COVID‐19 infection and Leser–Trelat sign: Is there an association?

Key Clinical Message The etiology of the Leser–Trélat sign is still unknown, it is likely that viral infections like COVID‐19 can be associated with eruptive seborrheic keratosis, although the exact pathogenesis is still not clear, but this phenomenon can be due to TNF‐alpha and TGF‐alpha and immunosuppression condition as well as in COVID‐19 infection. Abstract Seborrheic keratosis is a typical benign skin lesion that is almost always seen in elderly populations. The sudden increase in size or an increase in the number of these lesions is called Leser–Trelat sign, this sign is suggesting as a paraneoplastic appearance of internal malignancy. But, Leser–Trelat sign is also described in some nonmalignant conditions, for example, human immunodeficiency virus infection and human papillomavirus infection. Herein, we describe a patient with Leser–Trelat sign after recovery from COVID‐19 infection with no evidence of internal malignancy. This case was partially presented as a poster in the 102nd Annual Congress of British Association of Dermatologists in Glasgow, Scotland from July 5 2022 to July 7 2022. British Journal of Dermatology, 187, 2022 and 35. The patient signed written informed consent to permit the publication of the case report without identifying data and to use the photography for publication. The researchers committed to maintaining patient confidentiality. Institutional ethics committee approved the case report (ethics code: IR.sums.med.rec.1400.384).

The patient signed written informed consent to permit the publication of the case report without identifying data and to use the photography for publication. The researchers committed to maintaining patient confidentiality. Institutional ethics committee approved the case report (ethics code: IR.sums.med.rec.1400.384).
The sudden increase in size or an increase in the number of these lesions is called Leser-Trelat sign, this sign is suggesting as a paraneoplastic appearance of internal malignancy. 3 The most frequently associated malignancies are adenocarcinoma of the colon, stomach, lung, or breast, although the Leser-Trélat sign has also been reported in nonmalignant conditions, for example, lepromatous leprosy, 4 erythrodermic pityriasis rubra pilaris, 5 human immunodeficiency virus infection, 6 and human papillomavirus infection. 7 Leser-Trélat sign can also occur in healthy individuals in the absence of internal malignancy. 8 Herewith, we describe a case of Leser-Trelat sign, which presented after recovery from COVID-19 infection in a 50-year-old man.

| CASE REPORT
A 50-year-old man was referred to our dermatology clinic complaining of sudden appearance of multiple warty-like lesions on his back which had occurred 2 months after recovery from COVID-19 infection.
According to his medical history, the patient presented with dyspnea, fever, and cough, about 2 months prior to the appearance of the skin lesions. He was referred to a health center where a nasopharyngeal swab was taken, and his PCR test for COVID-19 was positive. In addition, bilateral patchy ground-glass infiltration was reported in his high-resolution computed tomography (HRCT) scan in favor of COVID-19 infection. The patient was then treated with acetaminophen, dexamethasone (intramuscular injection), salmeterol, and fluticasone inhaler, and his symptoms improved.
Two months after recovery from mild COVID-19 infection, multiple small asymptomatic pigmented wartylike papules appeared on the patient's back. Physical examination revealed multiple rough, oval-shaped, brownish papules varying in size from 2 mm in diameter to 15 × 5 × 2 mm ( Figure 1). Dermatoscopy of the lesions was also performed. Both clinical and dermoscopic findings were in favor of seborrheic keratosis ( Figure 2). In order to reach a final diagnosis, a skin biopsy was requested, and microscopic examination of the biopsy specimen showed hyperkeratosis, well-defined epidermal hyperplasia, composed mainly of the proliferation of benign-looking basaloid cells and fewer squamoid cells, horn cysts, and increased melanin, mostly in the dermo-epidermal junction. The dermis showed no significant change ( Figure 3). Based on the above findings, the patient was diagnosed with eruptive seborrheic keratosis.
To determine the possible cause of this eruption, the patient was further evaluated. In his past medical history, he F I G U R E 1 Small pigmented verrucous papules on the patient's back.

F I G U R E 2
Dermoscopic examination revealed a brown lesion with milia-like cysts, brown dots, and multiple comedone-like openings.
was generally healthy before his COVID-19 infection and had no history of comorbidities. The patient was then examined to rule out any internal malignancies. Laboratory tests revealed normal results and included a complete blood count (white blood cells 5300/mm 3 , red blood cells: 4.5 × 10 6 /mm 3 , platelets: 152000/mm 3 ), liver and kidney function tests, electrolytes, prostate-specific antigen, and urine analysis. Gastrointestinal endoscopy and colonoscopy ruled out any gastrointestinal malignancy. Chest Xray and high-resolution computed tomography (HRCT) scan revealed no malignant lesion. In addition, the patient's abdominopelvic sonography was normal. The patient had no family history of similar skin lesions and gave no history of any chronic inflammatory skin diseases or viral conditions. Therefore, the appearance of the Leser-Trelat sign after COVID-19 infection could be regarded as a possibility in this patient.

| DISCUSSION
Seborrheic keratosis is a typical benign skin lesion that is almost always seen in elderly populations, the sudden increase in size or an increase in the number of these lesions is called Leser-Trelat sign. The etiology of the Leser-Trélat sign is still unknown, although it has been considered as a paraneoplastic phenomenon. The most frequently associated malignancies are adenocarcinoma of the colon, stomach, lung, or breast. Some cases with the Leser-Trélat sign have occurred in nonmalignant patients, including patients with underlying infections like viral infections, 6,7,15 lepromatous leprosy, 4 in association with erythrodermic pityriasis rubra pilaris. 5 In addition, a case has been reported in a heart transplant patient treated with immunosuppressive drugs. 9 In addition, some observations have indicated that the Leser-Trélat sign may develop following viral infections. Inamadar and Palit 6 have reported a case with human immunodeficiency virus infection who developed the Leser-Trélat sign. In a study by Tsambaos et al., human papillomavirus (HPV) DNA was positive in 34 patients from among 173 cases with nongenital seborrheic keratosis. 7 Gushi et al. evaluated 104 nongenital seborrheic keratosis immunopotent patients for HPV DNA and showed that 30 of 104 seborrheic keratosis samples contained HPV DNA. 15 Some theories have associated its development to transforming growth factor (TGF)-alpha and epidermal growth factors secreted from tumor cells. According to previous studies, TGF-alpha is overexpressed in seborrheic keratosis, and it may play a significant role in the progression and increase in the number of seborrheic keratoses. 10,11 It has been shown that COVID-19 infection with lung injury can induce expression of TGF, 12 so there is the possibility of a similar mechanism in our patient, although severe lung findings were not reported. However Leser-Trelat sign is usually associated with a variety of immune suppression conditions such as malignancy or viral infection, so development of eruptive seborrheic keratosis may be due to immunosuppression situation caused by COVID-19 infection and not exactly due to TGF-alpha.
accordance with increased inflammatory cytokines such as TNF-alpha observed in COVID-19 patients. 14 Although, the development of Leser-Trelat sign in healthy persons does not fully support the theories of TNF-alpha and TGF-alpha and immunosuppression conditions. Therefore, it is likely that viral infections like COVID-19 can be associated with eruptive seborrheic keratosis, although the exact pathogenesis is still not clear.

FUNDING INFORMATION
There is no funding source for this scientific work.

CONFLICT OF INTEREST STATEMENT
The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions.