Cancer of the head and neck region in solid organ transplant recipients

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1 ORIGINAL ARTICLE Cancer of the head and neck region in solid organ transplant recipients Naomi Rabinovics, MD, 1 * Aviram Mizrachi, MD, 1 Tuvia Hadar, MD, 1 Dean Ad-El, MD, 2 Raphael Feinmesser, MD, 1 Dan Guttman, MD, 1 Thomas Shpitzer, MD, 1 Gideon Bachar, MD 1 1 Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, 2 Department of Plastic and Reconstructive Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Accepted 23 January 2013 Published online 2 April 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Solid organ recipients are at an increased risk of developing various malignancies. We investigated the incidence, clinical features, and outcome of patients diagnosed with head and neck cancer after organ transplantation. Methods. A retrospective analysis was undertaken of patients who underwent solid organ transplantation (kidney, liver, lung, heart) treated at our institution from 1992 to Results. Of 2817 organ recipients, 175 patients (6.1%) developed 391 head and neck malignancies. Cutaneous malignancies were the most common (93%): squamous cell carcinoma (SCC; 51%) and basal cell carcinoma (BCC; 42%). The average interval from transplantation to diagnosis of head and neck malignancy was 7.3 years, with liver recipients diagnosed earlier. Eighteen percent of patients presented with an aggressive pattern of head and neck cancer, including 24% of patients with cutaneous SCC. Conclusion. Organ transplantation recipients are at a higher risk to develop head and neck cancer with an aggressive behavior characterized by multiple recurrences and decreased survival. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: solid organ, transplantation, head and neck cancer, squamous cell carcinoma, skin INTRODUCTION Since its introduction in the 1960s, solid organ transplantation has become an accepted treatment for endstage organ failure, and the more recent development of novel immunosuppressive regimens has considerably improved patient survival. However, the long-standing immune suppression places patients at risk of toxicities, opportunistic infections, and neoplasms. 1 6 Solid organ transplantation recipients are at an increased risk of developing various malignancies. 1 3,7,8 The estimated rate of de novo malignancies in solid organ transplantation recipients is 3 to 5 times higher than in the general population, with the overall incidence ranging from 6% to 18%. 9,10 Nonmelanoma skin cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), are the most common, followed by non-hodgkin lymphoma and Kaposi sarcoma. 4,7,9,11 13 Rates of the more common malignancies in the general population, namely, lung, breast, and prostate cancer, are not higher in transplantation recipients. 9 Immunosuppressive treatments and sun exposure are both risk factors for the development of posttransplant malignancies, with the latter making the head and neck a common location. 3,13 The issue of sun exposure bares *Corresponding author: N. Rabinovics, Department of Otorhinolaryngology Head and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petach Tikva 49100, Israel. naomirab@gmail.com considerable risk, especially in warm climates such as the Mediterranean region. About half of all posttransplant malignancies have been reported to occur in the head and neck area. 1,11 Noncutaneous head and neck cancers account for 4% to 6% of posttransplant malignancies, which is higher than in the general population. 9 Pollard et al 11 identified nonlymphomatous malignancies in 11.2% of patients after a heart or lung transplantation, of which 96.4% were cutaneous and approximately half presented in the head and neck region. The risk of development of a posttransplant malignancy increases with time. 3,13 The estimated cumulative risk is 18% at 10 years after transplantation and increases to 50% at 20 years. 9 Head and neck malignancies in solid organ recipients tend to affect younger patients, have a more aggressive behavior, and a worse prognosis. 9,11 15 The purpose of the present study was to assess the incidence, clinical factors, and outcome of patients diagnosed with head and neck cancer after solid organ transplantation at a single tertiary medical center, and to identify factors predictive of recurrence. MATERIALS AND METHODS We conducted a retrospective search of the Cancer Registry of Rabin Medical Center, a major universityaffiliated hospital, for all patients who underwent solid organ transplantation (kidney, liver, lung, heart) who were treated in our institution between 1992 and The actual transplantations were performed from 1969 to HEAD & NECK DOI /HED FEBRUARY

2 RABINOVICS ET AL at the same or another institution. Patients who developed head and neck cancer after the transplantation (according to pathology and surgery reports) formed the study group. The patients medical charts (both paper and electronic) were reviewed, and the following data were extracted: demographics, pretransplantation diagnosis, type of transplantation, immunosuppressive medications, time to diagnosis of malignancy, type and location of malignancy, number of malignancies, treatment modalities, recurrence, follow-up, and final outcome. Exclusion criteria were missing data, presence of a tumor before transplantation, benign tumor, and diagnosis of in situ carcinoma or premalignant lesion. According to the National Comprehensive Cancer Network guidelines, patients were followed every 2 months during the first year, every 3 months during the second year, every 4 months during the third year, and then every 6 months. They underwent thorough physical examination and imaging studies when indicated. The study protocol was approved by the institution s research ethics board. Statistical analysis Continuous variables were expressed as mean 6 SD and categorical variables as percentages. Differences in mean continuous variables between groups were analyzed by t test and differences in categorical variables by chisquare test. Survival rate was calculated from the date of cancer diagnosis to the day of death or last follow-up, and were analyzed by the Kaplan Meier method; the logrank test was used to compare survival between groups. All reported p values are 2-tailed, with p <.05 considered statistically significant. For statistical analysis, we used SPSS software, version (SPSS, Chicago, IL). RESULTS Patient and clinical data A total of 2817 solid organ recipients were included in the study. After transplantation, 460 patients were treated for a posttransplant malignancy, representing 16% of all patients who underwent solid organ transplantation. A total of 175 patients (6.1% of total transplantation recipients) developed 391 head and neck malignancies; this consisted of our study cohort. The majority of the 2817 transplantation patients were men (n ¼ 1931; 69%) with a female:male ratio of 1:2.2, whereas the study group itself consisted of 37 women and 138 men (female:male ratio, 1:3.7). The mean age at diagnosis of the first malignancy was 56.8 years (range, years). The period of observation of the study group from transplantation to the end of follow-up, ranged from 1 to 41 years, with an average of 12.3 years. The time from transplantation to diagnosis of the first head and neck malignancy ranged from 2 months to 38 years, with an average of 7.3 years. One third of the tumors occurred within the first 3 years after transplantation and 78% developed cancer by the tenth year. Ten percent of the patients acquired malignancy 15 years or more after transplantation (Figure 1). The kidney was the most common organ transplanted (135 patients, 77%), followed by the liver (17 patients, 10%), lung (12 patients, 7%), and heart (11 patients, 6%). Twenty-two patients (13%) underwent 2 kidney transplantations (because of organ failure) and 4 patients (2%) underwent combined kidney and liver transplant. The most common indications for kidney transplant (n ¼ 135) were glomerular disease (n ¼ 21), adult-onset polycystic kidney disease (n ¼ 14), hypertension (n ¼ 12), and diabetes (n ¼ 9). The most common indication for liver transplant (n ¼ 17) was hepatitis C virus (n ¼ 7). Emphysema (n ¼ 8) and idiopathic pulmonary fibrosis (n ¼ 4) for lung transplant (n ¼ 12), and for heart transplant (n ¼ 11), ischemic cardiomyopathy (n ¼ 9). Patients were treated with the following immunosuppressive medications: prednisone (88%), cyclosporine (18%), tacrolimus (Prograf, 61%), mycophenolate mofetil (CellCept, 52%), azathioprine (Imuran, 16%), everolimus (6%), and sirolimus (11%). Analysis of type of transplantation by background and clinical factors revealed that kidney transplant recipients were diagnosed with head and neck cancer at a significantly younger age (mean, 55 years) than other solid FIGURE 1. The time interval from transplantation to diagnosis of the first head and neck cancer (n ¼ 168). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 182 HEAD & NECK DOI /HED FEBRUARY 2014

3 HEAD AND NECK CANCER AFTER TRANSPLANTS organs recipients (liver, 60.3 years; heart and lung, 62 years; p ¼.014). Liver transplant recipients were diagnosed significantly earlier (mean, 3.6 years from transplantation) than other solid organs recipients (kidney, 8 years; heart and lung, 5.4 years; p ¼.013). No correlation was found between type of malignancy and either age of onset or time to first diagnosis. Tumor characteristics The total number of posttransplantation head and neck malignancies identified was 391, and the average number of posttransplantation malignancies per patient was 2.2. Seventy-nine patients (45%) had 2 or more tumors; 30 patients (17%) had more than 4, and 3 patients (1.7%) had more than 11 (Figure 2). The vast majority of the posttransplantation head and neck cancers were cutaneous ones (93%; n ¼ 359). These included 51% cutaneous SCC (in 101 patients; n ¼ 198) and 42% cutaneous BCC (in 97 patients; n ¼ 163). The vast majority of the cutaneous SCC tumors were early stage I to II (69%, T1; 27%, T2), and the remainder were advanced stages III to IV (4%, T3 or T4; 3%, N1; 2%, N2; and 1%, M1). The noncutaneous malignancies (7% of all tumors; 1% of patients; n ¼ 30) included papillary thyroid carcinoma (2%, n ¼ 7), Kaposi sarcoma (both cutaneous and mucosal; 1%, n ¼ 6), SCC of the tongue (1%, n ¼ 5), in addition to other malignancies such as laryngeal cancer, lymphoma, and SCC of the oral cavity, nasal cavity, salivary duct, oropharynx, nasopharynx, and plasmacytoma (3%, n ¼ 12). Further analysis revealed that the majority of patients with cutaneous SCC were men (84%; p ¼.04). The most common primary sites were the nose (19%), forehead (13%), cheek (13%), scalp (12%), and ear (10%). There was no correlation between type of malignancy and time to first diagnosis or the age of onset. Aggressive malignancies An aggressive pattern was defined as persistent locally invasive tumor requiring repeated surgical procedures after subsequent positive margins; locally recurrent every documented recurrence of the disease according to pathology reports, after previous negative-margin resection; regional recurrence nodal involvement in the neck or parotid, and distant metastases included lung, bones, etc; and last, every tumor that required adjuvant therapy was defined as aggressive. Thirty-one patients (18%) presented with an aggressive course of posttransplantation malignancy; 26 of them were kidney transplant recipients. Four patients had 2 different aggressive malignancies each (including 2 patients with both BCC and SCC). The aggressive tumors consisted mostly of cutaneous SCC (24 patients), 2 patients with oral cavity SCC, 1 patient with BCC, 1 patient with papillary thyroid carcinoma, 1 patient with Kaposi sarcoma, 1 patient with plasmacytoma, and 1 patient with salivary duct carcinoma. Seven of the 31 patients (4%) had persistent disease, 20 (11%) had local recurrence, 18 (10%) had regional recurrence (to the neck, parotid), and 3 (1.7%) had distant metastases (lung, bones). Overall, 17 patients underwent adjuvant radiotherapy. Twenty-four of the 31 patients with aggressive disease had cutaneous SCC, representing 14% of the whole cohort and 24% of all patients were diagnosed with cutaneous SCC. Within this subgroup, 3 patients (3%) had persistent disease, 16 (16%) had local recurrence, 17 (17%) had regional recurrence, and 2 (2%) had distant metastases. Patients treated with Azathioprine (Imuran) had significantly more aggressive tumors than patients given other immunosuppressive drugs (p ¼.01). There was no correlation between the other immunosuppressive drugs and head and neck cancers or their degree of aggressiveness. Survival At the last follow-up, 111 patients (63%) were alive with no evidence of disease and 8 (5%) were alive with disease. Forty-five patients (26%) died during follow-up of other causes, and 11 (6%) died of the disease. Nine of the 11 patients who died of the disease had metastatic cutaneous SCC. Overall survival was 74% at 5 years and 51.6% at 10 years (Figure 3), and disease-specific survival for the whole cohort was 91.7% at 5 years and 89.4% at 10 years. FIGURE 2. Number of head and neck malignancies per patient (total malignancies ¼ 391). Fifty-five percent of patients had only 1 malignancy. FIGURE 3. Overall survival of solid organ transplantation recipients with posttransplantation head and neck cancer (n ¼ 173). HEAD & NECK DOI /HED FEBRUARY

4 RABINOVICS ET AL. During follow-up, recurrence was documented in 26 patients (15%). Disease-free survival rates were 80.8% at 5 years and 76.8% at 10 years. Separate analysis of the patients with cutaneous SCC (Figure 4) yielded a 5-year survival of 67.7% and 10-year survival of 40%. The differences from the group as a whole were not statistically significant. Five-year overall survival rates by type of transplantation were as follows: 76% for kidney transplants, 77% for liver, 57% for lung, and 43% for heart. These differences were not statistically significant. DISCUSSION The present study is one of the largest single-center investigations of the clinical findings and outcome of head and neck malignancies after solid organ transplantation. We report on 175 solid organ transplantation recipients who acquired head and neck malignancies over an 18-year period, representing 6.1% of all solid organ transplantation recipients in our study. The results are consistent with previous studies showing that organ transplantation recipients are at increased risk of head and neck cancer compared to the general population. 16 Skin cancer was the most common malignancy, mainly SCC, followed by BCC. Furthermore, our findings show that patients after undergoing solid organ transplantation tend to have multiple tumors with a more aggressive course, characterized by a high rate of persistent disease and locoregional recurrence. The increased incidence of malignancies after solid organ transplantation has been well established in the literature. 1 4,6,7,12 Head and neck cancers accounted for 15% of the total malignancies compared to 3% to 4% in the general population. Pollard et al 11 in a review of a series of 1069 cardiothoracic transplant recipients, found that 80 patients (7.4%) acquired head and neck cancer. FIGURE 4. Overall survival of patients with cutaneous squamous cell carcinoma (SCC) compared with patients with other head and neck malignancies. Note: 5-year survival for patients with SCC was 67.7% (broken line), whereas for patients with no SCC it was 83% (full line; n ¼ 173). M akitie et al 17 reported a 3.9% incidence of head and neck cancer (113 patients) in renal transplant recipients. The most common posttransplantation malignancies are nonmelanoma skin cancer, non-hodgkin lymphoma, and Kaposi sarcoma. 9 Several studies have shown that skin cancers are the most frequent malignancies after solid organ transplantation. 1,3,4,7,13 In our study, 93% of the posttransplantation head and neck malignancies were skin cancers, in line with the 96% rate reported in cardiothoracic transplant recipients 11 and the 80% rate reported in renal transplant recipients. 17 Most of the cutaneous malignancies were SCC (51%), followed by BCC (42%), whereas the reported ratio in the general population is reversed. 1,3,7,9,11 13,15 One percent of our transplantation recipients had noncutaneous malignancies, accounting for 7% of the total head and neck cancers. These included papillary thyroid carcinoma, Kaposi sarcoma, oral cavity, nasopharyngeal, and supraglottic SCC. The variety of noncutaneous malignancies is in accordance with other studies. 3,6,18,19 However, these are infrequent cases and were insufficient for statistical analysis. In the study by Pollard et al 11 in cardiothoracic transplant recipients, 3.6% of malignancies were noncutaneous, whereas in renal transplant recipients, the rate was only 0.8%. 17 Our results are in line with these studies. The mean age at onset of head and neck cancer in our study was 56.8 years; kidney transplant recipients were diagnosed at a younger age compared to recipients of other organ transplantations. This difference may be explained by the earlier age at transplantation or the suppressive medication prescribed after kidney transplant relative to other types of solid organ transplantation. The average 7.3-year interval from transplantation to first diagnosis of head and neck cancer in our cohort is close to the 8.4 years reported by Preciado et al 10 in 33 patients with SCC of the head and neck. This finding is compatible with the observation that nonlymphoproliferative malignancies develop in chronically immunosuppressed posttransplantation patients, as opposed to posttransplantation lymphoproliferative disorders, which usually occur early after solid organ transplantation. 10 In our study, liver transplant recipients were diagnosed earlier after transplantation than recipients of other solid organ transplantations. We also discovered that most cutaneous SCC patients were men, this was in line with previous studies. 1,3,4 Cutaneous SCC in organ transplantation recipients is more aggressive than in immune-competent patients. 1 3,12,14,15 Moreover, it tends to occur at a younger age, with an increased number of primary tumors, deep tissue invasion, high recurrence rate, and need for treatment with adjuvant radiation. 2 The risk of developing metastases, mostly nodal, in immune-competent patients is low, estimated as 2% to 5% Our cohort had a high incidence of aggressive head and neck cancer (18%). Although most patients with cutaneous SCC were early stage tumors according to the TNM staging system, 24% of them presented with an aggressive pattern. Three percent presented with repeated positive surgical margins or persistent tumors, 16% with regional recurrences, and 2% with distant metastases. It should be mentioned that although Mohs surgery is a powerful method for treating skin cancer, it was not used routinely 184 HEAD & NECK DOI /HED FEBRUARY 2014

5 HEAD AND NECK CANCER AFTER TRANSPLANTS on our patients. Our SCC recurrence rate is higher than the 13% reported by Lott et al 15 and the Expert Group on Renal Transplantations. 23 In other studies, the overall recurrence and metastatic rates were estimated to be 7% to 9%. 8,9,14 The high rate of aggressive cutaneous SCC in our study may be explained by the climate and the cumulative lifetime exposure of ultraviolet radiation in the Mediterranean region, where our study took place. The high occurrence of multiple primary malignancies supports the aggressive nature of the tumors. 1,6 We found an average of 2.2 tumors per patient, with half the cohort presenting with 2 malignancies or more. The earlier study in cardiothoracic transplant recipients reported a similar average of 2.3 malignancies per patient. 11 Smoking and alcohol are well-established risk factors for SCC of the head and neck. 18,19 Sunlight exposure in our region is another important risk factor for cutaneous head and neck malignancies. 1 Immunosuppressive medications and ultraviolet radiation have a synergistic effect on organ recipients, predisposing them to cutaneous malignancies. The first, impair the tumor surveillance mechanism of lymphocytes, whereas the latter alters the p53 suppressor gene in cutaneous cells predisposing them to neoplasia. These risk factors, coupled with newer potent immunosuppressive medications, improve transplantation recipients survival and consequently extend their exposure to these drugs. 1,3 The combination of all of these factors increases the risk of developing posttransplantation head and neck cancer. 1,13 It has been shown by Otley et al 24 and others 3,15 that cessation of immunosuppression in renal transplant recipients decreased the incidence of nonmelanoma skin cancer and prolonged disease-free survival. Among the immunosuppressive drugs known to have carcinogenic effects are azathioprine (Imuran) and calcineurin inhibitors (tacrolimus, cyclosporine). 12,13 In our study, the patients treated with azathioprine had more aggressive tumors, posing a surgical challenge in terms of achieving local or regional control. Therefore, the prescription of immunosuppressive medication should be considered with caution. Organ recipients, specifically those receiving Imuran, should be monitored closely for new evolving malignancies with early and decisive surgical interventions. 1,13 The 5-year survival rate in the present study was 74%. Overall survival at 5 years was significantly lower for patients with cutaneous SCC (67%) than patients with other head and neck cancers. The present study was limited by its retrospective design and lack of data on alcohol intake and smoking, known major risk factors for SCC of the head and neck. In addition, data on the specific incidence of cutaneous head and neck cancer in the general population were lacking or not adjusted to age and geographic location. This is largely because of the fact that many skin lesion excisions and biopsies are performed in outpatient settings and therefore some pathological results are not reported. This is a well-known limitation mentioned in other studies. However, the fact that there may be more patients with unreported tumors contributes to an even higher incidence of posttransplantation head and neck cancer. CONCLUSION In conclusion, solid organ recipients are at increased risk for developing head and neck malignancies (6%), at approximately double the incidence in the general population. They tend to have multiple tumors with an aggressive course. Clinicians should be alert to these findings during follow-up after transplantation. Special attention should be addressed to men after liver and kidney transplant because liver recipients developed head and neck cancer earlier after the transplantation and kidney recipients were diagnosed at an earlier age. Changing to less toxic immunosuppressive agents should be considered. Currently, there are no specific guidelines for posttransplantation patients with head and neck cancers. Therefore, head and neck surgeons should maintain a high index of suspicion on the appearance of new skin lesions or neck masses. Long-term follow-up of these patients is crucial and could lead to early recognition of posttransplantation malignancies, thereby reducing morbidity and mortality. Owing to the aggressive nature of these tumors, surgeons may tend to favor more radical procedures and adjuvant therapy. Further studies are needed on head and cancer after solid organ transplantation with adjustments of the general population data on cutaneous head and neck cancer to age and geographic location. REFERENCES 1. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med 2003;348: Moloney FJ, Kelly PO, Kay EW, Conlon P, Murphy GM. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg 2004;30(4 Pt 2): Moloney FJ, Comber H, O Lorcain P, O Kelly P, Conlon PJ, Murphy GM. 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6 RABINOVICS ET AL. 15. Lott DG, Manz R, Koch C, Lorenz RR. Aggressive behavior of nonmelanotic skin cancers in solid organ transplant recipients. Transplantation 2010;90: Marur S, Forastiere AA. Head and neck cancer: changing epidemiology, diagnosis, and treatment. Mayo Clin Proc 2008;83: M akitie AA, Lundberg M, Salmela K, Kyll onen L, Pukkala E. Head and neck cancer in renal transplant patients in Finland. Acta Otolaryngol 2008; 128: Duvoux C, Delacroix I, Richardet JP, et al. Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 1999;67: Scheifele C, Reichart PA, Hippler Benscheidt M, Neuhaus P, Neuhaus R. Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas among 1515 patients after liver transplantation. Oral Oncol 2005;41: O Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS. Incidence of cervical node involvement in metastatic cutaneous malignancy involving the parotid gland. Head Neck 2001;23: Veness MJ, Palme CE, Morgan GJ. High-risk cutaneous squamous cell carcinoma of the head and neck: results from 266 treated patients with metastatic lymph node disease. Cancer 2006;106: Veness MJ, Porceddu S, Palme CE, Morgan GJ. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007;29: EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.6.2. Cancer risk after renal transplantation. Skin cancers: prevention and treatment. Nephrol Dial Transplant 2002;17 Suppl 4: Otley CC, Coldiron BM, Stasko T, Goldman GD. Decreased skin cancer after cessation of therapy with transplant-associated immunosuppressants. Arch Dermatol 2001;137: HEAD & NECK DOI /HED FEBRUARY 2014