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Sign of Leser-Tre´lat
CLIMCAI REVIEW Sign of Leser-Trtlat Robert A. Schwartz, MD, M P H Newark, New Jersey The sign of Leser-Tr61at is rare. It is defined as the sudden eruption of multiple seborrheic keratoses caused by a malignancy. Because both seborrheic keratoses and cancer are common in the elderly, it is not always easy to tell from the literature or in any given patient if this sign is present. In fact, its validity has been questioned. Its association with malignant acanthosis nigricans is one of several of its features that support its legitimacy as a true paraneoplastic disorder. (J Am Acad Dermatol 1996;35:88-95.)
The sign of Leser-Trtlat may be defined as the abrupt appearance and rapid increase in size and number of multiple seborrheic keratoses as a result of cancer vs (Table I-IV). This definition is comparable to that of malignant acanthosis nigricans, 9 establishing both as paraneoplastic syndromes. Paradoxically, both multiple seborrheic keratoses and acanthosis nigricans are common and rarely linked with cancer (Table I). When present, however, the associated malignancy is usually aggressive and has a poor prognosis.
Table I. Comparison of acanthosis nigricans and eruptive seborrheic keratoses
HISTORY
AN, Acanthosis nigricans; CA, cancer; FCP, florid cutaneous papillomatosis; SLT, sign of Leser-Tr61at.
The description of this sign has been credited separately to Edmund Leser (1853-1916) and U1ysse Trtlat (1827-1890). 9-13 Leser was a German surgeon and Trtlat was a French professor of surgery in Bordeaux. 13 However, they both were observing cherry angiomas in patients with cancer rather than seborrheic keratoses; therefore the sign of LeserTrtlat is a misnomer. Hollander 11 first emphasized the association of internal cancer with seborrheic keratoses in 1900. 9, 10, 12, 13 The association of multiple eruptive cutaneous lesions and internal cancer has been explored for many years. 13-17This sign has been in disfavor with some and remains controversial. 1s-26 Because both seborrheic keratoses and cancer are common in the elderly and a clear description of "eruptive" may be difficult, some doubt the validity of this sign. From Dermatology, New Jersey Medical School. Reprint requests: R. A. Schwartz, MD, Dermatology, New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103-2714. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0
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Acanthosis nigricans
Multiple seborrheic keratoses
Common Inherited autosoma]
Common Inherited autosomal
dominant Usually not associated with cancer If CA, sudden and eruptive If CA, often seen with SLT + FCP
dominant Usually not associated with cancer If CA, sudden and eruptive If CA often seen with AN + FCP
INCIDENCE
Like malignant acanthosis nigficans, with which it is often associated, the sign of Leser-Trtlat is rare, even in patients with cancer. 9 A few studies have been performed, 15, 19-21 some with age- and sexmatched controls. 19,21 In one, 82 patients had recently diagnosed solid rumors. In a second, 36 patients between 50 and 80 years of age who had an underlying cancer were examined. In both studies the features of seborrheic keratoses did not differ significantly between patients and control subjects. These two negative case-control studies resemble the results of an autopsy study of malignant acanthosis nigricans in a small group of patients with cancer. 27 The data demonstrate only that both disorders are rare in these patients. A retrospective review of 1752 consecutive patients with seborrheic keratoses sought a possible association with malignant disease. 2° In 62 patients with seborrheic keratoses, a visceral malignancy was diagnosed within 1 year before or after diagnosis of the seborrheic keratoses.
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Schwartz 89
T a b l e I I . The sign o f Leser-Tr61at in 51 patients with 52 different types o f adenocarcinomas Site
[ No. of patients [
Reference (first author)
7
M. Cohen, si Liddell H9 (in 3 pts), Walter, 77 Br~uer, 22 Hodak, 7s Heng 26 (in 5 pts) Kameya,9x Stieler, 55'* Andreev,99 Sperry,126,3~Tutakne, l°7,§ Suzuki, 108 Hoffmann, 122 R. Schwartz, 7 Lindel6f 2° (in 2 pts), MiUard,42 Jablonska62 Curry 103 Elewski 116 Hirano59 Stieler, 55. Lynch 1°6 (in 2 pts), Venencie11511 (in 2 pts), Wiessmann-Katzenelson, l°2 Friedman-Birnbaum,114 Lindel6f 20 (in 2 pts), Josserand76 Holguin,92 Dingley53 Aylesworth51 Ronchese 1 Ktlh197 Gitlins2 Diaz127~[ Tajima, 93 Kazubasia1°1 Harrington,128 Lindel6f 20 Jacobs 129 Lee96 R. Schwartz, 6 Czarnecki68
Colon/rectum Stomach
12
Duodenum Esophagus Pancreas Breast
1 1 1 10
Ovary Endometrium Uterus Cervix Prostate Hypernephroma Hepatoma Gallbladder Bile duct Adenocarcinoma (site unknown)
2 1 1 1 1 3 2 1 1 2
*Patient had cancer of both stomachand breast. ~Colon adenocarcinomaexcised 10 years earlier. §Gastroesophagealjunction. IIMetastasizingparotid gland tmnor seven years later. ~Vleningiomaalso.
T a b l e I I I . The sign of Leser-Tr61at in 35 patients with disorders other than adenocarcinoma
Disorder Mycosis fungoides S6zary syndrome Lymphoma Leukemia Lung cancer (SCC) Lung small-cell cancer Osteogenic sarcoma Hemangiopericytoma Leiomyosarcoma Neurofibrosarcoma Melanoma Pleura Laryngeal SCC Transitional cell cancer, of urinary bladder Brain (germinoma of pineal body--presumptive)
O f these 62, six had keratoses that were multiple (>20) and eruptive, consistent with the sign o f Leser-Tr61at. B y comparison, o f 62 age- and sexmatched control patients without cancer, five also
No. of patients 4 4 7
Reference (first author) Toonstra,95 Lambert,79 Miyako,98 Sah]75 Dantzig, 3 J. Cohen, s° Horiuchi,46 Ikari 87 Halevy,m Wieselthier, 123 Safai, 11° Kaplan, 118 Wagner, 1°5 Holdiness, 4° Matsumoto86 Kechijian, 1°4 Greer 112 Doll, 125Lambert,79 Fretzin, 85 Czamecki,68 Rodriguez-Garcfa121 Hattori 113 Barron3s Benn s9 Horinchi, 124 Ishihara 109 Smalley 120 Fanti, 94 Ellis 43 Lindel6f 2o Gheeraert, 5 Rubisz-Brzezinska52 Yaniv 8 Westrom37
m e t the criteria. However, Ellis and Yates 28 stated that the results o f this study are inconclusive. Seborrheic keratoses are colnmon, 29-36 but their appearance during the second and third decades of
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Journal of the American Academy of Dermatology July 1996
Table IV. Eruptive multiple seborrheic keratoses
in seven patients with a benign neoplasm or pregnancy Disorder/ Condition
No. of patients
Testicular, benign Leydig cell tumor Brain (pituitary) Lung hamartomas Renal cyst Pregnancy Meningioma, hypernephroma
Fig. 1. Multiple seborrheic keratoses of sudden onset (the sign of Leser-Trdlat) in a patient with gastric adenocarcinoma.
