in Table 1, is broad, which renders the clinical diagnosis challenging. In most cases, due to its rarity, the diagnosis of Merkel cell carcinoma is often overlooked at the initial presentation. To improve physician awareness of Merkel cell carcinoma, Heath et al⁴ introduced the mnemonic “AEIOU”: Asymptomatic/lack of tenderness, Expanding rapidly (doubling in <3 months), Immunosuppression, Older than 50 years, Ultraviolet exposed skin site.

TABLE 1.

Common differential diagnoses of Merkel cell carcinoma

Benign tumors

Epidermoid cyst

Acneiform lesion

Lipoma

Dermatofibroma/fibroma

Vascular lesion

Malignant tumors

Amelanotic melanoma

Nonmelanoma skin carcinomas (basal cell carcinomas, squamous cell carcinomas) Lymphoma

Metastatic carcinoma

Sarcoma

Miscellaneous cutaneous lesions

Adnexal tumors

Pyogenic granuloma

Carcinoid

Retinoblastoma

Neuroblastoma

Leukemia cutis

The authors reviewed these 5 criteria in their series of 195 cases. Among the 62 patients on which all 5 criteria were available, they found that 89% of cases met 3 or more criteria, 52% met 4 or more, and 7% met all 5 criteria.⁴ Unfortunately, as many benign lesions will meet several of the criteria of the AEIOU mnemonic, there are no definite clinical criteria specific to the diagnosis of Merkel cell carcinoma. Thus, the key to establishing an accurate and timely diagnosis of Merkel cell carcinoma is a low clinical index of suspicion and prompt biopsy.

Diagnosis

The diagnosis of Merkel cell carcinoma is established by biopsy of a clinically suspicious lesion. Typically, a narrow-margin punch, elliptical excision, or saucerization is preferred to obtain tissue for histologic analysis. Elliptical excisions should be oriented parallel to dermal lymphatics, to minimize the risk of negatively influencing the reliability of a potential sentinel lymph node biopsy. This also facilitates subsequent definitive resection and reduces the need for a future skin graft. Histopathologic diagnosis involves routine hematoxylin and eosin (H&E) staining, which typically demonstrates small, round to oval blue cells with prominent hyperchromatic nuclei and a reduced cytoplasmic-to-nuclear ratio.⁵ However, this microscopic appearance is difficult to distinguish from other small round blue cell neoplasms, especially other neuroendocrine carcinomas such as small cell lung cancer. The diagnosis of Merkel cell carcinoma is confirmed by immunohistochemistry. Pertinent stains to differentiate Merkel cell carcinoma from small-cell lung cancer include cytokeratin-20 and thyroid transcription factor-1. Immunostaining of cytokeratin-20 in a characteristic paranuclear dot-like pattern can be detected in 89%-100% of Merkel cell tumors but is positive in only a third of small-cell lung cancers. Thyroid transcription factor-1 is generally absent in Merkel cell but is commonly expressed in small-cell lung cancer.⁶ Other commonly used, but less specific neuroendocrine markers include neuron-specific enolase, chromogranin A, neural cell adhesion molecule, and synaptophysin.^3,5 The principles of immunostaining for Merkel cell carcinoma will be discussed in greater detail later on in this text.

Staging and Prognosis

Until recently, there were 5 different staging systems described in the literature and in active use, leading to significant confusion among patients, physicians, and researchers. Beginning in late 2009, a new consensus staging system was adopted by the American Joint Committee on Cancer and by the International Union Against Cancer⁷ (Table 2). This new staging system was based on prognostic factors analysis of 5,823 Merkel cell carcinoma patients in the United States using information from the National Cancer DataBase.^7,8 As in all prior staging systems, the extent of disease was highly predictive of survival. For Merkel cell carcinoma patients, survival at 5 years (relative to age- and sex-matched control/population data) was 64% for local, 39% for regional nodal, and 18% for distant metastatic disease.^7,8

TABLE 2.

TNM criteria and stage groupings of the new AJCC staging system

T	N	M
Tx, Primary tumor cannot be assessed T0, No primary tumor Tis, In situ primary tumor T1, Primary tumor ≤2 cm T2, Primary tumor >2 but ≤5 cm T3, Primary tumor >5 cm T4, Primary tumor invades bone, muscle, fascia, or cartilage	Nx, Regional nodes cannot be assessed N0, No regional node metastasis* cN0, Nodes not clinically detectable* cN1, Nodes clinicallydetectable* pN0, Nodes negative by pathologic exam pNx, Nodes not examined pathologically N1a, Micrometastasis† N1b, Macrometastasis‡ N2, In-transit metastasis§	Mx, Distant metastasis cannot be assessed  M0, No distant metastasis M1, Distant metastasis¶  -M1a, distant skin, distant subcutaneous tissues or distant lymph nodes  -M1b, lung  -M1c, all other visceral sites

Stage	Stage Grouping
0	Tis	N0	M0
IA	T1	pN0	M0
IB	T1	cN0	M0
IIA	T2/T3	pN0	M0
IIB	T2/T3	cN0	M0
IIC	T4	N0	M0
IIIA	Any T	N1a	M0
IIIB	Any T	N1b/N2	M0
IV	Any T	Any N	M1

^*“N0” denotes negative nodes by clinical, pathologic, or both types of examination. Clinical detection of nodal disease may be via inspection, palpation, and/or imaging; cN0 is used only for patients who did not undergo pathologic node staging.

