Management of squamous cell carcinoma in organ transplant recipients

The number of skin cancers continues to rise with well over one million cases of skin cancer expected in the United States this year. Optimal management depends on early detection and treatment. The consequences of skin cancer may be particularly devastating in organ transplant recipients. In this article, management of squamous cell carcinoma in the organ transplant recipient is discussed.     

The pathogenesis of cutaneous squamous cell carcinoma in organ transplant recipients

The pathogenesis of keratinocyte carcinoma following organ transplantation is multifactorial, and recent evidence suggests a complex and often synergistic interplay between the carcinogenic effects of ultraviolet radiation, compromised immune surveillance, direct pro‐ and anticarcinogenic effects of drugs, oncogenic viruses (in particular, beta‐genus human papillomaviruses) and host genetic susceptibility factors. We present an overview of those factors for which there is currently the most convincing evidence and highlight important gaps in our knowledge. In particular, a clear understanding of the interdependence and relative contributions of these co‐factors is currently lacking, yet has important implications for rational development of clinically relevant biomarkers and targeted strategies for treatment and prevention of post‐transplant keratinocyte cancers.     

Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients

Although tremendous progress has been made in recent years in skin cancer care for organ transplant recipients, significant gaps remain in data‐driven clinical guidelines, particularly for the treatment and prevention of cutaneous squamous cell carcinoma (cSCC), the most common malignancy among this population. In this review, we aim to summarize current knowledge around the management of cSCC and highlight the most significant gaps in knowledge that continue to pose challenges in the delivery of skin cancer care for organ transplant recipients. We suggest future directions for research that will bridge existing gaps and establish evidence‐driven guidelines for primary prevention, screening and treatment of cSCC in this high‐risk patient population.     

Keratinocyte carcinoma in organ transplant recipients

Skin cancer commonly affects people who have received a solid organ transplant (heart, lung, liver and kidney). Transplant patients can get multiple skin cancers, some of which can grow very quickly. The commonest types of skin cancer are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Immunosuppressant medication is used to prevent rejection of the transplanted organ. This alters the body's immune system, which in turn means that transplant patients are more prone to skin cancers that can grow rapidly. Over the last 20 years, newer immunosuppressants have been introduced which are thought to lessen the risk of skin cancer. Previous studies have shown a lower risk of SCC with the newer medication, but no study to date has looked at BCC rates. This study, from Ireland, aimed to find out if the rate of skin cancer in transplant patients has reduced over the last 20 years, spanning the introduction of newer immunosuppressive medications. The National Cancer Registry of Ireland registers all skin cancers for the Republic of Ireland. The authors looked at the rate of skin cancer in people who received a solid organ transplant and compared this to the rate of skin cancer in the general population. They found that the rate of SCC and BCC in patients who received an organ transplant has significantly reduced over the last two decades. This change in risk of skin cancer coincided with changes in immunosuppressant medication, along with focused education and regular skin cancer screening for transplant recipients.     

Metastasis of skin squamous cell carcinoma in kidney transplant recipients

Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy in kidney transplant recipients (KTRs) as a result of immunosuppression. A worldwide increase in kidney transplantation justifies the determination of prognostic biomarkers by collecting detailed patient data on metastasis development. This study aims to characterize the clinical, epidemiological, and histopathological profiles of KTRs who developed metastasis of cSCC. We conducted a retrospective single-center study on 18 KTRs and 21 immunocompetent patients (ICs) with metastatic cSCC, using data from 2004 to 2021. ICs were older (median age 70.5 years) than KTRs (median age: 59.5 years). Both groups were predominantly male with Fitzpatrick skin phototype I/II. The primary tumor appeared around 83.5 months post-transplant, usually in sun-exposed areas (61.1%), though some non-exposed areas in ICs (23.8%) contradicted literature findings. KTRs took longer to develop metastasis (median: 11.0 months) compared to ICs (median: 5.5 months). The mean size of the primary tumor was smaller in KTRs (2.50 cm²) compared to ICs (4.55 cm²). The main lymph node chain affected by metastasis was parotid lymph nodes in KTRs (27.8%) and cervical/axillar lymph nodes in ICs (both 19.0%). Both groups exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.     

Squamous cell carcinoma in organ transplant recipients: approach to management

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.     

Mortality and clinicopathological features of cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort

Solid organ transplant recipients have a high incidence of cutaneous squamous cell carcinoma and often develop multiple and aggressive tumours. This retrospective study based on the Swedish organ transplant cohort, focuses on the deaths caused by cutaneous squamous cell carcinoma and aims to elucidate the clinicopathological features of these tumours. The cohort comprised 5931 patients who underwent organ transplantation during the period 1970 to 1997 and were registered in the Swedish In-patient Registry, Cancer Registry and Causes-of-Death Registry. A total of 544 cutaneous squamous cell carcinomas in 201 patients were re-examined. The dominating size of the tumours was 5-10 mm and one-third of the tumours were removed by methods other than excision surgery. Well-differentiated tumours and Clark level IV were predominant. Seven patients died from their tumours, all of which were localized on the head. The principal site of metastasis was the parotid gland. The mean duration between date of transplantation and death was 10.4 years (range 6-17 years). Mortality from cutaneous cell carcinoma was compared with that of the general population. There was a highly increased risk; standardized mortality ratio 52.2; 95% confidence interval 21.0-107.6. However, the mortality rate in the Swedish cohort appears to be lower than what has been reported previously from other countries.     

Cutaneous squamous cell carcinoma in organ transplant recipients: a study of the Swedish cohort with regard to tumor site

OBJECTIVE: To establish the anatomical site distribution of cutaneous squamous cell carcinoma (SCC) in organ transplant recipients (OTRs) with regard to age and sex. DESIGN: Retrospective population-based cohort study of OTRs. SETTING: Patients who underwent organ transplantation in Sweden from January 1, 1970, to December 31, 1997, registered in the Swedish In-patient Registry and national Swedish Cancer Registry. PATIENTS: From the cohort of 5931 OTRs, we could include 179 patients with 475 cutaneous SCCs. Information on the sites was received from the cancer registry and from the histopathological reports. RESULTS: The site of each SCC was registered in a computer program displaying the results on a 3-dimensional human figure. The head and neck were the predominant sites in male patients, and the trunk was the predominant site in female patients. The most common site in younger patients (born in 1940 or after) was the chest; and in older patients, the face. The ear was a common site in male patients, but, in contrast, no tumors were located there in female patients. Overall, the OTRs were younger compared with the overall Swedish population with cutaneous SCC. CONCLUSIONS: There are differences in the anatomical site distribution of cutaneous SCCs in OTRs with regard to sex and age, and with regard to the general distribution in Swedish patients. The level of sun exposure is considered the most important factor in explaining those differences, and highlights the importance of sun avoidance in this group of patients.     

Altered density,composition and microanatomical distribution of infiltrating immune cells in cutaneous squamous cell carcinoma of organ transplant recipients

Organ transplant recipients (OTR) who require the long‐term use of immunosuppressant medications to prevent organ rejection are more than 65 times more likely than the general population to develop squamous cell carcinoma of the skin (SCC), which is a type of skin cancer and the most frequent malignant tumor after organ transplantation. Allegedly, the immune system in the skin may influence the disease as SCCs tend to behave more aggressively in immunosuppressed patients. The aim of this study was to gain an insight into the distribution patterns of different immune cells in SCCs arising in immunosuppressed OTR and non‐transplant patients. The researchers from Heidelberg, Germany, stained different immune cell subsets in 20 SCCs from kidney transplant recipients and SCCs from thoroughly matched immunocompetent non‐transplant patients (IC). They compared quantities and tissue distribution of immune cells in tumors and surrounding skin in both groups by using a novel semi‐automatic technology and computerized microscopy. The investigators found that the density of immune cells in SCC and surrounding skin from OTR was overall reduced compared to IC, particularly at the tumor borders. In addition to reduced CD4+ immune cells at the tumor borders the density of CD8+ T cells (a subset of immune cells thought to help fight tumours), within the SCCs and tumor‐surrounding skin of OTR was significantly diminished. One possible explanation may be that immunosuppressants (drugs that suppress the immune system to stop the body rejecting the new, transplanted organ) influence the ability of immune cells to accumulate in the skin and position themselves at the site of a growing SCC in order to detect and defend against cancer. The authors note that additional studies must be done to learn more about the functional relevance of the particular immune cell subsets for the control of skin cancer.     

Immunosuppressive level and other risk factors for basal cell carcinoma and squamous cell carcinoma in heart transplant recipients

OBJECTIVES: To examine risk factors for the development of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in a cohort of heart transplant (HT) recipients and, in particular, to evaluate the role of the cumulative doses of different immunosuppressive drugs. DESIGN: Prospective nonconcurrent study. SETTING: A dermatology clinic at a university hospital. PATIENTS: A total of 230 HT recipients 18 years or older at the time of transplantation with at least 3 years of follow-up. MAIN OUTCOME MEASURES: The risk of SCC and BCC in HT recipients and the relationship between development of SCC and BCC and cumulative doses of different immunosuppressive agents, controlling for other potential risk factors (age, sex, sunlight exposure, skin type, and presence of warts). RESULTS: The cumulative immunosuppressive drug dose 3 years after transplantation (calculated by a weighted linear combination of azathioprine, cyclosporine, and corticosteroid cumulative doses [WLC]) was independently associated with an increased risk of developing SCC but not BCC. On multivariate analysis, patients receiving a WLC higher than the 75th percentile 3 years after HT had a 4 times higher risk of SCC than recipients of a WLC lower than the 50th percentile 3 years after HT (95% confidence interval, 1.4-11.4; P =.008). Other significant risk factors for SCC development were older age at transplantation and a greater occupational sunlight exposure. The risk of developing BCC was only associated with older age at transplantation and skin type II. CONCLUSIONS: The risk of SCC but not of BCC in HT recipients was related to the level of global immunosuppression rather than to 1 specific drug. The level of immunosuppression should be kept as low as possible consistent with survival and function of the transplanted organ.     

Clinical comparison of actinic changes preceding squamous cell carcinoma vs. intraepidermal carcinoma in renal transplant recipients

Intraepidermal carcinoma (IEC) is a type of in situ squamous cell carcinoma (SCC), although progression of IEC is rare. We sought to investigate differences between the actinic skin changes preceding the development of both SCC and IEC. Photographs of 63 skin sites at which either SCC or IEC subsequently developed in 37 renal transplant recipients (RTRs) were examined for features of actinic change. We found that areas of skin with an actinic keratosis (AK) > 1 cm² in size were four times more likely to develop SCC as opposed to IEC (OR = 4.42; 95% CI 1.25–15.60). Skin sites with ≥ 25% of the area affected by AK were again four times more likely to develop SCC than IEC. These results highlight the scale of visible actinic damage required for development of SCC compared with IEC, emphasizing the importance of treating areas of skin with marked visible actinic change to reduce SCC risk in RTRs.