life and an eruptive course are not. It has been postulated that seborrheic keratoses are essentially delayed hereditary nevi. 32 Multiple eruptive seborrheic keratoses tend to occur in older persons, in whom malignancy is also more common. 2s, 37-4oThe sign of Leser-Tr61at, however, has been described in two persons with underlying neoplasms during their second decade of life.2s, 3a PATHOGENESIS
The cause of the sign of Leser-Tr61at is as uncertain as that of the other eruptive paraneoplastic disorders often present with it, such as malignant acanthosis nigricans. These disorders are probably directly induced by the underlying neoplasm, most likely from a tumor-secreted growth factor.26, 41-47 However, no evidence of this exists other than a few case reports. Millard and Gould42 described two patients with tylosis (one with the sign of Leser-Trdlat) who had high levels of immunoreactive human growth hormone. Another patient had a small cutaneous melanoma, acanthosis nigricans, the sign of
Reference (first author)
1
Martin1°°
1 1 1 2 1
Kilmer47 Ellis28 Berman63 Garcia,66 Lindel6f 20 Diaz127
Leser-Tr61at, and multiple "acrochordons. ''43 Increased epidermal staining for the epidermal growth factor receptor was initially observed in specimens of acanthosis nigricans, seborrheic keratoses, and cutaneous papillomas; this staining and the urine level of transforming growth factor--~ both declined markedly after surgical removal of the primary nonmetastatic cutaneous melanoma. The supernatant of another patient's cultured peripheral lymphocytes showed increased epidermal growth factor activity in vitro. 46 These growth factors have been postulated to alter the extracellular matrix, possibly resulting in the formation of seborrheic keratoses.4s Ellis and Yates 2s suggested that the sign of Leser-Tr61at is a result of a growth factor like transforming growth factor-o~ reaching a critical threshold level and producing this sudden eruption if the affected person is genetically predisposed. However, the finding of transforming growth factor-oL has not been confirmed by others. Curth49, 50 suggested criteria for the diagnosis of cutaneous paraneoplastic syndromes and considered acanthosis nigricans to be an excellent example. It is noteworthy that multiple seborrheic keratoses and acanthosis nigricans do not conform to her criteria in two ways: both are common and both have approximately the same broad tumor distribution with which they are associated. However, Curth considered acanthosis nigricans to be almost always caused by an adenocarcinoma, usually of the gut. CLINICAL MANIFESTATIONS
This sudden eruption of multiple seborrheic keratoses may occur on any body surface (Figs. 1-3). Most are on the back and chest (76%), followed by the extremities (38%), face (21%), abdomen (15%),
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Fig. 2. Close-up view of seborrheic keratoses of sudden onset in patient with gastric adenocarcinoma. (From Schwartz RA. Cutis 1981;28:326.)
neck (13%), axillae (6%), and groin (3%). 28 Sometimes the eruption is described as appearing in a "Christmas tree" or "splash" pattern, although this may occur with eruptive seborrheic keratoses unassociated with malignancy. 26, a8 Eruptive seborrheic keratoses may be associated with other signs of internal malignancy, such as acquired ichthyosis, 44 Cowden's disease, 51 acrokeratosis of Bazex, 52 acquired hypertrichosis lanuginosa, 53, 54 tylosis,42 and florid cutaneous papillomatosis. 1,4, 5, 7, 44, 53, 55-57 However, malignant acanthosis nigricans is most frequently seen with the sign of Leser-Tr61at and is evident in about 35% of patients. 58 Pruritus accompanying the sign of Leser-Tr61at occurs in almost half the patients. 58 A sudden eruption and a rapid increase in the number and size of freckles may also be evident. 59 Capillary angiomas may be present, but they are not a consistent finding. 18Eruptive capillary angiomas have themselves been reported as a paraneoplastic sign, 6° but this has not been confirmed.16, 21 LABORATORY EVALUATION The tests that should be performed often depend on the clinical findings. A complete history and physical examination should be accompanied by routine blood and chemistry studies, a chest roentgenogram, mammographic and cervical cytologic
Fig. 3. Multiple seborrheic keratoses of sudden onset (the sign of Leser-Tr61at) in a patient with metastatic mucinous adenocarcinoma.
