Coexistence of acanthosis nigricans and the sign of Leser-Trelat in a patient with gastric adenocarcinoma: A case report and literature review James S. M. Yeh, MB ChB, BSc, MRCea Stephanie E. Munn, MB BS, BSc, MRCea Tim A. Plunkett, MB BS, BSc, MRCeb Peter G. Harper, FRCP,b Deborah J. Hopster, MB ChB, BSc, MRCPath,C Anthony IX! du Vivier, MD, FRCPa
The association of acanthosis nigricans (AN) with the sign of Leser-Trelat (LT) and gastric carcinoma is rare. Our patient was a 69-year-old man, who presented with hematemesis; a stage IV poorly differentiated, diffuse type, adenocarcinoma of the gastric antrum was diagnosed. The AN was striking, with florid cutaneous papillomatosis that also involved the mucous membranes of the mouth and eyelids, and keratoderma. AN and the sign of LT predated tumor detection by 6 months and regressed after chemotherapy in parallel with reduction of the tumor load, demonstrating the dermatoses as paraneoplastic phenomena. The patient died 7 months after completion of chemotherapy, The coexistence of AN and the sign of LT should prompt a search for underlying malignancy, The pathogenesis of both dermatoses is discussed. (J Am Acad Dermatol 2000;42:3 57-62.)
alignant acanthosis nigricans (AN) and the sign of Leser-Trelat (LT) are rare dermatologic manifestations of internal malignancy, most commonly associated with gastric adenocarcinoma.l-8 Both dermatoses rarely coexist in a single patient. Since 1942,22 such cases have been cited in the literatures-7,9: 13 of these were associated with gastric carcinoma (including 1 with a coexisting breast cancer), others were cancers of the head of the pancreas, ovary, uterus, gallbladder, lung, breast, parotid gland, melanoma, and carcinoma occulturn. As far as we are aware, this is the 14th case of AN with the sign of LT secondary to an underlying gastric carcinoma to be reported. Fig 1. Right axilla. Gross acanthosis nigricans ated skin tags.
CASE REPORT ORrHO areM*ror~~~L
This supplement is made possible through an educational grant from Ortho Dermatological to the American Academy of Dermatology. From the Departments of Dermatologya and Pathology,c King’s College Hospital, and Guy’s and St Thomas’ Cancer Centre, Guy’s Hospita1.b London. Reprint requests: Dr Anthony W. du Vivier. Consultant Dermatologist, Department of Dermatology, King’s College Hospital, Denmark Hill, London. SE5 9RS. UK. Copyright 0 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/4/98957
A 69-year-old white male London bus conductor was admitted to King’s College Hospital in November 1996, after a significant hematemesis. He had been lethargic with night sweats for 11 months. Apart from decreased appetite, there had been no other symptoms of dyspepsia. He had noticed itchy “warty” skin lesions on the forearms 6 months previously,
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Fig 2. Mouth. Cutaneous papillomatosis. Large cauliflower-like/filiform papilloma in left corner of the mouth; there are also numerous papillomas with “warty” surface on lips and surrounding skin.
Fig 4. Right lower leg. Sign of Leser-Trelat.Numerous discrete yellow-brown papules with “stuck-on” appearance. Surface looks greasy, scaly,some with fissuring. These are seborrheic keratoses (acanthotic variant). On examination he was mildly obese with evidence of cardiovascular compromise, due to acute upper gastrointestinal bleed, and melena in the colostomy bag. The axillary skin was thickened and hyperpigmented, with brown elevated ridges. It had a velvety feel to the touch, with multiple skin tags and a marked decrease in hair (Fig 1). Similar appearances were observed in the groins and nape of the neck. There was papillomatous involvement of the skin of the limbs, trunk and face, mucous membranes of the mouth (Fig 2) and eyelids-the latter with associated irritation conjunctivitis. The palms and soles were hyperkeratotic with prominence of the fissures and slight hyperpigmentation (Fig 3). There were also numerous seborrheic keratoses (SK) on the limbs and trunk (Fig 4).
Fig 3. Right sole. Keratoderma. Weight-bearing areas are hyperpigmented, thickened with prominent fissures.
became widespread. In 1990, the patient had a Dukes’ B adenocarcinoma of the rectum removed surgically, followed by postoperative pelvic irradiation. No recurrence of the disease had been noted in 5 years of follow-up. There was no other past medical or family history of note. He was an ex-smoker.
Investigations Complete blood count showed hemoglobin 10.9 g/dL (13-16.5 g/dL), platelets 476 x 109/L (150-450 x 109/L), total white cell count 18.9 x 109/I. (4-11 x 109/L), neutrophils 15.86 x 109/L (2.5-7.5 x 109/L), and monocytes 1.74 x 109/L (0.2-l x 109/L). Prothrombin and activated partial thromboplastin times were normal. Fibrinogen count was >6 g/I (1.5-4.5 g/L). Electrolytes, including calcium, were normal. Urea 10.8 mmol/L (3.3-6.7 mmol/L), creatinine 119 ltmol/L (5-120 l.tmolLL), glucose 5.7 mmol/L (3-7.8 mmol/L), albumin 33 g/L (35-50 g/L), and other liver function tests were normal. C-reactive protein
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Eh et al 2.
5. Low-power view of squamous ture of dermal papillae, hyperkeratosis nification, X40.)
cell papilloma from corner of mouth. Filiform architecand acanthosis. (Hematoxylin-eosin stain; original mag-
Fig 6. Low-power view of gastric mucosa. Infiltration by poorly differentiated adenocarcinoma with “signet-ring” formation. Inset: High-power view of “signet-ring” carcinoma cells. (Hematoxylin-eosin stain; original magnification, X100; inset, original magnification, x400.)
191 mg/L (~5 mg/L), erythrocyte sedimentation rate 74 mmk (l-10 mm/h), IgA 7.3 g/L (0.78-4.8 g/L), and IgG and IgM titers were normal. The ABO blood group
was A Rb D positive.
Endoscopy revealed a 1 x l-cm gastric ulcer in the antral
as the source
biopsy specimen was not taken because of the risk of rebleeding. However, in view of the striking and rapidly progressive dermatoses in our patient, a second endoscopy was performed to obtain histology in the search for an underlying malignancy Histopathology
of the cauliflower-like
from the corner of the mouth showed filiform projections of the dermal papillae, with acanthosis and hyperkeratosis, features consistent with benign squamous papilloma (Fig 5). Histopathology of the endoscopic biopsy specimen showed a poorly differentiated gastric adenocarcinoma of the diffuse type with numerous “signet-ring” forms (Fig 6). Rapid urease was negative using the test for Helicobacterp-ylori Camp.ylobacter-like organism test (CLOtest). Chest radiograph was normal. Computed tomography (CT) of the abdomen and chest showed thickening
of the gastric
antral wall and lymphadenopathy in the celiac axis, left para-aortic, right paratracheal, precarinal, and subcarinal regions. No metastases were detected elsewhere in the abdomen and chest. Bone scan was negative for metastasis. A diagnosis of stage IV poorly differentiated, diffuse-type adenocarcinoma of the gastric antrum, associated with AN and the sign of LT was made. Management and progress The patient was resuscitated and commenced on a proton pump inhibitor with no further hematemesis. Later, the patient underwent 6 cycles of combination chemotherapy using epirubicin, cisplatin, and 5-fluorouracil. After 3 cycles, the papillomas on the mouth had resolved and there were fewer SK. A repeat CT showed marked reduction of the mediastinal lymphadenopathy and resolution of the abdominal lymphadenopathy The patient remained well for 6 months after completing chemotherapy with no recurrence of the perioral skin lesions, but died a month later (10 months after presentation).
DISCUSSION Since 2 independent descriptions of AN in 1890 by Pollitzerlo and Janovsky,ll a vast array of conditions have been reported in association with this sign,l-4,9,12-32 AhI 1s associated with both benign and malignant conditions. The majority (80%)2 are either idiopathic or associated with benign conditions such as obesity, insulin resistance, and congenital syndromes. At least 26 different tumors have been reported in association with malignant AN. The commonest histologic type is adenocarcinoma, of which 70% to 90% are located intra-abdominally and 55% to 61% are gastric adenocarcinomasl-*>14>17 In general, the clinical course of AN correlates with the evolution of the underlying tumor, which is often advanced. AN rarely predates the detection of the tumor by many years, eg, 6 to 16 years, in 5 cases reviewed by Curth et al.1 The major features of AN are darkening and thickening of the skin, simulating brown, elevated ridges with a velvety feel to the touch. The major flexures are most commonly involved and, rarely is the entire skin affected.1 Gross and eruptive AN with florid cutaneous papillomatosis and palmar/plantar keratoderma are features typical of malignant AN. In addition, the hair may be shed and the nails brittle or ridged.i,15,33 The histologic features of AN consist of hyperkeratosis, papillomatosis, and alternate areas of acanthosis and apparent thinning.i,2,34 The sign of LT, first described around 1890, denotes an eruption of numerous SK.35-3’ It is associated with both benign and malignant conditions.
