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Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma
© Kang et al.; licensee BioMed Central Ltd. 2012
Received: 11 July 2012
Accepted: 13 October 2012
Published: 17 October 2012
Merkel cell carcinoma (MCC) is a rare tumour of skin. This study is a retrospective audit of patients with MCC from St Vincent’s and Mater Hospital, Sydney, Australia. The aim of this study was to investigate the influence of radiotherapy (RT) on the local and regional control of MCC lesions and survival of patients with MCC.
The data bases in anatomical pathology, RT and surgery. We searched for patients having a diagnosis of MCC between 1996 and 2007. Patient, tumour and treatment characteristics were collected and analysed. Univariate survival analysis of categorical variables was conducted with the Kaplan-Meier method together with the Log-Rank test for statistical significance. Continuous variables were assessed using the Cox regression method. Multivariate analysis was performed for significant univariate results.
Sixty seven patients were found. Sixty two who were stage I-III and were treated with radical intent were analysed. 68% were male. The median age was 74 years. Forty-two cases (68%) were stage I or II, and 20 cases (32%) were stage III. For the subset of 42 stage I and II patients, those that had RT to their primary site had a 2-year local recurrence free survival of 89% compared with 36% for patients not receiving RT (p<0.001). The cumulative 2-year regional recurrence free survival for patients having adjuvant regional RT was 84% compared with 43% for patients not receiving this treatment (p<0.001). Immune status at initial surgery was a significant predictor for OS and MCCSS. In a multivariate analysis combining macroscopic size (mm) and immune status at initial surgery, only immune status remained a significant predictor of overall survival (HR=2.096, 95% CI: 1.002-4.385, p=0.049).
RT is associated with significant improvement in local and regional control in Merkel cell carcinoma. Immunosuppression is an important factor in overall survival.
Merkel Cell Carcinoma (MCC) is an aggressive cutaneous neoplasm with malignant neuroendocrine differentiation. It was first reported by Toker in 1972. It is a rare tumour that predominantly afflicts the elderly white population with a male predominance[2–9]. MCC has early local invasion, nodal involvement, distant metastases and a high rate of recurrence[10–13]. There is controversy internationally in the relative roles of surgery and RT in treatment. There have been no completed randomised controlled trials reported in this disease as yet. Treatment regimes are variable. As MCC has been shown to have high radiosensitivity, adjuvant RT (adj RT) is supported by a number of studies[7, 15–17]. Surgery followed by adj RT to the primary site as well as the lymphatic basin is recommended by some previous studies[8, 18–22]. Few studies examined the effect of immune status on of MCC[1, 2, 5, 6, 23]. This study is a single institutional retrospective study of consecutive patients with MCC at St Vincent’s and Mater hospitals, both tertiary referral hospitals in Sydney. The aim of this study was to investigate the influence of RT on the local and regional control of MCC lesions and survival of patients with MCC.
Methods and materials
Research was carried out in compliance with the Helsinki Declaration and this project was approved by the St Vincent’s Hospital Human Research Ethics Committee. Patients with a histologically proven diagnosis of MCC who presented between January 1996 and June 2007 to the St. Vincent’s and Mater Hospitals, Sydney, Australia were identified by the International Code of Diseases index from medical records database in anatomical pathology, RT and surgical departments.
Patient tumour and treatment characteristics were collected and analysed. Patient factors include age, sex and any history of immunosuppression. Immunosuppressed patients were either six transplant patients [heart (3), lung (2) and kidney (1)] or eight patients that had been on long term steroids. They included seven patients with connective tissue diseases [Ulcerative colitis, Pyoderma gangredorsum, Scleroderma, Myasthenia gravis, Psoriatic arthritis, Rheumatoid arthritis and multiple myeloma] and one patient with long term kidney cancer. Some of these patients also had diabetes mellitus. There were no patients who had diabetes alone without either being a transplant patient or had not been on long term steroids. Tumour factors recorded included tumour site, size, and involvement of regional lymph nodes, distant metastatic disease and overall staging. Treatment characteristics recorded included whether wide local excision (WLE) is used or not, regional dissection, RT to the primary and regional sites and the use of chemotherapy both in the adjuvant and definitive settings.
Patients were staged by a four-tiered staging system developed by Memorial Sloan-Kettering Cancer Centre (MSKCC). The system is the most commonly used staging system consistent with the American Joint Committee on Cancer. For staging, most patients underwent computed tomography (CT) of the chest, upper abdomen, and regional nodes.
Our departmental policy of RT of MCC is detailed below.
RT treatment of the primary site
The primary site is treated with 46-50Gy in 2 Gy fractions to an area of skin that includes the lesion or scar with a five cm margin. Compromise may need to be made for nearby dose limiting organs e.g. eyes. An electron or superficial/orthovoltage technique is often used.
RT treatment of the regional lymph nodes
The target for regional treatment is the draining lymph nodes and is given with same dose using megavoltage techniques. Gross disease may be boosted to a higher dose e.g. to 60 Gy. Bolus is used to cover any scars or drain sites to achieve full dose on operated skin that is thought to be at risk. The field treating the primary is junctioned to the regional field if field edges are within 5cm and there is no danger of unnecessary toxicity. Axillary fields are treated as per Fogarty et al..
IBM SPSS Statistic v 19.0 was used to conduct all statistical analyses. Univariate survival analysis of categorical variables was conducted with the Kaplan-Meier method together with the Log-Rank test for statistical significance. All patient, tumour and treatment factors were tested for association with each survival outcome in univariate analysis and those found to be significant were then entered into a multivariate model. Continuous variables were assessed using the Cox regression method. A p-value less than 0.05 was considered statistically significant.
Local recurrence free survival was defined as the time from initial diagnosis to the first local recurrence or date of last follow-up. Regional recurrence free survival was defined as the time between initial diagnosis and first regional recurrence. The disease-free interval was defined as the months between the date of initial diagnosis with MCC and the patient’s first recurrence of MCC or date of last follow-up. MCC-specific survival (MCCSS) was defined as the interval between initial diagnosis and the date of last follow-up; death from MCC was considered an event, and all other cases were censored. Overall survival (OS) was assessed as the interval between initial diagnosis and date of last follow-up; death from MCC or other causes was considered an event.
Sixty-seven patients with MCC were identified. Five patients presented stage IV disease. These five patients were treated with palliative intent and were excluded from the analysis. The reported analysis is therefore a study of radical treatment of 62 patients with stage I-III disease.
Summary characteristics for the patient cohort
Age at Initial Diagnosis
Immunocompromised at initial diagnosis
Types of immunosuppression
Primary site of MCC
Head & Neck
Primary macroscopic size
n=53; Median=15 (range 5-60mm)
Final surgical treatment for primary
Adjuvant RT to the Primary site
RT to the Regional Node site
Status at Last Follow-up
Died of Disease
Died of other/Unknown
Forty-three patients (69%) received adjuvant RT to their primary site. The other 19 patients did not receive primary site RT. Of these 19 patients, 9 presented with nodal disease only, with unknown primary site. The remaining 10 were stage I (n=9) and stage II (n=1). Thirty two stage I and II cases received adjuvant RT to their primary site which was completed in a median of 79.5 (range 49–338) days after the diagnosis of the primary MCC. Out of these 32 patients, 25 additionally received prophylactic RT to their regional nodes completed in a median of 78 (range 54–338) days from the date of primary diagnosis. There was no significant or unexpected RT treatment toxicity reported for this cohort. Twenty patients died of disease.
Treatment Patterns for Primary MCC
RT Adjuvant to Primary Site
Unknown Primary Site
Of the 20 stage III patients, 19 were clinically positive; one clinically negative patient had positive 1st echelon nodes on histology after sampling. Fifteen of these 20 had lymphadenectomy and adj RT, 3 patients received RT only to the nodes, and 2 patients had lymphadenectomy only. There were 7 patients who received chemotherapy, 5 of them were stage III patients. All these patients received chemotherapy concurrently. Only 1 of 67 had Positron Emission Tomography (PET) scan. Sentinel Lymph Node Biopsy (SLNBx) was done in only 1 patient.
Nine patients (14%) experienced a local recurrence of their MCC. Sixteen (26%) developed a regional recurrence; all loco-regional recurrences were observed in stage I or II patients. No stage III patients had regional relapses observed with a median follow-up of 44 months (range 7–115 months). Distant recurrence status was known for 57 patients and, of these, 16 (28%) recurred in a distant site (11 stage I/II; 5 stage III).
Impact of radiotherapy on survival
Local recurrence free survival
Regional recurrence free survival
Disease-free survival for RT to primary site
Disease-free survival for RT to regional site
Adj RT to the primary site or to the regional nodes was not found to improve MCCSS in the cohort.
Adj RT to the primary site or to the regional nodes was not found to improve OS in the cohort.
Influence of other factors on survival
Summary of univariate and multivariate survival results
Patient Age (years)
HR=2.096, 95%CI: 1.002-4.385, p=0.049*
Macroscopic Size (mm)
HR=1.034, 95%CI: 1.006-1.062, p=0.015*
MCC-specific survival and Overall survival
Patient sex, patient age, and primary site were not found to significantly influence MCCSS or OS. The macroscopic size (mm) of the tumour was also a significant predictor of OS on univariate analysis (HR=1.034, 95%CI: 1.006-1.062, p=0.015). However, in a multivariate analysis combining macroscopic size (mm) and immune status, only immune status remained a significant predictor of OS (HR=2.096, 95% CI: 1.002-4.385, p=0.049).
Analysis of the influence of the site of the primary MCC on DFS was conducted using categories for head & neck, limbs, and trunk (including 1 buttocks case). There was no significant difference in DFS between head & neck and limbs, or between limbs and trunk. Additional factors which were not found to significantly impact DFS included patient sex, patient age, macroscopic size (mm) of the tumour, and whether a patient was immunocompromised at the time of initial diagnosis.
RT as an important part of the treatment paradigm of MCC is supported by our study. Local recurrence free survival and regional recurrence free survival were significantly increased with the addition of RT to the primary site and regional lymph nodes respectively. The addition of these fields was associated with increased DFS for the whole cohort. However, the addition of RT was not found to influence overall or MCCSS. This may be due to small numbers, but may also be because this group of older patients have significant competing risks of death, and have a disease that metastasises early to distant sites out of the treatment volumes of loco-regional RT.
Immune status at diagnosis was associated with increased MCCSS and OS on multivariate analysis in our study. This is understandable in a disease that is associated with distant spread in the immune-compromised. Immunosuppression appears to be an important risk factor for MCC[1, 2, 5, 6, 23]. Immunosuppression enhances the development of MCC in patients with human immunodeficiency virus. They have a relative risk of 13.4 for MCC compared to the general population[22, 34]. Studies have shown high risk of developing MCC at a younger age in organ transplantation at presentation[22, 35]. Long-term immunosuppressive therapies such as chemotherapy and steroids are associated with aggressive forms of non-melanoma skin cancers[6, 23].
Our study does add to the field as it represents a collection of patients treated in a uniform fashion with real conclusions being able to be drawn. However it has significant limitations. It is a retrospective single institutional study, with treatments done in an era where newer advances such as PET and SLNBx have not been incorporated, and so the data could be regarded as obsolete. Polyomavirus was not known in the treatment era of this study. The role of polyomavirus in MCC is one of recent findings that may lead to better therapeutics for MCC[15, 36, 37]. Our study suggests that local and regional RT are worthwhile treatments for MCC and stratification for immunosuppression should be factored into any future trial design. The limitations of this study include a small sample size and lack of inclusion of new technologies such as PET, SLNBx, and the knowledge of polyomavirus. Randomised studies are needed to guide management and should include RT as treatment and should stratify for immune status at diagnosis.
This retrospective single institution study of 67 consecutive patients with MCC supports the use of RT to local and regional sites to enhance loco-regional control and hence DFS. RT was not found to increase MCC-specific or overall survival in this disease of older patients that metastasises early to distant sites out of the field of RT. Patients immunocompromised at diagnosis do poorly.
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