Annals of Surgical Oncology Cite Track
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
10.1245/s10434-006-9327-y
Annals of Surgical Oncology 14:1943-1952 (2007)
© 2007 Society of Surgical Oncology
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jabbour, J.
Right arrow Articles by Lee, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jabbour, J.
Right arrow Articles by Lee, S.

Original Article

Merkel Cell Carcinoma: Assessing the Effect of Wide Local Excision, Lymph Node Dissection, and Radiotherapy on Recurrence and Survival in Early-Stage Disease—Results From a Review of 82 Consecutive Cases Diagnosed Between 1992 and 2004

James Jabbour, BSc(Med), MBBS, MPH1,2,3,4, Robert Cumming, MBBS, MPH, PhD2,5, Richard A. Scolyer, MD, FRCPA1,6,7,8, George Hruby, MBBS, FRANZCR7,9, John F. Thompson, MD, FRACS7,8 and Stephen Lee, MBBS, FACD10,11

1 Sydney Cancer Centre, Sydney, Australia
2 School of Public Health, University of Sydney, Sydney, Australia
3 St. Vincent’s Hospital, Sydney, Australia
4 Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia
5 Centre for Research in Aging (CERA), Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia
6 Department of Anatomical Pathology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
7 Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
8 Melanoma and Skin Cancer Research Institute (MASCRI), Sydney, Australia
9 Department of Radiation Oncology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
10 Department of Dermatology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia
11 Department of Dermatology, Concord Repatriation General Hospital, Hospital Road, Concord, NSW 2139, Australia

Correspondence: Address correspondence and reprint requests to: James Jabbour, BSc(Med), MBBS, MPH; 16 Kingsland Rd., Strathfield, New South Wales 2135, Australia; E-mail: j.jabbour{at}optusnet.com.au


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Wide surgical excision, lymph node dissection, and radiotherapy have been used with varying efficacy in the management of early-stage Merkel cell carcinoma.

Methods: Records of 82 patients with early-stage Merkel cell carcinoma between 1992 and 2004 were reviewed.

Results: Forty-two patients developed a recurrence, and 44 died during the study period. Twenty-nine patients presented with regional lymph node disease, which was independently associated with diminished survival (hazard ratio [HR], 4.08; 95% confidence interval [CI], 1.55–10.75; P = .005). Lymphadenectomy was independently associated with prolonged disease-free survival (median, 28.5 vs. 11.8 months; HR, .46; 95% CI, .22–.94; P = .034) but not overall survival (P = .25). Margin-negative excision of the primary tumor (60 of 73) was not significantly associated with either prolonged disease-free survival (median, 16 vs. 14 months) or overall survival (median, 54 vs. 34 months). Forty-eight patients received radiotherapy: 36 to the primary site and 31 to the regional lymph nodes. Radiotherapy to both sites was associated with a longer median time to first recurrence (primary site, 24.2 vs. 11.8 months; regional lymph nodes, 46.2 vs. 11.3 months) and survival (primary site, 53.9 vs. 45.7 months; regional lymph nodes, 103.1 vs. 34.2 months). Administration of any radiotherapy was significantly associated with a prolonged time to first recurrence (HR, .39; 95% CI, .20–.75; P = .004) and survival (HR, .39; 95% CI, .18–.82; P = .013) on the Cox regression multivariate analyses.

Conclusions: Adjuvant radiotherapy to the primary site after surgical excision is recommended in early-stage disease. Involved regional lymph nodes should be treated with radiotherapy with or without lymphadenectomy.

Key Words: Merkel • Radiotherapy • Margins • Survival • Recurrence • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Merkel cell carcinoma is a rare, potentially aggressive neuroendocrine tumor of the skin that has a high propensity for local, regional, and distant recurrence. It is mostly a disease of the elderly (median age, 67 years1–3), has a slight male preponderance,1–6 and predominantly affects sun-exposed areas of the body.1,7–11 Seventy-five percent of patients present with local disease, 22% with regional lymph node involvement, and 3% with metastatic disease.1,2,9,12–20 Ten to twenty percent of patients present solely with nodal disease and no primary tumor.1 Although spontaneous remissions have been reported,21 more than 50% of patients develop a regional and/or distant recurrence within a few years of diagnosis, particularly if the disease is left untreated.1,22 The reported 5-year survival rates range between 35% and 75%.1,8,13,18,22

The high rate of recurrence,1,20 the strong association between disease recurrence and mortality,11,13,23,24 and the orderly but rapid spread of disease7,9,24,25 have been the basis upon which oncologists have advocated early aggressive treatment.8 This retrospective consecutive case series sought to assess the effect of early treatment measures, such as wide surgical excision, lymphadenectomy, and radiotherapy, on recurrence and patient survival.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eighty-two consecutive patients with a histological diagnosis of Merkel cell carcinoma between January 1, 1992, and August 31, 2004, identified from the computerized records of the Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, were reviewed. Initially 94 patients were identified. Two patients were excluded because they were misclassified as having Merkel cell carcinoma, five because their diagnosis predated January 1, 1992, three because they were patients from abroad for whom no follow-up information was available, and two because they presented with metastatic disease.

