Clin Transl Oncol (2012) 14:401-412 DOI 10.1007/s12094-012-0817-z
E D U C AT I O N A L S E R I E S
Blue Series
AdvAnces in TrAnslATionAl oncology
Merkel cell carcinoma: What do we know about it and what should we do? Isabel Prieto Muñoz · José Pardo Masferrer · Jesús Olivera Vegas · José Ramón Fortes Alen · Ana M. Pérez Casas
Received: 2 January 2012 / Accepted: 10 March 2012
Abstract Merkel cell carcinoma (MCC) is a rare primary cutaneous carcinoma of the skin that is highly aggressive, and has a high risk of locoregional and distant spread, a mortality rate considerably higher than that of cutaneous melanoma and poor survival. Its incidence has increased during the past twenty years. The studies published since 2008 have introduced changes in the understanding of its epidemiology and pathogenesis, and consequently the therapeutic approach. Despite this, there is still controversy surrounding its optimal management, which requires clarification. This is the purpose of this review. Keywords Merkel cell carcinoma · Sentinel lymph node biopsy · Merkel cell polyomavirus
I. Prieto Muñoz · J. Olivera Vegas · A.M. Pérez Casas Department of Radiotherapy Capio Fundación Jiménez Díaz Madrid, Spain J. Pardo Masferrer (Y) Department of Radiotherapy Hospital Universitari Son Espases Ctra. de Valldemossa, 79 ES-07010 Palma de Mallorca, Baleares, Spain e-mail:
[email protected] J.R. Fortes Alen Department of Pathology Capio Fundación Jiménez Díaz Madrid, Spain
Introduction Merkel cell carcinoma (MCC) is a rare and very aggressive primary cutaneous carcinoma of the skin. It is associated with a high risk of locoregional and distant spread and, hence, poor survival. The mortality rate of MCC, at 33%, is considerably higher than that of cutaneous melanoma. The therapeutic approach is often unclear and considerable controversy exists about its optimal management and its pathogenesis. An increasing number of cases during the past two decades and the discovery by Feng of the Merkel cell polyomavirus (MCV) have focused attention of this cutaneous malignance [1, 2]. Actually, information regarding the biologic behaviour and optimal management of MCC is limited given the paucity of high-level evidence and the absence of prospective, randomised trials. The purpose of this review is to analyse the latest publications about this tumour that suggest, since 2008, changes in its epidemiology, pathogenesis, treatment and long-term survival terms. This review is based on an updated evaluation of the available data by an extensive Medline search.
History MCC was recognised as an entity in the 1970s, with defined pathologic criteria and increasingly characterised by distinctly clinical behaviour. In 1972 Toker [3] described five patients with unusual skin tumour where histologically trabeculae and cell nests in the dermis dominated, so he used the name “trabecular carcinoma of the skin” and thought that it was a variant of sweat gland carcinoma [1, 4]. The discovery of electron-dense neurosecretory granules in the tumour cells allowed for classification among
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the neuroendocrine carcinomas [5]. A few more years were necessary to discover the immunohistochemical differences between these tumours and to label the entity as MCC. The pathogenesis of MCC has remained a mystery and its therapeutic approach is often unclear.
Epidemiology MCC is a rare neoplasm with an overall age-adjusted incidence of 0.24 per 100,000 person-years, with most series showing a male predilection and a male-to-female ratio of 1.4:1 to 2.3:1 [6]. The mean age of patients at the time of initial diagnosis is about 70 years. It more commonly presents in white males and in immunosuppressed patients. The study of Koljonen et al. [7], using data of the Finnish National Renal Transplant Registry and the Finnish Cancer Registry, demonstrated a great increase of MCC among patients who had undergone renal transplantation. The role of ultraviolet light (UV) in the development of MCC is seen more as an immunosuppressive than a mutagenic/carcinogenic effect. According to the data from Surveillance, Epidemiology and End Results, in 1986–2001 there was a 3-fold increase in MCC cases [2, 8, 9]. The age-adapted incidence of MCC in this period rose with a statistically significant annual increase of 8%. This rise is more dramatic that the increased incidence of cutaneous melanoma. The change in the incidence of this cancer has been linked to a variety of environmental and population factors, such as a higher incidence of UV exposure and increasing numbers of immunosuppressed individuals within the population. The advancement in immunodiagnostic techniques may have also contributed to the increasing numbers of diagnosed cases [2]. The American Cancer Society has predicted that the incidence of MCC will thus exceed that of cutaneous T-cell lymphomas. Similar data has been reported for Australia [1, 5]. The Danish study [10] of the Epidemiology Research Department (1978-2006) showed MCC incidence of 2.2 cases per million person-years, and warned about the possible association between MCC and other cancers, particularly squamous cell carcinoma.
