Tumors developed in 2 old women presented with pathological findings similar to seborrheic keratosis, although the clinical feature of tumor showed typical keratoacanthoma. In addition to these two cases, we compared the pathological findings of a total of four cases, one case each of keratoacanthoma and seborrheic keratosis, which were clinically and histopathological typical. These two cases and the typical keratoacanthoma showed cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and infiltration of cytotoxic T cells. The keratoacanthoma in the decompensated stage may be histologically similar to seborrheic keratosis. TUNEL staining can help in the diagnosis of fading keratoacanthoma.

© 2023 The Author(s). Published by S. Karger AG, Basel

Keratoacanthoma is a rapidly growing skin tumor that forms a hemispherical nodule with a crater-like depression at its apex. The natural development of the tumor is divided into three phases: growth, quiescence, and resolution. During the growth phase, the tumor rapidly enlarges to form a hard hemispherical nodule with a crater-like depression on its surface with keratosis. The passage of keratoacanthoma is often followed by gradual shrinkage and disappearance. Keratoacanthoma is not a completely benign tumor; its diagnosis in conjunction with clinical findings is important as it presents with a variety of histopathological features depending on the stage of the lesion.

We report 2 cases presenting with typical clinical features of keratoacanthoma. However, seborrheic keratosis-like histopathological features were observed.

An 86-year-old woman was referred to us for a tumor on the right upper eyelid that had increased in size over a period of 4 weeks. A 12 × 10 × 7 mm nodule with good mobility to the lower bed was recognized (Fig. 1a). A skin biopsy from the tumor showed papillary proliferation of squamous epithelium and nucleoli enlargement; however, there were no findings of malignancy, making a definitive diagnosis difficult. Although the tumor showed a shrinking trend after skin biopsy, the tumor remained (Fig. 1b); therefore, total resection with a 1-mm margin was performed. The clinical findings and course were typical of keratoacanthoma; however, the histological findings of the excised tumor showed a seborrheic keratosis-like appearance with hyperplasia of the epithelium with a high nuclear/cytoplasmic (N/C) ratio accompanied by the formation of pseudokeratocysts (Fig. 1c).

a Initial findings: 12 × 10 × 7 mm nodule on the right upper eyelid. b The tumor showed shrinkage after skin biopsy. c Histological finding (Hematoxylin and eosin staining (H & E) stain ×4): epithelial hyperplasia with formation of pseudokeratinocyst within the epidermis and cells of high N/C ratio. d Initial findings: 8-mm-sized dark purple nodule with central keratinization on the right lower eyelid. e Histological finding (H & E stain ×4): pseudokeratinocyst formation in the epidermis and an inflammatory cell infiltrate consisting mainly of mononuclear cells in the upper dermis. f The clinical images of typical keratoacanthoma case. g The clinical images of typical seborrheic keratosis case.

A 79-year-old woman was referred to us for a tumor on the right lower eyelid that had increased in size over a period of 4 weeks. An 8-mm-sized dark purple nodule with central keratinization was detected (Fig. 1d). The clinical findings showed suspected keratoacanthoma. The histology of the biopsy showed pseudokeratinocyst formation in the epidermis and inflammatory cells consisting mainly of mononuclear cells in the upper dermis, which was suspicious of seborrheic keratosis (Fig. 1e).

Since the two cases were grossly keratoacanthoma but histologically seborrheic keratosis, we compared them with typical cases of keratoacanthoma (Fig. 1f) and seborrheic keratosis (Fig. 1g) regarding the histopathological findings, immunological staining of CD4 and CD8, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining because of its tendency for spontaneous regression. Case 1 (Fig. 2a, b), case 2 (Fig. 2f, g), and typical keratoacanthoma (Fig. 2k, l) showed cell apoptosis by TUNEL staining compared to typical seborrheic keratosis (Fig. 2d, h). CD8 stained more strongly in the case 1 (Fig. 2c, e), case 2 (Fig. 2h, j) and typical keratoacanthoma (Fig. 2m, o) compared to seborrheic keratosis (Fig. 2r, t), but CD4 was more strongly stained in typical seborrheic keratosis (Fig. 2r, s) compared to case 1 (Fig. 2c, d), case 2 (Fig. 2h, i) and typical keratoacanthoma (Fig. 2m, n).

a Case 1 HE staining. b Case 1 TUNEL stain staining. c Case 1 HE staining. d Case 1 CD4 staining. e Case 1 CD8 staining. f Case 2 HE staining. g Case 2 TUNEL staining. h Case 2 HE staining. i Case 2 CD4 staining. j Case 2 CD8 staining. k Typical keratoacanthoma HE staining. l Typical keratoacanthoma TUNEL staining. m Typical keratoacanthoma HE staining. n Typical keratoacanthoma CD4 staining. o Typical keratoacanthoma CD8 staining. p Typical seborrheic keratosis HE staining. q Typical seborrheic keratosis TUNEL staining. r Typical seborrheic keratosis HE staining. s Typical seborrheic keratosis CD4 staining. t Typical seborrheic keratosis CD8 staining.

Generally, keratoacanthoma is a hard, pink, hemispherical nodule skin tumor, which predominantly affects exposed areas of the skin in the elderly, especially the sun-exposed face and arms [1]. During the growth phase, the nodule grows rapidly over a period of 4–5 weeks, becoming a hard hemispherical nodule with an eruption-like depression on the surface that contains keratinized material, followed by gradual shrinkage and disappearance over a period of about 6 months [2]. Spontaneous resolution is thought to be influenced by the timing of biopsy or surgery, but the mechanism of it has not been established [3]. The nature of keratoacanthoma has long been discussed with some considering all to be spinous cell carcinoma (SCC), others to be benign tumors, or others to include both. But no consensus has been reached [4]. Even cases that can be clinically determined to be keratoacanthoma should be reviewed histopathological as early as possible because some cases may present with histopathologic findings that should be diagnosed as SCC. The diagnosis of keratoacanthoma is based on three principles: typical clinical presentation of a crateriform tumor, rapid (weeks to months) growth with a triphasic course, and histopathological examination of an appropriate biopsy specimen [5]. The histopathological features in keratoacanthoma vary depending on the stage of the lesion at the time of resection. The strong staining of case 1 and case 2 by TUNEL stain and the presence of many CD8-stained cells confirmed that the diagnosis was keratoacanthoma in the fading stage, i.e., undergoing the cell death process. It may suggest a strong antitumor immunity in the background. Although there have been reports of keratoacanthoma secondary to seborrheic keratosis [6], these stains are useful in discriminating between pathological keratoacanthoma and seborrheic keratosis.

The pathological findings of keratoacanthoma can be diverse and sometimes difficult to diagnose. Keratoacanthoma in the fading stage presented histopathologically with seborrheic keratosis-like findings. TUNEL staining is helpful in the histological evaluation of clinically suspected cases of keratoacanthoma. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529728).

The research was conducted in accordance with the Declaration of Helsinki. The patients provided written informed consent to publish their case studies, including publication of images. The paper is exempt from Ethical Committee approval because of the single case study. Ethical approval is not required for this study in accordance with local or national guidelines. This retrospective review of patient data did not require ethical approval in accordance with local guidelines.

The authors have declared that no competing interests exist.

The authors did not receive any financial support for the present study.

Mari Nakanishi and Keiichi Yamanaka treated the patient. Mari Nakanishi, Makoto Kondo, Koji Habe, Akinobu Hayashi, and Keiichi Yamanaka wrote the manuscript.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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