Sign of Leser-Trelat

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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. 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,[20, 8, 21] some with age- and sex-matched controls.[20, 21] 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,[22] which only demonstrated that both disorders are rare in patients with cancer.

Associations with nasopharyngeal carcinoma,[23] acute myeloid leukemia,[24] pre–B-cell acute lymphocytic leukemia,[25] and uterine leiomyosarcoma have been described.[26]

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.[27]

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.[28] 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.

Epidemiology

Frequency

United States

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

International

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

Mortality/Morbidity

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

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.[25]

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.[29] In another family, a mother and 3 daughters had generalized seborrheic keratoses that developed in their teens and 20s.[30] Seven families had multiple seborrheic keratoses. In 3, the investigators were able to trace the tumors through 3 generations.[31] In 3 generations of a family, multiple seborrheic keratoses appeared during or near puberty.[32]

Rarely, overlap may occur between the body areas involved by pulmonary adenocarcinoma and the seborrheic keratoses of the sign of Leser-Trélat.[33]

Physical

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.


View Image

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.[34]

Other rarely associated paraneoplastic entities include the following:

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,[41] 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.

Causes

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.[42]

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

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:

Imaging Studies

The following should be performed:

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.

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.

Further Outpatient Care

Patients should be periodically evaluated in an appropriate clinical setting.

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.

Prognosis

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 2 primary cancers: breast and stomach.[47]

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.[48]

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

Takeji Nishikawa, MD, Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Disclosure: Nothing to disclose.

