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