Skin Cancer as a Contraindication to Organ Transplantation

Transcription

1 American Journal of Transplantation 2005; 5: Blackwell Munksgaard Minireview Copyright C Blackwell Munksgaard 2005 doi: /j x Skin Cancer as a Contraindication to Organ Transplantation Clark C. Otley a,, Ryutaro Hirose b and Stuart J. Salasche c a Division of Dermatologic Surgery, Mayo Clinic, Rochester, Minnesota, USA b Department of Surgery, Division of Transplantation, University of California, San Francisco, California, USA c Division of Dermatology, University of Arizona Cancer Center, Tucson, Arizona, USA Corresponding author: Clark C. Otley, M.D., Otley.clark@mayo.edu Skin cancer is the most common malignancy worldwide. When patients with a history of skin cancer present for organ transplantation, the vast majority are appropriate candidates. However, there is little guidance in the literature regarding the advisability of transplantation in patients with a history of highrisk skin cancer. With limited allograft resources, it is important to allocate organs to patients who will derive the most benefit. Adverse outcomes that may be associated with prior skin cancer include recurrence, metastasis, or death from relapse or decreased quality of life from numerous new primary skin cancers. This review provides prognostic guidance to transplant physicians evaluating transplantation candidates who have a history of skin cancer. Key words: Basal cell carcinoma, immunosuppression, melanoma, metastasis, organ transplant, skin cancer, squamous cell carcinoma, transplantation Received 10 February 2005, revised and accepted for publication 2 June 2005 Background Among patients with a history of skin cancer who present for consideration of solid organ transplantation, the risk of recurrence or metastasis varies considerably. For most patients, the risk is minimal, and transplantation is appropriate. In contrast, patients with active metastatic skin cancer would not be considered candidates for transplantation. Between these extremes are patients who have a history of skin cancer with variable metastatic potential and who may conceivably harbor clinically and radiographically occult residual microscopic disease. Conceptually, the silent, residual skin cancer cells or micrometastases could proliferate more easily in the context of potent post-transplantation immunosuppression, resulting in recurrence or metastasis (1). In addition to the risk of recurrent skin cancer, a history of skin cancer identifies a group of patients who have an increased likelihood of de novo primary skin cancers developing at sites other than those of prior cancers. Rarely, the possibility of future de novo skin cancers might be a relative contraindication to transplantation. Although patients with a history of skin cancer are frequently evaluated for organ transplantation, this situation has not been addressed systematically in the transplantation or dermatology literature. We review the evaluation of these patients, the prognostic factors associated with skin cancer, which may assist in determining the appropriateness of transplantation and the limitations of the data available to guide these decisions. We present recommendations on when to avoid transplantation, when to proceed with transplantation and when to seek further detailed consultation with a transplant dermatologist for various types of skin cancer. Evaluation of Transplantation Candidates Who Have a History of Skin Cancer With limited availability of allografts, it is essential that organs be triaged to patients with the greatest likelihood of benefit. As with any malignancy, the optimal evaluation of candidates for solid organ transplantation with a history of skin cancer involves review of historical data, examination and assessment of the details of the prior cancers to estimate the risk of recurrence, metastasis or formation of new primary cancer (Table 1). For patients with a history of skin cancer that is not readily identifiable as low risk, transplant dermatologists and Mohs surgeons may be of assistance to assess the clinical, surgical and pathologic details of the prior skin cancer and estimate a prognosis, taking into account the time elapsed since the occurrence of the skin cancer. Radiologic imaging may be indicated on a case-by-case basis but is subject to false-positive and falsenegative findings. Positron emission tomography may be helpful in ascertaining any foci of metastatic melanoma, high-risk squamous cell carcinoma (SCC) or Merkel cell carcinoma, whereas computed tomography is only rarely helpful for detection of recurrent basal cell carcinoma (BCC) and other slow-growing tumors. 2079

2 Otley et al. Table 1: Evaluation of solid organ transplant candidates who have a history of skin cancer Obtain a complete history and perform a physical examination, paying specific attention to sites of prior skin cancers and palpating the regional nodal basin for high-risk skin cancers. Review clinical and pathologic details of prior skin cancers. Transplant dermatologists may be helpful in this regard. Using prognostic data, estimate the risk of recurrence, metastasis and development of new primary cancers. When estimating risk, consider the time elapsed since skin cancer was treated. Consult Table 2 for general recommendations on the appropriateness of transplantation. Assess risk of cancer recurrence, risk of end organ disease and risks of transplantation to determine transplant status. Consider the ethics of limited organ availability, which may differ depending on whether the donor is a living relative or a cadaver. If the potential for occult micrometastasis exists, radiographic staging should be performed before considering listing the patient on the organ transplant waiting list. Periodic examinations and imaging are appropriate for patients with prolonged waits for transplant organs. Effect of Transplant-Related Immunosuppression on Prior Skin Cancer Unfortunately, there are no prospective studies documenting outcomes related to prior skin cancers among patients who undergo transplantation and institution of immunosuppression (1). We can refer to small case series on outcomes from skin cancers before transplantation, examine the outcome of skin cancer arising after transplantation or extrapolate from validated prognostic indicators developed for use in immunocompetent patients. As a generalization, it appears that skin cancers that recur in patients after transplantation may be associated with a somewhat worse prognosis than in nonimmunosuppressed patients, but the precise degree remains uncertain. All sources of prognostic data have significant limitations. However, the limitations do not eliminate the need to make critical clinical decisions involving the appropriateness of transplantation in these patients. Prognostic Factors for Pre-Transplantation Skin Cancer The quality of prognostic staging data varies considerably among the various types of skin cancer. Reliable multivariate data are available for melanoma, univariate data may be helpful with SCC and the prognosis is almost always favorable for BCC. For less common tumors, assessment by an experienced transplant dermatologist or Mohs surgeon may be the most reliable means of assessing less well-defined risks. Table 2 outlines general recommendations for considering transplantation in patients with various skin cancers and specifies appropriate time frames for reassessment after the date of occurrence of the primary tumor. It is important to note that estimating the prognosis requires factoring in how recently the primary tumor occurred. Caution is recommended for all cancers with metastatic potential because the available data are primarily from nonimmunosuppressed patients and metastatic risk may be higher in immunosuppressed transplant patients. Allograft-Specific Considerations The type of allograft needed may influence considerations with respect to pre-transplantation skin cancer. With renal failure, patients can be maintained on hemodialysis while time elapses after a skin cancer occurrence, whereas for patients with hepatic or cardiac failure, a prolonged period off the organ transplant waiting list may prove fatal. However, the principle of triaging allografts to patients who will receive the most benefit would take precedence. Additionally, for patients who are candidates for a living-related kidney or liver allograft, the criteria may be different because transplantation would not deprive another candidate without a history of cancer from receiving a needed allograft. Basal Cell Carcinoma Risk of recurrence and death from pre-transplantation basal cell carcinoma The risk of death from BCC is vanishingly small. Therefore, in almost all cases, a history of BCC would not be a contraindication to transplantation when considering survival. Although rare, metastatic BCC is very difficult to treat, and thus it would represent an absolute contraindication to transplantation unless a disease-free interval of at least 5 years had passed since the last manifestation. Risk of multiple de novo nonmelanoma skin cancers post-transplantation Although death from nonmelanoma skin cancer (NMSC) is uncommon, pre-transplantation BCC or SCC is a marker for an increased likelihood of multiple de novo NMSCs after transplantation. Even among nonimmunosuppressed patients, in 44% of patients with prior BCC, another BCC develops within 3 years and in 6% an SCC develops within 3 years (2). Among nonimmunosuppressed patients with a history of SCC, new primary BCC develops in 45% and new primary SCC develops in 18% (2). Additionally, among patients who have had three or more NMSCs, the 3-year risk of having another skin cancer is 93% (2). Multiple NMSCs in transplant patients can decrease quality of life and may result in occasional high-risk skin cancers. Pretransplantation NMSC is not, however, a contraindication to transplantation, unless a patient has had many or very high-risk NMSCs. Rather, a history of NMSCs should be viewed as an opportunity to implement aggressive preventive treatments, including sun protection, under the close 2080 American Journal of Transplantation 2005; 5:

3 Table 2: Pre-transplantation skin cancer suggested assessment Skin Cancer and Organ Transplantation May Consult with Should not Re-evaluation interval after receive transplant receive primary tumor diagnosis Skin cancer transplant dermatologist transplant if denied transplant, y Basal cell carcinoma Primary X Metastatic, in remission X 5 Metastatic, not in remission X NA Squamous cell carcinoma Primary, low risk X Primary, high risk X 3 Metastatic, in remission X 3 5 Metastatic, not in remission X NA Melanoma In situ X Stage I X 3 10 Stage II X 5 10 Stage III X 10 Stage IV X 10 Merkel cell carcinoma Primary X 2 3 Metastatic, in remission X 3 5 Metastatic, not in remission X NA Kaposi sarcoma X NA Atypical fibroxanthoma X 3 Dermatofibrosarcoma protuberans X Sebaceous carcinoma X 3 Eccrine carcinoma X 3 Microcystic adnexal carcinoma X 3 Extramammary Paget disease X 3 NA: not applicable. surveillance of an experienced dermatologist before the patient is considered for organ transplantation. Squamous Cell Carcinoma Risk of recurrence and death from pre-transplantation squamous cell carcinoma In nonimmunosuppressed patients, cutaneous SCC has a 3.6% rate of metastasis (3). The rate of metastasis in immunosuppressed transplant recipients is nearly 7% (4). Thus, it appears that systemic immunosuppression approximately doubles the risk of a metastatic outcome. Multiple univariate features associated with an increased risk of metastatic potential for SCC have been identified (Table 3) (5). When assessing the risk of recurrence, metastasis and death from a pre-transplantation SCC, clinicians must weigh all relevant factors. A truly high-risk SCC could be a reason to delay consideration of transplantation. In the uncommon situation when transplantation is postponed because of a prior high-risk SCC, 90% of the metastatic risk passes within 3 years and it may be reasonable to reassess at that time (6). Patients with a history of metastatic SCC have a guarded prognosis; in immunosuppressed patients, 3-year survival is 56% and 5-year survival is 34% (7). Because of the sig- Table 3: Risk factors for metastasis with cutaneous squamous cell carcinoma Recurrent Deep invasion Large diameter Poor differentiation Perineural invasion High-risk anatomic sites (temple, scalp, ear and lip) Rapid growth Origin in scar Data from Rowe et al. (5). nificant risk of recurrence from metastatic SCC, a waiting period of 3 5 years would be appropriate before reevaluating a patient. Melanoma Risk of recurrence and death from pre-transplantation melanoma Contrary to common perception, most patients with melanoma do not die of the disease. The 5-year diseasespecific survival for all patients with invasive melanoma is approximately 80 85%. Thus, some patients with a history of very low-risk melanoma or a very remote history of invasive melanoma could be considered candidates for solid American Journal of Transplantation 2005; 5:

4 Otley et al. organ transplantation. The most reliable means to quantify the probability of survival of a patient with melanoma is staging with the 2001 American Joint Committee on Cancer system (8,9). Certain basic and well-recognized prognostic factors merit emphasis. Melanoma in situ, including lentigo maligna, is categorized as stage Tis and has a theoretical diseasespecific survival of 100%. Thus, for patients with in situ melanoma, exclusion from consideration for transplantation would be unwarranted. Approximately patients have melanoma in situ per year, all of whom could be considered potential transplant recipients. Clinical stage I or II disease, with melanoma localized to the primary tumor site, has an increasing risk of recurrence and death that correlates with increasing tumor thickness and histologic evidence of ulceration. Patients with melanoma less than 1 mm thick and without ulceration (stage I) generally have an excellent prognosis, with a 5-year survival of 95%, and could be considered for transplantation after a few years. Patients with very thick primary melanomas (>4 mm) have a high risk of micrometastasis and a poor prognosis, with a 5-year survival between 45% and 67%. For patients with a history of stage II or III melanoma, consideration for organ transplantation should be postponed for 5 10 years, and then only with the knowledge that recurrence is possible in a delayed time frame of years. In general, a history of metastatic melanoma would be an absolute contraindication to transplantation unless an extended disease-free interval has passed. The degree to which melanoma would behave more aggressively under the influence of immunosuppression is documented in uncontrolled case series only. With regard to patients with pre-transplantation melanoma, 30 patients from the Cincinnati Transplant Tumor Registry had a 19% recurrence after transplantation, which was within the range of expected risk (10). Data from the registry indicate a 30% mortality rate among patients in whom melanoma developed after transplantation, which is approximately 50% higher than in the general nonimmunosuppressed population (10). However, 69% of these patients had melanoma with Breslow thickness greater than 0.75 mm, and thus a 30% mortality rate may not be excessive. Penn recommended a waiting period of 5 years between the diagnosis of melanoma and the consideration of transplantation. We believe that prognosis should be assessed based on the specific case details, and then a risk-benefit analysis should be used to weigh the potential outcomes, both positive and negative, with and without transplantation. Uncommon Skin Cancers as a Pre-Transplantation Consideration Rare cutaneous neoplasms vary considerably in their biologic propensity to recur and metastasize. To guide pretransplantation considerations, we briefly review the biologic behavior, risk of recurrence and risk of metastasis and death related to uncommon cutaneous neoplasms. Consultation with a transplant dermatologist to review the specifics of individual cases may be helpful in determining the appropriateness of transplantation in patients with a history of these neoplasms, for which prognostic factors are less well defined. Merkel cell carcinoma Merkel cell carcinoma is an extremely aggressive cutaneous neoplasm, with an increased incidence after transplantation and a 5-year survival of 50 68% (11,12). Recurrence develops rapidly, with a median time to nodal metastasis of 7 8 months (12). Patients with nodal metastasis have a 5-year survival of less than 50%, in contrast to the 80% survival for patients without nodal disease (13). In Penn and First s (11) series of 41 patients with Merkel cell carcinoma after transplantation, only 29% of patients were alive and free from disease. In general, patients with a pre-transplantation history of Merkel cell carcinoma should have at least a 2- to 3-year period with no evidence of disease before considering a solid organ transplantation. Kaposi sarcoma Caused by human herpesvirus 8, Kaposi sarcoma is a lowgrade vascular malignancy involving the skin and viscera; the prevalence is increased 500 times in susceptible posttransplantation populations (14). In the uncommon event that a transplantation candidate would have Kaposi sarcoma before transplantation, the likelihood of recurrence and exacerbation with immunosuppression is high. Treatment of transplant-associated Kaposi sarcoma consists of cessation of immunosuppressive therapy, with an increased likelihood of allograft rejection and failure. In the largest detailed series of Kaposi sarcoma in transplant patients, Penn (14) noted that transplant recipients with cutaneous and oral Kaposi sarcoma had a 1% mortality, with a median follow-up of 25 months, whereas those with visceral involvement had a 41% disease-related mortality, with a median follow-up of 15 months. Until effective antiviral agents capable of eradicating human herpesvirus 8 become available, solid organ transplantation in patients with pre-existing Kaposi sarcoma may be associated with a high risk of allograft compromise. Atypical fibroxanthoma Atypical fibroxanthoma is an uncommon skin cancer that may be over-represented in patients after transplantation (15). Despite the aggressive histologic appearance of atypical fibroxanthoma, a lethal outcome has been reported in only three cases (16). With adequate local therapy, often with Mohs micrographic surgery, in a patient being considered for transplantation, atypical fibroxanthoma should be associated with a low risk of recurrence and transplantation could be reasonable (17). A waiting period of several 2082 American Journal of Transplantation 2005; 5:

5 Skin Cancer and Organ Transplantation years before reassessment may be warranted for large or complicated atypical fibroxanthoma. Dermatofibrosarcoma protuberans Dermatofibrosarcoma protuberans is a low-grade sarcoma of fibrous tissue with a minimal risk of metastasis. Owing to subclinical tumor extension, dermatofibrosarcoma protuberans has a high rate of local recurrence unless managed with diligent histologic margin control, particularly with Mohs micrographic surgery (18). Because there is no indication that immunity contains the growth of this tumor, a history of dermatofibrosarcoma protuberans in remission would not be a contraindication to transplantation. Sebaceous carcinoma Usually occurring in the periorbital region, sebaceous carcinoma has a low rate of metastasis (3%) but is prone to recurrence (19). Extraocular sebaceous carcinoma may metastasize in up to 40% of cases (20). Although not an absolute contraindication to transplantation, a history of sebaceous carcinoma may warrant passage of 3 years and subsequent examination by an ophthalmologist and dermatologist before offering the patient an organ transplant. Sweat gland carcinoma Sweat gland carcinomas comprise a heterogeneous group of neoplasms related by their origin in eccrine epithelium. Common subtypes include porocarcinoma, syringomatous carcinoma, ductal carcinoma, adenoid cystic carcinoma and mucinous eccrine carcinoma. Their behavior is highly variable: a 50% mortality is associated with ductal carcinoma and minimal mortality is associated with mucinous eccrine carcinoma (21). Because of the rarity of sweat gland carcinomas, consultation with a transplant dermatologist is the best approach to determine prognosis. Microcystic adnexal carcinoma A common subtype of eccrine carcinoma, microcystic adnexal carcinoma is rarely associated with metastasis (3%) or death (0.7%) and therefore would not be considered a contraindication to transplantation after dermatologic review of case details (22). Extramammary paget disease The primary importance of a history of extramammary Paget disease before transplantation is that the disease is associated with internal gastrointestinal or genitourinary malignancy in approximately 14 20% of cases (23,24). Invasive adenocarcinomatous extension may occur, with the potential for metastasis. Therefore, the passage of several years and a comprehensive gastrointestinal and genitourinary work-up for underlying malignancy would be recommended before transplantation. Management of Immunosuppression in Patients with Prior Skin Cancer In patients with prior skin cancer who are deemed to have an acceptable risk, transplant-associated immunosuppression may be tailored to minimize the risk of recurrent or de novo malignancies. Unfortunately, insufficient data exist to formulate specific recommendations, but general principles can be outlined. Observational studies have shown that cancer development correlates with the duration and intensity of immunosuppression. As the risk of rejection decreases and the risk of malignancy increases with time, it may be desirable to consider gradually decreasing immunosuppression while avoiding excessive risk of rejection. Regular review of transplant-associated immunosuppression may permit optimization of the risks and benefits. Preliminary data suggesting that mammalian target of rapamycin (mtor) inhibitors may be associated with a decreased incidence of skin cancer need to be confirmed by large-scale, long-term studies (25 27). Limitations of Data and Future Research As mentioned above, there are several limitations in the data that guide decisions. Although the prognostic staging system for melanoma is accurate, the data for SCC are suboptimal, requiring interpretation. Because of the excellent prognosis for BCC, transplantation is almost always appropriate. For the uncommon cutaneous neoplasms, clinicians must rely on a review of the case material and the expert opinion of an experienced dermatologist. A primary shortcoming is the limited data available on the effect of immunosuppression on the course of prior skin cancer. Thus, extrapolation of survival data from nonimmunosuppressed patients may underestimate the risks of recurrence and metastasis in immunosuppressed transplant patients; a cautious approach to skin cancer with metastatic potential is thus advised. These deficiencies are areas of active research for the International Transplant Skin Cancer Collaborative ( Conclusions The overriding principle of organ transplant allocation focuses on triaging allografts to patients who will benefit most, while minimizing the potential for allograft or patient loss. Most patients with a history of skin cancer would qualify as reasonable candidates for transplantation, owing to the low morbidity and high success of treatment for skin cancer. For patients with metastatic skin cancer or very high-risk tumors, the decision not to list the patient on the organ transplant waiting list may be relatively straightforward. Uncommonly, patients under consideration for transplantation will have a prior intermediate-risk skin cancer that warrants a detailed review of the risks of recurrence, American Journal of Transplantation 2005; 5:

6 Otley et al. metastasis and death. For patients with an intermediate or uncertain risk of recurrence, metastasis and death, consultation with a transplant dermatologist and reference to available prognostic data afford the best chance of making an optimal data-driven decision on the appropriateness of transplantation. Because of the unquantified effect of immunosuppression on pre-transplant malignancies, a cautious approach to recent skin cancers with metastatic potential is advised. References 1. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation 1993; 55: Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer in patients with a history of nonmelanoma skin cancer: a critical review of the literature and meta-analysis. Arch Dermatol 2000; 136: Chuang TY, Popescu NA, Su WPD, Chute CG. Squamous cell carcinoma: a population-based incidence study in Rochester, Minn. Arch Dermatol 1990; 126: Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002; 47: Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. J Am Acad Dermatol 1992; 26: Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 1992; 26: Martinez JC, Otley CC, Stasko T et al. Transplant-Skin Cancer Collaborative. Defining the clinical course of metastatic skin cancer in organ transplant recipients: a multicenter collaborative study. Arch Dermatol 2003; 139: Balch CM, Buzaid AC, Soong SJ et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 2001; 19: Balch CM, Soong SJ, Gershenwald JE et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2001; 19: Penn I. Malignant melanoma in organ allograft recipients. Transplantation 1996; 61: Penn I, First MR. Merkel s cell carcinoma in organ recipients: report of 41 cases. Transplantation 1999; 68: O Connor WJ, Brodland DG. Merkel cell carcinoma. Dermatol Surg 1996; 22: Pitale M, Sessions RB, Husain S. An analysis of prognostic factors in cutaneous neuroendocrine carcinoma. Laryngoscope 1992; 102: Penn I. Sarcomas in organ allograft recipients. Transplantation 1995; 60: Hafner J, Künzi W, Weinreich T. Malignant fibrous histiocytoma and atypical fibroxanthoma in renal transplant recipients. Dermatology 1999; 198: Rizzardi C, Angiero F, Melato M. Atypical fibroxanthoma and malignant fibrous histiocytoma of the skin. Anticancer Res 2003; 23: Davis JL, Randle HW, Zalla MJ, Roenigk RK, Brodland DG. A comparison of Mohs micrographic surgery and wide excision for the treatment of atypical fibroxanthoma. Dermatol Surg 1997; 23: Ratner D, Thomas CO, Johnson TM et al. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans: results of a multiinstitutional series with an analysis of the extent of microscopic spread. J Am Acad Dermatol 1997; 37: Muqit MMK, Roberts F, Lee WR, Kemp E. Improved survival rates in sebaceous carcinoma of the eyelid. Eye 2004; 18: Bassetto F, Baraziol R, Sottosanti MV, Scarpa C, Montesco M. Biological behavior of the sebaceous carcinoma of the head. Dermatol Surg 2004; 30: Wick MR, Goellner JR, Wolfe JT III, Su WPD. Adnexal carcinomas of the skin: I. Eccrine carcinomas. Cancer 1985; 56: Snow S, Madjar DD, Hardy S et al. Microcystic adnexal carcinoma: report of 13 cases and review of the literature. Dermatol Surg 2001; 27: O Connor WJ, Lim KK, Zalla MJ et al. Comparison of mohs micrographic surgery and wide excision for extramammary Paget s disease. Dermatol Surg 2003; 27: Pierie JPEN, Choudry U, Muzikansky A, Finkelstein DM, Ott MJ. Prognosis and management of extramammary Paget s disease and the association with secondary malignancies. J Am Coll Surg 2003; 196: Kahan BD, Knight R, Schoenberg L et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc 2003; 35(Suppl 3A): 25S 34S. 26. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004; 18: Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi s sarcoma. Transplantation 2004; 77: American Journal of Transplantation 2005; 5: