Widespread sebaceous neoplasms in the setting of chronic immunosuppression with near-complete clearance on isotretinoin

Introduction

Sebaceous neoplasms encompass a broad set of diagnoses ranging from benign entities, such as sebaceous adenomas and sebaceoma, to more concerning malignancies, such as sebaceous carcinoma.¹ The presence of sebaceous adenomas in the setting of underlying hereditary colorectal cancer encompasses Muir-Torre syndrome.² In the vast majority of instances, however, sebaceous neoplasms are not associated with the presence of internal occult malignancy but instead develop in response to more common triggers, such as normal aging, hormonal dysregulation, and UV irradiation.¹ Furthermore, few reports have alluded to an association between the development of sebaceous adenomas and the use of certain immunosuppressive agents.3, 4, 5, 6 More specifically, the use of calcineurin inhibitors cyclosporine and tacrolimus in the setting of organ transplantation has been implicated in the development of widespread sebaceous adenomas in multiple instances.⁷

Here, we describe a case of widespread sebaceous adenomas and hyperplasia in the setting of multiple immunosuppressive agents in a patient with systemic lupus erythematosus (SLE).

Case report

A 55-year-old man with a 20-year history of SLE complicated by lupus cerebritis and anti-phospholipid syndrome presented to the clinic with a worsening eruption of innumerable pink-tan colored papules on his face, neck, upper portion of the chest, and upper portion of the back (Fig 1). He endorsed that these lesions had developed almost 20 years ago, but have only been rapidly increasing more in number and severity over the past 3 years. Soon after the presentation of SLE in 1996, he developed Stevens-Johnson syndrome (SJS) the same year, possibly in response to therapy; however, an offending agent could not be identified at that time. He believed that the sebaceous neoplastic growth began soon after the resolution of his SJS. At the time of presentation, his long-standing medication list included azathioprine 200 mg daily, methotrexate 15 mg weekly, rituximab 2 g every 6 months, and prednisone 7 mg daily. Although the lesions were asymptomatic the majority of the time, he did endorse associated pain and discomfort coinciding with rapid lesion size increase in the setting of escalating prednisone dosing specifically. His family history was noncontributory, with no family history of colorectal cancer, hereditary non-polyposis colorectal cancer, or other familial cancer syndromes. Furthermore, he denied any constitutional or gastrointestinal symptoms that would be concerning for occult internal malignancy and had a normal colonoscopy within the past 12 months. The patient had 3 facial biopsies performed on both cheeks that were found to be consistent with sebaceous adenoma with immunohistochemical staining showing intact expression of MutL homolog 1 gene and MutS homolog 2/6 genes (Fig 2). The patient was also referred to a genetics specialist to assess the possibility of underlying genetic cancer syndromes; however, the patient declined this evaluation. Given the extent of involvement and concern for cosmesis, treatment with isotretinoin 50 mg daily (∼0.5 mg/kg) was initiated for the first 1 month, with the dose increased to 100 mg daily (∼1.0 mg/kg) after the first month (cumulative dose, 95 mg/kg). In addition to the initiation of isotretinoin treatment, rheumatology was consulted and the dosage of azathioprine was decreased from 200 mg to 150 mg daily and methotrexate from 15 mg to 12.5 mg weekly, starting 2 months after isotretinoin was initiated. Within the first month of isotretinoin therapy, his examination was notable for visible improvement with a smaller number of yellowish papules and significant flattening of the lesions (Fig 3). He continued to see even further improvement after the isotretinoin dose was increased and immunosuppressive doses decreased, owing to the likelihood that both interventions contributed to his significant clinical improvement. The patient is now on month 8 of isotretinoin therapy at 100 mg daily, with the plan to continue this dose for another 4 to 6 months until the optimal clearance is achieved and with a possible lower maintenance dose if needed.

Fig 1.

Clinical photographs of the facial eruption of innumerable raised, well-circumscribed pink-tan flesh-colored papules on the patient’s face consistent with sebaceous adenoma/hyperplasia. Similar eruptions could be appreciated on the neck, upper portion of the chest, and upper portion of the back.

Fig 2.

A cheek biopsy was taken to delineate the diagnosis and was consistent with sebaceous adenoma/hyperplasia. At the center of the dermis is a sharply demarcated multilobular lesion composed of mature sebocytes as well as immature peripheral cells with a high nuclear/cytoplasmic ratio. A, Significant atypia not identified. B, Staining for microsatellite instability genes showed intact expression of MutL homolog 1 gene and MutS homolog 2/6 gene.

Fig 3.

Clinical photographs after several months of oral isotretinoin treatment showcasing near-complete resolution of the sebaceous adenomatous eruption

Discussion

Although there are many reported cases linking calcineurin inhibitors to the development of sebaceous gland hyperplasia, there is a paucity of information linking this phenomenon to other immunosuppressive drug classes.^4,5,7 One prior report linked the use of prednisone with the development of sebaceous hyperplasia in a patient with Crohn’s disease⁸ whereas one other report described the association of combination prednisone and azathioprine use and sebaceous hyperplasia in patients who underwent a renal transplant.^4,5 Mechanistically, it is believed that both cyclosporine and prednisone’s lipophilic properties allow deposition in sebaceous glandular tissue, inducing the inhibition of sebocyte turnover.^8,9

The use of isotretinoin in treating sebaceous hyperplasia is believed to be because of the action of this agent in reducing both the proliferation and differentiation of basal sebocytes, in addition to other actions, such as reduction of sebaceous gland size, as well as inhibition of sebum production. Although isotretinoin’s effects on the sebaceous glandular unit are well established, several other less well-studied theories exist regarding this mechanism of action.⁹ It has been postulated that isotretinoin may also play a role in the metabolism of androgens, indirectly owing to its ability to act in an inhibitory fashion on the sebaceous unit. In the few cases in which isotretinoin has been successfully used to treat sebaceous hyperplasia, doses of anywhere from 10 to 20 mg/d for several months have traditionally been targeted; however, prior studies appear to point to a high relapse rate in patients who were not maintained on therapy.^8,9

In our patient’s case, the presence of sebaceous neoplasms with intact immunohistochemical staining for mismatch repair genes in the setting of a normal recent colonoscopy and noncontributory family history makes the possibility of an underlying genetic cancer syndrome like Muir-Torre syndrome very unlikely and sheds light on a more likely drug-induced process. Furthermore, it is interesting that his findings began soon after the resolution of his SJS decades ago. A review of the literature establishes only 1 prior report showcasing the development of sebaceous hyperplasia eruption in 2 patients after recovery from toxic epidermal necrolysis. Mechanistically, a local inflammatory response within the hair follicular unit in patients with SJS/toxic epidermal necrolysis may lead to the destruction and scarring of such structures that subsequently lead to the development of sebaceous hyperplasias.¹⁰ Overall, this case highlights an underreported phenomenon and emphasizes the need for a greater understanding of the large spectrum of immunosuppressive agents that could owe to this process. To our knowledge, this is the first reported case of a benign sebaceous neoplastic eruption in a patient with SLE on combination immunosuppressive therapy with a dramatic response to isotretinoin.

Conflicts of interest

None disclosed.