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examination in women, and prostate-specific antigen testing in men. Complete endoscopic examination of the gastrointestinal tract should also be considered. DIAGNOSIS
The sign of Leser-Tr61at is the sudden appearance and rapid increase in size and number of seborrheic keratoses as a result of an underlying malignancy. 3 The abruptness of the eruption is striking; it should not be confused with generalized seborrheic keratoses of gradual onset. Nevertheless, solid quantification as to the length of the eruptive period and the number of seborrheic keratoses required for the diagnosis is lacking. Some elderly patients are aware of this distinction. Some physicians believe that the recollection of an 80-year-old patient is of little value.~8 I and others have seen a widespread eruption of seborrheic keratoses develop in a patient with erythroderma without evidence of S6zary syndrome, lymphoma, or other internal malignancies. 61-65 In m y experience the patient usually has atopic dermatitis complicated by erythroderma. Crocker 65 observed the same more than 100 years ago: " T h e y are said to be very numerous sometimes in cancerous patients, and I have seen a very copious crop on the chest, associated with acute eczema, in an elderly w o m a n . " The sudden eruption of several hundred typical seborrheic keratoses confined to the skin of the breasts and inframammary area has also been reported in association with pregnancy. 66 A similar eruption has been observed in a patient with lepromatous leprosy. 67 With the sign of Leser-Tr61at, most patients have an adenocarcinoma, often of the stomach or c o l o n ) However, about 20% of patients have a l y m p h o m a or leukemia rather than an adenocarcinoma. 3 It is possible that this figure overrepresents this association and reflects a bias to report an apparently unusual linkage rather than the typical one and the propensity o f erythroderma with or without an underlying lymphoma-leukemia to induce an eruption of seborrheic keratoses in inflamed skin. COURSE/PROGNOSIS
The course of patients with the sign of LeserTrdlat is variable. 68q29 It often parallels that of the underlying tumor, 18, 2o, 26, 28, 39 although this is not uniformly tree. Most patients have a solitary malignancy, but one had primary cancers of the breast and
Journal of the American Academy of Dermatology July 1996
stomach. 55 Two other patients had a few malignant adenonomatous colonic polyps. 26 Because most of the malignant tumors behave aggressively, the lifespan of patients with the sign of Leser-Tr61at averages about 10.6 months. 39 REFERENCES 1. Ronchese F. Keratoses, cancer and "the sign of LeserTr41at." Cancer 1965;18:1003-6. 2. Schwartz RA. The sign of Leser-Tr41at. In: Demis DJ, editor. Clinical dermatology. 13th ed. Philadelphia: JB Lippincott, 1987;Unit 12-26A:1-3. 3. Dantzig PI. Sign of Leser-Tr61at. Arch Dermatol 1973; 108:700-1. 4. Schwartz RA. Acanthosis nigricans, florid cutaneous papillomatosis, and the sign of Leser-Tr61at.Curls 1981; 28:319-34. 5. Gheeraert P, Goens J, Schwartz RA, et al. Florid cutaneous papillomatosis, malignant acanthosis ni~gicans, and pulmonary squamous cell carcinoma, hat J Dermatol 1991 ;30:193-7. 6. Schwartz RA, Helmold ME, Janniger CK, et al. Sign of Leser-Tr61atwith a metastatic mucinous adenocarcinoma. Cutis 1991;47:258-60. 7. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;114:1803-6. 8. Yaniv R, Servadio Y, Feinstein A, et al. The sign of Leser-Tr61atassociated with transitional cell carcinoma of the urinary-bladder: a case report and short review. Clin Exp Dermatol 1994;19:142-5. 9. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1-19. 10. Leser E. Ueber ein die Krebskrankheit beim Menschen h~iufig begleitendes, noch wenig gekanntes Symptom. Mtinchener Med Wochenschr 1901;51:2035-6. 11. HollS_nderE. V. Beitr~igezur FfiJhdiagnosedes Darmcarcinomas (Heredith'tsverhS.lmisseund Hauwer'~ndemngen. Dtsch Med Wochenschr 1900;26:483-5. 12. Hollander E. Carcinom und Hautvefmademngen.Centralblatt Chimrg 1902;29:457-9. 13. De Bersaques J. Sign of Leser-Tr61at[letter]. J Am Acad Dermatol 1985;12:724. 14. Sebastinei F. Esame dello stato della cuti individui affetti da neoplasmi maligni. Diagnosi 1932;12:95-113. 15. Bald J. A verrucfik 6s rfik gyakori egyh'ttesel6fordulfisa. Orvosi Hetilap 1933;77:797-8. 16. Follmann J. A naevusok gyakorisfiggr61valamint a nae vusok 6srfik a k6z6tti 6sszeftiggdsekr61. Magyar Orvosi Archiv 1939;40:53-71. 17. DeBersaques J, Dockx P. Tumeurs malignes internes et sympt6mes cutands. Arch Belg Dermatol 1974;30:11758. 18. Rampen FHJ, Schwengle LEM. The sign of Leser-Trdlat: Does it exist? J Am Acad Dermatol 1989;21:50-5. 19. Schwengle LEM, Rampen FHJ, Wobbes T. Seborrhoeic keratoses and internal malignancies: a case control study. Clin Exp Dermatol 1988;13:177-9. 20. Lindel0f B, Sigurgeirsson B, Melander S. Seborrhoeic keratoses and cancer. J Am Acad Dermatol 1992;26: 947-50. 21. Grob JJ, Rava MC, Gouvernet J, et al. The relation between seborreic keratoses and malignant solid mmours: a case-control study. Acta Derm Venereol (Stockh) 1991;71:166-9.
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22. Br~uer J, Happle R, Gieler U, et al. The sign of Leser-Tr61at: Fact or myth? J Eur Acad Dermatol Venereol 1992;1:77-80. 23. Holdiness MR. Erythroderma, seborrheic keratoses and Leser-Trdlat sign [letter]. Acta Derm Venereol (Stockh) 1989;60:273. 24. Rampen FHJ, Schwengle LEM. Erythroderma, seborrheic keratoses and Leser-Trdlat sign [letter reply to Holdiness MR]. Acta Derm Venereol (Stockh) 1989; 60:273-4. 25. Sneddon IB, Roberts JBM. An incomplete form of acanthosis nigricans. Gut 1962;3:269-72. 26. Heng MCY, Soo-Hoo K, Levine S, et al. Linear seborrheic keratoses associated with underlying malignancy. J Am Acad Dermatol 1988;18:1316-21. 27. 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. 28. Ellis DL, Yates RA. Sign of Leser-Tr6lat. Clin Dermatol 1993;11:141-8. 29. Freudenthal W. Verruca senilis und Keratoma senile. Arch f Dermat u Syph (Berlin) 1926;152:505-28. 30. Rongioletti F, Corbella L, Rebora A. Multiple familial seborrheic keratoses. Dermatologica 1988;176:43-45. 31. Bedi TR. Familial congenital multiple seborrheic vermcae. Arch Dermatol 1977; 113:1441-2. 32. Jadassohn J. Die benignen Epitheliome. Trans Int Congress Med 1913. London: 1914, Section XIII, Dermat & Syph, pt 2, 29-56; [discussion] 57-80. 33. Reiches AJ. Seborrheic keratoses: Are they delayed hereditary nevi? Arch Dermatol Syphilol 1952;65:596600. 34. Dafter J. A text-book of dermatology. Authorized translation from the second French edition edited with notes by S. Pollitzer. Philadelphia: Lea & Febiger, 1920: 209-10. 35. Freudenthal W. Rumpfhautepitheliom (nebst Bemerkungen tiber die Vermca senilis und das Keratoma senilis. Arch f Dermat u Syph 1929;158:539-44. 36. Dubreuilh W. Des hyperkeratoses circonscrites. In: Pringle JJ, editor. Third International Congress of Dermatology held in the examination hall of the conjoint Royal Colleges of Physicians and Surgeons, London, August 4th to 8th, 1896. Official Transactions. London: Waterlow and Sons Ltd, 1898:125-76. 37. Westrom DR, Berger TG. The sign of Leser-Tr61at in a young man [letter]. Arch Dermatol 1986;122:1356-7. 38. Barron LA, Prendiville JS. The sign of Leser-Trdlat in a young woman with osteogenic sarcoma. J Am Acad Dermatol 1992;26:344-7. 39. Holdiness MR. The sign of Leser-Tr61at. Int J Dermatol 1986;25:564-72. 40. Holdiness MR. A case of Leser-Trdlat sign [letter]. J Am Acad Demlatol 1987;16:147-8. 41. AbeloffMD. Paraneoplastic syndromes: a window on the biology of cancer. N Engl J Med 1987;317:1598-600. 42. 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 1976; 1:363-8. 43. Ellis DL, Kafka SP, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Tr6lat, and multiple acrochordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med 1987;317:1582-7. 44. Hage E, Hage J. Malignant acanthosis nigrican: A para-
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65. Crocker HR. Diseases of the skin: their description, pathology, diagnosis, and treatment with special reference to the eruptions of children. 2nd ed. Philadelphia: P Blakiston & Son, 1893:390. 66. Garcia RL, Bishop ME. The rapid onset of seborrheic keratosis of the breasts dining pregnancy. J Assoc Mil Dermatol 1977;3(2): 13-4. 67. D'Souza M, Garg BR, Reddy BSN, et al. Lepromatous leprosy with extensive lmncal seborrheic keratoses and acral vermca vulgaris. Int J Dermatol 1994;33:498500. 68. Czamecki DB, Rotstein H, O'Brien TJ, et al. The sign of Leser-Tr61at. Australas J Dermatol 1983;24:93-9. 69. Pollitzer S. Acanthosis nigricans. In: Unna PG, Morris M, Besnier E, et al, editors. International atlas of rare skin diseases. London: HK Lewis, 1890:chap 10:1-3. 70. Forman L. Acanthosis nigricans with discrete warts and marked mucous membrane changes in a patient with vitiligo. Proc R Soc Med 1943;36:611. 71. Schwartz B. Acanthosis nigricans. Proc R Soc Med 1952;45:466. 72. Jablonska S, Kozminska A, Chorzelski T. Eine ungew/Shnfiche Variante von Akanthosis nigricans. (Zusmnmenhang zwischen Akanthosis nigricans and generalisierter Vermkose). Dermatol Wochenschr 1965;151:17785. 73. Gougerot H, Duperrat B. Dermatose verruqueuse "monitrice" d'un cancer viscdral. Ann Dermatol Syphil 1942;2: 193-9. 74. Cobum PR, Cream JJ. Eruptive seborrhoeic warts with gastric adenocarcinoma. J R Soc Med 1984;77:245-6. 75. Sahl WJ, Wittenberg GP, Barlow J. The sign of LeserTr61at associated with mycosis fungoides and lymphomatold papulosis. J Geriatr Dermatol 1995;3:119-23. 76. Josserand A, Dargent M, Mayer M. l~volution et involution simultan6es de carcinose du sein et de venues de la r6gion mammaire. Presse Med 1948;57:674-5. 77. Walter JA, Lewis JG, Robinson TWE. Eruptive basal cell papillomata with carcinoma of caecum. Proc R Soc Med 1972;65:595-6. 78. Hodak E, Halevy S, Ingber A, et al. Leser-Trdlat-Zeichen bei Adenokarzinom des Colon sigmoideum: eine seltene Erscheinung. Z Hautkr 1987;62:875-6. 79. Lambert D, Fort M, Legoux A, et al. Le signe de LeserTrglat: apropos de 2 observations. Ann Dermatol Venereol 1980;107:1035-41. 80. Cohen JH, Lessin SR, Vowels BR, et al. The sign of Leser-Trglat in association with Sgzary syndrome: simultaneous disappearance of seborrheic keratoses and malignant T-cell clone during combined therapy with photopheresis and interferon alfa. Arch Dermatol 1993;129: 1213-4. 81. Cohen MS, Classen RF. The sign of Leser-Trglat associated with adenocarcinoma of the rectum. Curls 1993;51: 255-7. 82. Gitlin MC, Pirozzi DJ. The sign of Leser-Trglat [letter]. Arch Dermatol 1975;111:792-3. 83. Mayou SC, Benn JJ, Sonksen PH, et al. Paraneoplastic rhinophyma and the Leser-Tr61at sign. Clin Exp Dermatol 1989;14:253-5. 84. Safai B, Grant JM, Good RA. Cutaneous manifestation of internal malignancies. II: the sign of Leser-Tr61at. Int J Dermatol 1978;17:494-5. 85. Fretzin DF. Malignant down. Arch Dermatol 1967;95: 294-7. 86. Matsumoto R, Hayashi M, Takahashi Y, et al. A case of
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102.
103. 104. 105. 106. 107.
sign of Leser-Trdlat. Rinsho Dermatol (Tokyo) 1985;27: 1015-9. Ikari Y, Ohkura M, Morita M, et al. Leser-Trglat sign associated with Sgzary syndrome. J Dermatol 1995 ;22:62-7. Hofslader SLR. Leser-Trglat and acanthosis nigricans preceding gastric cancer. In: Wyatt SK, editor. XVI Congressus International Dermatologiae. Tokyo: Tokyo University Press, 1982:213-4. Benn JJ, Firth RGR, S6nksen PH. Metabolic effects of an insulin-like factor causing hypoglycaemia in a patient with a haemangiopericytoma. Clin Endocrinol 1990;32: 769-80. Horiuchi Y, Katsuoka K, Tsukamoto K, et al. Leser-Tr61at sign associatedwith Sgzary syndrome. Curls 1985;36:40910. Kameya S, Noda A, Isobe E, et al. The sign of LeserTr61at associated with carcinoma of the stomach. Am J Gastroenterol 1988;83:664-6. Holguin T, Padilla RS, Ampuero F. Ovarian adenocarcinoma presenting with the sign of Leser-Trdlat. Gynecol Oncol 1986;25:128-32. Tajima H, Mitsuoka S, Ohtsuka E, et al. A case of hepatocellular carcinoma with the Sign of Leser-Trelat: a possible role of a cutaneous marker for internal malignancy. Jpn J Med 1991;30:53-6. Fanrl PA, Melri M, Pa~izi A. The sign of Leser-Tr61at associated with malignant melanoma. Curls 1989;44: 39-41. Toonstra J, Ramselaar CG, van der Putte SCJ. LeserTr61at sign in mycosis fungoides: a further case report. Dennatologica 1985;171:247-9. Lee CH, Clark AR, Thorpe ME, et al. Bile duct adenocarcinoma with Leser-Trelat sign and pure red blood cell aplasia. Cancer 1980;46:1657-60. Kuhl ICP, Bakos L, Zampesi M, et al. Sinai de LeserTr61at associado a carcinoma de colo utefino: relato de um caso e mvisfio bibliogrfifica. Med Cutfin lbero-Lat Am 1986;14:251-4. Miyako F, Dekio S, Tamura H, et al. Mycosis fungoides with Leser-Tr61at sign: the first report of a patient from Japan. J Dermatol 1994;21:189-93. Andreev VC, Boyanov L, Tsankov N. Generalized acanthosis nigricans. Dermatologica 1981;163:19-24. Martin RW lII, Rady P, Arany I, et al. Benign Leydig cell tumor of the testis associated with human papillomavims type 33 presenting with the sign of Leser-Tr61at. J Urol 1993;150:1246-50. Kazubasia TP, Kharkevich GI, Garkavtseva RF. LeserTr61at dermatosis in kidney cancer. Vopr Onkol 1993;39: 89-91. Wiessmann-Katzenelson V, Ingber A, Pullmann H, et al. Leser-Tr61at-Syndrom, Erythema anulare centrifugum Darier, Mammacarcinom und Basaliome bei einer Patientin. Z Hautkr 1982;57:1568-73. Curry SS, King LE. The sign of Leser-Tr61at: report of a case with adenocarcinoma of the duodenum. Arch Dermatol 1980;116:1059-60. Kechijian P, Sadick NS, Mariglio J, et al. Cytarabine-induced inflammation in the seborrheic keratoses of LeserTr61at. Ann Intern Med 1979;91:868-9. Wagner RF Jr, Wagner KD. Malignant neoplasms and the Leser-Tr61at sign. Arch Dermatol 1981; 117:598-9. Lynch HT, Fusaro RM, Pester JA, et al. Leser-Trelat sign in mother and daughter with breast cancer. J Med Genet 1982;19:218-21. Tutal~e MA, Das KD, Upadhyaya VK, et al. Leser Trelat
Journal of the American Academy of Dermatology Volume 35, Number 1
sign associated with carcinoma of gastro-oesophageal junction. Indian J Cancer 1983;20:32-4. 108. Suzuki Y, Matsuo I, Ogufi A, et al. A case of the sign of Leser-TrElat associated with stomach cancer. Jpn J Clin Dermatol 1979;33:261-5. 109. Ishihara K, Kihara T. Bizarre leiomyoblastoma of the iletml associated with sign of Leser-Trelat. lto Cho 1981; 16:1091-7. 110. Safai B, Grant JM, Good RA. Cutaneous manifestation of internal malignancies: II. the sign of Leser-Trtlat. Int J Dermatol 1978;17:494-5. 111. Halevy S, Halevy J, Feuerman EJ. The sign of LeserTrtlat in association with lymphocytic lymphoma. Dermatologica 1980;161:183-6. 112. Greer KE, Hawkins H, Hess C. Leser-Trtlat associated with acute leukemia [letter]. Arch Dermatol 1978; 114:1552. 113. Hattofi A, Umegae Y, Kataki S, et al. Small cell carcinoma of the lung with Leser-Trtlat sign. Arch Dermatol 1982;118:1017-8. 114. Friedman-Birnbaum R, Haim S. Seborrheic keratosis and papillomatosis: maJ:kers of breast adenocarcinoma. Cuffs 1983;32:161-2. 115. Venencie PY, Perry HO. Sign of Leser-Trelat: report of two cases and review of the literature. J Am Acad Dermatol 1984;10:83-8. 116. Elewski BE, Gilgor RS. Eruptive lesions and malignancy. Int J Dermatol 1985;24:617-29. 117. Kameya S, Noda A, Isobe E, et al. The sign of LeserTrtlat associated with carcinoma of the stomach. Am J Gastroenterol 1988;83:664-6. 118. Kaplan DL, Jegasothy B. The sign of Leser-Trtlat asso-
Schwartz 95
119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129.
ciated with primary lymphoma of the brain. Cuffs 1984; 34:164-5. Liddell K, White JE, Caldwell IW. Seborrhoeic keratoses and carcinoma of the large bowel: three cases exhibiting the sign of Leser-Trtlat. Br J Dermatol 1975;92:449-52. Smalley SR, Rubin J, Leiferman KM. Neurofibrosarcoma and the sign of Leser-Trtlat. CA Cancer J Cfin 1984;34: 295-8. Rodrfguez-Garcla JL, Perales J, Espafia A. Carcinoma pulmonar oculto y signo de Leser-Trtlat. Rev Clin Esp 1991;188:378-9. Hoffmann A, Steffen H-M, Mtiller R, et al. Das LeserTrtlat syndrom. Internist (Berl) 1989;30:457-8. Wieselthier JS, Bhawan J, Koh HI(. Transformation of Stzary syndrome and the sign of Leser-Trtlat: a histopathologic study. J Am Acad Derrnatol 1990;23:520-2. Horiuchi Y, Katsuoka K. Leser-Trtlat sign associated with leiomyosarcoma of the stomach. Int J Dermatol 1986;25:463-4. Doll DC, McCagh MF, Welton WA. Sign of Leser-Trtlat. JAMA 1977;238:236-7. Sperry K, Wall J. Adenocarcinoma of the stomach with eruptive seborrheic keratoses: the sign of Leser-Trtlat. Cancer 1980;45:2434-7. Diaz EG, Leviatan A, Okon E. Renal adenocarcinoma and meningioma [letter]. Arch Dermatol 1979; 115:1286. Harrington CI. Leser-Trtlat sign with porphyria cutanea tarda and malignant hepatoma [letter]. Arch Dermatol 1976; 112:730. Jacobs MI, Rigel DS. Acanthosis nigricans and the sign of Leser-Trtlat associated with adenocarcinoma of the gallbladder. Cancer 1981 ;48:325-8.
A V A I L A B I L I T Y O F J O U R N A L B A C K ISSUES As a service to our subscribers, copies of back issues of the Journal of the American Academy of Dermatology for the preceding 5 years are maintained and are available for purchase from the publisher, Mosby-Year Book, Inc., at a cost of $13.50 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby-Year Book, Inc. Subscription Services, 11830 Westline Industrial Dr., St. Louis, M O 63146-3318, or call (800) 453-4351 or (314) 453-4351 for information on availability of particular issues, ff unavailable from the publisher, photocopies of complete issues are available from UMI, 300 N. Zeeb Rd., Ann Arbor, M I 48106, (313)761-4700.
The sign of Leser-Trtlat may be defined as the abrupt appearance and rapid increase in size and number of multiple seborrheic keratoses as a result of cancer vs (Table I-IV). This definition is comparable to that of malignant acanthosis nigricans, 9 establishing both as paraneoplastic syndromes. Paradoxically, both multiple seborrheic keratoses and acanthosis nigricans are common and rarely linked with cancer (Table I). When present, however, the associated malignancy is usually aggressive and has a poor prognosis.
