CME Author: Vicki Brower
Study Authors: Joana Lanz, Jan Nice Bouwes Bavink, et al.
Target Audience and Goal Statement:
Dermatologists, oncologists, transplant surgeons, internists
To understand that squamous cell carcinoma (SCC) is the most frequent malignancy found in solid organ transplant recipients, and is associated with a more aggressive disease course and higher metastasis risk and death than in the general population. These patients have a 65-fold to 250-fold higher incidence of SCC compared with those who have not received solid transplants. Researchers recommend annual full skin examinations for patients who have received a solid organ transplant, and skin lesions should be removed as soon as they are found.
To understand the clinicopathologic features of aggressive SCC, and to identify factors that are associated with development of aggressive disease in recipients of solid organ transplant recipients.
Questions Addressed by this Study:
What is the extent of elevated risk of SCC in patients who have undergone solid organ transplantation? For these patients, on what sites does SCC preferentially appear? What are the risk factors associated with aggressive SCC in this population, what are the unique characteristics of these cancers, and what are the recommendations for care of this patient population?
Study Synopsis and Perspective:
“Although most SCCs will be successfully treated, some show a very aggressive clinical course,” wrote first author Joana Lanz, MD, of the University Hospital Zurich, and colleagues in JAMA Dermatology. Currently, the distinction between the many SCCs cured without sequelae, and the few SCCs with an aggressive course, can be hard to make at diagnosis,” they noted.
This small, multicenter case series-based study confirmed a number of risk factors associated with aggressive SCC in organ transplant recipients, and found prognosis to be poor for these patients. The authors reported that anatomical site, differentiation, tumor diameter, tumor depth, and perineural invasion were important risk factors in aggressive SCC in solid organ recipients.
While individuals who have received solid organs are at a considerably higher risk of SCC than the general population, the factors for developing SCC in this population are similar to those found in the general population: male sex, older age, cumulative UV radiation exposure, and fair skin, the authors wrote. Others factors are in immunosuppression and time from transplant.
Most patients in the study who developed SCC were men (84%) and had been kidney transplant recipients (78%).
Lanz’s group evaluated records of eight women and 43 men treated at five medical centers in Belgium, Spain, the Netherlands, England, and Switzerland from 2005 to 2015. The participants had a median age of 51 at the time of transplant and age 62 at the time of SCC diagnosis. Most of the patients (78%) in the study had received kidney transplants. Perineural invasion was present in 39% of patients and 45% of patients had a local recurrence.
Patients were included if they were recipients of a solid organ, and had an aggressive SCC consisting of nodal spread, distant metastasis, or death from their primary SCC. Patients were excluded if there was missing information in their health records or if they had mucosal head and neck SCC.
Among 51 patients who had received a solid organ transplant, the 5-year SCC-specific and overall survival (OS) rates were 30.5% and 23%, respectively. Survival rates were “unfavorable” for patients with primary SCC with aggressive characteristics in comparison with the general population. Other studies have shown 3-year disease-specific survival rates of 56% in metastatic SCC in transplant recipients; another study reported a 5-year OS of 35% and a disease-specific rate of 50% in patients with aggressive SCC of the trunk or extremities.
The SCCs in the study patients were localized on the face in 67% and 41% of tumors were poorly differentiated, with a median tumor diameter of 18 mm and median tumor depth of 6.2 mm. Lanz’s group noted that tumor depth “is highly associated with recurrence and metastasis, with tumor thickness greater than 2 mm having a 10-fold higher risk of local recurrence and 11-fold higher risk of metastasis.” The lymph nodes, parotid gland, and skin were the most common sites of metastases in their series.
JAMA Dermatology, Dec. 5, 2018; DOI:10.100/jamadermatol.2018.4406
Study Highlights: Explanation of Findings
When compared with individuals with no history of transplant, past studies have indicated that SCC incidence is 65 to 250 times greater in solid organ transplant recipients, and that the risk of SCC continues to increase with time post-transplant. One recent study found that organ transplant recipients’ risk of developing skin cancer was five times greater than the rates of all cancers put together in the general public.
The tumors generally appear on the face and scalp in these patients, and exhibit more aggressive features than SCC in the general population. Most of the tumors in this study were moderately or poorly differentiated. Another study found that like in other cancers, poor differentiation signaled a poorer prognosis. The median tumor size was 18 mm (range 4-46 mm).
A previous meta-analysis found that tumor diameter >2 cm is the risk factor most highly associated with disease-specific death, and a 19-fold higher risk of death from SCC compared with tumors with a smaller diameter <2 cm.
In this study, the median tumor thickness was 6.2 mm. Thickness was highly associated with recurrence and metastasis: tumor thickness >2 mm had a 10-fold higher metastasis risk. Another study found that tumor thickness >4 mm was associated with a 9% rate of metastasis, and for tumors ≥6 mm, that increased to a metastasis rate of 16%.
Perineural invasion in the general population is rare at an incidence of 2.5% to 5.0% for primary SCC, but occurred in 39% of this study’s patients. Recurrence occurred in 45%.
Most common sites for metastasis were the lymph nodes (including parotid gland and skin). Previous studies found the same areas to be the principal sites for metastasis.
The new study confirmed earlier results that showed that median age at transplant was 54.5, and 61.9 at diagnosis of aggressive disease. However, the earlier study showed no difference in breakdown of gender. A third study reported that SCC was diagnosed earlier in transplant patients, at median age 57, compared with immunocompetent patients, who developed SCC at age 67.
While the FDA recently approved the PD-1 inhibitor cemiplimab (Libtayo) for cutaneous SCC, a recent series suggested that immune checkpoints may play a role in preventing a patient’s immune system from rejecting transplanted organs, noting that more research is needed to determine the safety of these agents in this setting.
In an email, Lanz told MedPage Today that with no approved therapies for preventing future skin cancers, yearly education consultations focusing on primary prevention — modifying behavior, wearing appropriate clothing, applying sunscreen daily — is the best course of action for limiting SCC incidence in transplant patients.
“Annual full skin examinations are recommended to allow early recognition and removal of lesions of squamous cell carcinoma before these take a negative turn, thus avoiding development of cases as the one reported by us,” Lanz said. “Future studies should aim at not only treatment of actinic keratosis, basal cell carcinoma, squamous cell carcinoma, but should aim at prevention of future squamous cell carcinoma by regular application of… photodynamic therapy in skin areas with high sun damage.”
“Although our case series was not selected in a randomized fashion, our patient characteristics suggest that our series is typical for solid organ transplant recipients,” the authors wrote.
The investigators acknowledged certain limitations. The data were retrospective and based on a small sample from only a few contributing centers. Selection of tumors with outcomes like recurrence, metastasis, and death can bias the data toward clinical and pathologic factors linked with poor outcomes such as perineural invasion, they wrote.
Other limitations included that there was no data on skin type, sun exposure, or ethnicity, and there was no control group.
Original story on MedPage Today by Ashley Lyles
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner