On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.77 no.6 Rio de Janeiro Nov./Dec. 2002
Cowden's Syndrome - a new case report *
Patrícia de Barros GuimarãesI; Adeíza de Alencar BrancoII; Elaine CarvalhoIII; Francisco Eduardo LimaIV; José Roberto AlmeidaV; Josemir Belo dos SantosVI; Luisa VillaVII; Sílvia Helena RodriguesVIII; Roberta SiqueiraVIII; Tatiana De PerreliVIII
Dermatologist and Master of Tropical Medicine, Tropical Medicine Department,
IIM.D., Dermatologist and professor at UFPE
IIIOdontologist and Master of Buccal Pathology
IVSurgeon in Gastroenterology, professor at UFPE
VGastroenterologist, professor at UFPE
VIM.D., Dermatologist, professor at UFPE
VIIVirologist at the Ludwig Cancer Research Institute/São Paulo
Cowden's Syndrome (CS) or Multiple Hamartoma Syndrome (MHS) is a rare genodermatosis of autossomal-dominant inheritance with variable expressivity. It is characterized by multiple hamartomatous lesions of ectodermal, mesodermal and endodermal origins. The organ system that most consistently manifests this syndrome is the skin. Mucocutaneous lesions are present in 99 to 100% of cases. These signs precede the development of cancer by several years, and they serve as important clinical markers for identification of patients at high risk for malignancies of the breast or thyroid. Because of its potentially serious associations with internal malignancy, early and accurate diagnosis is essential. The gene locus for CS has been identified as chromosome 10 q22-23. Mutations in the human tumor suppressor gene, PTEN/MMAC1, located on the 10q23 chromosome, have been implicated in the development of breast cancer. The authors report a case of this rare entity, dealing with a male patient with the clinical characteristics of this syndrome.
Key words: neoplasms; Hamartoma Syndrome, Multiple.
In her research on internal diseases, the medical doctor is often assisted by the external signs of an underlying process.3 Given that diffusion of her knowledge may be useful for the diagnosis of internal abnormalities, a case report is presented here of Cowden's syndrome.
CS is a rare genodermatosis,4,5 of autossomal-dominant inheritance with variable expressivity. It is characterized by multiple hamartomatous lesions of ectodermal, mesodermal and endodermal origins.1,2,4,5-8 While most CS tumors that develop are benign, the prevalence of malignancy is higher than in the tumor population in general, especially in breast and thyroid carcinomas. This syndrome was first described by Lloyd and Dennis,2,5,6 in 1963, and called SC in reference to their patient,3,4 Rachel Cowden, who died from breast cancer.2 In 1972, Weary et al.3,7 reported five additional cases and suggested the name of Multiple Hamartoma Syndrome (MHS).
Ever since its first description, less than 200 cases have been documented.4,13 Reports grow in number as knowledge of the disease increases. Even so, Gentry et al.3 believe that frequency is more common than what is reported in the literature, due to the existing variable expressivity of this genodermatosis. The result is that many cases are not correctly diagnosed.3,10 Both sexes are equally affected,1 though some authors believe the disease to be more common in females.7 The majority of the patients reported are caucasians.2
A 38-year-old male patient was attended to at the Dermatology Outpatients Clinic of the Hospital das Clínicas in Pernambuco State (PE), due to type III skin (according to Fitzpatrick's classification). The patient had never been employed nor had he ever attended school. He was born in Olinda, PE, where he currently resides.
The patient showed multiple asymptomatic confluent papules in the gingivae, upper and lower lips, and on the back of the tongue, with an appearance and texture similar to small "round pebbles" (Figure 1).
Observation revealed solitary lipoma in the frontal region, adenoid facies, increased skull diameter and bone deformities in the ankles, in addition to moderate mental retardation. Physical examination of the cardiovascular, digestive and genitourinary organ and systems, and the nervous system were normal.
During childhood, the patient had undergone orthopedic surgery in the ankles. He had suffered complete dental extraction a few years earlier due to cavities, according to information gathered at the moment of the physical examination. Medical history taking was incomplete, because neither the patient nor his mother responded adequately to the inquiry.
Information on family antecedence was also compromised since the patient does not have any contact with his relatives, and nor does his genitor, who moreover did not show clinical characteristics of the syndrome being studied.
Routine hemogram and biochemical laboratory tests were normal.
RX thorax and the computerized axial tomography (CT scan) of the thoracic spin did not show significant alterations, nor did the laryngoscopy and USG breast biopsy.
Biopsy of the oral papules showed evidence of a polypoid lesion with epithelial hyperplasia at the expense of hyperkeratosis and acanthosis. Papilloma with conjunctive stroma rich in vessels, with a light lymphohistiocytic infiltrate, compatible with fibroepithelial papilloma (Figure 2). The electron microscope and immunohistology reveal an absence of HPV.
In the thyroidian investigation, T3, T4 and TSH hormone doses were administered, which were normal; the glandular USG showed evidence of 0.3 cm hypoecoic nodules in the right lobe; the punction - nodule biopsy with a cytological test - revealed Hashimoto's thyroiditis.
In the colonoscopy polyps were found in the rectum, transversal colon, ascendant colon, and cecum (Figure 4); the histopathologic study of intestinal lesions demonstrated hyperplastic and adenomatous polyps.
In brain magnetic resonance with contrast a suggestive image was found of angioma cavernoma, located at the level of the left frontal region and having the classic 'popcorn-like' aspect. There was no lesion found suggestive of hamartoma (Figure 5).
Based on these clinical and pathological findings, the patient was diagnosed as a carrier of Cowden's syndrome and is being followed up at the dermatology, endocrinology, gastroenterologic and neurological clinics.
CS is a rare genodermatosis with autossomal-dominant penetration and variable expressivity.4 It is represented by multiple hamartomatose lesions and neoplasias of the skin, mucose, breast, thyroid, and gastrointestinal tract, among other congenital abnormalities.2,4,6 The hamartomas are defined as tumor-like malformations, consisting of elements normally part of the organism in which it develops, but having an erroneous disposition.10
The organ most frequently manifesting the symptoms of this syndrome is the skin, the mucocutaneous findings of which are the most characteristic1,2 and constant,2,4,5,6 reported in a proportion varying from 99 to 100% of cases. As they anticipate the development of cancer by several years, they serve as important clinical markers for the identification of patients at high risk of contracting breast and thyroid malignancies.1,4,5,8,13
The most characteristic mucocutaneous lesions are multiple facial trichilemomma, oral papilloma and acral keratosis.
The trichilemommas, representing hamartomas of hair follicle tissue,2,4,12,13 has a preferential affectation for the face.7 It may be so numerous that orifice border and facial contours coalesce, thus becoming cosmetically unacceptable for the patient.2 They are characterized by 1 to 4 mm papules and nodules and, in most cases, they are manifested before the second or third decade of life,1,2 though they may occur between the fourth decade and 75-years of age.2 When multiple, these tumors are patognomonic and are frequently present prior to internal manifestations.2 Distribution of papules also occurs in distal extremities,2,7 including the palms of the hands, soles of the feet, neck and forearms.4 In the case reported, the patient did not present the characteristic trichilemomma.
Typical papilloma is usually between 1 and 3 mm, and affects the gingivae, underside of the tongue, buccal mucous, the palate, alveolar endothelium and tonsillar fossa, often taking on an aspect similar to "round pebbles". The verrucous lesions in the angles of the mouth and oral mucous may mimic perleche hypertrophy or benign gingival hyperplasia.3 The histological form of oral lesions considerably lacks specificity, representing essentially fibroepithelial hyperplasia.2,9 Notwithstanding the predisposition to neoplasia, oral squamous carcinoma is a very rare complication.5,13 The oral papillomatous lesions of the case studied were multiple and characteristic of the syndrome.
Acral keratosis is present in more than half of all patients.2,4,5 It occurs on the dorsal surface of the hands and feet, resembling spotted keratosis with a central depression.2 It belongs clinically to verruca vulgaris,2,13 yet papillomavirus has not been detected until now.13
In addition to these characteristic mucocutaneous findings, a variety of lesions has been regularly described in CS, including achrocordon, lipoma, angiolipoma, hemangioma,xanthomatosis, vitiligo and café-au-lait spots.1 In the case report the presence was observed of a solitary lipoma in the frontal region.
The importance of this disease arises from the cutaneous findings and malignant or benign disorders present in other systems and organs,3 in particular the thyroid gland, breast, gastrointestinal tract and nervous system. These extracutaneous findings are present in 90% of patients, and various congenital abnormalities are also involved.6
The most frequent extracutaneous manifestation is thyroid disease,2,7 which may occur in roughly 65% of patients,4,7,14 affecting both sexes equally.13 AAlthough the lesions are usually of benign nature, like goiter, adenomas, thyroiditis, hypo - and hyperthyroidism and thyroglossal duct cyst, thyroid cancer occurs in proportions varying from 3 to 10% of all individuals affected.15,16,19 The most frequent histological type in this neoplasia is follicular neoplasia, but papillar neoplasia is more rarely encountered. In the thyroidian investigation of the present case, hypoecoic nodule was made evident in the right lobe of the gland.
Breast affection translates as a fibrocystic disease,2,4,5 and has been encountered in all of the female patients.3 Fibroadenomas are also very common, occurring in roughly 80% of cases.2,3,4,7,13 Breast cancer is the most serious consequence in CS.7,13,15,19 It involves a proportion ranging from 30 to 50% of women affected. 25% of patients are at risk of contracting bilateral affliction of the neoplasia.13 The average age at which breast cancer appears is 40 years, which is earlier than for the malignancy not associated with the syndrome.2,13 Fibrocystic disease is always a precedent in patients who go on to develop breast cancer. In the original case, described by Lloyd and Dennis, the patient was submitted to a bilateral mastectomy due to an inflammatory ulcerated fibrocystic disease. Microscopic tests of the excised tissue revealed focuses of proliferation indistinguishable from intraductal carcinoma.3 Intraductal florida papilloma and atypical ductal hyperplasia, high risk markers for breast cancer, are often reported in the histopathological mammary substrate in women with CS. Patients with the syndrome have to be followed up by a mastologist, and often submitted to self-examinations and specialized examinations, including mammography. Some authors indicate bilateral prophylactic mastectomy.2,4,13 In male patients gynecomastia may be found,2 however no case of breast cancer in men has been described in association with CS.2,13
The abnormalities in TGI include polypoid lesions that may develop at some point in its course, like rectosigmoid colon, duodenum, Delgado intestine and esophagus,14 in decreasing order of affliction; the anus may be affected as well.2,13 Such polyposes are typically small, multiple and sessile. The histological form of the gastrointestinal lesions may be hamartomous, lipomatous, lymphomatous, inflammatory, hyperplastic and occasionally adenomatous.7 The degenerative potential of these polyps is low.2,8 Few cases of colon carcinoma have been reported, and a premalignant status of this syndrome has still not been established in relation with TGI.14 The esophagogastroduodenoscopy and colonoscopy performed in the case report demonstrate esophageal, gastric, duodenal, colonic, cecal and rectal polyposes.
The differential diagnosis of polyposis in CS includes familiar polyposis, Gardner's syndrome, Peutz Jeghers's syndrome, Turcot's syndrome, Cronkhite-Canada syndrome and multiple adenomatosous polyposis. Other findings included colonic cysts, hamartomas and hepatic cysts.3,13
The nervous system may be affected in diverse ways;3,4 ganglioneuroma and symptomatic or asymptomatic neurofibroma, which may be found incidentally or in association with cutaneous lesions.3 Recently Lhermitte-Duclos disease (DLD) was considered a neurological manifestation of CS.7,12,13,15,19 It is characterized by the peculiar proliferation of ganglionar cells in the brain, leading to the substitution of granular cells and Purkinje cells, which represent a hamartoma of the neural tissue.2 Patients customarily show signs of intracranial hypertension, hydrocephalus, cerebral and cranial nerve dysfunction.12,13 Koch et al.12 recommend a magnetic resonance exam of the skull in all patients, mainly those who show megalencephaly.12 Other neurological findings include pseudotumor cerebri, subarachnoid hemorrhage, arterio-venous malformation, meningeoma, and electroencephalographic alterations. The neurological sequelae include low intelligence, motor disturbance and convulsions.12
In children, only macrocephalus and mental retardation can be found. In the magnetic resonance performed, an image was found to be suggestive of cavernous hemangioma in the left frontal region, though without clinical repercussions.
The abnormalities in the female genitourinary tract commonly comprise menstrual irregularities,2,3 ovarian cysts and leiomyomas.2 Other less frequent tumors are teratoma, uterine fibromas, adenocarcinomas, urethral and cervical carcinomas, vaginal cysts, adenocarcinomas of the kidney and benign polyposes of the urethra.2,13 In the male genitourinary tract hydrocele, varicocele and hypoplastic testicules may be found.13
A third of SC patients have skeletal defects among which one finds increased skull circumference,2,4 characterizing one of the most common extracutaneous findings. Other skeletal alterations found are adenoid facies,5,7 cyphosis, cyphoscoleosis, pectus excavatum, big hands and feet and syndactyly.2,13 Structural abnormalities of the oral cavity include mandibular and maxilar hypoplasia, high arch of the hard palate,7microstomia, hyperplasia of the soft palate and uvula, scrotal tongue, periodontitis and extensive dental cavities.9,13
Regarding eye alterations, lenticular opacity, hypertelorism, congenital vascular abnormality of the bottom of the eye, glaucoma, angioid streaks, cerebral pseudotumor, retinal glioma and myopy. Yang et al.5report a case of CS associated with congenital nystagmus.