Table I. Comparison of acanthosis nigricans and eruptive seborrheic keratoses
HISTORY
AN, Acanthosis nigricans; CA, cancer; FCP, florid cutaneous papillomatosis; SLT, sign of Leser-Tr61at.
The description of this sign has been credited separately to Edmund Leser (1853-1916) and U1ysse Trtlat (1827-1890). 9-13 Leser was a German surgeon and Trtlat was a French professor of surgery in Bordeaux. 13 However, they both were observing cherry angiomas in patients with cancer rather than seborrheic keratoses; therefore the sign of LeserTrtlat is a misnomer. Hollander 11 first emphasized the association of internal cancer with seborrheic keratoses in 1900. 9, 10, 12, 13 The association of multiple eruptive cutaneous lesions and internal cancer has been explored for many years. 13-17This sign has been in disfavor with some and remains controversial. 1s-26 Because both seborrheic keratoses and cancer are common in the elderly and a clear description of "eruptive" may be difficult, some doubt the validity of this sign. From Dermatology, New Jersey Medical School. Reprint requests: R. A. Schwartz, MD, Dermatology, New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103-2714. Copyright © 1996 by the American Academy of Dermatology, Inc. 0190-9622/96 $5.00 + 0
88
16/1/70261
Acanthosis nigricans
Multiple seborrheic keratoses
Common Inherited autosoma]
Common Inherited autosomal
dominant Usually not associated with cancer If CA, sudden and eruptive If CA, often seen with SLT + FCP
dominant Usually not associated with cancer If CA, sudden and eruptive If CA often seen with AN + FCP
INCIDENCE
Like malignant acanthosis nigficans, with which it is often associated, the sign of Leser-Trtlat is rare, even in patients with cancer. 9 A few studies have been performed, 15, 19-21 some with age- and sexmatched controls. 19,21 In one, 82 patients had recently diagnosed solid rumors. In a second, 36 patients between 50 and 80 years of age who had an underlying cancer were examined. In both studies the features of seborrheic keratoses did not differ significantly between patients and control subjects. These two negative case-control studies resemble the results of an autopsy study of malignant acanthosis nigricans in a small group of patients with cancer. 27 The data demonstrate only that both disorders are rare in these patients. A retrospective review of 1752 consecutive patients with seborrheic keratoses sought a possible association with malignant disease. 2° In 62 patients with seborrheic keratoses, a visceral malignancy was diagnosed within 1 year before or after diagnosis of the seborrheic keratoses.
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Schwartz 89
T a b l e I I . The sign o f Leser-Tr61at in 51 patients with 52 different types o f adenocarcinomas Site
[ No. of patients [
Reference (first author)
7
M. Cohen, si Liddell H9 (in 3 pts), Walter, 77 Br~uer, 22 Hodak, 7s Heng 26 (in 5 pts) Kameya,9x Stieler, 55'* Andreev,99 Sperry,126,3~Tutakne, l°7,§ Suzuki, 108 Hoffmann, 122 R. Schwartz, 7 Lindel6f 2° (in 2 pts), MiUard,42 Jablonska62 Curry 103 Elewski 116 Hirano59 Stieler, 55. Lynch 1°6 (in 2 pts), Venencie11511 (in 2 pts), Wiessmann-Katzenelson, l°2 Friedman-Birnbaum,114 Lindel6f 20 (in 2 pts), Josserand76 Holguin,92 Dingley53 Aylesworth51 Ronchese 1 Ktlh197 Gitlins2 Diaz127~[ Tajima, 93 Kazubasia1°1 Harrington,128 Lindel6f 20 Jacobs 129 Lee96 R. Schwartz, 6 Czarnecki68
Colon/rectum Stomach
12
Duodenum Esophagus Pancreas Breast
1 1 1 10
Ovary Endometrium Uterus Cervix Prostate Hypernephroma Hepatoma Gallbladder Bile duct Adenocarcinoma (site unknown)
2 1 1 1 1 3 2 1 1 2
*Patient had cancer of both stomachand breast. ~Colon adenocarcinomaexcised 10 years earlier. §Gastroesophagealjunction. IIMetastasizingparotid gland tmnor seven years later. ~Vleningiomaalso.
T a b l e I I I . The sign of Leser-Tr61at in 35 patients with disorders other than adenocarcinoma
Disorder Mycosis fungoides S6zary syndrome Lymphoma Leukemia Lung cancer (SCC) Lung small-cell cancer Osteogenic sarcoma Hemangiopericytoma Leiomyosarcoma Neurofibrosarcoma Melanoma Pleura Laryngeal SCC Transitional cell cancer, of urinary bladder Brain (germinoma of pineal body--presumptive)
O f these 62, six had keratoses that were multiple (>20) and eruptive, consistent with the sign o f Leser-Tr61at. B y comparison, o f 62 age- and sexmatched control patients without cancer, five also
No. of patients 4 4 7
Reference (first author) Toonstra,95 Lambert,79 Miyako,98 Sah]75 Dantzig, 3 J. Cohen, s° Horiuchi,46 Ikari 87 Halevy,m Wieselthier, 123 Safai, 11° Kaplan, 118 Wagner, 1°5 Holdiness, 4° Matsumoto86 Kechijian, 1°4 Greer 112 Doll, 125Lambert,79 Fretzin, 85 Czamecki,68 Rodriguez-Garcfa121 Hattori 113 Barron3s Benn s9 Horinchi, 124 Ishihara 109 Smalley 120 Fanti, 94 Ellis 43 Lindel6f 2o Gheeraert, 5 Rubisz-Brzezinska52 Yaniv 8 Westrom37
m e t the criteria. However, Ellis and Yates 28 stated that the results o f this study are inconclusive. Seborrheic keratoses are colnmon, 29-36 but their appearance during the second and third decades of
90
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Journal of the American Academy of Dermatology July 1996
Table IV. Eruptive multiple seborrheic keratoses
in seven patients with a benign neoplasm or pregnancy Disorder/ Condition
No. of patients
Testicular, benign Leydig cell tumor Brain (pituitary) Lung hamartomas Renal cyst Pregnancy Meningioma, hypernephroma
Fig. 1. Multiple seborrheic keratoses of sudden onset (the sign of Leser-Trdlat) in a patient with gastric adenocarcinoma.
