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. 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.
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.
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:
- Both the neoplastic and paraneoplastic process began concurrently
- 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)
- The paraneoplastic process is associated with specific types of malignancy
- The skin lesions are not associated with any potential underlying genetic syndromes
- The skin lesions are not common in the general population
- 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.
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.
History and Physical
As previously mentioned, seborrheic keratoses are a nearly ubiquitous, benign skin lesion in patients greater than 40 years of age. The typical morphology of these lesions tends to vary extensively amongst patients and may present as a macule, papules, and plaques. They are well-circumscribed pigmented lesions with the color ranging from skin tone to tan or brown, and some lesions may appear black. The texture is typically described as waxy or velvety, and they may have a "stuck on" appearance. The presence of horn cysts on the surface of the lesions is also classic. Although these lesions are typically rather easy to distinguish from other melanocytic neoplasms, the histopathological examination may be required for lesions lacking typical exam findings.
Physical examination will typically reveal numerous seborrheic keratoses usually in a symmetric pattern on the back that may resemble a "Christmas tree," "splash," or "raindrop" pattern. Although the back is the most common location, additional sites may include the extremities, face, neck, and abdomen. Patients will often complain of pruritus associated with these lesions. Interestingly, many patients truly displaying the sign of Leser-Trelat will concurrently experience another paraneoplastic disease process so a careful examination and history cannot be overemphasized. Malignant acanthosis nigricans, characterized by velvety, symmetrical hyperpigmentation often in intertriginous sites (but may occur in any location on the body) occurs simultaneously in about 20% of cases displaying the sign of Leser-Trelat. The generalized presence pruritus and/or acanthosis nigricans should heighten the physician's suspicion for underlying malignancy.
Should the physician feel strongly that a patient is indeed displaying the sign of Leser-Trelat, screening for an underlying neoplasm would be indicated. Obtaining a thorough history, review or systems, and physical examination may help direct the workup of the patient towards a certain malignancy. Laboratory evaluation including a complete blood count (CBC) and complete metabolic panel (CMP) should be obtained along with gender-specific cancer screenings such as mammography, Pap smears, and prostate serum antigen (PSA) testing. Imaging such as a chest x-ray is recommended along with both upper and lower endoscopies given that the sign of Leser-Trelat is most commonly associated malignancy is a gastrointestinal adenocarcinoma.
Eruptive seborrheic keratoses have been reported in numerous other clinical scenarios including in patients with erythroderma, pregnant patients, HIV-infected patients, and transplant patients. Also, seborrheic keratoses may be confused with a plethora of other cutaneous growths including verruca vulgaris, acrochordons, nevi, solar lentigos, lichenoid keratoses, and even cutaneous malignancies such as squamous cell carcinoma or melanoma. However, given the abrupt onset of the seborrheic keratoses and their distinctive appearance misdiagnosis as another cutaneous entity would be unlikely.
Enhancing Healthcare Team Outcomes
The sudden appearance of a cluster of seborrheic keratosis may be encountered by the primary care provider, nurse practitioner, dermatologist or internist. It is important to bear in mind this feature may be associated with malignancy and hence, prompt referral to an oncologist is necessary. The treatment of seborrheic keratosis may be undertaken but at the same time work up to rule out an internal malignancy is necessary. [Level V]