REVIEW ARTICLE
Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of Skin) Mimicking Basal Cell Carcinoma With Review of Different Histopathologic Features Farah Succaria, MD,* Arash Radfar, MD, PhD,† and Jag Bhawan, MD*
Abstract: Merkel cell carcinoma (MCC) is a rare but highly aggressive malignancy, which often has typical histopathologic and immunohistochemical (IHC) features. Sometimes the diagnosis is missed because of atypical histological or aberrant IHC findings. A case of MCC that showed irregular lobules of basaloid cells with keratotic areas on the initial shave biopsy is being reported. IHC showed positive staining for high–molecular weight cytokeratin but negative staining for cytokeratin 20, findings consistent with basal cell carcinoma. Subsequent excision specimen showed histopathologic features more typical of MCC. IHC still was negative for cytokeratin 20 but positive for synaptophysin. Review of the literature shows other examples of MCC with basal cell carcinoma–like features. Various other histopathologic differentiations of MCC include those that demonstrate squamous cell and eccrine carcinoma features and those that show melanocytic, lymphomatous, sarcomatous, muscular, and atypical fibroxanthoma-like features. Different histopathologic patterns and mimics of MCC are reviewed to help prevent dermatopathologists from misdiagnosing this aggressive tumor. Key Words: Merkel cell carcinoma, primary neuroendocrine carcinoma of skin, IHC, melanoma, basal cell carcinoma (Am J Dermatopathol 2014;36:160–166)
INTRODUCTION In 1972, Toker1 described Merkel cell carcinoma (MCC), the primary small-cell neuroendocrine carcinoma of the skin, as trabecular carcinoma. A few years later, on the basis of electron microscopic studies showing neurosecretory granules, Tang and Toker2 suggested a neural crest derivation and that the Merkel cell was the proposed cell of origin, hence its nomenclature. However, in a recent review, Tilling and Moll3 elaborated on potential cells of origin for MCC, other than the Merkel cell, including epidermal and dermal stem cell origins. Therefore, the cell of origin of MCC remains unresolved. The discovery of the Merkel cell polyomavirus (MCPyV) has significantly aided in further understanding of the pathogenesis of MCC.4–6 The interaction of the MCC virus protein with p53 From the *Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA; and †Miraca Life Sciences, Newton, MA. The authors declare no funding or conflicts of interest. Reprints: Jag Bhawan, MD, Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, 609 Albany St, J-309, Boston, MA 02118 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
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and other members of the retinoblastoma (rb-) gene family is implicated in the malignant behavior of MCC.7,8 MCC commonly arises on sun-exposed skin, mainly the head and neck.9–11 Clinically, it can be extremely hard to distinguish MCC from other skin cancers. The tumor may present as a red nodule and thus resemble angiosarcoma or it may just present as granulation tissue.12,13 Interestingly enough, AEIOU, which stands for asymptomatic/lack of tenderness, expanding rapidly within less than or equal to 3 months, immune suppression, older than 50 years, and ultraviolet-exposed site,14 has been suggested as a reminder of the clinical features of MCC. MCC is a rare but highly aggressive malignancy, which has been on the rise over the last 2 decades, with an annual increase of 8% between 1986 and 2001 in the United States15 and now with an incidence rate estimated to be 6 cases per 1 million population.16 MCC, the second most common cause of death from nonmelanoma skin cancer, is described to be the most aggressive cutaneous malignancy with more than 30% of patients dying from complications within 5 years of diagnosis.9,17–19 A multivariate analysis has shown the tumor’s thickness, and the presence of a nodular growth pattern along with the absence of lymphovascular invasion were all statistically significantly associated with longer survival.20 Interestingly enough, MCPyV DNA-positive MCC having fewer regional nodal metastasis at the time of diagnosis had a better prognosis compared with MCPyV DNA-negative MCC.21 A precise and accurate early diagnosis is crucial to providing patients with optimal therapy because the stage at presentation may be the only independent predictor of survival.18 For this reason, one should be able to make the diagnosis of MCC based on the typical histological features while also to be aware of the distinctive differentiation patterns that may mimic other tumors/diseases, which could lead to improper or late diagnosis that may affect patient survival. We encountered a case of MCC, which was diagnosed as basal cell carcinoma (BCC) on the initial shave biopsy but later proven to be MCC on excisional specimen, as additional immunohistochemical (IHC) studies were performed. The aim of this article is to review the different histopathologic features of MCC that have been described in the literature (Table 1) and help recognize clues that aid in prompt diagnosis, thus leading to a better patient outcome.
CASE REPORT An 85-year-old woman presented with a crusted nodule on the leg for several months duration. Clinical diagnosis was that of nonmelanoma skin cancer. A skin biopsy was performed. The Am J Dermatopathol Volume 36, Number 2, February 2014
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TABLE 1. Various Differentiation Patterns of MCC BCC-Like Differentiation
Nested Growth Pattern, Mucinous Stroma, Clefting
Melanocytic differentiation Lymphomatous differentiation Ductular differentiation Squamous differentiation
Premelanosomes in tumor cells (ultrastructurally)
Sarcomatous differentiation Muscular differentiation Fibroxanthoma-like differentiation
Dense lymphocytic infiltrate with formation of lymphoid follicles Prominent microcystic features lined by hyperchromatic basaloid cells Cytoplasmic paranuclear globular aggregates of intermediate filaments, horn pearl formation, squamous eddies Intersecting fascicles of pleomorphic spindle cells between tumor cells Myofilaments and Z bands (ultrastructurally) Large bizarre epithelioid cells with giant cells
FIGURE 2. Positive immunostaining with high–molecular weight cytokeratin, ·45.
histopathology showed a rather shallow biopsy with prominent serum crust, irregular lobules of basaloid cells, and central keratinization (Fig. 1). Differential diagnosis included a BCC and an MCC. IHC staining with high–molecular weight cytokeratin was strongly positive (Fig. 2), whereas negative with CK20 (Fig. 3). These histopathologic and IHC features were consistent with a diagnosis of BCC with keratotic differentiation. About one and a half years later, patient presented with recurrence at the site of previous biopsy and excision was performed. The histopathologic features were similar, though the cytomorphology of the cells was even more suggestive of Merkel cells (Figs. 4, 5). Immunostaining was again negative for cytokeratin 20 (CK20) but positive for high–molecular weight cytokeratin (Fig. 6). However, the tumor expressed synaptophysin (Fig. 7). Synaptophysin immunostaining was then performed on the original biopsy, which also showed positivity (Fig. 8). Together, these findings were considered to be consistent with MCC. This case illustrates aberrant expression of high–molecular weight cytokeratin and loss of commonly expressed CK20 antigen.
DISCUSSION
amphophilic sparse cytoplasm with ill-defined cell borders.1 Mitoses and apoptotic bodies are abundant. Adnexa and papillary dermis are frequently spared.22 MCC exhibits 3 different histological growth patterns, a sheet-like growth being the most common, followed by the nested and trabecular types.1 Overlap features occur commonly, and the trabecular pattern may be limited to the peripheral area of the tumor.23 The tumor is usually separated from the epidermis by a grenz zone composed of dermal collagen. The tumor cells are usually restricted to the dermis, but they can also invade the subcutaneous fat, fascia, and muscle.24 MCC may have a predominant epidermotropic component in comparison with the dermal involvement.25 Furthermore, multiple studies have described MCC in situ where epidermal involvement presents as single cells or small nests along the basal layer or above it conferring a “pagetoid appearance.”26–28 Pseudorosettes29 are uncommonly seen. Additionally, focal necrosis and involvement of dermal lymphatics are also noted.23 The Azzopardi phenomenon, which is characterized by strongly hematoxyphilic blood
Most MCCs (primary neuroendocrine carcinoma of skin) show the typical histological appearance consisting of small, uniform-sized round to oval blue cells, which have an
FIGURE 1. Irregular lobule of basaloid cells and central keratinization and overly serum crust. Hematoxylin and eosin, ·45. Inset shows basaloid cells in higher magnification, ·90. 2013 Lippincott Williams & Wilkins
FIGURE 3. Negative immunostaining with CK20, ·45. www.amjdermatopathology.com |
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FIGURE 5. Sheets of round to oval cells with amphophilic sparse cytoplasm and ill-defined cell borders. Hematoxylin and eosin, ·90.
FIGURE 4. Excision specimen with island of blue cells. Hematoxylin and eosin, ·45.
have also been reported.40 Various differentiations and mimics of MCC are discussed below.
MCC With Histological Features of BCC vessels because of nuclear DNA deposition from tumor necrosis, is most uncommon.30 One study highlighted amyloid deposition.31 Increased vascularity is noted in 20% of cases,32 and this is important because an increased vascular proliferation,33 along with lymphovascular invasion, high tumor mast cell numbers,34 small cell size, and high mitotic rate,35 is associated with a worse prognosis. IHC staining is extremely helpful and crucial because MCC must be differentiated from other “small round blue-cell” tumors, such as small-cell melanoma, malignant lymphoma, and small-cell lung carcinoma (Table 2). MCC is positive for epithelial and neuroendocrine markers but negative for lymphoid and melanocytic markers.36 A highly sensitive stain that is extremely important in distinguishing MCC from other small round blue tumors is anti-CK20.37 Andres et al38 reported 97% staining with anti-CK20 in a “paranuclear dot-like pattern” in 34 cases of MCC. Merkel cell carcinoma is also positive for chromogranin A, synaptophysin, and neuron-specific enolase (NSE) and negative for cytokeratin 7 (CK7), thyroid transcription factor-1, S100, and leukocyte common antigen.14,37,39 However, a minority of CK20-negative and CK7-positive cases
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Ball et al41 evaluated BCC characteristics in a series of 30 MCC cases from 2 institutions. The diagnosis of MCC was made based on immunohistochemistry in all cases, with perinuclear globular staining with antibodies to CK20 and cam5.2 and diffuse cytoplasmic staining with antibodies to NSE, synaptophysin, or chromogranin A. Interestingly, all MCC cases showed stromal artifactual retraction and a mucinous stroma, which is typical of BCC.42 Fifty percent of MCC exhibited a nested growth pattern, with tumor cell nests approximately the same size as the nests of BCC.41 Authors described clefts between aggregates of MCC and the surrounding stroma at least focally in 90% of their cases.41 They reported that although this has been interpreted as lymphatic space permeation,43 the absence of CD31 and CD34 staining in the stromal rim of the retraction space confirms that retraction does not represent vascular invasion by MCC. None of their cases showed the widespread peripheral palisading, which is characteristic of BCC.44 Hence, given that both types of malignancy have completely different outcomes and prognosis, it is crucial to differentiate them based on histology and IHC despite some of the “BCC-like features” in MCC. 2013 Lippincott Williams & Wilkins
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FIGURE 7. Positive immunostaining with synaptophysin, ·45.
FIGURE 6. Positive immunostaining with high–molecular weight cytokeratin, ·45.
Merkel Cell With Melanocytic Differentiation MCC with melanocytic differentiation has been reported in very few cases. Because several studies support the neural crest derivation of MCC,2 it is not surprising that features of melanocytic differentiation may be observed in MCC given the fact that melanocytes are derived from the neural crest.45 A 62-year-old man with a histological diagnosis of MCC also displayed ultrastructurally premelanosomes in the tumor cells.46 Another case with all the histological features of a primary neuroendocrine cell carcinoma but with melanocytic differentiation on electron microscopy was reported in an 89-year-old man.47 However, ultrastructurally, there were few cells that showed mostly isolated or clustered dense cytoplasmic bodies with a microtubular structure or a paracrystalline morphology, resembling premelanosomes. It is important to note, however, that no IHC stains were done to prove that these cells actually have a melanocytic differentiation. This may not be a problem as IHC is routinely done to confirm the diagnosis. One can argue that these premelanosomes may have been phagocytized by tumor cells. It is interesting to note that 2013 Lippincott Williams & Wilkins
based on diffuse nuclear immunoreactivity of sex determining region Y -box 2 expression in normal human skin at or near established stem cell niches, Laga et al48 found SOX2 expression in Merkel cells (CK20/SOX2) and melanocytic cell lines (microphthalmia-associated transcription factor MITF/SOX2). Furthermore, SOX2 expression was found in 9 out of 9 samples of human primary and metastatic MCC and 9 out of 26 cases of melanoma.49 Their findings further support a neural crest origin for Merkel cells.49,50
FIGURE 8. Positive immunostaining with synaptophysin on the original biopsy, ·45. www.amjdermatopathology.com |
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TABLE 2. Common and Aberrant IHC Expression of MCC Common Aberrant Uncommon
CK20, NSE, CD56, Pancytokeratin, Chromogranin, Synaptophysin Vimentin, SOX2, CEA, cystic fibrosis-1, AE1, K903, desmin, smooth muscle actin, myogenin Thyroid transcription factor-1, CK7, PAX5, TdT
MCC With Lymphomatous Appearance MCC, being a blue-cell tumor, is also considered in the differential diagnosis of lymphoproliferative disorders involving the skin. Discohesive growth pattern, growth in a single file, and even crush artifact, features often seen in secondary cutaneous involvement by leukemia, may be seen in MCC.51,52 CD56 expression was found in 17 of 18 cases of MCC (which were positive for CK20).53 Also, terminal deoxynucleotidyl transferase positivity has been expressed in 8 out of 15 MCC cases, which had positive NSE among other neuroendocrine markers.54 This can create potential pitfalls in diagnosis. MCC cases with lymphocytic infiltrate have a more favorable prognosis, and spontaneous regression can occur. It has been suggested that the occurrence of apoptosis and cell-mediated immunity aided in regression of the tumor.55,56 MCC with a dense dermal lymphocytic infiltrate with the formation of lymphoid follicles is extremely rare and was first reported by Bastian et al57 in 1996 and then later by Vazmitel et al,32 who reported 2 additional cases. The 3 cases were very similar on histopathology. They had the typical MCC appearance and stained positive for CK20, NSE, and pancytokeratin. However, they exhibited a dense lymphocytic infiltrate and the formation of lymphoid follicles with germinative centers that were well circumscribed and contained occasional macrophages. The germinative centers were positive for CD20 and CD79a. There were also CD8positive small lymphocytes in the tumor; however, no monoclonality was found on IgH gene rearrangement studies.32
MCC With Ductal Differentiation In the original article, Toker1 suggested a sudoriferous origin for MCC, and hence, the description of ductal structures within an MCC is not new. Of all, 4.7% of MCCs have been reported to show eccrine differentiation.58 Two of 42 cases of MCCs had ductal cells with keratohyaline granules within the cytoplasm. These stained for carcinoembryonic antigen (CEA) and cystic fibrosis-1 (cystic fibrosis-1 monoclonal antibody that only stains eccrine duct and acrosyringium).58 Several cases of MCCs were reported to have eccrine/glandular/tubular features,59 but only as a focal histological finding. Two cases of MCCs with prominent microcystic features that comprised more than 50% of the tumor have been reported.60 These features mimicked tubuloglandular structures and were lined by hyperchromatic basaloid cells. The authors argue that eccrine carcinoma with neuroendocrine differentiation was less likely, as both CEA and epithelial membrane antigen were negative. In a more recent study, 7 cases of MCCs with eccrine differentiation were reported.61 These cases showed, along with the morphological and IHC criteria of MCC, eccrine differentiation, which was confirmed by CEA and CK7 reactivity, that was restricted to the small ductal structures.
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MCC With Squamous Differentiation The intimate connection between Merkel cells and keratinocytes has been well described. It is known that Merkel cells appear first in the epidermis and then some migrate into the dermis. Furthermore, “transitional cells” have been demonstrated to share features of both keratinocytes and Merkel cells in the epidermal touch receptors of newborn and 13-day-old rats.62 The desmosomal attachments with adjacent keratinocytes and the presence of “transitional cells” with both dense granules and tonofibrils in the perinuclear cytoplasm also support this connection.63 MCC cases that have squamous differentiation show AE1 and K903 positivity.64 The most prominent finding to support this is the presence of cytoplasmic paranuclear globular aggregates of intermediate filaments on ultrastructural examination.65 MCC with squamous differentiation is not uncommon.66 Hwang et al64 reported the first case of MCC that exhibited both squamous and sarcomatous differentiation, and they gave each component an approximate proportion (10% squamous cells, 45% spindle cells, and 45% small cells). The squamous cells were positive for AE1 and K903, the sarcomatous cells were positive for vimentin, and the typical Merkel cells were positive for CK20. In another study, 1 out of 42 cases of MCC showed foci of typical keratinizing squamous differentiation (identified with keratin positivity) with horn pearl formation within the sheets of small cells.58 Similarly, 7 out of 36 cases of MCCs were shown to have small collections of squamoid differentiation resembling squamous eddies.67 It is important to point out, however, that squamoid differentiation in MCC is different from the occurrence of squamous cell carcinoma and MCC in the same lesion.68
MCC With Sarcomatous/Pseudosarcomatous Differentiation Only 7 cases of MCCs with sarcomatous or pseudosarcomatous differentiation have been reported.69 MCCs with sarcomatous differentiation typically show vimentin positivity unlike the typical Merkel cell.64 Four out of the 7 cases displayed both sarcomatous and squamous differentiation. The pathology showed a nodular ulcerating tumor composed of islands of small cells showing nuclear molding and scant cytoplasm adjacent to and merged with smaller islands of squamous cells, clearly malignant spindle cells, and myxoid stroma.64,70,71 A case of MCC that exhibited sheets of small- to intermediate-sized cells with granular nuclear chromatin, indistinct nucleoli, and frequent mitotic activity was reported. However, these sheets of cells were separated by intersecting fascicles of pleomorphic, hyperchromatic, and mitotically active spindle-shaped cells, resembling a fibrosarcoma.72 Immunohistochemistry revealed the sheets of small cells to be positive for CK20, NSE, chromogranin, and synaptophysin and negative for S100, smooth muscle actin, vimetin, desmin, HMB-45, Melan-A, thyroid transcription factor-1, and CD34. On the other hand, the spindle cell population was positive for vimentin and negative for all the other markers listed. This tumor was classified as MCC with fibrosarcomatous differentiation. 2013 Lippincott Williams & Wilkins
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MCC With Muscular Differentiation Heterologous rhabdomyoblastic differentiation in MCC is extremely rare, as only 3 cases have been reported in the literature. Two cases showed the typical features of MCC by conventional light microscopy but displayed co-expression of CK20, synaptophysin, desmin, and myogenin.73,74 One of the 3 cases showed typical histological and IHC findings of MCC in the primary tumor, but there was an evidence of skeletal muscle differentiation in a lymph node, highlighted by ultrastructural evidence of myofilaments and Z bands and positive staining for vimentin, actin, myoglobin, and desmin.65 Interestingly, the latest case reported also showed MCPyV positivity.74 Leiomyosarcomatous differentiation in MCC also has been rarely described. A case of MCC that had the typical histological and IHC features within the primary tumor but with strong vimentin- and desmin-positive spindle cells within a regional lymph node containing metastatic Merkel cell tumor was described.75 Furthermore, a recent article demonstrated leiomyosarcomatous differentiation (highlighted by vimentin, desmin, and smooth muscle actin antibodies) in a primary MCC.70
MCC With Fibroxanthoma-Like Features One case of MCC was identified as having atypical fibroxanthoma-like features. It was a recurrent MCC that has been irradiated, and on the final excision, the histopathology revealed a subcutaneous tumor composed of bizarre epithelioid large pleomorphic cells with scattered giant cells. These large cells were positive for NSE, chromogranin, paranuclear dot-like positivity for monokeratin, high–molecular weight cytokeratin, and epithelial membrane antigen. IHC stains for vimentin, actin, desmin, S100, and HMB-45 were negative.71 Therefore, this was identified as a case of MCC that had fibroxanthoma-like features. However, it is quite possible that atypical fibroxanthoma-like features are as a result of irradiation 2 months before final excision.
CONCLUSIONS Because MCC is a very aggressive tumor, early accurate diagnosis is important. MCC can have many differentiation and mimics. IHC may have aberrant expression in some cases, which may sometimes cause a diagnostic pitfall. It is essential that the dermatopathologist be aware of the various forms of MCC to avoid misdiagnosis and thereby allow a better patient outcome. REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105: 107–110. 2. Tang CK, Toker C. Trabecular carcinoma of the skin: an ultrastructural study. Cancer. 1978;42:2311–2321. 3. Tilling T, Moll I. Which are the cells of origin in Merkel cell carcinoma? J Skin Cancer. 2012;2012:680410. 4. Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100. 5. Schrama D, Ugurel S, Becker JC. Merkel cell carcinoma: recent insights and new treatment options. Curr Opin Oncol. 2012;24:141–149. 6. Kuwamoto S. Recent advances in the biology of Merkel cell carcinoma. Hum Pathol. 2011;42:1063–1077. 7. Becker JC, Houben R, Ugurel S, et al. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol. 2009;129:248–250.
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35. Skelton HG, Smith KJ, Hitchcock CL, et al. Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol. 1997;37:734–739. 36. McCardle TW, Sondak VK, Zager J, et al. Merkel cell carcinoma: pathologic findings and prognostic factors. Curr Probl Cancer. 2010;34:47–64. 37. Bobos M, Hytiroglou P, Kostopoulous I, et al. Immunohistochemical distinction between Merkel cell carcinoma and small cell carcinoma of the lung. Am J Dermatopathol. 2006;28:99–104. 38. Andres C, Belloni B, Jaeger T, et al. Immunohistochemical features of Merkel cell carcinoma in correlation with presence of Merkel cell polyomavirus DNA. Acta Derm Venereol. 2011;91:722–723. 39. Becker J, Mauch C, Kortmann RD, et al. Short German guidelines: Merkel cell carcinoma. J Dtsch Dermatol Ges. 2008;6:S15–S16. 40. Calder KB, Coplowitz S, Schlauder S, et al. A case series and immunophenotypic analysis of CK20-/CK7+ primary neuroendocrine carcinoma of the skin. J Cutan Pathol. 2007;34:918–923. 41. Ball NJ, Tanhuanco-Kho G. Merkel cell carcinoma frequently shows histologic features of basal cell carcinoma: a study of 30 cases. J Cutan Pathol. 2007;34:612–619. 42. Goltz RW, Fusaro RM, Jarvis J. The carbohydrates in basal cell epitheliomas; a histochemical study. J Invest Dermatol. 1959;32:629–640. 43. Sidhu GS, Feiner H, Flotte TJ, et al. Merkel cell neoplasms. Histology, electron microscopy, biology, and histogenesis. Am J Dermatopathol. 1980;2:101–119. 44. de Faria J. Basal cell carcinoma of the skin with areas of squamous cell carcinoma: a basosquamous cell carcinoma? J Clin Pathol. 1985;38: 1273–1277. 45. Hall BK. The neural crest and neural crest cells: discovery and significance for theories of embryonic organization. J Biosci. 2008;33:781–793. 46. Wong SW, Dao AH, Glick AD. Trabecular carcinoma of the skin: a case report. Hum Pathol. 1981;12:838–840. 47. Isimbaldi G, Sironi M, Taccagni G, et al. Tripartite differentiation (squamous, glandular, and melanocytic) of a primary cutaneous neuroendocrine carcinoma. An immunocytochemical and ultrastructural study. Am J Dermatopathol. 1993;15:260–264. 48. Laga AC, Lai CY, Zhan Q, et al. Expression of the embryonic stem cell transcription factor SOX2 in human skin: relevance to melanocyte and Merkel cell biology. Am J Pathol. 2010;176:903–913. 49. Szeder V, Grim M, Halata Z, et al. Neural crest origin of mammalian Merkel cells. Dev Biol. 2003;253:258–263. 50. Boulais N, Misery L: Merkel cells. J Am Acad Dermatol. 2007;57:147–165. 51. Boudova L, Kazakov DV, Sima R, et al. Cutaneous lymphoid hyperplasia and other lymphoid infiltrates of the breast nipple: a retrospective clinicopathologic study of fifty-six patients. Am J Dermatopathol. 2005;27:375–386. 52. Kazakov DV, Belousova IE, Michaelis S, et al. Unusual manifestation of specific cutaneous involvement by B-cell chronic lymphocytic leukemia: spontaneous regression with scar formation. Dermatology. 2003;207:111–115. 53. McNiff JM, Cowper SE, Lazova R, et al. CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both? J Cutan Pathol. 2005;32:541–545. 54. Sur M, AlArdati H, Ross C, et al. TdT expression in Merkel cell carcinoma: potential diagnostic pitfall with blastic hematological malignancies and expanded immunohistochemical analysis. Mod Pathol. 2007;20: 1113–1120. 55. Kayashima K, Ono T, Johno M, et al. Spontaneous regression in Merkel cell (neuroendocrine) carcinoma of the skin. Arch Dermatol. 1991;127: 550–553.
56. Takenaka H, Kishimoto S, Shibagaki R, et al. Merkel cell carcinoma with partial spontaneous regression: an immunohistochemical, ultrastructural, and TUNEL labeling study. Am J Dermatopathol. 1997;19:614–618. 57. Bastian BC, Kreipe HH, Brocker EB. Primary neuroendocrine carcinoma of the skin with an unusual follicular lymphocytic infiltrate of the dermis. Am J Dermatopathol. 1996;18:625–628. 58. Gould E, Albores-Saavedra J, Dubner B, et al. Eccrine and squamous differentiation in Merkel cell carcinoma. An immunohistochemical study. Am J Surg Pathol. 1988;12:768–772. 59. McLoone NM, McKenna K, Edgar D, et al. Merkel cell carcinoma in a patient with chronic sarcoidosis. Clin Exp Dermatol. 2005;30:580–582. 60. Li N, Wolgamot G, Argenyi Z. Primary cutaneous neuroendocrine cell carcinoma (Merkel cell carcinoma) with prominent microcystic features, mimicking eccrine carcinoma. J Cutan Pathol. 2007;34:410–414. 61. Saeb-Lima M, Montante-Montes de Oca D, Albores-Saavedra J. Merkel cell carcinoma with eccrine differentiation: a clinicopathologic study of 7 cases. Ann Diagn Pathol. 2008;12:410–414. 62. English KB. Morphogenesis of Haarscheiben in rats. J Invest Dermatol. 1977;69:58–67. 63. Sidhu GS, Chandra P, Cassai ND. Merkel cells, normal and neoplastic: an update. Ultrastruct Pathol. 2005;29:287–294. 64. Hwang JH, Alanen K, Dabbs KD, et al. Merkel cell carcinoma with squamous and sarcomatous differentiation. J Cutan Pathol. 2008;35: 955–959. 65. Fernandez-Figueras MT, Puig L, Gilaberte M, et al. Merkel cell (primary neuroendocrine) carcinoma of the skin with nodal metastasis showing rhabdomyosarcomatous differentiation. J Cutan Pathol. 2002;29:619–622. 66. Walsh NM. Primary neuroendocrine (Merkel cell) carcinoma of the skin: morphologic diversity and implications thereof. Hum Pathol. 2001;32: 680–689. 67. Smith PD, Patterson JW. Merkel cell carcinoma (neuroendocrine carcinoma of the skin). Am J Clin Pathol. 2001;115:S68–S78. 68. Iacocca MV, Abernethy JL, Stefanato CM, et al. Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin. J Am Acad Dermatol. 1998;39:882–887. 69. Gomez-Moyano E, Vera-Casano A, Sanz-Trelles A, et al. Merkel cell carcinoma with sarcomatous differentiation: is it a poor prognostic factor? Int J Dermatol. 2013;52:93–95. 70. Covello R, Licci S, Ferrari A, et al. Merkel cell carcinoma of the thumb with squamous and leiomyosarcomatous differentiation. Eur J Dermatol. 2010;20:529–530. 71. Boutilier R, Desormeau L, Cragg F, et al. Merkel cell carcinoma: squamous and atypical fibroxanthoma-like differentiation in successive local tumor recurrences. Am J Dermatopathol. 2001;23:46–49. 72. Tan KB, Murali R, Karim RZ, et al. Merkel cell carcinoma with fibrosarcomatous differentiation. Pathology. 2008;40:314–316. 73. Eusebi V, Damiani S, Pasquinelli G, et al. Small cell neuroendocrine carcinoma with skeletal muscle differentiation: report of three cases. Am J Surg Pathol. 2000;24:223–230. 74. Adhikari LA, McCalmont TH, Folpe AL. Merkel cell carcinoma with heterologous rhabdomyoblastic differentiation: the role of immunohistochemistry for Merkel cell polyomavirus large T-antigen in confirmation. J Cutan Pathol. 2012;39:47–51. 75. Cooper L, Debono R, Alsanjari N, et al. Merkel cell tumour with leiomyosarcomatous differentiation. Histopathology. 2000;36:540–543.
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Merkel Cell Carcinoma (Primary Neuroendocrine Carcinoma of Skin) Mimicking Basal Cell Carcinoma With Review of Different Histopathologic Features Farah Succaria, MD,* Arash Radfar, MD, PhD,† and Jag Bhawan, MD*
Abstract: Merkel cell carcinoma (MCC) is a rare but highly aggressive malignancy, which often has typical histopathologic and immunohistochemical (IHC) features. Sometimes the diagnosis is missed because of atypical histological or aberrant IHC findings. A case of MCC that showed irregular lobules of basaloid cells with keratotic areas on the initial shave biopsy is being reported. IHC showed positive staining for high–molecular weight cytokeratin but negative staining for cytokeratin 20, findings consistent with basal cell carcinoma. Subsequent excision specimen showed histopathologic features more typical of MCC. IHC still was negative for cytokeratin 20 but positive for synaptophysin. Review of the literature shows other examples of MCC with basal cell carcinoma–like features. Various other histopathologic differentiations of MCC include those that demonstrate squamous cell and eccrine carcinoma features and those that show melanocytic, lymphomatous, sarcomatous, muscular, and atypical fibroxanthoma-like features. Different histopathologic patterns and mimics of MCC are reviewed to help prevent dermatopathologists from misdiagnosing this aggressive tumor. Key Words: Merkel cell carcinoma, primary neuroendocrine carcinoma of skin, IHC, melanoma, basal cell carcinoma (Am J Dermatopathol 2014;36:160–166)
INTRODUCTION In 1972, Toker1 described Merkel cell carcinoma (MCC), the primary small-cell neuroendocrine carcinoma of the skin, as trabecular carcinoma. A few years later, on the basis of electron microscopic studies showing neurosecretory granules, Tang and Toker2 suggested a neural crest derivation and that the Merkel cell was the proposed cell of origin, hence its nomenclature. However, in a recent review, Tilling and Moll3 elaborated on potential cells of origin for MCC, other than the Merkel cell, including epidermal and dermal stem cell origins. Therefore, the cell of origin of MCC remains unresolved. The discovery of the Merkel cell polyomavirus (MCPyV) has significantly aided in further understanding of the pathogenesis of MCC.4–6 The interaction of the MCC virus protein with p53 From the *Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA; and †Miraca Life Sciences, Newton, MA. The authors declare no funding or conflicts of interest. Reprints: Jag Bhawan, MD, Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, 609 Albany St, J-309, Boston, MA 02118 (e-mail: [email protected]). © 2013 Lippincott Williams & Wilkins
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and other members of the retinoblastoma (rb-) gene family is implicated in the malignant behavior of MCC.7,8 MCC commonly arises on sun-exposed skin, mainly the head and neck.9–11 Clinically, it can be extremely hard to distinguish MCC from other skin cancers. The tumor may present as a red nodule and thus resemble angiosarcoma or it may just present as granulation tissue.12,13 Interestingly enough, AEIOU, which stands for asymptomatic/lack of tenderness, expanding rapidly within less than or equal to 3 months, immune suppression, older than 50 years, and ultraviolet-exposed site,14 has been suggested as a reminder of the clinical features of MCC. MCC is a rare but highly aggressive malignancy, which has been on the rise over the last 2 decades, with an annual increase of 8% between 1986 and 2001 in the United States15 and now with an incidence rate estimated to be 6 cases per 1 million population.16 MCC, the second most common cause of death from nonmelanoma skin cancer, is described to be the most aggressive cutaneous malignancy with more than 30% of patients dying from complications within 5 years of diagnosis.9,17–19 A multivariate analysis has shown the tumor’s thickness, and the presence of a nodular growth pattern along with the absence of lymphovascular invasion were all statistically significantly associated with longer survival.20 Interestingly enough, MCPyV DNA-positive MCC having fewer regional nodal metastasis at the time of diagnosis had a better prognosis compared with MCPyV DNA-negative MCC.21 A precise and accurate early diagnosis is crucial to providing patients with optimal therapy because the stage at presentation may be the only independent predictor of survival.18 For this reason, one should be able to make the diagnosis of MCC based on the typical histological features while also to be aware of the distinctive differentiation patterns that may mimic other tumors/diseases, which could lead to improper or late diagnosis that may affect patient survival. We encountered a case of MCC, which was diagnosed as basal cell carcinoma (BCC) on the initial shave biopsy but later proven to be MCC on excisional specimen, as additional immunohistochemical (IHC) studies were performed. The aim of this article is to review the different histopathologic features of MCC that have been described in the literature (Table 1) and help recognize clues that aid in prompt diagnosis, thus leading to a better patient outcome.
CASE REPORT An 85-year-old woman presented with a crusted nodule on the leg for several months duration. Clinical diagnosis was that of nonmelanoma skin cancer. A skin biopsy was performed. The Am J Dermatopathol Volume 36, Number 2, February 2014
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TABLE 1. Various Differentiation Patterns of MCC BCC-Like Differentiation
Nested Growth Pattern, Mucinous Stroma, Clefting
Melanocytic differentiation Lymphomatous differentiation Ductular differentiation Squamous differentiation
Premelanosomes in tumor cells (ultrastructurally)
Sarcomatous differentiation Muscular differentiation Fibroxanthoma-like differentiation
Dense lymphocytic infiltrate with formation of lymphoid follicles Prominent microcystic features lined by hyperchromatic basaloid cells Cytoplasmic paranuclear globular aggregates of intermediate filaments, horn pearl formation, squamous eddies Intersecting fascicles of pleomorphic spindle cells between tumor cells Myofilaments and Z bands (ultrastructurally) Large bizarre epithelioid cells with giant cells
FIGURE 2. Positive immunostaining with high–molecular weight cytokeratin, ·45.
histopathology showed a rather shallow biopsy with prominent serum crust, irregular lobules of basaloid cells, and central keratinization (Fig. 1). Differential diagnosis included a BCC and an MCC. IHC staining with high–molecular weight cytokeratin was strongly positive (Fig. 2), whereas negative with CK20 (Fig. 3). These histopathologic and IHC features were consistent with a diagnosis of BCC with keratotic differentiation. About one and a half years later, patient presented with recurrence at the site of previous biopsy and excision was performed. The histopathologic features were similar, though the cytomorphology of the cells was even more suggestive of Merkel cells (Figs. 4, 5). Immunostaining was again negative for cytokeratin 20 (CK20) but positive for high–molecular weight cytokeratin (Fig. 6). However, the tumor expressed synaptophysin (Fig. 7). Synaptophysin immunostaining was then performed on the original biopsy, which also showed positivity (Fig. 8). Together, these findings were considered to be consistent with MCC. This case illustrates aberrant expression of high–molecular weight cytokeratin and loss of commonly expressed CK20 antigen.
DISCUSSION
amphophilic sparse cytoplasm with ill-defined cell borders.1 Mitoses and apoptotic bodies are abundant. Adnexa and papillary dermis are frequently spared.22 MCC exhibits 3 different histological growth patterns, a sheet-like growth being the most common, followed by the nested and trabecular types.1 Overlap features occur commonly, and the trabecular pattern may be limited to the peripheral area of the tumor.23 The tumor is usually separated from the epidermis by a grenz zone composed of dermal collagen. The tumor cells are usually restricted to the dermis, but they can also invade the subcutaneous fat, fascia, and muscle.24 MCC may have a predominant epidermotropic component in comparison with the dermal involvement.25 Furthermore, multiple studies have described MCC in situ where epidermal involvement presents as single cells or small nests along the basal layer or above it conferring a “pagetoid appearance.”26–28 Pseudorosettes29 are uncommonly seen. Additionally, focal necrosis and involvement of dermal lymphatics are also noted.23 The Azzopardi phenomenon, which is characterized by strongly hematoxyphilic blood
Most MCCs (primary neuroendocrine carcinoma of skin) show the typical histological appearance consisting of small, uniform-sized round to oval blue cells, which have an
FIGURE 1. Irregular lobule of basaloid cells and central keratinization and overly serum crust. Hematoxylin and eosin, ·45. Inset shows basaloid cells in higher magnification, ·90. 2013 Lippincott Williams & Wilkins
FIGURE 3. Negative immunostaining with CK20, ·45. www.amjdermatopathology.com |
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FIGURE 5. Sheets of round to oval cells with amphophilic sparse cytoplasm and ill-defined cell borders. Hematoxylin and eosin, ·90.
FIGURE 4. Excision specimen with island of blue cells. Hematoxylin and eosin, ·45.
have also been reported.40 Various differentiations and mimics of MCC are discussed below.
MCC With Histological Features of BCC vessels because of nuclear DNA deposition from tumor necrosis, is most uncommon.30 One study highlighted amyloid deposition.31 Increased vascularity is noted in 20% of cases,32 and this is important because an increased vascular proliferation,33 along with lymphovascular invasion, high tumor mast cell numbers,34 small cell size, and high mitotic rate,35 is associated with a worse prognosis. IHC staining is extremely helpful and crucial because MCC must be differentiated from other “small round blue-cell” tumors, such as small-cell melanoma, malignant lymphoma, and small-cell lung carcinoma (Table 2). MCC is positive for epithelial and neuroendocrine markers but negative for lymphoid and melanocytic markers.36 A highly sensitive stain that is extremely important in distinguishing MCC from other small round blue tumors is anti-CK20.37 Andres et al38 reported 97% staining with anti-CK20 in a “paranuclear dot-like pattern” in 34 cases of MCC. Merkel cell carcinoma is also positive for chromogranin A, synaptophysin, and neuron-specific enolase (NSE) and negative for cytokeratin 7 (CK7), thyroid transcription factor-1, S100, and leukocyte common antigen.14,37,39 However, a minority of CK20-negative and CK7-positive cases
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Ball et al41 evaluated BCC characteristics in a series of 30 MCC cases from 2 institutions. The diagnosis of MCC was made based on immunohistochemistry in all cases, with perinuclear globular staining with antibodies to CK20 and cam5.2 and diffuse cytoplasmic staining with antibodies to NSE, synaptophysin, or chromogranin A. Interestingly, all MCC cases showed stromal artifactual retraction and a mucinous stroma, which is typical of BCC.42 Fifty percent of MCC exhibited a nested growth pattern, with tumor cell nests approximately the same size as the nests of BCC.41 Authors described clefts between aggregates of MCC and the surrounding stroma at least focally in 90% of their cases.41 They reported that although this has been interpreted as lymphatic space permeation,43 the absence of CD31 and CD34 staining in the stromal rim of the retraction space confirms that retraction does not represent vascular invasion by MCC. None of their cases showed the widespread peripheral palisading, which is characteristic of BCC.44 Hence, given that both types of malignancy have completely different outcomes and prognosis, it is crucial to differentiate them based on histology and IHC despite some of the “BCC-like features” in MCC. 2013 Lippincott Williams & Wilkins
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FIGURE 7. Positive immunostaining with synaptophysin, ·45.
FIGURE 6. Positive immunostaining with high–molecular weight cytokeratin, ·45.
Merkel Cell With Melanocytic Differentiation MCC with melanocytic differentiation has been reported in very few cases. Because several studies support the neural crest derivation of MCC,2 it is not surprising that features of melanocytic differentiation may be observed in MCC given the fact that melanocytes are derived from the neural crest.45 A 62-year-old man with a histological diagnosis of MCC also displayed ultrastructurally premelanosomes in the tumor cells.46 Another case with all the histological features of a primary neuroendocrine cell carcinoma but with melanocytic differentiation on electron microscopy was reported in an 89-year-old man.47 However, ultrastructurally, there were few cells that showed mostly isolated or clustered dense cytoplasmic bodies with a microtubular structure or a paracrystalline morphology, resembling premelanosomes. It is important to note, however, that no IHC stains were done to prove that these cells actually have a melanocytic differentiation. This may not be a problem as IHC is routinely done to confirm the diagnosis. One can argue that these premelanosomes may have been phagocytized by tumor cells. It is interesting to note that 2013 Lippincott Williams & Wilkins
based on diffuse nuclear immunoreactivity of sex determining region Y -box 2 expression in normal human skin at or near established stem cell niches, Laga et al48 found SOX2 expression in Merkel cells (CK20/SOX2) and melanocytic cell lines (microphthalmia-associated transcription factor MITF/SOX2). Furthermore, SOX2 expression was found in 9 out of 9 samples of human primary and metastatic MCC and 9 out of 26 cases of melanoma.49 Their findings further support a neural crest origin for Merkel cells.49,50
FIGURE 8. Positive immunostaining with synaptophysin on the original biopsy, ·45. www.amjdermatopathology.com |
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TABLE 2. Common and Aberrant IHC Expression of MCC Common Aberrant Uncommon
CK20, NSE, CD56, Pancytokeratin, Chromogranin, Synaptophysin Vimentin, SOX2, CEA, cystic fibrosis-1, AE1, K903, desmin, smooth muscle actin, myogenin Thyroid transcription factor-1, CK7, PAX5, TdT
MCC With Lymphomatous Appearance MCC, being a blue-cell tumor, is also considered in the differential diagnosis of lymphoproliferative disorders involving the skin. Discohesive growth pattern, growth in a single file, and even crush artifact, features often seen in secondary cutaneous involvement by leukemia, may be seen in MCC.51,52 CD56 expression was found in 17 of 18 cases of MCC (which were positive for CK20).53 Also, terminal deoxynucleotidyl transferase positivity has been expressed in 8 out of 15 MCC cases, which had positive NSE among other neuroendocrine markers.54 This can create potential pitfalls in diagnosis. MCC cases with lymphocytic infiltrate have a more favorable prognosis, and spontaneous regression can occur. It has been suggested that the occurrence of apoptosis and cell-mediated immunity aided in regression of the tumor.55,56 MCC with a dense dermal lymphocytic infiltrate with the formation of lymphoid follicles is extremely rare and was first reported by Bastian et al57 in 1996 and then later by Vazmitel et al,32 who reported 2 additional cases. The 3 cases were very similar on histopathology. They had the typical MCC appearance and stained positive for CK20, NSE, and pancytokeratin. However, they exhibited a dense lymphocytic infiltrate and the formation of lymphoid follicles with germinative centers that were well circumscribed and contained occasional macrophages. The germinative centers were positive for CD20 and CD79a. There were also CD8positive small lymphocytes in the tumor; however, no monoclonality was found on IgH gene rearrangement studies.32
MCC With Ductal Differentiation In the original article, Toker1 suggested a sudoriferous origin for MCC, and hence, the description of ductal structures within an MCC is not new. Of all, 4.7% of MCCs have been reported to show eccrine differentiation.58 Two of 42 cases of MCCs had ductal cells with keratohyaline granules within the cytoplasm. These stained for carcinoembryonic antigen (CEA) and cystic fibrosis-1 (cystic fibrosis-1 monoclonal antibody that only stains eccrine duct and acrosyringium).58 Several cases of MCCs were reported to have eccrine/glandular/tubular features,59 but only as a focal histological finding. Two cases of MCCs with prominent microcystic features that comprised more than 50% of the tumor have been reported.60 These features mimicked tubuloglandular structures and were lined by hyperchromatic basaloid cells. The authors argue that eccrine carcinoma with neuroendocrine differentiation was less likely, as both CEA and epithelial membrane antigen were negative. In a more recent study, 7 cases of MCCs with eccrine differentiation were reported.61 These cases showed, along with the morphological and IHC criteria of MCC, eccrine differentiation, which was confirmed by CEA and CK7 reactivity, that was restricted to the small ductal structures.
