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.

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.

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 ).

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: http://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 ).

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 ).

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 ).

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 ).