Incidence of Merkel cell carcinoma in renal transplant recipients

MCC and renal transplant

14. Heidland A, Bahner U, Vamvakas S. Incidence and spectrum of dialysis-associated cancer in three continents. Am J Kidney Dis 2000; 35: 347–351 15. Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs 2007; 67: 1167–1198 16. Layman AB, Engels EA. Kidney and bladder cancers among people with AIDS in the United States. J A I D S 2008; 48: 365–367 17. Pond F, Serpell JW, Webster A. Thyroid cancer in the renal transplant population: epidemiological study. Aust N Z J Surg 2005; 75: 106–109 18. Campion EC, Wangel AG, Lawrence JR. Hepatitis B antigen, autoantibodies and liver disease in a haemodialysis and transplantation unit. Aust N Z J Med 1975; 5: 314–318 19. Niu MT, Coleman PJ, Alter MJ. Multicenter study of hepatitis C virus infection in chronic hemodialysis patients and hemodialysis center staff members. Am J Kidney Dis 1993; 22: 568–573 20. Clifford GM, Rickenbach M, Polesel J et al. and the Swiss HIV Cohort Study. Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma. AIDS 2008; 22: 2135–2141 21. van Leeuwen MT, Grulich AE, McDonald SP et al. The association between immunosuppression and lip cancer after kidney transplantation. Cancer Epidemiol Biomarkers Prev 2009; 18: 561–569 22. van Leeuwen MT, Grulich AE, Webster AC et al. Immunosupression and other risk factors for early and late non-Hodgkin lymphoma after kidney transplantation. Blood 2009, May 14 [Epub ahead of print] 23. Vajdic CM, van Leeuwen MT, Webster AC et al. Cutaneous melanoma is related to immune suppression in kidney transplant recipients. Cancer Epidemiol Biomarkers Prev in press 24. Webster AC, Craig JC, Simpson JM et al. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15 183 recipients. Am J Transplant 2007; 7: 2140– 2151 Received for publication: 4.4.09; Accepted in revised form: 15.6.09

Nephrol Dial Transplant (2009) 24: 3231–3235 doi: 10.1093/ndt/gfp334 Advance Access publication 8 July 2009

Incidence of Merkel cell carcinoma in renal transplant recipients Virve Koljonen1 , Heli Kukko1 , Erkki Tukiainen1 , Tom B¨ohling2 , Risto Sankila3 , Eero Pukkala3 , Harri Sihto4 , Heikki Joensuu5 , Lauri Kyll¨onen6 and Heikki M¨akisalo6 1

Department of Plastic Surgery, Helsinki University Hospital, 2 Department of Pathology, Helsinki University and HUSLAB, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, 4 Laboratory of Molecular Oncology, Biomedicum Helsinki, 5 Department of Oncology and 6 Division of Transplantation, 4th Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland 3

Correspondence and offprint requests to: Virve Koljonen; E-mail: [email protected]

Abstract Background. The risk factors for Merkel cell carcinoma (MCC), a rare type of skin cancer, are poorly understood. Some evidence suggests that MCC is more common in individuals with abnormal immune function resulting from viral infection, autoimmune disease or organ transplantation. Methods. The national Renal Transplant Registry and the Finnish Cancer Registry data were searched for recipients

of a renal transplant who were diagnosed with MCC. The MCC diagnoses were confirmed using immunohistochemistry. Results. Three cases of MCC were detected among 4200 individuals who underwent renal transplantation from 1967 to 2005 [expected number 0.05, standardized incidence ratio (SIR) 66, 95% CI 14–194, P 0), the sample was considered positive. Each PCR product generated was treated with an ExoSAP-IT enzyme mix (product number 78201, USB Corporation, Cleveland, OH, USA) according to the manufacturer’s protocol and then sequenced by using BigDye3 termination chemistry and an ABI 3100 Genetic Analyzer (both from Applied Biosystems, Foster City, CA, USA). The sequences were compared with the reference sequences of Merkel cell polyomavirus isolates obtained from the National Center for Biotechnology Information (NCBI) Entrez Nucleotide database by using LaserGene 7.2 software (DNASTAR Inc, Madison, WI, USA). Statistical analysis The observed number of MCC cases was compared with the expected number of cases based on cancer incidence in the national population, stratified by age, gender, and calendar time. Standardized incidence ratios (SIRs) were calculated as observed to expected ratios. Exact 95% confidence intervals (CIs) were defined under the assumption that the observed number of cases followed a Poisson distribution.

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Merkel cell carcinoma (MCC) is an unusual primary neuroendocrine carcinoma of the skin. According to the surveillance, epidemiology and end results (SEER) registry of the United States, the annual incidence of MCC increased from 1.5 cases per million in 1986 to 4.4 cases per million in 2001 [1]. Early MCC can be cured by surgery with or without postoperative radiation therapy, whereas advanced MCC is currently considered incurable. MCC often gives rise to metastases in the regional lymph nodes, which decreases disease-specific survival to 52% [2], and when distant metastases are present, expected survival is short with fewer than 10% surviving for 3 years [3]. The age-specific incidence of MCC is highest among the elderly in the Caucasian population [1]. Only few MCCs are diagnosed in individuals younger than 50. In such cases, the disease is usually associated with immunosuppression [4]. The causative factors remain largely unknown [5], but several articles have linked immunosuppression to MCC by case reports and cancer registry or transplant registry linkage studies [4,6,7]. Recently, a new virus named as Merkel cell polyoma virus (MCPyV) was detected in ∼80% of MCCs [8]. Patients whose MCC contains the MCPyV genome generally have a more favourable disease course than those whose cancer does not contain the viral DNA [9]. The purpose of this study was to investigate the incidence of MCC among patients who have undergone renal transplantation. To our knowledge, none of the prior studies addressing the incidence of MCC following organ transplantation is based on a nationwide database. In Finland, all renal transplants are performed at a single centre (Helsinki University Central Hospital), which allows centralized monitoring of survival and adverse effects associated with the procedure. Subjects diagnosed with cancer are registered in Finland in a nationwide cancer registry (the Finnish Cancer Registry) with a coverage approaching to 100%, which allows identification of subjects diagnosed with MCC. In the present study, we identified subjects diagnosed with MCC from the files of the Finnish Cancer Registry and the national Transplant Registry, and reviewed the histological diagnoses. These two nationwide registries allow reliable assessment of the incidence of MCC among renal transplant recipients.

V. Koljonen et al.

Died of MCC 0.5

Regional lymph node and distant metastases at the time of the diagnosis Repeated local recurrences of the tumour 44/M 3

MCC, Merkel cell carcinoma; MCPyV, Merkel cell polyoma virus. a Age at the diagnosis with MCC. b Latency between a second renal transplant and the diagnosis of MCC.

66/M 2

Rheumatoid arthritis, amyloidosis, nephrotic syndrome

Azathioprine, cyclosporin Right cheek A, methylprednisolone

Yes

6

19 Azathioprine, methylprednisolone

Right earlobe No

Radical excision + neck dissection, postoperative radiation therapy, chemotherapy Radical excision + sentinel node biopsy, postoperative radiation therapy

Died of MCC 0.7 Neck metastases found 6 months after surgery 8b Radical excision, postoperative radiation therapy No Left cheek Cyclosporin A, methylprednisolone

Chronic autoimmune glomerulonephritis/chronic rejection Chronic autoimmune glomerulonephritis

Site of MCC

Presence of MCPyV in tumour Treatment of MCC Post-transplant immunosuppressive medication Agea / Patient gender Renal disease

We found a SIR as high as 66 (95% CI, 14–194) for a diagnosis of MCC among individuals who had undergone kidney transplantation. To the best of our knowledge, the current study is the first one to provide a SIR for the risk of MCC following renal transplantation. This SIR is based

Table 1. Demographic data of kidney transplant patients diagnosed with Merkel cell carcinoma

Discussion

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A total of 4200 individuals received a renal transplant during the study period, 1967–2005; this yielded a total of 36 811 person years at risk by the end of 2005. 60% were men, with the largest number of patients identified in the 45–59 age group (1516, 36%). Based on data from Finnish Cancer Registry and histopathological review of the tumour tissue samples, 172 patients (119 women and 53 men) were reported to FCR of being diagnosed with MCC within the time period 1979–2006. All the patients were Caucasian and mostly elderly. Only four patients (2.3%) were 0.1). Their age ranged from 44 to 68 at the time of the diagnosis. The latency period between a renal transplant and the diagnosis of MCC ranged from 6 to 19 years. The reason for renal transplant in all three cases was considered an autoimmune disease; two patients had chronic glomerulonephritis and one rheumatoid arthritis. Their mean age at the time of the MCC diagnosis was 59 years. All the patients were treated with methylprednisolone following the transplant; two also received azathioprine and two cyclosporin A. All MCCs occurred in the skin of the head, two in a cheek and one in an earlobe. The longest tumour diameters at diagnosis were 15 mm, 16 mm and 20 mm; two patients had local (stage I) disease (patients 1 and 3 in Table 1), whereas one patient (patient 2, Table 1) presented with regional and systemic metastases (stage III). Patient 1 was also diagnosed with several basal cell carcinomas and squamous cell carcinomas in the skin of the head and neck region. The MCCs were treated with surgery and postoperative radiation therapy. All three patients died from progressive MCC with a survival time after the diagnosis ranging only from 0.5 to 2.1 years. In a quantitative PCR analysis, Merkel cell polyoma virus was present in only one of the three MCCs.

Latency between transplant and MCC (years) Course of MCC

Results

68/M

Outcome

The study was approved by an Ethics Committee of Helsinki University Central Hospital. Permission to collect and analyse paraffin-embedded tumour tissue was obtained from the National Authority of Medicolegal Affairs, Finland.

1

Permissions

Died of MCC 2.1

3233 Survival after diagnosis of MCC (years)

MCC and renal transplant

3234

The proportions of skin cancers also differ among organ recipients from those found in the general population. Basal cell carcinomas are more frequent than squamous cell carcinomas in the general population, whereas the opposite may be the case among organ transplant recipients [32]. In the present study, MCCs were diagnosed 6–19 years after receiving a renal transplant, a latency time in line with case reports [11,33,34,35] and data from the Cincinnati Transplant Tumor Registry, where the mean time from renal transplant to the diagnosis of MCC was 7.5 years (range, from 5 months to 23 years) [4]. The rate of MCC increased from 0.15 cases per 100 000 in 1986 to 0.44 cases per 100 000 in 2001 [1], and agespecific incidence is highest in the most elderly, 4.28 per 100 000 in the 85+ age group [1]. In the literature, it was difficult to find standardized incidence ratios of MCC in organ recipients; this may be due to the rarity of the tumour and lack of proper registries. The rarity of the tumour makes it tempting to publish case reports and reciprocally makes it difficult to collect large series, producing a publication bias. Eventually we found that Williams et al. referred to a personal communication by Dr I Penn [11]; the approximate incidence of MCC in Cincinnati Transplant Tumor Registry was three cases per 1000 patients in 1997. Further, many of the compared variables (e.g. ages, mean ages, types of concurrent cancers) are not comparable as such, rather depending on the follow-up time and age of the patient at the time of the transplant operation. Therefore, we suggest that instead of constantly changing variables, the comparison should be based on absolute estimates like the standardized incidence ratio (SIR) or the absolute incidence such as cancers per 100 000 person years. These absolute estimates are comparable among different cohorts and eventually provide accurate and equal information, translated to better patient care. We conclude that incidence of MCC is very high among subjects who have received a renal transplant. MCCs are usually diagnosed only several years after transplant surgery. In this patient population, MCC appears often to have an aggressive clinical course, frequently resulting in a fatal outcome. Although MCCs are rare, the risk of MCC needs to be borne in mind when organ transplant has been carried out, since early detection and surgical removal might lead to cure. Other skin cancers than MCC are also common among renal transplant recipients, which places further emphasis on the importance of inspecting the skin as a part of the physical examination of these patients. Conflict of interest statement. None declared.

References 1. Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005; 89: 1–4 2. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003; 49: 832–841 3. Allen PJ, Bowne WB, Jaques DP et al. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 2005; 23: 2300–2309 4. Penn I, First MR. Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999; 68: 1717–1721

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on linkage of two nationwide registries that both cover the entire population of Finland. The largest epidemiological study on the incidence of MCC among organ transplant patients performed thus far is based on the Cincinnati Transplant Tumor Registry (now called the Israel Penn International Transplant Tumor Registry), which is a web-based registry that collects tumour data from organ transplant recipients worldwide. A report from this registry included 41 cases of MCC diagnosed following an organ transplant suggesting that the incidence of MCC may be increased among organ recipients, but no SIR could be provided [4]. An approximate incidence of MCC in the Cincinnati Transplant Tumor Registry is three cases per 1000 patients in 1997 [11]. Since the demographic features and follow-up times may differ markedly between study cohorts, we suggest that the cohorts are best compared using absolute estimates such as the SIR or the absolute incidence of cancers per 100 000 person years. None of the prior registry-based studies [4,6,7] included verification of the diagnosis of MCC using immunohistochemistry, which is a limitation, because the histopathological diagnosis of MCC may be demanding and MCC also lacks distinguishing clinical features [12]. The diagnosis of MCC should be confirmed by immunohistochemistry [13], since no tissue morphological features distinguish MCC with certainty from other small round blue cell tumours. Organ transplantation and subsequent immunosuppression are risk factors for some epithelial and nonepithelial cancers [14,15]. The risk of MCC related to any single immunosuppressive drug is difficult to estimate from the available data. The reports addressing the role of cyclosporin A in the pathogenesis of skin malignancies in organ transplant patients are conflicting [16,17], and these risks may be related to the degree of global immunosuppression rather than to any one specific drug [18,19]. Friedlaender et al. reported a terminally ill patient where withdrawal of cyclosprin may have resulted in the temporary regression of MCC [20]. Ultraviolet radiation may contribute to the development in MCC [21,22], and the risk of MCC may rise along with an increased exposure to solar UV-B [7]. Recently, a small polyomavirus with double-stranded DNA, MCPyV, was found to be clonally integrated in the MCC tumour genomes, suggesting a role for this virus in the pathogenesis of this disease [8]. MCPyV has been found in ∼70–80% of the MCCs examined [8,23,24,25,26]. Another polyomavirus, the BK virus, can cause haemorrhagic cystitis, urethral stenosis and interstitial nephritis leading to irreversible chronic allograft dysfunction in kidney transplant recipients [27,28]. MCCs that arise following an organ transplant may not be similar to those that occur in other patient populations. Our patients were relatively young in this survey in keeping with previous studies [4,29], and the clinical behaviour of the tumours was aggressive. All tumours were located in the head, but ∼50% of MCCs occur in skin of the head and neck area [30]. In the present study, only one of the three MCC cases was MCPyV positive, suggesting that MCPyV is not associated with development of MCC in all organ transplant recipients. Non-melanoma skin cancers are by far the most common type of malignancy among organ transplant recipients [31].

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