life and an eruptive course are not. It has been postulated that seborrheic keratoses are essentially delayed hereditary nevi. 32 Multiple eruptive seborrheic keratoses tend to occur in older persons, in whom malignancy is also more common. 2s, 37-4oThe sign of Leser-Tr61at, however, has been described in two persons with underlying neoplasms during their second decade of life.2s, 3a PATHOGENESIS
The cause of the sign of Leser-Tr61at is as uncertain as that of the other eruptive paraneoplastic disorders often present with it, such as malignant acanthosis nigricans. These disorders are probably directly induced by the underlying neoplasm, most likely from a tumor-secreted growth factor.26, 41-47 However, no evidence of this exists other than a few case reports. Millard and Gould42 described two patients with tylosis (one with the sign of Leser-Trdlat) who had high levels of immunoreactive human growth hormone. Another patient had a small cutaneous melanoma, acanthosis nigricans, the sign of
Reference (first author)
1
Martin1°°
1 1 1 2 1
Kilmer47 Ellis28 Berman63 Garcia,66 Lindel6f 20 Diaz127
Leser-Tr61at, and multiple "acrochordons. ''43 Increased epidermal staining for the epidermal growth factor receptor was initially observed in specimens of acanthosis nigricans, seborrheic keratoses, and cutaneous papillomas; this staining and the urine level of transforming growth factor--~ both declined markedly after surgical removal of the primary nonmetastatic cutaneous melanoma. The supernatant of another patient's cultured peripheral lymphocytes showed increased epidermal growth factor activity in vitro. 46 These growth factors have been postulated to alter the extracellular matrix, possibly resulting in the formation of seborrheic keratoses.4s Ellis and Yates 2s suggested that the sign of Leser-Tr61at is a result of a growth factor like transforming growth factor-o~ reaching a critical threshold level and producing this sudden eruption if the affected person is genetically predisposed. However, the finding of transforming growth factor-oL has not been confirmed by others. Curth49, 50 suggested criteria for the diagnosis of cutaneous paraneoplastic syndromes and considered acanthosis nigricans to be an excellent example. It is noteworthy that multiple seborrheic keratoses and acanthosis nigricans do not conform to her criteria in two ways: both are common and both have approximately the same broad tumor distribution with which they are associated. However, Curth considered acanthosis nigricans to be almost always caused by an adenocarcinoma, usually of the gut. CLINICAL MANIFESTATIONS
This sudden eruption of multiple seborrheic keratoses may occur on any body surface (Figs. 1-3). Most are on the back and chest (76%), followed by the extremities (38%), face (21%), abdomen (15%),
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Schwartz 91
Fig. 2. Close-up view of seborrheic keratoses of sudden onset in patient with gastric adenocarcinoma. (From Schwartz RA. Cutis 1981;28:326.)
neck (13%), axillae (6%), and groin (3%). 28 Sometimes the eruption is described as appearing in a "Christmas tree" or "splash" pattern, although this may occur with eruptive seborrheic keratoses unassociated with malignancy. 26, a8 Eruptive seborrheic keratoses may be associated with other signs of internal malignancy, such as acquired ichthyosis, 44 Cowden's disease, 51 acrokeratosis of Bazex, 52 acquired hypertrichosis lanuginosa, 53, 54 tylosis,42 and florid cutaneous papillomatosis. 1,4, 5, 7, 44, 53, 55-57 However, malignant acanthosis nigricans is most frequently seen with the sign of Leser-Tr61at and is evident in about 35% of patients. 58 Pruritus accompanying the sign of Leser-Tr61at occurs in almost half the patients. 58 A sudden eruption and a rapid increase in the number and size of freckles may also be evident. 59 Capillary angiomas may be present, but they are not a consistent finding. 18Eruptive capillary angiomas have themselves been reported as a paraneoplastic sign, 6° but this has not been confirmed.16, 21 LABORATORY EVALUATION The tests that should be performed often depend on the clinical findings. A complete history and physical examination should be accompanied by routine blood and chemistry studies, a chest roentgenogram, mammographic and cervical cytologic
Fig. 3. Multiple seborrheic keratoses of sudden onset (the sign of Leser-Tr61at) in a patient with metastatic mucinous adenocarcinoma.
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examination in women, and prostate-specific antigen testing in men. Complete endoscopic examination of the gastrointestinal tract should also be considered. DIAGNOSIS
The sign of Leser-Tr61at is the sudden appearance and rapid increase in size and number of seborrheic keratoses as a result of an underlying malignancy. 3 The abruptness of the eruption is striking; it should not be confused with generalized seborrheic keratoses of gradual onset. Nevertheless, solid quantification as to the length of the eruptive period and the number of seborrheic keratoses required for the diagnosis is lacking. Some elderly patients are aware of this distinction. Some physicians believe that the recollection of an 80-year-old patient is of little value.~8 I and others have seen a widespread eruption of seborrheic keratoses develop in a patient with erythroderma without evidence of S6zary syndrome, lymphoma, or other internal malignancies. 61-65 In m y experience the patient usually has atopic dermatitis complicated by erythroderma. Crocker 65 observed the same more than 100 years ago: " T h e y are said to be very numerous sometimes in cancerous patients, and I have seen a very copious crop on the chest, associated with acute eczema, in an elderly w o m a n . " The sudden eruption of several hundred typical seborrheic keratoses confined to the skin of the breasts and inframammary area has also been reported in association with pregnancy. 66 A similar eruption has been observed in a patient with lepromatous leprosy. 67 With the sign of Leser-Tr61at, most patients have an adenocarcinoma, often of the stomach or c o l o n ) However, about 20% of patients have a l y m p h o m a or leukemia rather than an adenocarcinoma. 3 It is possible that this figure overrepresents this association and reflects a bias to report an apparently unusual linkage rather than the typical one and the propensity o f erythroderma with or without an underlying lymphoma-leukemia to induce an eruption of seborrheic keratoses in inflamed skin. COURSE/PROGNOSIS
