Merkel Cell Carcinomas

Hematol Oncol Clin N Am 21 (2007) 527–544

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

Merkel Cell Carcinomas Vy Dinh, MDa, Lynn Feun, MDb,*, George Elgart, MDc, Niramol Savaraj, MDd a

Department of Internal Medicine, University of Miami School of Medicine, 1600 NW 12 Avenue, Miami, FL 33136, USA b Division of Hematology and Oncology, University of Miami School of Medicine, 1475 NW 12th Avenue, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA c Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1444 NW 9th Avenue, 3rd floor, Miami, FL 33136, USA d Division of Hematology and Oncology, University of Miami School of Medicine, 1201 NW 16th Street, Room D1010, Veterans Affairs Medical Center, Miami, FL 33125, USA

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erkel cell carcinoma (MCC) is a rare but extremely aggressive malignancy of the skin. The cell of origin, the Merkel cell, was first described by Friedrich S. Merkel in 1875 as ‘‘clear cells’’ at the epidermal layer of the skin [1]. At that time, it was thought that the cell was a primary touch receptor. In 1978, Toker detected electron-dense neurosecretory granules in cytoplasm of what he called ‘‘trabecular cell carcinoma’’ cells. These granules are common in Merkel cells as well as in neuroendocrine cells [2]. A few years later, Wolff-Peeters and colleagues [3] proposed the name ‘‘Merkel cell carcinoma.’’ Today, it is generally believed that MCC originates from a neuroendocrine cell that is found within the basal layer of the epidermis and functions as slowly adapting type I mechanoreceptors [4,5]; however, others believe that the tumor emerges from a cell that is of epidermal origin (eg, keratinocytes) [6]. With such controversy over the origin of this tumor, many names have been proposed, such as primary neuroendocrine cancer of the skin, small cell carcinoma of the skin, small cell undifferentiated carcinoma, cutaneous small cell tumor, and anaplastic cancer of the skin. EPIDEMIOLOGY MCC is a rare skin malignancy. Approximately 2000 cases have been reported in the last 3 decades. In the Surveillance, Epidemiology, and End Results (SEER) database (representing nine areas of the United States or about 10% of the total population), about 470 cases were reported from 1986 to 1994 [7]. The annual incidence per 100,000 population when adjusted for age is 0.23 for whites and 0.01 for blacks. When compared with melanoma, the ratio is about 65 to 1 among whites. When data are extended to 2001, the overall *Corresponding author. E-mail address: [email protected] (L. Feun). 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.04.008

ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com

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incidence increases from 0.15 to 1.44 cases per 100,000 population; however, this increase may be due to better diagnostic capabilities or to the discovery of new biomarkers [8]. In another study by Agelli and Clegg [9], data from the SEER database were analyzed from 11 geographic areas (about 14% of the population). The median age of patients in these reported cases was 73 years for males and 76 years for females. The incidence in the elderly (patients over 65 years of age) is 15 times higher than the incidence in patients younger than 65 years. In total, the elderly population comprises 76% of reported cases. When comparing the sexes, MCC seems to have predominance in males, with a ratio of 1.5 to 2:1 in all ethnic groups. Among different ethnic groups, whites have the highest incidence overall at 94% of the cases, which is 11 times the incidence in blacks. This finding may indicate that darker skin can provide some level of protection against MCC. An interesting observation was made among immunocompromised patients in whom MCC developed. In patients who had undergone organ transplantation, the mean age of diagnosis was about 10 years earlier when compared with patients who were not immunocompromised. Among organ transplant patients, 29% were less than 50 years of age compared with a 5% overall incidence in the general population [10]. There have also been several case reports of MCC developing in HIV-infected patients [11–18]. In many of these patients, MCC developed before the diagnosis of HIV, implying that the risk of disease is high even with moderate immunosuppression. The relative risk of MCC in HIV-infected patients is 13.4 when compared with the general population [14]. Other studies have reported MCC in patients with chronic lymphocytic leukemia as well [19]. CLINICAL PRESENTATION Initial presentations of MCC begin with a simple skin lesion noticed by the patient. The most common description is a solitary, red or blue, firm, nontender, dome-shaped nodule or indurated plaque [20,21]. The authors and others have also observed MCC arising in the subcutaneous fat with intact overlying skin [22]. Patients usually seek medical attention owing to the tendency for the malignancy to rapidly increase in size over a few weeks to months. MCC has been reported to appear on the face, neck, trunk, upper and lower limbs, and less frequently on mucosal anatomic sites (nasal, oral, pharyngeal, laryngeal) [23– 31]. There have been a few reports of occurrences in sun-protected areas such as the vulva [27–29], penis [30,31], or oral mucosa [32–34]. The most frequent sites are on sun-exposed areas, occurring on the head and neck in 50% of cases, on the extremities in 40% of cases, and on the trunk and genitals in the last 10% of cases [23–26]. In males aged less than 65 years, there seems to be a predilection for MCC on the trunk and limb when compared with older males [9]. Tumor size is usually less than 20 mm, but the lesions are known to range from as little as 2 mm to as large as 200 mm [7]. Although MCC seems to have a predilection for areas most vulnerable to sun damage, sun exposure has not yet been proved to be a definite risk factor.

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In a review of 1024 cases, 13% of patients with MCC also had a history of other diseases associated with UV radiation, mainly squamous cell carcinoma of the skin [35]. In the study by Penn and First [10], 91% of immunosuppressed patients with MCC who also had a second malignancy had squamous cell carcinoma. MCC is an aggressive tumor. It frequently spreads to the skin (28%), lymph nodes (27%), liver (13%), lung (10%), bones (10%), and brain (6%) [36]. There is even one case of a patient with metastases to the leptomeninges [37]. The skin and lymph nodes account for almost 60% of metastases [36]. If local symptoms develop, they are due to tumor growth or involvement of the lymph nodes. There have been reported cases in which MCC has led to superior vena cava syndrome [38,39] or paraneoplastic complications (eg, Lambert-Eaton syndrome) [40,41]. ETIOLOGY Because MCC is a rare malignancy, little is known about the etiologic causes of the disease. Like other skin malignancies, it has been associated with sun exposure owing to its preference for vulnerable areas of the skin [42]. The face, neck, and extremities are the most frequent sites. There is a correlation between the incidence of MCC and an increasing solar ultraviolet B (UVB) index as measured in different regions of the United States. This trend mirrors exactly that for melanoma [43]. Further evidence to strengthen the correlation between MCC and sun exposure includes an association with a p53 mutation known to be caused by UVB [44]. Another study detected an increased incidence of MCC in patients who had been treated with methoxsalen and UVA for psoriasis [45]. Arsenic exposure has also been suggested as a cause of MCC [46,47]. Immunosuppression seems to have a role in MCC as well. Of the reports in which data on immunosuppressive therapy were included, 15% of the patients were immunosuppressed secondary to HIV infection [35] or were undergoing therapy for other diseases such as rheumatoid arthritis or autoimmune hepatitis [48,49]. In the Cincinnati Tumor Registry, 41 cases were reported in patients after organ transplantation [10]. Other cases include a bone transplant patient [50] and chronic lymphocytic leukemia patients [19,51]. The mean age at diagnosis for immunosuppressed patients is about 10 years earlier (53 years) when compared with patients who are not immunocompromised. In transplant patients, the disease appears from 5 to 286 months after the transplant is performed. When the disease develops in immunosuppressed patients, it seems to be more aggressive, with more than 60% of patients progressing to lymph node metastases and about 56% eventually dying [10]. MOLECULAR ASPECTS Many chromosomal abnormalities have been proposed in MCC. One suggestion is a deletion on the short arm of chromosome 1 (1p36) that has been frequently associated with MCC [52,53]. A gene for p73, a protein that is similar to the tumor suppressor p53, has been found in that region and has frequently

