Merkel cell carcinoma

1477-7819-4-7 1477-7819 Review Merkel cell carcinoma Koljonen Virve virve.koljonen@hus.fi

Department of Plastic Surgery, Helsinki University Hospital, Helsinki Finland

World Journal of Surgical Oncology 1477-7819 2006 4 1 7 http://www.wjso.com/content/4/1/7 16466578 10.1186/1477-7819-4-7 18 9 2005 08 2 2006 08 2 2006 2006 Koljonen; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

Merkel cell carcinoma (MCC) is an unusual primary neuroendocrine carcinoma of the skin. MCC is a fatal disease, and patients have a poor chance of survival. Moreover, MCC lacks distinguishing clinical features, and thus by the time the diagnosis is made, the tumour usually have metastasized. MCC mainly affects sun-exposed areas of elderly persons. Half of the tumours are located in the head and neck region.

Methods

MCC was first described in 1972. Since then, most of the cases reported, have been in small series of patients. Most of the reports concern single cases or epidemiological studies. The present study reviews the world literature on MCC. The purpose of this article is to shed light on this unknown neuroendocrine carcinoma and provide the latest information on prognostic markers and treatment options.

Results

The epidemiological studies have revealed that large tumour size, male sex, truncal site, nodal/distant disease at presentation, and duration of disease before presentation, are poor prognostic factors. The recommended initial treatment is extensive local excision. Adjuvant radiation therapy has recently been shown to improve survival. Thus far, no chemotherapy protocol have achieved the same objective.

Conclusion

Although rare, the fatality of this malignancy makes is important to understand the etiology and pathophysiology. During the last few years, the research on MCC has produced prognostic markers, which can be translated into clinical patient care.

Background

The Merkel cell

The Merkel cell (MC) was first described by the German histopathologist Friedrich Sigmund Merkel in his classic article published in 1875: Merkel F: "Tastzellen und Tastkörperchen bei den Haustieren und beim Menschen" 1. He demonstrated the existence of touch cells in the snout skin of pigs, calling them "Tastzellen" because of their putative function in the touch sensation. Merkel postulated that the cells acted as mechanoreceptors in all animals.

Distribution of Merkel cells

MCs are normal constituents of the basal layer of the epidermis and the follicular epithelium 2 (Figure 1). They are scarce in normal skin, but are present in high numbers and form clusters in areas of sensory perception. In close association with primary nerve endings in the skin, they form the MC-axon complex.

Figure 1

Solitary Merkel cells in the normal skin, expressing cytokeratin-20

Solitary Merkel cells in the normal skin, expressing cytokeratin-20.

On light microscopy, MCs are large, oval, amphophilic, clear cells situated in the basal or suprabasal layer of the epidermis. They are not easily distinguished from other nonkeratinocytic epidermal cells, e.g. melanocytes and Langerhans cells, by light microscopic immunohistochemistry. Special techniques such as immunohistochemistry, electron microscopy or transmission electron microscopy are therefore required for their identification.

Function in developing embryo and adult

In human development, MCs can be detected in the epidermis in the 8^thgestational week 3. In the developing embryo, MCs are thought to be involved in the formation of the subepidermal nerve plexus 45, and in the formation and proliferation of eccrine sweat glands and hair follicles 6. In the adult MCs are thought to act as slow acting type-I mechanoreceptors. Together with sensory nerve endings, they form MC-axon complexes that are activated by steady skin indentation 7. The function of MCs in this complex is, however, enigmatic. Two possible functions have been proposed: either they may act as attracters of developing or regenerating type I nerve fibres 8 or they may have neuromodulatory or neuroregulatory functions in the basal epidermis, such as keratinocyte proliferation stimulation, maintenance of the differentiation of keratinocytes, or the release of bioactive substances to subepidermal structures 9.

Origin of the Merkel cell

The origin of the MC is still controversial. The cell may derive either from the epithelial cells of the epidermis or from the neural crest migrating to the epidermis during embryogenesis. In the 1980s and 1990s, the epidermal origin from keratinocytes with an aberrant differentiation 10 was the prevailing hypothesis 3111213, as suggested by the epidermal location of the MC, the expression of cytokeratins and the results of skin transplantation experiments 1415. Recent studies, however, have provided strong evidence in support of the neural crest origin 1617.

Merkel cell carcinoma

The Merkel cell carcinoma (MCC) was first described in 1972, when Toker presented the first five cases under the name "trabecular carcinoma of the skin", assuming them to represent an eccrine, sweat gland-derived carcinoma 18. In electron microscopic (EM) studies, Tang and Toker later identified dense-core neuroendocrine granules within the tumour cells, thus demonstrating their origin from MCs 19.

The "cell of origin" of MCC is, however, still speculative. There are morphological and biological similarities between the MC and MCC. The common presence of neuroendocrine granules 20 and the positive immunostaining for cytokeratin-20 (CK-20), for instance, provide evidence for MC origin 21, although this may indicate differentiation rather than origin. However, certain differences also exist between the MC and MCC, such as the fibrous whorls and neurofilaments that are seen in MCC but not in normal MCs. Another argument against the MC as the cell of origin for MCC is that mitoses have not been detected in human MCs 322. There is a contradiction between the location of the cell in the skin in MCs and in MCC, the tumour practically always involves the dermis, sparing the epidermal structures.

Toker called the first five cases of MCC "trabecular carcinoma of the skin." This name derived from the trabecular architecture of the tumour, which is the most characteristic, but the uncommon, configuration of three histological patterns. Over the years, the name of this tumour has been the subject of lively discussion. Several names and synonyms have been proposed; either based on histological features or derived from the term "Merkel cell". These include derivatives such as "Malignant Merkel-cell tumour" 23, "Merkel cell tumour" 24 or "Merkel cell tumour of the skin" 25. It was not until the mid 1980s that the term "Merkel cell carcinoma" was established. In the year 1980, Johannessen and co-workers seem to have used this term for the first time 26. The term "Primary neuroendocrine carcinoma of the skin" was coined to reflect the pathophysiology of the disease.

Histology

The histology of MCC is typical of small round blue cell tumours, an entity that includes a wide variety of highly malignant tumours: the Ewing family of tumours, olfactory neuroblastoma (esthesioblastoma), rhabdomyosarcoma, neuroblastoma, lymphoma, desmoplastic small cell tumour, osteosarcoma, small cell lung carcinoma (SCLC), small cell melanoma and mesenchymal chondrosarcoma 2728.

Histologically, MCC can be classified into three distinct subtypes 293031. In haematoxylin-eosin staining, typical histology of the MCC is small blue cells with sparse cytoplasm. Nuclei are medium-sized. Mitoses are abundantly and the tumour expands frequently to subcutaneous tissue. Chromatin is displayed in typical salt and pepper pattern.

The classification to the subtypes is usually reserved for the anatomical studies. The first of these is the trabecular subtype, described originally by Toker18. This is the least frequent histological pattern. Cells are arranged in distinctly organoid clusters and trabeculae with occasional ribbons. This type of tumour usually occurs adjacent to adnexal structures, particularly hair follicles.

The intermediate subtype is the most frequent histological subtype 32. It exhibits a solid and diffuse growth pattern. Cells are less compactly arranged, and the cytoplasm is less abundant than in the trabecular type. Mitoses and focal areas of necrosis are frequent. These tumours usually arise adjacent to adnexa, but may invade the epidermis. The clinical behaviour is more aggressive than that of tumours of the trabecular type. The small cell type mimics small cell tumours of other sites, e.g. SCLC 33. The tumours arise in the dermis and appear as solid sheets and clusters of cells. The clinical behaviour of this subtype appears to be as similar as the small cell tumours of other origins.

Diagnosis

Diagnosis is based on typical histology representation on haematoxylin-eosin -stained slides together with the results of immunohistochemistry 32. A typical histological finding in MCC is the presence of tumour tissue within the dermis with repeated extensions to underlying subcutaneous tissue (Figure 2). The epidermis, papillary dermis and adnexal structures are not usually involved. Cytological features include sparse cytoplasm with uniform, monotonous medium-sized nuclei and abundant mitoses 34. All these cytomorphological features can be present as well in fine needle aspirates 35. EM studies show that the ultrastructure of neuroendocrine granules of the tumour is similar to that of normal MCs. The most consistent findings are the aggregation of intermediate filaments in a paranuclear location and the existence of membrane-bound dense core granules. Only 10 % of all MCC tumours are intraepidermal 36.

Figure 2

Immunohistochemical staining of primary Merkel cell carcinoma for differential diagnosis and neuroendocrine differentiation

Immunohistochemical staining of primary Merkel cell carcinoma for differential diagnosis and neuroendocrine differentiation. A. Hematoxylin-eosin staining, the tumour cells have round nuclei, original magnification 200×. B. Positive cytokeratin-20 staining, showing typical punctate pattern of immunostaining, original magnification 400×. C. Negative staining for Thyroid-transcriptor factor-1, original magnification 400×. D. chromogranin -A staining, original magnification 400× and E. synaptophysin staining, original magnification 400×.

Immunohistochemistry – differentiation

The tumour expresses both epithelial and neuroendocrine markers, and thus exhibits both epithelial and neuroendocrine differentiation.

Epithelial differentiation

Of the intermediate filaments, MCC expresses low-molecular-weight cytokeratins (keratins 8,18,19 and 20), the simple epithelial type being the most marked 2037. The most important keratin in differential diagnostics is cytokeratin-20 (CK-20). CK-20 is a low-molecular-weight cytokeratin, in normal tissues it is only expressed in the gastrointestinal epithelium, urothelium, and MCs 38. It has been shown that CK-20-positivity in MCC serves to distinguish it from pulmonary small cell carcinoma. Considered a sensitive and specific marker for MCC, CK-20 is helpful in efforts to distinguish between MCC and other malignant neoplasms, since it is not usually expressed in neuroendocrine carcinomas of other sites, such as SCLC 3940 (Figure 2). Although up to 30 % of metastatic neuroendocrine carcinoma from lung might stain for CK-20, but they always stain for TTF-1, which is negative in MCC 41. In some 5 – 25% of MCC cases, CK-20 is negative 4243.

Tissue-specific transcription factors control cell determination and differentiation. Thyroid transcription factor 1 (TTF-1) is a tissue specific transcription factor expressed in epithelial cells of the thyroid and lung, as well as in certain areas of the brain 44. TTF-1 is employed to differentiate between MCC and small-cell tumours 4546, MCC is negative for TTF-1 47 (Figure 2).

Combining TTF-1 with CK-20 provides a sound basis for diagnosis. Most adenocarcinomas from other sites (breast, lung, endometrium) and neuroendocrine carcinomas such as SCLC are essentially negative for CK-20 40 while most are negative for CK-20, those from the lung are postitive for TTF-1. Table 1 presents the immunohistochemistry for the differentiation diagnosis of MCC.

Table 1

Immunohistochemical markers in the differential diagnosis of MCC.

CK-20

TTF-1

NSE

S-100

GrA

SYP

NFP

CD56

MAP-2

LCA

MCC

+/-

SCLC

+/-

-/+

LGNEC

-/+

Malignant lymphoma

-/+

+ positive, +/- mostly positive, -/+ mostly negative, - negative. CK-20 cytokeratin 20, TTF-1 thyroid transcription factor 1, NSE neuron-spesific enolase, GrA gromogranin A, NFP neurofilament proteins, CD56 neural adhesion molecule, MAP-2 microtubule associated protein 2, LCA leukocyte common antigen SCLC small cell lung carcinoma, MM malignant melanoma, LGNEC low grade neuroendocrine carcinomas

Neuroendocrine differentiation

Due to neuroendocrine differentiation, MCC always stains positively for neuron-specific enolase (NSE), which is a general marker of neuroendocrine tumours 484950. CD56, or neural cell adhesion molecule (NCAM), has recently been demonstrated to be a neuroendocrine marker of the pulmonary neuroendocrine cell system as well as MCC 5152. Although, McNiff and co-workers recently reminded of the pitfalls in using CD56 marker for MCC diagnosis 53 Chromogranin A (CrA), a member of the chromogranin family, is a major protein that accounts for a large amount of the soluble matrix of neurosecretory granules. First isolated from chromaffin cells of the adrenal medulla, CrA is the most widely distributed marker of endocrine tumours 54. MCC shows a focal, positive immunoreaction to CrA 5556 (Figure 2). Synaptophysin is a transmembrane channel protein of small presynaptic vesicles. It is expressed in neuroendocrine and neural cells and diffusely in neuroendocrine system cells 5758. Both primary and metastatic neuroendocrine carcinomas are habitually synaptophysin positive 5960. MCC consistently shows positive immunoreactions to synaptophysin 5661 (Figure 2).

Newer markers of neuroendocrine differentiation introduced for MCC are the microtubule-associated proteins (MAPs). These are the major component of the cytoskeleton family of proteins associated with the microtubule assembly of the central and peripheral nervous system 6263. Specific MAPs have been identified in specific cell types. MAP-2, for instance, is a highly sensitive and specific marker of neuroendocrine differentiation 626364. Liu et al, demonstrated MAP-2 expression in all MCC samples, even though CK-20 staining was negative 65. In general, MCC shows a high degree of neuroendocrine differentiation. A higher expression of CrA and synaptophysin associated with more indolent behaviour 56.

DNA copy number changes

Different types of chromosomal irregularities have been documented in MCC tumours and cell lines 666768. The most common aberrations engage chromosomes 1, 6, 11 and 13. Trisomy of chromosome 6 is a widely considered as recurrent aberration 6970. Trisomy of chromosome 1 appears to be typical of MCC 71. In the chromosome 11 a partial trisomy has been documented 72 as well as complete trisomy 73. In chromosome 13 loss was recognizable 72 in addition to LOH 74. So far it seems that high-copy number amplifications for chromosomal subregions are a rare event in MCC 75. Although DNA copy number changes have not been established as prognostic factor for MCC, primary tumours expressing DNA alterations were predominantly distinguished in large sized tumours, and risk of metastatic dissemination was three-fold compared to tumours with no DNA alterations 76.

Clinical presentation and staging

The clinical presentation of this tumour is rather non-specific. MCC is usually, at least at early stages of the disease, defined as a small painless erythematous intradermal mass, usually with no ulceration 7778. Especially small tumours in particular can appear somewhat benign, whereas large tumours have an unquestionably malignant appearance. Because of the rare nature of this neoplasm, it is often mistaken for more common skin tumours of epithelial origin. Most common presumptive clinical diagnosis is cyst.

There is no classification scheme for MCC such as there is for most carcinomas or sarcomas. At present, staging of most malignant tumours is based on the T(umour) N(odes) M(etastasis) classification (TNM classification of malignant tumours – 6th edition, 2002). Concerning the skin malignancies the TNM classification applies to carcinomas of the skin in general and malignant melanoma. In most published series MCC is not classified according to the TNM system.

Yiengpruksawan has, however, proposed a staging system that has been widely recognised in the treatment of MCC 77, which is presented in Table 2.

Table 2

Yiengpruksawan proposed staging system with treatment recommendation, SLNB = sentinel lymph node biopsy

Stage

Treatment Recommendation

Localized disease

Surgery: local excision > 2 m margins, SLNB Radiation therapy: adjuvant after resection

≤ 2 m primary tumour

> 2 cm primary tumour

Regional lymph node involvement

Surgery: local excision > 2 m margins, lymph node dissection

Radiation therapy: adjuvant, primary site and lymph node region

III

Distant metastases

Radiation therapy: palliative use

Incidence and clinical behaviour of MCC

The reported annual incidence of MCC ranges from 0.2 to 0.45 per 100 000 7980. Incidence has tripled since 1986:1986 0.15 per 100,000 and 2001 0.44 per 100,000 81. It is 100 times as rare as melanoma 82. MCC is principally a disease of the Caucasian race. The annual age-adjusted incidence of MCC is 0.23 per 100,000 for whites and 0.01 for blacks 83. The literature contains only single case reports of black Africans or African-Americans with MCC 848586. Both sexes are affected, though earlier studies showed a slight male predominance 878889. The number of reported patient series is, however growing, and recent investigations have shown an equal distribution of the sexes or even a minor female prevalence 909192. MCC mainly affects the elderly, the mean age at presentation being about 75 years 9394. Age-specific incidence was highest in the elderly, 4.28 per 100,000 in the 85+ age group 81 Only a few cases occur before the age of 50, and is usually related to immunosuppression 95.

MCC usually occurs in sun-damaged skin. The tumours are often found in close proximity to other lesions of actinically damaged skin, for instance, in cases of Bowen disease, squamous cell carcinoma, basal cell carcinoma, solar keratosis and lentigo maligna. The most common site is the head and neck region 96. Pathogenetic factors such as UV irradiation may contribute to tumour development 6897. Miller and Rabkin have calculated that the incidence of MCC rises along with an increase in potential exposure to solar UVB. They found statistical significance between the incidence of MCC and UVB exposure 83.

The natural history of MCC is variable and dependent on the stage of disease at presentation 98. Typically MCC has a tendency to progress rapidly, and in just a few months, the tumour may attain a large diameter. Therefore, early diagnosis and surgery are strongly advocated. Several studies established a close correlation between overall survival and tumour size. The overall survival rate is largely influenced by tumour size (≥ 2 cm) 99100. In some studies dense lymphocytic infiltrates have been associated with poor prognosis 101.

The typical clinical course of the disease is rapid progression of the primary tumour with early and frequent metastasis to the regional lymph nodes. The sentinel lymph node biopsy (SLNB) technique has provided information on the metastatic dissemination at the presentation. In a meta-analysis of 60 MCC patients, Mehrany and co-workers detected 33% of the patients having metastatic dissemination in the sentinel lymph node at the presentation 102. Then again, Hohaus and co-workers in their 17 patients retrospective analysis reported only 3 (18%) of the patients at stage II at the presentation 103. Allen and co-workers detected 5/26 (19%) of the patients having positive lymph nodes at the presentation 104.

Recurrences are frequent. Allen et al, at the Memorial Sloan-Kettering Cancer Center's identified 251 patients who had been treated between 1970 and 2002. The median time to recurrence was 9 months, and 102 patients (43%) recurred 98. Primary site on the lower limb had an adverse effect on locoregional recurrencies 105.

Although the natural course of MCC is usually defined with metastatic spread, there are some reports in the literature (10 cases) of spontaneous regression 106107. Mori and co-workers have studied the apoptosis in eight cases of MCC 108 and found high apoptotic rate in MCC samples. Inoue et al have examined the mechanisms behind the spontaneous regression in seven MCC samples 109. The TUNEL index and number of lymphocytes around the tumour nests was increased in the samples with spontaneous regression, furthermore the majority of the infiltrating lymphocytes were T-cells 109. They concluded that apoptosis and local T-cell mediated immune response might be involved in spontaneous regression of MCC.

Co-existing malignancies

MCC has been associated with other skin tumours (squamous cell carcinoma, basal cell carcinoma) and haematological (B-cell) malignancies 110111112. In addition, adenocarcinomas of the breast and ovaries have been shown to have an association with MCC. Co-malignancies, whether they appear before, after or simultaneously with MCC, are associated with higher MCC-specific mortality 113114.

Immunosuppression: therapeutic and acquired

The incidence of MCC is abnormally high (8%) among immunosuppressed patients. Such patients are moreover younger, 49% being under the age of 50 115116. Weakened immunity increases the risk of MCC; HIV patients, for example, have a 13.4 times increased risk of acquiring MCC 117.

Prognosis

The prognosis is rather poor. The 2-year survival rate is 30 – 50% 118119, Kokoska included 35 and Linjawi 10 patients in his study. Agelli and Clegg have studied the epidemiology of MCC in the United States in a patient population of 1034 by using Surveillance, Epidemiology, and End Results Program. The 5-year survival rate in their study was 75%, 59% and 25% for localised, regional and distant MCC, respectively 120. Overall survival (OS) is associated with the stage of disease at presentation. Female sex, localized disease, and younger age were positive predictors of survival 78120121. The risk of recurrence or metastasis was 19 times as great in sentinel node biopsy-positive patients as in biopsy-negative patients (p = 0.005) 102.

Local recurrences are frequent, occurring in up to 44% of patients 308893. There have been some reports of lymph node metastasis alone, with no detectable primary tumour 122123. Depending on the length of the follow-up period up to 36% of the patients develop regional lymph node metastasis 124. Distant dissemination is not infrequent, up to 40–50% of patients developing visceral metastasis 125126127, particularly to the lungs, liver and bone 128129.

Surgical treatment

Because of the rarity of the tumour, there is multitude of treatment protocols. However, the surgical treatment seems to be the corner stone of the different treatment protocols.

Early, radical surgery is the recommended procedure for the treatment of primary MCC 92130. Margins of 2 – 5 cm are recommended for better local control. Nevertheless, consensus on the width of margins has not yet been reached. Yiengpruksawan and co-workers, O'Connor and Brodland reported better local control with margins of > 3 cm 77131. Then again, there have been reports that larger free margins confer no advantage on survival 124. Gillenwater and co-workers had sixty-six head and neck MCC cases included in their study, but only eighteen patient's data was sufficient for the statistical analysis. They state themselves that the small patient population in their study might explain this result. Because lymph node metastases develop in approximately 50% of patients in the course of the disease, some authors recommend prophylactic lymphadenectomy in all patients 97118. Then again, the patient materials are small: Lawenda had nine patient study population and Kokoska 35. Silva and co-workers recommend lymphadenectomy for tumours with 10 or more mitoses per high-power field, in cases of lymphatic invasion, or when tumours are composed of small cells, that is, the small-cell subtype 132.

According to the literature on MCC, the sentinel lymphnode biopsy (SLNB) technique was used in approximately 100 cases between 1976 and 2002. Most reports advocate SLNB because morbidity is low, and because it provides an easy and reliable way of locating occult metastasis 102133134. Recent studies have investigated the efficacy of SLNB in helping to determine whether lymph basin evacuation is necessary. These studies have been conducted on only a small series of patients, but even so, the results suggest that a negative sentinel node may obviate the need for neck dissection. SLNB is strongly advocated in the treatment and staging of individual tumours. Its use will improve the accrual of patients to adjuvant and further surgical treatment protocols 102135. Especially for the MCC cases occurring in the head and neck region the SLNB seems to be a safe and reliable technique for regional staging 136.

