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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2009 September 21; 15(35): 4372-4379

TOPIC HIGHLIGHT

Paraneoplastic dermatological manifestation of gastrointestinal malignancies
 

Lyubomir A Dourmishev, Peter V Draganov


Lyubomir A Dourmishev, Department of Dermatology and Venereology, Medical University, 1431 Sofia, Bulgaria

Peter V Draganov, Department of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, Florida 32610, United States

Author contributions: Dourmishev LA and Draganov PV contributed equaly to this work.

Correspondence to: Peter V Draganov, MD, Associate Professor of Medicine, Department of Gastroenterology, Hepatology and Nutrition, University of Florida, 1600 SW Archer Road, Room HD 602, PO Box 100214, Gainesville, FL 32610, United States. dragapv@medicine.ufl.edu

Telephone: +1-352-3922877  Fax: +1-352-3923618

Received: March 5, 2009       Revised: May 12, 2009

Accepted: May 19, 2009

Published online: September 21, 2009

 

Abstract

Numerous dermatological disorders have been associated with underlining malignancies of the gastrointestinal (GI) tract. Such cutaneous manifestations might have an important diagnostic value if they are the sole expressions of otherwise asymptomatic carcinomas. The recognition of some typical paraneoplastic dermatologic disorders can lead to the prompt diagnosis of the underlying malignancy, timely administration of therapy, and ultimately, better prognosis. In this review we discuss the most common paraneoplastic dermatological syndromes from the perspective of the practicing gastroenterologist. We also outline a comprehensive practical approach for the evaluation for occult malignancy in patients presenting with cutaneous findings potentially associated with GI cancers.

 

© 2009 The WJG Press and Baishideng. All rights reserved.

 

Key words: Paraneoplastic; Dermatological; Gastrointestinal; Cancer; Malingnancy

 

Peer reviewer: Vincent W Yang, Professor and Director, 201 Whitehead Research Building, 615 Michael Street, Atlanta, GA 30322, United States

 

Dourmishev LA, Draganov PV. Paraneoplastic dermatological manifestation of gastrointestinal malignancies. World J Gastroenterol 2009; 15(35): 4372-4379  Available from: URL: http://www.wjgnet.com/1007-9327/15/4372.asp  DOI: http://dx.doi.org/10.3748/wjg.15.4372

 

INTRODUCTION

Numerous cutaneous disorders have been associated with underlining malignancies of the gastrointestinal (GI) tract. In some cases the skin can be directly infiltrated by cancer cells that represent metastatic spread from a GI malignancy (e.g. a Sister Mary Joseph nodule). In other cases, the skin lesions are related to the underlying presence of malignancy, but they do not contain malignant cells and are referred to as paraneoplastic dermatological syndromes[1]. Some of them, such as Muir-Torre, Peutz-Jeghers, and Cronkhite-Canada syndromes, are inherited and are caused by genetic factors, others however, have unknown etiologies and unpredictable expression and prognosis.

Dermatologists have the advantage of recognizing certain cutaneous signs, which hint at underlying visceral malignancies. From a practical perspective, such cutaneous manifestations might have an important diagnostic value if they are the sole expressions of otherwise asymptomatic carcinomas. The recognition of some typical paraneoplastic dermatologic disorders can lead to prompt diagnosis of the underlying GI malignancy, timely administration of therapy, and ultimately, better prognosis. In this review we will discuss the most common paraneoplastic dermatologic syndromes from the perspective of the practicing gastroenterologist (Table 1).

 

ACANTHOSIS NIGRICANS

Acanthosis nigricans (AN) is a classic example of a paraneoplastic dermatosis, and its frequent relation with GI tract malignancies was emphasized by Darier at the end of the 19th century[2]. The disease initiates with symmetric skin hyperpigmentation in the axillary and inguinal folds, submammary region, around the mammilla, umbilical, and ano-genital regions. Later, the skin lesions can infiltrate and become slightly hyperkeratotic pigmented velvety plaques surrounded by acrochordons (Figure 1). The neck region is frequently affected in childhood. Similar pigmented papillomatous lesions can be observed on the mucous membranes of the oral cavity, nasal, and laryngeal mucosa, and vulva. The areola of the nipple can also be affected. Nails are brittle and hyperkeratotic, and leukonychia have been reported. Noncicatricial alopecia in the axilla and pubic regions is also possible.

AN can be idiopathic when related to endocrine disorders (obesity, insulin resistance, or overt diabetes mellitus), and only in some cases is it associated with malignancy[3]. Only 20 cases of oral malignant AN were reported in the English language literature from 1968 to 2002[4]. In malignancy-associated acanthosis nigricans the lesions are often more extensive and severe than when the cause is benign, and skin irritation can be a prominent and distressing symptom. Moreover, the skin lesions usually appear before the onset of any other GI symptoms[5]. Malignancy-associated acanthosis nigricans is frequently seen with GI cancers[6-8].

Anderson et al[8] presented a 66-year-old male patient with poorly differentiated, metastatic gastric adenocarcinoma, who complained of severe pruritus and developed severe AN on the chest and nipples. The patient was treated with 5-fluorouracil, cisplatin and epirubicin chemotherapy resulting in dramatic improvement of the dermatological disorder and quality of life; however, the patient died six months latter due to lymphangitic carcinomatosis. The authors assumed that factors affecting epidermal proliferation are involved because of the reduction in papillomatosis and increase in cutaneous pigmentation after chemotherapy administration[8]. Pentenero et al[4] reported a case of a 53-year-old man with gastric adenocarcinoma who suddenly developed hyperkeratotic, verrucous, slightly pigmented, brownish papules in the axillae and thickened mucosa with a velvety and papillomatous surface, without hyperpigmentation on the lips, buccal mucosa and palate. Skin biopsies, performed from the buccal mucosa and the axilla, confirmed the diagnosis of AN with mucosal localization[4].

Palmo-plantar keratoderma or “tripe palms” is a recognized feature of acanthosis nigricans and presents with epidermal thickening with a rugose appearance and broadened rete ridges bounded by deep sulci of the palms and fingers[4,9] (Figure 2). Breathnach and Wells describe five patients with palmo-plantar keratoderma and acanthosis nigricans associated with gastric adenocarcinoma and in two patients they found squamous cell carcinoma[9].

The exact pathophysiological mechanism of the paraneoplastic AN has not been well defined, but it could be related to cancer byproducts. Transforming growth factor alpha, structurally related to epidermal growth factor (EGF), has been considered as possible causative agent[3,4].

The prognosis of the malignancy associated acanthosis nigricans tends to be poor because the underlying malignancy appears to behave aggressively. The average survival time of patients with signs of paraneoplastic AN is two years, although cases in which patients have survived for more than 10 years have been reported. Importantly, older patients with new onset AN usually have associated internal malignancy and therefore targeted investigation should be carried out (see below).

 

ACROKERATOSIS PARANEOPLASTICA (BAZEX SYNDROME)

The first patient with this entity was described by Bazex et al[10] in 1965, as “paraneoplastic syndrome with hyperkeratosis of the extremities”. Clinical manifestations include erythematous or livid squamous plaques resembling psoriasis, which are symmetrically distributed in acral regions and affect mainly the hands, feet, ears, nose, elbows and knees[11]. Skin biopsies usually reveal nonspecific findings, including hyperkeratosis, acanthosis, parakeratosis, vacuolar degeneration, pigment incontinence, and a perivascular infiltrate of lymphocytes and histiocytes and occasionally dyskeratotic keratinocytes[11].

Bazex syndrome predominates in males over 40 years and is most commonly associated with squamous cell carcinoma (SCC) of the upper bronchial and GI tracts[11,12]. Adenocarcinomas of the stomach[13], colon[14], biliary system and hepatocellular carcinoma[11], are also described in the literature. In a retrospective study of the primary location of malignancies in 113 patients with Bazex syndrome, Bolognia et al[15] reported the following results: oropharynx and larynx (48.6%), lung (17.7%), unknown location (16%), esophagus (10.6%, one of them with an associated pyriform sinus carcinoma), and isolated cases in the prostate, liver, stomach, uterus, vulva, and bone marrow.

 

LESER-TRÉLAT SYNDROME

Ulysse Trélat (1884) and Edmund Leser (1901)[16], both surgeons, were the first to propose that multiple seborrheic keratoses could be associated with internal malignancy. Denucé, who was a resident of Trélat, wrote in 1899 that the professor had often stressed the symptom of “Trélat’s nevi” associated with deep tumors of the abdomen and pelvis in his lectures[17]. The indication of Leser-Trélat or Leser-Trélat syndrome (LTS) is an eruptive appearance of, or at least a sudden increase in, the number or size of multiple seborrheic keratoses in association with an internal malignancy[18,19]. No evidence of dermatitis or erythroderma precedes the seborrheic keratoses appearance on the skin and pruritus is a leading symptom in about half of the cases[20]. Seborrheic keratoses associated with malignancy show no clinical or histological differences compared to patients without neoplasia[21]. The majority of patients with LTS have adenocarcinomas, most commonly of the stomach[22,23], colon or rectum[19,21,24-28], and less frequently carcinomas of esophagus[29], duodenum[30], pancreas[31], gallbladder[32] or hepatocellular carcinoma[33].

We observed a 66-year-old man who presented with multiple flat, sharply demarcated, yellowish to brown lesions with a verrucous surface located mainly on the trunk arms and thighs, which were clinically very suggestive of seborrheic keratoses (Figure 3). The patient developed fever and night sweats. A barium enema detected a tumor in the rectum. Computed tomography (CT) showed no evidence of distant metastasis. The rectal lesion was removed surgically, and histology showed moderately differentiated rectal adenocarcinoma involving muscularis propria with no evidence of perirectal lymph node involvement. However, three months after the operation, seven lung metastases were visualized by CT. During courses of 5-fluorouracil, oxaliplatin and capecitabine chemotherapy, the cutaneous lesions markedly diminished but did not completely disappear[19]. We found 14 other published cases of Leser-Trélat syndrome associated with colorectal adenocarcinoma in the literature from 1972 to 2004[19].

About two-thirds of patients with LTS can have other paraneoplastic disorders, the most frequent of which is acanthosis nigricans, which accounts for one third of these cases[34]. Moreover, Andreev et al[35] considered that Leser-Trélat syndrome represents a particular clinical variant of acanthosis nigricans. The pathogenesis of LTS remains unclear. As in malignant acanthosis nigricans, an increased epidermal staining for the transforming growth factor alpha receptor has been observed[36].

 

MUIR-TORRE SYNDROME

In 1967 Muir et al[37], and later Torre[38], reported patients with multiple sebaceous neoplasms and visceral malignancies. Muir-Torre syndrome (MTS) is defined by the development of internal malignancy, most commonly colon cancer, in association with sebaceous adenomas and epitheliomas, sebaceous carcinomas and multiple or early-onset keratoacanthomas[39]. The syndrome has autosomal dominant inheritance, and is considered as a subtype of hereditary nonpolyposis colorectal cancer syndrome (HNPCCS). Sixty percent of patients with MTS have a strong family history of visceral malignancy and show clinicopathological overlap with HNPCCS[40]. The pathogenesis includes mutations in the DNA mismatch repair genes (MLH-1 or MSH-2)[39]. HNPCC and MTS usually result from an inherited defect in one allele of either MLH1 or MSH2[41]; however, Muir-Torre syndrome more commonly involves a mutation of MSH2, while HNPCC shows a roughly equal prevalence of MLH1 and MSH2[42].

Sebaceous gland tumors in MTS include sebaceous adenoma, sebaceous carcinoma and keratoacanthoma with sebaceous differentiation[40]. Sebaceous hyperplasia and ectopic sebaceous glands do not appear to be significant markers of the syndrome. Sebaceous adenoma is believed to be the most specific lesion of Muir-Torre syndrome and these can sometimes show cystic change or keratoacanthoma-like architecture[42]. Between 24%-30% of patients with MTS have sebaceous carcinomas[39,43].

Cancers of the GI tract comprise more than 60% of the visceral malignancies in MTS, and colorectal cancer is the predominant neoplasm[39,44]. Tumors are located predominantly in the proximal colon (cecum to splenic flexure), in contrast to the general populace, whose colorectal tumors are usually distal to the splenic flexure[44,45]. An association with colorectal adenomatous polyps was observed in 26% of patients with MTS[45].

Recently, a 54-year-old Japanese man with MTS who developed a sebaceous carcinoma and concurrently adenocarcinoma of the colon was reported[46]. A novel germline mutation of the MSH2 gene with duplication of the genomic region involving exon 7 was identified[46].

Multiple sebaceous tumors or sebaceous tumors occurring before the age of 50 years are strong indicators of Muir-Torre syndrome. Moreover, MTS should be suspected in all cases when sebaceous gland tumors or multiple keratoacanthomas have been diagnosed. Some authors suggest that all patients with sebaceous-gland neoplasms should be screened for MTS in contrast to those with keratoacanthomas because they are less likely to be markers of MTS[47]. All patients with MTS should undergo a colonoscopy to detect colorectal neoplasms.

 

PARANEOPLASTIC DERMATOMYOSITIS

The first report of paraneoplastic dermatomyositis (PDM) was by Stertz[48], who in 1916 observed a patient with proximal muscle weakness, eyelid changes, muscle biopsy evidence of myositis, associated with gastric cancer. Dermatomyositis (DM) is a rare idiopathic inflammatory myopathy that presents clinically with proximal muscle weakness and characteristic cutaneous manifestations[49]. Skin lesions can be classified as pathognomonic, characteristic, and compatible with DM[50]. The more specific or pathognomic manifestations of DM are the periorbital heliotrope rash, and erythematous maculo-papular lesions covering bony prominences, described by Gottron in 1931 and named after him as Gottron papules and Gottron sign[49,50]. The “Heliotrope” rash presents as a red to purple-colored confluent, macular erythema involving symmetrically the eyelids, upper cheeks, forehead, and the temples and is often associated with edema of the eyelids and periorbital tissues (Figure 4). Other characteristic skin lesions include: shawl sign (a violaceous erythema disposed in a “shawl” distribution over the neck, upper back, and shoulders), photosensitive poikiloderma, diffuse redness and shininess of the nail folds, “mechanic’s hands” hyperkeratosis, cutaneous calcinosis, and scalp erythema[49,51]. Other contemporary criteria for diagnosis of DM include the appearance of symmetric proximal muscle weakness, an elevation of serum skeletal-muscle enzymes levels, abnormal electromyography, features of inflammatory infiltration in muscle biopsy, autoantibodies against RNA syththetase antigens (Jo-1, PL-7, PL-12, and OJ) or against Mi2 or SRP  antigens in patients’ sera[52].

The increased risk for developing cancer in DM patients has been convincingly demonstrated in several studies from Sweden[53], Australia[54], and Scotland[55]. The malignancy can precede, occur concurrently with, or follow the diagnosis of dermatomyositis. In patients with dermatomyositis several predictive factors for the presence of underlying malignancy have been described including: age over 50 years, male gender, the presence of cutaneous necroses and ulcers, increased erythrocyte sedimentation rate and C-reactive protein, and highly elevated or normal serum creatinine kinase[56-58].

Different types of tumors are observed in dermato­myositis patients. Adenocarcinomas are the most common and, in general, the frequency of each cancer type corresponds to those in the general population. In a study of 750 patients with polymyositis or dermatomyositis in Sweden, Sigurgeirsson et al[53] reported that the colon (including the rectum) and the lungs were the most frequent cancer sites. Hatada et al[59] mentioned that in Japan, gastric cancer was the most frequent malignant disease (25.4%) among patients with dermatomyositis. In South-Eastern Asia, the incidence of nasopharyngeal carcinoma is elevated in the male population with or without dermatomyositis[60]. In another retrospective study, 12 patients with internal malignancy were described among group of 64 patients with polymyositis and 28 patients with dermatomyositis[61]. Of those 12 patients, four had GI tract malignancies (two male patients, 74- and 75-year-old respectively had gastric carcinoma; another 51-year-old female had pharyngeal carcinoma and one female had pancreatic cancer)[61]. From 1941 to 1988 only one case of paraneoplastic dermatomyositis associated with gastric cancer has been reported in Bulgaria[62]. Since then, twelve additional PDM cases have been documented[63]. Two of these 12 cases in our retrospective study of patients with PDM, had GI malignancy; a 54-year-old female who had rectal adenocarcinoma and a 64-year-old patient with pancreatic cancer[59].

Many authors have stressed the importance of early investigation targeted at detecting malignancy in dermatomyositis. A detailed search for malignancy should be carried out during the first three to five years after the disease onset, however the optimal cancer-screening regimen necessary for patients with a recently diagnosed myositis remains uncertain.

 

PARANEOPLASTIC PEMPHIGUS

Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease characterized by the production of various autoantibodies against plakin proteins in keratinocytes. The disease was described by Anhalt
et al[64] in 1990. Patients with paraneoplastic pemphigus
have to fulfill at least four of the following five criteria: polymorphic eruption on skin and mucous membranes, histopathological features that include intraepidermal acantholysis and dyskeratosis with vacuolar changes, intraepidermal and/or basal membrane zone deposition of IgG and C3 on direct immunofluorescence (IF), and serum autoantibodies against 250, 230, 210 and 190 kDa antigens (mainly desmoglein 1 and 3, periplakin and envoplakin) in immunoblotting[64,65].

The mucosal involvement includes erosions of the oral cavity, conjunctiva, pharynx, anogenital areas and even the GI mucosa[65,66]. Cutaneous manifestations of PNP are heterogeneous, and include vesicles and blisters, erythematous to violaceous maculae, papules, plaques, and even erythroderma (Figure 5). The morphology of the lesions resembles a variety of dermatological diseases, including pemphigus vulgaris, bullous pemphigoid, erythema multiforme, and lichen planus[64,66,67].

Paraneoplastic pemphigus cases have been reported more often in patients with a history of lymphomas, chronic lymphocytic leukemia, poorly differentiated sarcoma and Castleman’s disease. In a retrospective study of 163 cases with paraneoplastic pemphigus reported between 1990 and 2003 carcinomas were diagnosed in 14 cases; consisting of adenocarcinoma in seven, squamous cell carcinoma in two, multiple basal cell carcinomas in one, and bronchogenic carcinoma also in one patient[68]. Ostezan et al[69] presented a patient with severe mucocutaneous involvement of PNP associated with hepatocellular carcinoma. However, PNP is not always accompanied by neoplasia[69], suggesting that other factors such as drugs and inflammatory diseases can trigger autoantibody formation related to PNP in the absence of a neoplasm[70].

In 2001, Nguyen et al[71] proposed a new term for this disease-“paraneoplastic autoimmune multiorgan syndrome” (PAMS), which, according to them, reflects the presence of target antigens and the pathologic damage frequently occurring in multiple organ systems including lung, kidney, and muscle.

 

PEUTZ-JEGHERS SYNDROME (HEREDITARY INTESTINAL POLYPOSIS SYNDROME)

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder described in 1921 by Peutz, who noted a relationship between the intestinal hamartomatous polyps and mucocutaneous macules in a Dutch family[72]. The syndrome is caused by mutations in STK11/LKB1, serine/threonine kinase 11 genes, located on band 19p13.3[73].

Cutaneous lesions consist of 1-5 mm diameter hyperpigmented macules, irregularly distributed over the buccal mucosa, gums, hard palate and lips, mainly on the lower lip. Lentigines usually appear during early childhood, and have a tendency to increase in size[74]. Larger maculae (melanosis) are rarely seen over the back of the hands, the tips of the fingers and toes, and over the palms and soles[75].

GI tract manifestations include numerous intestinal polyps in the jejunum, ileum and less frequently in the colon, rectum, stomach and duodenum that are typical hamartomas[75]. Histology reveals pseudo invasion of the epithelial cells, forming benign glands surrounded by smooth muscle. About half of PJS patients die from cancer before the age of 60. The cumulative risk for developing GI tract associated cancers in patients with PJS aged 15-64 years varies according to the localization from 0.5% for the esophagus, 29% for the stomach, 13% for the small intestine, 36% for the pancreas to 39% for the colon and rectum[76].

 

CRONKHITE-CANADA SYNDROME

In 1955 Cronkhite et al[77] described two women with acquired generalized GI polyps with features of hamartomatous polyps and epidermal changes.

Cutaneous lesions in patients with Cronkhite-Canada syndrome (CCS) include hyperpigmented macules ranging from a few millimeters to 10 cm in diameter, localized on the dorsal surface of the hands, palms, arms, neck, face and scalp[74]. Fingernails and toenails have discoloration, atrophy, nail plate separation and shedding. Alopecia occurs rapidly and in some cases leads to total hair loss[74,78].

GI lesions in CCS are hamartomatous polyps histologically revealing pseudopolypoid-inflammatory changes. Although considered a benign condition, in 1967, Gomes da Cruz[79] reported an association of this syndrome with a cancer of the cecum and descending colon. Among 387 cases published in literature by the end of 2002, Cronkhite-Canada syndrome associated with colon cancer has been reported in 31 (8%) cases, and other 19 CCS patients (5%) had concomitant gastric cancer[80].

Some authors propose phenotypic overlap between the features of CCS, and Peutz-Jegher syndrome, particular in the morphology of cutaneous and intestinal lesions[81,82]. In contrast to PJS, however, no underlying genetic mechanism has been found so far in Cronkhite-Canada syndrome.

 

PARANEOPLASTIC HYPERTRICHOSIS LANUGINOSA ACQUISITA

In 1865, Turner reported a woman with breast cancer whose face and body in two or three weeks became covered with a thick crop of short and white downy hair[83]. Lanugo hairs are long, thin and unpigmented, affecting the face and spreading in a caudal direction on the entire integument. Paraneoplastic hypertrichosis lanuginosa acquisita (PHLA) is predominant in women, and colorectal carcinoma is the most frequently associated malignancy, followed by lung and breast cancer[84-86]. Patients usually have metastatic disease at the time of diagnosis and a poor prognosis[86]. PHLA is associated with other paraneoplastic disorders such as acanthosis nigricans (which supports the hypothesis of tumor-produced cytokines stimulation over hair follicles).

 

EVALUATION OF PATIENTS WITH DERMATOLOGICAL MANIFESTATIONS ASSOCIATED WITH GI MALIGNANCY

The described dermatologic syndromes are not always associated with malignancy, but in many cases can be idiopathic. Therefore the practicing physician is confronted with the great challenge of carrying out a comprehensive search for underlying cancer in a systematic and cost effective manner. There are no universally accepted algorithms for the scope of the evaluation in such a patient, but, in general, the work-up should be guided by the following principles: (1) Initial thorough medical history and physical examination (including rectal exam in both sexes, pelvic exam in women and prostate exam in men) followed by basic laboratory testing (complete blood count, erythrocyte sedimentation rate, serum chemistry panel, and urinalysis). At that point, targeted evaluation of any specific patient symptoms or laboratory abnormalities should be pursued (e.g. iron deficiency anemia should be investigated with colonoscopy and upper endoscopy); (2) If the patient is asymptomatic or has no risk factors for a particular type of cancer, age-appropriate cancer screening tests should be carried out (e.g. colonoscopy in patients older than 50); and (3) Limited additional testing, such as CT scan of the chest, abdomen, and pelvis, are recommended for patients with significantly increased risk of malignancy (e.g. smoking, positive family history for cancer). The role of screening with serum prostate specific antigen (PSA), CA125, and CA19-9 has not been well determined.

 

CONCLUSION

A wide variety of dermatologic signs have been associated with GI malignancy. Cutaneous manifestations might develop before the GI neoplasm is recognized and their prompt recognition can significantly aid in the diagnosis. Once one of the cutaneous lesions associated with GI cancer is diagnosed, an evaluation for underlying malignancy should be undertaken. The evaluation for cancer should start with thorough medical history, physical examination, and basic laboratory testing. In asymptomatic patients, age-appropriate cancer screening tests should be carried out. Targeted additional testing, such as CT scans of the chest, abdomen, and pelvis, is recommended for patients with significantly increased risk of malignancy.

 

REFERENCES

1      Andreev VC. Skin manifestations in visceral cancer. Curr Probl Dermatol 1978; 8: 1-168  PubMed   

2      Andreev VC. Acanthosis nigricans. Stomatologia 1963; 11: 5 (in Bulgarian) 

3      Schwartz RA. Acanthosis nigricans. J Am Acad Dermatol 1994; 31: 1-19; quiz 20-22  PubMed   DOI

4      Pentenero M, Carrozzo M, Pagano M, Gandolfo S. Oral acanthosis nigricans, tripe palms and sign of leser-trélat in a patient with gastric adenocarcinoma. Int J Dermatol 2004; 43: 530-532  PubMed   DOI

5      Nishidoi H, Koga S, Kanbe N. [Gastrointestinal carcinoma with skin diseases from the standpoint of surgery] Gan To Kagaku Ryoho 1988; 15: 1560-1563  PubMed   

6      Brown J, Winkelmann RK. Acanthosis nigricans: a study of 90 cases. Medicine (Baltimore) 1968; 47: 33-51  PubMed   

7      White H. Acanthosis nigricans and wart-like lesions associated with metastatic carcinoma of the stomach. Cutis 1976; 17: 931-933  PubMed   

8      Anderson SH, Hudson-Peacock M, Muller AF. Malignant acanthosis nigricans: potential role of chemotherapy. Br J Dermatol 1999; 141: 714-716  PubMed   DOI

9      Breathnach SM, Wells GC. Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy. Clin Exp Dermatol 1980; 5: 181-189  PubMed   DOI

10    Bazex A, Salvador R, Dupré A, Christol B. Syndrome paranéoplasique à type d’hyperkératose des extremités. Guérison après le traitement de l’épithelioma laryngé. Bull Soc Fr Dermatol Syphiligr 1965; 72: 182 

11    Bolognia JL. Bazex syndrome: acrokeratosis paraneoplastica. Semin Dermatol 1995; 14: 84-89  PubMed   

12    Estrela F, Pinto GM, Pinto LM, Afonso A. Acrokeratosis paraneoplastica (Bazex syndrome) with oropharyngeal squamous cell carcinoma. Cutis 1995; 55: 233-236  PubMed   

13    Votion V, Mineur P, Mirgaux M, Aupaix M. [Palmar and plantar hyperkeratosis associated with a gastric adenocarcinoma] Dermatologica 1982; 165: 660-663  PubMed   

14    Hsu YS, Lien GS, Lai HH, Cheng YS, Hu CH, Hsieh MC, Fang CL, Pan S. Acrokeratosis paraneoplastica (Bazex syndrome) with adenocarcinoma of the colon: report of a case and review of the literature. J Gastroenterol 2000; 35: 460-464  PubMed   DOI

15    Bolognia JL, Brewer YP, Cooper DL. Bazex syndrome (acrokeratosis paraneoplastica). An analytic review. Medicine (Baltimore) 1991; 70: 269-280  PubMed   DOI

16    Leser E. Ueber ein die Krebskrankheit beim Menschen haufig begleitendes, noch wenig gekanntes Symptom. Munchener. Med Wochenschr 1901; 51: 2035-2036 

17    Denucé M. A symptom of malignancy (symptom of Trélat’s noevi) applicable to the deep tumours of the abdomen and pelvis. Revue des maladies cancéreuses (Paris) 1899; 5: 146-156 

18    Rampen HJ, Schwengle LE. The sign of Leser-Trélat: does it exist? J Am Acad Dermatol 1989; 21: 50-55  PubMed   DOI

19    Dourmishev L. Multiple seborrheic keratoses associated with rectal adenocarcinoma. CEEDVA 2004; 6: 27-30 

20    Schwartz RA, Helmold ME, Janniger CK, Gascon P. Sign of Leser-Trélat with a metastatic mucinous adenocarcinoma. Cutis 1991; 47: 258-260  PubMed   

21    Cohn MS, Classen RF. The sign of Leser-Trélat associated with adenocarcinoma of the rectum. Cutis 1993; 51: 255-257  PubMed   

22    Yeh JS, Munn SE, Plunkett TA, Harper PG, Hopster DJ, du Vivier AW. Coexistence of acanthosis nigricans and the sign of Leser-Trélat in a patient with gastric adenocarcinoma: a case report and literature review. J Am Acad Dermatol 2000; 42: 357-362  PubMed   DOI

23    Kameya S, Noda A, Isobe E, Watanabe T. The sign of Leser-Trélat associated with carcinoma of the stomach. Am J Gastroenterol 1988; 83: 664-666  PubMed   

24    Liddell K, White JE, Caldwell IW. Seborrhoeic keratoses and carcinoma of the large bowel. Three cases exhibiting the sign of Lester-Trélat. Br J Dermatol 1975; 92: 449-452  PubMed   DOI

25    Hodak E, Halevy S, Ingber A, Engelstein D, Sandbank M. [Leser-Trélat sign in adenocarcinoma of the sigmoid colon--a rare clinical picture] Z Hautkr 1987; 62: 875-876  PubMed   

26    Heng MC, Soo-Hoo K, Levine S, Petresek D. Linear seborrheic keratoses associated with underlying malignancy. J Am Acad Dermatol 1988; 18: 1316-1321  PubMed   DOI

27    Bräuer J, Happle R, Gieler U, Effendy I. The sign of Lerser-Trélat: Fact and myth? J Eur Acad Dermatol Venereol 1992; 1: 77-8   DOI

28    Ginarte M, Sánchez-Aguilar D, Toribio J. Sign of Leser-Trélat associated with adenocarcinoma of the rectum. Eur J Dermatol 2001; 11: 251-253  PubMed   

29    Tutakne MA, Das KD, Upadhyaya VK, Ramachandra S, Narayanaswamy AS, Sarkar SK. Leser Trelat sign associated with carcinoma of gastro-oesophageal junction. Indian J Cancer 1983; 20: 32-34  PubMed   

30    Klimopoulos S, Kounoudes C, Pantelidaki C, Skrepetou K, Papoudos M, Katsoulis H. The leser-trelat sign in association with carcinoma of the ampulla of Vater. Am J Gastroenterol 2001; 96: 1623-1626  PubMed   DOI

31    Ohashi N, Hidaka N. Pancreatic carcinoma associated with the Leser-Trélat sign. Int J Pancreatol 1997; 22: 155-160  PubMed   

32    Kocyigit P, Akay BN, Arica E, Anadolu RY, Erdem C. Post-renal transplantation Leser-Trélat sign associated with carcinoma of the gallbladder: a rare association. Scand J Gastroenterol 2007; 42: 779-781  PubMed   DOI

33    Tajima H, Mitsuoka S, Ohtsuka E, Nakamura Y, Nakayama T, Satoh Y, Shima M, Nakata K, Kusumoto Y, Koji T. 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: 53-56  PubMed   

34    Holdiness MR. On the classification of the sign of Leser-Trélat. J Am Acad Dermatol 1988; 19: 754-757  PubMed   DOI

35    Andreev VC, Boyanov L, Tsankov N. Generalized acanthosis nigricans. Dermatologica 1981; 163: 19-24  PubMed   

36    Ellis DL, Kafka SP, Chow JC, Nanney LB, Inman WH, McCadden ME, King LE Jr. Melanoma, growth factors, acanthosis nigricans, the sign of Leser-Trélat, and multiple acrochordons. A possible role for alpha-transforming growth factor in cutaneous paraneoplastic syndromes. N Engl J Med 1987; 317: 1582-1587  PubMed   

37    Muir EG, Bell AJ, Barlow KA. Multiple primary carcinomata of the colon, duodenum, and larynx associated with kerato-acanthomata of the face. Br J Surg 1967; 54: 191-195  PubMed   

38    Torre D. Multiple sebaceous tumors. Arch Dermatol 1968; 98: 549-551  PubMed   

39    Cohen PR, Kohn SR, Kurzrock R. Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med 1991; 90: 606-613  PubMed   DOI

40    Schwartz RA, Torre DP. The Muir-Torre syndrome: a 25-year retrospect. J Am Acad Dermatol 1995; 33: 90-104  PubMed   DOI

41    Kruse R, Rütten A, Hosseiny-Malayeri HR, Bisceglia M, Friedl W, Propping P, Ruzicka T, Mangold E. "Second hit" in sebaceous tumors from Muir-Torre patients with germline mutations in MSH2: allele loss is not the preferred mode of inactivation. J Invest Dermatol 2001; 116: 463-465  PubMed   DOI

42    Lazar AJ, Lyle S, Calonje E. Sebaceous neoplasia and Torre-Muir syndrome. Curr Diagn Pathol 2007; 13: 301-319  PubMed   DOI

43    Cohen PR. Sebaceous carcinomas of the ocular adnexa and the Muir-Torre syndrome. J Am Acad Dermatol 1992; 27: 279-280  PubMed   DOI

44    Cohen PR, Kohn SR, Davis DA, Kurzrock R. Muir-Torre syndrome. Dermatol Clin 1995; 13: 79-89  PubMed   

45    Serleth HJ, Kisken WA. A Muir-Torre syndrome family. Am Surg 1998; 64: 365-369  PubMed   

46    Yanaba K, Nakagawa H, Takeda Y, Koyama N, Sugano K. Muir-Torre syndrome caused by partial duplication of MSH2 gene by Alu-mediated nonhomologous recombination. Br J Dermatol 2008; 158: 150-156  PubMed   

47    Ponti G, Losi L, Di Gregorio C, Roncucci L, Pedroni M, Scarselli A, Benatti P, Seidenari S, Pellacani G, Lembo L, Rossi G, Marino M, Lucci-Cordisco E, Ponz de Leon M. Identification of Muir-Torre syndrome among patients with sebaceous tumors and keratoacanthomas: role of clinical features, microsatellite instability, and immunohistochemistry. Cancer 2005; 103: 1018-1025  PubMed   DOI

48    Stertz G. Polymyositis. Berl Klin Wochenshr 1916; 53: 489 

49    Dourmishev LA, Dourmishev AL, Schwartz RA. Dermatomyositis: cutaneous manifestations of its variants. Int J Dermatol 2002; 41: 625-630  PubMed   DOI

50    Santmyire-Rosenberger B, Dugan EM. Skin involvement in dermatomyositis. Curr Opin Rheumatol 2003; 15: 714-722  PubMed   DOI

51    Kovacs SO, Kovacs SC. Dermatomyositis. J Am Acad Dermatol 1998; 39: 899-920; quiz 921-922  PubMed   DOI

52    Targoff IN, Miller FW, Medsger TA Jr, Oddis CV. Classification criteria for the idiopathic inflammatory myopathies. Curr Opin Rheumatol 1997; 9: 527-535  PubMed   DOI

53    Sigurgeirsson B, Lindelöf B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. A population-based study. N Engl J Med 1992; 326: 363-367  PubMed   

54    Buchbinder R, Forbes A, Hall S, Dennett X, Giles G. Incidence of malignant disease in biopsy-proven inflammatory myopathy. A population-based cohort study. Ann Intern Med 2001; 134: 1087-1095  PubMed   

55    Stockton D, Doherty VR, Brewster DH. Risk of cancer in patients with dermatomyositis or polymyositis, and follow-up implications: a Scottish population-based cohort study. Br J Cancer 2001; 85: 41-45  PubMed   DOI

56    Basset-Seguin N, Roujeau JC, Gherardi R, Guillaume JC, Revuz J, Touraine R. Prognostic factors and predictive signs of malignancy in adult dermatomyositis. A study of 32 cases. Arch Dermatol 1990; 126: 633-637  PubMed   DOI

57    Dourmishev LA. Dermatomyositis associated with malignancy. 12 case reports. Adv Exp Med Biol 1999; 455: 193-199  PubMed   

58    Chen YJ, Wu CY, Shen JL. Predicting factors of malignancy in dermatomyositis and polymyositis: a case-control study. Br J Dermatol 2001; 144: 825-831  PubMed   DOI

59    Hatada T, Aoki I, Ikeda H, Tamura T, Okada K, Nakai T, Utsunomiya J. Dermatomyositis and malignancy: case report and review of the Japanese literature. Tumori 1996; 82: 273-275  PubMed   