The course of patients with the sign of LeserTrdlat is variable. 68q29 It often parallels that of the underlying tumor, 18, 2o, 26, 28, 39 although this is not uniformly tree. Most patients have a solitary malignancy, but one had primary cancers of the breast and
Journal of the American Academy of Dermatology July 1996
stomach. 55 Two other patients had a few malignant adenonomatous colonic polyps. 26 Because most of the malignant tumors behave aggressively, the lifespan of patients with the sign of Leser-Tr61at averages about 10.6 months. 39 REFERENCES 1. Ronchese F. Keratoses, cancer and "the sign of LeserTr41at." Cancer 1965;18:1003-6. 2. Schwartz RA. The sign of Leser-Tr41at. In: Demis DJ, editor. Clinical dermatology. 13th ed. Philadelphia: JB Lippincott, 1987;Unit 12-26A:1-3. 3. Dantzig PI. Sign of Leser-Tr61at. Arch Dermatol 1973; 108:700-1. 4. Schwartz RA. Acanthosis nigricans, florid cutaneous papillomatosis, and the sign of Leser-Tr61at.Curls 1981; 28:319-34. 5. Gheeraert P, Goens J, Schwartz RA, et al. Florid cutaneous papillomatosis, malignant acanthosis ni~gicans, and pulmonary squamous cell carcinoma, hat J Dermatol 1991 ;30:193-7. 6. Schwartz RA, Helmold ME, Janniger CK, et al. Sign of Leser-Tr61atwith a metastatic mucinous adenocarcinoma. Cutis 1991;47:258-60. 7. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;114:1803-6. 8. Yaniv R, Servadio Y, Feinstein A, et al. The sign of Leser-Tr61atassociated with transitional cell carcinoma of the urinary-bladder: a case report and short review. Clin Exp Dermatol 1994;19:142-5. 9. Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994;31:1-19. 10. Leser E. Ueber ein die Krebskrankheit beim Menschen h~iufig begleitendes, noch wenig gekanntes Symptom. Mtinchener Med Wochenschr 1901;51:2035-6. 11. HollS_nderE. V. Beitr~igezur FfiJhdiagnosedes Darmcarcinomas (Heredith'tsverhS.lmisseund Hauwer'~ndemngen. Dtsch Med Wochenschr 1900;26:483-5. 12. Hollander E. Carcinom und Hautvefmademngen.Centralblatt Chimrg 1902;29:457-9. 13. De Bersaques J. Sign of Leser-Tr61at[letter]. J Am Acad Dermatol 1985;12:724. 14. Sebastinei F. Esame dello stato della cuti individui affetti da neoplasmi maligni. Diagnosi 1932;12:95-113. 15. Bald J. A verrucfik 6s rfik gyakori egyh'ttesel6fordulfisa. Orvosi Hetilap 1933;77:797-8. 16. Follmann J. A naevusok gyakorisfiggr61valamint a nae vusok 6srfik a k6z6tti 6sszeftiggdsekr61. Magyar Orvosi Archiv 1939;40:53-71. 17. DeBersaques J, Dockx P. Tumeurs malignes internes et sympt6mes cutands. Arch Belg Dermatol 1974;30:11758. 18. Rampen FHJ, Schwengle LEM. The sign of Leser-Trdlat: Does it exist? J Am Acad Dermatol 1989;21:50-5. 19. Schwengle LEM, Rampen FHJ, Wobbes T. Seborrhoeic keratoses and internal malignancies: a case control study. Clin Exp Dermatol 1988;13:177-9. 20. Lindel0f B, Sigurgeirsson B, Melander S. Seborrhoeic keratoses and cancer. J Am Acad Dermatol 1992;26: 947-50. 21. Grob JJ, Rava MC, Gouvernet J, et al. The relation between seborreic keratoses and malignant solid mmours: a case-control study. Acta Derm Venereol (Stockh) 1991;71:166-9.
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22. Br~uer J, Happle R, Gieler U, et al. The sign of Leser-Tr61at: Fact or myth? J Eur Acad Dermatol Venereol 1992;1:77-80. 23. Holdiness MR. Erythroderma, seborrheic keratoses and Leser-Trdlat sign [letter]. Acta Derm Venereol (Stockh) 1989;60:273. 24. Rampen FHJ, Schwengle LEM. Erythroderma, seborrheic keratoses and Leser-Trdlat sign [letter reply to Holdiness MR]. Acta Derm Venereol (Stockh) 1989; 60:273-4. 25. Sneddon IB, Roberts JBM. An incomplete form of acanthosis nigricans. Gut 1962;3:269-72. 26. Heng MCY, Soo-Hoo K, Levine S, et al. Linear seborrheic keratoses associated with underlying malignancy. J Am Acad Dermatol 1988;18:1316-21. 27. 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. 28. Ellis DL, Yates RA. Sign of Leser-Tr6lat. Clin Dermatol 1993;11:141-8. 29. Freudenthal W. Verruca senilis und Keratoma senile. Arch f Dermat u Syph (Berlin) 1926;152:505-28. 30. Rongioletti F, Corbella L, Rebora A. Multiple familial seborrheic keratoses. Dermatologica 1988;176:43-45. 31. Bedi TR. Familial congenital multiple seborrheic vermcae. Arch Dermatol 1977; 113:1441-2. 32. Jadassohn J. Die benignen Epitheliome. Trans Int Congress Med 1913. London: 1914, Section XIII, Dermat & Syph, pt 2, 29-56; [discussion] 57-80. 33. Reiches AJ. Seborrheic keratoses: Are they delayed hereditary nevi? Arch Dermatol Syphilol 1952;65:596600. 34. Dafter J. A text-book of dermatology. Authorized translation from the second French edition edited with notes by S. Pollitzer. Philadelphia: Lea & Febiger, 1920: 209-10. 35. Freudenthal W. Rumpfhautepitheliom (nebst Bemerkungen tiber die Vermca senilis und das Keratoma senilis. Arch f Dermat u Syph 1929;158:539-44. 36. Dubreuilh W. Des hyperkeratoses circonscrites. In: Pringle JJ, editor. Third International Congress of Dermatology held in the examination hall of the conjoint Royal Colleges of Physicians and Surgeons, London, August 4th to 8th, 1896. Official Transactions. London: Waterlow and Sons Ltd, 1898:125-76. 37. Westrom DR, Berger TG. The sign of Leser-Tr61at in a young man [letter]. Arch Dermatol 1986;122:1356-7. 38. Barron LA, Prendiville JS. The sign of Leser-Trdlat in a young woman with osteogenic sarcoma. J Am Acad Dermatol 1992;26:344-7. 39. Holdiness MR. The sign of Leser-Tr61at. Int J Dermatol 1986;25:564-72. 40. Holdiness MR. A case of Leser-Trdlat sign [letter]. J Am Acad Demlatol 1987;16:147-8. 41. AbeloffMD. Paraneoplastic syndromes: a window on the biology of cancer. N Engl J Med 1987;317:1598-600. 42. 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 1976; 1:363-8. 43. Ellis DL, Kafka SP, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Tr6lat, and multiple acrochordons: a possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med 1987;317:1582-7. 44. Hage E, Hage J. Malignant acanthosis nigrican: A para-
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45.
46.
47.
48.
49. 50.
51.
52.
53.
54.
55.
56. 57.
58. 59.
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Journal of the American Academy of Dermatology Volume 35, Number 1
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