It is widely accepted that patients with regional node metastases or local or regional recurrence should undergo excision of the primary lesion and lymph node dissection 130. Adjuvant radiation therapy to the primary site and regional nodes is generally recommended in addition to lymph node dissection. Tumours arising in the head and neck region with parotid gland metastasis seem to have even poorer prognosis 137. As a result elective lymph node dissection has been recommended for younger patients with large tumours or tumours of the head and neck region 138139140.

Mohs micrographic surgery is a surgical technique developed by Frederick Mohs in the 1930s at the university of Wisconsin 141. Briefly, the technique consists of debulking the tumour with a semisharp curette, in order to outline the skin tumour. Subsequently, a scalpel is used to remove the tissue in a horizontal fashion with 2 mm clinical margins. The tissue sample is taken to the laboratory for the processing. The patient is bandaged and waiting for the microscopic results. The horizontal frozen sections are cut from the undersurface of the tissue parallel to the skin surface, rather than vertically. This method allows for microscopic examination of the entire deep and peripheral margins of the surgical specimen. The surgeon does the microscopic examination. These steps are then repeated until the margins are free from the tumour, and the defect is closed.

Mohs micrographic surgery has been recommended as an advanced technique for local control, especially in areas calling for excellent cosmetic results (i.e. head and neck region) without compromising the principles of cancer surgery 142143. Then again, Brissett and co-workers reported inferior 2-year survival with patients undergoing Mohs micrographic surgery compared to patients who had wide local excision alone or wide local excision and lymphnode basin evacuation, 33%, 68% and 100% respectively 130.

Oncological treatment

Chemotherapy is generally reserved for stage III (distant metastasis) cases of MCC. The carcinoma has often been shown to respond to chemotherapy but, as in SCLC, remission is brief. Recently, Waldman and co-workers reported a complete remission that lasted for 6 months. The remission was achieved through the use of high-dose polychemotherapy following autologous blood stem cell transplantation 144. Some months previously, Voog et al reported similar results, the rates of response to second-line (n = 33) and third-line (n = 10) chemotherapy being 45% and 20%, respectively 145. No chemotherapeutic protocol has, however, been able to achieve a significant increase in survival rate 105.

No standard chemotherapy protocol has yet been established for the treatment of MCC. Because of the morphological and immunohistochemical similarity of MCC to SCLC, chemotherapy has been performed with protocols based largely on agents active in SCLC. A wide variety of chemotherapeutic agents, including the cytostatic drugs cyclophosphamide, doxorubicin, epirubicin, vincristine, etoposide, cisplatine, carboplastin, 5-fluorouracil, dacarbazine, mitoxantrone, bleomycine and iphosphamide, have been discussed 8796145146147. Unfortunately, reports to date consist of only small studies and anecdotal evidence. A few reports have shown markedly high mortality among MCC patients receiving chemotherapy for metastatic disease. Tai and co-workers reported seven (3.4%) toxic deaths among 204 cases 96. Voog and co-workers gave even higher mortality, the rate of toxic death during first-line treatment being 7.7% in 101 patients 145.

MCC is a highly radiosensitive tumour, which has been demonstrated in in vitro studies 148. Many authors have recommended post-operative radiotherapy based on the retrospective comparison of patients treated with surgery alone with patients treated with surgery and post-operative radiotherapy 149150. In a recent series of 37 MCC patients Veness et al. reported a significantly longer median disease free survival with patients treated with surgery and adjuvant radiotherapy and than those undergoing surgery alone (23 months vs. 6 months) 151. Moreover, outcome improved markedly in patients receiving adjuvant radiotherapy after surgery 152. Radiation is most commonly used as an adjuvant therapy after surgery but it may be used to as the only treatment especially in patients who are too weak to undergo surgical treatments 153154

Conclusion

Recent advances in the research of MCC have revealed features in the natural biology of this malignancy. However, several questions regarding the biology and pathology of the tumour remain to be addressed. The molecular events leading to oncogenic alterations must be identified. Mechanisms of metastasis are still largely concealed. Revealing these biological properties, hopefully, will lead to discovery of new treatments, e.g. the role of anti-angiogenic medication is still uncertain. Of the surgical treatments, the sentinel lymph node biopsy has proven its efficacy in finding the clinically occult metastasis and accrual of patients to adjuvant and further surgical and oncological treatment protocols.

Several markers for prognosis have been studied, but none have proven its value like large, ≥ 2 cm, primary tumour size. The wide range of the factors associated to survival may reflect the absence of large institutional studies.

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

VK: concived the idea, did literature search, wrote the article and edited it for its final content.

