ORIGINAL ARTICLE
Merkel cell carcinoma: Overall survival after open biopsy versus wide local excision Georg Haymerle, MD,1 Alexandra Fochtmann, MD,2 Rainer Kunstfeld, MD,3 Johannes Pammer, MD,4 Boban M. Erovic, MD1* 1
Department of Otolaryngology – Head and Neck Surgery, Medical University of Vienna, Vienna, Austria, 2Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria, 3Department of Dermatology, Medical University of Vienna, Vienna, Austria, 4Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
Accepted 31 May 2015 Published online 18 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24148
ABSTRACT: Background. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with a dismal prognosis. Methods. We conducted a retrospective medical chart review of patients with MCC who were initially diagnosed with an open biopsy (n 5 30) or wide local excision (n 5 24). Results. Stages I, II, and III disease was found in 38%, 20%, and 16%, respectively. The 2-year and 5-year overall and disease-specific survival rates were 64.8% and 38.8% versus 45.2% and 26.4%, respectively. Cox regression multivariate model, including tissue sampling technique, re-resection, therapy modalities, pathological staging, and T and N classifications, showed that patients diagnosed initially with an open
biopsy have significant worse overall (p 5 .014) and disease-free (p 5 .005) survival rates compared with patients who had a wide local excision. Conclusion. This study showed an improved overall survival in patients with MCC after wide local excision compared to open biopsy of the priC 2015 Wiley Periodicals, Inc. Head Neck mary site at first diagnosis. V 38: E1014–E1018, 2016
INTRODUCTION
ologic examination. Hence, biopsies or non in sano excisions are very common. Tumor spread because of operation or biopsy is known to influence patient outcome in other head and neck tumor entities.8 Therefore, we conducted a retrospective analysis to investigate any possible differences in disease-specific survival, disease-free interval, and overall survival of patients who underwent either biopsy or wide local excision at their initial presentation.
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy first described by Toker1 in 1972. It is most commonly located in the head and neck region followed by the extremities with a high tendency for local recurrence and regional lymph node metastasis. The therapy of choice is wide surgical excision, whereas adjuvant radiotherapy to the primary site and regional lymph nodes reduces the risk of local recurrence.2 Negative prognostic features are male sex, age over 65 years, fair skin, sun exposure, lymph node metastasis, and primary tumor size larger than 2 cm.3 Metastatic disease is highly predictive of poor outcome.4 Recent studies suggest an increased risk of lymphatic invasion associated with the diameter of the primary site.5 Furthermore, Feng et al6 discovered a polyomavirus that represents a potential etiological factor for the development of this skin tumor. Because guidelines for the optimal treatment of MCC are still heterogeneous, prognostic factors represent an important role in the staging and therapeutic approach. Because of the rarity of this tumor entity and the nonspecific presentation, first diagnosis is often delayed.7 In the majority of cases, diagnosis is only achieved by path-
*Corresponding author: B. M. Erovic, Department of Otolaryngology – Head and Neck Surgery, Medical University of Vienna, W€ahringer G€urtel 18–20, 1090 Vienna, Austria. E-mail: [email protected] This work was presented as a poster at the Austrian Ear, Nose, and Throat meeting, Vienna, Austria, September 29 to October 2, 2013.
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KEY WORDS: Merkel cell carcinoma, overall survival, open biopsy, wide local excision, retrospective
MATERIALS AND METHODS A retrospective medical chart review was performed of patients treated for MCC between 1992 and 2012 at the Vienna General Hospital. Approval of the institutional research ethics board was obtained before the medical chart review (1798 of 2013). Patients with histologically confirmed diagnosis of MCC were included in this study. Patients with distant metastatic disease at first diagnosis were not included in statistical analysis. Sociodemographic, clinicopathologic, and outcome data were obtained from hospital medical reports. The oncologic workup was generally initiated with sonography of the primary tumor site followed by the draining lymph node stations. MCCs of the head and neck region where investigated with MRI. Distant metastases were excluded with CT of the thorax and abdomen or positron emission tomography scans. Characteristics of each patient, tumor, treatment modality, and follow-up were obtained. The 2010 American Joint Committee on Cancer staging system was used. Last
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Patients Sex Female Male Age, y (at first diagnosis) Mean Median Range Tumor site No primary Head and neck Trunk Extremities Initial tissue sampling Open biopsy Wide local excision Radiotherapy Yes No
MERKEL
CELL CARCINOMA
RESULTS
TABLE 1. Demographics and treatment data of 54 patients with Merkel cell carcinoma. Characteristics
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Patient data Value (%)*
54 27 (50) 27 (50) 73 76 46–93 7 (13) 26 (48) 4 (7) 17 (32) 30 (56) 24 (44) 24 (45) 29 (55)
* Values represent the number of patients (%) except as otherwise stated.
follow-up was defined as death or disease status at the chosen endpoint. Treatment modality was assessed regarding surgical management of the primary tumor, administration of adjuvant radiation therapy, and treatment modality of recurrence. Open biopsy and non in sano excision were compared to wide local excision. Recurrence rate and overall survival time at last follow-up were statistically analyzed. Diagnosis was confirmed by immunohistochemistry (cytokeratin 20, chromogranin-A, neuron specific enolase [NSE]). Biopsy and non in sano resection of the primary tumor were defined as positive tumor cells at the surgical resection margin.
Statistical analysis Statistical analysis was performed using the SPSS software version 15.0. Demographic and pathologic data were summarized using descriptive statistics. Recurrence and survival rates were calculated from the date of first diagnosis to the event of interest. Recurrences were classified as local, regional, or distant. The primary endpoint was defined as the time from surgery to the date when recurrent disease was diagnosed (disease-free survival), or patients’ death because of the disease (disease-specific survival) or last follow-up (overall survival). Survival analysis was performed using the Kaplan–Meier method. Potential prognostic variables achieving significance level of 0.20 or less on univariate analysis were subsequently entered into a multivariable Cox proportional hazards model and stepwise model-building was used to determine the simplest model that best described the association in the data. All statistical tests were 2-tailed, and a p value of < .05 was considered significant.
Fifty-nine patients with MCC were eligible for inclusion in the study. Five patients were excluded from statistical analysis because of distant metastatic disease at first presentation. Of the analyzed cohort (n 5 54), 27 were women and 27 were men, with a median age at first diagnosis of 76 years (range, 46–93 years). Patients’ characteristics are shown in Table 1. At first presentation, MCC was located in the head and neck region in 26 patients (48%), in the extremities in 17 patients (32%), and in the trunk in 4 patients (7%). Seven patients were diagnosed with MCC with unknown site of primary tumor (13%). Most of the patients (58%; n 5 32) presented with early local disease (stage I/II), whereas 9 patients (16%) presented with stage III disease (Tables 2 and 3).
Treatment All patients underwent either open biopsy (n 5 30) or primary wide local excision (n 5 24) at the first presentation for diagnostic workup. In 40 cases, re-resection of the primary site was performed. After diagnostic tissue sampling, 19 patients (35%) underwent in sano reresection, 6 patients (11%) non in sano re-resection, and TABLE 2. Histopathological and outcome data of 54 patients with Merkel cell carcinoma. Characteristic
Value* (%) †
Stage at diagnosis I II III IV Unknown CUP Recurrence rate Open biopsy Wide local excision Location of recurrent disease
Locoregional Distant Cytokeratin 20 Positive N/A Chromogranin A Positive Negative N/A NSE Positive Negative N/A
21 (39) 11 (20) 9 (17) 0 (0) 6 (11) 7 (13) 17 (55) 10 (45) Open biopsy
Wide excision
10 (37) 7 (27)
5 (18) 5 (18)
Total
15 (55) 12 (45) 39 (72) 15 (28) 32 (59) 4 (8) 18 (33) 15 (28) 1 (2) 38 (70)
Abbreviations: CUP, cancer of unknown primary; N/A, not available; NSE, neuron specific enolase. * Values represent the number of patients (%) except as otherwise stated. † Stage at diagnosis according to the American Joint Committee on Cancer.
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TABLE 3. Clinical and histopathological data — open biopsy versus wide local excision in 54 patients.
Characteristics
Female Male Age, y, median TNM classification Tx T1 T2 N1 N2 M N/A Stage at diagnosis I II III IIIb N/A Adjuvant radiotherapy Re-resection Margins negative Margins positive Recurrence-free time: median (mean) Follow-up ANED DNED DOD
Open biopsy n 5 30 (%)*
Wide excision n 5 24 (%)*
18 (60) 12 (40) 76
9 (38) 15 (62) 73
1 (3) 17 (57) 9 (30) 7 (23) 1 (3) 0 3 (10)
6 (25) 9 (38) 6 (25) 9 (38) 1 (4) 0 3 (12)
14 (47) 7 (23) 5 (17) 1 (3) 3 (10) 16 (53) 26 (87) 18 (69) 4 (15) 13 (35)
7 (29) 4 (13) 4 (13) 6 (25) 3 (12) 8 (33) 12 (50) 0 0 37 (53)
7 (23) 11 (37) 12 (40)
11 (46) 5 (21) 8 (33)
Abbreviations: N/A, not available; ANED, alive with no evidence of disease; DNED, Died with no evidence of disease; DOD, died of disease. * Values represent number of patients (%) except as stated otherwise.
15 patients (27%) had no residual tumor tissue found. In the 6 cases of non in sano re-resection, 2 specimens showed tumor tissue at the resection margin, but no further resection was performed. Two patients were treated with radiotherapy or radiochemotherapy because of an advanced primary disease. In the remaining 2 patients, the residual tumor was excised 4 months later. Both patients died of other causes 2 months thereafter without signs of the primary tumor. Twenty-seven patients underwent sentinel node biopsy and 17 of those patients (63%) showed positive lymph node involvement. Twenty-four patients (44%) received postoperative radiotherapy and 4 patients (7%) underwent adjuvant chemotherapy because of advanced disease at first diagnosis (Table 3).
Outcome The overall median and mean follow-up time was 36 months (range, 1–213 months) and 54 months, respectively. The median and mean follow-up time for patients alive at last follow-up was 86 and 97 months (range, 4–230 months), respectively. The 2-year and 5-year overall survival rate was 64.8% and 38.8%, respectively. The 2-year and 5-year disease-specific survival rate was 45.2% and 26.4%, respectively. After open biopsy, 12 patients (60%) died of the disease compared with 8 patients (40%) after wide local excision. At last follow-up, 18 patients were alive without disease. The disease-free survival rate was 19 months (range, 1–37 months), with no difference between groups. However, patients with stage III had a significant worse disease-free survival rate compared with patients with stage I and II disease (Figure 1). In this study, recurrent disease was observed in 27 patients (50%), of which 17 patients (55%) had open biopsy and 10 patients (45%) had wide local excision. Locoregional recurrence was observed in 10 patients (37%) after open biopsy, compared to only 5 patients (18%) after wide local excision. Distant recurrent disease was found in 7 patients after open biopsy, and in 5 patients after wide local excision, respectively. Treatment of recurrent disease involved surgery and adjuvant radiotherapy or chemotherapy in case of distant metastases.
Prognostic factors Univariate analysis revealed prolonged disease-specific (p 5 .029) and overall (p 5 .024) survival in the excision compared to the biopsy group. Moreover, advanced staging was significantly linked to a shortened disease-free survival rate (p 5 .004). Biopsy versus local excision, N classification, stage disease, and re-resection achieved the significance level of 0.20 or less on univariate analysis and were subsequently
Histopathology Of the entire cohort, 30 specimens (56%) showed positive margins at the time of first diagnosis. Eight patients (15%) underwent further neck dissection, of which 6 patients (75%) showed pathologic evidence of nodal disease. The median and mean numbers of positive lymph nodes were 18.5 (range, 2–43) and 20.5, respectively. Cytokeratin 20 staining was positive in 100% (all of 39 patients), chromogranin-A in 88% (32 of 36), and NSE in 93% (15 of 16). The numbers represent the specimens in which immunohistochemistry were performed. E1016
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FIGURE 1. Disease-free survival curves for patients with Merkel cell carcinoma with respect to the tumor staging. Patients with staging III have a significant worse disease-free survival rate compared with patients with stage I and II.
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FIGURE 2. Kaplan–Meier curves for overall (A) and diseasespecific survival (B) after open biopsy or wide local excision. Patients with Merkel cell carcinoma undergoing wide local excision at the time of first diagnosis have a significant better overall and disease-specific survival rate than patients after open biopsy.
entered into a multivariable Cox proportional hazards model and stepwise model-building. The Cox regression multivariate model demonstrated that patients with MCC undergoing wide local excision as the initial way of tissue sampling had a significant better overall survival rate (p 5 .014) than patients undergoing open biopsy (see Figure 2).
DISCUSSION MCC frequently presents with locally or regionally recurrent disease and, therefore, primary aggressive treatment with lymph node biopsy and adjuvant radiation therapy is proposed in recent literature.9,10 Because of the rarity of this tumor entity and the unspecific presentation, first diagnosis is often delayed. Biopsies or non in sano excisions are very common. There is still limited data on optimal treatment regimens of the primary tumor as well as of recurrent disease. Therefore, we conducted a retrospective analysis of 54 patients with MCC undergoing either biopsy or wide local excision for diagnostic purposes, with a median follow-up of 86 months. Although our study was limited in numbers, it suggests wide local
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MERKEL
CELL CARCINOMA
excision as the primary choice for diagnostic workup of patients with MCC. The median age of our patients at first presentation was 76 years, which is consistent with previous studies. In contrary to literature, which reports a male predominance in MCC,5,11 we observed equal sex distribution in the entire study group. Similar to previous studies, the preponderant site of occurrence was the head and neck region, followed by the extremities. In patients with MCC, high recurrence rates have been reported with local, regional, and distant recurrence from 3% to 14%, 12% to 26%, and 12% to 28%, respectively.12–14 Again, in our study, cohort similar locoregional (26%) and distant (22%) recurrence rates could be observed. Wide local resection margins for MCC have been controversial in the head and neck region.15–17 Initial publications proposed 1 to 2 cm resection margins for all tumor locations.18,19 Boccara et al20 adapted the German and American guidelines for diagnosis and therapy of MCC and proposed biopsy as means of histologic examination and thereafter a resection margin of 2 to 3 cm.20 Because of standard routine of open biopsy of skin tumors, wide local excision is rarely performed. In our current study, only 24 patients were treated with wide local excision of the primary tumor. Recurrent disease occurred in 17 of 30 patients after open biopsy and in 10 patients after wide local excision. Especially locoregional recurrence was found more in patients who underwent an open biopsy approach. Interestingly, the distribution of distant metastases was almost equal among the groups. Although adjuvant radiotherapy has been shown to improve locoregional control,14 positive resection margins at first diagnosis could not be redeemed by postoperative radiotherapy. This fact can be underlined by our observation that more patients died of the disease in case of open biopsy and, thus, positive margins at the initial presentation. Moreover, patients undergoing wide local excision had a significant better overall and disease-specific survival rate than patients who initially underwent open biopsy for diagnostic workup. In summary, we describe our experience in the management of a rare skin tumor entity. Our results are concomitant with previous studies showing a peak incidence in the elderly patient. We also observed high recurrence rates and poor patient outcome, despite the treatment used. Furthermore, our single-institutional study identified open biopsy as a prognostic factor for poor overall survival in patients with MCC. On the basis of our results, we therefore suggest an alteration of the treatment guidelines. Clinical suspicion of MCC should lead to wide local excision of the primary tumor site instead of diagnostic biopsies at the patients’ initial presentation.
Acknowledgment The authors thank Margit Hemetsberger, MD, for critical reading of the manuscript.
REFERENCES 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105:107– 110. 2. Morrison WH, Peters LJ, Silva EG, Wendt CD, Ang KK, Goepfert H. The essential role of radiation therapy in securing locoregional control of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 1990;19:583–591.
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HAYMERLE ET AL. 3. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832–841. 4. Tarantola TI, Vallow LA, Halyard MY, et al. Unknown primary Merkel cell carcinoma: 23 new cases and a review. J Am Acad Dermatol 2013;68: 433–440. 5. Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29: 1036–1041. 6. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008;319:1096–1100. 7. Gioacchini FM, Postacchini V, Simonetti O, Offidani A, Magliulo G, Re M. Merkel cell carcinoma: a systematic review of ENT presentations. Eur Arch Otorhinolaryngol 2013;270:2191–2199. 8. Spiro RH, Guillamondegui O, Paulino AF, Huvos AG. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck 1999;21:408–413. 9. Hui AC, Stillie AL, Seel M, Ainslie J. Merkel cell carcinoma: 27-year experience at the Peter MacCallum Cancer Centre. Int J Radiat Oncol Biol Phys 2011;80:1430–1435. 10. Reichgelt BA, Visser O. Epidemiology and survival of Merkel cell carcinoma in the Netherlands. A population-based study of 808 cases in 1993– 2007. Eur J Cancer 2011;47:579–585. 11. Eftekhari F, Wallace S, Silva EG, Lenzi R. Merkel cell carcinoma of the skin: imaging and clinical features in 93 cases. Br J Radiol 1996;69:226– 233.
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12. Haerle SK, Shiau C, Goldstein DP, et al. Merkel cell carcinoma of the head and neck: potential histopathologic predictors. Laryngoscope 2013;123: 3043–3048. 13. Fields RC, Busam KJ, Chou JF, et al. Recurrence after complete resection and selective use of adjuvant therapy for stage I through III Merkel cell carcinoma. Cancer 2012;118:3311–3320. 14. Kang SH, Haydu LE, Goh RY, Fogarty GB. Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma. Radiat Oncol 2012;7:171. 15. Allen PJ, Zhang ZF, Coit DG. Surgical management of Merkel cell carcinoma. Ann Surg 1999;229:97–105. 16. 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;127:149–154. 17. 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;23:929–933. 18. Goepfert H, Remmler D, Silva E, Wheeler B. Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 1984; 110:707–712. 19. Ott MJ, Tanabe KK, Gadd MA, et al. Multimodality management of Merkel cell carcinoma. Arch Surg 1999;134:388–392; discussion 392–393. 20. Boccara O, Girard C, Mortier L, et al. Guidelines for the diagnosis and treatment of Merkel cell carcinoma – Cutaneous Oncology Group of the French Society of Dermatology. Eur J Dermatol 2012;22:375–379.
Merkel cell carcinoma: Overall survival after open biopsy versus wide local excision Georg Haymerle, MD,1 Alexandra Fochtmann, MD,2 Rainer Kunstfeld, MD,3 Johannes Pammer, MD,4 Boban M. Erovic, MD1* 1
Department of Otolaryngology – Head and Neck Surgery, Medical University of Vienna, Vienna, Austria, 2Department of Plastic and Reconstructive Surgery, Medical University of Vienna, Vienna, Austria, 3Department of Dermatology, Medical University of Vienna, Vienna, Austria, 4Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria
Accepted 31 May 2015 Published online 18 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24148
ABSTRACT: Background. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with a dismal prognosis. Methods. We conducted a retrospective medical chart review of patients with MCC who were initially diagnosed with an open biopsy (n 5 30) or wide local excision (n 5 24). Results. Stages I, II, and III disease was found in 38%, 20%, and 16%, respectively. The 2-year and 5-year overall and disease-specific survival rates were 64.8% and 38.8% versus 45.2% and 26.4%, respectively. Cox regression multivariate model, including tissue sampling technique, re-resection, therapy modalities, pathological staging, and T and N classifications, showed that patients diagnosed initially with an open
biopsy have significant worse overall (p 5 .014) and disease-free (p 5 .005) survival rates compared with patients who had a wide local excision. Conclusion. This study showed an improved overall survival in patients with MCC after wide local excision compared to open biopsy of the priC 2015 Wiley Periodicals, Inc. Head Neck mary site at first diagnosis. V 38: E1014–E1018, 2016
INTRODUCTION
ologic examination. Hence, biopsies or non in sano excisions are very common. Tumor spread because of operation or biopsy is known to influence patient outcome in other head and neck tumor entities.8 Therefore, we conducted a retrospective analysis to investigate any possible differences in disease-specific survival, disease-free interval, and overall survival of patients who underwent either biopsy or wide local excision at their initial presentation.
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy first described by Toker1 in 1972. It is most commonly located in the head and neck region followed by the extremities with a high tendency for local recurrence and regional lymph node metastasis. The therapy of choice is wide surgical excision, whereas adjuvant radiotherapy to the primary site and regional lymph nodes reduces the risk of local recurrence.2 Negative prognostic features are male sex, age over 65 years, fair skin, sun exposure, lymph node metastasis, and primary tumor size larger than 2 cm.3 Metastatic disease is highly predictive of poor outcome.4 Recent studies suggest an increased risk of lymphatic invasion associated with the diameter of the primary site.5 Furthermore, Feng et al6 discovered a polyomavirus that represents a potential etiological factor for the development of this skin tumor. Because guidelines for the optimal treatment of MCC are still heterogeneous, prognostic factors represent an important role in the staging and therapeutic approach. Because of the rarity of this tumor entity and the nonspecific presentation, first diagnosis is often delayed.7 In the majority of cases, diagnosis is only achieved by path-
*Corresponding author: B. M. Erovic, Department of Otolaryngology – Head and Neck Surgery, Medical University of Vienna, W€ahringer G€urtel 18–20, 1090 Vienna, Austria. E-mail: [email protected] This work was presented as a poster at the Austrian Ear, Nose, and Throat meeting, Vienna, Austria, September 29 to October 2, 2013.
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KEY WORDS: Merkel cell carcinoma, overall survival, open biopsy, wide local excision, retrospective
MATERIALS AND METHODS A retrospective medical chart review was performed of patients treated for MCC between 1992 and 2012 at the Vienna General Hospital. Approval of the institutional research ethics board was obtained before the medical chart review (1798 of 2013). Patients with histologically confirmed diagnosis of MCC were included in this study. Patients with distant metastatic disease at first diagnosis were not included in statistical analysis. Sociodemographic, clinicopathologic, and outcome data were obtained from hospital medical reports. The oncologic workup was generally initiated with sonography of the primary tumor site followed by the draining lymph node stations. MCCs of the head and neck region where investigated with MRI. Distant metastases were excluded with CT of the thorax and abdomen or positron emission tomography scans. Characteristics of each patient, tumor, treatment modality, and follow-up were obtained. The 2010 American Joint Committee on Cancer staging system was used. Last
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Patients Sex Female Male Age, y (at first diagnosis) Mean Median Range Tumor site No primary Head and neck Trunk Extremities Initial tissue sampling Open biopsy Wide local excision Radiotherapy Yes No
MERKEL
CELL CARCINOMA
RESULTS
TABLE 1. Demographics and treatment data of 54 patients with Merkel cell carcinoma. Characteristics
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Patient data Value (%)*
54 27 (50) 27 (50) 73 76 46–93 7 (13) 26 (48) 4 (7) 17 (32) 30 (56) 24 (44) 24 (45) 29 (55)
* Values represent the number of patients (%) except as otherwise stated.
follow-up was defined as death or disease status at the chosen endpoint. Treatment modality was assessed regarding surgical management of the primary tumor, administration of adjuvant radiation therapy, and treatment modality of recurrence. Open biopsy and non in sano excision were compared to wide local excision. Recurrence rate and overall survival time at last follow-up were statistically analyzed. Diagnosis was confirmed by immunohistochemistry (cytokeratin 20, chromogranin-A, neuron specific enolase [NSE]). Biopsy and non in sano resection of the primary tumor were defined as positive tumor cells at the surgical resection margin.
Statistical analysis Statistical analysis was performed using the SPSS software version 15.0. Demographic and pathologic data were summarized using descriptive statistics. Recurrence and survival rates were calculated from the date of first diagnosis to the event of interest. Recurrences were classified as local, regional, or distant. The primary endpoint was defined as the time from surgery to the date when recurrent disease was diagnosed (disease-free survival), or patients’ death because of the disease (disease-specific survival) or last follow-up (overall survival). Survival analysis was performed using the Kaplan–Meier method. Potential prognostic variables achieving significance level of 0.20 or less on univariate analysis were subsequently entered into a multivariable Cox proportional hazards model and stepwise model-building was used to determine the simplest model that best described the association in the data. All statistical tests were 2-tailed, and a p value of < .05 was considered significant.
Fifty-nine patients with MCC were eligible for inclusion in the study. Five patients were excluded from statistical analysis because of distant metastatic disease at first presentation. Of the analyzed cohort (n 5 54), 27 were women and 27 were men, with a median age at first diagnosis of 76 years (range, 46–93 years). Patients’ characteristics are shown in Table 1. At first presentation, MCC was located in the head and neck region in 26 patients (48%), in the extremities in 17 patients (32%), and in the trunk in 4 patients (7%). Seven patients were diagnosed with MCC with unknown site of primary tumor (13%). Most of the patients (58%; n 5 32) presented with early local disease (stage I/II), whereas 9 patients (16%) presented with stage III disease (Tables 2 and 3).
Treatment All patients underwent either open biopsy (n 5 30) or primary wide local excision (n 5 24) at the first presentation for diagnostic workup. In 40 cases, re-resection of the primary site was performed. After diagnostic tissue sampling, 19 patients (35%) underwent in sano reresection, 6 patients (11%) non in sano re-resection, and TABLE 2. Histopathological and outcome data of 54 patients with Merkel cell carcinoma. Characteristic
Value* (%) †
Stage at diagnosis I II III IV Unknown CUP Recurrence rate Open biopsy Wide local excision Location of recurrent disease
Locoregional Distant Cytokeratin 20 Positive N/A Chromogranin A Positive Negative N/A NSE Positive Negative N/A
21 (39) 11 (20) 9 (17) 0 (0) 6 (11) 7 (13) 17 (55) 10 (45) Open biopsy
Wide excision
10 (37) 7 (27)
5 (18) 5 (18)
Total
15 (55) 12 (45) 39 (72) 15 (28) 32 (59) 4 (8) 18 (33) 15 (28) 1 (2) 38 (70)
Abbreviations: CUP, cancer of unknown primary; N/A, not available; NSE, neuron specific enolase. * Values represent the number of patients (%) except as otherwise stated. † Stage at diagnosis according to the American Joint Committee on Cancer.
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TABLE 3. Clinical and histopathological data — open biopsy versus wide local excision in 54 patients.
Characteristics
Female Male Age, y, median TNM classification Tx T1 T2 N1 N2 M N/A Stage at diagnosis I II III IIIb N/A Adjuvant radiotherapy Re-resection Margins negative Margins positive Recurrence-free time: median (mean) Follow-up ANED DNED DOD
Open biopsy n 5 30 (%)*
Wide excision n 5 24 (%)*
18 (60) 12 (40) 76
9 (38) 15 (62) 73
1 (3) 17 (57) 9 (30) 7 (23) 1 (3) 0 3 (10)
6 (25) 9 (38) 6 (25) 9 (38) 1 (4) 0 3 (12)
14 (47) 7 (23) 5 (17) 1 (3) 3 (10) 16 (53) 26 (87) 18 (69) 4 (15) 13 (35)
7 (29) 4 (13) 4 (13) 6 (25) 3 (12) 8 (33) 12 (50) 0 0 37 (53)
7 (23) 11 (37) 12 (40)
11 (46) 5 (21) 8 (33)
Abbreviations: N/A, not available; ANED, alive with no evidence of disease; DNED, Died with no evidence of disease; DOD, died of disease. * Values represent number of patients (%) except as stated otherwise.
15 patients (27%) had no residual tumor tissue found. In the 6 cases of non in sano re-resection, 2 specimens showed tumor tissue at the resection margin, but no further resection was performed. Two patients were treated with radiotherapy or radiochemotherapy because of an advanced primary disease. In the remaining 2 patients, the residual tumor was excised 4 months later. Both patients died of other causes 2 months thereafter without signs of the primary tumor. Twenty-seven patients underwent sentinel node biopsy and 17 of those patients (63%) showed positive lymph node involvement. Twenty-four patients (44%) received postoperative radiotherapy and 4 patients (7%) underwent adjuvant chemotherapy because of advanced disease at first diagnosis (Table 3).
Outcome The overall median and mean follow-up time was 36 months (range, 1–213 months) and 54 months, respectively. The median and mean follow-up time for patients alive at last follow-up was 86 and 97 months (range, 4–230 months), respectively. The 2-year and 5-year overall survival rate was 64.8% and 38.8%, respectively. The 2-year and 5-year disease-specific survival rate was 45.2% and 26.4%, respectively. After open biopsy, 12 patients (60%) died of the disease compared with 8 patients (40%) after wide local excision. At last follow-up, 18 patients were alive without disease. The disease-free survival rate was 19 months (range, 1–37 months), with no difference between groups. However, patients with stage III had a significant worse disease-free survival rate compared with patients with stage I and II disease (Figure 1). In this study, recurrent disease was observed in 27 patients (50%), of which 17 patients (55%) had open biopsy and 10 patients (45%) had wide local excision. Locoregional recurrence was observed in 10 patients (37%) after open biopsy, compared to only 5 patients (18%) after wide local excision. Distant recurrent disease was found in 7 patients after open biopsy, and in 5 patients after wide local excision, respectively. Treatment of recurrent disease involved surgery and adjuvant radiotherapy or chemotherapy in case of distant metastases.
Prognostic factors Univariate analysis revealed prolonged disease-specific (p 5 .029) and overall (p 5 .024) survival in the excision compared to the biopsy group. Moreover, advanced staging was significantly linked to a shortened disease-free survival rate (p 5 .004). Biopsy versus local excision, N classification, stage disease, and re-resection achieved the significance level of 0.20 or less on univariate analysis and were subsequently
Histopathology Of the entire cohort, 30 specimens (56%) showed positive margins at the time of first diagnosis. Eight patients (15%) underwent further neck dissection, of which 6 patients (75%) showed pathologic evidence of nodal disease. The median and mean numbers of positive lymph nodes were 18.5 (range, 2–43) and 20.5, respectively. Cytokeratin 20 staining was positive in 100% (all of 39 patients), chromogranin-A in 88% (32 of 36), and NSE in 93% (15 of 16). The numbers represent the specimens in which immunohistochemistry were performed. E1016
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FIGURE 1. Disease-free survival curves for patients with Merkel cell carcinoma with respect to the tumor staging. Patients with staging III have a significant worse disease-free survival rate compared with patients with stage I and II.
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FIGURE 2. Kaplan–Meier curves for overall (A) and diseasespecific survival (B) after open biopsy or wide local excision. Patients with Merkel cell carcinoma undergoing wide local excision at the time of first diagnosis have a significant better overall and disease-specific survival rate than patients after open biopsy.
entered into a multivariable Cox proportional hazards model and stepwise model-building. The Cox regression multivariate model demonstrated that patients with MCC undergoing wide local excision as the initial way of tissue sampling had a significant better overall survival rate (p 5 .014) than patients undergoing open biopsy (see Figure 2).
DISCUSSION MCC frequently presents with locally or regionally recurrent disease and, therefore, primary aggressive treatment with lymph node biopsy and adjuvant radiation therapy is proposed in recent literature.9,10 Because of the rarity of this tumor entity and the unspecific presentation, first diagnosis is often delayed. Biopsies or non in sano excisions are very common. There is still limited data on optimal treatment regimens of the primary tumor as well as of recurrent disease. Therefore, we conducted a retrospective analysis of 54 patients with MCC undergoing either biopsy or wide local excision for diagnostic purposes, with a median follow-up of 86 months. Although our study was limited in numbers, it suggests wide local
LOCAL EXCISION FOR
MERKEL
CELL CARCINOMA
excision as the primary choice for diagnostic workup of patients with MCC. The median age of our patients at first presentation was 76 years, which is consistent with previous studies. In contrary to literature, which reports a male predominance in MCC,5,11 we observed equal sex distribution in the entire study group. Similar to previous studies, the preponderant site of occurrence was the head and neck region, followed by the extremities. In patients with MCC, high recurrence rates have been reported with local, regional, and distant recurrence from 3% to 14%, 12% to 26%, and 12% to 28%, respectively.12–14 Again, in our study, cohort similar locoregional (26%) and distant (22%) recurrence rates could be observed. Wide local resection margins for MCC have been controversial in the head and neck region.15–17 Initial publications proposed 1 to 2 cm resection margins for all tumor locations.18,19 Boccara et al20 adapted the German and American guidelines for diagnosis and therapy of MCC and proposed biopsy as means of histologic examination and thereafter a resection margin of 2 to 3 cm.20 Because of standard routine of open biopsy of skin tumors, wide local excision is rarely performed. In our current study, only 24 patients were treated with wide local excision of the primary tumor. Recurrent disease occurred in 17 of 30 patients after open biopsy and in 10 patients after wide local excision. Especially locoregional recurrence was found more in patients who underwent an open biopsy approach. Interestingly, the distribution of distant metastases was almost equal among the groups. Although adjuvant radiotherapy has been shown to improve locoregional control,14 positive resection margins at first diagnosis could not be redeemed by postoperative radiotherapy. This fact can be underlined by our observation that more patients died of the disease in case of open biopsy and, thus, positive margins at the initial presentation. Moreover, patients undergoing wide local excision had a significant better overall and disease-specific survival rate than patients who initially underwent open biopsy for diagnostic workup. In summary, we describe our experience in the management of a rare skin tumor entity. Our results are concomitant with previous studies showing a peak incidence in the elderly patient. We also observed high recurrence rates and poor patient outcome, despite the treatment used. Furthermore, our single-institutional study identified open biopsy as a prognostic factor for poor overall survival in patients with MCC. On the basis of our results, we therefore suggest an alteration of the treatment guidelines. Clinical suspicion of MCC should lead to wide local excision of the primary tumor site instead of diagnostic biopsies at the patients’ initial presentation.
Acknowledgment The authors thank Margit Hemetsberger, MD, for critical reading of the manuscript.
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