Beyond the factors used to assign T, N, or M categories, no additional prognostic factors are required for stage grouping.

Prognosis in MCC is based primarily on the extent of disease at presentation, which formed the basis of the first AJCC staging system.² Recent analysis of overall survival in an expanded and more contemporary cohort of 9,387 patients with MCC from the NCDB validated the previous staging system and confirmed the correlation between primary tumor size, as well as extent of disease at presentation, and prognosis (Figures Figure 2 and Figure 3). A significant limitation of NCDB data is the lack of disease-specific survival data and reliance on overall survival rates. Particularly in a patient population with a median age of 76, such as in MCC, overall survival is significantly influenced by the rate of death from unrelated causes. The previous analysis of NCDB data calculated relative survival by adjusting overall survival data using age- and sex-matched life expectancy information.² Because this adjustment was not performed in the most recent NCDB reanalysis, survival curves must be viewed in that context, rather than by comparing absolute rates. MCC-specific survival rates are expected to be more favorable than the overall survival rates shown here.

Consistent with other AJCC staging systems, the current prognostic stage groups for MCC are separated by clinical and pathological staging. The previous inclusion of the extent of pathological nodal evaluation into Stage I and II substages (i.e., IA/IB and IIA/IIB) does not apply to the current system. A patient in whom pathological evaluation of the regional lymph node basin (i.e., most commonly by SLNB) has not been performed is no longer staged as IB (or IIB if the primary tumor is >2 cm). Analogous to melanoma, this patient will be assigned category pNX and staged as prognostic stage group I or II based on characteristics of the primary tumor. Survival rates of patients in the NCDB cohort with localized disease based on clinical staging only (i.e., those who did not undergo pathological nodal evaluation) are shown in Figure Figure 4. Survival rates of patients with clinically staged nodal or distant metastases (i.e. those who did not undergo pathological confirmation of clinically detected presumed metastatic disease) are not included due to the small number of patients with inconsistent data in the NCDB dataset.

Primary Tumor Size

The clinically measured largest diameter of an MCC remains the only parameter of the primary tumor that is shown to be predictive of survival and has been independently validated by multiple cohorts^2,13,17,28 (AJCC Level of Evidence: I). Measurement is performed clinically, preferably before biopsy, by determining the largest diameter of the tumor in centimeters. Unfortunately, this measurement is subject to an inherent degree of inaccuracy and subjectivity. However, previous studies showing a correlation between tumor size and prognosis were based on this parameter, which therefore is maintained until more accurate parameters have been validated. Categories are divided into primary tumors measuring ≤2 cm (T1), those >2 cm but ≤5 cm (T2), and those >5 cm (T3). Histologic measurement of tumor diameter is subject to underestimation due to shrinkage of formalin-fixed tissue and inaccuracy in measuring the largest diameter of oval tumors.⁷ If clinical tumor size is unavailable, histopathologic gross or microscopic measurement should be used for staging.

Unknown Primary Tumor

A new addition to the current staging system is based on the consistent observation in several independent cohorts that patients presenting with metastatic MCC in a lymph node, in the absence of a primary tumor (T0), have a significantly more favorable prognosis than those presenting with a primary tumor and synchronous lymph node metastasis.^18-20 Survival rates for patients presenting with a lymph node metastasis of MCC and unknown primary tumor are consistently similar to the rates for patients presenting with a primary tumor and occult nodal metastases detected by SLNB [pN1a(sn) or pN1a]. This finding is supported by analysis of the NCDB cohort (Figure Figure 5; AJCC Level of Evidence: I). Based on these data, patients presenting with a clinically or radiologically detected, pathologically confirmed, nodal MCC metastasis (pN1b) without a primary cutaneous tumor are staged in prognostic group IIIA rather than IIIB, as in the previous system. Because this represents a diagnosis of exclusion, clinical examination to rule out a primary cutaneous tumor must be thorough and should include examination of mucosal surfaces for lymph node metastases in the cervical or inguinal basins.

