Case Letter
Comment
The potential increased risk for malignancy in patients with sarcoidosis has been well documented.3-6 Brincker and Wilbek3 first reported this association after studying 2544 patients with pulmonary sarcoidosis from 1962 to 1971. In particular, they noted a difference between the expected and observed number of cases of malignancy, particularly lung cancer and lymphoma, in the sarcoidosis population.3 In a study of 10,037 hospitalized sarcoidosis patients from 1964 to 2004, Ji et al5 noted a 40% overall increase in the incidence of cancer and found that the risk for malignancy was highest in the year following hospitalization. Interestingly, they found that the risk for developing cutaneous SCC was elevated in sarcoidosis patients even after the first year following hospitalization.5 In a retrospective cohort study examining more than 9000 patients, Askling et al4 also confirmed the increased incidence of malignancy in sarcoidosis patients. Specifically, the authors found a higher than expected occurrence of skin cancer, both melanoma (standardized incidence ratio, 1.6; 95% confidence interval, 1.1-2.3) and nonmelanoma skin cancer (standardized incidence ratio, 2.8; 95% confidence interval, 2.0-3.8) in patients with sarcoidosis.4 Reich et al7 cross-matched 30,000 cases from the Kaiser Permanente Northwest Region Tumor Registry against a sarcoidosis registry of 243 cases to evaluate for evidence of linkage between sarcoidosis and malignancy. They concluded that there may be an etiologic relationship between sarcoidosis and malignancy in at least one-quarter of cases in which both are present and hypothesized that granulomas may be the result of a cell-mediated reaction to tumor antigens.7
Few published studies specifically address the incidence of malignancy in patients with primarily cutaneous sarcoidosis. Cutaneous sarcoidosis includes nonspecific lesions, such as erythema nodosum, as well as specific lesions, such as papules, plaques, nodules, and lupus pernio.8 Alexandrescu et al6 evaluated 110 patients with a diagnosis of both sarcoidosis (cutaneous and noncutaneous) and malignancy. Through their analysis, they found that cutaneous sarcoidosis is seen more commonly in patients presenting with sarcoidosis and malignancy (56.4%) than in the total sarcoidosis population (20%–25%). From these findings, the authors concluded that cutaneous sarcoidosis appears to be a subtype of sarcoidosis associated with cancer.6
We report 3 cases that specifically illustrate a link between cutaneous sarcoidosis and an increased risk for cutaneous SCC. Because sarcoidosis commonly affects the skin, patients often present to dermatologists for care. Once the initial diagnosis of cutaneous sarcoidosis is made via biopsy, it is natural to be tempted to attribute any new skin lesions to worsening or active disease; however, as cutaneous sarcoidosis may take on a variety of nonspecific forms, it is important to biopsy any unusual lesions. In our case series, patient 3 presented at several different points with scaly scalp lesions. Upon biopsy, several of these lesions were found to be SCCs, while others demonstrated regions of granulomatous inflammation consistent with a diagnosis of cutaneous sarcoidosis. On further review of pathology during the preparation of this manuscript after the initial diagnoses were made, it was further noted that it is challenging to distinguish granulomatous inflammation with reactive pseudoepitheliomatous hyperplasia from SCC. The fact that these lesions were clinically indistinguishable illustrates the critical importance of appropriate-depth biopsy in this situation, and the histopathologic challenges highlighted herein are important for pathologists to remember.
Patients 1 and 2 were both black women, and the fact that these patients both presented with cutaneous SCCs—one of whom was immunosuppressed due to treatment with adalimumab, the other without systemic immunosuppression—exemplifies the need for comprehensive skin examinations in sarcoidosis patients as well as for biopsies of new or unusual lesions.
The mechanism for the development of malignancy in patients with sarcoidosis is unknown and likely is multifactorial. Multiple theories have been proposed.1,2,5,6,8 Sarcoidosis is marked by the development of granulomas secondary to the interaction between CD4+ T cells and antigen-presenting cells, which is mediated by various cytokines and chemokines, including IL-2 and IFN-γ. Patients with sarcoidosis have been found to have oligoclonal T-cell lineages with a limited receptor repertoire, suggestive of selective immune system activation, as well as a deficiency of certain types of regulatory cells, namely natural killer cells.1,2 This immune dysregulation has been postulated to play an etiologic role in the development of malignancy in sarcoidosis patients.1,2,5 Furthermore, the chronic inflammation found in the organs commonly affected by both sarcoidosis and malignancy is another possible mechanism.6,8 Finally, immunosuppression and mutagenesis secondary to the treatment modalities used in sarcoidosis may be another contributing factor.6
Conclusion
An association between sarcoidosis and malignancy has been suggested for several decades. We specifically report 3 cases of patients with cutaneous sarcoidosis who presented with concurrent cutaneous SCCs. Given the varied and often nonspecific nature of cutaneous sarcoidosis, these cases highlight the importance of biopsy when sarcoidosis patients present with new and unusual skin lesions. Additionally, they illustrate the importance of thorough skin examinations in sarcoidosis patients as well as some of the challenges these patients pose for dermatologists.
