J. A. Carucci MD, PhD
Mohs Micrographic and Dermatologic Surgery, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY
Skin cancer, particularly squamous cell carcinoma (SCC), continues to be a significant cause of morbidity and even mortality in organ transplant recipients (OTRs). As the number of organ transplant patients continues to increase, dermatologists will be faced with the challenge of diagnosing and managing their skin cancers. Evaluation, management and follow up of organ transplant recipients with high risk SCC will be discussed.
Key Words: squamous cell carcinoma, organ transplant, skin cancer
Approximately 23,000 organ transplantations were performed in the United States in 2000 with the majority being kidney transplants.1 Survival after transplant continues to improve and with longer survival comes increased risk for skin cancers, particularly SCC.1-3 The pathogenesis of skin cancer on OTRs is multi-factorial involving immunosuppression1,4-7 ultraviolet light,8 human papillomavirus,9,10 and other factors including fair complexion,3 blue eyes,11 male sex,11,12 and older age at transplant. Opinion differs as to whether certain HLA types confer protection or risk.3,13,14 Regardless of the etiology, SCCs in OTRs tend to occur more frequently and be more severe.
Evaluation and Management of SCC in Organ Transplant Recipients
It is key to remember that SCC in an OTR is considered to be a high-risk lesion as defined by Rowe, et al.15 When managing SCC in an OTR it is important to differentiate those lesions which are “highest risk” for recurrence or metastasis. Lower risk lesions include actinic keratoses and porokeratoses, both of which are common in transplant recipients.
Moderate risk lesions include well-differentiated lesions on the trunk and extremities that do not invade beyond papillary dermis. Highest risk for recurrence and metastasis may be associated with factors including rapid growth, large diameter, location on ear, lip or scalp, aggressive histology, and recurrent SCC.1,15 Careful inspection of the surrounding skin to exclude the presence of satellite lesions is necessary as is the examination of the draining lymph nodes.1 SCC in organ transplant recipients is managed by standard modalities including Mohs surgery, standard excision, destruction and radiation therapy (Figure 1).1 Strategies for managing high risk or multiple lesions may include the use of oral retinoids and reduction of immunosuppression. Management should include careful evaluation for nodal metastases.1,16 Management options discussed below are often best used in varying combinations when treating patients with multiple lesions.
Mohs Micrographic Surgery
Mohs micrographic surgery offers the highest cure rates for SCC and should be considered for lesions with high risk attributes such as larger diameter, high risk location, recurrent lesion, aggressive histology, and scar carcinoma.17,18 Subclinical tumor extension was shown to be greater in SCCs from OTRs, strengthening the indication for Mohs surgery for SCC in these patients.19
Standard excision with postoperative margin assessment may be used in the treatment of higher risk lesions.20 Margins of 6mm may be most appropriate for higher risk lesions not treated by Mohs surgery.20 Margins from standard excision are assessed from representative sections of the specimen in “breadloaf” fashion allowing for examination of approximately 3% of the excisional margin of the specimen.21 This degree of examination may occasionally result in a false negative assessment of clear margins in cases of infiltrating, or aggressive growth cancers. Similar misdiagnosis may result when vertically cut frozen specimens are relied upon for intraoperative margin control.
Destructive methods such as electrodesication and curettage (ED and C) and are best reserved for superficial lesions not located on high risk areas.22 Cryosurgery is best reserved for treatment of actinic keratoses in this group of patients.23
Radiation therapy (XRT) is a treatment option for SCC but is limited by the inability to definitively confirm the tumor margins.17 XRT, in properly fractionated doses, may be indicated when the patient’s health, or size or extent of tumor precludes surgical extirpation. Consideration of the permanent tissue effects of XRT must include anticipation and management of recurrence. Adjunctive postoperative XRT may be useful in postoperative management of SCC with perineural invasion.24,25
Topical therapy with imiquimod26 or 5-fluorouracil27 can be used on superficial lesions. In one study, SCC in situ in five OTRs was effectively managed by using these agents in combination.28
Retinoids have been used as chemoprophylaxis against skin cancers in OTRs. Previous studies favor the use of acitretin over isotretinoin due to better side effect profile. The first report of acitretin chemoprophylaxis was by Vandeghinste, et al, who reported the cessation of new dysplastic skin lesions during acitretin treatment.29 Other studies support the use of oral retinoids in this group.30-32 While results in these studies are encouraging, the use of retinoids should be discussed with the primary transplant physician prior to use.
Reduction of Immunosuppresion
Reduction of immunosuppressive therapy maybe considered in cases of severe life threatening skin cancer.1 In a recent report concerning six patients in whom skin immunosuppressive therapy was discontinued, four patients experienced decreased development of skin cancers.33 It must be remembered that reducing immunosuppression may predispose to rejection and therefore any decisions regarding alteration of immunosuppression must be reached in cooperation with the primary transplant physician.
Sentinel Lymph Node Biopsy
Sentinel lymph node biopsy is gaining popularity in high risk SCC. Reschly, et al, reviewed the utility of sentinel lymph node dissection in patients with high risk SCC on the trunk or extremities.34 Nine patients received preoperative lymphoscintigraphy and sentinel lymphadenectomy for high-risk cutaneous SCC without clinically appreciable nodal disease. Histologically positive nodes were found in 4 of 9 cases (44%). Two of the four patients with positive sentinel nodes died of metastatic disease within 2 years. All five patients with negative sentinel nodes were at a median follow-up of 8 months (mean of 13 months). Altinyollar, et al, reported on sentinel lymph node biopsy (SLNB) in SCC of the lip.35 In their study, intraoperative lymphatic mapping and sentinel lymph node biopsy was performed in 20 patients with tumor size greater than 2cm (T2) and clinically non-palpable regional lymph nodes (N0). Sentinel lymph nodes were identified in 18 of the patients (90%). Intraoperative or postoperative histopathologic examination of the sentinel lymph node showed tumor metastasis in three of the patients (16.6%). In two of the three patients with metastatic sentinel lymph nodes, non-sentinel lymph nodes were free of metastases. Although not considered standard of care, SLND may be considered in selected high risk SCC in the appropriate setting.
In Transit Metastases from Cutaneous SCC
In some cases of SCC, satellite or in transit metastatic lesions appear either with the primary or recurrent lesions or as a manifestation of recurrent disease.1,16 These lesions are usually clinically nondescript subcutaneous papules that are histologically similar to the primary lesion but are not contiguous with it. The presence of in transit metastatic disease is a poor prognostic indicator and represents a therapeutic challenge. Management of in transit metastasis is usually multidisciplinary by nature and must proceed on a case by case basis. Management strategy may include excision and radiation therapy. Appropriate work up to exclude nodal and distant metastasis should be performed.
Longitudinal Evaluation of OTRs at Risk for Skin Cancer
Transplant recipients usually need more frequent dermatologic follow up than non-OTRs.1 Patients with multiple or severe, life threatening cancers may need to be followed as frequently as every 1-2 months while those with a skin type greater than three, or patients with no history of actinic keratoses or skin cancers may be evaluated annually. Follow-up should include evaluation of previously treated areas for signs of recurrence and careful examination of draining lymph nodes to exclude regional disease.
As the number of solid organ transplant patients continues to rise, dermatologists and dermatologic surgeons will be called upon to rationally manage skin cancers in this group of patients. Reduction of the morbidity and potential mortality from skin cancer in this group will require education of both transplant physicians and patients regarding the need for periodic evaluation by a dermatologist.