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been suggested to be the gene responsible for MCC; however, a recent study searching for this mutation found that only 1 of 10 MCC patients had an abnormal p73 gene [44]. A mutant p53 tumor suppressor protein has also been implicated with MCC. In one study, it was identified in six of nine patients who had a poor clinical outcome. The mutation was not found in any of the ten patients who had a better prognosis [54]. Another possibility is the loss of heterozygosity in chromosome 3p21, an area where the ras association domain family 1 gene is suspected to be located [55]. This abnormality is important in the consideration of MCC, because this region is affected in 90% of small cell lung cancer, which is also of neuroendocrine origin and, like MCC, is identified on histology as small blue cells [56,57]. PATHOLOGY MCC has been and remains a significant challenge in skin pathology because of its technical assessment from a pathology standpoint and because of the complicated issues brought forth from a clinical perspective. This issue represents one of the major new challenges in dermatopathology. From its first description by Toker, it has been recognized that MCC is a complex entity with potentially serious consequences [2]. As is true for nearly all skin tumors, the vast majority of MCCs are diagnosed in a straightforward fashion employing only routine histology with hematoxylin and eosin. Most experts will additionally perform immunohistochemistry to confirm the diagnosis. The vast majority of examples of this tumor simply demonstrate a mid to upper dermal aggregate of dense or more dispersed tumor cells. Obvious features include the intense basophilic staining (Fig. 1) of the tumor and the prominent nuclear characteristics. Beyond the obvious blue-staining tumor aggregates in the dermis, it is useful to consider the nuclear features. Most nuclei have a dispersed pattern of chromatin and nucleoli that are not at all prominent, a feature that may be useful in differential diagnosis. Mitoses are prominent, and beyond metaphase examples

Fig. 1. Dense basophilic staining of MCC (hematoxylin-eosin, original magnification 40).

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may include ‘‘starburst’’ or other unusual patterns. Nuclear membranes are often distinct, and the nuclei are generally large, usually two to three times the size of a mature lymphocyte. Also distinctly common is the tendency to observe zones of necrosis or individual necrotic cells. Most examples are notable for dense collections of dark nuclei with inconspicuous cytoplasm and prominent nuclear molding (Fig. 2). Crush artifact at the margins of incompletely excised specimens is a routine feature [58]. Although most cases demonstrate a purely dermal process, occasional examples show the tumor extending to the base of the epidermis or uncommonly entering into it in an ‘‘epidermotropic’’ or ‘‘pagetoid’’ pattern [59]. These unusual examples of an intraepidermal ‘‘epithelioma-like’’ presentation or ‘‘Borst-Jadassohn phenomenon’’ can lead to challenges in differential diagnoses. Fortunately, these examples are unusual. Of more routine use is the observation of the extension of the lesion in irregular branches into the surrounding dermis at the margins of the tumor. These extensions are the ‘‘trabeculae’’ observed by Toker. Squamous differentiation, which may be interpreted as overlying or colliding examples of squamous cell carcinoma, is reported too commonly to discount [60]; therefore, basaloid collections seen along with apparent squamous cell carcinoma of the skin are a suggestive sign that may lead to early diagnosis of MCC. Because MCC is so avid for hematoxylin staining, the differentiation of a suspected case may bring up several entities, which routinely or occasionally demonstrate confounding features. Basal cell carcinoma is so commonly seen in pathology laboratories that its familiarity may lead to difficulty in appreciating the considerably more rare entity of MCC. This difficulty is compounded by the common practice of sampling skin tumors by the ‘‘shave’’ technique, which provides an inadequate sample size for an accurate pathologic diagnosis. Beyond basal cell carcinoma, the foremost entities requiring differentiation

Fig. 2. Prominent nuclear molding, dispersed chromatin, and high mitotic index in MCC (hematoxylin-eosin, original magnification 400).

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include neural tumors such as neuroblastoma, primary peripheral primitive neuroectodermal tumors, and small cell variants of melanoma as well as hematologic malignancies. In addition, historically, it has been at times impossible to differentiate MCC from metastatic undifferentiated (oat cell) carcinoma of pulmonary origin. Immunohistochemistry is routinely applied to most cases of MCC to separate these challenging differential considerations. The mainstay of diagnosis for MCC routinely includes employment of immunohistochemical techniques to differentiate the entities mentioned previously. Historically, neuron-specific enolase has widely used because its presence is common in MCC and not generally appreciated in basal cell carcinoma [61]; however, that stain is of inconstant expression even in known cases of MCC and is occasionally positive in oat cell carcinomas and other entities of differential diagnostic significance. Recently, there has been great interest in the use of specific keratin antibodies to separate a variety of epithelial malignancies. Of particular importance is the unique staining pattern appreciated in most cases of MCC. These tumors routinely demonstrate staining with low molecular weight keratins, especially keratin 20, with an unusual aggregation of these keratins forming a clump adjacent to the nucleus [62,63]. This ‘‘perinuclear dot’’ pattern (Fig. 3) is highly characteristic and is uncommon or unheard of in virtually all of the differential considerations [64]. Cytokeratin 20 staining may be combined with several other common antibody stains and can confirm the diagnosis of MCC with a high level of clinical certainty [65]. Interestingly, these aggregates of keratin adjacent to the nucleus were appreciated ultrastructurally by Kuhajda and colleagues [66]; however, the availability of specific antibodies to the different keratin proteins and the appreciation that these could be employed in tumor differentiation awaited the work of Moll and Franke [67]. This important work represented a landmark not only with regard to MCC but also in the differentiation of many epithelial malignancies and