Pathogenesis The pathogenesis of MCC has remained a mystery despite its association with various chromosomal abnormalities and with growing signalling and apoptotic pathways. Among the most viable hypotheses is the role of mast cells in tumorigenesis, hypermethylation by silencing p14ARF, aminoacid substitution in exon 10 of platelet-derived growth factor and, notably, the novel MCV [2, 11]. The recent discovery of this virus improved our understanding of this aggressive lesion.
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We have reviewed the most frequent factors and hypotheses related to the pathogenesis of the tumour: – The role of UV light in the development of this tumour is seen more as an immunosuppressive than as a mutagenic/carcinogenic effect. Pathogenetically, in addition to disturbed antigen presentation, the induction of immunosuppressive cytokines such as interleukin (IL)-1 and tumour necrosis factor α (TNF-α), the isomerisation of trans-urocanic acid to cis-urocanic acid, and the formation of reactive oxygen species are blamed [1]. – Multiple chromosomal abnormalities have been found in MCC, the most common of which is the deletion of the short arm of chromosome 1 (1p36), a structural aberration found in up to 40% of MCCs. Deletions in chromosome 1 have also been found in cases of malignant melanoma and neuroblastoma. Aberrations in other chromosomes, such as loss of heterozygosity in band 3p21 (an abnormality also reported in small-cell carcinoma) 10q23, and chromosome 13 have also been reported. The heterozygous loss of chromosome 10 or the long arm of chromosome 10 in MCC suggests that the tumour suppressor PTEN encoded there plays a relevant role. A recent study using MCC tissue arrays to measure the exposition of various proteins (especially matrix metalloproteinases) revealed that PTEN could hardly be identified in the samples examined, which could indicate inactivation of the second allele [5, 12]. Other abnormalities also found in MCC include trisomy 1, trisomy 6, trisomy 11, trisomy 18 and deletion of chromosome 7 [2]. – It has been suggested that the rapid growth seen in MCC is associated with dysregulation of various normal growth factor receptors. A multitude of functions has been described for the tumour suppressor p53 and mutations are occasionally observed in MCC [1, 13]. High expression of the bcl-2 proto-oncogene, which is capable of inhibiting apoptosis, thereby promoting cell survival and contributing to tumour growth, was observed in 5 of 19 patients with MCC, although no relation between gene expression and survival was observed [14]. – The classical cascade for tumorigenesis, with several known proteins implicated, such as the mitogen-activated protein (MAP) kinase, the Raf/MEK/ERK cascade and the B-Raf mutation, has been found without activity in MCC. This finding distinguishes MCC from other tumours such as melanoma [5]. – Finally, the discovery by Feng et al. [15] in 2008 of MCV or MCPyV in 8 of 10 MCC tumours has provided yet another clue to the pathogenesis of this cancer. MCV is most closely related to a lymphotropic polyomavirus found in African green monkeys, the only polyomavirus known to naturally infect B lymphocytes. MCV has previously been found at low copy number in peripheral blood, as well as skin and
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gut tissues, of persons without MCC, suggesting that it too may be lymphotropic [16]. Polyomaviruses are a group of icosahedral, doublestranded DNA viruses that encode a large T (umor)antigen oncoprotein known to cause tumours in animal models. As yet there is no definitive proof that they play a relevant role in human carcinogenesis. Polyomaviruses often induce latent infections without manifest disease, but can, for example in an immunosuppressed host, induce tumours [5]. The viral stimulation of the cell cycle is believed to be the driving force of the oncogenetic potential in polyomaviruses. MCV integrates into band 3p14 at the human protein tyrosine phosphatase, receptor type, a tumour suppressor gene. When inserted into the host DNA, the viral T antigen is expressed as large T and small T antigens. These T antigens target and alter the behaviour of tumour suppressor and cell cycle regulatory proteins, including Rb, p53, protein phosphatase 2ª and Bub 1. Two distinct mutagenic steps are believed to be required for MCC development: first, integration of MCV into the host genome; and second, prevention of autonomous viral replication by T antigen mutations. Risk factors, such as increased exposure to UV and ionising radiation, may be involved in