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MCC With Squamous Differentiation The intimate connection between Merkel cells and keratinocytes has been well described. It is known that Merkel cells appear first in the epidermis and then some migrate into the dermis. Furthermore, “transitional cells” have been demonstrated to share features of both keratinocytes and Merkel cells in the epidermal touch receptors of newborn and 13-day-old rats.62 The desmosomal attachments with adjacent keratinocytes and the presence of “transitional cells” with both dense granules and tonofibrils in the perinuclear cytoplasm also support this connection.63 MCC cases that have squamous differentiation show AE1 and K903 positivity.64 The most prominent finding to support this is the presence of cytoplasmic paranuclear globular aggregates of intermediate filaments on ultrastructural examination.65 MCC with squamous differentiation is not uncommon.66 Hwang et al64 reported the first case of MCC that exhibited both squamous and sarcomatous differentiation, and they gave each component an approximate proportion (10% squamous cells, 45% spindle cells, and 45% small cells). The squamous cells were positive for AE1 and K903, the sarcomatous cells were positive for vimentin, and the typical Merkel cells were positive for CK20. In another study, 1 out of 42 cases of MCC showed foci of typical keratinizing squamous differentiation (identified with keratin positivity) with horn pearl formation within the sheets of small cells.58 Similarly, 7 out of 36 cases of MCCs were shown to have small collections of squamoid differentiation resembling squamous eddies.67 It is important to point out, however, that squamoid differentiation in MCC is different from the occurrence of squamous cell carcinoma and MCC in the same lesion.68
MCC With Sarcomatous/Pseudosarcomatous Differentiation Only 7 cases of MCCs with sarcomatous or pseudosarcomatous differentiation have been reported.69 MCCs with sarcomatous differentiation typically show vimentin positivity unlike the typical Merkel cell.64 Four out of the 7 cases displayed both sarcomatous and squamous differentiation. The pathology showed a nodular ulcerating tumor composed of islands of small cells showing nuclear molding and scant cytoplasm adjacent to and merged with smaller islands of squamous cells, clearly malignant spindle cells, and myxoid stroma.64,70,71 A case of MCC that exhibited sheets of small- to intermediate-sized cells with granular nuclear chromatin, indistinct nucleoli, and frequent mitotic activity was reported. However, these sheets of cells were separated by intersecting fascicles of pleomorphic, hyperchromatic, and mitotically active spindle-shaped cells, resembling a fibrosarcoma.72 Immunohistochemistry revealed the sheets of small cells to be positive for CK20, NSE, chromogranin, and synaptophysin and negative for S100, smooth muscle actin, vimetin, desmin, HMB-45, Melan-A, thyroid transcription factor-1, and CD34. On the other hand, the spindle cell population was positive for vimentin and negative for all the other markers listed. This tumor was classified as MCC with fibrosarcomatous differentiation. 2013 Lippincott Williams & Wilkins
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MCC With Muscular Differentiation Heterologous rhabdomyoblastic differentiation in MCC is extremely rare, as only 3 cases have been reported in the literature. Two cases showed the typical features of MCC by conventional light microscopy but displayed co-expression of CK20, synaptophysin, desmin, and myogenin.73,74 One of the 3 cases showed typical histological and IHC findings of MCC in the primary tumor, but there was an evidence of skeletal muscle differentiation in a lymph node, highlighted by ultrastructural evidence of myofilaments and Z bands and positive staining for vimentin, actin, myoglobin, and desmin.65 Interestingly, the latest case reported also showed MCPyV positivity.74 Leiomyosarcomatous differentiation in MCC also has been rarely described. A case of MCC that had the typical histological and IHC features within the primary tumor but with strong vimentin- and desmin-positive spindle cells within a regional lymph node containing metastatic Merkel cell tumor was described.75 Furthermore, a recent article demonstrated leiomyosarcomatous differentiation (highlighted by vimentin, desmin, and smooth muscle actin antibodies) in a primary MCC.70
MCC With Fibroxanthoma-Like Features One case of MCC was identified as having atypical fibroxanthoma-like features. It was a recurrent MCC that has been irradiated, and on the final excision, the histopathology revealed a subcutaneous tumor composed of bizarre epithelioid large pleomorphic cells with scattered giant cells. These large cells were positive for NSE, chromogranin, paranuclear dot-like positivity for monokeratin, high–molecular weight cytokeratin, and epithelial membrane antigen. IHC stains for vimentin, actin, desmin, S100, and HMB-45 were negative.71 Therefore, this was identified as a case of MCC that had fibroxanthoma-like features. However, it is quite possible that atypical fibroxanthoma-like features are as a result of irradiation 2 months before final excision.
CONCLUSIONS Because MCC is a very aggressive tumor, early accurate diagnosis is important. MCC can have many differentiation and mimics. IHC may have aberrant expression in some cases, which may sometimes cause a diagnostic pitfall. It is essential that the dermatopathologist be aware of the various forms of MCC to avoid misdiagnosis and thereby allow a better patient outcome. REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol. 1972;105: 107–110. 2. Tang CK, Toker C. Trabecular carcinoma of the skin: an ultrastructural study. Cancer. 1978;42:2311–2321. 3. Tilling T, Moll I. Which are the cells of origin in Merkel cell carcinoma? J Skin Cancer. 2012;2012:680410. 4. Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319:1096–1100. 5. Schrama D, Ugurel S, Becker JC. Merkel cell carcinoma: recent insights and new treatment options. Curr Opin Oncol. 2012;24:141–149. 6. Kuwamoto S. Recent advances in the biology of Merkel cell carcinoma. Hum Pathol. 2011;42:1063–1077. 7. Becker JC, Houben R, Ugurel S, et al. MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol. 2009;129:248–250.
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