Continuing Education Activity

The Leser-Trélat sign is a rare paraneoplastic cutaneous marker associated with internal malignancies characterized by the abrupt eruption of multiple seborrheic keratoses. The sign of Leser-Trélat is frequently found in connection with colon, breast, or stomach adenocarcinomas but has also been associated with renal, hepatic, and pancreatic malignancies. Although these lesions are typically relatively easy to distinguish from other melanocytic neoplasms, a histopathological examination may be required.

This course explores the complexities surrounding this dermatological phenomenon, including the current diagnostic challenges and elusive pathophysiology, exploring the suspected role of cytokines and growth factors in seborrheic keratosis eruption. This activity for healthcare professionals is designed to enhance the learner's competence in identifying the Leser-Trélat sign, performing the recommended evaluation, and implementing an appropriate interprofessional approach when managing this condition.  

Objectives:

• Identify malignancies most commonly associated with the Leser-Trélat sign.

• Identify the typical presentation of the Leser-Trélat sign.

• Determine the appropriate evaluation of a patient with the Leser-Trélat sign.

• Collaborate with interprofessional team members to improve care coordination for patients with the Leser-Trélat sign and patient outcomes.

Introduction

The Leser-Trélat sign is a relatively rare paraneoplastic cutaneous marker of internal malignancy characterized as the finding of multiple seborrheic keratoses that have abruptly erupted. However, no standardized or quantified diagnostic criteria currently define the sign of Leser-Trélat. The sign of Leser-Trélat is frequently found in connection with colon, breast, or stomach adenocarcinomas but has also been associated with renal, hepatic, and pancreatic malignancies. The exact pathophysiology underlying the sign of Leser-Trélat remains elusive, but some experts strongly suspect that the release of cytokines and growth factors from the neoplasm stimulates the eruptive growth of the seborrheic keratoses. However, 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.[1][2][3][4]

Seborrheic keratoses are nearly ubiquitous benign skin lesions in patients greater than 40 years of age, typically appearing as brown, waxy lesions of varying shapes and sizes on examination. Seborrheic keratoses described in the Leser-Trélat sign are commonly homogenous, well-circumscribed pigmented macules, papules, and plaques with pigmentation ranging from light tones to dark brown or black. The lesions are generally described as having a waxy or velvety texture with a stuck-on appearance but often are in a Christmas tree pattern on the chest, abdomen, or back with or without pruritus.[5] Although these lesions are typically relatively easy to distinguish from other melanocytic neoplasms, a histopathological examination may be required. Clinicians suspecting the Leser-Trélat sign on examination should evaluate the patient for an underlying neoplasm. The primary treatment for Leser-Trélat lesions involves the management of the underlying malignancy, which resolves approximately 50% of associated seborrheic keratoses. In addition, symptomatic lesions may be managed with antipruritic topical creams or more aggressively destroyed with various modalities, including cryotherapy, curettage, shave removal, and electrodesiccation.[6] 

The Leser-Trélat sign was first described separately in the 1800s by Edmund Leser and Ulysse Trélat during their study of cherry angiomas in oncology patients. In 1900, Hollander was the first to describe seborrheic keratoses associated with malignancy, but the names Leser and Trélat remained affixed to the condition.[7] By 1988, 60 documented case presentations of the sign were noted.[5] 

Etiology

The Leser-Trélat sign is a clinical indication of a potential underlying visceral malignancy. The sign of Leser-Trélat may precede, occur concurrently, or start after the diagnosis of malignancy. In a minority of patients with the Leser-Trélat sign, no malignant process is identified, referred to as the pseudo-Leser-Trélat sign.[8] The most commonly implicated malignant etiologies include:

• Gastrointestinal adenocarcinomas (eg, gastric, colon, rectal, esophagus), with gastric adenocarcinoma being the most common cause.[9]
• Breast cancer [10]
• Lymphoproliferative disorders or lymphoma
• Pancreas [11]
• Prostate
• Lung [12]
• Kidney
• Larynx
• Ovary and uterus
• Bladder
• Nasopharyngeal carcinoma
• Melanoma
• Mycosis fungoides
• Hepatocellular carcinoma
• Squamous cell carcinoma [13]

The common nonmalignant conditions include:

• COVID-19 [14]
• Lepromatous leprosy [15]
• Erythrodermic pityriasis rubra pilaris [16]
• Human immunodeficiency virus infection [17]
• Human papillomavirus infection [18]

Epidemiology

Patients presenting with the Leser-Trélat sign have an average age of onset of 61 years. No increased predilection amongst either sex or any race has been reported. However, case reports of the sign of Leser-Trélat 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 this age.[19]

Pathophysiology

The exact pathophysiology underlying the sign of Leser-Trélat remains elusive. However, experts believe the association may be due to the release of cytokines and growth factors from the neoplasm stimulating the eruptive growth of the seborrheic keratoses. Moreover, the overexpression of epidermal growth factor-α, transforming growth factor-α, and amphiregulin may contribute to the eruptive nature of these lesions.[20] Additional growth factors involved may include human growth hormone, fibroblast growth factor receptor 3 (FGFR3), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA), and insulin-like growth factor.[21] Seborrheic keratoses are common epidermal neoplasms occurring due to the clonal expansion of immature keratinocytes.[22]

Histopathology

Histopathological examination of a biopsied seborrheic keratosis from a patient suspected to exhibit the sign of Leser-Trélat 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, the most common variant, hyperkeratotic, reticulated, clonal, and melanoacanthoma. Any of these distinct variations may also become irritated or inflamed, at which time they may display squamous eddy formation (ie, spindled cells) or lymphocyte infiltration, respectively. However, there does not appear to be an increased frequency of a specific histopathological variation of seborrheic keratoses that correlates with the Leser-Trélat sign.[5]

History and Physical

Clinical Features

Seborrheic keratoses are a nearly ubiquitous, benign skin lesion in patients aged >40 years. The typical morphology of these lesions tends to vary extensively amongst patients presenting as well-circumscribed pigmented macules, papules, and plaques with pigmentation ranging from light tones to dark brown or black. The lesions are typically described as having a waxy or velvety texture with a stuck-on appearance. The presence of horn cysts on the surface of the lesions is also classic. Although these lesions are typically relatively easy to distinguish from other melanocytic neoplasms, a 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 described as a Christmas tree, splash, or raindrop. 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 Leser-Trélat sign will concurrently experience another paraneoplastic disease process. Therefore, a careful examination and history is critical. Malignant acanthosis nigricans, characterized by velvety and symmetrical hyperpigmentation often in intertriginous sites, though lesions may occur in any location on the body, are found simultaneously in about 20% of patients with the Leser-Trélat sign. The generalized presence of pruritus or acanthosis nigricans should heighten the clinician's suspicion of an underlying malignancy. Clinicians should also obtain a history of recent unexpected weight loss, malaise, fatigue, melena, and cancer risk factors, including smoking history and family cancer history. Findings of eruptive, atypical, monomorphic lesions in a patient without a known history of seborrheic keratoses should be approached with a high index of suspicion. Unlike benign seborrheic keratoses, which develop over several years, Leser-Trélat sign lesions have a short interval between the initial onset and rapid spread, frequently within 1 year.[11] 

Curth Postulates

Curth postulates were indicators created to help evaluate the temporal relationship between an underlying paraneoplastic syndrome and a specific dermatological condition. The diagnosis of a paraneoplastic syndrome was based on the following clinical criteria:[23]

1. Both the neoplastic and paraneoplastic processes began concurrently.
2. Both the neoplastic and paraneoplastic processes have a parallel disease course (ie, the paraneoplastic process resolves with treatment of the underlying malignancy, and the paraneoplastic process relapses if the 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. A strong statistical association between the paraneoplastic process and truly having an underlying malignancy exists.

However, the sign of Leser-Trélat has been met with an abundance of skepticism by many experts due to the inability of the sign of Leser-Trélat to fulfill all of the Curth postulates consistently.

Evaluation

Clinicians suspecting the Leser-Trélat sign on examination should evaluate the patient for an underlying neoplasm. A thorough history, system review, and physical examination are necessary to direct which diagnostic studies are indicated. Diagnostic laboratory evaluation, including a complete blood count (CBC) and complete metabolic panel (CMP), should be obtained, and additional screening studies, including mammography, Pap smears, and prostate serum antigen (PSA) testing, should be performed as indicated. In some cases, histopathological studies are performed to confirm the skin lesions are seborrheic keratoses. Findings commonly seen with biopsy of seborrheic keratosis lesions include basaloid keratinocyte proliferation with hyperplastic epidermal cells arranged in wide connected columns.[24]

Furthermore, diagnostic imaging is often the primary modality utilized to assess for internal malignancy. Clinical assessment will direct which anatomical structure is imaged, such as a chest x-ray, pelvic ultrasound, or computer tomography (CT) of the chest, abdomen, and pelvis. CT abdomen with contrast along with both upper and lower endoscopies is often indicated, given that the sign of Leser-Trélat is most commonly associated with gastrointestinal adenocarcinoma.[25][24][25]

Treatment / Management

The primary treatment for Leser-Trélat lesions involves the management of the underlying malignancy, which resolves approximately 50% of associated seborrheic keratoses. In addition, symptomatic lesions may be managed with antipruritic topical creams or more aggressively destroyed with various modalities, including cryotherapy, curettage, shave removal, and electrodesiccation. Patients with asymptomatic lesions require no further treatment for the seborrheic keratoses besides the treatment of their malignancy.[6]

Differential Diagnosis

Eruptive seborrheic keratoses have been reported in numerous other conditions, including:

• Erythroderma
• Pregnancy
• HIV-infection
• Post-transplant patientsg[24]

Seborrheic keratoses may be confused with a plethora of other cutaneous growths, including:

• Verruca Vulgaris
• Extramammary Paget’s disease
• Acanthosis nigricans
• Acrochordons
• Nevi
• Solar lentigos
• Lichenoid keratoses
• Cutaneous malignancies (eg, pigmented basal cell carcinoma, squamous cell carcinoma, verrucous melanoma.[24]

However, given the abrupt onset of the seborrheic keratoses and their distinctive appearance, misdiagnosis as another cutaneous entity would be unlikely. Seborrheic keratoses-like lesions localized to tattoos also form an important differential diagnosis.

Prognosis

The management of the underlying malignancy results in the resolution of associated seborrheic keratoses in about 50% of patients.

Complications

When diagnosed early enough, management of the underlying malignancy contributing to the seborrheic keratosis lesions in the sign of Leser-Trélat can lead to a better prognosis.

Deterrence and Patient Education

The general public should be educated to seek early medical advice if they encounter the rapid appearance of new skin lesions. Tumor screening is recommended in case of abrupt appearance of multiple pruritic seborrheic keratoses.[6] Clinicians should also counsel patients that the seborrheic keratosis lesions of Leser-Trélat sign only regress with underlying malignancy treatment in 50% of cases. Regression or persistence should not be relied upon to determine the treatment efficacy of the underlying malignancy. 

Enhancing Healthcare Team Outcomes

Addressing Leser-Trélat Sign necessitates a collaborative effort among various healthcare professionals to ensure patient-centered care, optimal outcomes, patient safety, and effective team performance. Primary care clinicians and dermatologists often manage the onset and monitoring of seborrheic keratoses. Primary care, dermatology, or internal medicine clinicians may encounter the sudden appearance of a cluster of seborrheic keratosis. Because seborrheic keratoses may be associated with malignancy, prompt referral to an oncologist is necessary. The treatment of seborrheic keratoses may be undertaken, but at the same time, work up to ruling out an internal malignancy is needed. Efficient interprofessional communication is essential to ensure all appropriate cancer history and screenings are completed in this setting. This collaborative approach ensures a holistic and well-coordinated response, enhancing patient-centered care, improving outcomes, prioritizing patient safety, and optimizing overall team performance in addressing Leser-Trélat Sign.