T-antigen mutations. The association of MCC with a virus may explain the higher incidence of MCC in immunosuppressed patients. MCC cell polyomavirus DNA can be detected in 75– 89% of MCC. Shuda et al. [16] have found that 70% of CK20-positive MCC tumours have uniform cancer cell expression of the MCV T antigen using a specific monoclonal antibody. Varga et al. [17] concluded, after examining nine patients with MCC, that MCV infection may well be specific for MCC, and that MCV may play a role in the pathogenesis of MCC. Their results were very similar to those of Feng et al. Several primary and secondary malignancies are significantly associated with MCC, particularly chronic lymphocytic leukaemia (CLL). It is not known if CLL or other lymphoid malignancies share a fundamental pathologic link with MCC [16]. In 2011, Sihto et al., from Helsinki University Central Hospital, demonstrated MCV DNA-positive MCC has different clinical and molecular features than MCV DNAnegative cancers [18]. MCV-associated MCC express RB (retinoblastoma protein) but may not have TP53 mutations. The findings of this work provide further support that MCV causes the majority of MCC.
Histology The neoplastic cells in MCC were thought to arise from the Merkel cells of the epidermis, hair sheath or sweat ducts. These cells were described in 1875 by Friedrich Sigmund Merkel and considered part of the diffuse neuroendocrine
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Fig. 1 H&E low power view. MCC is an intradermal neoplasm without epidermotropism, dense cellularity with necrotic foci
system. Merkel cells are believed to originate from the neural crest cells and MCC is believed to be derived from Merkel cells, since they both possess dense core neuroendocrine granules, neurofilament and CK20 expression. However, the cell origin of MCC is still being debated and during the last two decades several nonendocrine epithelial cells and sarcomatous elements have been identified in some of the tumours, suggesting that MCC probably arises from stem cells, which are able to differentiate along different cell lines. The rarity of such epidermal involvement has led some to consider this pluripotent dermal stem cell of origin [2, 14]. Histologically, MCC presents predominantly as a dermal-based lesion composed of strands or nests of uniform, small round cells with scanty cytoplasm, round to oval nucleus with powdery dispersed chromatin and inconspicuous nucleoli. The tumour spreads to the reticular dermis, generally sparing the papillary dermis, epidermis and adnexa (Fig. 1) [2]. Epidermal involvement has been reported in 5–30% of tumours either in the form of epidermotropism or carcinoma in situ. Most cases of intraepidermal MCC have been observed in association with squamous cell atypia [14, 19]. Irregular nested groups of infiltrating cells with an Azzopardi effect, single-cell necrosis, frequent mitoses, vascular invasion, perineural invasion and epidermal involvement via pagetoid spread may also be present. A desmoplastic response is often present in the surrounding dermis, and ulceration of the epidermis overlying the lesion has also been described in more advanced lesions [2]. The tumour cells are characterised by a large, relatively pale nucleus. The cytoplasm is scant and contains argyrophil granules and often displays thread-like extensions. The mitotic index is very high and many atypical mitoses are seen. According to the arrangement and appearance of the tumour cells, three histological patterns are differentiated, although clinically insignificant: the trabecular, the inter-
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A
C
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B
D
mediate and the small-cell type. The trabecular type originally described by Toker [3] is relatively rare (at 10%); the tumour cells are somewhat larger than in the other types and grow in a distinct trabecular fashion in the dermis. Their cells are round to polygonal with abundant cytoplasm. The intermediate type is the most frequent (80%). The tumour cells are medium-sized, possess large, lobed nuclei and scant, pale-stained cytoplasm. This variant also shows solid nodules made of diffuse sheets of basophilic cells. The tumour cells of small-cell MCC are small and possess a hyperchromatic nucleus. Mixed and transitional forms between the three types are very frequent. MCC may also express squamoid, eccrine, glandular and melanocytic differentiation. Transmission electron microscopy reveals characteristic electron-dense cytoplasmic granules (diameter approx. 100 nm) as well as intermediate filaments [1, 2].
Fig. 2A (H&E ×40) Undifferentiated tumour. Cells with scanty cytoplasm and angulated nuclei with coarse chromatin. Microscopic necrotic foci and frequent mitotic figures. B CK-20. Intense and diffuse dot-like paranuclear expression. C Chromogranin. Faint and diffuse cytoplasmic positivity. D Absence of TTF-1 expression is characteristic of Merkel cell tumour
cyte common antigen (LCA), thyroid transcription factor 1 (TTF-1) and vimentin, which are usually negative. Furthermore, the tumour cells of MCC expressed a wide range of markers with varying frequency and intensity; these include, among others, chromogranin A, synaptophysin, bombesin, somatostatin, vasoactive intestinal peptide, proconvertases PC1/PC3 and PC2.7, tenascin-C and CD56, as well as various neurofilaments. They also expressed epithelial markers such as AE/1AE3, CAM 5.2, pan-cytokeratin, epithelial membrane antigen and Ber-EP4. However, it is negative for TTF-1, S100 and LCA/CD45 [1, 2]. CK20 is a fairly specific and sensitive marker for MCC, with a characteristic paranuclear dotlike positivity (Fig. 2). It is the most widely used and accepted immunohistochemical stain in the work-up of MCC [1, 2, 6].
Clinical features and clinical course Immunohistochemical findings Due to the uncharacteristic histomorphological cellular features of MCC, immunohistochemistry is required for definitive diagnosis. This is especially necessary to differentiate as small-cell carcinoma, small B-cell lymphomas or anaplastic small-cell melanomas. MCC is unique in that it possesses both neuroendocrine and epithelial features. In general the immunohistochemical identification of cytokeratin (CK) 20 and neuron-specific enolase (NSE) is performed, with the former being quite specific but not always positive and the latter usually positive but relatively unspecific. These tests are combined with stains for leuko-
MCC has a nonspecific clinical appearance. It most commonly presents as a persistent asymptomatic red/pink cystic lesion, smaller than 2 cm, which rapidly increases in size over a period of weeks to months on chronically exposed, sun-damaged skin (Fig. 3). Other dermatologic presentations include acneiform lesions; blue or red, firm, solitary, dome-shaped nodules; or plaque-like growths, especially on the trunk. The typical clinical features of MCC can be explained by the fact the tumour usually grows in a hemispherical fashion to the outside and in an iceberg-like fashion in depth, so that the intact epidermis is stretched. Even initially MCC grows in an infiltrating manner, but ulcerations are observed only in very ad-
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lymph node basin (27–60%), followed by distant skin (9–30%), lung (10–30%), central nervous system (18%), bone (10–15%) and liver (13%). Other reported areas of distant metastasis include testis, pancreas, heart, bone marrow, pleura, parotid, gastrointestinal tract, prostate and bladder. Locoregional recurrence, which usually develops within 8 months of diagnosis, is strongly associated with later distant metastases. Distant metastatic disease is usually found at a mean of 18 months and mortality within this group is very high, with a mean survival of