The pathologic diagnosis was made on the basis of both characteristic histological features and immunohistochemical staining (positivity for neuroendocrine and cytokeratin markers). Patients were staged according the absence (stage I) or presence (stage II) of regional lymphadenopathy and the presence of systemic metastases (stage III). This staging system, devised by Yiengpruksawan et al.,12 and the one used by the Memorial Sloan-Kettering Cancer Center13,26 divide node-negative patients according to tumor size (≤ 2 or > 2 cm) because this was an independent predictor of survival in the Memorial Sloan-Kettering Cancer Center review.26

The information gathered for each patient included demographic data, medical history, and tumor- and treatment-related details. This data collection was approved by both the Royal Prince Alfred Hospital and Concord Hospital ethics review boards. Patients were followed up until the date of death or the censor date. The collected demographic and medical variables were age, sex, race, a history of immunosuppression or previous squamous cell skin cancers, and the presence of other significant clinical disease at the time of diagnosis. The last variable was graded according to the Charlson index—a validated weighted index of comorbid disease that seeks to measure the risk of mortality arising from causes other than the disease of interest.27–29

Tumor-related details included site, size, the presence of lymphatic invasion, the minimum margin (whether deep or lateral) on the pathology specimen, the cumulative minimum margin of excision after wide local re-excision of the primary site (the minimum distance from disease to the edge of the tissue added to the minimum distance from the scar to the edge of the tissue on the re-excised specimen), regional and distant lymph node status (established clinically, pathologically, or radiologically), the presence of metastases, and the date of recurrence. Lymph node staging was guided by the lymphatic drainage patterns described by Uren et al.30 from their extensive experience with lymphoscintigraphy.31 Other treatment-related variables documented were the timing, site, dose, type, and adverse effects of radiotherapy and whether lymphadenectomy or combination chemoradiotherapy was used. Radiotherapy fields with radial margins of at least 2 to 3 cm were directed to the primary site. Wherever feasible, the in-transit area and draining lymph nodes were included in the fields.

Overall and disease-free survival times were calculated from the date of histological diagnosis to the date of death (or censor date) and to the date of first recurrence (or censor date), respectively. Survival curves were generated by using SPSS software (SPSS Inc., Chicago, IL) according to the Kaplan-Meier method and compared by using the log-rank test and the univariate Cox proportional hazards regression model. Factors moderately associated (P < .30) with recurrence (or survival) were entered into a multivariate Cox regression analysis. Separate Cox multivariate regression analyses were performed for the subgroup of patients receiving radiotherapy either to the primary site or to the draining lymph nodes.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient- and Tumor-Related Characteristics
The median age at diagnosis was 72 years. There was a male predominance, and a large proportion of patients (34.1%) had a history of squamous cell cancer (Table 1Go). Fifty-six (68.2%) of 82 patients scored ≤ 1 on the Charlson index. A small proportion of patients (15.8%) had preexisting immunosuppression—most commonly long-term corticosteroid or cytotoxic therapy (e.g., methotrexate for rheumatoid arthritis).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Patient- and tumor-related characteristics of the 82 consecutive patients with stage I and II Merkel cell cancer forming the study samplea
 
The head was the most common site of primary disease, followed by other areas of increased sun exposure (Table 1Go). The size of the primary tumor was ≤ 2 cm for most cases (79.5%; Table 1Go). Fifty (61.0%) of 82 patients presented with primary disease only (stage I). Twenty-nine patients (35.4%) presented with regional lymph node disease; however, in nine of these cases a primary tumor was not found. Eight of the 15 patients who underwent a sentinel lymph node biopsy and 9 of the 10 patients staged by ultrasonography had disease in the regional lymph nodes. Forty-four (53.7%) of 82 patients died, and 42 patients (51.2%) developed a recurrence. The median time to recurrence was 10.0 months (25th percentile, 4.5 months; 75th percentile, 28.3 months), and the median survival time was 27.1 months (25th percentile, 10.1 months; 75th percentile, 52.7 months). The most common site of recurrence was the regional lymph nodes, followed closely by distant lymph nodes (Table 1Go).

Treatment-Related Characteristics
Twenty-seven (38%) of 73 patients had involvement of the surgical margin after the first excision. The tumor was completely excised with negative margins for most patients (60 of 73) after wide local excision (Table 2Go). The median (cumulative) minimum margin of excision was 3 mm (25th percentile, .4 mm; 75th percentile, 8.0 mm). Of the 48 patients who received radiotherapy, 36 received radiation treatment to the primary site and 31 to the regional lymph nodes. Nineteen patients received radiotherapy to both the primary site and the regional lymph nodes. The in-transit area was included in either of these radiotherapy fields for 26 patients. The acute side effects experienced with radiotherapy were never serious enough to interrupt treatment. Radiation treatment was not completed by one patient with metastatic disease. Table 2Go documents the type of radiotherapy applied to each site. The most commonly used radiotherapy regimen to both the primary site and the regional lymph nodes was 50 Gy in 25 fractions over 5 weeks. Of the 29 patients with regional lymphadenopathy at the time of presentation, 25 underwent lymphadenectomy, 19 received radiotherapy, and 17 received both treatments. Two patients with regional lymph node disease received primary radiation treatment only. Two patients received no treatment of their diseased regional lymph nodes. One patient died of other causes before having any treatment, and the other was deemed too old and frail to withstand either radiotherapy or lymphadenectomy. Twelve node-negative patients had elective nodal radiotherapy. Concomitant etoposide and carboplatin were used in eight of nine patients who received combination chemoradiotherapy.32,33


View this table:
[in this window]
[in a new window]

  		TABLE 2. Treatment-related characteristics of the 82 consecutive patients with stage I and II Merkel cell cancer forming the study samplea
 
Time to First Recurrence
On univariate analysis, any radiotherapy, radiotherapy to the regional lymph nodes, and lymphadenectomy (when adjusted for age) were significantly associated with a prolonged time to first recurrence (Table 3Go). The presence of lymphatic invasion, previous squamous cell cancers or immunosuppression, and the site of the cancer were not significantly associated with disease-free survival. The time to first recurrence shortened as the tumor size increased; however, this trend was also not statistically significant (Table 3Go). The (cumulative) minimum margin of excision and negative margins were not significantly associated with the time to first recurrence, but patients with surgical margins free of disease had a longer median disease-free survival (Table 3Go).


View this table:
[in this window]
[in a new window]

  		TABLE 3. Univariate Cox regression statistics for time to first recurrence
 
On multivariate analysis, age (hazard ratio [HR], .96; 95% confidence interval [CI], .93–.99; P = .017), lymphadenectomy (HR, .46; 95% CI, .22–.94; P = .034), and any radiotherapy (HR, .39; 95% CI, .20–.75; P = .004) were independently associated with a prolonged time to first recurrence. A large proportion of patients (19 of 36; 52.8%) who had radiotherapy to the primary site also had it to the regional lymph nodes. Hence, "radiotherapy to the regional lymph nodes" was excluded from the multivariate model because of collinearity with "any radiotherapy."

Survival
Univariate log-rank and Cox regression analyses revealed age at diagnosis, any radiotherapy, regional lymph node metastasis, and lymphadenectomy (the last two when adjusted for age) to be significantly associated with survival (Table 4Go). Figure 1Go demonstrates the difference in the Kaplan-Meier survival curves between patients who did and did not receive any radiotherapy. Tumor site, the presence of lymphatic invasion, and a history of squamous cell cancer or immunosuppression were not significantly associated with enhanced survival on univariate analysis. Age, sex, involvement of the regional lymph nodes at diagnosis, and any radiotherapy were all independently associated with survival (Table 5Go). Although the (cumulative) minimum margin of excision and involvement of the surgical margin after re-excision were not significantly associated with survival on univariate or multivariate analysis, "disease in the surgical margin after the first excision" was retained as an independently significant variable in the final multivariate model (P = .049).


View this table:
[in this window]
[in a new window]

  		TABLE 4. Univariate Cox regression statistics for survival
 

Figure 1
View larger version (11K):
[in this window]
[in a new window]

  		FIG. 1. Kaplan-Meier curves for survival by exposure to any radiotherapy.

 

View this table:
[in this window]
[in a new window]

  		TABLE 5. Best multivariate Cox regression model for survival
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
As far as we are aware, this is the first study to demonstrate a statistically significant association between radiotherapy and enhanced survival on multivariate Cox regression analysis in patients with Merkel cell cancer. This finding is probably related to the long median follow-up time (23 months), during which a large proportion of patients experienced a recurrence (51.2%) or died (53.7%). Most previous studies have found a statistically significant association between radiotherapy and enhanced survival on univariate analysis only,7,8,34–38 if any at all.3,20,34,39 This weak association may be related to both the short follow-up period of these studies and the fact that patients with more aggressive disease (e.g., greater tumor size, lymphatic invasion, or regional lymph node involvement) were selected to receive radiotherapy.20 Radiation treatment enhanced survival in our study despite the aforementioned selection bias.

Most of the published literature on Merkel cell carcinoma supports the use of radiation treatment in improving local and regional control.1–3,5,7–9,12,14,17,18,20,21,23,24,34–47 The numbers of patients receiving radiotherapy in the two studies that question the association between adjuvant radiotherapy and disease-free survival were probably too small to detect a significant difference.12,13 Despite this, patients receiving adjuvant radiation treatment to the regional lymph nodes in the Memorial Sloan-Kettering Cancer Center study had half the number of recurrences of those who did not.13 Patients receiving any radiotherapy in our study were .39 times as likely to develop a recurrence. Patients who received adjuvant radiotherapy to the primary site had more than twice the median time to recurrence of patients who were treated solely by surgery (Table 3Go). The vast majority of these patients (60 of 73) had the primary tumor excised with negative margins. These findings challenge the proposition that adjuvant radiotherapy is unnecessary in the treatment of stage I disease as long as the primary tumor is completely excised.13 They suggest that adjuvant radiotherapy plays an integral role in the management of early-stage Merkel cell cancer and that patients from rural localities should be referred to regional radiation oncology centers for further treatment of this potentially fatal disease.

Most case series to date have not been able to distinguish between the effects of local and regional radiation treatment on time to recurrence (and survival) because of their small sample sizes and because most patients receiving adjuvant treatment to the primary site subsequently receive treatment to the draining lymph nodes.7,14,20,35,39,46 Similarly, the smaller subgroups specifying the site of radiotherapy in our study were not significantly associated with survival (Table 4Go). Considered collectively, however, "any radiotherapy" independently enhanced both disease-free and overall survival (Table 5Go).

Most authors who champion lymphadenectomy have been able to demonstrate only enhanced disease-free—not overall—survival.13,48–50 Although there was a trend toward prolonged overall survival after lymphadenectomy, this association was not statistically significant (Table 4Go). The absence of a strong association between lymph node dissection and survival may be related to the 100% incidence of micrometastatic spread of disease reported with this procedure.2,51

Elective radiotherapy treatment of the draining lymph nodes has been widely advocated by many authors because Merkel cell carcinoma is a radio-sensitive tumor with a high propensity for lymphatic spread.5,7,8,20,22,35,37,39,40,48,52–56 However, other authors advocate elective lymph node dissection9,12,22,26,35,49,51,57,58 in patients with poor-prognostic features.15,59–61 Because most patients who received radiotherapy to the regional lymph nodes (19 of 32) or who underwent lymphadenectomy (25 of 28) in our dataset had regional metastases at the time of diagnosis, it is not possible to make definitive conclusions about these modalities as elective therapy. However, because radiotherapy was strongly associated with both disease-free and overall survival, it probably should be the first-line option for the elective treatment of regional lymph nodes.

Total excision of the primary tumor with negative margins has been shown by several authors to be significantly associated with both a prolonged time to first recurrence (local, regional, or both) and survival on univariate analysis.8,12,26,39 Like us, other authors have observed a nonsignificant trend toward prolonged survival and time to first recurrence with clear margins of excision.12,13,18,35,39 Clear margins after the first excision of the primary tumor were significantly associated with enhanced survival in our study on multivariate analysis. However, this would not have appeared in the multivariate model if stricter inclusion criteria (e.g., P < .05) had been used. Similarly, delays to radiotherapy have been associated with a more rapid progression of disease.62,63 Most studies have been unable to separate out the effect of wide surgical excision from other treatment variables such as lymphadenectomy and adjuvant radiotherapy.8,13

The (cumulative) minimum margin of excision in our study was more often the summation of the deep rather than the lateral margins. Some authors have shown the status of the deep margin to be associated with the risk of local recurrence.12,64 Boyer et al.46 argue that Mohs surgery has a lower rate of recurrence than standard surgical excision because it is a more reliable method of totally excising the primary tumor, particularly from the deep margin, while sparing normal tissue.23,46,49,52,55,65 However, the (cumulative) minimum margin of excision in our study was not significantly related to locoregional recurrence or survival in any of the univariate or multivariate models (Tables 3Go–5GoGo). The margins we report have not been adjusted for the 15% to 25% shrinkage that occurs after excision and fixation.3,20,34,39 Although a simple validated formula derived from surgical experience with melanoma may be used to convert in vitro to in vivo margins,20,34 it made little difference to our statistical analysis.3,20,34,39 We recommend lateral and deep surgical margins of excision that encompass the entire primary tumor for all patients with a new diagnosis of early-stage Merkel cell carcinoma.9,10,12,13,15,18,22–24,39,43,52,55,65,66

In keeping with other studies, lymph node involvement was significantly associated with poorer overall survival on univariate1,8,17 and multivariate7,12,13,18,35 analyses (Tables 4Go and 5Go). Because regional disease was mostly treated, lymphadenopathy at presentation was associated with prolonged disease-free survival (Table 3Go). Our study, like most in the literature, did not observe any significant trend in survival or time to first recurrence with increasing tumor size, perhaps because very few patients in our series (15 of 73) had a tumor > 2 cm. Men formed the majority of patients in our study.5,7,12–14,40,49 As demonstrated by others,7,9,13,15,35,60 male sex was found to be independently predictive of poorer overall survival (Table 5Go). These results may reflect adverse behavioral patterns among men such as overexposure to UV radiation, cigarette smoking, and delayed presentation. A total of 15.8% of patients (cf. 14.5% in the Medina-Franco review1) had some form of immunosuppression, which has been reported to play a role in the etiology of Merkel cell carcinoma.1,2,19,67–69

Sun-exposed areas, particularly the head and neck, were the most common sites of primary disease in our study1,7–11 (Table 1Go). Several authors have reported primary tumors on the head to be significantly associated with enhanced survival on univariate analysis.8,9,12,13,18,35 Ott et al.35 also demonstrated truncal location to be associated with poorer survival on multivariate analysis. However, like many other reviewers,7,17,25,46 we were not able to detect a statistically significant association between tumor location and either time to first recurrence (P = .89) or survival (P = .40). A larger proportion of patients in our dataset (24.3%) had been treated for two or more squamous cell skin cancers before their diagnosis than has previously been reported in the literature. This may be related to the difference in sun exposure between the northern and southern hemispheres.

The limitations of this study include the retrospective and nonrandomized design, the small sample size, the long duration over which the cases were collected, the selection and possible referral biases, and possible misclassification errors. The detection of Merkel cell carcinoma steadily increased throughout the study period.2,3,55,70–72 It is not known whether the increasing incidence of Merkel cell carcinoma in the Central Sydney Area Health Service during the period of the study solely reflected a growing capacity among pathologists to diagnose Merkel cell carcinoma or represented an increasing exposure to etiological factors in the population. Patients with more aggressive disease were probably selected out for treatment, whereas elderly, frail patients with advanced disease were probably omitted. This study focuses on management at the point of diagnosis and ignores any treatment beyond the point of first recurrence. Treatment after the time of first recurrence would have confounded the association between treatment at the point of diagnosis and survival. It would not have been possible to meaningfully include all later treatment in our analysis because of the paucity of medical information available and the complexity of the treatments. Misclassification error in the assessment of lymph node status may have occurred in our study because only a few patients were staged by sentinel lymph node biopsy (15 patients) or ultrasound (10 patients). Allen et al.13 found that 16 of 71 patients in their study who had been labeled clinically as node negative did in fact have pathologically involved lymph nodes on biopsy.

Merkel cell cancer is a potentially rapidly progressive and life-threatening condition that requires prompt medical attention. Surgical removal of diseased regional lymph nodes and radiation treatment both independently improve locoregional control in patients who present with early-stage disease. Radiotherapy also independently enhances overall survival in such patients.


   ACKNOWLEDGMENTS
 
The authors thank Dr. Fran Boyle (Clinical Oncology, Royal North Shore Hospital, Sydney), Christine Hill (Anatomical Pathology, Royal Prince Alfred Hospital, Sydney), Janice Falzon (Medical Records, Royal Prince Alfred Hospital, Sydney), and Vasuki Pious (Medical Records, Concord Repatriation General Hospital, Sydney) for their tireless assistance and support.

Received for publication July 14, 2006. Accepted for publication November 20, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Medina-Franco H, Marshall MU, Fiveash J, et al. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2000; 8:204–8.
  2. Poulson M. Merkel-cell carcinoma of the skin. Lancet Oncol 2004; 5:593–9.[CrossRef][Medline]
  3. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002; 20:588–98.[Free Full Text]
  4. Tang C, Toker C. Trabecular carcinoma of the skin: an ultrastructural study. Cancer 1978; 42:2311–21.[CrossRef][Medline]
  5. Boyle F, Pendlebury S, Bell D. Further insights into the natural history and management of primary cutaneous neuroendocrine (Merkel cell) carcinoma. Int J Radiat Oncol Biol Phys 1995; 31:315–23.[CrossRef][Medline]
  6. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972; 105:107–10.[Abstract/Free Full Text]
  7. Meeuwissen JA, Bourne RG, Kearsley JH. The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1995; 31:325–31.[CrossRef][Medline]
  8. Kokoska ER, Kokoska MS, Brian IC, et al. Early aggressive treatment for Merkel cell carcinoma improves outcome. Am J Surg 1997; 174:688–93.[CrossRef][Medline]
  9. Shaw JHF, Rumball E. Merkel cell tumour: clinical behaviour and treatment. Br J Surg 1991; 78:138–42.[Medline]
  10. Meland NB, Jackson IT. Merkel cell tumour: diagnosis, prognosis, and management. Plast Reconstr Surg 1986; 77:632–8.[Medline]
  11. Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: aetiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999; 8:153–8.[Abstract/Free Full Text]
  12. Yiengpruksawan A, Coit DG, Howard TT, et al. Merkel cell carcinoma. Prognosis and management. Arch Surg 1991; 126:1514–9.[Abstract/Free Full Text]
  13. Allen PJ, Bowne WB, Jacques DP, et al. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005; 23:2300–9.[Abstract/Free Full Text]
  14. Eng TY, Naguib M, Fuller CD, et al. Treatment of recurrent Merkel cell carcinoma: an analysis of 46 cases. Am J Clin Oncol 2004; 27:576–83.[CrossRef][Medline]
  15. Hitchcock CL, Bland KI, Laney RG, et al. Neuroendocrine (Merkel cell) carcinoma of the skin: its natural history, diagnosis, and treatment. Ann Surg 1988; 207:201–7.[Medline]
  16. Meyer-Pannwitt U, Kummerfeldt K, Boubaris P, et al. Merkel cell tumour or neuroendocrine skin carcinoma. Langenbecks Arch Chir 1997; 382:349–358.[Medline]
  17. Eng TY, Boersma MGK, Fuller CD, et al. Treatment of Merkel cell carcinoma. Am J Clin Oncol 2004; 27:510–5.[CrossRef][Medline]
  18. Allen PJ, Zhang ZF, Coit DG. Surgical management of Merkel cell carcinoma: prognosis and management. Ann Surg 1999; 229:97–105.[CrossRef][Medline]
  19. McAfee WJ, Morris CG, Mendenhall CM, et al. Merkel cell carcinoma: treatment and outcomes. Cancer 2005; 15:1761–4.
  20. Muller A, Keus R, Neumann N, Lammering G, et al. Management of Merkel cell carcinoma: case series of 36 patients. Oncol Rep 2003; 10:577–85.[Medline]
  21. Connelly TJ, Cribier B, Brown TJ, et al. Complete spontaneous regression of the Merkel cell carcinoma: a review of the ten reported cases. Dermatol Surg 2000; 26:853–6.[CrossRef][Medline]
  22. Goepfert H, Remmler D, Silva E, et al. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984; 110:707–12.[Abstract/Free Full Text]
  23. O’Connor WJ, Roenigk RK, Brodland DG. Merkel cell carcinoma: comparison of Mohs micrographic surgery and wide excision in eighty-six patients. Dermatol Surg 1997; 23:929–33.[CrossRef][Medline]
  24. Poulsen M, Harvey J. Is there a diminishing role for surgery for Merkel cell carcinoma of the skin? A review of current management. Aust N Z J Surg 2002; 72:142–6.[CrossRef]
  25. Fenig E, Brenner B, Katz A, et al. The role of radiation therapy and chemotherapy in the treatment of Merkel cell carcinoma. Cancer 1997; 80:881–5.[CrossRef][Medline]
  26. Allen PJ, Zhang ZF, Coit DG. The surgical management of Merkel cell carcinoma. Ann Surg 1999; 229:97–105.[CrossRef][Medline]
  27. Charlson ME, Sax FL, MacKenzie CR, et al. Assessing illness severity: does clinical judgment work?. J Chronic Dis 1986; 39:439–52.[CrossRef][Medline]
  28. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–83.[CrossRef][Medline]
  29. Charlson M, Szatrowski TP, Peterson J, et al. Validation of a combined comorbidity index. J Clin Epidemiol 1994; 47:1245–51.[CrossRef][Medline]
  30. Uren RF, Howman-Giles R, Thompson JF, et al. Patterns of lymphatic drainage from the skin in patients with melanoma. J Nucl Med 2003; 44:570–82.[Abstract/Free Full Text]
  31. De Wilt JH, Thompson JF, Uren RF, et al. Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg 2004; 239:544–52.[CrossRef][Medline]
  32. Poulsen M, Rischin D, Walpole E, et al. Analysis of toxicity of Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study. Int J Radiat Oncol Biol Phys 2001; 51:153–63.[CrossRef]
  33. Poulsen M, Rischin D, Walpole E, et al. High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/ etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study—TROG 96:07. J Clin Oncol 2003; 21:4371–6.[Abstract/Free Full Text]
  34. Venness MJ, Perera L, McCourt J, et al. Merkel cell carcinoma: improved outcome with adjuvant radiotherapy. Aust N Z J Surg 2005; 75:275–81.[CrossRef]
  35. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg 1999; 134:388–93.[Abstract/Free Full Text]
  36. Wilder RB, Harari PM, Graham AR, et al. Improved locoregional control with postoperative radiation therapy. Cancer 1991; 68:1004–8.[CrossRef][Medline]
  37. Marks ME, Kim RY, Salter MM. Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 1990; 5:60–4.
  38. Tennvall J, Biorklund A, Johansson L, et al. Merkel cell carcinoma: management of primary, recurrent and metastatic disease. A clinicopathologic study of 17 patients. Eur J Surg Oncol 1989; 15:1–9.[Medline]
  39. Gillenwater AM, Hessel AC, Morrison WH, et al. Merkel cell carcinoma of the head and neck: effect of surgical excision and radiation on recurrence and survival. Arch Otolaryngol Head Neck Surg 2001; 127:149–54.[Abstract/Free Full Text]
  40. Morrison WH, Peters LJ, Silva EG, et al. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1990; 19:583–91.[Medline]
  41. Bielamowicz S, Smith D, Abemayor E. Merkel cell carcinoma: an aggressive skin neoplasm. Laryngoscope 1990; 104:528–32.
  42. Wong KC, Zuletta F, Clarke J, et al. Clinical management and treatment outcomes of Merkel cell carcinoma. Aust N Z J Surg 1998; 68:354–8.[Medline]
  43. O’Connor WJ, Brodland DG. Merkel cell carcinoma. Dermatol Surg 1996; 22:262–7.[CrossRef][Medline]
  44. Perez JA, Poblete MT, Castillo P, et al. Merkel cell carcinoma. Report of 4 cases (in Spanish). Rev Med Chil 1998; 126:553–8.[Medline]
  45. Pergolizzi J, Pelczar M, Conaway GL. Merkel cell carcinoma: an aggressive malignancy. Am Surg 1997; 63:450–4.[Medline]
  46. Boyer JD, Zitelli JA, Brodland DG, et al. Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. Dermatol Surg 2002; 47:885–92.
  47. Veness MJ. Merkel cell carcinoma: improved outcome with the addition of adjuvant therapy. J Clin Oncol 2005; 23:7235–6.[Free Full Text]
  48. Bourne RG, O’Rourke MG. Management of Merkel cell tumour. Aust N Z J Surg 1988; 58:971–4.[Medline]
  49. Smith DE, Bielamowicz S, Kagan AR, et al. Cutaneous neuroendocrine (Merkel cell) carcinoma. Am J Clin Oncol 1995; 18:199–204.[Medline]
  50. Mehrany K, Otley CC, Weenig RH, et al. A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg 2002; 28:113–7.[CrossRef][Medline]
  51. Victor NS, Morton B, Smith JW. Merkel cell cancer: is prophylactic lymph node dissection indicated?. Am Surg 1996; 62:879–82.[Medline]
  52. Gollard R, Weber R, Kosty MP, et al. Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 2000; 88:1842–51.[CrossRef][Medline]
  53. Eich HT, Eich D, Staar S, et al. Role of post-operative radiotherapy in the management of Merkel cell carcinoma. Am J Clin Oncol 2002; 25:50–6.[CrossRef][Medline]
  54. Voog E, Biron P, Martin JP, et al. Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 1999; 15:2589–95.
  55. Haag M, Glass LF, Fenske NA. Merkel cell carcinoma: diagnosis and treatment. Dermatol Surg 1995; 21:669–83.[CrossRef][Medline]
  56. Suntharalingam M, Rudoltz M, Mendenhall W, et al. Radiotherapy for Merkel cell carcinoma of the skin of the head and neck. Head Neck 1995; 17:96–101.[Medline]
  57. Raaf JH, Urmacher C, Knapper WK, et al. Trabecular (Merkel cell) carcinoma of the skin: treatment of primary, recurrent, and metastatic disease. Cancer 1986; 57:178–82.[CrossRef][Medline]
  58. Pilotti S, Rilke F, Bartoli C, et al. Clinicopathologic correlations of cutaneous neuroendocrine Merkel cell carcinoma. J Clin Oncol 1988; 6:1863–73.[Abstract]
  59. Silva EG, Mackay B, Goepfert H, et al. Endocrine carcinoma of the skin (Merkel cell carcinoma). Pathol Ann 1984; 19:1–30.[Free Full Text]
  60. Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992; 102:244–9.[Medline]
  61. Cotlar AM, Gates JO, Gibbs FA. Merkel cell carcinoma: combined surgery and radiation therapy. Am Surg 1986; 52:159–64.[Medline]
  62. Tsang G, O’Brien P, Robertson R, et al. All delays before radiotherapy risk progression of Merkel cell carcinoma. Australas Radiol 2004; 48:371–5.[CrossRef][Medline]
  63. Bischof M, Van Kampen M, Huber P, et al. Merkel cell carcinoma: the role of radiation therapy in general management. Strahlenther Onkol 1999; 175:611–5.[CrossRef][Medline]
  64. Gould EV, Moll R, Moll I, et al. Biology of disease: neuroendocrine (Merkel) cells of the skin—hyperplasias, dysplasias, and neoplasms. Lab Invest 1985; 52:334–53.[Medline]
  65. Ratner D, Nelson BR, Brown MD, et al. Merkel cell carcinoma. J Am Acad Dermatol 1999; 29:143–56.
  66. Al-Ghazal SK, Arora DS, Simpson RH, et al. Merkel cell carcinoma of the skin. Br J Plast Surg 1996; 49:491–6.[CrossRef][Medline]
  67. Buell JF, Trofe J, Hanaway MJ, et al. Immunosuppression and Merkel cell cancer. Transplant Proc 2002; 34:1780–1.[CrossRef][Medline]
  68. Bordea C, Wonjnarowska F, Millard PR, et al. Skin cancers in renal-transplant recipients occur more commonly than previously recognized in a temperate climate. Transplantation 2004; 77:574–9.[Medline]
  69. Engels E, Frisch M, Goedart J, et al. Merkel cell carcinoma and HIV infection. Lancet 2002; 359:497–8.[CrossRef][Medline]
  70. Scott MP, Helm KF. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. Am J Dermatopathol 1999; 21:16–20.[CrossRef][Medline]
  71. Hanly AJ, Elgart GW, Jorda M, et al. Analysis of thyroid transcription factor-1 and cytokeratin 20 separates Merkel cell carcinoma from small cell carcinoma of lung. J Cutan Pathol 2000; 27:118–20.[CrossRef][Medline]
  72. Haneke E, Schulze HJ, Mahrle G, et al. Immunohistochemical and immunoelectron microscopic demonstration of chromogranin A in formalin-fixed tissue of Merkel cell carcinoma. J Am Acad Dermatol 1993; 28:222–6.[Medline]



This article has been cited by other articles:


Home page
 Ann. Surg. Oncol.Home page
R. E. Warner, M. J. Quinn, G. Hruby, R. A. Scolyer, R. F. Uren, and J. F. Thompson
Management of Merkel Cell Carcinoma: The Roles of Lymphoscintigraphy, Sentinel Lymph Node Biopsy and Adjuvant Radiotherapy
Ann. Surg. Oncol., September 1, 2008; 15(9): 2509 - 2518.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
P. M. Busse, J. R. Clark, V. V. Muse, and V. Liu
Case 19-2008 -- A 63-Year-Old HIV-Positive Man with Cutaneous Merkel-Cell Carcinoma
N. Engl. J. Med., June 19, 2008; 358(25): 2717 - 2723.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jabbour, J.
Right arrow Articles by Lee, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jabbour, J.
Right arrow Articles by Lee, S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS