Skin cancers after liver transplantation: What to do?
Article Outline
Skin cancers are the most common malignancies in organ transplant recipients in general [1], and this appears to be the case also in liver transplant recipients (LTR) [2], [3], [4]. However, while skin diseases have been widely studied in kidney and heart transplant patients, in-depth reports on LTR are sparse [5], [6], [7], [8]. Most data concerning skin cancers in LTR are briefly provided in series dealing with tumoral or other complications after liver transplantation (LT). Although skin cancers occurring in LTR share a number of clinical features with tumors developing in recipients of other transplants, there seem to exist some epidemiological differences which could be due to factors specifically related to LT, such as a relatively lower incidence of skin carcinomas and a possibly higher proportion of Kaposi's sarcoma as compared to transplantations of other organs. The cumulative risk for skin carcinomas increases with length of immunosuppression; therefore physicians caring for LTR should be familiar with the management of long-term complications, particularly considering that the number of LTs performed during childhood is increasing. Because of the lack of specific data on LTR, part of these guidelines inevitably result from the experience obtained on recipients of other organ transplants. This review will nevertheless attempt to highlight the specific aspects concerning the liver transplant population.
A review of the literature reveals that the majority of skin tumors in LTR are accounted for by skin carcinomas (95%), followed by Kaposi's sarcoma and melanoma (Table 1). Other rare skin tumors (such as Merkel cell carcinoma and anogenital cancers), known to be increased in transplant patients [1], have also been occasionally reported in LTR [9], [10].
Table 1. Incidence and distribution of skin cancers in liver transplant recipients worldwide
| Origin | Ref. | No of patients with skin cancer | BCC | SCC | BCC+SCC | Melanoma | Kaposi's sarcoma | Other skin cancers |
|---|---|---|---|---|---|---|---|---|
| Dallas 1993 | 2 | 9/556 (1.6%) | 5 p | 2 p | 2 p | – | 1 | – |
| Berlin 1997 | 9 | 8/458 (1.6%) | 2 p | 3 p | 1 p | – | 1 | Merkel cell carcinoma |
| Pittsburgh 1997 | 15 | 35/1657 (2.1%) | 16 t | 13 t | NA | 4 t | 2 | – |
| Pittsburgh 1998 | 16 | 24/1000 (2.4%) | 9 p | 11 p | 0 | 2 p | 2 | – |
| Pittsburgh 2001 | 13 | 35/1000 (3.5%) | NA | NA | NA | 2 p | 2 | – |
| Groningen 2001 | 10 | 12/174 (6.9%) | 5 p | 6 p | 1 p | – | 1 (HIV) | Vulvar carcinoma |
| Barcelona 2001 | 14 | 14/134 (10.2%) | 16 t | 5 t | NA | – | – | – |
| Boston 2002 | 7 | 34/151 (22.5%) | 16 p 23 t | 23 p 56 t | NA | 6 p, 7 t | NA | – |
| London 2002 | 4 | 13/1140 (1.1%) | 5 p | 6 p | 1 p | – | 1 | Bowen ‘s disease |
| Besançon 2002 | 6 | 12/86 (14%) | 11 t | 7 t | NA | – | – | – |
| Dallas 2002 | 3 | ?/1421 41 t | 16 t | 25 t | NA | 2 | – | |
| Pamplona 2005 | 8 | 27/170 (16%) | 15 p 21 t | 16 p 22 t | 4 p |
1. Skin carcinomas
1.1. Epidemiology
The incidence of skin cancers increases with the duration of immunosuppression, reportedly reaching 70% of renal transplant patients 20 years post-transplant. Because of the shorter follow-up as compared with renal transplant recipients, the risk in LTR has not been accurately assessed, but could be similar. In two studies, it was found that the relative risk for non-melanoma skin cancer is 20–70-fold higher in LTR as compared to the matched general populations [8], [10]. The cumulative patient risk for skin and lip cancer was estimated to 4 and 13% after 5 and 10 years respectively, which is equivalent to the risk in renal transplant patients of the same country [11]. While in early data from the Cincinnati Transplant Tumor Registry (containing 329 tumors developed in 324 LTR), skin and lip cancers accounted for 15% of the total number of cancers [12], in most recent publications this percentage is much higher, ranging from 30 to 52% [3], [4], [10], [13], [14]. A direct comparison between groups is difficult since some series provide the number of tumors and others the number of patients; furthermore, post-transplant lymphoproliferative diseases were included in most [2], [3], [9], [10], [13], [14] but not in all series [4], [15], [16].
The prevalence of skin cancers in various groups of LTR worldwide was reported to vary from 1.1 to 22.5% (Table 1). Differences in epidemiological methods and follow-up are not the only explanation for these discrepancies, and the overall incidence is likely to be underestimated by many authors. Indeed, a study performed in Boston showed that out of 151 LTR who responded to a questionnaire, 34 (22.5%) with a median follow-up longer than 4 years after LT mentioned having had post-transplant skin carcinomas [7]. Reportedly these had been often removed by primary care physicians rather than by physicians in transplant centers.
1.2. Clinical features
The interval between LT and the diagnosis of skin malignancy is similar to that observed in kidney and heart transplant patients and varies from 3 to 5 years for patients grafted after the age of 50 years [4], [6], [15], [16]. It is shorter in patients older at transplantation. These figures show that data presently available on skin cancers concern mostly the oldest patients. While squamous cell carcinoma (SCC) is the most common skin cancer in transplant patients (as opposed to basal cell carcinoma—BCC—which outnumbers SCC in non-immunosuppressed patients), the reversal of the SCC:BCC ratio observed in other organ transplant recipients (4:1) does not seem to be as pronounced in LTR; indeed, in several series concerning LTR, SCC and BCC are almost equally represented [4], [8], [9], [10], [15]. In our experience, BCC outnumber SCC in LTR, in keeping with a Spanish study [14]. This could be due to a relatively short follow-up, given that the SCC:BCC ratio increases with time post-graft. In Dallas, early studies reported a higher prevalence of BCC than SCC [2], but the same group subsequently found SCC to outnumber BCC [3]. One study with a median follow-up longer than 4 years found a SCC:BCC ratio at 2.4:1 [7]. Most skin carcinomas are located on sun-exposed areas, especially the head and neck, followed by the limbs, the trunk and the hands [4], [6], [7], [8], [15], [16]. In two studies where the lips were considered separately, this location concerned 10–33% of patients with skin carcinomas [8], [10]. LTR reportedly also develop multiple skin carcinomas [6], [7], [16]. In one study, 34 patients developed 56 SCC, 23 BCC and 7 melanomas. 9 of the 34 patients (26%) had more than one type of skin cancer, and 16 of them (47%) had multiple lesions of the same type [7]. Multiple SCC increases the risk of aggressive course, and metastatic spread has been reported in several studies [2], [4]. Skin cancers may be associated with warts, premalignant lesions, such as actinic keratoses and/or Bowen's disease [6], [15]. Keratoacanthoma, an epithelial skin tumor clinically and histologically indistinguishable from highly differentiated SCC and considered equivalent to SCC in transplant patients, seems to be less frequent in LTR comparatively with other organ transplant patients. All these lesions may clinically mimic each other, therefore the precise diagnosis requires histological examination.
1.3. Risk factors
The incidence of skin cancer in transplant patients may be lowered by reducing risk factors and by screening high-risk individuals. As with recipients of other organs, the pathogenesis of skin carcinoma involves multiple intrinsic and extrinsic factors including mainly sun exposure and immunosuppressive treatment. Most in-depth pathogenic studies on genetic risk factors and human papillomavirus infections have been performed in kidney transplant patients [1], but it can be reasonably speculated that they apply also to LTR. However, although various human papillomavirus strains may be cocarcinogenic, their precise role is still subject to debate. Intrinsic factors include higher age at transplantation [10], male sex (imparting a 6.5-fold higher risk for skin cancer) [7], fair skin type [8], fair eyes, red hair (odds ratio 112) [7], and several genetic factors such as p53 polymorphism and genetic variations in enzymes involved in free-radical metabolism [1].
Some risk factors specific to LTR have been considered, including the primary liver disease that led to transplantation and the immunosuppressive treatment. The role of the primary liver disease is debated. Some diseases, such as hepatocarcinoma [14] and primary sclerosing cholangitis, were reported to significantly increase the risk of skin cancer (odds ratio: 4.15) [7]. The higher incidence of skin cancer could be attributable to the additional immunosuppression given pretransplantation to treat occasionally associated inflammatory bowel disease. Furthermore, duration of pre-transplant immunosuppression over 1 year was identified as an independent risk factor for developing malignancy in candidates to LT for autoimmune diseases [10]. Alcoholic cirrhosis seems to be associated with an increased risk for developing cancer in general [4], and, along with hepatitis C, for skin carcinomas [7]. However, alcohol consumption is often associated with smoking, a currently recognized risk factor of SCC.
The role of the immunosuppressive treatments in the increased risk of skin cancer is widely admitted, and a decrease of tumors after treatment tapering has been documented [17]. More substantial weaning of immunosuppressive therapy is possible after LT as compared with other organ transplants, suggesting that in the long-term skin cancers could expectedly be less frequent in LTR. Transplant physicians need to be aware of the precise impact of immunosuppressive drugs on carcinogenesis [17], [18]. Prolonged use of steroids in non-transplant patients has been found to increase the risk of SCC, consequently steroid-free regimens, which are more frequently used in LTR, probably contribute to reducing the oncogenic risk. It had been shown initially that renal transplant patients with skin cancers had an increased red blood cell concentration of the active azathioprine metabolite 6-thioguanine nucleotide compared with patients taking similar azathioprine dosages without skin cancer. This was explained later by genetic variations in thiopurine methyltransferase activity, regulating the blood levels of active azathioprine metabolites. A prospective study in renal transplant patients showed that low-dose cyclosporine regimens were associated with a lower incidence of tumors compared to standard regimens [19]. Consequently, the increased risk of skin cancers has been believed to result mainly from immunosuppression per se [11], but recent studies suggest a direct oncogenic effect of calcineurin inhibitors [18], seemingly mediated by transforming growth factor-ß (TGF-ß). Whether cyclosporine- versus tacrolimus-based immunosuppressive regimens have different oncogenic potential is not yet firmly established [3], [4], [7], [9], [15]. However, in one recent study, LTR receiving cyclosporine tended to develop skin cancers more frequently and earlier compared with patients taking tacrolimus (odds ratio 4.43) [7]. Despite the fact that the majority of cyclosporine-treated LTR had been transplanted in the earlier part of the study, in a multivariate analysis the use of cyclosporine remained a strong predictor of skin carcinoma development. On the other hand, it was shown that tacrolimus is associated with lower TGF-ß levels as compared with cyclosporine, suggesting that the former could be less oncogenic [20]. The current experience suggests that mycophenolate mofetil has no direct oncogenic properties; its use could allow lowering of anticalcineurin dosages. Chronic maintenance of immunosuppression seems to be a stronger factor for the development of tumors than short periods of intense immunosuppression (such as for treatment of rejection episodes or OKT3 use) and retransplantation [3].
1.4. Treatment
The management of skin carcinomas in LTR is similar to the one proposed for other organ transplant patients [1], consisting in local tumor treatment and in additional therapeutic measures in order to reduce the risk of new tumor development. Superficial lesions can be treated by electrocautery and curettage or cryotherapy. Nodular lesions require surgical excision with histological examination allowing accurate diagnosis, verification of excision margins and assessment of the aggressiveness of the tumor. Plastic surgery or Mohs micrographic surgery may be required for large tumors, especially on the face, for locally recurring or for rapidly growing tumors. Metastasis to a single regional lymph node necessitates lymphadenectomy alone if there is no extracapsular spread, otherwise adjuvant radiotherapy is necessary. Due to the high risk of subsequent multiple tumors within the years following the excision of SCC, revision of immunosuppression should be considered, especially for patients with multiple or aggressive lesions. This may merely consist in a reduction of the drug dosages, although the risk of graft rejection has to be weighed. Switch from calcineurin inhibitors to rapamycin could be of interest since preliminary reports have shown a reduction in the rate of skin malignancies in renal transplant patients treated de novo with rapamycin vs those treated with cyclosporine [21]. Furthermore, various malignancies have been successfully treated after conversion from cyclosporine to rapamycin along with minimization of immunosuppression [22]. However, experience with the use of rapamycin after LTR is still limited [23]; further studies are clearly warranted in order to better assess its efficacy and tolerance in this setting.
Systemic retinoids have been shown to reduce the development of new actinic keratoses and skin carcinomas in renal transplant patients, even at low doses [24]. However, after discontinuation, new tumors develop again so that therapeutic effect requires a long-term prescription which is often associated with side-effects. Therefore, thanks to the new possibilities offered by altering the immunosuppressive treatment, the use of systemic retinoids in this setting appears nowadays more limited. Topical retinoids are still useful for the treatment of actinic keratoses. The introduction of new topical immune response modifiers such as imiquimod for the treatment of superficial basal cell carcinomas and actinic keratoses has yielded promising results, but the efficacy and safety of these agents in transplant patients is still under assessment. Topical photodynamic therapy is a possible therapeutic option for multiple or superficial (pre)malignant skin tumors in organ transplant patients [25].
2. Kaposi's sarcoma (KS)
2.1. Epidemiology
The incidence of KS in recipients of solid organ transplants is much higher (up to 500-fold) than in the general population. The reported incidence in LTR varies from 0.14% [26] to 2.8% [27]. KS affects predominantly LTR originating from areas with higher classic KS incidence and HHV-8 seroprevalence (i.e., of Mediterranean, African or Arabic origin) [26], [27], [28], [29], [30]. KS accounts for .2 [10] to 3.5% [16] of all de novo malignancies developing in LTR. Whether KS is more prevalent in LTR as compared with renal transplant recipients is a matter of debate [28], [29], [31], [32]. Immunosuppressive regimens including calcineurin inhibitors (tacrolimus and cyclosporine) seem to be associated with a higher risk for developing KS, at least after renal transplantation [32], a shorter delay from transplantation to disease onset and a more severe clinical presentation, including visceral lesions [28].
2.2. Clinical features
A review of the literature on 51 relevant cases reported with sufficient details reveals that KS appears in LTR on average 11.7 months post-transplantation (range 1–126). The vast majority of patients (94%) are male with a mean age of 49 years, i.e. much younger than in classic KS. 62% of LTR with KS have (muco)cutaneous lesions, 47% have also visceral ones, whereas 15% of LTR have purely visceral lesions. As compared with kidney transplant recipients, KS in LTR seems to present more frequently with visceral or mixed vs purely cutaneous forms. This could be due to HHV-8 transmission via the liver allograft. Cutaneous lesions are usually similar to the classic/Mediterranean form, manifesting with red-violaceous angiomatous lesions predominating on the lower limbs (Fig. 1) and frequently causing lymphedema; however, they may be widespread, affecting areas such as the chest and abdomen. Mucosal lesions are mainly located in the oropharynx. Visceral lesions mainly concern lymph nodes and the gastrointestinal tract [33], including the liver allograft itself [34]. Postmortem examination often reveals diffuse disease, extending to the lungs, kidneys, mesentery, pericardium, retroperitoneum, diaphragmatic pleura and colon [34]. In the case of mixed forms, cutaneous lesions usually precede the discovery of visceral ones, but the visceral lesions may rarely precede cutaneous ones [34].
Fig. 1.
Kaposi's sarcoma involving lower limbs and genitalia 4 months after liver transplantation.
2.3. Etiology and pathogenesis
KS is closely associated with Human Herpes Virus 8 (HHV-8), an oncogenic γ-herpesvirus encoding for cytokines and growth factors involved in cell proliferation, apoptosis and immune responses, and exerting a transforming activity on human endothelial cells. HHV-8 is detected in KS tissue and in peripheral blood mononuclear cells, where viral load seems to correlate with disease stage and progression [35]. HHV-8 seroprevalence varies according to the geographic area (less than 5% in north America, north Europe and Asia, 5–20% in the Mediterranean, Middle-East and the Caribbean, over 50% in central and southern Africa). Most cases of KS developing after renal transplantation seem to develop as a result of viral reactivation [36], but HHV-8 can also be transmitted from the graft [37]. Data concerning LTR are much more sparse. HHV-8 seroconversion seems to be more frequent among liver as compared with renal graft recipients, but does not necessarily result in the development of KS [31]. In one recent study on 122 LTR, none of three HHV-8 seropositive patients prior to grafting developed KS during the over 2-year follow-up period. By contrast, two out of four LTR who became seropositive after grafting developed fulminant KS; therefore, systematic donor testing as a prophylactic measure against HHV-8 transmission might be warranted in areas with high HHV-8 seroprevalence, not necessarily to exclude the graft but to know the serological status and to monitor the recipient adequately [35].