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital

Disclosure: Abvie Honoraria Speaking and teaching

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

References

  1. Turan E, Yesilova Y, Yurt N, Koçarslan S. Leser-Trélat sign: does it really exist?. Acta Dermatovenerol Croat. Aug 2013;21(2):123-7. [View Abstract]
  2. Leser E. Ueber ein die Krebskrankheit beim Menschen haufig begleitendes, noch wenig gekanntes Symptom. Munchener Med Wochenschr. 1901;51:2035-2036.
  3. De Bersaques J. Sign of Leser-Trelat. J Am Acad Dermatol. 1985;12:724.
  4. Hollander E. V. Beitrage zur Fruhdiagnose des Darmcarcinomas (Hereditatsverhaltnisse und Hautveranderungen. Deutsche Medicinische Wochenschrift. 1900;26:483-485.
  5. Dubreuilh W. Official Transactions. Des hyperkeratoses circonscrites. Third International Congress of Dermatology held in the examination hall of the conjoint Royal Colleges of Physicians and Surgeons, London: Waterlow & Sons Ltd; August 4-8, 1896.
  6. Freudenthal W. Verruca senilis und Keratoma senile. Arch F Dermat U Syph (Berlin). 1926;152:505-528.
  7. Garcia RL, Bishop ME. The rapid onset of seborrheic keratoses of the breasts during pregnancy. J Assoc Mil Dermatol. 1977;3 (2):13-4.
  8. Lindelöf B, Sigurgeirsson B, Melander S. Seborrheic keratoses and cancer. J Am Acad Dermatol. Jun 1992;26(6):947-50. [View Abstract]
  9. Kilmer SL, Berman B, Morhenn VB. Eruptive seborrheic keratoses in a young woman with acromegaly. J Am Acad Dermatol. Nov 1990;23(5 Pt 2):991-4. [View Abstract]
  10. Martin RW 3rd, Rady P, Arany I, Tyring SK. Benign Leydig cell tumor of the testis associated with human papillomavirus type 33 presenting with the sign of Leser-Trelat. J Urol. Oct 1993;150(4):1246-50. [View Abstract]
  11. Inamadar AC, Palit A. Eruptive seborrhoeic keratosis in human immunodeficiency virus infection: a coincidence or 'the sign of Leser-Trelat'?. Br J Dermatol. Aug 2003;149(2):435-6. [View Abstract]
  12. Eastman KL, Knezevich SR, Raugi GJ. Eruptive seborrheic keratoses associated with adalimumab use. J Dermatol Case Rep. Jun 30 2013;7(2):60-3. [View Abstract]
  13. Millard LG, Gould DJ. Hyperkeratosis of the palms and soles associated with internal malignancy and elevated levels of immunoreactive human growth hormone. Clin Exp Dermatol. Dec 1976;1(4):363-8. [View Abstract]
  14. Ellis DL, Kafka SP, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons. A possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med. Dec 17 1987;317(25):1582-7. [View Abstract]
  15. Horiuchi Y, Katsuoka K, Takezaki S, Nishiyama S. Study of epidermal growth activity in cultured human keratinocytes from peripheral-blood lymphocytes of a patient with Sezary syndrome associated with the Leser-Trelat sign. Arch Dermatol Res. 1985;278(1):74-6. [View Abstract]
  16. Ellis DL, Yates RA. Sign of Leser-Trelat. Clin Dermatol. Jan-Mar 1993;11(1):141-8. [View Abstract]
  17. Ponti G, Luppi G, Losi L, Giannetti A, Seidenari S. Leser-Trélat syndrome in patients affected by six multiple metachronous primitive cancers. J Hematol Oncol. Jan 11 2010;3:2. [View Abstract]
  18. Barron LA, Prendiville JS. The sign of Leser-Trelat in a young woman with osteogenic sarcoma. J Am Acad Dermatol. Feb 1992;26(2 Pt 2):344-7. [View Abstract]
  19. Westrom DR, Berger TG. The sign of Leser-Trelat in a young man. Arch Dermatol. Dec 1986;122(12):1356-7. [View Abstract]
  20. Schwengle LE, Rampen FH, Wobbes T. Seborrhoeic keratoses and internal malignancies. A case control study. Clin Exp Dermatol. May 1988;13(3):177-9. [View Abstract]
  21. Grob JJ, Rava MC, Gouvernet J, et al. The relation between seborrheic keratoses and malignant solid tumours. A case-control study. Acta Derm Venereol. 1991;71(2):166-9. [View Abstract]
  22. Kierland RR. Acanthosis nigricans: an analysis of data in twenty-two cases and a study of its frequency in necropsy material. J Invest Dermatol. 1947;9:299-305.
  23. Li M, Yang LJ, Zhu XH, et al. The Leser-Trelat sign is associated with nasopharyngeal carcinoma: case report and review of cases reported in China. Clin Exp Dermatol. Jan 2009;34(1):52-4. [View Abstract]
  24. Yavasoglu I, Kadikoylu G, Bolaman Z. The Leser-Trelat sign is a associated with acute myeloid leukemia. Ann Hematol. Mar 2011;90(3):363. [View Abstract]
  25. Fasoldt JJ, Brumwell ER, Lackey JN. Leser-Trélat sign presenting in a patient with recurrent pre-B-cell acute lymphocytic leukemia. Cutis. Jan 2012;89(1):33-5. [View Abstract]
  26. Abakka S, Elhalouat H, Khoummane N, Achaaban M, ElAmrani S, Bargach S, et al. Uterine leiomyosarcoma and Leser-Trélat sign. Lancet. Jan 5 2013;381(9860):88. [View Abstract]
  27. Siedek V, Schuh T, Wollenberg A. Leser-Trelat sign in metastasized malignant melanoma. Eur Arch Otorhinolaryngol. Feb 2009;266(2):297-9. [View Abstract]
  28. Fink AM, Filz D, Krajnik G, Jurecka W, Ludwig H, Steiner A. Seborrhoeic keratoses in patients with internal malignancies: a case-control study with prospective accrual of patients. J Eur Acad Dermatol Venereol. Nov 2009;23(11):1316-9. [View Abstract]
  29. Bedi TR. Familial congenital multiple seborrheic verrucae. Arch Dermatol. Oct 1977;113(10):1441-2. [View Abstract]
  30. Jadassohn J. Die benignen Epitheliome. Arch f Dermatol u Syph (Wien). 1913;116:117.
  31. Reiches AJ. Seborrheic keratoses; are they delayed hereditary nevi?. AMA Arch Derm Syphilol. May 1952;65(5):596-600. [View Abstract]
  32. Rongioletti F, Corbella L, Rebora A. Multiple familial seborrheic keratoses. Dermatologica. 1988;176(1):43-5. [View Abstract]
  33. Dasanu CA, Alexandrescu DT. Bilateral Leser-Trelat sign mirroring lung adenocarcinoma with early metastases to the contralateral lung. South Med J. Feb 2009;102(2):216-8. [View Abstract]
  34. Janniger EJ, Schwartz RA. Florid cutaneous papillomatosis. J Surg Oncol. Nov 1 2010;102(6):709-12. [View Abstract]
  35. Jemec GB. Hypertrichosis lanuginosa acquisita. Report of a case and review of the literature. Arch Dermatol. Jul 1986;122(7):805-8. [View Abstract]
  36. Hage E, Hage J. Malignant acanthosis nigricans--a para-endocrine syndrome?. Acta Derm Venereol. 1977;57(2):169-72. [View Abstract]
  37. Aylesworth R, Vance JC. Multiple hamartoma syndrome with endometrial carcinoma and the sign of Leser-Trelat. Arch Dermatol. Feb 1982;118(2):136-8. [View Abstract]
  38. Rubisz-Brzezinska J, Zebracka T, Musialowicz D. [Coexistence of 2 paraneoplastic syndromes - acrokeratosis bazex and Leser-Trelat syndrome - in a case of squamous-cell laryngeal cancer]. Przegl Dermatol. Mar-Apr 1983;70(2):205-8. [View Abstract]
  39. Kebria MM, Belinson J, Kim R, Mekhail TM. Malignant acanthosis nigricans, tripe palms and the sign of Leser-Trelat, a hint to the diagnosis of early stage ovarian cancer: a case report and review of the literature. Gynecol Oncol. May 2006;101(2):353-5. [View Abstract]
  40. da Rosa AC, Pinto GM, Bortoluzzi JS, Duquia RP, de Almeida HL Jr. Three simultaneous paraneoplastic manifestations (ichthyosis acquisita, Bazex syndrome, and Leser-Trélat sign) with prostate adenocarcinoma. J Am Acad Dermatol. Sep 2009;61(3):538-40. [View Abstract]
  41. Pembroke AC, Grice K, Levantine AV, Warin AP. Eruptive angiomata in malignant disease. Clin Exp Dermatol. Jun 1978;3(2):147-56. [View Abstract]
  42. Siedek V, Schuh T, Wollenberg A. Leser-Trelat sign in metastasized malignant melanoma. Eur Arch Otorhinolaryngol. Feb 2009;266(2):297-9. [View Abstract]
  43. Patton T, Zirwas M, Nieland-Fisher N, Jukic D. Inflammation of seborrheic keratoses caused by cytarabine: a pseudo sign of Leser-Trelat. J Drugs Dermatol. Sep-Oct 2004;3(5):565-6. [View Abstract]
  44. Peterson J, Shook BA, Wells MJ, Rodriguez M. Cupric keratosis: green seborrheic keratoses secondary to external copper exposure. Cutis. Jan 2006;77(1):39-41. [View Abstract]
