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Sign of leser — Trélat
Sign of Leser - T&at DARREL L. ELLIS, MD RUTH A. YATES, MD
T
he sign of Leser - Trelat is usually defined as the eruptive appearance of numerous seborrheic keratoses or the sudden increase in the number and size of previous seborrheic keratoses in association with an internal malignancy.’ Difficulties with this definition include how “eruptive” is defined, what a “significant” increase in number and size of previous seborrheic keratoses is, and that the sign has been reported in non-“internal” cancers such as melanomas and cutaneous T-cell lymphomas. Nevertheless, the sign of Leser - Trelat as defined is useful for suggesting when an underlying malignancy should be sought.
History The paraneoplastic syndrome of eruptive seborrheic keratoses associated with an internal malignancy is historically connected with the German surgeon Edmund Leser and the French surgeon Ulysse Trelat, who independently described the appearance of cutaneous senile angiomas as a sign of mammary carcinoma and visceral malignancies in the 1890s. l-3 Hollander may be the first author to associate seborrheic keratoses with internal malignancy.” Although the “sign of Leser - Trelat” may thus be a misnomer, the cutaneous paraneoplastic syndrome is deeply entrenched in the literature, and should be used to maintain continuity.
Incidence The incidence of the sign of Leser-Trelat is unknown. Table 1 is a modification and update of a table from the
excellent review article by Holdiness.5 Most reports have been case reports, with no large series studied. Two papers attempted to define the incidence of the sign of Leser-Trelat by studying patients with internal malignancies in comparison with age-matched control patients.69J0 Unfortunately, both of these studies were small (3669 and 82’O patients and controls, respectively). Neither of these studies showed an increase in the eruptive appearance of seborrheic keratoses in patients with malignancies. As we found 68 cases of the sign of LeserTrelat described in the literature, one would predict its incidence is relatively rare. These small negative studies do not tell whether the sign of Leser-Trelat is rare (as predicted from the literature) or nonexistent. Recently, 1752 consecutive cases of seborrheic keratoses were studied for the sign of Leser-Trelat.‘l Six patients with eruptive seborrheic keratoses and an associated malignancy consistent with the sign of Leser-T&at were found. There were also five control patients who had eruptive seborrheic keratoses, but without cancer. Lindelof et al concluded that eruptive seborrheic keratoses were not related to internal cancer risk’*; however, this retrospective review of patient records reported one of the control patients was pregnant, and whether other control patients received extensive workups to rule out small tumors (such as gastrointestinal villous adenomas) or other sources of growth factors underlying their eruptive seborrheic keratoses was not reported. Whether eruptive seborrheic keratoses are related to internal cancer risk if other sources of growth factors are eliminated is therefore still unknown.
Clinical Manifestations From the Division of Dermatology, Department ofMedicine, Vanderbilt University School of Medicine, Nashville, Tennessee. Address correspondenceto: Darrel L Ellis, MD, c/o Carolyn W. Caldwell, 1212 21st Avenue South, 608 Medical Arts Building, Nashville, TN 37212-1226.
0 2993 by Elsevier Science Publishing Co., Inc.
l
0738-081x/93/$6.00
The sign of Leser - Trelat as defined in this article requires the sudden appearance of seborrheic keratoses or the sudden increase in the number and size of seborrheic keratoses and an associated malignancy. Some authors have
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AND
Clinics in Dermatology 1993;11:141-148
YATES
Table 2. Sign of Leser-Trilat:
Summary of Case Reports
Age/Sex
Pruritus
AN*
SK Onset? (Months)
Carcinoma occulturn AC head of pancreas AC breast AC stomach
62F 64M 32F 45M
+ -
+ + +
11 7 6 after 1
56F 46M 58M 54F 58M 69M
+ + -
+ + + + + -
8 5 after 6 1 after 24 after NR
16
AC ovaries AC stomach AC stomach AC uterus AC stomach Undifferentiated Ca AC cecum
84F
+
-
1
12 13 14 15 16
17 18 19 20 20
CTCL (Sezary) AC stomach AC prostate AC transverse colon AC rectum
55M 63M 64M 72M 67F
+ -
+ -
4
17 18 19 20 21 22 23
20 21 22 23 24 25 26
AC sigmoid colon Gastric neoplasm AC stomach Hepatoma AC stomach SCC lung AMML
71M 74M 63M 72M 71F 69M 72M
+ + + + -
+ + -
NR 3 10 after NR NR Concurrent Concurrent
24
27
Lymphoma
73M
+
-
After/NR
25 26 27
27 28 29
61M 64F 62F
+ -
+ -
30
CTCL AC stomach AC kidney and spinal cord meningioma Myelogenous leukemia
66F
-
-
31 31 32 33
CTCL SCC lung AC duodenum AC stomach and rectosigmoid
87M 49M 63M 69M
+ + -
-
34 35
AC bile duct Lymphocytic lymphoma, poorly differentiated AC stomach AC gallbladder Lymphocytic lymphoma, poorly differentiated, and AC rectosigmoid Leiomyoblastoma ileum AC stomach Small cell Ca lung Intihrating ductal Ca breast (patients 41 and 42) AC uterus myometrium Ductal Ca breast AC breasts
70F 63M
+ -
-
62M 56F 59F
+ + -
+ + -
2 Few months before 2 3 2
62M 43M 72M 41F 67F 57F 46F 61F
+ + +
+ -
NR 4 Concurrent 6 3 Weeks NR Concurrent
Patient
5 6 7 8 9 10
29 30 31 32
Malignancy
Reference
35 36 37
36 37 38
38 39 40 41 42 43 44 45
39 40 41 42 42 43 44 45
bronchogenic
2 after 2.5 5 6 Concurrent 17 after 12 2
Correlation of SK and Tumor Regression NR NR Regressed Increased 6 months postop New SKs postop NR NR NR NR NR Decreased postop NR NR NR NR Initially decreased /XRT Persisted postop NR NR NR Decreased postop Decreased postop Decreased with chemoTx Decreased with chemoTx NR NR NR Inflamed with chemoTx Decreased with e beam NR NR Resolved after surgery for tirst AC NR NR NR NR Persisted and increased in size/number during chemoTx NR NR Increased until death No change postop Increased postop NR Increased after TX NR
Histology NR SK NR AN, verrucous hyperplasia AN AN AN AN, SK AN, SK NR Acanthosis/ hyperplasia NR AN NR NR NR NR SK Keratosis NR AN NR SK SK NR AN, SK SK
NR NR NR NR NR SK SK SK, AN SK SK
SK NR SK SK SK NR SK SK
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Clinics in Dermatology 1993;21:142-148
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OF LESER - TRkLAT
Table 1. Sign of Leser-Trilat: Summary of Case Reports (Continued) SK Onsett
Age/Sex
Pruritus
AN*
62M 79F 56F
+ + -
-
+
14 after Concurrent 1 after
AC breast and parotid gland tumor Neurolibrosarcoma
58F
+
+
5 after
40F
-
-
16 after
Non-Hodgkin’s lymphoma, poorly differentiated
80F
NR
-
AC esophagus CTCL SCzary/CTCL
69F 61F 71F
+ + +
-
54
Lung Ca (moderately differentiated SCC and AC)
71M
NR
+
56 57 58
55 56 57
Leiomyosarcoma stomach Ovarian AC Intracranial germinoma
41M 76F 22M
+ + NR
-
59
58
Lymphocytic lymphoma, nodular, poorly differentiated
48F
-
-
60 61 62
59 60 61
Malignant melanoma Lymphoma (mixed cell) Gastic Ca
54M 64M 54F
NR + -
-
63 64 65
62 63,64 65
Malignant melanoma Hemangiopericytoma Pituitary tumor and acromegaly
69M 42F 26F
+ NR +
66 67 68
66 67 68
CTCL/SCzary Hepatocellular Ca Mutinous AC, metastatic to liver
58M 57M 59F
+ + -
Malignancy
Patient
Reference
46 47 48
46 46 47
SCC lung AC unknown AC breast
49
47
50
48
51
49
52 53 54
50 51 52‘53
55
origin
+
-
+
-
-
-
-
(Months)
Concurrent
3 2 12/Concurrent erythroderma NR
24 8 1 after 5 - 6 after
3 19
Correlation of SK and Tumor Regression Decreased postop Unchanged with chemoTx Unchanged postop Appeared after chemoTx Persisted after chemo/ XRT (tumor response?) Increased with mets Decreased with PUVA Decreased with chemoTx Decreased postop, increased as tumor spread Some decrease postop NR Onset: tumor lysis, decreased after XRT Decreased with treatment,increased with mets Decreased postop Unchanged after XRT
Decreasedpostop, increased with mets Unchanged postop Unchanged postop
Decreasedpostop/ post-XRT Decreased with e beam NR NR
Histology SK, AN NR SK NR
SK NR
SK NR SK
SK, AN
NR SK SK NR
SK, AN, PEP SK SK SK SK SK SK/lymphoma SK SK
*AN, acanthosis ni@canr SK seborrheic keratosis; AC, adenocarcinoma; NR not reported; Ca, cancer; XRT, radiation therapy; SCC, squamous cell carcinoma; AMMO ac,,te leukemia; chemoTx, chemotherapy; CTCL, cutaneous T-cell lymphoma; e beam, electron beam; TX, treatment; mets, metastases; pw~, psoralen wirh ultraoioletA light; FEP, fibroepithelial polyp. t Onset of seborrheic keratoses in months prior to the diagnosis of cancer. Modified, with permission, from HoZdiness.5
myelOmOnOqtic
emphasized the pattern of seborrheic keratoses, for example, the “Christmas tree” and “splash” patterns reported in leukemias and IymphomaP; however, similar patterns may also be observed in patients without an associated malignancy. Figure 1 shows the back of a patient with eruptive seborrheic keratoses, which are clinically typical of the appearance of the sign of Leser-Trelat. He had benign hamartomas of the lung, and therefore by definition did not have the sign of Leser-Trelat; however, this case points out possible similar pathophysiologic mechanisms for benign and malignant sources of eruptive seborrheic keratoses (see Pathophysiology).
Previous authors have reported the association of acanthosis nigricans and pruritus with the sign of LeserTrelat. In our review of the literature, we found associated acanthosis nigricans in 29% of the patients reported (20/ 68). Pruritus was present in 5 1% of the cases that could be assessed (32/63). Both acanthosis nigricans and pruritus were present in 16% of the cases (11/67). The seborrheic keratoses found in the sign of LeserTrilat are similar in clinical appearance to normal seborrheic keratoses (Fig 2). Biopsy-proven seborrheic keratoses were found in 57% of the cases (39/68). Anatomic locations of the seborrheic keratoses were similar to those
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Table 2. Malignancies Associated With the Sign of Leser-Tre’lat
Figure 1. Photograph of the back of a patient who had the eruptive onset of seborrheic keratoses associated with hamartomas of the lung. The clinical picture is consistent with that seen in the sign of Leser-Tre’lat, although the associated tumor was benign.
observed for seborrheic keratoses in the general population. Most lesions were on the back and chest (76%), followed by the extremities (38%), face (21%), abdomen (15%), neck (13%), axillae (6%), generalized (6%), and groin (3%). The upper extremities were more frequently involved than the lower extremities (35% versus 25%).
Figure 2. Closeup photograph of a seborrheic keratosis on the back of the patient in Fig 1, demonstrating the ordina y appearance of the seborrheic keratosis.
Adenocarcinoma Gastrointestinal Gynecologic Breast Unknown primary Prostate Kidney Lymphoproliferative Squamous cell carcinoma of lung Breast (ductal) Melanoma Hepatocellular Not reported Miscellaneous (one of each) Leiomyoblastoma Lung (small cell) Neurofibrosarcoma Leiomyosarcoma (stomach) Germinoma (intracranial) Hemangiopericytoma Pituitary tumor Undifferentiated bronchogenic Meningioma (spinal cord)
34/68=50% 22/68=32% 4/68=6% 4/68=6% 2/68=3% l/68 = 1.5% l/68 = 1.5% 14/68 = 20.6% 4/6&?=6% 2/68=3% 2/68=3% 2/68=3% 2/6&3=3% l/68=1.5%
Histopathology The histopathology of seborrheic keratoses found in the sign of Leser - TrClat is identical to that of common seborrheic keratoses.72 The hyperkeratotic form of seborrheic keratosis is also indistinguishable from acanthosis nigricans.72This suggests possible similar mechanisms of pathophysiology for the two lesions.
