Transformation of Seborrheic Keratosis into Bowenoid Actinic Keratosis via Three Steps of Histological Change in a Patient with Rheumatoid Arthritis Treated with Multiple Immunosuppressants

Seborrheic keratosis (SK) has generally been considered a benign tumor, without any apparent potential for malignant transformation. On the other hand, although rare, cases of SK associated with squamous cell carcinoma (SCC) in situarising within the SK have been reported[1-10]. Here, we describe a case of SK that transformed into bowenoid actinic keratosis (AK) via three steps of histological change in a 77-year-old woman.

The patient was referred to us by her attending physician in the Division of Rheumatology at Kita-Harima Medical Center for evaluation of a skin lesion on the right cheek in December 2018. The patient had been diagnosed with rheumatoid arthritis at a clinic at the age of 42 years and had been treated with several medicines, including methotrexate, salazosulfapyridine, prednisolone, tacrolimus, abatacept, and tofacitinib citrate, which were changed depending on the symptoms and the appearance of side effects at the clinic until June 2017 and thereafter in the Division of Rheumatology at Kita-Harima Medical Center. The patient reported that the skin lesion had been present for many years as a brownish lesion, and some months prior to her referral she had noticed a pinkish lesion developing within the brownish lesion. Physical examination revealed a well-circumscribed, round, slightly raised nodule measuring 13 × 12 mm on the lateral side of the right upper cheek (Fig. 1a). The lesion consisted of three regions: a brownish hyperkeratotic region with fine unevenness on the surface of the upper part; a pinkish, glossy region with tiny brown dots on part of the surface skin in the lower portion; and a slightly dented, narrow, band-like region with a normal-looking skin surface between the brownish hyperkeratotic and pinkish glossy regions. The nodular lesion was resected en block with a 1- to 2-mm margin. Tissue sections were made to include all three regions (Fig. 1b). Histopathologically, the specimen consisted of four zones (A–D in Fig. 1c). Zones A and B clinically corresponded to the brownish hyperkeratotic region. The epidermis of zone A showed hyperkeratosis, acanthosis, and hyperpigmentation in the basal cell layer and comprised mainly basaloid keratinocytes (Fig. 1c, d). The epidermis of zone B showed hyperkeratosis and reticulated acanthosis mainly comprising squamoid keratinocytes, with interspersed pseudohorn cysts filled with keratin (Fig. 1c, e). The epidermis of zone C, which clinically corresponded to the dented, narrow, band-like region, was slightly hyperkeratotic and atrophic and showed irregular buds extending to the dermis (Fig. 1f). Atypical cells with large hyperchromatic nuclei were found both in and directly above the basal cell layer. Prominent infiltration of inflammatory cells and solar elastosis were present in the upper dermis. Zone D, which clinically corresponded to the pinkish, glossy region, showed acanthotic epidermis with hyperkeratosis and parakeratosis (Fig. 1g). The entire epidermis was occupied with atypical keratinocytes with a disorderly arrangement, together with atypical mitoses. Severe infiltrates of inflammatory cells and solar elastosis were present in the upper epidermis. Based on these clinical and histopathological findings, the nodular skin lesion was diagnosed as SK associated with atrophic and bowenoid AK within the SK lesion.

When a malignant cutaneous tumor arises within or in close proximity to SK, there has been a debate over whether the malignant tumor has actually originated from SK or instead represents a collision tumor. In previously reported cases of SK associated with SCC in situ, the region of SCC in situ has been seen on histopathological examination to be in direct contact with the SK region and most authors have considered that SK transforms directly to SCC in situ [1-10]. On the other hand, in the present case, we have observed two different histopathological regions between the main SK region and the region of bowenoid AK. This observation suggests that SK transformed to bowenoid AK via at least three steps of histological change.

Our patient had been treated with several immunosuppressants before the AK lesion had developed, and immunosuppression has been reported as a risk factor for developing SCC in SK [8, 10]. In addition, our patient showed no other AK lesions beyond that arising within the area of SK, whereas AK usually develops as multiple lesions. These observations support the idea that, at least in the present case, bowenoid AK developed from SK by malignant transformation.

Informed consent was obtained from the patient. The study complied with the Declaration of Helsinki.

The authors declare no conflict of interest.

None of the authors received any financial support for the present study.

All authors have contributed significantly. Dr. Oka conducted the dermatological examinations of the patient and wrote the manuscript. Dr. Yamamoto performed the histological analyses. Dr. Fujii treated the patient surgically. All authors are in agreement with the content of the manuscript.