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Journal of Plastic, Reconstructive & Aesthetic Surgery (2015) xx, 1e6
Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management Philippa C. Jackson a,*, Katy Wallis b, Victoria Allgar c, Michael J. Lind d, Paul R.W. Stanley e a
Department of Plastic Surgery, Leeds General Infirmary, Leeds, United Kingdom Department of Plastic Surgery, University Hospitals Coventry & Warwickshire, Coventry, United Kingdom c Department of Statistics, Hull & York Medical School, Hull, United Kingdom d Department of Oncology, Castle Hill Hospital, Hull, United Kingdom e Department of Plastic Surgery, Castle Hill Hospital, Hull, United Kingdom b
Received 16 May 2014; accepted 13 December 2014
KEYWORDS Merkel cell carcinoma; Skin cancer; Treatment; Yorkshire
Summary Introduction: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumour of the skin. The incidence is rising and it is associated with sun exposure and immunosuppression. Our aim was to perform a 10-year retrospective review of MCC treated in East Yorkshire and to examine disease progression, surgical and adjuvant management, and outcomes. Methods: A 10-year retrospective review was undertaken of patients identified through the histopathology database. Case notes and digital patient records were examined for patient demographics, disease characteristics, management and outcome. Disease stage was calculated using the 2010 AJCC TNM classification. Results: Thirty-seven patients with complete records were included. Twenty-one patients were male and 16 female, with mean age 76.7 years at presentation. Pre-malignant or malignant skin changes were documented in 15 patients, and immunosuppression in 15 patients. Mean duration of lesion was 17.5 weeks. Following diagnosis 22/37 patients underwent further surgery with 11 patients undergoing sentinel lymph node (LN) biopsy. LN disease was palpable at presentation in 8 patients. Three year survival is 40%. Conclusions: There is no standardised management of MCC and randomised trials are challenging due to relatively small numbers. There has been little progress made in terms of improving survival. Development of a national database for patients with this condition would
* Corresponding author. Plastic Surgery Department, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, United Kingdom. E-mail address: [email protected] (P.C. Jackson). http://dx.doi.org/10.1016/j.bjps.2014.12.021 1748-6815/ª 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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P.C. Jackson et al. allow prospective data collection and more accurate assessment of current treatment protocols and their efficacy. Level of Evidence: IV ª 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction
Results
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour of the skin. Originally described by Toker in 19721 it was initially thought to be an indolent disease but experience of this malignancy has demonstrated it to be a highly aggressive process. The natural history of the disease is predictable with spread via lymphatics before metastatic disease presents. The reported incidence of MCC is on the rise2 and this is likely multifactorial. MCC typically affects older generations and as the population ages skin malignancies associated with increasing age, immunosuppression and lifetime sun exposure are increasing. In particular MCC has demonstrated a significant increase in age-adapted incidence.3 Other contributing factors to a rising incidence include improved pathological examination and diagnosis, and a higher index of suspicion for skin cancer in general. Recently the discovery of Merkel cell polyomavirus infection (MCPyV) has been linked to MCC and the role of this infection and possible influence are under investigation.4,5 Treatment of MCC is a controversial issue and includes surgery, radiotherapy and chemotherapy. In East Yorkshire the Plastic Surgery department undertakes the management of patients diagnosed with MCC. There is currently no clear consensus locally, nationally or internationally on the best practice for managing these patients. As a result we decided to analyse our local population who have MCC, examine our treatment and outcomes, and determine whether we could draw any conclusions on best management.
Patient demographics and tumour characteristics
Methods Patients with a diagnosis of MCC between 2001 and 2011 were identified through a database kept prospectively by the histopathology department at Hull and East Yorkshire (HEY) NHS Trust. This search included those patients whose diagnosis was made in another hospital and their details transferred to HEY NHS Trust for discussion at the multidisciplinary team meeting. A retrospective review of the notes was performed. Data collected included basic patient demographic details, past medical history, tumour characteristics and treatment undertaken including surgical and adjuvant therapies. The tumours were staged according to the American Joint Committee on Cancer (AJCC) Staging Manual 2010.2 Data is presented descriptively: The mean (sd) for continuous data and n (%) for categorical data. Kaplan Meier survival curves were drawn for time from diagnosis to death or last follow-up, with a, log rank test to compare stage at presentation. All analyses were undertaken on SPSS (v19).
Forty-two patients were identified through the database as having a diagnosis of MCC. Five patients were excluded due to unavailability of their notes for review or incomplete documentation. Therefore 37 patients were included of which 21 were male and 16 were female, the mean age at presentation was 76.7 years (median 79 years, range 53e93 years). In 34 patients the median duration of the lesion prior to presentation was 12 weeks (range 4e104 weeks). Location of the primary tumours were as follows e head and neck 17 (46%), upper limb 7 (19%), trunk 3 (8%), lower limb 10 (27%) (Figure 1). Treatment was undertaken by the Plastic Surgery department in 84% of cases (31 patients), with the remainder of cases under the care of Dermatology (3 patients), Otolaryngology (2 patients) and Maxillofacial surgeons (1 patient). Fifteen patients (40.5%) were noted to have or have had a diagnosis of a skin malignancy (BCC or SCC, n Z 10) or a predisposing skin condition (Bowen’s disease or actinic keratosis n Z 5) prior to or concurrently with the diagnosis of MCC. Eleven patients (30%) were identified as being immune-compromised due to haematological malignancy, other primary organ malignancy and immunosuppression following organ transplant. Disease stage at presentation is shown in Figure 2. Stage I disease was diagnosed in 40.5% of patients at presentation, stage II disease in 27%, stage III disease in 21.5%, and stage IV disease in 8% of patients. Staging was not possible in one patient whose tumour size was not commented upon.
Figure 1
Location of primary tumour.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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MCC in East Yorkshire
3 positive in a further 3 patients (total 11 patients (29.7%) with evidence of nodal disease at presentation). SLNB was negative in 5 patients, all of whom remained free of regional lymph node disease although 1 developed distant metastases. Block dissections were performed for 12 patients e 5 with palpable lymph node disease at presentation, 1 with nodes visible on CT scan, 2 with positive SLNB, and 4 who developed palpable disease at a later stage (3 months (n Z 2), 4 months and 10 months respectively).
Metastasis
Figure 2 Disease stage at presentation using AJCC 2010 staging guidelines.
Diagnosis Diagnosis was made by excision biopsy in 23 cases, incision biopsy in 13 cases and shave biopsy in 1 case. Of the 23 excision biopsies 12 were complete on histological analysis (52%; 32% of all biopsies performed). Diagnosis was made following biopsy by a hospital specialist in 86% of cases. There was no uniform histological presentation of tumour information.
Management Primary lesion Thirteen patients (35%) had no further surgery following the biopsy to confirm diagnosis. Of these, 2 patients had stage IV disease at presentation, 4 patients had another primary malignancy, 5 were considered unfit for further surgery, and 2 patients survived. The median duration of survival following diagnosis of MCC was 7 months (range 1e82 months). Two survivors were a 65-year old woman with a 3 mm stage Ib MCC on the nose which was completely excised, and a 92-year old man with a 3.5 cm stage IIb MCC on the leg which was also completely excised. Both patients were followed up to 3 years and then discharged. Twenty-two patients (59%) underwent wide local excision (WLE) with 0.5e3 cm peripheral margins and depth from ‘to fascia’ to ‘full thickness’. Histology demonstrated clear margins in 73% of WLE cases, and of the incomplete excisions 4 patients (67%) went on to have a complete second wide excision. No specimens with a deep margin including fascia or muscle returned an incomplete excision. One patient underwent a block dissection (but no WLE) 10 months after a complete excision biopsy, and one patient had excision of local recurrence 7 months following complete excision biopsy. Median survival after diagnosis of MCC, following WLE, is 19.5 months (range 4e86 months).
Metastatic disease was present in 3 patients at the time of diagnosis and subsequently developed in 13 patients (see Figure 3 for site of metastatic disease). Median survival from diagnosis of MCC is 13 months overall (range 2e82 months), and following the diagnosis of metastatic disease median survival is 4 months (mean 9.3 months, range 0.5e33 months). Recurrent disease occurred in 6 patients (16%).
Adjuvant therapy Post-operative radiotherapy was performed in 1 case and palliative radiotherapy in 9 cases. Eight patients received chemotherapy with the standard regime being carboplatin and etoposide. One patient received topetacan as a second line chemotherapy treatment, and one patient received ifosfamide in addition to carboplatin and etoposide.
Survival At 1 year following diagnosis survival was 65%, at 2 years 49%, at 3 years 40% and at 4 years survival was 35% (Figure 4). Survival was related to disease stage at diagnosis with high stage disease resulting in poorer survival as expected (Figure 5).
Discussion We have described one of the largest series of MCC. This has shown MCC to be an aggressive neuroendocrine malignancy
Regional lymph nodes Lymph node disease was palpable in 8 patients (22%) at presentation and sentinel lymph node biopsy (SLNB) was
Figure 3 Site of metastatic disease. For each patient if metastases developed at multiple sites these have been counted separately.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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Figure 4
Overall mortality for MCC patients.
with a high mortality rate. The data presented here supports previous evidence that it affects predominantly an older population, and that it is associated with UV exposure, evidenced by conditions known to be caused by sun exposure in 40.5% of this population. We have demonstrated a strong association with immunosuppression in line with other studies.6 Management of the primary tumour is not standardised but it is widely accepted that complete surgical excision is required. Excision margins are poorly qualified in the literature and in the past Mohs micrographic surgery has been shown to have comparable outcomes with standard surgical excision.7 The variation in excision and depth margins taken in a single institution in our data suggests standardisation would be beneficial and excision including deep fascia as a minimum is recommended. This is supported by current guidelines published by the National Comprehensive Cancer Network (NCCN), which state that a
Figure 5
1e2 cm margin including deep investing fascia should be taken.8 Disease free survival in patients who underwent WLE after tissue diagnosis was higher than those who had no further surgery, but overall survival was not affected in our cohort. This is likely reflective of concurrent comorbidity at the time of diagnosis. Lymph node disease was present in approximately 30% of patients at presentation, once again indicating the highly aggressive behaviour of this malignancy. Given that 4 more patients developed lymph node disease, 3 within 4 months of presentation, it is possible that had SLNB been performed an even higher percentage of patients would have been found to have lymph node disease at presentation and therefore a higher disease stage. SLNB was demonstrated to upstage 50% of patients in a study from Australia9 and identified occult disease in 30% of patients in an American study.10 The relevance of the status of the regional nodes lies in the need for further surgery and precise staging of the disease to provide accurate prognostic information.11 Had SLNB demonstrated positive nodal disease in those patients who subsequently developed lymph node metastases the data presented here on patient mortality according to disease stage would be more accurate. At present our mortality data according to stage demonstrates that stage I and II disease have poorer than expected outcomes and it is possible that this is secondary to clinical, rather than pathological, nodal assessment and staging. Post-operative adjunctive radiotherapy was not commonly used in our department and this modality was reserved for local disease control following recurrence or to manage metastatic disease symptoms. However a review of the literature has revealed that radiotherapy is considered an appropriate alternative for inoperable MCC with
Survival per stage of disease at presentation for 100 months.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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MCC in East Yorkshire comparable outcomes,12 and it is as efficacious as block dissection in regional control when used in isolation.13 It has also been found to be effective in reducing the risk of locoregional recurrence in a prospective randomised trial for stage I disease.14 Authors recommend routine application of post-operative radiotherapy to reduce locoregional recurrence.15e17 The NCCN guidelines suggest considering radiotherapy for all patients with MCC at any stage, and to include the lymph node basin in those with negative SLNB if the primary site is on the head and neck.8 However, the physical and social impact of a radiotherapy regime must be taken into consideration, particularly in an elderly population with multiple co-morbidites. Post-operative adjunctive therapies are now considered routinely in any patient diagnosed with MCC and the precise modality and dosage used is recorded to facilitate future analysis. Taking this information and our own experience into consideration we agree with Lyhne et al.18 that ideal initial management should include WLE, SLNB, and post-operative radiotherapy. The role of CT and PET to assess nodal and distant disease spread is yet to be established19 but assessment of metastatic disease should clearly also play a role in the initial assessment and management of these patients. Furthermore, reducing immunosuppression has been shown to occasionally cause regression of MCC although this may be challenging to achieve.20 Whilst the data presented here is from relatively small numbers of patients this is comparable to other case series reported in the literature and of note there is no significant improvement in survival. The information continues to support the suppositions around who is affected by MCC and how the disease behaves including its natural history. Development of a national database would allow prospective data collection, simplify entry into clinical trials, and permit accurate assessment of current treatment protocols and their efficacy. We believe this would be best done in the context of centralised specialist multidisciplinary teams to support standardised and consistent post surgical adjuvant treatments and allow research into future outcomes.
Conclusion MCC is a rare malignancy with rising incidence, which is still poorly understood and affects elderly and immunosuppressed people with a history of sun exposure. Assessment and management of patients with this condition remain contentious and the path to a clear and concise gold standard of care is hampered by small case numbers and variation in local management, as acknowledged by the NCCN.8 Further work is required to qualify the role of chemotherapy and the optimal excision margins, as well as the ongoing work being undertaken with a connection to the polyomavirus. In addition, the importance of immunosuppression requires further examination and clinicians should have an increased index of suspicion when considering skin malignancy in a patient known to be immunosuppressed. We advocate WLE with clearance at the peripheral margin but importantly to include deep fascia as a minimum wherever possible, and SLNB. Raising awareness of the highly malignant nature of this disease and its
5 propensity for the immunosuppressed with primary care physicians and patients may reduce time to presentation and therefore improve outcomes. Finally considering the rarity of this condition we feel a national registry or database and minimum reporting dataset for histological analysis would add to the knowledge base of this condition in the long term.
Ethical approval Not required.
Funding None declared.
Conflict of interests None declared.
References 1. Toker C. Trabecular carcinoma of the skin. Arch Dermatol 1972;105(1):107e10. 2. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005;89(1):1e4. 3. Agelli M, Clegg LX, Becker JC, Rollison DR. The etiology and epidemiology of Merkel cell carcinoma. Curr Probl Cancer 2010;34:14e37. 4. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 2008; 319(5866):1096e100. 5. Sastre-Garau X, Peter M, Avril M-F, et al. Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. J Pathol 2009;218(1):48e56. 6. Penn I, First MR. Merkel cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999;68(11):1717e21. 7. 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;23:929e33. 8. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: Merkel cell carcinoma. Version 1. 2014. Available at: www.nccn.org. 9. Howle J, Veness M. Sentinel lymph node biopsy in patients with Merkel cell carcinoma: an emerging role and the Westmead hospital experience. Australas J Dermatol 2012;53(1):26e31. 10. Fields RC, Busam KJ, Chou JF, et al. Recurrence and survival in patients undergoing sentinel lymph node biopsy for Merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol 2011;18(9):2529e37. 11. Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. Am J Acad Dermatol 2010;63(5):751e61. 12. Pape E, Rezvoy N, Penel N, et al. Radiotherapy alone for Merkel cell carcinoma: a comparative and retrospective study of 25 patients. J Am Acad Dermatol 2011;65(5):983e90. 13. Fang LC, Lemos B, Douglas J, Iyer J, Nghiem P. Radiation monotherapy as regional treatment for lymph node positive Merkel cell carcinoma. Cancer 2010;116(7):1783e90. 14. Jouary T, Leyral C, Dreno B, et al. Adjuvant prophylactic regional radiotherapy versus observation in stage I Merkel cell
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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6 carcinoma: a multicentric prospective randomized study. Ann Oncol 2012;23(4):1074e80. 15. Medina-Franco H, Urist MM, Fiveash J, Heslin MJ, Bland KI, Beenken SW. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8(3):204e8. 16. Khan L, Barnes EA. Radiotherapy for Merkel cell carcinoma: a review of the literature. J Skin Cancer 2012 [Epub]. 17. Howle JR, Hughes TM, Gebski V, Veness MJ. Merkel cell carcinoma: an Australian perspective and the importance of addressing the regional lymph nodes in clinically node-negative patients. J Am Acad Dermatol 2012;67(1):33e40 [Epub Oct 2011].
P.C. Jackson et al. 18. Lyhne D, Lock-Andersen J, Dahlstrom K, et al. Rising incidence of Merkel cell carcinoma. J Plast Surg Hand Surg 2011;45(6): 274e80. 19. Colgan MB, Tarantola TI, Weaver AL, et al. The predictive value of imaging studies in evaluating regional lymph node involvement in Merkel cell carcinoma. J Am Acad Dermatol 2012; 67(6):1250e6. 20. Muirhead R, Ritchie DM. Partial regression of MCC in response to withdrawal of azathioprine in an immunosuppressioninduced case of metastatic Merkel cell carcinoma. Clin Oncol 2007;19(1):96.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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Journal of Plastic, Reconstructive & Aesthetic Surgery (2015) xx, 1e6
Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management Philippa C. Jackson a,*, Katy Wallis b, Victoria Allgar c, Michael J. Lind d, Paul R.W. Stanley e a
Department of Plastic Surgery, Leeds General Infirmary, Leeds, United Kingdom Department of Plastic Surgery, University Hospitals Coventry & Warwickshire, Coventry, United Kingdom c Department of Statistics, Hull & York Medical School, Hull, United Kingdom d Department of Oncology, Castle Hill Hospital, Hull, United Kingdom e Department of Plastic Surgery, Castle Hill Hospital, Hull, United Kingdom b
Received 16 May 2014; accepted 13 December 2014
KEYWORDS Merkel cell carcinoma; Skin cancer; Treatment; Yorkshire
Summary Introduction: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumour of the skin. The incidence is rising and it is associated with sun exposure and immunosuppression. Our aim was to perform a 10-year retrospective review of MCC treated in East Yorkshire and to examine disease progression, surgical and adjuvant management, and outcomes. Methods: A 10-year retrospective review was undertaken of patients identified through the histopathology database. Case notes and digital patient records were examined for patient demographics, disease characteristics, management and outcome. Disease stage was calculated using the 2010 AJCC TNM classification. Results: Thirty-seven patients with complete records were included. Twenty-one patients were male and 16 female, with mean age 76.7 years at presentation. Pre-malignant or malignant skin changes were documented in 15 patients, and immunosuppression in 15 patients. Mean duration of lesion was 17.5 weeks. Following diagnosis 22/37 patients underwent further surgery with 11 patients undergoing sentinel lymph node (LN) biopsy. LN disease was palpable at presentation in 8 patients. Three year survival is 40%. Conclusions: There is no standardised management of MCC and randomised trials are challenging due to relatively small numbers. There has been little progress made in terms of improving survival. Development of a national database for patients with this condition would
* Corresponding author. Plastic Surgery Department, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, United Kingdom. E-mail address: [email protected] (P.C. Jackson). http://dx.doi.org/10.1016/j.bjps.2014.12.021 1748-6815/ª 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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P.C. Jackson et al. allow prospective data collection and more accurate assessment of current treatment protocols and their efficacy. Level of Evidence: IV ª 2015 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Introduction
Results
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour of the skin. Originally described by Toker in 19721 it was initially thought to be an indolent disease but experience of this malignancy has demonstrated it to be a highly aggressive process. The natural history of the disease is predictable with spread via lymphatics before metastatic disease presents. The reported incidence of MCC is on the rise2 and this is likely multifactorial. MCC typically affects older generations and as the population ages skin malignancies associated with increasing age, immunosuppression and lifetime sun exposure are increasing. In particular MCC has demonstrated a significant increase in age-adapted incidence.3 Other contributing factors to a rising incidence include improved pathological examination and diagnosis, and a higher index of suspicion for skin cancer in general. Recently the discovery of Merkel cell polyomavirus infection (MCPyV) has been linked to MCC and the role of this infection and possible influence are under investigation.4,5 Treatment of MCC is a controversial issue and includes surgery, radiotherapy and chemotherapy. In East Yorkshire the Plastic Surgery department undertakes the management of patients diagnosed with MCC. There is currently no clear consensus locally, nationally or internationally on the best practice for managing these patients. As a result we decided to analyse our local population who have MCC, examine our treatment and outcomes, and determine whether we could draw any conclusions on best management.
Patient demographics and tumour characteristics
Methods Patients with a diagnosis of MCC between 2001 and 2011 were identified through a database kept prospectively by the histopathology department at Hull and East Yorkshire (HEY) NHS Trust. This search included those patients whose diagnosis was made in another hospital and their details transferred to HEY NHS Trust for discussion at the multidisciplinary team meeting. A retrospective review of the notes was performed. Data collected included basic patient demographic details, past medical history, tumour characteristics and treatment undertaken including surgical and adjuvant therapies. The tumours were staged according to the American Joint Committee on Cancer (AJCC) Staging Manual 2010.2 Data is presented descriptively: The mean (sd) for continuous data and n (%) for categorical data. Kaplan Meier survival curves were drawn for time from diagnosis to death or last follow-up, with a, log rank test to compare stage at presentation. All analyses were undertaken on SPSS (v19).
Forty-two patients were identified through the database as having a diagnosis of MCC. Five patients were excluded due to unavailability of their notes for review or incomplete documentation. Therefore 37 patients were included of which 21 were male and 16 were female, the mean age at presentation was 76.7 years (median 79 years, range 53e93 years). In 34 patients the median duration of the lesion prior to presentation was 12 weeks (range 4e104 weeks). Location of the primary tumours were as follows e head and neck 17 (46%), upper limb 7 (19%), trunk 3 (8%), lower limb 10 (27%) (Figure 1). Treatment was undertaken by the Plastic Surgery department in 84% of cases (31 patients), with the remainder of cases under the care of Dermatology (3 patients), Otolaryngology (2 patients) and Maxillofacial surgeons (1 patient). Fifteen patients (40.5%) were noted to have or have had a diagnosis of a skin malignancy (BCC or SCC, n Z 10) or a predisposing skin condition (Bowen’s disease or actinic keratosis n Z 5) prior to or concurrently with the diagnosis of MCC. Eleven patients (30%) were identified as being immune-compromised due to haematological malignancy, other primary organ malignancy and immunosuppression following organ transplant. Disease stage at presentation is shown in Figure 2. Stage I disease was diagnosed in 40.5% of patients at presentation, stage II disease in 27%, stage III disease in 21.5%, and stage IV disease in 8% of patients. Staging was not possible in one patient whose tumour size was not commented upon.
Figure 1
Location of primary tumour.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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MCC in East Yorkshire
3 positive in a further 3 patients (total 11 patients (29.7%) with evidence of nodal disease at presentation). SLNB was negative in 5 patients, all of whom remained free of regional lymph node disease although 1 developed distant metastases. Block dissections were performed for 12 patients e 5 with palpable lymph node disease at presentation, 1 with nodes visible on CT scan, 2 with positive SLNB, and 4 who developed palpable disease at a later stage (3 months (n Z 2), 4 months and 10 months respectively).
Metastasis
Figure 2 Disease stage at presentation using AJCC 2010 staging guidelines.
Diagnosis Diagnosis was made by excision biopsy in 23 cases, incision biopsy in 13 cases and shave biopsy in 1 case. Of the 23 excision biopsies 12 were complete on histological analysis (52%; 32% of all biopsies performed). Diagnosis was made following biopsy by a hospital specialist in 86% of cases. There was no uniform histological presentation of tumour information.
Management Primary lesion Thirteen patients (35%) had no further surgery following the biopsy to confirm diagnosis. Of these, 2 patients had stage IV disease at presentation, 4 patients had another primary malignancy, 5 were considered unfit for further surgery, and 2 patients survived. The median duration of survival following diagnosis of MCC was 7 months (range 1e82 months). Two survivors were a 65-year old woman with a 3 mm stage Ib MCC on the nose which was completely excised, and a 92-year old man with a 3.5 cm stage IIb MCC on the leg which was also completely excised. Both patients were followed up to 3 years and then discharged. Twenty-two patients (59%) underwent wide local excision (WLE) with 0.5e3 cm peripheral margins and depth from ‘to fascia’ to ‘full thickness’. Histology demonstrated clear margins in 73% of WLE cases, and of the incomplete excisions 4 patients (67%) went on to have a complete second wide excision. No specimens with a deep margin including fascia or muscle returned an incomplete excision. One patient underwent a block dissection (but no WLE) 10 months after a complete excision biopsy, and one patient had excision of local recurrence 7 months following complete excision biopsy. Median survival after diagnosis of MCC, following WLE, is 19.5 months (range 4e86 months).
Metastatic disease was present in 3 patients at the time of diagnosis and subsequently developed in 13 patients (see Figure 3 for site of metastatic disease). Median survival from diagnosis of MCC is 13 months overall (range 2e82 months), and following the diagnosis of metastatic disease median survival is 4 months (mean 9.3 months, range 0.5e33 months). Recurrent disease occurred in 6 patients (16%).
Adjuvant therapy Post-operative radiotherapy was performed in 1 case and palliative radiotherapy in 9 cases. Eight patients received chemotherapy with the standard regime being carboplatin and etoposide. One patient received topetacan as a second line chemotherapy treatment, and one patient received ifosfamide in addition to carboplatin and etoposide.
Survival At 1 year following diagnosis survival was 65%, at 2 years 49%, at 3 years 40% and at 4 years survival was 35% (Figure 4). Survival was related to disease stage at diagnosis with high stage disease resulting in poorer survival as expected (Figure 5).
Discussion We have described one of the largest series of MCC. This has shown MCC to be an aggressive neuroendocrine malignancy
Regional lymph nodes Lymph node disease was palpable in 8 patients (22%) at presentation and sentinel lymph node biopsy (SLNB) was
Figure 3 Site of metastatic disease. For each patient if metastases developed at multiple sites these have been counted separately.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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Figure 4
Overall mortality for MCC patients.
with a high mortality rate. The data presented here supports previous evidence that it affects predominantly an older population, and that it is associated with UV exposure, evidenced by conditions known to be caused by sun exposure in 40.5% of this population. We have demonstrated a strong association with immunosuppression in line with other studies.6 Management of the primary tumour is not standardised but it is widely accepted that complete surgical excision is required. Excision margins are poorly qualified in the literature and in the past Mohs micrographic surgery has been shown to have comparable outcomes with standard surgical excision.7 The variation in excision and depth margins taken in a single institution in our data suggests standardisation would be beneficial and excision including deep fascia as a minimum is recommended. This is supported by current guidelines published by the National Comprehensive Cancer Network (NCCN), which state that a
Figure 5
1e2 cm margin including deep investing fascia should be taken.8 Disease free survival in patients who underwent WLE after tissue diagnosis was higher than those who had no further surgery, but overall survival was not affected in our cohort. This is likely reflective of concurrent comorbidity at the time of diagnosis. Lymph node disease was present in approximately 30% of patients at presentation, once again indicating the highly aggressive behaviour of this malignancy. Given that 4 more patients developed lymph node disease, 3 within 4 months of presentation, it is possible that had SLNB been performed an even higher percentage of patients would have been found to have lymph node disease at presentation and therefore a higher disease stage. SLNB was demonstrated to upstage 50% of patients in a study from Australia9 and identified occult disease in 30% of patients in an American study.10 The relevance of the status of the regional nodes lies in the need for further surgery and precise staging of the disease to provide accurate prognostic information.11 Had SLNB demonstrated positive nodal disease in those patients who subsequently developed lymph node metastases the data presented here on patient mortality according to disease stage would be more accurate. At present our mortality data according to stage demonstrates that stage I and II disease have poorer than expected outcomes and it is possible that this is secondary to clinical, rather than pathological, nodal assessment and staging. Post-operative adjunctive radiotherapy was not commonly used in our department and this modality was reserved for local disease control following recurrence or to manage metastatic disease symptoms. However a review of the literature has revealed that radiotherapy is considered an appropriate alternative for inoperable MCC with
Survival per stage of disease at presentation for 100 months.
Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
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MCC in East Yorkshire comparable outcomes,12 and it is as efficacious as block dissection in regional control when used in isolation.13 It has also been found to be effective in reducing the risk of locoregional recurrence in a prospective randomised trial for stage I disease.14 Authors recommend routine application of post-operative radiotherapy to reduce locoregional recurrence.15e17 The NCCN guidelines suggest considering radiotherapy for all patients with MCC at any stage, and to include the lymph node basin in those with negative SLNB if the primary site is on the head and neck.8 However, the physical and social impact of a radiotherapy regime must be taken into consideration, particularly in an elderly population with multiple co-morbidites. Post-operative adjunctive therapies are now considered routinely in any patient diagnosed with MCC and the precise modality and dosage used is recorded to facilitate future analysis. Taking this information and our own experience into consideration we agree with Lyhne et al.18 that ideal initial management should include WLE, SLNB, and post-operative radiotherapy. The role of CT and PET to assess nodal and distant disease spread is yet to be established19 but assessment of metastatic disease should clearly also play a role in the initial assessment and management of these patients. Furthermore, reducing immunosuppression has been shown to occasionally cause regression of MCC although this may be challenging to achieve.20 Whilst the data presented here is from relatively small numbers of patients this is comparable to other case series reported in the literature and of note there is no significant improvement in survival. The information continues to support the suppositions around who is affected by MCC and how the disease behaves including its natural history. Development of a national database would allow prospective data collection, simplify entry into clinical trials, and permit accurate assessment of current treatment protocols and their efficacy. We believe this would be best done in the context of centralised specialist multidisciplinary teams to support standardised and consistent post surgical adjuvant treatments and allow research into future outcomes.
Conclusion MCC is a rare malignancy with rising incidence, which is still poorly understood and affects elderly and immunosuppressed people with a history of sun exposure. Assessment and management of patients with this condition remain contentious and the path to a clear and concise gold standard of care is hampered by small case numbers and variation in local management, as acknowledged by the NCCN.8 Further work is required to qualify the role of chemotherapy and the optimal excision margins, as well as the ongoing work being undertaken with a connection to the polyomavirus. In addition, the importance of immunosuppression requires further examination and clinicians should have an increased index of suspicion when considering skin malignancy in a patient known to be immunosuppressed. We advocate WLE with clearance at the peripheral margin but importantly to include deep fascia as a minimum wherever possible, and SLNB. Raising awareness of the highly malignant nature of this disease and its
5 propensity for the immunosuppressed with primary care physicians and patients may reduce time to presentation and therefore improve outcomes. Finally considering the rarity of this condition we feel a national registry or database and minimum reporting dataset for histological analysis would add to the knowledge base of this condition in the long term.
Ethical approval Not required.
Funding None declared.
Conflict of interests None declared.
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Please cite this article in press as: Jackson PC, et al., Merkel cell carcinoma in East Yorkshire: A case series and literature review of current management, Journal of Plastic, Reconstructive & Aesthetic Surgery (2015), http://dx.doi.org/10.1016/j.bjps.2014.12.021