Tastzellen und Tastkörperchen bei den Haustieren und beim Menschen Merkel F Arkiv für Mikroskopische Anatomie und Entwicklungsmechanik 1875 11 636 652 The epidermal-dermal junction Briggaman RA Wheeler CEJ J Invest Dermatol 1975 65 71 84 10.1111/1523-1747.ep12598050 1097542 Proliferative Merkel cells were not detected in human skin Moll I Zieger W Schmelz M Arch Dermatol Res 1996 288 184 187 10.1007/s004030050044 8967790 Biological significanse of dermal Merkel cells in development of cutaneus nerves in the human fetal skin Narisawa Y Hashimoto K Nihei Y Pietruk T Journal of Histochemistry & Cutochemistry 1992 40 65 71 Merkel cells in vitro: production of nerve growht factor and selective interactions with sensory neuros Vos P Starck F Pittman RN Developmental Biology 1991 144 281 300 10.1016/0012-1606(91)90422-Y 2010033 The appearance, density, and distributin of Merkel cells in human embryonic and fetal skin: their relation to sweat gland and hair follicle development Kim DK Holbrook KA The Journal of Investigative Dermatology 1995 104 411 416 10.1111/1523-1747.ep12665903 7532197 The Merkel cell as a possible mechanoreceptor cell Ogawa H Prog Neurobiol 1996 49 317 334 8888113 Chemosensitivity of the rat type I slowly adapting mechanoreceptor He L Tuckett RP English KB Biol Signals Receptors 1999 8 382 389 10.1159/000014612 The Merkel cell: recent findings and unresolved problems Tachibana T Arch Histol Cytol 1995 58 379 396 8562130 Cancer Cytogenetics Heim S Mitelman F New York, Wiley-Liss 1995 2nd Human Merkel cell regeneration in skin derived from cultured keratinocyte grafts Compton CC Regauer S Seiler GR Landry DB Laboratory Investigation 1990 63 233 241 1696332 Formation of epidermal and dermal Merkel cells during human fetal skin development Moll I Moll R Franke WW The Journal of Investigative Dermatology 1986 87 779 789 10.1111/1523-1747.ep12458993 3782861 Merkel cell carcinoma of the skin: the structure and origin of normal Merkel cells Frigerio B Capella C Eusebi V Tenti P Azzobardi JG Histopathology 1983 7 229 240 6852784 Development of rat Merkel cells English KB Burgess PR Kavka-Van Norman D J Comp Neurol 1980 194 475 496 10.1002/cne.901940212 7440811 Merkel cells in sheep epidermis during fetal development Lyne AG Hollis DE J Ultrastruct Res 1971 34 464 472 10.1016/S0022-5320(71)80059-X 4324460 Developmental origin of avian Merkel cells Grim M Halata Z Anatomy and Embryology 2000 202 410 410 10.1007/s004290000121 Neural crest origin of mammalian Merkel cells Szeder V Grim M Halata Z Sieber-Blum M Dev Biol 2003 253 258 263 10.1016/S0012-1606(02)00015-5 12645929 Trabecular Carcinoma of the Skin Toker C Arch Derm 1972 105 107 1110 10.1001/archderm.105.1.107 5009611 Trabecular Carcinoma of the Skin An Ultrastructural Study Tang CK Toker C Cancer 1978 42 2311 22321 719609 Neuroendocrine carcinoma of the skin (Merkel cell carcinoma): ultrastructural and immunohistochemical demonstration of neurofilaments Miettinen M Lehto VP Virtanen I Asko-Seljavaara S Pitkanen J Dahl D Ultrastruct Pathol 1983 4 219 225 6349064 Merkel cell tumor coexpressing cytokeratin and neurofilament proteins Sadahira Y Nakamoto S Mori M Hsueh CL Awai M Acta Pathol Jpn 1987 37 331 337 2440231 The majority of epidermal Merkel cells are non-proliferative: a quantitative immunofluorescence analysis Vaigot P Pisani A Darmon YM Ortonne JP Acta Derm Venereol 1987 67 517 520 2451378 Malignant Merkel-cell tumor is a more accurate description than trabecular carcinoma Rywlin AM Am J Dermatopathol 1982 4 513 515 7165060 [Merkel cell tumor] Fetissof F Arbeille-Brassart B Colombat P Lorette G Monegier du Sorbier C Jobard P Ann Pathol 1983 3 285 291 6667285 [Merkel cell tumor of the skin. Light and electron microscopic study of 5 cases] Cremer H Totovic V Pathologe 1983 4 287 293 6664956 Neuroendocrine skin carcinoma associated with calcitonin production: a Merkel cell carcinoma? Johannessen JV Gould VE Hum Pathol 1980 11 586 588 7429511 The diagnostic use of cytogenetic and molecular genetic techniques in the assessment of small round cell tumours Tarkkanen M Knuutila S Current Diagnostic Pathology 2002 8 338 348 10.1016/S0968-6053(02)90135-3 Recent advances in the molecular biology, diagnosis and novel therapies for various small blue cell tumors Pisick E Skarin AT Salgia R Anticancer Res 2003 23 3379 3396 12926079 Merkel Cell Carcinoma Ratner D Nelson BR Brown MD Johnson T Journal of the American Academy of Dermatology 1993 29 143 1156 8335732 Merkel cell carcinoma. Diagnosis and treatment Haag ML Glass LF Fenske NA Dermatol Surg 1995 21 669 683 10.1016/1076-0512(95)97513-6 7633811 Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms Gould VE Moll R Moll I Lee I Franke WW Lab Invest 1985 52 334 353 2580118 Immunohistochemical examination of 25 cases of Merkel cell carcinoma: a comparison with small cell carcinoma of the lung and oesophagus, and a review of the literature Johansson L Tennvall J Akerman M Apmis 1990 98 741 752 1698390 Cytokeratin and neurofilament protein staining in Merkel cell carcinoma of the small cell type and small cell carcinoma of the lung Schmidt U Muller U Metz KA Leder LD Am J Dermatopathol 1998 20 346 351 10.1097/00000372-199808000-00004 9700371 Merkel cells and Merkel cell tumors. Ultrastructure, immunocytochemistry and review of the literature Warner TF Uno H Hafez GR Burgess J Bolles C Lloyd RV Oka M Cancer 1983 52 238 245 6344978 Neuroendocrine (Merkel-cell) carcinoma of the skin: immunocytochemical and cytomorphologic analysis on fine-needle aspirates Skoog L Schmitt FC Tani E Diagn Cytopathol 1990 6 53 57 1691073 Intraepidermal Merkel cell carcinoma with no dermal involment Brown HA Sawyer DM Woo T American Journal of Dermapathology 2000 22 65 69 10.1097/00000372-200002000-00013 Variability of expression and arrangement of cytokeratin and neurofilaments in cutaneous neuroendocrine carcinomas (Merkel cell tumors): immunocytochemical and biochemical analysis of twelve cases Moll R Osborn M Hartschuh W Moll I Mahrle G Weber K Ultrastruct Pathol 1986 10 473 495 2435039 Keratin 20: immunohistochemical marker for gastrointestinal, urothelial, and Merkel cell carcinomas Miettinen M Mod Pathol 1995 8 384 388 7567935 Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma Scott MP Helm KF Am J Dermatopathol 1999 21 16 20 10.1097/00000372-199902000-00003 10027519 Cytokeratin 20 in human carcinomas. A new histodiagnostic marker detected by monoclonal antibodies Moll R Lowe A Laufer J Franke WW Am J Pathol 1992 140 427 447 1371204 Analysis of thyroid transcription factor-1 and cytokeratin 20 separates merkel cell carcinoma from small cell carcinoma of lung Hanly AJ Elgart GW Jorda M Smith J Nadji M J Cutan Pathol 2000 27 118 120 10.1034/j.1600-0560.2000.027003118.x 10728812 Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites Chan JK Suster S Wenig BM Tsang WY Chan JB Lau AL Am J Surg Pathol 1997 21 226 234 10.1097/00000478-199702000-00014 9042291 An immunohistological study of cytokeratin 20 in human and mammalian oral epithelium Barrett AW Cort EM Patel P Berkovitz BK Arch Oral Biol 2000 45 879 887 10.1016/S0003-9969(00)00050-9 10973561 The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain Lazzaro D Price M de Felice M Di Lauro R Development 1991 113 1093 1104 1811929 Differential expression of thyroid transcription factor 1 in small cell lung carcinoma and Merkel cell tumor Byrd-Gloster AL Khoor A Glass LF Messina JL Whitsett JA Livingston SK Cagle PT Hum Pathol 2000 31 58 62 10.1016/S0046-8177(00)80199-9 10665914 Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas Cheuk W Kwan MY Suster S Chan JK Arch Pathol Lab Med 2001 125 228 231 11175640 Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas Ordonez NG Am J Surg Pathol 2000 24 1217 1223 10976695 Merkel cell carcinoma of the eyelid: histological and immunohistochemical features with special respect to differential diagnosis Metz KA Jacob M Schmidt U Steuhl KP Leder LD Graefes Arch Clin Exp Ophthalmol 1998 236 561 566 10.1007/s004170050121 9717649 Criteria for the diagnosis of primary endocrine carcinoma of the skin (Merkel cell carcinoma). A histological, immunohistochemical and ultrastructural study of 13 cases Leong AS Phillips GE Pieterse AS Milios J Pathology 1986 18 393 399 2434904 Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 cases Sibley RK Dahl D Am J Surg Pathol 1985 9 109 116 2579592 CD56: a useful marker for diagnosing Merkel cell carcinoma Kurokawa M Nabeshima K Akiyama Y Maeda S Nishida T Nakayama F Amano M Ogata K Setoyama M J Dermatol Sci 2003 31 219 224 10.1016/S0923-1811(03)00029-X 12727026 Neural cell adhesion molecule immunoreactivity in Merkel cells and Merkel cell tumours Gallego R Garcia-Caballero T Fraga M Beiras A Forteza J Virchows Arch 1995 426 317 321 10.1007/BF00191370 7773512 CD56 staining in Merkel cell carcinoma and natural killer-cell lymphoma: magic bullet, diagnostic pitfall, or both? McNiff JM Cowper SE Lazova R Subtil A Glusac EJ J Cutan Pathol 2005 32 541 545 10.1111/j.0303-6987.2005.00378.x 16115052 Immunological studies on the occurrence and properties of chromogranin A and B and secretogranin II in endocrine tumors Weiler R Fischer-Colbrie R Schmid KW Feichtinger H Bussolati G Grimelius L Krisch K Kerl H O'Connor D Winkler H Am J Surg Pathol 1988 12 877 884 2847571 Immunohistochemical and immunoelectron microscopic demonstration of chromogranin A in formalin-fixed tissue of Merkel cell carcinoma Haneke E Schulze HJ Mahrle G J Am Acad Dermatol 1993 28 222 226 8432919 Neuroendocrine differentiation in primary Merkel cell carcinoma--possible prognostic significance Koljonen V Haglund C Tukiainen E Bohling T Anticancer Res 2005 25 853 858 15868919 Synaptophysin: a marker protein for neuroendocrine cells and neoplasms Wiedenmann B Franke WW Kuhn C Moll R Gould VE Proc Natl Acad Sci U S A 1986 83 3500 3504 323544 3010302 Synaptophysin and chromogranins/secretogranins--widespread constituents of distinct types of neuroendocrine vesicles and new tools in tumor diagnosis Wiedenmann B Huttner WB Virchows Arch B Cell Pathol Incl Mol Pathol 1989 58 95 121 2575822 Synaptophysin and neurofilament proteins as markers for neuroendocrine tumors Miettinen M Arch Pathol Lab Med 1987 111 813 818 2820344 Synaptophysin expression in neuroendocrine neoplasms as determined by immunocytochemistry Gould VE Wiedenmann B Lee I Schwechheimer K Dockhorn-Dworniczak B Radosevich JA Moll R Franke WW Am J Pathol 1987 126 243 257 3103452 Synaptophysin immunoreactivity and small clear vesicles in neuroendocrine cells and related tumours Buffa R Rindi G Sessa F Gini A Capella C Jahn R Navone F De Camilli P Solcia E Mol Cell Probes 1987 1 367 381 10.1016/0890-8508(87)90018-1 3134611 Microtubule-associated protein-2: a new sensitive and specific marker for pulmonary carcinoid tumor and small cell carcinoma Liu Y Sturgis CD Grzybicki DM Jasnosz KM Olson PR Tong M Dabbs DD Raab SS Silverman JF Mod Pathol 2001 14 880 885 10.1038/modpathol.3880406 11557784 Diagnostic Value of Microtubule-Associated Protein-2 (MAP-2) for Neuroendocrine Neoplasms Liu Y Saad RS Shen SS Silverman JF Adv Anat Pathol 2003 10 101 106 10.1097/00125480-200303000-00005 12605092 Expression of microtubule-associated protein 2 in benign and malignant melanocytes: implications for differentiation and progression of cutaneous melanoma Fang D Hallman J Sangha N Kute TE Hammarback JA White WL Setaluri V Am J Pathol 2001 158 2107 2115 11395388 Diagnostic value of microtubule-associated protein-2 in Merkel cell carcinoma Liu Y Mangini J Saad R Silverman AR Abell E Tung MY Graner SR Silverman JF Appl Immunohistochem Mol Morphol 2003 11 326 329 14663358 Molecular analysis of 1p36 breakpoints in two Merkel cell carcinomas Van Gele M Van Roy N Ronan SG Messiaen L Vandesompele J Geerts ML Naeyaert JM Blennow E Bar-Am I Das Gupta TK van der Drift P Versteeg R Leonard JH Speleman F Genes, Chromosomes and Cancer 1998 23 67 71 10.1002/(SICI)1098-2264(199809)23:1<67::AID-GCC10>3.0.CO;2-B Combined karytyping, CGH and M-FISH analysis allows detailed characterization of unidnetified chromosomal rearrangements in Merkel cell carcinoma Van Gele M Leonard JH Van Roy N Van Limbergen H Van Belle S Cocquyt V Salwen H De Paepe A Speleman F International Journal of Cancer 2002 101 137 145 10.1002/ijc.10591 UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas Popp S Waltering S Herbst C Moll I Boukamp P Int J Cancer 2002 99 352 360 10.1002/ijc.10321 11992403 Trisomy 6 in Merkel cell carcinoma: a recurrent chromosomal aberration Gancberg D Feoli F Hamels J de Saint-Aubain N Andre J Rouas G Verhest A Larsimont D Histopathology 2000 37 445 451 10.1046/j.1365-2559.2000.01011.x 11119126 Chromosome 6 trisomy as sole anomaly in a primary Merkel cell carcinoma Larsimont D Verhest A Virchows Arch 1996 428 305 309 10.1007/BF00196706 8764942 Genetic changes associated with primary Merkel cell carcinoma Vortmeyer AO Merino MJ Boni R Liotta LA Cavazzana A Zhuang Z Am J Clin Pathol 1998 109 565 570 9576574 Chromosomes 1, 11, and 13 are frequently involved in karyotypic abnormalities in metastatic Merkel cell carcinoma Leonard JH Leonard P Kearsley JH Cancer Genet Cytogenet 1993 67 65 70 10.1016/0165-4608(93)90046-O 8504402 Diagnostic relevance of chromosomal in-situ hybridization in Merkel cell carcinoma: targeted interphase cytogenetic tumour analyses Amo-Takyi BK Tietze L Tory K Guerreiro P Gunther K Bhardwaj RS Mittermayer C Handt S Histopathology 1999 34 163 169 10.1046/j.1365-2559.1999.00580.x 10064396 Loss of heterozygosity of chromosome 13 in Merkel cell carcinoma Leonard JH Hayard N Genes Chromosomes Cancer 1997 20 93 97 10.1002/(SICI)1098-2264(199709)20:1<93::AID-GCC14>3.0.CO;2-G 9290960 Characteristic pattern of chromosomal gains and losses in Merkel cell carcinoma detected by comparative genomic hybridization Van Gele M Speleman F Vandesompele J Van Roy N Leonard JH Cancer Research 1998 58 1503 1508 9537255 Recurrent DNA copy number changes revealed by comparative genomic hybridization in primary Merkel cell carcinomas Larramendy ML Koljonen V Bohling T Tukiainen E Knuutila S Mod Pathol 2004 17 561 567 10.1038/modpathol.3800091 15001998 Merkel cell carcinoma. Prognosis and management Yiengpruksawan A Coit DG Thaler HT Urmacher C Knapper WK Arch Surg 1991 126 1514 1519 1842182 Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment Hitchcock CL Bland KI Laney RG Franzini D Harris B Copeland EM Ann Surg 1988 207 201 207 3277546 Incidence of cutaneous T cell lymphoma and other rare skin cancers in a defined population Chuang TY Su WP Muller SA J Am Acad Dermatol 1990 23 254 256 2170468 Merkel Cell Carcinoma: Five Case reports Using Sentinel Lymph Node Biopsy and Review of 110 New Cases Pan D Naryan D Ariyan S Plastic and Reconstructive surgery 2002 110 1259 11265 10.1097/00006534-200210000-00007 Merkel cell carcinoma: changing incidence trends Hodgson NC J Surg Oncol 2005 89 1 4 10.1002/jso.20167 15611998 Cancer statistics, 1998 Landis SH Murray T Bolden S Wingo PA CA Cancer J Clin 1998 48 6 29 9449931 Merkel cell carcinoma and melanoma: etiological similarities and differences Miller RW Rabkin CS Cancer Epidemiol Biomarkers Prev 1999 8 153 158 10067813 Neuroendocrine carcinoma of the skin (Merkel cell carcinoma) in a black Anderson LL Phipps TJ McCollough ML J Dermatol Surg Oncol 1992 18 375 380 1607460 Merkel cell tumor of the back detected during pregnancy Chao TC Park JM Rhee H Greager JA Plast Reconstr Surg 1990 86 347 351 2367585 Merkel cell carcinoma in a black human immunodeficiency virus-infected patient Matichard E Descamps V Grossin M Genin R Bouvet E Crickx B Br J Dermatol 2002 146 671 673 10.1046/j.1365-2133.2002.04592.x 11966703 Chemotherapy for metastatic Merkel cell carcinoma. Review of the M.D. Anderson Hospital's experience Feun LG Savaraj N Legha SS Silva EG Benjamin RS Burgess MA Cancer 1988 62 683 685 3293760 Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma Boyle F Pendlebury S Bell D Int J Radiat Oncol Biol Phys 1995 31 315 323 10.1016/0360-3016(93)E0110-R 7836085 The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma Meeuwissen JA Bourne RG Kearsley JH Int J Radiat Oncol Biol Phys 1995 31 325 331 10.1016/0360-3016(94)E0145-A 7836086 Merkel cell carcinoma: report of 10 cases and review of the literature Akhtar S Oza KK Wright J J Am Acad Dermatol 2000 43 755 767 10.1067/mjd.2000.106505 11050578 Multimodality management of Merkel cell carcinoma Ott MJ Tanabe KK Gadd MA Stark P Smith BL Finkelstein DM Souba WW Arch Surg 1999 134 388 92; discussion 392-3 10.1001/archsurg.134.4.388 10199311 Merkel cell carcinoma: clinicopathologic correlation, management, and follow-up in five patients Colombo F Holbach LM Junemann AG Schlotzer-Schrehardt U Naumann GO Ophthal Plast Reconstr Surg 2000 16 453 458 10.1097/00002341-200011000-00010 11106191 Merkel cell carcinoma: an aggressive malignancy Pergolizzi JJ Sardi A Pelczar M Conaway GL Am Surg 1997 63 450 454 9128236 The natural history and management of Merkel cell carcinoma of the skin: a review of 22 patients treated at the Royal Marsden Hospital Savage P Constenla D Fisher C Thomas JM Gore ME Clin Oncol (R Coll Radiol) 1997 9 164 167 9269548 Merkel's cell carcinoma in organ recipients: report of 41 cases Penn I First MR Transplantation 1999 68 1717 1721 10.1097/00007890-199912150-00015 10609948 Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases Tai PT Yu E Winquist E Hammond A Stitt L Tonita J Gilchrist J J Clin Oncol 2000 18 2493 2499 10856110 Merkel cell carcinoma arising in the head and neck: optimizing therapy Lawenda BD Thiringer JK Foss RD Johnstone PA Am J Clin Oncol 2001 24 35 42 10.1097/00000421-200102000-00006 11232947 Merkel cell carcinoma: prognosis and treatment of patients from a single institution Allen PJ Bowne WB Jaques DP Brennan MF Busam K Coit DG J Clin Oncol 2005 23 2300 2309 10.1200/JCO.2005.02.329 15800320 Merkel cell carcinoma of the skin Tai PT Yu E Tonita J Gilchrist J J Cutan Med Surg 2000 4 186 195 11231196 Merkel cell carcinoma: a clinicopathological study of 34 patients Koljonen V Bohling T Granhroth G Tukiainen E Eur J Surg Oncol 2003 29 607 610 10.1016/S0748-7983(03)00110-0 12943628 Merkel cell carcinoma: a clinicopathologic study with prognostic implications Mott RT Smoller BR Morgan MB J Cut Pathol 2004 31 217 10.1111/j.0303-6987.2004.00149.x A Meta-analysis of the Prognostic Significance of Sentinel Lymph Node Status in Merkel Cell Carcinoma Mehrany K Otley CC Weenig RH Phillips PK Roenigk RK Nguyen TH Dermatol Surg 2002 28 113 117 10.1046/j.1524-4725.2002.02901.x 11860419 Merkel cell carcinoma--a retrospective analysis of 17 cases Hohaus K Kostler E Schonlebe J Klemm E Wollina U J Eur Acad Dermatol Venereol 2003 17 20 24 10.1046/j.1468-3083.2003.00592.x 12602962 Immunohistochemical analysis of sentinel lymph nodes from patients with Merkel cell carcinoma Allen PJ Busam K Hill AD Stojadinovic A Coit DG Cancer 2001 92 1650 1655 10.1002/1097-0142(20010915)92:6<1650::AID-CNCR1491>3.0.CO;2-8 11745244 Does chemotherapy improve survival in high-risk stage I and II merkel cell carcinoma of the skin? Poulsen MG Rischin D Porter I Walpole E Harvey J Hamilton C Keller J Tripcony L Int J Radiat Oncol Biol Phys 2005 Complete spontaneous regression of Merkel cell carcinoma: a review of the 10 reported cases Connelly TJ Cribier B Brown TJ Yanguas I Dermatol Surg 2000 26 853 856 10.1046/j.1524-4725.2000.00054.x 10971559 Complete spontaneous regression of Merkel cell carcinoma Junquera L Torre A Vicente JC Garcia-Consuegra L Fresno MF Ann Otol Rhinol Laryngol 2005 114 376 380 15966524 A study of apoptosis in Merkel cell carcinoma: an immunohistochemical, ultrastructural, DNA ladder, and TUNEL labeling study Mori Y Hashimoto K Tanaka K Cui CY Mehregan DR Stiff MA Am J Dermatopathol 2001 23 16 23 11176047 Spontaneous regression of merkel cell carcinoma: a comparative study of TUNEL index and tumor-infiltrating lymphocytes between spontaneous regression and non-regression group Inoue T Yoneda K Manabe M Demitsu T J Dermatol Sci 2000 24 203 211 10.1016/S0923-1811(00)00103-1 11084302 Two cases of merkel cell tumour arising in patients with chronic lymphocytic leukaemia Ziprin P Smith S Salerno G Rosin RD Br J Dermatol 2000 142 525 528 10.1046/j.1365-2133.2000.03370.x 10735964 Merkel cell carcinoma of the eyelid in association with chronic lymphocytic leukaemia Sinclair N Mireskandari K Forbes J Crow J Br J Ophthalmol 2003 87 240 10.1136/bjo.87.2.240 12543759 A case repot of Merkel cell carcinoma on chronic lymphocytic leukemia: differential diagnosis of coexisting lymphadenopathy and indications for early aggressive treatment Papageorgiou KI Kaniorou-Larai MM BMC Cancer 2005 5 106 1208865 16111484 10.1186/1471-2407-5-106 Second Neoplasms in Patients with Merkel Cell carcinoma Brenner B Sulkes A Rakowsky E Feinmesser M Yukelson A Bar-Heim E Katz A Idelevich E Neuman A Barhana M Fenig E Cancer 2001 91 1358 11362 10.1002/1097-0142(20010401)91:7<1358::AID-CNCR1139>3.0.CO;2-C 11283937 Lymphatic Mapping for Merkel Cell Carcinoma Kurul S Mudun A Aksakal N Aygen M Plastic and Reconstructive surgery 2000 105 680 6683 Immunosuppression and Merkel cell carcinoma Buell JF Trofe J Hanaway