Associated Malignancies The type of malignancy most commonly associated (50%) with the sign of Leser-Trelat is adenocarcinoma (Table 2). Adenocarcinoma of the gastrointestinal tract is responsible for 32% of the total cases reported. Lymphoproliferative disorders are responsible for 21% of the cases, although some of these cases may have been related to cutaneous inflammation leading to increased seborrheic keratoses. We have attempted to eliminate from our review cases in which cutaneous inflammation appeared to be the source of increased seborrheic keratoses.
Laboratory Findings The laboratory findings are those associated with the tumor involved. In addition, one group has reported a slight elevation of epidermal growth factor (EGF) in the urine,61 another found an increased insulin-like growth
ELLIS AND YATES SIGN OF LESER - TRkLAT
Clinics in Dermatology 2993:11:141- 148 factor,63 and we found transforming growth (TGF-a) to be increased in the urine.59
Differential
factor (Y
Diagnosis
The most difficult element of the sign of Leser-Trelat is discerning if the seborrheic keratoses truly had a recent eruptive onset or increase in size and number. Some authors suggest that older patients may not know whether their seborrheic keratoses have recently changed. In our experience, although the eruptive onset of seborrheic keratoses is rare, the patient usually is quite cognizant of it. The largest segment of the population with multiple seborrheic keratoses probably comprises “normal” patients who have slowly acquired the lesions over several years. These patients do not require extensive examination for carcinoma. Other causes of eruptive seborrheic keratoses, such as pregnancy (see Pathophysiology), also need to be ruled out.
Treatment The initial treatment for the sign of Leser - Trelat is treatment of the underlying carcinoma. In 56% of cases in which responses of seborrheic keratoses to treatment have been recorded, treatment resulted in involution of the seborrheic keratoses. Seborrheic keratoses are benign and do not require treatment; however, for troublesome lesions (irritated or bleeding), physical treatments such as cryosurgery, shave biopsy, electrodesiccation, and curettage may be used. For smaller macular lesions, topical retinoic acid may be useful. 73As the pathogenesis of seborrheic keratoses becomes understood, new therapies should evolve.
Pathogenesis Criteria for paraneoplastic syndromes have been defined by Curth” and Orth. 75According to Curth, (1) the tumor and the paraneoplastic syndrome have a simultaneous onset; (2) the course of both conditions is parallel; (3) a specific tumor occurs in connection with a certain paraneoplastic sign; (4) the dermatosis is usually rare; and (5) there is a high percentage of association between the two conditions. Orth’s Clinical criteria consist of association of a neoplasm with a paraneoplastic syndrome; association of a neoplasm with inappropriately elevated plasma or urine hormone levels; failure of plasma or urinary hormone levels to respond to normal homeostatic suppres-
145
sion; absence of other possible causal mechanisms; fall in hormone levels after tumor-specific therapy; arteriovenous step-up gradient of the hormone across the tumor capillary bed; and presence of the hormone in tumor tissue. Orth’s laboratory criteria are in vitro hormone synthesis and release by tumor tissue and presence of hormone-specific mRNA in tumor tissue. Some or all of these criteria should be met to establish the specific etiologic agent(s) of a cutaneous paraneoplastic syndrome; however, even for most commonly accepted cutaneous paraneoplastic syndromes, the criteria of Orth have not been completely met. Orth’s criteria do outline a clinical and laboratory method of associating a paraneoplastic syndrome with a given tumor, in contrast to the purely clinical criteria of Curth. Several tumors might also produce the same “hormone(s)” that causes a given paraneoplastic syndrome, although some tumors may be more likely to overproduce the hormone than others. The sign of Leser-Trelat has been postulated to be caused by tumor-secreted “growth factors,” which result in the epidermal hyperproliferation that produces multiple seborrheic keratoses. Curry and King first suggested that EGF may be a growth factor with potential to cause the sign of Leser- Trelat, although the patient they studied did not have elevated levels of EGF.32 Kameya et al, however, found slightly elevated levels of EGF in a 24hour urine specimen from a patient with advanced gastric cancer whose seborrheic keratoses had faded with initial resection of the tumor, but returned when the cancer retumed.61 Horiuchi et al observed keratinocyte proliferation on incubation with preconditioned medium from peripheral blood lymphocytes from a patient with Sezary syndrome and the sign of Leser-Trelat.53 The factor responsible for the observed proliferation in their study was not EGF immunologically. Benn et al found a circulating insulin-like growth factor in a patient with a hemangiopericytoma, fasting hypoglycemia, and the sign of Leser Trelat.63 We observed a man with the sign of Leser-Trelat, acanthosis nigricans, multiple acrochordons, and cutaneous melanoma.59 In this patient, removal of the primary melanoma resulted in the simultaneous involution of his seborrheic keratoses, skin tags, and acanthosis nigricans. Although his urinary level of EGF was within the normal range for his age and sex, TGF-a observed in the urine preoperatively resolved postoperatively. The patient’s seborrheic keratoses, acrochordons, and acanthosis nigricans biopsy specimens all had elevated levels of EGF receptor (EGFR) by immunohistochemistry preoperatively; these normal returned to postoperatively. The EGFR is a common receptor for the EGF and TGF-c~ ligands, and melanomas are known to secrete TGF-cx.‘~ We
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Clinics in Dermatology 1993;11:141-148
therefore postulated that TGF-cr produced by the melanoma in this case caused the sign of Leser-TrClat. We suggest the sign of Leser-Trelat is the result of a tumor secreting a factor causing epidermal proliferation (such as TGF-cu), which results in the sudden appearance of multiple seborrheic keratoses in genetically predisposed patients. When the carcinoma increases the level of the epidermal proliferation factor to a critical threshold level, the sudden eruption of multiple seborrheic keratoses may then occur. A genetic susceptibility to developing multiple seborrheic keratoses is also required; otherwise more cancer patients would be expected to have the sign of Leser - Trelat. Multiple seborrheic keratoses are common, and often genetically linked. Both common acquired benign seborrheic keratoses and the sign of Leser-TrClat may occur through a common final pathway. We have found that growing seborrheic keratoses in patients without the sign of Leser-Trelat also have increased EGFR,” lending support to this hypothesis. Indeed, we have observed increased EGFR in seborrheic keratoses appearing with pregnancy,‘a where TGF-a should be secreted by the placenta and fetus. Thus, “tumors of pregnancy” may produce multiple seborrheic keratoses by a mechanism similar to that for the production of the sign of Leser - Trelat. The case shown in Fig 1 may have also occurred through a similar final common pathway, although hamartomas were the source of the proliferating factor instead of a carcinoma.
