Cutaneous Disease in Kidney Transplantation Patients





Introduction


Organ transplant recipients (OTRs), which include renal transplant patients, are significantly affected by cutaneous disease as a result of a prolonged immunosuppressed state. Renal transplant recipients have a 5-year survival rate of 85%. Therefore with promising odds for survival, the chronic nature of skin disease may become challenging to manage for these patients. Because the skin is visible, cutaneous disease may significantly affect patient quality of life. Renal transplantation is also unique in that the return to hemodialysis is an option, so the risks and benefits of side effects of transplantation and the immunosuppression regimen must be heavily weighed if the skin cancer burden is extreme or life threatening.


In terms of cutaneous disease, the most significant and burdensome complication of organ transplantation is skin cancer. The transplant physician should be aware of the importance of evaluation for cutaneous malignancy in the pretransplant and posttransplant periods. This chapter will discuss the approach to OTRs with cutaneous malignancy. In these patients, the transplant physician and dermatologist should work closely together for the benefit of the patient. Understanding the risk factors in posttransplant skin cancer is vital to the care of these patients for targeted screening and prevention. The International Transplant Skin Cancer Collaborative (ITSCC) and the Transplant Skin Cancer Network (TSCN) are valuable resources for further information on this topic.


In addition, OTRs often demonstrate increased rates of premalignant and benign cutaneous tumors, and infectious and inflammatory cutaneous conditions. These will be discussed in this chapter; however, the main focus of this chapter is to inform the transplant physician on the pressing matter of cutaneous malignancy in OTRs.




Cutaneous Malignancy in Renal Transplant Patients


Nonmelanoma Skin Cancer


Epidemiology and Pathogenesis


OTRs are at an increased risk of malignancy compared with the general population because of immunosuppression. Skin cancer is the most frequently reported posttransplant malignancy. In particular, nonmelanoma skin cancer (NMSC) represents 95% of posttransplant skin cancer. The incidence of posttransplant skin cancer has been reported at 1427 per 100,000 person-years. Interestingly, in the general population, basal cell carcinoma (BCC) is the most common type of NMSC and squamous cell carcinoma (SCC) is the second most common type of NMSC, whereas the ratio in the OTR population is reversed. Organ transplantation increases the risk of cutaneous SCC by 65-fold and BCC by 10-fold. Furthermore, SCC is more likely to be aggressive in OTRs. Specifically, in the general population, the risk of metastasis of SCC is 0.5% but increases to about 8% for OTRs.


The factors associated with risk of NMSC posttransplant include the following: Fitzpatrick skin type I or II (fair skin), increasing age at transplantation, duration and level of immunosuppression, type of organ transplant (heart and lung > kidney > liver), previous transplant, history of SCC pretransplant, history of lymphoma, pretransplant end-organ disease (rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis), and liver transplant recipients with a history of psoriasis on previous biologic therapy or psoralen plus ultraviolent A light ( Table 34.1 ). To simplify risk stratification, a recent study from the TSCN from 26 centers with more than 10,000 patients identified the following statistically significant risk factors for posttransplant skin cancer: pretransplant skin cancer, male sex, white race, and age at transplant 50 years or older.



Table 34.1

Risk Factors for Development of Skin Cancer in Organ Transplant Patients

From Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: Part 1. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011;65:253–61.





















Fitzpatrick skin type I to III
Increasing age at transplantation
Duration and level of immunosuppression
Type of organ transplant (heart/lung > kidney > liver)
Previous transplant
Squamous cell carcinoma before transplant
History of lymphoma pre-/posttransplant
Pretransplant end organ disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, or autoimmune hepatitis)
Liver transplant recipients with psoriasis on previous biologic therapy/psoralen plus ultraviolet A light phototherapy


An additional predictive index was developed for a comprehensive and cost effective targeted surveillance strategy for skin cancer in renal transplant patients so that those at high risk can be easily recognized early on posttransplant. Patient age, outdoor exposure, ultraviolet light exposure, pretransplant skin cancer, childhood sunburn, and skin type were selected as predictors. A score >7 was designated as high risk for NMSC within 2 years, and of these patients, the chance of being SCC-free at 2 years was 43%, and at 5 years was 17%. In contrast, with a score <4, 99% were free from SCC at 6 months, 95% at 2 years, and 89% at 5 years.


The direct association of duration and degree of immunosuppression with the risk of NMSC in OTRs suggests that immunosuppression is key to the pathogenesis of NMSC in OTRs. The pathogenesis of NMSC is multifactorial. Ultraviolet light causes genetic mutations, in particular in the p53 gene in SCC, and these mutations eventually accumulate and lead to carcinogenesis. This is supported by the fact that NMSC in OTRs is associated with latitude and that Australian OTRs have a higher risk of NMSC than patients in England. Ultraviolet light causes a characteristic type of mutation, resulting in cytosine to thymine transitions through the formation of cyclobutane dimers, which are commonly found in NMSC p53 mutations. The immune system normally functions to provide surveillance and eliminate precancer. This is evidenced by the effectiveness of immunomodulatory medications, such as imiquimod, in treating premalignant actinic keratosis. In addition, the immunosuppressive medications themselves may be directly carcinogenic, the most prominent example of which is azathioprine. Cyclosporine may also be carcinogenic.


More recently, the role of the human papillomavirus (HPV) infection in OTRs in NMSC pathogenesis has become more widely appreciated. OTRs have greater quantities of HPV deoxyribonucleic acid (DNA) found in SCC samples. HPV viral proteins E6 and E7 are oncoproteins involved in regulating cell cycle checkpoints. This may also be observed clinically in the warty appearance of many SCC in OTRs. Of consequence, a recent study found that NMSC in nonwhite OTRs was more likely to occur in nonsun-exposed areas, in particular, on the genitals. This is suggestive of the role of sexually transmitted HPV in NMSC in nonwhite OTRs. The value of pretransplant or posttransplant HPV vaccination for preventing NMSC has yet to be studied and warrants further investigation.


In summary, NMSC incidence is increased in OTRs because of immunosuppression, ultraviolet carcinogenesis, drug carcinogenicity, and possibly because of HPV infection, particularly in nonwhite OTRs.


Clinical Presentation


SCCs may vary in clinical appearance, but as previously noted, they are the most prevalent skin cancer in OTRs; therefore any suspicious growing lesion should be biopsied. In general, both BCC and SCC commonly arise on sun-exposed areas of the body. SCCs are often erythematous, keratotic plaques that may also ulcerate ( Fig. 34.1 ). The subtype of keratoacanthoma is a crateriform appearing SCC that is rapidly growing. SCCs are often tender. BCCs are classically described as “pink, pearly papules” but may also become ulcerated.




Fig. 34.1


Squamous cell carcinoma on the left temple.


Field cancerization is a term that describes a heavy burden of cancer in an area or “field” of skin. It commonly refers to extensive areas of sun damage with multiple keratotic neoplasms including actinic keratosis, SCC in situ, and SCC. Both “transplant hands” ( Fig. 34.2 ) and “transplant scalp” are common descriptors of field cancerization in the OTR population.




Fig. 34.2


Field cancerization on the hands, also known as transplant hands.


In general, physical examination should be performed of the draining lymph node basins in transplant patients with a high-risk SCC. SCCs can be aggressive, metastasizing to the lymph nodes, and can cause death. The risk of local recurrence of high-risk SCC is 13.4%, usually within the first 6 months after excision. The risk of metastasis of SCC in the general population is 0.5 to 5%. The risk increases to 8% for OTRs. This is a poor prognostic sign, with a 3-year overall survival for OTRs with metastatic SCC of 48%. In contrast, BCCs rarely metastasize but can be locally aggressive and cause physical destruction.


In SCC, high-risk features include the following: large size >2 cm, high-risk location (ear, lip, scalp, temple), tumor depth >2 mm, recurrent, poor differentiation, perineural invasion, and lymphovascular invasion , ( Table 34.2 ).



Table 34.2

High-Risk Features of Squamous Cell Carcinoma in Organ Transplant Patients

From Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: Part 2. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011;65:263–79.





















Large size (>2 cm)
Multiple squamous cell carcinomas
High-risk location (ear, lips, over parotid gland, scalp, or temple)
In-transit metastatic lesion
Recurrence
Histology
Poorly differentiated
Perineural invasion
Deep invasion


Management


The management of NMSC in OTRs involves prevention, treatment, and surveillance. Of these, prevention is of the utmost importance and should begin in the pretransplant evaluation. Prevention also includes continued education on sun protective measures and on self-skin examination. In severe cases, prevention may also involve chemoprevention with medication, which will be discussed later. The treatment of NMSC in OTRs is often complicated in that the risks and benefits of various medical and surgical procedures must be weighed. Surveillance is particularly important for SCC, which has a higher rate of metastasis in OTRs compared with the general population.


Prevention


Chemoprevention may be used in OTRs with numerous NMSCs. The options are discussed later. Retinoid derivatives, such as acitretin, have been shown to be effective in the suppression of SCC development, including reduction in actinic keratoses and SCCs. Indications for the initiation of systemic retinoids in organ transplant patients are the following: development of multiple SCCs per year (5–10/year); development of multiple SCCs in high-risk locations (head/neck); patients with a history of lymphoma/leukemia and SCCs; a single SCC with high metastatic risk; metastatic SCC; explosive SCC development; and eruptive keratoacanthomas. Low-dose acitretin (10 mg) therapy should be started to minimize side effects with slow titration by 10 mg increments at 2- to 4-week intervals to the target dose of 20 to 25 mg daily. Side effects are dose related, with dry eyes and mouth being the most common; dry skin and pruritus are less common. Acitretin is a known teratogen (pregnancy category X) and its use should be carefully considered in childbearing women who wish to conceive within 3 years. Severe hyperlipidemia that is refractory to standard treatment is a contraindication. Laboratory monitoring must be performed frequently, including a baseline pregnancy test, complete blood count, fasting lipid panel, liver panel, and serum creatinine. Chemoprevention with oral retinoids is a lifelong treatment. When the medication is discontinued, a rebound effect occurs that is difficult to control. Patients can experience the eruption of multiple aggressive SCCs over a relatively short period of time. Thus reduction of the dosage of acitretin is usually successful at maintaining patient compliance while still benefiting from chemoprevention.


Capecitabine, a prodrug of 5-deoxy-5-fluorouridine, is metabolized by the liver to 5-FU and is less commonly used for NMSC chemoprevention. Initially used for the treatment of metastatic breast and colon cancer, the use of systemic 5-FU has been shown to be beneficial in reducing the development of precancerous and cancerous lesions in organ transplant patients. In a retrospective review performed at the University of Minnesota, organ transplant patients who were given low-dose capecitabine had lower rates of developing NMSC and actinic keratoses compared with the period before capecitabine treatment. However, grade 3 and 4 toxicities were common, causing discontinuation. Prospective studies are needed to determine the long-term efficacy and safety of lower doses.


More recently, a randomized controlled trial demonstrated efficacy of nicotinamide in preventing NMSC. This offers an appealing alternative to acitretin or capecitabine because of a limited side effect profile for nicotinamide. This study was not performed in OTRs but included patients with at least two NMSC in the previous 5 years. Patients received nicotinamide 500 mg twice daily or placebo for 12 months. At 12 months, the rate of new NMSC was lowered by 23% in the nicotinamide group compared with the rate of new NMSC in the placebo group. The efficacy of nicotinamide in reducing NMSC in OTRs requires further study.


Overall, patient education on sun protective behaviors and early signs of skin cancer is very important in the OTR population. Specifically, patients should be taught to use daily broad-spectrum sunscreen, protective clothing, and avoidance of sun tanning and tanning beds. A helpful resource for patients and clinicians is the ITSCC patient education brochure “After Transplantation – Reduce Incidence of Skin Cancer” (AT-RISC Alliance: at-risc.org/ ).


Treatment


Topical therapies are used for precancerous actinic keratosis, BCC, and SCC. In particular, topical therapies may be appropriate for the superficial variant of BCC and SCC in-situ. 5-fluorouracil 5% cream is a topical chemotherapy cream and imiquimod is a topical immunomodulatory agent that targets toll-like receptor 7. These are effective for the treatment of actinic keratosis, superficial BCC, and SCC in-situ and for chemoprevention. These therapies cause an inflammatory and crusted reaction, which may be intolerable to patients. Some patients, however, prefer this treatment to surgery because it does not require a doctor’s visit and is often nonscarring. Many male transplant patients with hair loss benefit from regular use of 5-flourouracil cream on the scalp to prevent SCC formation.


Photodynamic therapy (PDT) is another treatment modality for actinic keratosis and superficial NMSC, particularly if there is a large area such as the scalp involved. PDT involves the use of an exogenously administered precursor of photosensitizer protoporphyrin IX synthesis (usually either aminolevulinic acid or methyl aminolevulinate) that is activated by light, producing reactive oxygen species and destroying tumor cells. PDT has been effective in the treatment of actinic keratosis and superficial NMSC in OTRs. , PDT must be administered under physician supervision in a clinic setting. Common side effects are pain and erythema.


The simplest surgical procedure for treatment of NMSC is electrodessication and curettage. , This is similar to a biopsy but with the addition of three passes of electrodessication and curettage to the base of the lesion. This is a simple procedure that may be performed at the time of biopsy, which is preferable for many OTRs with frequent doctors’ visits. The downsides are a slightly lower cure rate than excision and often a large circular hypopigmented scar in contrast to a linear scar from an excision.


Wide local excision or Mohs surgery are the preferred modalities for treatment of infiltrative BCC and SCC. , Wide local excision is often performed with 4-mm margins for NMSC and a surgical pathologist subsequently evaluates all of the tissue margins postoperatively. Mohs surgery entails removing one thin layer of tissue at a time; each layer is evaluated through frozen section histology for the presence of remaining tumor. If the circumferential and deep margins are clear, the surgery is ended. If not, another layer is removed from the margin where tumor was noted, and the procedure is repeated until all margins of the final tissue sample are clear of cancer. This offers better margin control, minimal tissue defect, and has higher cure rates than wide local excision. Mohs surgery is preferred for NMSC on the face, large lesions, and recurrent NMSC. ,


The most concerning outcome in SCC in OTRs is metastasis, either to lymph nodes or systemically because of the worsened prognosis, as mentioned earlier. The role of imaging in cutaneous SCC is somewhat controversial. Patients with palpable lymph nodes should undergo sentinel lymph node biopsy and dissection. , Otherwise, a sentinel lymph node biopsy should be considered for OTR patients with high-risk SCC or lymph nodes found on imaging performed in the appropriate patient. A recent consensus article suggested consideration of imaging in patients with possible bony invasion, possible orbital invasion, for assessment of extent of tumor invasion in soft tissue, for staging evaluation in high-risk SCC, for evaluation of potential perineural spread, and for postoperative surveillance for recurrent disease.


For metastatic SCC, medical, surgical, and radiation therapies should be combined. , Currently, there are limited medical therapies for metastatic SCC and most of these have been studied in immunocompetent patients. Radiotherapy may also be used adjunctively. , The most important medical intervention is to decrease immunosuppression if possible. Chemotherapy traditionally included cisplatin and 5-flourouracil. More recently, epidermal growth factor receptor inhibitors such as gefitinib, erlotinib, and cetuximab have been used to treat metastatic SCC. , , , Furthermore, programmed cell death receptor 1 (PD1) or its ligand (PDL1) inhibitors such as pembrolizumab and nivolumab have been used in single patients with metastatic SCC but there have been no randomized controlled studies. Pharmaceutical companies Regeneron and Sanofi are planning trials for cemiplimab for cutaneous SCC. Importantly, the effect of using an immune checkpoint inhibitor on a transplant patient’s graft function is unknown and may be problematic.


For metastatic BCC in OTRs, there is a Food and Drug Administration–approved medication, vismodegib. Vismodegib is a smoothened inhibitor in the sonic hedgehog pathway. Efficacy is approximately 30% with many systemic side effects including electrolyte abnormalities, alopecia, taste loss, and muscle cramps. Additionally, a recent study showed an increased risk of SCC with vismodegib treatment, which may be of particular concern in OTRs with NMSC. Interestingly, a subsequent study did not show an increased risk of SCC in patients on vismodegib. The use of vismodegib and risk of SCC remains unclear and requires further study and careful application in the transplant population.


Surveillance


Patients with a history of NMSC and organ transplantation should be followed-up with every 3 to 6 months, and examination should include a lymph node examination for high-risk SCC ( Table 34.3 ). For patients with high-risk SCC with concerning features on follow-up physical examination (i.e., lymphadenopathy, neurologic signs) should undergo a positron emission tomography (PET)/computed tomography (CT) for evaluation for recurrent disease. The frequency of long-term follow-up may be stratified by risk (see Table 34.3 ).



Table 34.3

Follow-up Intervals for Total Body Skin Examination for Solid-Organ Transplantation

From Zwald F, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: Part 2. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011;65:263–79.

























Patient Risk Factor Interval for Total Body Skin Examination (No. of Months)
No skin cancer/field disease 12
Field disease 3–6
One nonmelanoma skin cancer 3–6
Multiple nonmelanoma skin cancers 3
High-risk squamous cell carcinoma or melanoma 3
Metastatic squamous cell carcinoma or melanoma 1–3


Pretransplant Delay


From the perspective of the transplant physician, a previous diagnosis of a cutaneous malignancy may affect the decision to proceed with solid-organ transplantation. A consensus guideline from the ITSCC was developed for recommendations regarding solid-organ transplantation with a pretransplant SCC, melanoma, and Merkel cell carcinoma. As stated previously, one of the major risk factors for posttransplant skin cancer is pretransplant skin cancer. For renal transplant patients with a history of pretransplant SCC, there is a 40% to 80% chance of posttransplant SCC. The ITSCC guidelines are based on the principle that a patient should have at least a 5-year survival from malignancy of 60% to ethically transplant an organ. For SCC, the consensus panel recommends the following: no delay in transplantation for stage T1 and T2b, a 2-year delay after clearance of tumor for high-risk SCC (large size >2 cm, high-risk location [ear, lip, scalp, temple], tumor depth >2 mm, recurrent, poor differentiation), and a 2- to 3-year delay after clearance for tumor for high-risk SCC with perineural invasion ( Table 34.4 ).



Table 34.4

Recommended Wait Times Pretransplantation for Patients With a History of Skin Cancer Before Transplantation

From Zwald F, Leitenberger J, Zeitouni N, et al. Recommendations for solid organ transplantation for transplant candidates with a pretransplant diagnosis of cutaneous squamous cell carcinoma, Merkel cell carcinoma and melanoma: a consensus opinion from the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant 2016;16(2):407–13.






































































Skin Malignancy Appropriate Treatment Pretransplantation Wait Time Before Transplantation After Treatment
Squamous Cell Carcinoma
No history of SCC but high risk for SCC Treatment of field disease No delay
Low-risk SCC Surgical excision with clear margins of Mohs micrographic surgery No delay
High-risk SCC a other than perineural invasion Surgical excision with clear margins of Mohs micrographic surgery 2 years
High-risk SCC a with perineural invasion or ≥2 high-risk features Surgical excision with clear margins of Mohs micrographic surgery +/− radiotherapy 2–3 years
High-risk SCC with local nodal metastasis Surgical excision with clear margins of Mohs micrographic surgery + radiotherapy 5 years
Distant metastasis Refer for oncology opinion Not eligible for transplantation
Merkel Cell Carcinoma
Local with negative sentinel lymph node biopsy Wide local excision +/− radiotherapy 2 years
Local with nodal metastasis Wide local excision, lymph node dissection + radiotherapy 3–5 years
Distant metastasis Refer for oncology opinion Not eligible for transplantation
Melanoma
In situ melanoma Wide local excision No delay, follow-up posttransplantation 3 months
Stage Ib melanoma Wide local excision 2 years
Stage Ib/IIa melanoma Wide local excision +/− sentinel lymph node biopsy 2–5 years
Stage IIb/IIc melanoma Wide local excision + sentinel lymph node biopsy 5 years
Stage III or IV melanoma Refer for oncology opinion Not eligible for transplantation

a large size >2 cm, high-risk location (ear, lip, scalp, temple), tumor depth <2 mm, recurrence, poor differentiation, perineural invasion.



Melanoma


Epidemiology and Pathogenesis


Melanoma is an immunogenic cutaneous malignancy with higher risk of metastasis, and its incidence continues to increase. The relationship between melanoma risk and organ transplantation is less clear than that for NMSC. The transplant physician should be aware of a history of pretransplant melanoma and screen for melanoma in the posttransplant period. For melanoma, there are reports ranging from a 3- to 5-fold increased risk in OTRs compared with the general population. , In renal transplant recipients, a large study found a 3.6-fold increased risk of melanoma in renal transplant recipients. African American OTRs have a 1.72-fold increased risk for melanoma. The mean duration from transplantation to posttransplant melanoma is 5 years.


