Cowden disease or multiple hamartoma syndrome - cutaneous clue to internal malignancy

ARTICLE

Skin tumors may serve as markers for inheritable disorders and may herald internal malignancy [1]. Cowden disease (CD, MIM #158350) as well as Muir-Torre syndrome, Gardner syndrome, multiple endocrine neoplasia 1 and 2B, tuberous sclerosis and neurofibromatosis 1 and 2 are familial cancer predisposition syndromes, all of which exhibit mostly benign cutaneous tumors indicative of internal malignancies. An extensive review of this field has recently been published [2]. Patients with CD have an increased potential to develop benign and malignant neoplasms in a variety of tissues. Multiple hamartomatous lesions derived from all three germ layers, of ectodermal, endodermal and mesodermal origins, are associated with an elevated risk for malignant tumours, in particular of the breast, the thyroid and the endometrium. The mucocutaneous lesions in CD are the most characteristic and constant features and are the key to the diagnosis: multiple smooth and keratotic facial papules around the orifices, acral keratoses, oral mucosal papillomatosis and palmoplantar keratosis. These findings are strongly associated with internal malignant neoplasms. The skin lesions may precede the development of the internal manifestations by many years.

Case reports

Family 1 (Patients 1-3 from 7 affected family members)

History: A 41-year-old woman was referred to our department for multiple small keratotic, verruca-like skin nodules on her face and extremities dating back to childhood. Several of these papillomas have been removed from her face and hands by a local dermatologist. At the age of 34 years the patient underwent a hysterectomy for cervical carcinoma in situ. A partial thyroidectomy for thyroid adenoma had been performed. A benign fibrotic breast lesion had been removed. Family history revealed that her father, grandfather, great-grandfather, her uncle, her sister and her son had similar skin lesions.

Examination: On physical examination numerous keratotic, flesh-colored, wartlike papules varying in size from 2-4 mm were found on the dorsum of her hands and feet. There were also multiple skin-colored keratotic small papules on her face, clustered in the periorbital area, in the nasolabial folds and around the ears. Similar flesh-colored papules were aggregated on the labial and gingival mucosa with a tendency to coalesce giving the mucosa a cobblestone appearance (Fig. 1). Increased ridging of the fingertips and pitted keratoses were present on palms and soles (Fig. 2).

Histology: Microscopic examination of several verrucous papules from the dorsum of the left hand disclosed papillomatous lesions with hyperkeratotic stratum corneum and acanthotic epidermis (Fig. 3).

We also examined 2 of her family members, her father and her son:

Her 67-year-old father had had verrucous papular skin lesions in the periorbital area and on the distal dorsal aspect of forearms and legs since puberty. We found multiple confluent papules on the buccal mucosa and pitted keratosis on the palms and soles. His history revealed a colon resection for ileus. Details of the cause of this ileus could not be obtained. At the age of 64 years a squamous cell carcinoma of the left lung was diagnosed. He underwent treatment with chemotherapy and radiotherapy and a complete remission was achieved. But recently he died from a recurrence of his lung cancer. Biopsies from wart-like papules on the forearmes showed verruca vulgaris- like lesions.

The 17-year-old son has a 5-year-history of papular verrucous lesions on the neck and on the knees. He has a prominent macrocephaly with increased head circumference (Fig. 4). He suffers from thyroidal dysfunction. A biopsy from a papule of the knee showed hyperparakeratosis, papillomatosis, acanthosis, hypergranulosis and vacuolized keratinocytes, consistent with a viral wart. A verrucous lesion from the neck histologically presented as a clear cell acanthoma.

Family 2 (Patient 4)

History: A 76-year-old female patient consulted our clinic suffering from severe itching of verrucous lesions in the genital and perianal area for many years. Her gynaecologist had treated these lesions periodically by CO₂-laser-evaporation. Her medical history was remarkable for several benign and malignant tumours. At the age of 7 years she underwent thyroid surgery for nodular goiter. This was followed by a total thyroidectomy at the age of 20 years for recurrent benign thyroideal adenoma. At the age of 46 years a hysterectomy was performed for endometrial carcinoma. She was operated on by bilateral mastectomy for bilateral breast carcinoma. At present the patient is under treatment for extensive laryngeal papillomatosis. The patient has no children. She gave no family history of similar mucocutaneous lesions.

Examination: Examination of the skin showed multiple keratotic, flesh-colored, verrucous, slightly scaling confluent papules on the dorsum of her hands and feet, on her forearms and lower legs (Fig. 5). On her face we found skin-colored papules aggregated in the periorificial areas (Fig. 6). Multiple small papillomatous keratotic lesions were also located in the genital and perianal area. Several keratotic translucent papules and pits up to 4 mm in diameter were scattered over both palms and soles. Examination of the oral cavity revealed whitish fibropapillomatous mucosal lesions and a fissured tongue. There were typical scars from bilateral mastectomy and thyroid surgery (Fig. 7).

Histology: Microscopy of 3 papillomatous perianal lesions revealed a hyperkeratotic stratum corneum with focal parakeratosis. The epithelium exhibited acanthosis and elongated plump rete ridges. Histology of other keratotic papules showed trichilemmomas (Fig. 8).

History

Cowden disease was first described by Lloyd and Dennis in 1963 [3]. They named the syndrome after the family name of their patient, R. Cowden, a 20-year-old female with adenoid facies, hypoplasia of the mandible and maxilla, high arched palate, hypoplasia of the soft palate and uvula, microstomia, papillomatosis of the lips and oral pharynx, scrotal tongue, multiple thyroid adenomas, bilateral virginal hypertrophy of the breasts with advanced fibrocystic disease and early malignant degeneration, pectus excavatum, scoliosis, space-occupying lesions in the liver and bone and abnormalities of the central nervous system (Tables I and II). She died at 30 years of age as a result of infiltrating ductal carcinoma of the breast. She had a family history of forme fruste or incomplete penetrance of the syndrome in other family members. Two maternal aunts had breast cancer, and one sister had thyroid adenoma, a high arched palate, pectus excavatum, mental retardation and multiple skin tumours. The second report on this condition appeared in 1972: Weary et al. [4] described another five cases and established CD as a distinctive entity. They proposed the term "multiple hamartoma syndrome", indicating the common hamartomatous character of the lesions in the various organ systems. They also recognized the autosomal dominant inheritance of CD. In 1979 Brownstein et al. [5] identified many of the facial papules to be trichilemmomas and concluded that all patients with multiple facial trichilemmomas have CD. Since then over 150 cases of CD have been reported in the literature, 21 of them by Starink [6], who further particularized the clinical spectrum. The criteria of the disease have been expanded. In 1983 Salem and Steck [7] reviewed the literature and defined a scheme of diagnostic criteria to standardize the diagnosis of CD (Table III). In 1996 the International Cowden Consortium proposed further diagnosis criteria [8], which were revised in 2000 (Table IV) [9]. Nelen et al. [8] determined the gene locus for CD to be on chromosome 10q22-23. One year later a putative tumor suppressor gene, PTEN, was isolated on chromosome 10q23.3 and subsequently several germline mutations in the PTEN gene have been detected in patients with Cowden disease [10-12].

Clinical presentation (Tables I and II)

Patients with CD present with a variety of mucocutaneous findings which usually are the first presenting lesions of the disease beginning in the late teens or twenties. The mucocutaneous lesions as the most constant features are present in 99% to 100% of cases [13]: multiple skin color-ed or yellowish 1-4 mm smooth and keratotic facial papules clustered around the eyes, mouth, ears and nose (Fig. 9), which may coalesce and then resemble common warts. Acral verrucous keratotic papules, most commonly located on the dorsal site of hands, forearms and feet, are another prominent finding. Translucent keratotic papules with central depression are found over palms and soles. Mucosal lesions consisting of small whitish or pink papules may involve any mucosal surface but appear mostly on the gingival, palatal and labial mucosa. They often coalesce imparting a cobblestone appearance to the oral cavity. A scrotal tongue is another frequent finding. Additional cutaneous manifestations in patients with CD include lipomas and angiomas [14], xanthomas, dermal fibromas, skin tags and café au lait spots. Squamous cell carcinoma of the skin [15, 16], of the lips [17] and of the tongue [18], basal cell carcinoma [10, 18], malignant melanoma [19-21], Merkel cell carcinoma [22] and trichilemmomal carcinoma [23] all have been reported in patients with CD.

The systemic manifestations of CD are multiple. Skeletal, thyroid, breast, gastrointestinal and genitourinary anomalies are the most frequent [24].

Lloyd and Dennis [3] described adenoid facies, hypoplasia of mandible and maxilla, high arched palate, hypoplasia of the soft palate and uvula, microstomia, pectus excavatum and scoliosis. In their series of 21 patients Starink et al. [6] observed craniomegaly in 80% of affected patients. In more recent reports macrocephaly (> 97th percentile) has been observed in 39% [25].

About two thirds of patients have thyroid involvement [25], most frequently palpable goiters and follicular adenomas, hyper- or hypothyreoidism. Follicular adenocarcinomas have been reported in 10% of affected individuals. Thyreoglossal duct cysts and thyroiditis have been described [26].

Breast lesions are very common in women with CD. Lesions include fibrocystic disease, which is often extensive [27], anatomic abnormalities of the nipple and areola as well as virginal hypertrophy. Approximately 30 to 50% of women with CD develop breast cancer [28], a ductal adenocarcinoma [29], the most frequent malignancy associated with CD. The adenocarcinomas of the breast develop usually at an early age, most of them being diagnosed in patients less then 40 years. In one third of cases the breast carcinoma is bilateral [30]. Fackenthal et al. [31] recently reported on two cases of breast carcinoma in male patients with CD.

The frequency of gastrointestinal involvement is approximately 70-85%. Multiple polyps of various benign histopathologic types may be found anywhere throughout the gastrointestinal tract from the mouth to the anus, but most commonly in the colon [32]. Histologically the polyps are hyperplastic, lipomatous, fibromatous, hamartomatous, ganglioneuromatous, inflammatory, lymphoid and less frequently, adenomatous. The malignant potential of these polyps is small [32] with only a few reported cases of adenocarcinomas of the colon [17, 31, 33, 34]. Diffuse esophageal glycogenic acanthosis is a characteristic feature. Kay et al. [35] proposed that this finding in conjunction with benign gastrointestinal polyposis should be considered pathognomonic for CD. Other gastrointestinal lesions observed with increased frequency are diverticula of the colon, ganglioneuromas and neuromas, epitheloid leiomyomas of the rectosigmoid colon [32] and hepatic hamartomas or cysts. Hepatocellular carcinoma also has been described [36].

The most frequent changes in the female genitourinary tract are functional menstrual irregularities and ovarian cysts. Less frequent are uterine fibroids and uterine leiomyomas, teratomas, vaginal and vulvar cysts. Cancer of the endometrium has been reported in 6% and cervical cancer in 3% of women with CD. In men varicocele and hydrocele, benign polyps and adenoangiomyolipoma of the urethra have been observed. Laugier [37] reported on a carcinoma of the bladder and Haibach [21] reported on a renal cell carcinoma in a male patient with CD.

Eye lesions include myopia and congenital blood vessel anomalies, angioid streaks [38] and cataract.