  45. Pastar Z, Lipozencic J, Rados J, Stajminger G. Regressing seborrheic keratosis - clinically and dermoscopically mimicking a regressing melanoma. Acta Dermatovenerol Croat. 2007;15(1):24-6. [View Abstract]
  46. Saraiya A, Al-Shoha A, Brodell RT. Hyperinsulinemia Associated with Acanthosis Nigricans, Finger Pebbles, Acrochordons, and the Sign of Leser-Trelat. Endocr Pract. Feb 20 2013;1-15. [View Abstract]
  47. Stieler W, Plewig G. [Acanthosis nigricans maligna and Leser-Trélat sign in double malignancy of the breast and stomach]. Z Hautkr. Mar 1 1987;62(5):344-66. [View Abstract]
  48. Holdiness MR. A case of Leser-Trélat sign. J Am Acad Dermatol. Jan 1987;16(1 Pt 1):147-8. [View Abstract]
  49. Abeloff MD. Paraneoplastic syndromes: a window on the biology of cancer. N Engl J Med. Dec 17 1987;317(25):1598-600. [View Abstract]
  50. Achten G, Ledoux-Corbusier M, Goens J. [Classification and pathogenesis of cutaneous paraneoplastic syndromes]. Ann Med Interne (Paris). 1984;135(8):646-53. [View Abstract]
  51. Balo J. A verrucak es rak gyakori egyuttes elofordulasa. Orvosi Hetilop. 1933;77:797-798.
  52. Barth G, Basten O, Ruschoff J, Rompel R. [Clinical and histopathological characteristics of early Leser-Trelat syndrome]. Hautarzt. Jul 2001;52(7):649-52. [View Abstract]
  53. Bordeleau L, Weatherhead L. Eruptive seborrheic keratoses and Crohn's disease. Canadian J Dermatol. 1993;5:495-496.
  54. Brauer J, Happle R, Gieler U. The sign of Leser-Trelat: fact or myth?. J Europ Acad Dermatol Venereol. 1992;1:77-80.
  55. Carrera C, Segura S, Palou J, et al. Seborrheic keratosislike melanoma with folliculotropism. Arch Dermatol. Mar 2007;143(3):373-6. [View Abstract]
  56. Ceylan C, Alper S, Kilinc I. Leser-Trelat sign. Int J Dermatol. Oct 2002;41(10):687-8. [View Abstract]
  57. Curth HO. Skin lesions and internal carcinoma. In: Cancer of the Skin. Biology-Diagnosis-Management. Philadelphia, Pa: WB Saunders; 1976:1308-41.
  58. Curth HO. Skin manifestations of internal malignant tumors. Md State Med J. Dec 1972;21(12):52-6. [View Abstract]
  59. Dantzig PI. Sign of Leser-Trelat. Arch Dermatol. Nov 1973;108(5):700-1. [View Abstract]
  60. Darier J. Authorized translation from the second French edition edited with notes by S. Pollitzer. Philadelphia, Pa: Lea & Febinger; 1920:209-10.
  61. De Bersaques J, Dockx P. [Internal malignant tumors and cutaneous symptoms]. Arch Belg Dermatol. Jul-Sep 1974;30(3):117-58. [View Abstract]
  62. Dingley ER, Marten RH. Adenocarcinoma of the ovary presenting as acanthosis nigricans. J Obstet Gynaecol Br Emp. Dec 1957;64(6):898-900. [View Abstract]
  63. Flugman SL, McClain SA, Clark RA. Transient eruptive seborrheic keratoses associated with erythrodermic psoriasis and erythrodermic drug eruption: report of two cases. J Am Acad Dermatol. Dec 2001;45(6 Suppl):S212-4. [View Abstract]
  64. Follmann J. A naevusok gyakorisagarol valamint a naevusok es a kozotti osszefuggesekrol. Magyar Orvosi Archivum. 1939;40:53-71.
  65. Freudenthal W. Rumpfhautepitheliom (nebst Bemerkungen uber die Verruca senilis und das Keratoma senilis. Arch F Dermat U Syph (Berlin). 1929;158:539-544.
  66. Gheeraert P, Goens J, Schwartz RA, Lambert WC, Schroeder F, Debusscher L. Florid cutaneous papillomatosis, malignant acanthosis nigricans, and pulmonary squamous cell carcinoma. Int J Dermatol. Mar 1991;30(3):193-7. [View Abstract]
  67. Heng MC, Soo-Hoo K, Levine S, Petresek D. Linear seborrheic keratoses associated with underlying malignancy. J Am Acad Dermatol. Jun 1988;18(6):1316-21. [View Abstract]
  68. Hirano T, Yoshioka H, Manabe T. A case of pancreatic cancer with the sign of Leser-Trelat. Nippon Geka Hokan. Jul 1 1993;62(4):203-8. [View Abstract]
  69. Holdiness MR. Erythroderma, seborrheic keratoses and Leser-Trelat sign. Acta Derm Venereol. 1989;69(3):273-4. [View Abstract]
  70. Holdiness MR. On the classification of the sign of Leser-Trelat. J Am Acad Dermatol. Oct 1988;19(4):754-7. [View Abstract]
  71. Holdiness MR. The sign of Leser-Trelat. Int J Dermatol. Nov 1986;25(9):564-72. [View Abstract]
  72. Hollander E. Carcinom und Hautveranderungen. Centralblatt F Chirurg. 1902;29:457-459.
  73. Klimopoulos S, Kounoudes C, Pantelidaki C, Skrepetou K, Papoudos M, Katsoulis H. The leser-trelat sign in association with carcinoma of the ampulla of Vater. Am J Gastroenterol. May 2001;96(5):1623-6. [View Abstract]
  74. Kowalzick L, Truhm B, Eickenscheidt L. Sign and pseudo-sign of Leser-Trelat. J Drugs Dermatol. Jan 2014;13(1):14. [View Abstract]
  75. Micali G, Nasca MR, Pasquale R. Familial multiple seborrheic keratoses. Report of a kindred. Giornale Ital Dermatol Venerol. 2002;137:169.
  76. Moore RL, Devere TS. Epidermal manifestations of internal malignancy. Dermatol Clin. Jan 2008;26(1):17-29, vii. [View Abstract]
  77. Pentenero M, Carrozzo M, Pagano M, Gandolfo S. Oral acanthosis nigricans, tripe palms and sign of leser-trelat in a patient with gastric adenocarcinoma. Int J Dermatol. Jul 2004;43(7):530-2. [View Abstract]
  78. Rampen HJ, Schwengle LE. Erythroderma, seborrheic keratoses and Leser-Trelat sign. Response to Dr. Mark Holdiness' letter. Acta Derm Venereol (Stockh). 1989;60:273-274.
  79. Rampen HJ, Schwengle LE. The sign of Leser-Trelat: does it exist?. J Am Acad Dermatol. Jul 1989;21(1):50-5. [View Abstract]
  80. Ronchese F. Keratoses, cancer and "the sign of Leser-Trelat". Cancer. Aug 1965;18:1003-6. [View Abstract]
  81. Schwartz RA. Acanthosis nigricans, florid cutaneous papillomatosis and the sign of Leser-Trelat. Cutis. Sep 1981;28(3):319-22, 326-7, 330-1 passim. [View Abstract]
  82. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol. Jul 1994;31(1):1-19; quiz 20-2. [View Abstract]
  83. Schwartz RA. The sign of leser-trelat. In: Demis DJ, ed. Clinical Dermatology. 26A. 13th ed. Philadelphia, Pa: JB Lippincott; 1987:1-3.
  84. Schwartz RA. Florid cutaneous papillomatosis. Clin Dermatol. Jan-Mar 1993;11(1):89-91. [View Abstract]
  85. Schwartz RA. Sign of Leser-Trelat. J Am Acad Dermatol. Jul 1996;35(1):88-95. [View Abstract]
  86. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol. Dec 1978;114(12):1803-6. [View Abstract]
  87. Schwartz RA, Helmold ME, Janniger CK, Gascon P. Sign of Leser-Trelat with a metastatic mucinous adenocarcinoma. Cutis. Apr 1991;47(4):258-60. [View Abstract]
  88. Scully C, Barrett WA, Gilkes J, Rees M, Sarner M, Southcott RJ. Oral acanthosis nigricans, the sign of Leser-Trelat and cholangiocarcinoma. Br J Dermatol. Sep 2001;145(3):506-7. [View Abstract]
  89. Sebastinei F. Esame dello stato della cuti individui affetti da neoplasmi maligni. Diagnosi. 1932;12:95-113.
  90. Sneddon IB, Roberts JB. An incomplete from of acanthosis nigricans. Gut. Sep 1962;3:269-72. [View Abstract]
  91. Stone OJ. The sign of Leser-Trelat: a cutaneous sign of internal malignancy: weakened subepithelial matrix from the effect of neoplasms on the extracellular matrix of the host. Med Hypotheses. Jun 1993;40(6):360-3. [View Abstract]
  92. Vielhauer V, Herzinger T, Korting HC. The sign of Leser-Trelat: a paraneoplastic cutaneous syndrome that facilitates early diagnosis of occult cancer. Eur J Med Res. Dec 29 2000;5(12):512-6. [View Abstract]
  93. Williams MG. Acanthoma appearing after eczema. Brit J Dermatol Syph. 1956;68:268-271.
  94. Yaniv R, Servadio Y, Feinstein A, Trau H. The sign of Leser-Trelat associated with transitional cell carcinoma of the urinary-bladder--a case report and short review. Clin Exp Dermatol. Mar 1994;19(2):142-5. [View Abstract]

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

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