2.4. Course & prognosis
The course of KS in LTR is variable, and seems to depend on the level of immunosuppression. The disease usually, although by no means invariably [16], [34], regresses upon discontinuation of immunosuppression. Fulminant KS cases have been reported, namely following HHV-8 seroconversion, resulting in a rapidly fatal outcome from multiorgan failure [35]. However, cases with prolonged remissions (up to 66 months) have been reported [9], [31]. Survival depends on disease extent, and is shorter in the presence of visceral lesions [28].
2.5. Treatment
The first therapeutic measure for post-transplant KS should be progressive tapering of immunosuppressive treatment, since this often results in partial or complete regression of the lesions. A recent study in renal transplant patients showed that switch from cyclosporine and mycophenolate mofetil to sirolimus (rapamycin), an immunosuppressant with anti-angiogenic and anti-tumor effects, induces healing of cutaneous KS [22], and this could also be the case in LTR. Additional treatment may be needed in case of persisting functional disability or life-threatening disease, and includes chemotherapy with vincristine or vinblastine, bleomycin, doxorubicin (singly or in various combinations), liposomal daunorubicin, paclitaxel, etoposide, dactinomycin and cisplatin [1]. Radiotherapy and interferon-alpha [38] may be effective in KS, but they should be used with caution, if at all, because of the risk of development of skin cancer and graft rejection, respectively [26]. Isolated lesions can be excised surgically or treated with cryotherapy. The efficacy of antiviral drugs (foscarnet, ganciclovir, cidofovir, adefovir) that show in vitro activity against HHV-8, has not yet been clinically adequately documented, but seems at best partial [39]. The use of anti-CD20 monoclonal antibodies (that seem able to reduce viral load in cases of HHV-8-associated multicentric Castleman's disease) seems interesting, but has not yet been studied in the setting of KS.
Concerning prevention, further clinico-epidemiologic studies are warranted in order to define whether organ donation from HHV-8 seropositive donors to HHV-8 seronegative recipients should be excluded, especially in the case of LT where KS transmission from the allograft seems to be more frequent and severe [35].
3. Other skin tumours
The risk of de novo melanoma in organ transplant patients is increased by a factor of 1.6–4 [1]. Several cases have been reported in LTR, but some of these patients may have been included in more than one series [7], [13], [15], [16], [40]. At least two patients died of widespread metastases [7], [15], [16]. Melanomas occur mainly in fair skinned and fair-eyed patients. Large numbers of melanocytic nevi are a risk factor for melanoma, especially in children. The prognosis depends on tumor thickness (Breslow index). Treatment includes wide surgical excision and sentinel lymph node biopsy, along with revision of immunosuppression. Screening pretransplant melanoma should be performed because of the high risk of recurrence and metastasis after transplantation, even several years after excision of the primary lesion. The length of the waiting period has to be weighed against the vital risk. Transmission of donor melanoma may occur, and results in metastatic spread [40].
Cancers of the external anogenital region are increased in organ transplant recipients by a factor of 30–100 [1]. Risk factors include mainly HPV infection, heavy smoking, the presence of skin cancers and deep immunosuppression. Lesions tend to be multiple and extensive. One case of vulvar SCC associated with long-lasting, widespread condylomata acuminata who underwent successful removal of the bladder, uterus and vulva has been reported in a LTR [10].
Other rare skin tumors such as Merkel cell carcinoma [8], [16] have been reported after LT. In most cases, along with local excision with generous margins (2–3
cm), revision of the immunosuppressive treatment is recommended.
In conclusion, skin cancers account for the commonest malignancies after LT. A substantial number of them could be avoided by adequate preventive measures, including a regular dermatological screening for early detection and ablation of premalignant lesions. Furthermore, all patients must avoid direct sun exposure, use appropriate clothing for outdoor activities and apply sunscreens with high sun protection factor. Transplant units should provide their patients written practical detailed guidelines for sun protection. Such guidelines can now be found on the web (http://www.scopnetwork.org, http://www.itscc.org). If skin carcinomas develop, revision of the immunosuppressive treatment should be considered. Rapamycin emerges as a new promising agent for the prevention of skin carcinomas developing after organ transplantation. However, this drug requires further studies.
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PII: S0168-8278(05)00676-8
doi:10.1016/j.jhep.2005.10.010
© 2006 Published by Elsevier Inc.