Risk factors for developing melanoma specifically in renal transplant patients have recently been outlined in a cohort study of a large national data registry and include older age, male sex, recipient white race, less than four human leukocyte antigens (HLA) mismatches, living donors, and sirolimus and cyclosporine therapy. Transplant clinicians can identify these risks factors and close skin surveillance should be provided for patients with higher risk characteristics.


Immunosuppression also appears to deleteriously affect the course of melanoma in transplant patients. In the largest study of melanoma in the OTR population, patients who developed melanoma demonstrated worse overall survival compared with expected survival in control subjects. In addition, patients with thicker melanomas appear to have increased risk of dying of metastatic melanoma. Large multicenter studies are needed to provide better understanding of the role of immunosuppression on the behavior of melanoma in OTRs.


With the advent of immunotherapy in treating melanoma, it is known that the immune system plays a role in melanoma pathogenesis. The less defined relationship between melanoma and OTR is likely due to the multifactorial nature of melanoma pathogenesis. Melanoma risk is also increased with ultraviolet light exposure, in particular with tanning bed use, and genetic factors such as mutations in the p16 gene. , An illustrative example of the role of immunity in melanoma pathogenesis is the case report of a renal transplant patient who developed metastatic melanoma from a donor kidney. The donor did not have clinical symptoms of metastatic melanoma, suggesting that the donor immune system was keeping the melanoma in check. However, when the transplant allograft was placed in a host on immunosuppressive medication, metastatic melanoma developed. Therefore melanoma risk is likely related to immunosuppression but appears to be less clearly linked than NMSC is to immunosuppression.


Clinical Presentation


In general, melanomas are pigmented lesions, with the exception of the rare variant of amelanotic melanoma. The subtypes of melanoma are the following: superficial spreading, lentigo maligna, nodular, and acral lentiginous. The “ABCDE” acronym summarizes the clinical features of melanoma: asymmetry, border irregularity, color variation, diameter more than 6 mm, and evolution. Loss of color should also raise suspicion. Any suspicious lesion should be biopsied, and treatment is based on the pathology (Breslow depth ± ulceration or mitoses) and lymph node involvement of melanoma. Therefore a lymph node examination for the draining lymph nodes in an OTR with melanoma is imperative.


Management


Melanoma should be managed surgically with wide local excision with consideration of a sentinel lymph node biopsy based on the severity of the tumor. The following surgical margins are appropriate: 5 mm for melanoma in-situ, 1 cm for melanoma <1 mm Breslow depth, and 2 cm for melanoma >2 mm Breslow depth. Sentinel lymph node biopsy should be considered for melanomas with Breslow depth >1 mm and some argue >0.75 mm. A large prospective trial showed there was no survival benefit to complete lymph node dissection in node-positive melanoma, and this may eventually change the surgical management of these patients, particularly in the era of improved medical therapies.


For metastatic melanoma, several emerging therapies are rapidly advancing the field. BRAF inhibitors such as vemurafenib and dabrafenib are available for metastatic melanoma. In addition, immunotherapies such as ipilimumab and PD-1 inhibitors are being widely used in melanoma for the possibility of a durable response. The effects of these therapies on graft function are unknown. In life-threatening melanoma, immunosuppression changes and/or reduction should also be considered.


Surveillance


Patients with a history of melanoma and organ transplantation should be followed-up with every 3 months, and examination should include a lymph node examination and examination for in-transit metastases (see Table 34.3 ).


Pretransplant Delay


As mentioned in the NMSC section, a consensus guideline was developed for management of the pretransplant SCC, melanoma, and Merkel cell carcinoma. For melanoma, case control studies have shown that the immunosuppression has a differential effect on melanoma in the context of transplantation, such that a thin melanoma (Breslow depth 1.5–2 mm) may behave comparably to melanoma in immunocompetent individuals, whereas thick melanomas (Breslow depth >2 mm) may behave more aggressively and be associated with increased mortality risk. Patients with melanoma in-situ, stage Ia, Ib, IIa, IIb, and IIIa are considered organ transplant candidates, but stages IIc, IIIb, IIIc, and IV should not be considered organ transplant candidates. The consensus guideline recommends the following wait time for pretransplant melanoma: no delay for melanoma in-situ, a 2-year delay after wide local excision for stage Ia melanoma, a 2-year delay after wide local excision +/− sentinel lymph node biopsy for stage Ib/IIa melanoma, a 2- to 5-year delay after wide local excision +/− sentinel lymph node biopsy for stage IIb/IIc melanoma, and that stage III and IV melanoma patients are not candidates for organ transplantation (see Table 34.4 ).


Merkel Cell Carcinoma


Epidemiology and Pathogenesis


Merkel cell carcinoma (MCC) is a rare cutaneous malignancy of neuroendocrine origin, but is particularly aggressive and concerning in organ transplant patients. Therefore reduction of immunosuppression may be recommended in OTRs who develop MCC. There is a 10-fold increased risk of MCC in OTRs compared with the general population. , MCC tends to develop 7 to 8 years posttransplant. , The pathogenesis of MCC involves ultraviolet light, demonstrated by the increased incidence of MCC on the head and neck, and also infection with the human polyoma virus in the majority but not all patients. Logically, the more aggressive nature of MCC in OTRs makes sense given its frequent viral association. Overall, MCC in OTRs metastasize to lymph nodes in 68% of cases and cause death in 56% of cases. ,


Clinical Presentation


MCCs do not have a distinct appearance and are often biopsied to rule out NMSC. Many of these lesions present on the head and neck. Lesions present as dome-shaped pinkish-red to bluish-brown papules or nodules and are frequently ulcerated. A full skin examination for satellite lesions, a sign of in-transit spread, and a lymph node examination of draining lymph node basins are necessary.


Management and Treatment


All MCCs require surgical treatment with wide local excision or Mohs surgery. , Given the aggressive nature of MCC, all MCC in OTRs need a sentinel lymph node biopsy performed. , Management includes surgery with a wide local excision with at least 2.5- to 3-cm margins or Mohs surgery and radiotherapy to the site and regional lymph nodes. , Immunosuppression may need to be reduced with MCC given the high malignancy mortality rate of over 50%. ,


For patients with advanced MCC, treatment is challenging. A recent phase II study demonstrated that for 26 patients with unresectable MCC, pembrolizumab (anti-PD1) therapy was used and resulted in a 56% objective response rate, with four patients with a complete response. Responses were seen in virus-positive and virus-negative tumors. These patients were not OTRs. Nevertheless, this may be a promising new therapy for advanced MCC in which few treatment options exist.


Surveillance


Patients with a MCC and organ transplantation should be followed-up with every 3 months and examination should include a lymph node examination and examination for in-transit metastases (see Table 34.3 ).


Pretransplant Delay


As mentioned in the NMSC and melanoma sections, a consensus guideline was developed for management of the pretransplant SCC, melanoma, and MCC. For MCC, the consensus guidelines recommend the following: at least a 2-year delay for patients with stage IIb or less MCC (local disease, tumor size <2 cm, negative sentinel lymph node biopsy), and that patients with stage III and higher (regional lymph node disease or metastasis) are not organ transplantation candidates (see Table 34.4 ).


Rare Cutaneous Malignancies


Atypical Fibroxanthoma and Undifferentiated Pleomorphic Sarcoma


Atypical fibroxanthoma (AFX) is a rare spindle cell neoplasm that presents as a solitary pink to red nodule, usually arising on the head and neck, often biopsied to evaluate for NMSC. AFX is considered to be an indeterminate lesion, a less aggressive superficial variant of undifferentiated pleomorphic sarcoma. In OTRs, both AFX and undifferentiated pleomorphic sarcoma have a higher rate of local recurrence and metastasis than in the general population. Treatment should be aggressive, with Mohs surgery or wide local excision with 2-cm margins, followed by adjuvant radiation therapy.


Kaposi Sarcoma


Classically, Kaposi sarcoma (KS) is associated with HIV/AIDS but may present similarly in immunosuppressed OTR patients. KS in OTRs is very rare. KS presents with violaceous plaques, most often on the extremities. KS is mediated by the herpesvirus 8. KS may be managed with destruction of lesions, chemotherapy, radiation therapy, but most importantly in OTRs, by reducing immunosuppression.

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Dec 26, 2019 | Posted by in NEPHROLOGY | Comments Off on Cutaneous Disease in Kidney Transplantation Patients
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