MJ Beebe TM Gross TG Alloway RR First MR Woodle ES Transplantation Proceedings 2002 34 1780 1781 10.1016/S0041-1345(02)03065-8 12176573 Merkel cell carcinoma arising after therapeutic immusuppression Gooptu C Woollons A Ross J Proce M Wojnarowska F Morris PJ Bunker CB British Journal of Dermatology 1997 137 637 641 9390346 Merkel cell carcinoma and HIV infection Engels EA Frisch M Goedert JJ Biggar RJ Miller RW Lancet 2002 359 497 498 10.1016/S0140-6736(02)07668-7 11853800 Early aggressive treatment for Merkel cell carcinoma improves outcome Kokoska ER Kokoska MS Collins BT Stapleton DR Wade TP Am J Surg 1997 174 688 693 10.1016/S0002-9610(97)00193-1 9409598 Merkel cell carcinoma: important aspects of diagnosis and management Linjawi A Jamison WB Meterissian S Am Surg 2001 67 943 947 11603550 Epidemiology of primary Merkel cell carcinoma in the United States Agelli M Clegg LX J Am Acad Dermatol 2003 49 832 841 10.1016/S0190-9622(03)02108-X 14576661 Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases Medina-Franco H Urist MM Fiveash J Heslin MJ Bland KI Beenken SW Ann Surg Oncol 2001 8 204 208 11314935 Neuroendocrine carcinoma within lymph nodes in the absence of a primary tumor, with special reference to Merkel cell carcinoma Eusebi V Capella C Cossu A Rosai J Am J Surg Pathol 1992 16 658 666 1530107 Lymph node Merkel cell carcinoma with no evidence of cutaneous tumor--report of two cases Ferrara G Ianniello GP Di Vizio D Nappi O Tumori 1997 83 868 872 9428924 Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival Gillenwater AM Hessel AC Morrison WH Burgess M Silva EG Roberts D Goepfert H Arch Otolaryngol Head Neck Surg 2001 127 149 154 11177031 Trabecular (Merkel cell) carcinoma of the skin. Treatment of primary, recurrent, and metastatic disease Raaf JH Urmacher C Knapper WK Shiu MH Cheng EW Cancer 1986 57 178 182 3940617 Merkel cell carcinoma Hanke WC Conner AC Temofeew RK Lingeman RE Arch Dermatol 1989 125 1096 1100 10.1001/archderm.125.8.1096 2757407 Primary neuroendocrine (Merkel cell?) carcinoma of the skin. I. A clinicopathologic and ultrastructural study of 43 cases Sibley RK Dehner LP Rosai J Am J Surg Pathol 1985 9 95 108 2579594 Merkel cell tumor. A chemosensitive skin cancer Wynne CJ Kearsley JH Cancer 1988 62 28 31 3383119 Is aggressive surgical management justified in the treatment of Merkel cell carcinoma? Shack RB Barton RM DeLozier J Rees RS Lynch JB Plast Reconstr Surg 1994 94 970 975 7661915 Merkel cell carcinoma of the head and neck: a retrospective case series Brissett AE Olsen KD Kasperbauer JL Lewis JE Goellner JR Spotts BE Weaver AL Strome SE Head Neck 2002 24 982 988 10.1002/hed.10153 12410532 Merkel cell carcinoma O'Connor WJ Brodland DG Dermatol Surg 1996 22 262 267 10.1016/1076-0512(95)00580-3 8599738 Endocrine carcinoma of the skin (Merkel cell carcinoma) Silva EG Mackay B Goepfert H Burgess MA Fields RS Pathol Annu 1984 19 Pt 2 1 30 6209606 Radiolocalization of the sentinel lymph node in Merkel cell carcinoma: a clinical analysis of seven cases Ames SE Krag DN Brady MS J Surg Oncol 1998 67 251 254 10.1002/(SICI)1096-9098(199804)67:4<251::AID-JSO8>3.0.CO;2-7 9579373 Early experience with sentinel lymph node mapping for Merkel cell carcinoma Rodrigues LK Leong SP Kashani-Sabet M Wong JH J Am Acad Dermatol 2001 45 303 308 10.1067/mjd.2001.114749 11464197 Applicability of the sentinel node technique to Merkel cell carcinoma Wasserberg N Schachter J Fenig E Feinmesser M Gutman H Dermatol Surg 2000 26 138 141 10.1046/j.1524-4725.2000.99213.x 10691943 Reliability of sentinel lymph node biopsy for regional staging of head and neck merkel cell carcinoma Schmalbach CE Lowe L Teknos TN Johnson TM Bradford CR Arch Otolaryngol Head Neck Surg 2005 131 610 614 10.1001/archotol.131.7.610 16027284 [Cervicofacial involvement of primary cutaneous neuroendocrine carcinomas or Merkel cell tumors: therapeutic considerations] de Mortillet S Laurent B Fassio E Zimmann F Bonin B Brie J Goga D Ballon G Rev Stomatol Chir Maxillofac 1995 96 33 35 7899811 Merkel cell tumour: clinical behaviour and treatment Shaw JH Rumball E Br J Surg 1991 78 138 142 2015460 Merkel cell cancer: is prophylactic lymph node dissection indicated? Victor NS Morton B Smith JW Am Surg 1996 62 879 882 8895705 Surgical management of Merkel cell carcinoma Allen PJ Zhang ZF Coit DG Ann Surg 1999 229 97 105 10.1097/00000658-199901000-00013 9923806 Essentials of Mohs micrographic surgery Cottel WI Bailin PL Albom MJ Bernstein G Braun M Hanke CW Sutnick TB Swanson NA J Dermatol Surg Oncol 1988 14 11 13 3275699 Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation Boyer JD Zitelli JA Brodland DG D'Angelo G J Am Acad Dermatol 2002 47 885 892 10.1067/mjd.2002.125083 12451374 Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients O'Connor WJ Roenigk RK Brodland DG Dermatol Surg 1997 23 929 933 10.1016/S1076-0512(97)00292-6 9357504 Transient complete remission of metastasized Merkel cell carcinoma by high-dose polychemotherapy and autologous peripheral blood stem cell transplantation Waldmann V Goldschmidt H Jackel A Deichmann M Hegenbart U Hartschuh W Ho A Naher H Br J Dermatol 2000 143 837 839 10.1046/j.1365-2133.2000.03852.x 11069467 Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma Voog E Biron P Martin JP Blay JY Cancer 1999 85 2589 2595 10.1002/(SICI)1097-0142(19990615)85:12<2589::AID-CNCR15>3.0.CO;2-F 10375107 Merkel cell carcinoma: a case series of twelve patients and review of the literature Samonis G Mantadakis E Kononas TC Rigatos SK Stathopoulos GP Anticancer Res 2001 21 4173 4177 11911314 The use of cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of Merkel cell carcinoma Fenig E Lurie H Sulkes A Am J Clin Oncol 1993 16 54 57 8424405 Radiation sensitivity of Merkel cell carcinoma cell lines Leonard JH Ramsay JR Kearsley JH Birrell GW Int J Radiat Oncol Biol Phys 1995 32 1401 1407 10.1016/0360-3016(94)00610-W 7635780 Management of Merkel cell tumour Bourne RG O'Rourke MG Aust N Z J Surg 1988 58 971 974 3202731 The standard of care for Merkel cell carcinoma should include adjuvant radiation and lymph node surgery Herbst A Haynes HA Nghiem P J Am Acad Dermatol 2002 46 640 642 10.1067/mjd.2002.119667 11907528 Adjuvant locoregional radiotherapy as best practice in patients with Merkel cell carcinoma of the head and neck Veness MJ Morgan GJ Gebski V Head Neck 2005 27 208 216 10.1002/hed.20134 15627249 Merkel cell carcinoma: improved outcome with adjuvant radiotherapy Veness MJ Perera L McCourt J Shannon J Hughes TM Morgan GJ Gebski V ANZ J Surg 2005 75 275 281 10.1111/j.1445-2197.2005.03353.x 15932436 Radiotherapy alone for primary Merkel cell carcinoma Mortier L Mirabel X Fournier C Piette F Lartigau E Arch Dermatol 2003 139 1587 1590 10.1001/archderm.139.12.1587 14676075 The role of radiotherapy in the management of primary cutaneous neuroendocrine tumors (Merkel cell or trabecular carcinoma): experience at the Peter MacCallum Cancer Institute (Melbourne, Australia) Pacella J Ashby M Ainslie J Minty C Int J Radiat Oncol Biol Phys 1988 14 1077 1084 3384714