60    Leow YH, Goh CL. Malignancy in adult dermatomyositis. Int J Dermatol 1997; 36: 904-907  PubMed   DOI

61    Wakata N, Kurihara T, Saito E, Kinoshita M. Polymyositis and dermatomyositis associated with malignancy: a 30-year retrospective study. Int J Dermatol 2002; 41: 729-734  PubMed   DOI

62    Bajdekov B, Zlatkov N, Naumov V. Dermatomyositis as paraneoplastic disease. Oncology (Sofia) 1969; 6: 39-32 (in Bulgarian) 

63    Dourmishev LA. Dermatomyositis: Current aspects. Sofia: PhD thesis, 2002: 140 (in Bulgarian) 

64    Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H 3rd, Mutasim D, Ariss-Abdo L. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 1990; 323: 1729-1735  PubMed   

65    Joly P, Richard C, Gilbert D, Courville P, Chosidow O, Roujeau JC, Beylot-Barry M, D'incan M, Martel P, Lauret P, Tron F. Sensitivity and specificity of clinical, histologic, and immunologic features in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol 2000; 43: 619-626  PubMed   DOI

66    Anhalt GJ. Paraneoplastic pemphigus. J Investig Dermatol Symp Proc 2004; 9: 29-33  PubMed   DOI

67    Stevens SR, Griffiths CE, Anhalt GJ, Cooper KD. Paraneoplastic pemphigus presenting as a lichen planus pemphigoides-like eruption. Arch Dermatol 1993; 129: 866-869  PubMed   DOI

68    Kaplan I, Hodak E, Ackerman L, Mimouni D, Anhalt GJ, Calderon S. Neoplasms associated with paraneoplastic pemphigus: a review with emphasis on non-hematologic malignancy and oral mucosal manifestations. Oral Oncol 2004; 40: 553-562  PubMed   DOI

69    Ostezan LB, Fabré VC, Caughman SW, Swerlick RA, Korman NJ, Callen JP. Paraneoplastic pemphigus in the absence of a known neoplasm. J Am Acad Dermatol 1995; 33: 312-315  PubMed   DOI

70    Park GT, Lee JH, Yun SJ, Lee SC, Lee JB. Paraneoplastic pemphigus without an underlying neoplasm. Br J Dermatol 2007; 156: 563-566  PubMed   DOI

71    Nguyen VT, Ndoye A, Bassler KD, Shultz LD, Shields MC, Ruben BS, Webber RJ, Pittelkow MR, Lynch PJ, Grando SA. Classification, clinical manifestations, and immunopathological mechanisms of the epithelial variant of paraneoplastic autoimmune multiorgan syndrome: a reappraisal of paraneoplastic pemphigus. Arch Dermatol 2001; 137: 193-206  PubMed   

72    Jeghers H, McKusick VA, Katz KH. Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance. N Engl J Med 1949; 241: 993, illust; passim  PubMed   

73    Sanchez-Cespedes M. A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene 2007; 26: 7825-7832  PubMed   DOI

74    Dourmishev A. Disorders of the Skin Pigmentation. Sofia: Med Fizk Publications House, 1986: 79 (in Bulgarian) 

75    Shivaswamy KN, Shyamprasad AL, Sumathy TK, Ranganathan C. Peutz-Jeghers syndrome with prominent palmoplantar pigmentation. Indian J Dermatol Venereol Leprol 2008; 74: 154-155  PubMed   DOI

76    Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000; 119: 1447-1453  PubMed   DOI

77   Cronkhite LW Jr, Canada WJ. Generalized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 1955; 252: 1011-1015  PubMed   

78    Allbritton J, Simmons-O'Brien E, Hutcheons D, Whitmore SE. Cronkhite-Canada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option. Cutis 1998; 61: 229-232  PubMed   

79    Gomes da Cruz GM. Generalized gastrointestinal polyposis. An unusual syndrome of adenomatous polyposis, alopecia, onychorotrophia. Am J Gastroenterol 1967; 47: 504-510  PubMed   

80    Yashiro M, Kobayashi H, Kubo N, Nishiguchi Y, Wakasa K, Hirakawa K. Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions. Digestion 2004; 69: 57-62  PubMed   DOI

81    de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer 2004; 4: 769-780  PubMed   DOI

82    Samoha S, Arber N. Cronkhite-Canada syndrome. Digestion 2005; 71: 199-200  PubMed   DOI

83    Turner M. Case of a woman whose face and body in two or three weeks’ time became covered with a thick crop of short and white downy hair. Med Time Gaz 1865; 2: 507 

84    Brinkmann J, Breier B, Goos M. [Hypertrichosis lanuginosa acquisita in ulcerative colitis with colon cancer] Hautarzt 1992; 43: 714-716  PubMed   

85    Slee PH, van der Waal RI, Schagen van Leeuwen JH, Tupker RA, Timmer R, Seldenrijk CA, van Steensel MA. Paraneoplastic hypertrichosis lanuginosa acquisita: uncommon or overlooked? Br J Dermatol 2007; 157: 1087-1092  PubMed   DOI

86    Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad Dermatol 2003; 48: 161-179; quiz 180-181  PubMed   DOI

 

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