Fig. 3. Perinuclear dot pattern in cytokeratin 20–stained section (cytokeratin 20, original magnification 100).

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metastatic tumors in skin and other organs. Current use generally employs a panel of antibodies directed at cytokeratin 20, thyroid transcription factor 1, and other markers (Table 1) to confirm the diagnosis or eliminate differential considerations [68]. DIAGNOSIS The first step after detection of the skin lesion is an incisional or excisional biopsy. The specimen is then sent to histopathology for diagnosis. Most clinicians then recommend a wide surgical resection of the primary lesion, usually with 2- to 3-cm margins. Patients who have evidence of regional disease as well undergo a lymph node dissection. For patients with evidence of local disease only, many clinicians still advocate elective lymph node dissection (ELND), because MCC is found in the regional lymph nodes in 10% to 30% of patients who undergo lymph node dissection at the time of initial presentation [20,21]. With ELND, all lymph nodes are excised in the search for any possible disease in the lymph nodes; however, this technique carries with it a certain level of morbidity, especially when it involves the axillary lymph nodes. Complications include infection, pain, numbness, hemorrhage, and postoperative lymphedema [69]. Because it has proved useful for the staging of melanoma, some clinicians have advocated for sentinel lymph node biopsy (SLNB) as part of the management of MCC [68,70]. After an intradermal injection of a technetium-labeled sulfur colloid with or without a blue dye, a gamma probe is used to search transcutaneously for the area of highest radioactive intensity—the area of the sentinel node. Next, surgical excision commences in search of the sentinel node. The blue dye, if used in addition to the colloid, serves to ensure that the gamma probe is accurate. In many studies, this technique has proven to have less morbidity and to be more effective than ELND. On the other hand, this technique is more difficult to perform, and accuracy is dependent Table 1 Immunohistochemical analysis of Merkel cell carcinoma Antibody

Specificity

Clinical use

Cytokeratin 20 CD 117 (c-kit receptor) Thyroid transcription factor 1 Neuron-specific enolase Chromogranin

MCC Many tumors Lung cancer

Neurofilament protein Synaptophysin

Many MCC Seen in some MCC

CAM 5.2 Neural cell adhesion molecule CD56

Positive in nearly all MCC Highly expressed in MCC

Confirm MCC Common in MCC Exclude metastatic oat cell carcinoma Confirm MCC Seen in most MCC and oat cell carcinoma Usually negative in SCCA May be associated with better outcome Perinuclear dot pattern Confirm MCC

Positive in most MCC Neuroendocrine tumors

Abbreviation: SCCA, small cell lung cancer.

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on the familiarity of surgeons, pathologists, and nuclear medicine technicians with SLNB [71]. The histology of the sentinel lymph node seems to be a good predictor of regional lymph node status; therefore, it may help in selecting those patients most appropriate for a therapeutic lymph node dissection [69,72]. For the evaluation of distant disease, patients should undergo CT or MRI of the chest, abdomen, and pelvis. Imaging of the chest is especially important to exclude a lung mass to rule out small cell lung cancer, which can metastasize to skin [73]. As is true for other cancers, positron emission tomography (PET) has proven useful to stage MCC and for follow-up after chemotherapy [74–77]. In a few cases, PET was able to detect other sites of disease that were not detectable via CT scan [75]. In 1992, Kwekkeboom and colleagues noted the presence of somatostain receptors on MCC cells; therefore, octreotide scintigraphy, a procedure used more commonly for the staging and treatment of gastrointestinal and endocrine tumors, has been proposed as another way of detecting metastatic disease in patients who have MCC. Images are collected after the injection of a somatostatin analogue called octreotide. Any area that shows increased uptake is suspicious for metastatic disease. Several studies suggest the improved sensitivity of octreotide scintigraphy in the detection of primary MCC and its metastases. In the future, octreotide may be useful for therapeutic reasons as well [78,79]. STAGING When patients present with MCC, the majority of them (70%–80%) have localized disease. Less than one third have involvement of the lymph nodes, and less than 5% have distant metastases at presentation. There is not yet a general consensus on the appropriate staging system, but the one suggested by Yiengpruksawan and colleagues [20] has been used most widely. Stage I is considered localized skin disease and is subdivided into IA with tumors 2 cm or less and IB for tumors greater than 2 cm. Stage II is regional lymph node disease, and stage III is metastatic disease beyond the regional lymph nodes. In recent reviews of the literature, the 5-year survival rate for patients with stage I disease is 64%, with a median survival of 30 months for stage IA and 26 months for stage IB. For stage II disease, the survival rate is 46% with a median survival of 18 months. For stage III disease, the median survival is 5 months with no survivors at 5 years [7,20]. PROGNOSIS When the disease was initially described, it was believed that MCC was a malignancy with a relatively good prognosis because a small percentage of patients died of the disease; however, throughout the years, it has proven to be as aggressive a disease as small cell lung cancer and melanoma when rates of recurrence, metastatic spread, and mortality are compared [7]. The overall recurrence rate of MCC is 55% to 79%, most often at the site of the primary lesion or in the lymph nodes [20,21,24,80,81]. Most recurrences appear within the first 6 to 12 months

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after initial diagnosis [7]. Favorable prognostic factors include a location of the primary tumor on the head and neck, a lack of lymph node involvement, tumors 2 cm or less in size, and female sex [20,21,24,42,82,83]. In addition, the magnitude of lymphatic involvement and the depth of invasion are strong predictors of disease outcome [64]. The long-term prognosis is poor, but when MCC is treated aggressively with surgery and locoregional radiotherapy, patients can have a 50% chance of cure [84]. TREATMENT Currently, there is no consensus on the appropriate mode of treatment for MCC owing to its rarity and the lack of patients for a randomized, prospective trial to compare different modalities. With local disease, the treatment of choice is surgical resection with margins of 2 to 3 cm [20,82,85]; however, this margin is not ideal in certain areas such as the face, where wide margins would affect function as well as esthetic appearance. Recent evidence suggests that Mohs micrographic surgery is even more effective at controlling local disease [86–89]. This type of surgery inspects 100% of all major borders, including the deep margins. Because MCC tends to invade vertically (even into muscle), the surgery can detect and remove the tumor more completely. This method reduces the margins from 3 cm to only 1.5 cm [88,89]. Radiotherapy after Mohs surgery may decrease the risk of recurrence, especially in cases in which complete resection can not be obtained [86,88,89]. The value of lymph node dissection, whether ELND or SLNB, needs to be determined. Because the prognosis of MCC is poor owing to its aggressive tendency to metastasize despite surgical countermeasures, searching for early nodal disease would, in theory, prevent the development of distant disease. In one study, 35 patients were treated with either surgical excision alone or excision with locoregional therapy. In the group with only excision, there was a 65% recurrence rate and a 29% mortality rate. In contrast, in the group who also had lymph node dissection, the recurrence rate was 27% and the mortality rate 14% [90]. The controversy lies with the choice of either ELND or SLNB. ELND has been useful for detecting occult nodal metastases [21] but involves a high degree of morbidity. SLNB has proven to eliminate some of the side effects of ELND with comparable rates of detection [71], but further studies are needed to determine its usefulness. Surgical resection, in general, decreases local recurrence but has not been proven to improve survival [82]. Surgery alone has been shown to be associated with a high recurrence rate [80,91]; therefore, other modalities are being studied as adjuncts to surgery. Published studies show that neuroendocrine tumors are readily responsive to radiotherapy; therefore, it has been proposed that radiotherapy should have an important role in the treatment of MCC. Nevertheless, there are mixed reviews of local radiotherapy. Although some evidence in the literature suggests that radiotherapy prolongs survival in MCC patients [82,91–94], not enough patients have been studied to render an adequate conclusion. Retrospective analysis of clinical data strongly suggests

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that radiotherapy, in the least, can obtain locoregional control; 89% of patients were without evidence of local recurrence after radiotherapy compared with 47% of patients who did not receive adjuvant radiation [35]. A dose of 46 to 50 Gy at 2 Gy per fraction to the tumor bed and draining lymphatics is usually employed [7]; however, some studies have reported marginal recurrence despite radiation at this dose [95]. It has also been suggested that one include nodal basins in the area to be radiated in the effort to decrease the dose of total radiation and chemotherapy; however, the effectiveness of this approach has not yet been proved [35]. In addition to being considered as adjuvant therapy, radiation alone is considered definitive therapy for patients who are not suitable for gross total resection or for patients who have an incomplete macroscopic resection [84]. Although MCC is thought to be a chemosensitive tumor [96], the role of chemotherapy in treatment is not yet clear. One problem is the lack of patients to enroll into a prospective, randomized clinical trial. MCC is so rare that it is difficult to recruit participants in a study. In addition, many patients with MCC are elderly and may not be able to tolerate aggressive chemotherapy [97]. Patients who have gone through chemotherapy are usually those who have failed or have not qualified for surgery with radiotherapy and chemotherapy was the last resort. Chemotherapy is also considered for patients who present with such advanced disease that resection is not possible. In published studies, approximately 200 patients with MCC have been treated with this modality. The drugs most commonly used are those given for small cell lung cancer and neuroendocrine tumors [96,98]. These drugs include etoposide plus cisplatin and cyclophosphamide plus doxorubicin plus vincristine. Table 2 [99–103] summarizes the different regimens that have been used for MCC. In the study by Poulsen and colleagues [104], 53 patients with high-risk localized MCC were enrolled in a prospective study to evaluate the effectiveness of carboplatin and etoposide as adjuvant therapy. Each patient underwent resection followed by chemotherapy concurrently with radiation. The 3-year overall survival rate was 76%. Locoregional control was found to be 75% and distant control was 76%. Tai and colleagues [105] performed a review of 204 cases from published studies analyzing their responses to chemotherapy. With the regimen containing cyclophosphamide, doxorubicin (or epirubicin), and vincristine, with or without prednisone, the response rate was 75.7% with a total of 47 cases. Etoposide and cisplatin (or carboplatin) was associated with a response rate of 60% in 27 cases. The median overall survival for all 204 patients was 21.5 months, with only 17% alive at 5 years. In general, overall response rates have been high with chemotherapy, but the long-term prognosis is still poor. Chemotherapy may have a role in the treatment of high-risk patients with extensive local disease, but randomized controlled trials are needed to determine this. Other research is focusing on alternative agents for treatment. A few studies have been conducted with interferon [106–109] and tumor necrosis factor (TNF) [108,110,111] as biologic agents against MCC. Direct injection of

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Table 2 Chemotherapy regimens used in Merkel cell carcinoma Study

Regimens

Feun et al, 1988 [97]

CAV  DIC DC þ DIC MTX þ DDP þ BLEO Cyclophosphamide þ vincristine þactinomycin CMF EP Etoposide alone CAV EP

Fenig et al, 1997 [99]

Pectasides et al, 1995 [100] Boyle et al, 1995 [80]

Raaf et al 1986 [25]

Grosh et al, 1987 [101] Crown et al, 1991 [102] Bourne et al, 1988 [103] Wynne et al, 1988 [96]

Etoposide þ carboplatin Etoposide CAV or cyclophosphamide þ epirubicin þ vincristine Chlorambucil 5-FU þ STZ STZ þ doxorubicin 5-FU DC þ vincristine DC  vincristine  prednisone DC þ vincristine þ prednisone DC þ vincristine  prednisone

Number of patients

Overall response rate (%)

4 2 2 1

100 100 100 0

10 10 4 2 3

60 60 100 50 66

3 7 6

66 57 33

3 1 2 1 4 6

33 100 100 0 50 66

4

100

3

100

Abbreviations: BLEO, bleomycin; CAV, cyclophosphamide/doxorubicin/vincristine; DC, doxorubicin/cyclophosphamide; DDP, cisplatin; DIC, imidazole carboxamide; EP, etoposide/cisplatin; 5-FU, 5-fluorouracil; MTX, methotrexate; STZ, streptozotocin.

TNF into the tumor offers some promise in achieving local control without recurrence of disease [110,111]. Other potential agents in the treatment of MCC include farnesylthiosalicylic acid, a nerve growth factor that inhibits the ras signal transduction [112], and bcl-2 antisense oligonucleotides [113–116] that prevent the resistance of tumor cells to apoptosis. These agents have only been tested on severe combined immunodeficient mice. An ongoing phase II Intergroup trial is in progress studying the effect of imatinib mesylate in metastatic or unresectable MCC [117]. Imatinib is an inhibitor of the BCR-ABL and other tyrosine kinases that are responsible for the deregulation of intracellular signaling. The tyrosine kinases are responsible for the strengthened capability of tumor cells to proliferate and their ability to resist apoptosis [118]. As an inhibitor of these tyrosine kinases, imatinib can halt a cancer cell’s ability to multiply. Studies have shown that this drug is effective for malignancies such as chronic myeloid leukemia [119,120]. Further

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research has shown that imatinib can also inhibit the tyrosine kinase activity of ARG, c-kit, PDGFR a, and PDGFR b [121,122]. The drug has demonstrated significant antitumor activity in gastrointestinal stromal tumors that are c-kit positive [123,124]. MCC has been shown to also express c-kit; therefore, imatinib offers some hope for another therapeutic option for this disease. DISCUSSION MCC is a rare skin cancer that arises from primary neural cells. It affects less than 500 people in the United States annually. Etiologic factors seem to be sun exposure and immunosuppression. Pathologically, MCC should be distinguished from extrapulmonary small cell lung cancer or metastatic small cell lung cancer or a small cell variant of melanoma. Immunohistochemical staining for S100, thyroid transcription factor 1, CK20, and CK7 is useful to aid in diagnosis. A disease that was once thought to be easily treated with simple excision, MCC is now known to be an extremely aggressive and lethal disease. At initial presentation, the disease often involves the regional lymph nodes and has a significant potential for hematogenous spread. The prognosis is based largely on the stage of disease at the time of presentation. Staging work-up includes CT or MRI scans. Other scanning techniques such as PET or octreotide scans may also be useful. Treatment for MCC is wide excision of the primary tumor. Sentinel lymph node mapping and biopsy may provide useful information about the prognosis and need for lymph node dissection. Although randomized, controlled trials are lacking, adjuvant radiotherapy to the regional lymph nodes may improve local control and survival. Chemotherapy is useful for palliative treatment of advanced disease; however, the disease usually recurs afterwards and can be rapidly fatal. Its role in the adjuvant setting has not been established. Novel therapies based on the understanding of the molecular aspects of MCC offer hope in the treatment of this rare but aggressive disease. References [1] Moll I, Roessler M, Brandner JM, et al. Human Merkel cells—aspects of cell biology, distribution and functions. Eur J Cell Biol 2005;84(2–3):259–71. [2] Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105(1):107–10. [3] De Wolff Peeters C, Marien K, Mebis J, et al. A cutaneous APUDoma or Merkel cell tumor? A morphologically recognizable tumor with a biological and histological malignant aspect in contrast with its clinical behavior. Cancer 1980;46(8):1810–6. [4] Winkelmann RK, Breathnach AS. The Merkel cell. J Invest Dermatol 1973;60:2–15. [5] Pinkus F. Uber einen bisher unbekannten Nebenapparat am Haarsystem des Menschen: Haarscheiben. Dermatologische Zeitschrift 1902;9:465–9. [6] Moll I, Zieger W, Schmelz M. Proliferative Merkel cells were not detected on human skin. Arch Dermatol Res 1996;288:184–7. [7] Goessling W, McKee P, Mayer R. Merkel cell carcinoma. J Clin Oncol 2002;20(2): 588–98. [8] Hodgson N. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2004;89(1): 1–4. [9] Agelli M, Clegg L. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49(5):832–41.

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