In relation to the cardiovascular system, hypertension was observed, as were defects in the atrial septum, mitral valve prolapse and aortic and mitral insufficiency.7 Nevertheless, it is difficult to know whether these findings are part of the syndrome or only coincidences.2
Respiratory tract abnormalities associated with CS are rarely described. Findings consist of hamartomas, larynx polyps, pulmonary cysts, and arterio-venous malformations.6 Solli et al.6 described a case of multiple bilateral pulmonary lipomatosa. Performing computerized thoracic axial tomography did not demonstrate any significant alterations.
Seldom described associations with CS include merckel cell carcinoma, renal cell carcinoma, cutaneous squamous cell carcinoma, transitional cell bladder carcinomas, endometrial adenocarcinoma, lymphomas,4,5 leukemias5 and malignant melanoma.13,17
In spite of the wealth of clinical manifestations, most characteristic with CS are mucocutaneous lesions that translate into a combination of orofacial hamartomas and acral keratosis.4,5,6 Yet many patients do not show the complete form, due to variable degrees of penetration in the syndrome.
Based on these aspects, Salem and Steck,2,5,18 in 1983, proposed the following diagnostic criteria, divided into major and minor criteria, and family history. (Table 1)
The diagnosis was considered definitive in the presence of two larger criteria; a major criterion and minor one; a major criterion and positive family history, or two minor criteria and positive family history.
The genetic and molecular aspects in CS have been investigated in depth.6,7 The PTEN/MMAC1 gene, a tumor suppressor gene, was recently localized in chromosome 10q 22-2312,13,16,19 and made responsible by the breast and thyroid malignancies found in CS. Mutations in the PTEN gene identified in acquaintances and patients with CS may be the cause behind the tendency for disordenate tissue proliferation, leading to the formation of hamartomas.12,15,19
The syndrome is inherited with an autossomal-dominant trace, exhibiting a high degree of penetration and large variation of expressivity,1 which enables the identification of discreet manifestations among the patient's relatives or even cases of negative family history. Identification of the gene involved in CS enables the pre-symptomatic diagnosis of the disorder.15
CS treatment is controversial and aims principally toward improving the aesthetic aspect of the lesion and to the active search for associated neoplasias.
Facial trichilemmomas and oral papillomas may be excised by means of laser,2,21 electrosurgery, dermoabrasion or liquid nitrogen,21 which is more beneficial for the patient. However all removed lesions recur quickly. Topical applications of tritinoin have little therapeutic success.21
As with the skin, the experiment conducted by Gentry et al.3 demonstrated that excision of polyps, with fulguration of the base, does not eradicate the lesions. The sigmoidoscopic exam segment showed evidence in two cases of the recurrence of benign lesions at the same site as previous neoplasms. Cnudde et al.10 report a case of CS associated with psoriasis, in which acitretine was introduced in a 0.75 mg per kg daily dose for treatment of the latter. Regression of the psoriatic and SC-related cutaneous lesions was detected over a three-month period, though follow-up to the digestive lesion was not performed. The mucocutaneous manifestations show particular sensitivity to oral retinoids,10 but the regression of lesions was transitory, with the initial aspect reappearing when the retinoid dose was tapered or the treatment interrupted.
Thivolet et al.,11 in turn report a case of a CS patient treated with 30 mg daily of etritinate for nine months, which confirmed the spectacular disappearance of cutaneous manifestations and the marked reduction of rectal polyposis.
To be sure, medical doctors and odontologists must be able to recognize the presence of CS signs and symptoms as clinical markers for the identification of patients at high risk of developing internal neoplasias. The possibility of breast and thyroid carcinoma must always be borne in mind. As such, all of the patients have to be rigorously submitted to a search for hidden malignancies, with an emphasis on the breasts, thyroid gland, gastrointestinal tract and nervous system. Early recognition and management of these associations may reduce the morbidity and mortality present in Cowden's syndrome.5
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Patricia de Barros Guimarães
Rua da Harmonia 430/804
Casa Amarela Recife PE 52051-390
Tel/Fax: (81) 3441-5792
Received in March,
12th of 2001.
Approved by the Consultive Council and accepted for publication in March, 23th of 2002.
* Work done at "Hospital das Clínicas da Universidade Federal de Pernambuco"