Anomalies of the nervous system include neuromas, neurofibromas, meningiomas [4, 39], hearing loss, coordination disorders, epilepsy [40], mental impairment and Lhermitte-Duclos disease (LDD), a benign congenital cerebellar hamartoma [41-45]. LDD is considered to be a hamartomatous overgrowth of cerebellar ganglion cells, which replace granular cells and Purkinje cells [46].

Laryngeal polyps, lung cysts, arteriovenous malformations and pulmonary hamartomas are rare respiratory manifestations in CD. Solli et al. [47] observed multiple hamartomatous, lipomatous and lymphoid pulmonary lesions in a patient with CD.

Hypertension, atrial septal defect, mitral valve prolaps and aortic and mitral valve insufficiency are cardiovascular disorders in patients with CD.

One case of non-Hodgkin's lymphoma [48] and a case with leukemia [49] is reported in the literature.

Histopathology of the mucocutaneous lesions

Four mucocutaneous lesions are associated with CD: facial papules, extrafacial lesions including acral and palmoplantar keratoses, and oral mucosal papules.

Facial lesions

Follicular abnormalities are the most common changes in facial biopsies. Weary et al. [4] described on the one hand "lichenoid lesions of follicular origin with squamous eddies identical to those in inverted follicular keratoses" and on the other hand "papillomatous verrucoid lesions with irregular acanthotic and hyperkeratotic epidermis". Brownstein et al. [5] classified 29 (54%) of 53 facial lesions of 19 patients as trichilemmomas and 23 (43%) as non-specific benign verrucous acanthomas. A few of the facial tumors displayed features intermediate between trichilemmoma and inverted follicular keratosis, respectively trichilemmoma and tumor of follicular infundibulum. They emphasized the difficulty of making the diagnosis of trichilemmoma and pointed out that often multiple biopsies are necessary to uncover the trichilemmoma. They found that all patients with multiple facial trichilemmomas had CD. Starink et al. [50, 51] examined 40 facial biopsies of 7 CD patients. In their series they found a spectrum of trichilemmomas and related follicular malformations including cylindrical, lobulate, and keratinizing trichilemmomas, 2 tumors intermediate between trichilemmoma and inverted follicular keratosis, 3 tumors of follicular infundibulum and in addition 2 verruca vulgaris-like lesions, 5 dermal fibromas, 3 acrochordons and 1 neurilemmoma. Sclerotic fibromas, also called circumscribed storiform collagenomas, have been reported in association with CD [5, 50] and as solitary lesions [52]. Requena et al. [53] consider multiple sclerotic fibromas of the skin as another cutaneous marker of CD. Chapman et al. [42] observed a patient with recurrent LDD in whom the presence of a sclerotic fibroma led to a diagnosis of CD. Sclerotic fibroma is a symmetric and well circumscribed dermal nodule composed of paucicellular hyaline collagen containing numerous cleft-like spaces. The clefts are randomely oriented and impart a storiform pattern. Rare scattered fibroblasts are interposed between collagen bundles [54]. Schrager et al. [27] examined 19 CD patients. Thirty seven per cent had either frank fibroadenomas or fibroadenomatous changes of the breast. The observed fibroadenomas of the breast showed a spectrum of dense hyalinization of both the lobule and the stroma. The presence of those dense, hypocellular, hyaline nodules appeared to be the most characteristic feature of the benign breast disease of CD and the observed hyalinization process shared striking similarities with the sclerotic nodules seen in the skin of CD individuals.

Shapiro et al. [55] described the facial papules as "very much like viral warts". And indeed sometimes hypergranulosis and vacuolization of keratinocytes can be seen that support a diagnosis of viral papillomas. But Johnson et al. [56] could not prove a viral genesis in electronmicroscopic examinations and also Starink et al. [51, 57] failed to prove a viral genesis in immunohistochemical examinations. On the other hand Guérin et al. [58] found that epithelial cells from a gingival lesion of a young patient with CD were positive with an antipapillomavirus monoclonal antibody. Schaller et al. [59] recently examined facial papules of CD patients by HPV-polymerase chain reaction and documented human papillomavirus types, as they are typically found in epidermodysplasia verruciformis. It remains to be seen, whether the presence of HPV shown by PCR is causal or coincidental.

In summary most facial lesions of CD form a spectrum of related follicular malformations, representing follicular hamartomas, including cylindrical and lobulated types of trichilemommas, tumors of follicular infundibulum, inverted follicular keratosis and transitional forms of these tumors. In addition epidermal verruca vulgaris-like lesions and dermal sclerotic fibromas are associated with CD. The question of the viral genesis of the mucocutaneous lesions has to be further examined.

Extrafacial lesions

Extrafacial lesions on the limbs, located particularly on the dorsal and volar aspects of the hands and feet, are generally verruca vulgaris-like with a marked compact hyperkeratosis, hypergranulosis and a prominent acanthosis of the underlying epidermis, in some cases with a follicular and trichilemmomal differentiation [4, 5, 50, 57].

Additionally solitary lesions of acrokeratosis verruciformis-like papules, dermal fibromas, benign haemangiomas, xanthomas, lipomas, lymphangiomas and inverted follicular keratosis have been found [5, 50].

In our patient 1 we observed a verrucous acanthoma on the dorsum of the hand (Fig. 3). In patient 2 we found verruca vulgaris-like lesions on the forearm. In patient 3 we examined a papillomatous tumor of the knee consistent with a viral wart and a clear cell acanthoma of the neck. Clear cell acanthomas have not been described in association with CD so far. The presence of the clear cell acanthoma in our patient may be coincidental rather than really associated with CD. In patient 4 we found trichilemmomas (Fig. 8) and hyperparakeratotic acanthotic perianal tumors.