Regional Nodal Tumor Burden

Consistent with the previous staging system, tumor burden in the regional draining lymph nodes is maintained as a prognostic parameter for staging (AJCC Level of Evidence: I). Multiple studies have consistently shown that patients presenting with a primary cutaneous MCC and clinically or radiologically detected regional lymph node metastasis (pN1b) have a worse prognosis than those with a primary tumor and occult nodal metastasis detected by SLNB.^{2,15,17,28,29} This finding is supported by analysis of the NCDB cohort (Figure Figure 5). Moreover, based on the updated NCDB analysis, patients with localized MCC and pathologically proven negative lymph node(s) (pathological stage groups I and IIA) have a more favorable prognosis than those with occult nodal metastases in the draining nodal basin (IIIA; Figure Figure 6). This finding is consistent with most other independent cohorts.^{2,15,17,28,30} Finally, the 5-year overall survival advantage of pathologically staged versus clinically staged node-negative patients (stage I, 62.8% vs. 45.0%; stage IIA, 54.6% vs. 30.9%; and stage IIB, 34.8% vs. 27.3%, respectively) signifies the prognostic value of pathologic nodal evaluation for clinically node-negative patients (Figures Figure 4 and Figure 6). These findings, combined with the high rate (at least 30%) of clinically occult nodal metastases in the draining regional lymph nodes, strongly support the recommendation to perform SLNB routinely in all patients with localized MCC, if clinically feasible.^{2,16,17,24,30,31} Early detection likely will improve control of the regional lymph node basin and may have a favorable impact on survival.

Tumor Thickness

Tumor thickness, also known as Breslow thickness in cutaneous melanoma, is measured microscopically from the granular layer of the overlying epidermis to the deepest point of tumor invasion. Breslow thickness is the principal prognostic parameter for primary melanoma and forms the basis of the AJCC staging system. Based on the spherical shape of a primary MCC, one intuitively would expect tumor thickness to correlate with tumor diameter, an established prognostic factor currently required for the T category. Several single-institution studies demonstrated a correlation between tumor thickness and prognosis in MCC^17,32,33 (AJCC Level of Evidence: II). However, consistent synoptic reporting of various histopathologic parameters, including tumor thickness, is not performed uniformly for MCC; therefore, this information is available only sparsely in large national datasets such as the NCDB. Consistent recording is strongly encouraged to validate or refute prognostic correlations identified in smaller, single-institution cohorts.

Immunosuppression

The strong association between immunosuppression and MCC is well known^10,34,35 (AJCC Level of Evidence: I). Whether compromised immune surveillance is the result of an underlying comorbidity, such as chronic lymphocytic leukemia, or immunosuppressive medication to prevent organ rejection, it increases the risk of developing MCC and negatively influences the subsequent immune response against the tumor, resulting in a higher mortality rate. Similarly, immune senescence, the natural decline of the immune system with age, is believed to be a contributing factor in the continually increasing incidence of MCC with advancing age.³⁶ Because of the subjective nature of this known prognostic factor, immunosuppression is not incorporated in the staging system. However, the practitioner is strongly encouraged to maintain a higher level of suspicion for the development of MCC in an immunocompromised patient, and to bear in mind the more aggressive course of MCC in the context of suppressed immune status when considering treatment options and surveillance for such patients.³⁷

Lymphovascular Invasion and Other Histopathologic Parameters

Lymphovascular invasion (LVI), also referred to as angiolymphatic invasion, is defined as the presence of tumor cells within the endothelium-lined spaces without distinguishing between lymphatic channels and blood vessels. Although LVI generally is considered a poor prognostic indicator in melanoma and other malignancies, inconsistent data regarding this parameter exist for MCC^16,17,29 (AJCC Level of Evidence: III). Moreover, nonuniform detection methods, including the use of immunohistochemical staining of endothelial cells, and inconsistent reporting limit the ability to draw definitive conclusions about the prognostic value of this parameter from larger datasets. Consistent synoptic reporting of LVI is strongly encouraged. Other parameters not routinely collected include ulceration, mitotic rate, and the presence of tumor-infiltrating lymphocytes. Consistent recording of such variables is strongly encouraged to validate or refute prognostic correlations identified in smaller, single-institution cohorts.

Merkel Cell Polyomavirus (MCPyV)

The association between MCC and the novel virus MCPyV was first described in 2008.⁴ Since then, mounting evidence has emerged that MCPyV viral proteins have a causal role in MCC development.^5,38 However, a subset of MCCs consistently are MCPyV negative, suggesting alternate mechanisms of tumorigenesis.³⁹ It has been suggested that a geographic variation in contributions of causative factors for MCC may exist. UV radiation may be a more prevalent factor in the development of MCPyV-negative MCCs, in which a higher overall mutation burden with a prominent UV-signature pattern has been identified.^40,41 Although a trend may suggest a more favorable outcome for patients with virus-positive tumors, the prognostic significance of MCPyV status remains unclear and controversial.^42-44

p63

Recently, relatively small studies suggested a strong correlation between immunohistochemical expression of p63 and worse outcome in patients with MCC.^43,45 However, other studies could not confirm the correlation with prognosis and did not report the high rate of p63 positivity previously observed.^41,46 The prognostic value and clinical utility of this marker with variable expression remain unclear.

Imaging

Several new and emerging imaging modalities are described in the recent literature. With regard to lymphoscintigraphy for sentinel lymph node detection, the use of single-photon emission CT/CT imaging may contribute to improved detection of radiolabeled lymph nodes close to the primary tumor/radiotracer injection site (e.g., primary tumors located in the head/neck region).⁴⁷ In addition, the use of intraoperative gamma camera technology may further assist surgeons in the intraoperative detection and localization of sentinel lymph nodes during surgery, as well as verify the excision of sentinel lymph node(s).⁴⁸ The use of [indium-111]-pentetretotide scintigraphy and [gallium-68 (⁶⁸Ga)]-DOTATATE, -DOTATOC, and -DOTANOC PET/CT imaging has been described based on expression of somatostatin receptor (SSTR) in MCC.^49,50 Somatostatin analogs labeled with PET radioisotopes (e.g., ⁶⁸Ga, copper-64) may offer additional diagnostic imaging information about the sites and extent of MCC involvement throughout the body beyond the typical anatomic information provided by CT and MR imaging or the metabolic information of FDG PET.⁵¹ Further clinical trials are needed to compare these emerging imaging approaches with standard imaging methods.

There is no recommended histologic grading system at this time.

