Sign of Leser-Trelat 

Updated: Apr 05, 2021
Author: Robert A Schwartz, MD, MPH; Chief Editor: Dirk M Elston, MD 

Overview

Background

The sign of Leser-Trélat, a rare finding, is the sudden eruption of multiple seborrheic keratoses caused by a malignancy. The sign of Leser-Trélat often occurs with malignant acanthosis nigricans, a more accepted sign of internal cancer. However, because seborrheic keratoses (also known as seborrheic warts, keratosis pigmentosa, and verruca senilis) and cancer are both common in elderly people and because a clear history of eruptive lesions may be difficult to ascertain, determining if this sign is present in older patients is difficult. In fact, the validity of the sign of Leser-Trélat has been challenged.[1] Many cases in the literature are poorly documented. Its linkage with malignant acanthosis nigricans is one of a number of its features that support its classification as a true paraneoplastic syndrome.

The sign of Leser-Trélat may be more precisely defined as the abrupt appearance of multiple seborrheic keratoses caused by an associated cancer and the rapid increase in their size and number. This definition is parallel to that of malignant acanthosis nigricans; both conditions are obligate paraneoplastic syndromes. Paradoxically, both multiple seborrheic keratoses and acanthosis nigricans are common and rarely linked with cancer. The sign of Leser-Trélat should be considered part of a spectrum of eruptions with internal malignancy that occur relatively commonly with acanthosis nigricans. The associated malignancy is usually aggressive and usually has a poor prognosis. However, neither malignant acanthosis nigricans nor malignancy-induced multiple seborrheic keratoses are cancerous.

Two European surgeons, Edmund Leser (1828-1916) and Ulysse Trélat (1828-1890), are separately credited with providing the first description of this sign. Leser[2] was a German surgeon who was the first assistant to Wolkmann, a professor of surgery; Trélat was a professor of surgery in Bordeaux, France.[3] However, they were apparently observing cherry angiomatosis in patients with cancer rather than seborrheic keratoses; therefore, the sign of Leser-Trélat is a misnomer. Hollander[4] first linked internal cancer with seborrheic keratoses in 1900.

In 1898, Dubreuilh debated "the aetiology and varieties of keratosis" with Unna and Brooke in a formal morning session of the Third International Congress of Dermatology in London.[5] At that time, Dubreuilh's paper described verrue séborrhéique, emphasizing that it required distinction from kératome senile (actinic keratosis) and verrucae vulgaris. He also commented that seborrheic keratosis does not evolve into skin cancer, unlike actinic keratosis. In 1926, Freudenthal[6] clearly delineated seborrheic keratoses from actinic keratoses on the basis of both the clinical features and the histologic features.

Only malignant neoplasms meet the definition of the sign of Leser-Trélat, although a benign neoplasm or a fetus might, in theory, also produce eruptive multiple seborrheic keratoses.[7, 8] At least 6 patients have had cases in this category, and 2 patients have had benign adenomatous neoplasms (eg, pituitary adenoma, benign Leydig cell tumor of the testes).[9, 10]

Eruptive seborrheic keratoses in human immunodeficiency virus infection is rare, but has been described.[11] They are probably best viewed as a coincidental finding rather than as representing the sign of Leser-Trélat. Similarly, eruptive seborrheic keratoses may be linked rarely with inflammatory dermatoses and medication eruptions, including use of adalimumab.[12]

Some related articles are as follows:

  • Paraneoplastic Diseases

  • Florid Cutaneous Papillomatosis

  • Cowden Disease (Multiple Hamartoma Syndrome)

  • Seborrheic Keratosis

Pathophysiology

Growth factors

In 1976, Millard and Gould[13] had 2 patients with tylosis. One had the sign of Leser-Trélat with high levels of immunoreactive human growth hormone. The other patient had a small cutaneous melanoma, acanthosis nigricans, the sign of Leser-Trélat, and multiple acrochordons; in this patient, the cutaneous lesions were stimulated by the epidermal growth factor receptor.[14] Increased epidermal staining for the epidermal growth factor receptor was initially evident in skin specimens of acanthosis nigricans, seborrheic keratoses, and cutaneous papillomas; this staining and the urine level of alpha-transforming growth factor both declined markedly after the primary nonmetastatic cutaneous melanoma was surgically removed.

Alpha-transforming growth factor is structurally related to but antigenically distinct from epidermal growth factor. The supernatant of a patient's peripheral lymphocytes showed increased epidermal growth factor activity in vitro.[15] Such growth factors may alter the extracellular matrix tissue, possibly resulting in the formation of seborrheic keratoses. In 1993, Ellis and Yates[16] postulated that the sign of Leser-Trélat is a result of a growth factor (eg, alpha-transforming growth factor) reaching a critical threshold level and causing the sudden eruption in an individual who is genetically predisposed. A patient with the sign of Leser-Trélat in association with occult gastric adenocarcinoma and a history of 5 other cancers had epidermal growth factor receptor (EGFR) immunohistochemical expression analysis of multiple seborrheic keratoses. It showed intense membranous staining in the basal keratinocytes and in all the upper epidermal layers.[17]

Controversy

The existence of the sign of Leser-Trélat has been questioned. A few epidemiologic studies have not established a causative link between multiple eruptive seborrheic keratoses and cancer. The appearance of the sign of Leser-Trélat in a 20-year-old woman with osteogenic sarcoma is significant,[18] as it is in a 22-year-old man with a probable germinoma of the pineal body.[19] The sign of Leser-Trélat in these 2 patients, who would not otherwise be likely to have multiple seborrheic keratoses, provides evidence of the validity of the sign of Leser-Trélat.

In the author's experience, the sign of Leser-Trélat is usually associated with an adenocarcinoma, often in the stomach and the colon, although squamous cell carcinoma, lymphoma, and leukemias may also be observed. However, about 20% of patients reportedly have a lymphoma or a leukemia rather than an adenocarcinoma.[20] The distribution of the underlying cancer is similar to that of malignant acanthosis nigricans, that is, adenocarcinomas predominate, especially in the stomach and the colon. This observation provides further evidence of the authenticity of the sign of Leser-Trélat.

Association with cancer

Multiple eruptive seborrheic keratoses occur in older persons, in whom malignancy is also statistically more common. However, the early appearance of these keratoses in individuals aged 0-30 years and their eruptive nature are not common (see History).

The sign of Leser-Trélat has been described in at least 2 people aged 10-20 years with underlying neoplasms.

A few studies of these patients have been conducted,[8, 21, 22] some with age- and sex-matched controls.[21, 22] In one study, 82 patients had solid tumors that were recently diagnosed. In a second study, 36 patients aged 50-80 years with an underlying cancer were examined. In both studies, the features of seborrheic keratoses did not significantly differ between patients and control subjects. The negative findings in these 2 case-control studies remind this author of the negative findings of the autopsy study conducted to assess malignant acanthosis nigricans among a small group of patients with cancer,[23] which only demonstrated that both disorders are rare in patients with cancer.

Associations with nasopharyngeal carcinoma,[24] , laryngeal carcinoma,[25, 26] acute myeloid leukemia,[27] pre–B-cell acute lymphocytic leukemia,[28] hepatocellular carcinoma,[29, 30] thymic carcinoma,[31] and uterine leiomyosarcoma have been described.[32]

A retrospective review was performed to investigate a possible association with malignant disease.[8] Medical records in 1752 consecutive cases of seborrheic keratoses were selected from the Swedish Cancer Registry. In 62 patients with seborrheic keratoses, a visceral malignancy was diagnosed within 1 year before or after the diagnosis of seborrheic keratoses. Of these 62 patients, 6 had seborrheic keratoses that were multiple (>20) and eruptive, fulfilling the diagnostic criteria for the sign of Leser-Trélat. However, of 62 age- and sex-matched control subjects without cancer, 5 also met the cutaneous diagnostic criteria for the sign of Leser-Trélat. One of these control subjects was pregnant, and the diagnostic evaluation of the others was not specified. This sign may also be associated with metastasized melanoma.[33, 34, 35]

This study provides no evidence to support the validity of the sign of Leser-Trélat. The author also concurs with Ellis and Yates[16] in that the results of this study are inconclusive, as to whether eruptive seborrheic keratoses are related to visceral cancer.

