The sign of Leser-Trelat is considered to be a fairly rare paraneoplastic cutaneous marker of internal malignancy with the hallmark finding being an abrupt eruption of multiple seborrheic keratoses. [1][2][3][4]To date, there have been no standardized or quantified diagnostic criteria defining the sign of Leser-Trelat, but instead, the colloquial definition includes an increase in the number and/or size of the seborrheic keratoses. Seborrheic keratoses (SK) are a nearly ubiquitous benign skin lesion in patients greater than 40 years of age, and generally, even healthy patients may have multiple seborrheic keratoses. This “sign” has been met with a significant amount of skepticism by many considering the commonality of both seborrheic keratoses and malignancy in elderly patients.

The sign of Leser-Trelat was first described by in the 1800s by Edmund Leser and Ulysse Trelat, but instead of eruptive seborrheic keratoses, they were studying the presence of cherry angiomas in oncology patients. In 1900, Hollander was the first to describe seborrheic keratoses in association with malignancy, but the names Leser and Trelat remained affixed to the condition.[5]

As previously mentioned, the underlying etiology of the sign of Leser-Trelat is believed to be an internal malignancy. The sign of Leser-Trelat may precede, occur concurrently, or start after the diagnosis of malignancy. The most commonly implicated malignancies include gastrointestinal adenocarcinomas (gastric, colon, rectal), with gastric adenocarcinoma being the overall most common malignancy, followed by breast cancer, and lymphoproliferative disorders/lymphoma. Additional malignancies reported to display the sign of Leser-Trelat include melanoma, prostate, lung, kidney, laryngeal, ovarian, mycosis fungoides, hepatocellular carcinoma, bladder cancer, nasopharyngeal carcinoma, and squamous cell carcinoma.[6]

Curth's postulates are a well-known set of clinical criteria that were created to help evaluate the temporal relationship between an underlying malignancy and a specific dermatological condition. The criteria are as follows:

1. Both the neoplastic and paraneoplastic process began concurrently
2. Both the neoplastic and paraneoplastic processes have a parallel disease course (i.e., paraneoplastic process resolves with treatment of the underlying malignancy, and paraneoplastic process relapses if malignancy returns)
3. The paraneoplastic process is associated with specific types of malignancy
4. The skin lesions are not associated with any potential underlying genetic syndromes
5. The skin lesions are not common in the general population
6. There is a strong statistical association of the paraneoplastic process with truly having an underlying malignancy.

As previously mentioned, the sign of Leser-Trelat has been met with an abundance of skepticism by many physicians, likely due to the inability of the sign of Leser-Trelat to confidently fulfill all of Curth's postulates.

The average age of onset of the sign of Leser-Trelat has been quoted to be approximately 61 years of age. There is no reported increased predilection amongst either sex or any race. Reports of the sign of Leser-Trelat in patients in the second decade of life in association with malignancy do increase the legitimacy of this sign as an accurate predictor of internal malignancy given the relative rarity of seborrheic keratoses in patients of this age.[7]

The exact pathophysiology underlying the sign of Leser-Trelat remains elusive, but there is strong suspicion that the release of cytokines and growth factors from the neoplasm are stimulating the eruptive growth of the seborrheic keratoses. Particularly, the overexpression of EGF-alpha and EGFR (epidermal growth factor receptor) may contribute to the eruptive nature of these lesions. Additional named growth factors include human-growth-hormone, transforming growth factor-alpha, and insulin-like growth factor.

Histopathological examination of a biopsied seborrheic keratosis from a patient suspected to exhibit the sign of Leser-Trelat does not show any significant difference when compared to a seborrheic keratosis in a patient without underlying malignancy. Various subtypes of seborrheic keratoses exist including acanthotic (most common variant), hyperkeratotic, reticulated, clonal and melanoacanthoma. Any of these distinct variations may also become irritated or inflamed, displaying either squamous eddy formation (spindled cells) or lymphocyte infiltration, respectively. There does not appear to be an increased frequency of a specific histopathological variation of seborrheic keratoses that correlates with the sign of Leser-Trelat.