1. Tang CK, Toker C. Trabecular carcinoma of the skin: an ultrastructural study. Cancer. Nov 1978;42(5):2311-2321.
2. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. Journal of the American Academy of Dermatology. Nov 2010;63(5):751-761.
3. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. Aug 15 2001;19(16):3622-3634.
4. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. Feb 22 2008;319(5866):1096-1100.
5. Verhaegen ME, Mangelberger D, Harms PW, et al. Merkel cell polyomavirus small T antigen is oncogenic in transgenic mice. The Journal of investigative dermatology. May 2015;135(5):1415-1424.
6. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. Journal of the American Academy of Dermatology. Mar 2008;58(3):375-381.
7. Schwartz JL, Bichakjian CK, Lowe L, et al. Clinicopathologic features of primary Merkel cell carcinoma: a detailed descriptive analysis of a large contemporary cohort. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. Jul 2013;39(7):1009-1016.
8. Brewer JD, Shanafelt TD, Call TG, et al. Increased incidence of malignant melanoma and other rare cutaneous cancers in the setting of chronic lymphocytic leukemia. Int J Dermatol. Aug 2015;54(8):e287-293.
9. Kanitakis J, Euvrard S, Chouvet B, Butnaru AC, Claudy A. Merkel cell carcinoma in organ-transplant recipients: report of two cases with unusual histological features and literature review. J Cutan Pathol. Oct 2006;33(10):686-694.
10. Penn I, First MR. Merkel's cell carcinoma in organ recipients: report of 41 cases. Transplantation. Dec 15 1999;68(11):1717-1721.
11. Fitzgerald TL, Dennis S, Kachare SD, Vohra NA, Wong JH, Zervos EE. Dramatic Increase in the Incidence and Mortality from Merkel Cell Carcinoma in the United States. The American surgeon. Aug 2015;81(8):802-806.
12. Lemos B, Nghiem P. Merkel cell carcinoma: more deaths but still no pathway to blame. The Journal of investigative dermatology.Sep 2007;127(9):2100-2103.
13. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Annals of surgical oncology. Apr 2001;8(3):204-208.
14. Moshiri AS, Nghiem P. Milestones in the staging, classification, and biology of Merkel cell carcinoma. Journal of the National Comprehensive Cancer Network : JNCCN. Sep 2014;12(9):1255-1262.
15. Iyer JG, Storer BE, Paulson KG, et al. Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. Journal of the American Academy of Dermatology. Apr 2014;70(4):637-643.
16. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol. Mar 10 2011;29(8):1036-1041.
17. Smith FO, Yue B, Marzban SS, et al. Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. Cancer. Sep 15 2015;121(18):3252-3260.
18. Tarantola TI, Vallow LA, Halyard MY, et al. Unknown primary Merkel cell carcinoma: 23 new cases and a review. Journal of the American Academy of Dermatology. Mar 2013;68(3):433-440.
19. Chen KT, Papavasiliou P, Edwards K, et al. A better prognosis for Merkel cell carcinoma of unknown primary origin. American journal of surgery. Nov 2013;206(5):752-757.
20. Foote M, Veness M, Zarate D, Poulsen M. Merkel cell carcinoma: the prognostic implications of an occult primary in stage IIIB (nodal) disease. Journal of the American Academy of Dermatology. Sep 2012;67(3):395-399.
21. Maricich SM, Wellnitz SA, Nelson AM, et al. Merkel cells are essential for light-touch responses. Science. Jun 19 2009;324(5934):1580-1582.
22. Tilling T, Moll I. Which are the cells of origin in merkel cell carcinoma? J Skin Cancer. 2012;2012:680410.
23. Bichakjian CK, Lowe L, Lao CD, et al. Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer. Jul 1 2007;110(1):1-12.
24. Bichakjian CK, Olencki T, Alam M, et al. Merkel cell carcinoma, version 1.2014. Journal of the National Comprehensive Cancer Network : JNCCN. Mar 1 2014;12(3):410-424.
25. Hawryluk EB, O'Regan KN, Sheehy N, et al. Positron emission tomography/computed tomography imaging in Merkel cell carcinoma: a study of 270 scans in 97 patients at the Dana-Farber/Brigham and Women's Cancer Center. Journal of the American Academy of Dermatology. Apr 2013;68(4):592-599.
26. Byrne K, Siva S, Chait L, et al. 15-Year Experience of 18F-FDG PET Imaging in Response Assessment and Restaging After Definitive Treatment of Merkel Cell Carcinoma. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Sep 2015;56(9):1328-1333.
27. Sollini M, Taralli S, Milella M, et al. Somatostatin receptor positron emission tomography/computed tomography imaging in Merkel cell carcinoma. J Eur Acad Dermatol Venereol. Oct 7 2015.
28. Allen PJ, Bowne WB, Jaques DP, Brennan MF, Busam K, Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol. Apr 1 2005;23(10):2300-2309.
29. Fields RC, Busam KJ, Chou JF, et al. Five hundred patients with Merkel cell carcinoma evaluated at a single institution. Annals of surgery. Sep 2011;254(3):465-473; discussion 473-465.
30. Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. Journal of the American Academy of Dermatology. Mar 2013;68(3):425-432.
31. Grotz TE, Joseph RW, Pockaj BA, et al. Negative Sentinel Lymph Node Biopsy in Merkel Cell Carcinoma is Associated with a Low Risk of Same-Nodal-Basin Recurrences. Annals of surgical oncology. Nov 2015;22(12):4060-4066.
32. Andea AA, Coit DG, Amin B, Busam KJ. Merkel cell carcinoma: histologic features and prognosis. Cancer. Nov 1 2008;113(9):2549-2558.
33. Fields RC, Coit DG. Is a "Merkel" just like a melanoma? The pathologic analysis of Merkel cell carcinoma specimens. Annals of surgical oncology. Oct 2012;19(11):3304-3306.
34. An KP, Ratner D. Merkel cell carcinoma in the setting of HIV infection. Journal of the American Academy of Dermatology. Aug 2001;45(2):309-312.
35. Brewer JD, Shanafelt TD, Otley CC, et al. Chronic lymphocytic leukemia is associated with decreased survival of patients with malignant melanoma and Merkel cell carcinoma in a SEER population-based study. J Clin Oncol. Mar 10 2012;30(8):843-849.
36. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Feb 1999;8(2):153-158.
37. Paulson KG, Iyer JG, Blom A, et al. Systemic immune spanpression predicts diminished Merkel cell carcinoma-specific survival independent of stage. The Journal of investigative dermatology. Mar 2013;133(3):642-646.
38. Santos-Juanes J, Fernandez-Vega I, Fuentes N, et al. Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis. Br J Dermatol. Jul 2015;173(1):42-49.
39. Harms PW, Patel RM, Verhaegen ME, et al. Distinct gene expression profiles of viral- and nonviral-associated merkel cell carcinoma revealed by transcriptome analysis. The Journal of investigative dermatology. Apr 2013;133(4):936-945.
40. Harms PW, Vats P, Verhaegen ME, et al. The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma. Cancer Res. Sep 15 2015;75(18):3720-3727.
41. Dabner M, McClure RJ, Harvey NT, et al. Merkel cell polyomavirus and p63 status in Merkel cell carcinoma by immunohistochemistry: Merkel cell polyomavirus positivity is inversely correlated with sun damage, but neither is correlated with outcome. Pathology. Apr 2014;46(3):205-210.
42. Schrama D, Peitsch WK, Zapatka M, et al. Merkel cell polyomavirus status is not associated with clinical course of Merkel cell carcinoma. The Journal of investigative dermatology. Aug 2011;131(8):1631-1638.
43. Hall BJ, Pincus LB, Yu SS, Oh DH, Wilson AR, McCalmont TH. Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome. J Cutan Pathol. Oct 2012;39(10):911-917.
44. Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome. Int J Cancer. Sep 1 2010;127(6):1493-1496.
45. Asioli S, Righi A, de Biase D, et al. Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Nov 2011;24(11):1451-1461.
46. Stetsenko GY, Malekirad J, Paulson KG, et al. p63 expression in Merkel cell carcinoma predicts poorer survival yet may have limited clinical utility. Am J Clin Pathol. Dec 2013;140(6):838-844.
47. Jimenez-Heffernan A, Ellmann A, Sado H, et al. Results of a Prospective Multicenter International Atomic Energy Agency Sentinel Node Trial on the Value of SPECT/CT Over Planar Imaging in Various Malignancies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Sep 2015;56(9):1338-1344.
48. Olcott P, Pratx G, Johnson D, Mittra E, Niederkohr R, Levin CS. Clinical evaluation of a novel intraoperative handheld gamma camera for sentinel lymph node biopsy. Phys Med. May 2014;30(3):340-345.
49. Lu Y, Fleming SE, Fields RC, Coit DG, Carrasquillo JA. Comparison of 18F-FDG PET/CT and 111In pentetreotide scan for detection of Merkel cell carcinoma. Clinical nuclear medicine. Aug 2012;37(8):759-762.
50. Buder K, Lapa C, Kreissl MC, et al. Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging. BMC cancer. 2014;14:268.
51. Pfeifer A, Knigge U, Binderup T, et al. 64Cu-DOTATATE PET for Neuroendocrine Tumors: A Prospective Head-to-Head Comparison with 111In-DTPA-Octreotide in 112 Patients. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. Jun 2015;56(6):847-854.
52. Kattan MW, Hess KR, Amin MB, et al. American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine. CA: a cancer journal for clinicians. Jan 19 2016.