Another study of 150 oncological patients and 150 matched controls observed that seborrheic keratoses did not differ significantly between patients with internal malignancies and controls, challenging the validity of this sign.[36] Note that 2 patients in this survey fulfilled the criteria of the Leser-Trélat sign, defined as the eruption of numerous seborrheic keratoses as a cutaneous marker of an underlying internal malignancy.

Etiology

The cause of the sign of Leser-Trélat is unknown. It may be due to the same unknown factors that induce malignant acanthosis nigricans. These paraneoplastic syndromes are probably directly caused by their underlying neoplasms, presumably from a tumor-secreted growth factor; however, evidence of this concept is lacking. The sign of Leser-Trélat is usually linked with visceral cancer, but it has also been described in metastasized malignant melanoma.[37] Insulin growth factor 2 secretion, presumably by a retroperitoneal malignant fibrous tumor, was described in a patient with the sign of Leser-Trélat.[38]

The sign of Leser-Trélat may be linked with cytokine alterations (see Pathophysiology).

Epidemiology

Frequency

The sign of Leser-Trélat is rare, even among patients with cancer.

Race

No known racial predisposition exists.

Sex

No known sexual predisposition exists.

Age

Multiple eruptive seborrheic keratoses occur in older persons, in whom malignancy is also statistically more common. However, the early appearance of these keratoses in individuals aged 0-30 years and their eruptive nature are not common (see History).

The sign of Leser-Trélat has been described in at least 2 people aged 10-20 years with underlying neoplasms and in a 20-year-old man with pre–B-cell acute lymphocytic leukemia.[28]

Prognosis

Discomfort from pruritus is the main morbidity. Mortality results from the associated malignancy.

The course of the sign of Leser-Trélat is variable. It often parallels the underlying malignancy, although this is not uniformly true. Most patients with it have a solitary malignancy. One patient had two primary cancers: breast and stomach.[39]

Most of the malignant tumors associated with this sign behave in an aggressive manner. Thus, the prognosis of patients with the sign of Leser-Trélat is not good; the survival rate averages about 10.6 months.[40]

 

Presentation

History

A complete medical history should be obtained.

The sudden eruption of multiple seborrheic keratoses is diffusely evident on any body surface, most strikingly on the trunk. The face, the neck, the axillae, the groin, and the extremities may also be affected. The abruptness of the eruption is noteworthy; it should not be confused with generalized seborrheic keratoses of gradual onset. Nevertheless, for the purposes of diagnosis, precise quantification of the length of the eruptive period and the number of seborrheic keratoses is lacking. In the author's experience, many but not all elderly patients are able to provide a clear history.

Pruritus may be the only symptom of the sign of Leser-Trélat. Pruritus occurs in almost one half of patients, but it may also occur with eruptive seborrheic keratoses unassociated with malignancy.

Seborrheic keratoses are common findings. However, the early appearance of these keratoses in individuals aged 0-30 years and their eruptive nature are not common. In a few families, seborrheic keratoses were autosomal dominant, and the lesions were rarely present at birth or in individuals aged 10-30 years. Members of a family from India had multiple seborrheic keratoses since birth.[41] In another family, a mother and 3 daughters had generalized seborrheic keratoses that developed in their teens and 20s.[42] Seven families had multiple seborrheic keratoses. In 3, the investigators were able to trace the tumors through 3 generations.[43] In 3 generations of a family, multiple seborrheic keratoses appeared during or near puberty.[44]

Rarely, overlap may occur between the body areas involved by pulmonary adenocarcinoma and the seborrheic keratoses of the sign of Leser-Trélat.[45]

Physical Examination

A complete physical examination should include an examination of the lymph nodes; the liver; the spleen; the prostate in men; the rectum; the breasts; and the pelvic area, including the ovaries, in women.

Warty nodules that proliferate cutaneously are evident. Each nodule usually appears distinct, with its characteristic warty stuck-on morphologic features and brownish black or yellowish coloration. The author recommends that a biopsy specimen be obtained to confirm the diagnosis.

The eruption may appear in a Christmas tree or splash pattern, although these patterns are not specific for this sign and may occur with eruptive seborrheic keratoses unassociated with malignancy. Note the image below.

Middle-aged woman with a Christmas tree-like distr Middle-aged woman with a Christmas tree-like distribution of seborrheic keratoses on her back with no evidence of internal cancer.

Malignant acanthosis nigricans is frequently evident with the sign of Leser-Trélat. Malignant acanthosis nigricans occurs in about 35% of patients. Florid cutaneous papillomatosis is less common.[46]

Other rarely associated paraneoplastic entities include the following:

  • Acquired hypertrichosis lanuginosa[47]

  • Acquired ichthyosis[48]

  • Cowden disease[49]

  • Tylosis[13]

  • Acrokeratosis of Bazex[25]

  • Tripe palms[50, 51]

  • Simultaneous paraneoplastic manifestations, including both ichthyosis acquisita and Bazex syndrome[52]

The sudden eruption and the rapid increase in the number and the size of freckles, along with seborrheic keratoses, may occur.

A proliferation of papillary angiomas may occur.

Eruptive capillary angiomas have been described as a paraneoplastic sign,[53] although this sign is not widely accepted. The author has observed 1 patient with eruptive capillary angiomas and a visceral malignancy in whom no eruptive seborrheic keratoses were present.

The sign of Leser-Trélat, malignant acanthosis nigricans, and florid cutaneous papillomatosis are 3 paraneoplastic entities that constitute a continuum. These conditions more commonly accompany each other than any other paraneoplastic disorder. Florid cutaneous papillomatosis is a sudden and widespread eruption of what appears to be common viral warts on clinical examination. Acanthosis nigricans is a widespread dermatosis with a verrucous tendency anywhere on the surface of the body, especially around the lips, the eyes, and the axillae.

Patients with erythroderma may develop a widespread eruption of multiple seborrheic keratoses without associated malignancies. In the author's experience, these patients usually have atopic dermatitis complicated by erythroderma.

The sudden eruption of hundreds of typical seborrheic keratoses confined to the skin of the breasts and a small area below them is described in association with pregnancy.

Complications

The reappearance of the sign of Leser-Trélat after it is eliminated with removal or treatment of the underlying cancer may signify cancer recurrence.

 

DDx

Diagnostic Considerations

The chemotherapeutic agent cytarabine may cause a rare reaction of inflammation of existing seborrheic keratoses, mimicking the sign of Leser-Trélat.[54]

Cupric keratoses have been described as green seborrheic keratoses secondary to external copper exposure.[55]

Regressing seborrheic keratoses may clinically and dermoscopically mimic a regressing melanoma.[56]

Distinguishing eruptive seborrheic keratoses from the sign of Leser-Trélat is often difficult. Eruptive seborrheic keratoses may occur with diabetes mellitus and acanthosis nigricans with underlying insulin resistance,[57] but it may occur without them too. No linkage should be implied.

Also consider mycosis fungoides with multiple seborrheic keratosis–like hyperkeratotic, tumorous nodules on the back and extremities.[58]

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory abnormalities are due to the associated malignancy. Appropriate clinical tests should be performed, depending on the clinical setting. The author recommends the following:

  • Routine blood and chemistry studies, including a complete blood cell count with differential and absolute platelet counts

  • Examination of the stool for occult blood

  • Carcinoembryonic antigen test

  • Urinalysis with cytologic examination

  • Papanicolaou test in women

  • Cervical cytologic examination in women

  • Prostate-specific antigen testing in men

Imaging Studies

The following should be performed:

  • Chest radiography

  • Mammography in women

  • Upper and lower gastrointestinal radiographic studies

CT scanning of the abdomen and the pelvis should be considered.

Procedures

The author recommends that a biopsy specimen be obtained to confirm the diagnosis. Complete colorectal and gastric endoscopic examinations should also be performed if no malignancy is detected.

Histologic Findings

In this syndrome, seborrheic keratoses are the same as the common type of seborrheic keratosis. Both types involve epidermal hyperkeratosis, papillomatosis, and acanthosis with cystic inclusion of keratinous material (eg, horn pseudocysts). Variants, such as adenoid-type seborrheic keratoses, have not yet been described.

 

Treatment

Medical Care

The best approach is treatment of the underlying malignant process.

Surgical Care

The best approach is treatment of the underlying malignant process. For local treatment, the author often uses cryosurgery, sometimes followed by curettage. Other locally destructive techniques may be used.

Long-Term Monitoring

Patients should be periodically evaluated in an appropriate clinical setting.