Oral mucosal lesions

Lloyd and Dennis [3] in 1963 obtained biopsies from the lips, tongue and alveolar ridges. They observed epithelial hyperplasia, papillomatosis, and focal areas of parakeratosis and acanthosis with moderate elongation of the rete ridges in all specimens. Also other authors have described the oral lesions as unspecific papillomas [5, 50].

Genetics

CD is inherited as an autosomal dominant trait with incomplete but high penetrance and variable expressivity. Linkage analysis of 12 families with CD have determined the locus for CD to chromosome 10q22-23 [8]. Subsequently, a putative tumour suppressive gene, PTEN (phosphatase and tensin homologue deleted from chromosome 10), also called MMAC1 (mutated in multiple advanced cancers) or TEP1 (TGFbeta-regulated and epithelial cell-enriched phosphatase), was identified in the CD critical region [60, 61]. Soon after germline mutations in the PTEN gene could be demonstrated in patients with CD [10-12] as with Bannayan-Zonana syndrome [62-64], a multiple hamartoma syndrome with macrocephaly, developmental delay and hypotonia, intestinal hamartomatous polyposis, subcutaneous and visceral lipomas, vascular malformations and pigmented macules of the penis. However, there is no increased risk for malignancy in Bannayan-Zonana-syndrome. On the basis of clinical and genetical overlap, it has been suggested that these two syndromes are two different phenotypic expressions of the same disorder [65, 66]. Several patients with both features of CD and features of Bannayan-Zonana syndrome have been described [63, 65]. Very recently Zhou et al. [66] found germline mutations in the PTEN tumour suppressor gene in another hamartoma syndrome: in Proteus syndrome (PS) and Proteus like syndrome (PS like). They identified de novo germline mutations in 2 of 9 patients with PS and 3 of 5 patients with PS-like. In PS, benign and sporadically malignant neoplasms have been observed [67]. The most common neoplasms in PS are ovarian cystadenomas and adenomas of the parotid gland [68]. The three syndromes, CD, Bannayan-Zonana-syndrome and PS have several features in common. In all three syndromes macrocephaly, vascular malformations and lipomatosis can be seen.

However, PTEN mutations could not be found in all examined patients with CD. This suggests that CD is a genetically heterogeneous disease. PTEN, located on chromosome subband 10q23.3, encodes a dual-specifity phosphatase with lipid and protein phosphatase activity. The major substrates for PTEN are phosphatidylinositol 3,4 diphosphate and phosphatidylinositol 3,4,5 triphosphate. This lipid phosphatase activity of PTEN plays a role in the regulation of phosphoinositol 3-kinase (PI 3-K) and in this function may be relevant in limiting cell cycle progression and promoting apoptosis and thus suppressing cell survival.

The PTEN locus is associated with loss of heterozygosity in a subset of CD tumors [69-71]. Somatic PTEN mutations have been found in a variety of sporadic cancers also among patients without Cowden disease: in glioblastomas [61], meningiomas, melanoma [72], benign and malignant thyroid tumours, primary ductal adenocarcinoma of the breast [60, 61], lung cancer, cervical, vulvar and endometrial carcinoma [73], renal cell carcinoma [61], bladder and prostate cancer [61], acute myeloid leukemia and in hepatocellular carcinoma. PTEN is considered as one of the most frequent mutated genes in human cancers and may be critical for tumor suppression in various tissues. Though in familial breast cancer without CD, PTEN do not seem to be a major determinant of non-BRCA1/BRCA2 familial breast cancer. Zhang and Steinberg [74] examined HPV-6 or HPV-11 positive laryngeal papillomas. They found that PTEN protein is overexpressed and PI 3-K activity is elevated in laryngeal papilloma tissue.

The spectrum of neoplasia observed in pten^+/- mice partially overlaps with the types of tumors occurring in CD, so that pten^+/- mice might represent a useful animal model for the investigation of PTEN-related hamartoma syndromes [75]. Mice null for pten die very early during embryogenesis. Mice heterozygous for pten are highly susceptible to develop breast and endometrial neoplasias and hamartomatous tumors of the gastrointestinal tract. Unlike the humans with CD, pten^+/- mice form also tumors of the prostate, adrenal gland and lymphoid tissue, but not tumors of the thyroid, skin and central nervous system. Stambolic et al. [75] showed that nearly all of the investigated tumors of pten^+/- mice displayed loss of heterozygosity at the pten locus, indicating the importance for loss of PTEN function in tumor formation.

With the identification of germline mutations of PTEN in CD, predictive and diagnostic DNA-based testing has become possible. Family members of patients with CD, even if not obviously affected, but carrying the family-specific PTEN mutation, should be managed with heightened cancer surveillance.

Diagnosis

In 1983 Salem and Steck [7] proposed diagnostic criteria for CD (Table III). They defined cutaneous facial papules and oral papillomatosis as major criteria and acral keratoses and palmoplantar keratoses as minor criteria. A definitive diagnosis of CD may be made in the presence of 2 major criteria, 1 major and 1 minor criterion, 1 major criterion and a positive family history, or 2 minor criteria and a positive family history. In 1996 the International diagnostic criteria were established [8] and they were revised in 2000 (Table. IV) [9]. Pathognomonic criteria are distinguished from major and minor criteria. Pathognomonic criteria include facial trichilemmomas, acral keratoses, papillomatous lesions and mucosal lesions. Major criteria include breast cancer, thyroid cancer, macrocephaly, Lhermitte-Duclos-Disease and endometrial cancer. Thyroid lesions, mental retardation, gastrointestinal hamartomas, fibrocystic disease of the breast, lipomas, fibromas and genitourinary tumours or malformations are defined as minor criteria. Diagnosis of CD is considered definite if there are 6 or more facial papules, of which 3 or more must be trichilemmomas. The diagnosis of CD can also be made on the basis of cutaneous facial papules and oral mucosal papillomatosis, or oral mucosal papillomatosis and acral keratosis, or palmoplantar keratosis. Moreover 2 major criteria, where one is either Lhermitte-Duclos disease or macrocephaly, 1 major with 3 minor criteria, or 4 minor criteria, are considered diagnostic for CD.

Differential diagnosis

The multiple skin-colored facial papules may resemble viral warts. They may be mistaken for syringomas, trichoepitheliomas, cylindromas, seborrhoic keratoses, angiofibromas in tuberous sclerosis, Darier-White disease, steatoma multiplex, basal cell carcinomas in basal cell nevus syndrome, fibrofolliculomas, neurofibromas in Recklinghausen's disease or epidermodysplasia verruciformis.

Differential diagnosis of the oral papillomatous lesions include multiple traumatic fibromas, oral fibromas in tuberous sclerosis, Darier-White disease, Heck's disease (focal epithelial hyperplasia), lymphangioma, pyogenic granuloma, fibroepithelial polyps, lipoid proteinosis, florid oral papillomatosis, oral papillomas in Goltz syndrome, mucosal neuromas of multiple endocrine adenomatosis, acanthosis nigricans, pseudoepitheliomatous hyperplasia and squamous cell carcinoma.

Acral keratosis must be differentiated clinically from viral warts, epidermodysplasia verruciformis, Darier-White disease, acrokeratosis verruciformis Hopf, stucco keratoses, seborrhoic keratosis and epidermolytic hyperkeratosis.

Management (Table V)

Once the diagnosis of Cowden disease is made, these patients have to be considered as high risk patients for developing malignancies. Women with CD have a 30 to 50% risk for breast cancer. Regular mammographies should be performed every six months, professional physical examination quarterly. The women should carry out a monthly self examination. Some authors have recommended prophylactic bilateral mastectomy, particularly in women with extensive fibrocystic breast disease or breast carcinoma in one breast [30, 76-78]. Considering the recent reports of breast carcinoma in male patients [31] a prophylactic bilateral mastectomy in men with CD seems to be opportune.

Yearly gynecologic examinations for early diagnosis of cervical or endometrial cancer are recommended. Patients with CD should avoid estrogen therapy.

Functional thyroid examinations and thyroid scanning should be performed as baseline diagnostic examinations. In case of anomalies fine needle aspiration or surgical biopsies are indicated. In addition a complete blood cell count, liver and renal function test, urine analysis and a chest radiography belong to the baseline diagnostic examinations and are repeated as needed.

Because of the immense number and the low degenerative potential of the gastrointestinal polyps, endoscopic screening tests do not seem to be effective enough and should be performed only when there are symptoms.

The facial papules may cause a considerable cosmetic problem. They can be treated physically by CO₂-laser ablation or surgical removal or chemically by topical 5-Fluorouracil. Cnudde et al. [79] observed good cosmetic results for all mucocutaneous lesions during a systemic therapy with acitretine 0,75 mg/kg/d. The effect of systemic retinoids is of course transient with reappearance of the lesions after interruption of the therapy. Whether retinoids are canceroprotective has to be proved in the future. Retinoid acid analogues have been shown to decrease growth fraction and to induce differentiation and apoptosis in organotypic cultures of ovarian carcinoma [80].

Newly appearing headaches should arouse suspicion for Lhermitte-Duclos disease and should be examined by MR imaging of the brain [45].

A thorough family history and an appropriate screening of family members is important to detect further CD cases as early as possible.

To make the diagnosis and to manage the patient with CD is an interdisciplinary responsibility. Of course the clinical diagnosis relies mainly on dermatologic criteria. But it is of particular importance that general practitioners, internists, dentists [36, 81, 82], gastroenterologists, gynaecologists and radiologists are also familiar with the features of the syndrome, because they may be the first health care professionals to recognize the syndrome and prevent and cure avoidable malignancies.

Increased alertness for the presence of mucocutaneous lesions, facial papules and acral keratoses in association with oral papillomatosis, should arouse any physician's suspicion to the presence of CD. With a deepened awareness of the mucocutaneous features of CD this diagnosis can probably be made earlier and more frequently and so these high-risk patients for malignancy may be identified before complications occur. A life-long follow up is absolutely necessary. A thorough personal and familial screening is essential.

CONCLUSION

Acknowledgements

We thank Dr. Peter Schiller (Department of Dermatology, University Hospital Basel) for the photographic documentation of the histologic sections.

Article accepted on 27/2/02

REFERENCES

1. Hauck RM, Manders EK. Familial syndromes with skin tumor markers. Ann Plast Surg 1994; 33: 102-11.

2. Tsao H. Update on familial cancer syndromes and the skin. J Am Acad Dermatol 2000; 42: 939-69.

3. Lloyd KM, Dennis M. Cowden's disease: a possible new symptom complex with multiple system involvement. Ann Intern Med 1963; 58: 136-42.

4. Weary PE, Gorlin RJ, Gentry WC Jr., Comer JE, Greer KE. Multiple hamartoma syndrome (Cowden's disease). Arch Dermatol 1972; 106: 682-90.

5. Brownstein MH, Mehregan AH, Bikowski JB, Lupulescu A, Patterson JC. The dermatopathology of Cowden's syndrome. Br J Dermatol 1979; 100: 667-73.

6. Starink TM, Van der Veen JPW, Arwert F, De Waal LP, De Lange GG, Gille JJP, Eriksson AW. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986; 29: 222-33.

7. Salem OS, Steck WD. Cowden's disease (multiple hamartoma and neoplasia syndrome): a case report and review of the English literature. J Am Acad Dermatol 1983; 8: 686-96.

8. Nelen MR, Padberg GW, Peeters EAJ, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MMM, Easton DF, Eeles, RA, Hodgson S, Mulvihill JJ, Murday VA, Tucker MA, Mariman ECM, Starink TM, Ponder BAJ, Ropers HH, Kremer H, Longy M, Eng C. Localization of the gene for Cowden disease to chromosome 10q22-23. Nat Genet 1996; 13: 114-6.

9. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000; 37: 828-30.

10. Celebi JT, Ping XL, Zhang H, Remington T, Sulica VI, Tsou HC, Peacocke M. Germline mutations in three families with Cowden syndrome. Exp Dermatol 2000; 9: 152-6.

11. Kubo Y, Urano Y, Hida Y, Ikeuchi T, Nomoto M, Kunitomo K, Arase S. A novel PTEN mutation in a Japanese patient with Cowden disease. Br J Dermatol 2000; 142: 1100-5.

12. Liaw D, Marsh DJ, Li J, Dahia PLM, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16: 64-7.

13. Starink TM. Cowden's disease: analysis of fourteen new cases. J Am Acad Dermatol 1984; 11: 1127-41.

14. Burnett JW, Goldner R, Calton GJ. Cowden disease. Report of two additional cases. Br J Dermatol 1975; 93: 329-36.

15. Bart RS, Kopf AW. Tumor Conference #35. Cowden's disease (multiple hamartoma syndrome). J Dermatol Surg Oncol 1981; 7: 378-80.

16. Nuss DD, Aeling JL, Clemons DE, Weber WN. Multiple hamartoma syndrome (Cowden's disease). Arch Dermatol 1978; 114: 743-6.

17. Gorensek M, Matko I, Skralovnik A, Rode M, Satler J, Jutersek A. Disseminated hereditary gastrointestinal polyposis with orocutaneous hamartomatosis (Cowden's disease). Endoscopy 1984; 16: 59-63.

18. Camisa C, Bikowski JB, McDonald SG. Cowden's Disease. Association with squamous cell carcinoma of the tongue and perianal basal cell carcinoma. Arch Dermatol 1984; 120: 677-8.

19. Greene SL, Thomas JR, Doyle JA. Cowden's disease with associated malignant melanoma. Int J Dermatol 1984; 23: 466-7.

20. Siegel JM. Cowden's disease. Report of a case with malignant melanoma. Cutis (New York) 1975; 16: 155-8.

21. Hildenbrand C, Burgdorf WHC, Lautenschlager S. Cowden syndrome - diagnostic skin signs. Dermatology 2001; 202: 362-6.

22. Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ. Multiple hamartoma Syndrome (Cowden's disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). J Clin Pathol 1992; 97: 705-12.

23. O'Hare AM, Cooper PH, Parlette HL. Trichilemmomal carcinomas in a patient with Cowden's disease (multiple hamartoma syndrome). J Am Acad Dermatol 1997; 36: 1021-3.

24. Mallory SB. Cowden syndrome (Multiple hamartoma syndrome). Dermatol Clin 1995; 13: 27-31.

25. Hanssen AMN, Fryns JP. Cowden syndrome. J Med Genet 1995; 32: 117-9.

26. Krasovec M, Elsner P, Burg G. Cowden-Syndrom. Hautarzt 1995; 46: 472-6.

27. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Similarities of cutaneous and breast pathology in Cowden's disease. Exp Dermatol 1998; 7: 380-90.

28. Schweitzer S, Hogge JP, Grimes M, Bear HD, de Paredes ES. Cowden disease: a cutaneous marker for increased risk of breast cancer. Am J Roentgenol 1999; 172: 349-51.

29. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Clinical and pathological features of breast disease in Cowden's syndrome. An underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 1998; 29: 47-53.

30. Williard W, Borgen P, Bol R, Tiwari R, Osborne M. Cowden's disease. A case report with analysis at the molecular level. Cancer 1992; 69: 2969-74.

31. Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Robinson BG, Olopade OI. Male breast cancer in Cowden syndrome patients with germline mutations. J Med Genet 2001; 38: 159-64.

32. Ortonne JP, Lambert R, Daudet J, Berthet P, Gianadda E. Involvement of the digestive tract in Cowden's disease. Int J Dermatol 1980; 19: 570-6.

33. Hover AR, Cawthern T, McDaniel W. Cowden's disease. A hereditary polyposis syndrome diagnosable by mucocutaneous inspection. J Clin Gastroenterol 1986; 8: 576-9.

34. Wade TR. Cowden's disease. Cutis 1979; 24: 537-41.

35. Kay PS, Soetikno RM, Mindelzun R, Young HS. Diffuse esophageal glycogenic acanthosis: an endoscopic marker of Cowden's disease. Am J Gastroenterol 1997; 92: 1038-40.

36. Takenoshita Y, Kubo S, Takeuchi T, Iida M. Oral and facial lesions in Cowden's disease: report of two cases and a review of the literature. J Oral Maxillofac Surg 1993; 51: 682-7.

37. Laugier P, Kuffer R, Olmos L, Hunziker N, Rougier M, Fiore-Donno G. Maladie de Cowden: à propos de 8 cas familiaux. Ann Dermatol Venereol 1979; 106: 453-63.

38. Allen BS, Fitch MH, Smith JG Jr. Multiple hamartoma syndrome: a report of a new case with associated carcinoma of the uterine cervix and angioid streaks of the eyes. J Am Acad Dermatol 1980; 2: 303-8.

39. Lyons CJ, Wilson CB, Horton JC. Association between meningioma and Cowden's disease. Neurology 1993; 43: 1436-7.

40. Asklöf G, Johansson J, Svensson A. Cowden's disease (multiple hamartoma syndrome), an underdiagnosed syndrome with increased risk of malignant development. J Eur Acad Dermatol Venereol 1995; 4: 66-70.

41. Albrecht S, Haber RM, Goodman JC, Duvic M. Cowden syndrome and Lhermitte-Duclos disease. Cancer 1992; 70: 869-76.

42. Chapman MS, Perry AE, Baughman RD. Cowden's syndrome, Lhermitte-Duclos disease, and sclerotic fibroma. Am J Dermatopathol 1998; 20: 413-6.

43. Koch R, Scholz M, Nelen MR, Schwechheimer K, Epplen JT, Harders AG. Lhermitte-Duclos disease as a component of Cowden's syndrome. Case report and review of the literature. J Neurosurg 1999; 90: 776-9.

44. Robinson S, Cohen AR. Cowden disease and Lhermitte-Duclos disease: characterization of a new phakomatosis. Neurosurgery 2000; 46: 371-83.

45. Vinchon M, Blond S, Lejeune JP, Krivosik I, Fossati P, Assaker R, Christiaens JL. Association of Lhermitte-Duclos and Cowden disease: report of a new case and review of the literature. J Neurol Neurosurg Psychiatry 1994; 57: 699-704.

46. Braud AC, de Rocquancourt A, Marty M, Espie M. Cowden disease and Lhermitte Duclos disease, markers of breast carcinoma: report of two patients. Ann Oncol 1999; 10: 1241-3.

47. Solli P, Rossi G, Carbognani P, Spaggiari L, Gabrielli M, Tincani TG, Rusca M. Pulmonary abnormalities in Cowden's disease. J Cardiovasc Surg 1999; 40: 753-5.

48. Elston DM, James WD, Rodman OG, Raham GF. Multiple hamartoma syndrome (Cowden's disease) associated with non-Hodgkin's lymphoma. Arch Dermatol 1986; 122: 572-5.

49. Ruschak PJ, Kauh JC, Luscombe HA. Cowden's disease associated with immunodeficiency. Arch Dermatol 1981; 117: 573-5.

50. Starink TM, Meijer CJ, Brownstein MH. The cutaneous pathology of Cowden's disease: new findings. J Cutan Pathol 1985; 12: 83-93.

51. Starink TM, Hausman R. The cutaneous pathology of facial lesions in Cowden's disease. J Cutan Pathol 1984; 11: 331-7.

52. Hanft VN, Shea CR, McNutt NS, Pullitzer D, Horenstein MG, Prieto VG. Expression of CD34 in sclerotic ("plywood") fibromas. Am J Dermatopathol 2000; 22: 17-21.

53. Requena L, Gutirrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin. A cutaneous marker of Cowden's disease. J Cutan Pathol 1992; 19: 346-51.

54. Granter SR, Fletcher CDM. Fibrous and fibrohistiocytic tumors. In: Barnhill RL, ed. Textbook of dermatopathology. New York: McGraw-Hill, 1998: 660-1.

55. Shapiro SD, Lambert WC, Schwartz RA. Cowden's disease, a marker for malignancy. Int J Dermatol 1988; 27: 232-7.

56. Johnson BL, Kramer EM, Lavker RM. The keratotic tumors of Cowden's disease: an electronmicroscopic study. J Cutan Pathol 1987; 14: 291-8.

57. Starink TM, Hausman R. The cutaneous pathology of extrafacial lesions in Cowden's disease. J Cutan Pathol 1984; 11: 338-44.

58. Guérin V, Bene MC, Judlin P, Beurey J, Landes P, Faure G. Cowden disease in a young girl: gynecologic and immunologic overview in a case and in the literature. Obstet Gynecol 1989; 73: 890-2.

59. Schaller J, Rohwedder A, Itin P, Lautenschlager S, Burgdorf WHC. Nachweis Epidermodysplasia-verruciformis-assoziierter HPV-DNA in Tumoren beim Cowden-Syndrom. Z Hautkr 2001; 76: 166.

60. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275: 1943-7.

61. Steck PA, Pershouse MA, Jasser SA, Yung WKA, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DHF, Tavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 1997; 15: 356-62.

62. Celebi JT, Tsou HC, Chen FF, Zhang H, Ping XL, Lebwohl MG, Kezis J, Peacocke M. Phenotypic findings of Cowden syndrome and Bannayan-Zonana syndrome in a family associated with a single germline mutation in PTEN. J Med Genet 1999; 36: 360-4.

63. Marsh DJ, Kum JB, Lunetta KL, Bennett MJ, Gorlin RJ, Ahmed SF, Bodurtha J, Crowe C, Curtis MA, Dasouki M, Dunn T, Feit H, Geraghty MT, Graham Jr JM, Hodgson SV, Hunter A, Korf BR, Manchester D, Miesfeldt S, Murday VA, Nathanson KL, Parisi M, Pober B, Romano C, Tolmie JL, Trembath R, Winter RM, Zackai EH, Zori RT, Wenig LP, Dahia PLM, Eng C. PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Hum Mol Genet 1999; 8: 1461-72.

64. Wanner M, Celebi JT, Peacocke M. Identification of a PTEN mutation in a family with Cowden syndrome and Bannayan-Zonana syndrome. J Am Acad Dermatol 2001; 44: 183-7.

65. Perriard J, Saurat JH, Harms M. An overlap of Cowden's disease and Bannayan-Riley-Ruvalcaba syndrome in the same family. J Am Acad Dermatol 2000; 42: 348-50.

66. Zhou XP, Hampel H, Thiele H, Gorlin RJ, Hennekam RCM, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001; 358: 210-1.

67. Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr. Neoplasms in Proteus syndrome. Am J Med Genet 1995; 57: 74-8.

68. Biesecker LG. The multifaceted challenges of Proteus syndrome. JAMA 2001; 285: 2240-3.

69. Dahia PLM, Marsh DJ, Zheng Z, Zedenius J, Komminoth P, Frisk T, Wallin G, Parsons R, Longy M, Larsson C, Eng C. Somatic deletions and mutations in the Cowden disease gene, PTEN, in sporadic thyroid tumours. Cancer Research 1997; 57: 4710-3.

70. Gimm O, Perren A, Weng LP, Marsh DJ, Yeh JJ, Ziebold U, Gil E, Hinze R, Delbridge L, Lees JA, Mutter GL, Robinson BG, Komminoth P, Dralle H, Eng C. Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial tumors. Am J Pathol 2000; 156: 1693-700.

71. Marsh DJ, Zheng Z, Zedenius J, Kremer H, Padberg GW, Larsson C, Longy M, Eng C. Differential loss of heterozygosity in the region of the Cowden locus within 10q22-23 in follicular thyroid adenomas and carcinomas. Cancer Research 1997; 57: 500-3.

72. Celebi JT, Shendrik I, Silvers DN, Peacocke M. Identification of PTEN mutations in metastatic melanoma specimens. J Med Genet 2000; 37: 653-7.

73. Risinger JI, Hayes AK, Berchuk A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res 1997; 57: 4736-8.

74. Zhang P, Steinberg BM. Overexpresion of PTEN/MMAC1 and decreased activation of Akt in human papillomavirus-infected laryngeal papillomas. Cancer Res 2000; 60: 1457-62.

75. Stambolic V, Tsao M-S, Macpherson D, Suzuki A, Chapman WB, Mak TW. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten^+/- mice. Cancer Res 2000; 60: 3605-11.

76. Brownstein MH, Wolf M, Bikowski JB. Cowden's diesease. A cutaneous marker of breast cancer. Cancer 1978; 41: 2393-8.

77. Lynch HAT, Lynch J, Conway T, Watson P, Feunteun J, Lenoir G, Narod S, Fitzgibbons R. Hereditary breast cancer and family cancer syndromes. World J Surg 1994; 18: 21-31.

78. Walton BJ, Morain WD, Baughan RD, Jordon A, Crichlow R. Cowden's disease: a further indivation for prophylactic mastectomy. Surgery 1986; 99: 82-6.

79. Cnudde, FR, Boulard F, Muller P, Chevallier J, Teron-Abou B. Maladie de Cowden: traitement par acitrétine. Ann Dermatol Venerol 1996; 23: 739-41.

80. Guruswamy S, Lightfoot S, Gold MA, Hassan R, Berlin KD, Ivey RT, Benbrook DM. Effects of retinoids on cancerous phenotype and apoptosis in organotypic cultures of ovarian carcinoma. J Natl Cancer Inst 2001; 93: 516-25.

81. Bagan JV, Penarrocha M, Vera-Sempere F. Cowden Syndrome: Clinical and pathological considerations in two new cases. J Oral Maxillofac Surg 1989; 47: 291-4.

82. Mignogna MD, Lo Muzio L, Ruocco V, Bucci E. Early diagnosis of multiple hamartoma and neoplasia syndrome (Cowden disease), the role of the dentist. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 285-299.

83. Marth T, Schmitt-Gräff A, Zimmer T, Riecken EO, Wiedenmann B. Gastrale Hamartome und Schilddrüsenkarzinom mit follikulärer und neuroendokriner Differenzierung bei Cowden-syndrom. Z Gastrenterol 1996; 34: 30-5.

84. Thyresson HN, Doyle JA. Cowden's disease (Multiple hamartoma syndrome). Mayo Clin Proc 1981; 56: 179-84.

85. Yen BC, Kahn H, Schiller AL, Klein MJ, Phelps RG, Lebwohl MG. Multiple hamartoma syndrome with osteosarcoma. Arch Pathol Lab Med 1993; 117: 1252-4.

86. Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden's disease. Surgery 1995; 118: 115-7.

87. Mulvihill JJ, McKeen EA. Discussion: genetics of multiple primary tumors. A clinical etiologic approach illustrated by three patients. Cancer 1977; 40: 1867-71.

88. Aylesworth R, Vance JC. Multiple hamartoma syndrome with endometrial carcinoma and the sign of Leser-Trélat. Arch Dermatol 1982; 118: 136-8.

89. Grupper C, Bourgeois-Spinasse J, Briche R. Maladie de Cowden ou syndrome des hamartomes multiples (2 cas francais). Effets favorables de l'acide rétinoïque en applications locales et de l'acide rétinoique per os. Bull Soc Fr Derm Siphilig 1975; 82: 250.

90. Hauser H, Ody B, Plojoux O, Wettstein P. Radiological findings in multiple hamartoma syndrome (Cowden disease): a report of three cases. Radiology 1980; 137: 317-23.

91. Kuffer R, Rougier M, Laugier P, Fiore-Donno G. Cowden's disease: a report on two cases in Swiss families. Rev Stomatol Chir Maxillofac 1979; 80: 246-56.

92. Kacem M, Zili J, Zakhama A, Hadi Youssef F, Mahjoub S, Boubakri C, El May M. Multinodular goiter and parotid carcinoma: a new case of Cowden's disease. Ann Endocrinol (Paris) 2000; 61: 159-63.