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Pregnancy, certain benign tumors, and more than 32 different malignancies have been reported in association with this sign, gastric adenocarcinoma being the commonest.*-7,9,3a The sign of LT is associated with pruritus in 43% of malignant cases. In 20% of malignant LT cases, AN is also present or appears after a period.5 There may be considerable overlap between the histologic features of SK and the papilloma of [email protected]
Some regard the sign of LT as an early stage or incomplete form of ANQ41; however, this is inconsistent with the observation that the sign of LT has never been reported in conditions associated with benign AN. We believe AN and the sign of LT are 2 separate clinical entities and coexistence of both in a patient strongly suggests an underlying malignancy Recognition of the dermatoses in our patient played an important role in the diagnosis of his underlying malignancy. Both the dermatoses and lymphadenopathy regressed after chemotherapy, lending support to the paraneoplastic nature of the skin diseases. The dermatoses were unlikely to be associated with his previous rectal adenocarcinoma. Although recognized, this association is much less common than that with gastric adenocarcinoma, and furthermore the coexistence of both dermatoses has never been reported in colorectal cancer. A postmortem was not performed in our patient, therefore it is not known whether he died from progression of the gastric adenocarcinoma, or other causes. The pathogenesis of AN and the sign of LT is poorly understood. Both dermatoses are associated with a heterogeneous group of conditions, suggesting a multifactorial pathogenesis with a final common pathway that leads to epithelial cell hyperplasia, resulting in AN or the sign of LT. Not all persons with the associated conditions develop AN or the sign of LT, thus susceptibilities are involved. The genetic and environmental susceptibilities to malignant AN or the sign of LT are not known. No familial cases, racial variation in incidence, genetic syndromes, animal models, environmental control studies using twin, spouse, or adoption studies, or genetic markers for linkage/association have been reported for these dermatoses, in contrast to benign AN.4~1s~20~23~42~43 However, malignant AN and the sign of LT are particularly associated with gastric adenocarcinoma. The diffuse type gastric adenocarcinoma has a genetic susceptibility based on familial studies and its association with ABO blood group A.44-47 Therefore, one can postulate that genetic susceptibility is implicated in both dermatoses, should their association with the diffuse type gastric adenocarcinoma or a particular blood group be demonstrated. The association of a blood group with a disease
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means either the allele for that blood group is linked in disequilibrium with another gene that confers susceptibility to the disease, or that such association arises from a pleiotropic effect of the gene that determines the blood group antigen.“s We propose a S-hit model for the pathogenesis of malignant AN and the sign of LT: (1) development of a malignancy; (2) presence of an inducer, eg, an unidentified tumor product (or tumor-induced autoantibody), which may act as a ligand for growth factor receptor, or interfere with the normal insulin signaling,‘+9 resulting in unopposed insulin-mediated anabolic effects, on the epithelial cells; and (3) susceptibility of the epithelial cells to react characteristically to the inducer, eg, hyperplasia. Moreover, the critical process may be either tumor product production or target cell susceptibility to the tumor product, hence criterion (3) may not be necessary. In malignant AN, a positive correlation between the level of urine- or serum- transforming growth factor alpha (TGF-a) and the degree of AN has been reported in 2 patients previously,g, 50 consistent with TGF-a as the hypothetical inducer. However, a causal relationship cannot yet be established as TGFa was not demonstrated in the cutaneous lesions. Our S-hit model can explain the rare occurrence of malignant AN and the sign of LT. The increased association of either dermatosis with gastric adenocarcinoma may be due to the characteristics of the tumor’s mutagenesis producing the relevant inducer, or because susceptibility to each of the 3 conditions is somehow linked. We thank the Department of Medical Photography at King’s College Hospital for providing the clinical photographs, Dr Andrew Macpherson, PhD, MRCP for referring the patient to us for dermatologic assessment, and Dr Andrew Medford, MRCP for proof reading and comments. REFERENCES 1. Curth HO, Hilberg AW, Machacek GF. The site and the cancer associated with malignant acanthosis Cancer 1962;15:364-82. 2. Brown J, Winkelmann RK. Acanthosis cases. Medicine 1968;47:33-51.
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