^†Micrometastases are diagnosed after sentinel or elective lymphadenectomy.

^‡Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically by biopsy or therapeutic lymphadenectomy.

^§In-transit metastasis is a tumor distinct from the primary lesion and located either (1) between the primary lesion and the draining regional lymph nodes or (2) distal to the primary lesion.

^¶Because there are no data to suggest a significant effect of M categories on survival in Merkel cell carcinoma, M1a-c are included in the same stage grouping.

Similar to some of the previous systems, extent of disease in the new staging system is divided into stage I (primary tumor diameter ≤2.0 cm) and stage II (diameter >2.0 cm), stage III (regional nodal), and stage IV (distant metastatic). A major development in the new staging system is that the method of lymph node evaluation (clinical vs pathologic examination) is a factor in determining stage as this is unusually important in Merkel cell carcinoma. Indeed, if regional nodes are only clinically examined, there is a 32% risk that microscopic nodal involvement will be missed.⁹ This is a far higher fraction than is the case for melanoma. An average melanoma has a thickness of 0.62 mm,¹⁰ and there is approximately a 1% risk of occult nodal disease for melanomas of this thickness.¹¹ Patients with Merkel cell carcinoma who underwent a node-negative sentinel lymph node biopsy had significantly better survival (76% relative survival at 5 years) than those who only underwent clinical nodal evaluation (59% at 5 years).^7,8 An additional feature that is newly incorporated in the staging system is extent of nodal involvement. Merkel cell carcinoma patients who had only microscopic nodal involvement (eg, as revealed by sentinel lymph node biopsy) had 42% survival at 5 years compared with 26% survival for those who presented with clinically apparent nodal disease.^7,8

In addition to diameter and presence of metastatic disease, there are other factors emerging that may be important in determining the prognosis of patients with Merkel cell carcinoma. A number of studies have investigated the association of tumor thickness rather than diameter to patient outcome. While the results have been mixed, recent relatively large studies have reported a positive association of thickness with likelihood of nodal metastasis¹² and poor survival.¹³ A multivariate analysis has revealed that the absence of lymphovascular invasion as well as a nodular rather than infiltrative microscopic growth pattern are favorable histologic features.¹³ Recent studies have suggested that a few novel, unconventional factors may be useful to incorporate in future staging systems. One study found that Merkel cell carcinoma patients who were immunosuppressed due to a history of solid organ transplantation typically presented with more advanced disease and had a worse prognosis compared with patients who were not transplant recipients.¹⁴ Expression of p63, a marker for epidermal and basal cell differentiation was found to be a negative prognostic factor. In that study of 47 patients, p63 expression was associated with an overall survival of <10%, while a lack of p63 expression was associated with >90% overall survival (P < 0.0001).¹⁵ Finally, a polyomavirus has recently been associated with a subset of Merkel cell tumors, and investigations are underway to determine whether there are outcome differences between virus-positive and virus-negative patients.^3,16

New Diagnostic Codes for Merkel Cell Carcinoma

Prior to October of 2009, Merkel cell carcinoma was classified together with many other cancers as a “Malignant neoplasm of the skin” (code 173x in the International Classification of Diseases). This was problematic because this disease category includes a large number of common and relatively benign diagnoses such as basal cell carcinoma that rarely require hospitalization, systemic imaging, chemotherapy, or sentinel lymph node biopsy. Because insurance companies use these diagnostic codes to determine approval or denial for management requests, this caused rejection of appropriate requests for the care of Merkel cell carcinoma patients. The lack of specific codes also made it far more difficult to track the costs and impact of Merkel cell carcinoma on the health care system as these are the codes used to track billing and insurance fees. The Merkel cell carcinoma Multicenter Interest Group¹⁷ realized that this issue was an impediment in management and petitioned the US Centers for Disease Control and Prevention to address this.¹⁸ Merkel cell carcinoma was thus assigned 7 new, disease-specific codes (Table 3) that were made active on October 1, 2009. These codes should now be used worldwide in the care of Merkel cell carcinoma patients and will aid in better management and tracking of this disease.

TABLE 3.

New Merkel cell carcinoma–specific ICD-disease codes adopted in 2009

ICD CODE
209.31	Merkel cell carcinoma of the face
209.32	Merkel cell carcinoma of the scalp and neck
209.33	Merkel cell carcinoma of the upper limb
209.34	Merkel cell carcinoma of the lower limb
209.35	Merkel cell carcinoma of the trunk
209.36	Merkel cell carcinoma of other sites
209.75	Secondary Merkel cell carcinoma*
V10.91	Personal history of malignant neuroendocrine tumor

^*Secondary Merkel cell carcinoma here refers to MCC presenting in nodal or visceral sites without a known primary.

The Role of the Multidisciplinary Management Team

Given the overall poor prognosis of Merkel cell carcinoma, no one modality is sufficient to optimize care of the patient. Therefore, the treatment of Merkel cell carcinoma mandates multidisciplinary care. This concept is espoused by the current National Comprehensive Cancer Network treatment guidelines, which specifically advocates a multidisciplinary tumor board to facilitate the coordination of care among multiple medical specialties.¹⁹ Recently, the Institute of Medicine (IOM) proposed 6 aims for high-quality care: care must be effective, safe, equitable, timely, efficient, and patient-centered.²⁰ A multidisciplinary management team that is highly familiar with Merkel cell carcinoma is required to satisfy these aims.

The first aim of the IOM, which in fact is the central aim, is that care must be effective.²⁰ Effective care of rare and aggressive conditions such as Merkel cell carcinoma mandates that the treating physician keeps current in the recent clinical evidence reported in the literature. For Merkel cell carcinoma, this involves synthesis of data from a myriad of disparate disciplines including: surgical oncology, radiation oncology, medical oncology, pathology, dermatology, mental health care, and even virology. It is unlikely for one clinician to remain up to date in all these areas. Therefore, a multidisciplinary board comprises members from each field is vital to maintain current and effective guidelines that will allow evidence-based treatment recommendations appropriate for the individual patient.

High-quality medical care must also be safe and equitable. Recently, a panel of experts from the National Cancer Institute reviewed the application of IOM aims to the field of oncology. They found that cancer patients frequently received suboptimal care due to the failure to adhere to established standardized treatment guidelines.²¹ An additional report from Europe found that significant deviations from acceptable melanoma practices occurred in settings outside of academic centers.²² A major challenge in treating Merkel cell carcinoma is that reports in the literature are often conflicting regarding optimal treatment. Even the National Comprehensive Cancer Network guidelines often outline many possible approaches to care.²³ Therefore, to maximize the chance that all patients are offered safe and optimal care, a multidisciplinary approach is required to establish a consensus treatment strategy. This allows appropriate treatment that is individualized to each patient and also is acceptable care based on the most recent evidence.

Additional recommended aims of the IOM involves care to be timely and efficient.²⁰ A multidisciplinary team allows for timely care as it minimizes the number of physician visits. This also promotes communication and a sense of teamwork. It also prevents the fragmentation of care that commonly occurs when patient care is divided between different single disciplines. A study has demonstrated that multidisciplinary care in an academic setting results in more cost-efficient care than a conventional community-based setting.²⁴ In addition, the multidisciplinary setting results in an improvement in future delivery of care. The multidisciplinary approach allows a centralized setting that can serve as a regional, national, and international referral center. This facilitates the collection of prospective data on a meaningful number of patients who is critical for advances in both clinical and basic research.

Finally but perhaps most importantly, high-quality care must be patient-centered.²⁰ For a rare disease like Merkel cell carcinoma, education is an essential component of patient care, which can often be complex. In a survey of cancer patients, a majority of patients reported their physician did not provide them with adequate information about their disease process and treatment options.²⁵ Multidisciplinary clinics allow a single setting where shared decision-making between physicians from different fields and their patients can occur. A recent report described results of an educational video for melanoma patients created by physicians from multiple disciplines. The authors demonstrated an increase in knowledge and decrease in anxiety for patients who took advantage of this resource.²⁶ Thus, the multidisciplinary setting is ideal for patient-centered care, which is a critical factor in high-quality care for patients.

Conclusions

In summary, Merkel cell carcinoma is a rare but often lethal malignancy of the skin, whose incidence is increasing. Due to its nonspecific presenting features, initial clinical diagnosis is challenging, and cases are typically identified by immunohistochemical studies. The recent development of a worldwide consensus staging/prognostic system for Merkel cell carcinoma and the creation of Merkel cell–specific diagnostic codes are anticipated to help in clinical management and research relating to this challenging disease. Finally, multidisciplinary management of patients with Merkel cell carcinoma is recommended to provide the highest quality care and optimize patient outcome.