Recommended Evaluation Patients with eruptive seborrheic keratoses or a sudden increase in size and number of seborrheic keratoses should have a complete history and physical examination. This should include a complete cutaneous examination to check for the presence of tumors such as melanoma. Laboratory tests should include a complete blood count, chemistry profile, urinalysis, and chest x-ray. Other special laboratory tests such as mammography and prostate-specific antigen should be considered if the patient is in the age/sex group in which these tumors are likely. Because most of the internal malignancies reported with the sign of Leser - Trelat have been associated with adenocarcinomas of the gastrointestinal tract, specific examinations such as upper and lower gastrointestinal endoscopy (or radiography if endoscopy is not available) should be considered if a tumor is not found on the initial history and physical examination. Biopsy for confirmation of the diagnosis of a seborrheic keratosis is recommended, particularly for cases to be reported in the literature.
Conclusions The sign of Leser - T&at has been a source of controversy in the literature. Although more studies are required to further delineate the pathogenesis of this sign, evidence exists that the underlying malignancy secretes an epiderma1 proliferating factor (EGF, TGF-a, and insulin-like growth factor peptides have been suggested to date). Threshold levels of this proliferating factor may then cause eruptive seborrheic keratoses in a susceptible patient. Consequently, the constellation of the sudden eruption of multiple seborrheic keratoses or the sudden increase in multiple seborrheic keratoses should alert the clinician to the possibility of an underlying neoplasm. Concurrent signs such as pruritus and acanthosis nigricans should raise the index of suspicion for carcinoma.
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in a
sign. J Am Acad
59. Ellis DL, Kafka SF’, Chow JC, et al. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trelat, and multiple acrochordons. N Engl J Med 1987;317: 1582-7. 60. Halevy S, Sandbank M. Transformation of lymphocytoma cutis into a malignant lymphoma in association with the sign of Leser-Trelat. Acta Derm Venereol (Stockh) 1987;67:172-5. 61. Kameya S, Noda A, Isobe E, et al. The sign of Leser - Trelat associated with carcinoma of the stomach. Am J Gastroenterol 1988;83:664-6. 62. Fanti PA, Metri M, Patrizi A. The sign of Leser-Trelat associated with malignant melanoma. Cutis 1989;44:39-41. 63. Benn JJ, Fiith GR, Sonksen PH. Metabolic effects of an insulin-like factor causing hypoglycaemia in a patient with a haemangiopericytoma. Clin Endocrinol (Oxford) 1990;32:769 - 80. 64. Mayou SC, Benn JJ, Sonksen PH, et al. Paraneoplastic rhinophyma and the Leser-Trelat sign. Clin Exp Dermatol 1989;14:253-5.
65. Kilmer SL, Berman B, Morhenn VB. Eruptive seborrheic keratoses in a young woman with acromegaly. J Am Acad Dermatol 1990;23:991-4. of 66. Wieselthier JS, Bhawan J, Koh HK. Transformation Sezary syndrome and the sign of Leser- TrClat: A histopathologic study. J Am Acad Dermatol 1990;23:520-2. 67. Tajima H, Mitsuoka S, Ohtsuka E, et al. A case of hepatocellular carcinoma with the sign of Leser-TrClat: A possible role of a cutaneous marker for internal malignancy. Jpn J Med 1991;30:53-6. 68. Schwartz RA, Helmold ME, Janniger CK, et al. Sign of Leser-Trelat with a metastatic mutinous adenocarcinoma. Cutis 1991;47:258-60. 69. Schwengle LEM, Rampen FHJ, Wobbes TH. Seborrheic keratoses and internal malignancies. A case control study. Clin Exp Dermatol 1988;13:177-9. 70. Grob JJ, Rava MC, Gouvemet J, et al. The relation between seborreic keratoses and malignant solid tumours. Acta Derm Venereol (Stockh) 1991;71:166-9. 71. Lindelof B, S&urge&son B, Melander S. Seborrheic keratoses and cancer. J Am Acad Dermatol 1992;26:947-50. 72. Leser-Trelat sign. In: Lever WF, Schaumburg-Lever G, editors. Histopathology of the skin. 7th ed. Philadelphia: JB Lippincott, 1990: 532-3. 73. Rafal ES, Griffiths CEM, Ditre CM, et al. Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage. N Engl J Med 1992;326:368-74. 74. Curth HO. Skin lesions and internal carcinoma. In: Andrade R, Gumport SL, Popkin GL, et al, editors. Cancer and the skin. Philadelphia: WB Saunders 1976;2:1308-41. 75. Orth DN. Ectopic hormone production. In: Felig P, Baxter JD, Broadus AE, et al, editors. Endocrinology and metabolism. New York: McGraw-Hill, 1987: 1692-1735. Derynck R, Goeddel DV, Ullrich A, et al. Synthesis of mes76. senger RNAs for transforming growth factors (Y and /? and the epidermal growth factor receptor by human tumors. Cancer Res 1987;47:707- 12. 77. Nanney LB, Ellis DL, Levine J, et al. Epidermal growth factor receptors in idiopathic and virally induced skin diseases. Am J Path01 1992;140:915-25. 78. Ellis DL, Nanney LB, King LE. Increased epidermal growth factor receptors in seborrheic keratoses and acrochordons of patients with the dysplastic nevus syndrome. J Am Acad Dermatol 1990;23:1070-7.
T
he sign of Leser - Trelat is usually defined as the eruptive appearance of numerous seborrheic keratoses or the sudden increase in the number and size of previous seborrheic keratoses in association with an internal malignancy.’ Difficulties with this definition include how “eruptive” is defined, what a “significant” increase in number and size of previous seborrheic keratoses is, and that the sign has been reported in non-“internal” cancers such as melanomas and cutaneous T-cell lymphomas. Nevertheless, the sign of Leser - Trelat as defined is useful for suggesting when an underlying malignancy should be sought.
History The paraneoplastic syndrome of eruptive seborrheic keratoses associated with an internal malignancy is historically connected with the German surgeon Edmund Leser and the French surgeon Ulysse Trelat, who independently described the appearance of cutaneous senile angiomas as a sign of mammary carcinoma and visceral malignancies in the 1890s. l-3 Hollander may be the first author to associate seborrheic keratoses with internal malignancy.” Although the “sign of Leser - Trelat” may thus be a misnomer, the cutaneous paraneoplastic syndrome is deeply entrenched in the literature, and should be used to maintain continuity.
Incidence The incidence of the sign of Leser-Trelat is unknown. Table 1 is a modification and update of a table from the
excellent review article by Holdiness.5 Most reports have been case reports, with no large series studied. Two papers attempted to define the incidence of the sign of Leser-Trelat by studying patients with internal malignancies in comparison with age-matched control patients.69J0 Unfortunately, both of these studies were small (3669 and 82’O patients and controls, respectively). Neither of these studies showed an increase in the eruptive appearance of seborrheic keratoses in patients with malignancies. As we found 68 cases of the sign of LeserTrelat described in the literature, one would predict its incidence is relatively rare. These small negative studies do not tell whether the sign of Leser-Trelat is rare (as predicted from the literature) or nonexistent. Recently, 1752 consecutive cases of seborrheic keratoses were studied for the sign of Leser-Trelat.‘l Six patients with eruptive seborrheic keratoses and an associated malignancy consistent with the sign of Leser-T&at were found. There were also five control patients who had eruptive seborrheic keratoses, but without cancer. Lindelof et al concluded that eruptive seborrheic keratoses were not related to internal cancer risk’*; however, this retrospective review of patient records reported one of the control patients was pregnant, and whether other control patients received extensive workups to rule out small tumors (such as gastrointestinal villous adenomas) or other sources of growth factors underlying their eruptive seborrheic keratoses was not reported. Whether eruptive seborrheic keratoses are related to internal cancer risk if other sources of growth factors are eliminated is therefore still unknown.
Clinical Manifestations From the Division of Dermatology, Department ofMedicine, Vanderbilt University School of Medicine, Nashville, Tennessee. Address correspondenceto: Darrel L Ellis, MD, c/o Carolyn W. Caldwell, 1212 21st Avenue South, 608 Medical Arts Building, Nashville, TN 37212-1226.
0 2993 by Elsevier Science Publishing Co., Inc.
l
0738-081x/93/$6.00
The sign of Leser - Trelat as defined in this article requires the sudden appearance of seborrheic keratoses or the sudden increase in the number and size of seborrheic keratoses and an associated malignancy. Some authors have
141
142
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AND
Clinics in Dermatology 1993;11:141-148
YATES
Table 2. Sign of Leser-Trilat:
Summary of Case Reports
Age/Sex
Pruritus
AN*
SK Onset? (Months)
Carcinoma occulturn AC head of pancreas AC breast AC stomach
62F 64M 32F 45M
+ -
+ + +
11 7 6 after 1
56F 46M 58M 54F 58M 69M
+ + -
+ + + + + -
8 5 after 6 1 after 24 after NR
16
AC ovaries AC stomach AC stomach AC uterus AC stomach Undifferentiated Ca AC cecum
84F
+
-
1
12 13 14 15 16
17 18 19 20 20
CTCL (Sezary) AC stomach AC prostate AC transverse colon AC rectum
55M 63M 64M 72M 67F
+ -
+ -
4
17 18 19 20 21 22 23
20 21 22 23 24 25 26
AC sigmoid colon Gastric neoplasm AC stomach Hepatoma AC stomach SCC lung AMML
71M 74M 63M 72M 71F 69M 72M
+ + + + -
+ + -
NR 3 10 after NR NR Concurrent Concurrent
24
27
Lymphoma
73M
+
-
After/NR
25 26 27
27 28 29
61M 64F 62F
+ -
+ -
30
CTCL AC stomach AC kidney and spinal cord meningioma Myelogenous leukemia
66F
-
-
31 31 32 33
CTCL SCC lung AC duodenum AC stomach and rectosigmoid
87M 49M 63M 69M
+ + -
-
34 35
AC bile duct Lymphocytic lymphoma, poorly differentiated AC stomach AC gallbladder Lymphocytic lymphoma, poorly differentiated, and AC rectosigmoid Leiomyoblastoma ileum AC stomach Small cell Ca lung Intihrating ductal Ca breast (patients 41 and 42) AC uterus myometrium Ductal Ca breast AC breasts
70F 63M
+ -
-
62M 56F 59F
+ + -
+ + -
2 Few months before 2 3 2
62M 43M 72M 41F 67F 57F 46F 61F
+ + +
+ -
NR 4 Concurrent 6 3 Weeks NR Concurrent
Patient
5 6 7 8 9 10
29 30 31 32
Malignancy
Reference
35 36 37
36 37 38
38 39 40 41 42 43 44 45
39 40 41 42 42 43 44 45
bronchogenic
2 after 2.5 5 6 Concurrent 17 after 12 2
Correlation of SK and Tumor Regression NR NR Regressed Increased 6 months postop New SKs postop NR NR NR NR NR Decreased postop NR NR NR NR Initially decreased /XRT Persisted postop NR NR NR Decreased postop Decreased postop Decreased with chemoTx Decreased with chemoTx NR NR NR Inflamed with chemoTx Decreased with e beam NR NR Resolved after surgery for tirst AC NR NR NR NR Persisted and increased in size/number during chemoTx NR NR Increased until death No change postop Increased postop NR Increased after TX NR
Histology NR SK NR AN, verrucous hyperplasia AN AN AN AN, SK AN, SK NR Acanthosis/ hyperplasia NR AN NR NR NR NR SK Keratosis NR AN NR SK SK NR AN, SK SK
NR NR NR NR NR SK SK SK, AN SK SK
SK NR SK SK SK NR SK SK
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Clinics in Dermatology 1993;21:142-148
SIGN
AND
YATES
143
OF LESER - TRkLAT
Table 1. Sign of Leser-Trilat: Summary of Case Reports (Continued) SK Onsett
Age/Sex
Pruritus
AN*
62M 79F 56F
+ + -
-
+
14 after Concurrent 1 after
AC breast and parotid gland tumor Neurolibrosarcoma
58F
+
+
5 after
40F
-
-
16 after
Non-Hodgkin’s lymphoma, poorly differentiated
80F
NR
-
AC esophagus CTCL SCzary/CTCL
69F 61F 71F
+ + +
-
54
Lung Ca (moderately differentiated SCC and AC)
71M
NR
+
56 57 58
55 56 57
Leiomyosarcoma stomach Ovarian AC Intracranial germinoma
41M 76F 22M
+ + NR
-
59
58
Lymphocytic lymphoma, nodular, poorly differentiated
48F
-
-
60 61 62
59 60 61
Malignant melanoma Lymphoma (mixed cell) Gastic Ca
54M 64M 54F
NR + -
-
63 64 65
62 63,64 65
Malignant melanoma Hemangiopericytoma Pituitary tumor and acromegaly
69M 42F 26F
+ NR +
66 67 68
66 67 68
CTCL/SCzary Hepatocellular Ca Mutinous AC, metastatic to liver
58M 57M 59F
+ + -
Malignancy
Patient
Reference
46 47 48
46 46 47
SCC lung AC unknown AC breast
49
47
50
48
51
49
52 53 54
50 51 52‘53
55
origin
+
-
+
-
-
-
-
(Months)
Concurrent
3 2 12/Concurrent erythroderma NR
24 8 1 after 5 - 6 after
3 19
Correlation of SK and Tumor Regression Decreased postop Unchanged with chemoTx Unchanged postop Appeared after chemoTx Persisted after chemo/ XRT (tumor response?) Increased with mets Decreased with PUVA Decreased with chemoTx Decreased postop, increased as tumor spread Some decrease postop NR Onset: tumor lysis, decreased after XRT Decreased with treatment,increased with mets Decreased postop Unchanged after XRT
Decreasedpostop, increased with mets Unchanged postop Unchanged postop
Decreasedpostop/ post-XRT Decreased with e beam NR NR
Histology SK, AN NR SK NR
SK NR
SK NR SK
SK, AN
NR SK SK NR
SK, AN, PEP SK SK SK SK SK SK/lymphoma SK SK
*AN, acanthosis ni@canr SK seborrheic keratosis; AC, adenocarcinoma; NR not reported; Ca, cancer; XRT, radiation therapy; SCC, squamous cell carcinoma; AMMO ac,,te leukemia; chemoTx, chemotherapy; CTCL, cutaneous T-cell lymphoma; e beam, electron beam; TX, treatment; mets, metastases; pw~, psoralen wirh ultraoioletA light; FEP, fibroepithelial polyp. t Onset of seborrheic keratoses in months prior to the diagnosis of cancer. Modified, with permission, from HoZdiness.5
myelOmOnOqtic
emphasized the pattern of seborrheic keratoses, for example, the “Christmas tree” and “splash” patterns reported in leukemias and IymphomaP; however, similar patterns may also be observed in patients without an associated malignancy. Figure 1 shows the back of a patient with eruptive seborrheic keratoses, which are clinically typical of the appearance of the sign of Leser-Trelat. He had benign hamartomas of the lung, and therefore by definition did not have the sign of Leser-Trelat; however, this case points out possible similar pathophysiologic mechanisms for benign and malignant sources of eruptive seborrheic keratoses (see Pathophysiology).
Previous authors have reported the association of acanthosis nigricans and pruritus with the sign of LeserTrelat. In our review of the literature, we found associated acanthosis nigricans in 29% of the patients reported (20/ 68). Pruritus was present in 5 1% of the cases that could be assessed (32/63). Both acanthosis nigricans and pruritus were present in 16% of the cases (11/67). The seborrheic keratoses found in the sign of LeserTrilat are similar in clinical appearance to normal seborrheic keratoses (Fig 2). Biopsy-proven seborrheic keratoses were found in 57% of the cases (39/68). Anatomic locations of the seborrheic keratoses were similar to those
144
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Clinics in Dermatology
YATES
1993;11:241-148
Table 2. Malignancies Associated With the Sign of Leser-Tre’lat
Figure 1. Photograph of the back of a patient who had the eruptive onset of seborrheic keratoses associated with hamartomas of the lung. The clinical picture is consistent with that seen in the sign of Leser-Tre’lat, although the associated tumor was benign.
observed for seborrheic keratoses in the general population. Most lesions were on the back and chest (76%), followed by the extremities (38%), face (21%), abdomen (15%), neck (13%), axillae (6%), generalized (6%), and groin (3%). The upper extremities were more frequently involved than the lower extremities (35% versus 25%).
Figure 2. Closeup photograph of a seborrheic keratosis on the back of the patient in Fig 1, demonstrating the ordina y appearance of the seborrheic keratosis.
Adenocarcinoma Gastrointestinal Gynecologic Breast Unknown primary Prostate Kidney Lymphoproliferative Squamous cell carcinoma of lung Breast (ductal) Melanoma Hepatocellular Not reported Miscellaneous (one of each) Leiomyoblastoma Lung (small cell) Neurofibrosarcoma Leiomyosarcoma (stomach) Germinoma (intracranial) Hemangiopericytoma Pituitary tumor Undifferentiated bronchogenic Meningioma (spinal cord)
34/68=50% 22/68=32% 4/68=6% 4/68=6% 2/68=3% l/68 = 1.5% l/68 = 1.5% 14/68 = 20.6% 4/6&?=6% 2/68=3% 2/68=3% 2/68=3% 2/6&3=3% l/68=1.5%
Histopathology The histopathology of seborrheic keratoses found in the sign of Leser - TrClat is identical to that of common seborrheic keratoses.72 The hyperkeratotic form of seborrheic keratosis is also indistinguishable from acanthosis nigricans.72This suggests possible similar mechanisms of pathophysiology for the two lesions.
Associated Malignancies The type of malignancy most commonly associated (50%) with the sign of Leser-Trelat is adenocarcinoma (Table 2). Adenocarcinoma of the gastrointestinal tract is responsible for 32% of the total cases reported. Lymphoproliferative disorders are responsible for 21% of the cases, although some of these cases may have been related to cutaneous inflammation leading to increased seborrheic keratoses. We have attempted to eliminate from our review cases in which cutaneous inflammation appeared to be the source of increased seborrheic keratoses.
Laboratory Findings The laboratory findings are those associated with the tumor involved. In addition, one group has reported a slight elevation of epidermal growth factor (EGF) in the urine,61 another found an increased insulin-like growth
ELLIS AND YATES SIGN OF LESER - TRkLAT
Clinics in Dermatology 2993:11:141- 148 factor,63 and we found transforming growth (TGF-a) to be increased in the urine.59
Differential
factor (Y
Diagnosis
The most difficult element of the sign of Leser-Trelat is discerning if the seborrheic keratoses truly had a recent eruptive onset or increase in size and number. Some authors suggest that older patients may not know whether their seborrheic keratoses have recently changed. In our experience, although the eruptive onset of seborrheic keratoses is rare, the patient usually is quite cognizant of it. The largest segment of the population with multiple seborrheic keratoses probably comprises “normal” patients who have slowly acquired the lesions over several years. These patients do not require extensive examination for carcinoma. Other causes of eruptive seborrheic keratoses, such as pregnancy (see Pathophysiology), also need to be ruled out.
Treatment The initial treatment for the sign of Leser - Trelat is treatment of the underlying carcinoma. In 56% of cases in which responses of seborrheic keratoses to treatment have been recorded, treatment resulted in involution of the seborrheic keratoses. Seborrheic keratoses are benign and do not require treatment; however, for troublesome lesions (irritated or bleeding), physical treatments such as cryosurgery, shave biopsy, electrodesiccation, and curettage may be used. For smaller macular lesions, topical retinoic acid may be useful. 73As the pathogenesis of seborrheic keratoses becomes understood, new therapies should evolve.
Pathogenesis Criteria for paraneoplastic syndromes have been defined by Curth” and Orth. 75According to Curth, (1) the tumor and the paraneoplastic syndrome have a simultaneous onset; (2) the course of both conditions is parallel; (3) a specific tumor occurs in connection with a certain paraneoplastic sign; (4) the dermatosis is usually rare; and (5) there is a high percentage of association between the two conditions. Orth’s Clinical criteria consist of association of a neoplasm with a paraneoplastic syndrome; association of a neoplasm with inappropriately elevated plasma or urine hormone levels; failure of plasma or urinary hormone levels to respond to normal homeostatic suppres-
145
sion; absence of other possible causal mechanisms; fall in hormone levels after tumor-specific therapy; arteriovenous step-up gradient of the hormone across the tumor capillary bed; and presence of the hormone in tumor tissue. Orth’s laboratory criteria are in vitro hormone synthesis and release by tumor tissue and presence of hormone-specific mRNA in tumor tissue. Some or all of these criteria should be met to establish the specific etiologic agent(s) of a cutaneous paraneoplastic syndrome; however, even for most commonly accepted cutaneous paraneoplastic syndromes, the criteria of Orth have not been completely met. Orth’s criteria do outline a clinical and laboratory method of associating a paraneoplastic syndrome with a given tumor, in contrast to the purely clinical criteria of Curth. Several tumors might also produce the same “hormone(s)” that causes a given paraneoplastic syndrome, although some tumors may be more likely to overproduce the hormone than others. The sign of Leser-Trelat has been postulated to be caused by tumor-secreted “growth factors,” which result in the epidermal hyperproliferation that produces multiple seborrheic keratoses. Curry and King first suggested that EGF may be a growth factor with potential to cause the sign of Leser- Trelat, although the patient they studied did not have elevated levels of EGF.32 Kameya et al, however, found slightly elevated levels of EGF in a 24hour urine specimen from a patient with advanced gastric cancer whose seborrheic keratoses had faded with initial resection of the tumor, but returned when the cancer retumed.61 Horiuchi et al observed keratinocyte proliferation on incubation with preconditioned medium from peripheral blood lymphocytes from a patient with Sezary syndrome and the sign of Leser-Trelat.53 The factor responsible for the observed proliferation in their study was not EGF immunologically. Benn et al found a circulating insulin-like growth factor in a patient with a hemangiopericytoma, fasting hypoglycemia, and the sign of Leser Trelat.63 We observed a man with the sign of Leser-Trelat, acanthosis nigricans, multiple acrochordons, and cutaneous melanoma.59 In this patient, removal of the primary melanoma resulted in the simultaneous involution of his seborrheic keratoses, skin tags, and acanthosis nigricans. Although his urinary level of EGF was within the normal range for his age and sex, TGF-a observed in the urine preoperatively resolved postoperatively. The patient’s seborrheic keratoses, acrochordons, and acanthosis nigricans biopsy specimens all had elevated levels of EGF receptor (EGFR) by immunohistochemistry preoperatively; these normal returned to postoperatively. The EGFR is a common receptor for the EGF and TGF-c~ ligands, and melanomas are known to secrete TGF-cx.‘~ We
146
ELLIS AND YATES
Clinics in Dermatology 1993;11:141-148
therefore postulated that TGF-cr produced by the melanoma in this case caused the sign of Leser-TrClat. We suggest the sign of Leser-Trelat is the result of a tumor secreting a factor causing epidermal proliferation (such as TGF-cu), which results in the sudden appearance of multiple seborrheic keratoses in genetically predisposed patients. When the carcinoma increases the level of the epidermal proliferation factor to a critical threshold level, the sudden eruption of multiple seborrheic keratoses may then occur. A genetic susceptibility to developing multiple seborrheic keratoses is also required; otherwise more cancer patients would be expected to have the sign of Leser - Trelat. Multiple seborrheic keratoses are common, and often genetically linked. Both common acquired benign seborrheic keratoses and the sign of Leser-TrClat may occur through a common final pathway. We have found that growing seborrheic keratoses in patients without the sign of Leser-Trelat also have increased EGFR,” lending support to this hypothesis. Indeed, we have observed increased EGFR in seborrheic keratoses appearing with pregnancy,‘a where TGF-a should be secreted by the placenta and fetus. Thus, “tumors of pregnancy” may produce multiple seborrheic keratoses by a mechanism similar to that for the production of the sign of Leser - Trelat. The case shown in Fig 1 may have also occurred through a similar final common pathway, although hamartomas were the source of the proliferating factor instead of a carcinoma.
Recommended Evaluation Patients with eruptive seborrheic keratoses or a sudden increase in size and number of seborrheic keratoses should have a complete history and physical examination. This should include a complete cutaneous examination to check for the presence of tumors such as melanoma. Laboratory tests should include a complete blood count, chemistry profile, urinalysis, and chest x-ray. Other special laboratory tests such as mammography and prostate-specific antigen should be considered if the patient is in the age/sex group in which these tumors are likely. Because most of the internal malignancies reported with the sign of Leser - Trelat have been associated with adenocarcinomas of the gastrointestinal tract, specific examinations such as upper and lower gastrointestinal endoscopy (or radiography if endoscopy is not available) should be considered if a tumor is not found on the initial history and physical examination. Biopsy for confirmation of the diagnosis of a seborrheic keratosis is recommended, particularly for cases to be reported in the literature.
Conclusions The sign of Leser - T&at has been a source of controversy in the literature. Although more studies are required to further delineate the pathogenesis of this sign, evidence exists that the underlying malignancy secretes an epiderma1 proliferating factor (EGF, TGF-a, and insulin-like growth factor peptides have been suggested to date). Threshold levels of this proliferating factor may then cause eruptive seborrheic keratoses in a susceptible patient. Consequently, the constellation of the sudden eruption of multiple seborrheic keratoses or the sudden increase in multiple seborrheic keratoses should alert the clinician to the possibility of an underlying neoplasm. Concurrent signs such as pruritus and acanthosis nigricans should raise the index of suspicion for carcinoma.
References 1. Rampen FHJ, Schwengle LEM. The sign of Leser-Trelat: Does it exist? J Am Acad Dermatol 1989;21:50-5. 2. De Bersaques J. Sign of Leser-Trelat Dermatol 1985;12:724.
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3. Leser E. Ueber ein die Krebskrankheit beim Menschen haufig begleitendes, noch wenig bekanntes Symptom. Munthen Wochnschr 1901;48:2035 - 6. 4. Hollander E. Beitrage zur Fruhdiagnose des Darmcarcinoms (Hereditatsverhaltnisse und Hautveranderungen). Dtsch Med Wochnschr 1900;26:483-5. 5. Holdiness MR. The sign of Leser-T&at. 1986;25:564-72.
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6. Shelly WB, Crissey JT, Stokes JH, editors. Sigmund Pollitzer. Classics in clinical dermatology. Springfield: Charles C Thomas, 1953: 240-5. 7. Gougerat H, Duperrat B. Dermatose verruqueuse “montrite” dun cancer visceral. Ann Dermatol Syph 1942; 2:193-9. 8. Josserand A, Dargdent M, Mayer M. Evaluation et involution siumultanees de car&rose du sein et de venues de la region mammaire. Presse Med 1948;56:674. 9. Schwartz B. Acanthosis nigricans. Proc R Sot Med 1952;45:466. 10. Dingley ER, Marten RH. Adenocarcinoma of the ovary presenting as acanthosis nigricans. J Obstet Gynaecol Br Emp 1957;64:898-900. 11. Sneddon IB, Roberts JBM. An incomplete form of acanthosis nigricans. Gut 1962;3:269 - 72. 12. Ronchese F. Keratoses, cancer and the sign of Leser-Trelat. Cancer 1965;18:1003-6. 13. Curth HO. The necessity of distinguishing three types of acanthosis nigricans. In: Pillsbury EDM, Livingood CS, editors. Proceedings of the International Congress of Der-
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20. Liddell K, White JE, Caldwell IW. Seborrheic keratoses and carcinoma of the large bowel. Br J Dermatol 1975;92: 449-52. 21 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. 22. White H. Acanthosis nigricans and wart-like lesions associated with metastatic carcinoma of the stomach. Cutis 1976;17:931-3. 23. Harrington CI. Leser-Trelat sign with porphyria cutanea tarda and malignant hepatoma. Arch Dermatol 1976; 112:730. acanthosis nigricansA 24. Hage E, Hage J. Malignant paraendocrine syndrome. Acta Derm Venereol (Stockh) 1977;57:169-72. 25. Doll DC, McCagh MF, Welton WA. Sign of Leser-Trelat. JAMA 1977;238:236-7. 26. Greer KE. Leser-TrPlat associated with acute leukemia. Arch Dermatol 1978;114:1552. 27. Safai B, Grant JM, Good RA. Cutaneous manifestations of internal malignancies (II): The sign of Leser-Trelat. Int J Dermatol 1978;17:494-5. 28. Schwartz RA, Burgess GH. Florid cutaneous papillomatosis. Arch Dermatol 1978;144:1083-6. 29. Diaz EG, Leviatan A, Okom E. Renal adenocarcinoma meningioma. Arch Dermatol 1979;115:1286.
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30. Kechijian I’, Sadick NS, Mariglio J, et al. Cytarabine-induced inflammation in the seborrheic keratosis of LeserTrelat. Ann Intern Med 1979;91:868-9. 31. Lambert D, Fort M, Legoux A, et al. The signe de LeserTrelat. A propos de 2 observation. Ann Dermatol Venereol 1980;107:1035-41. 32. Curry SS, King LE. The sign of Leser-Trelat. to1 1980;116:1059-60.
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