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ECR 2019 / C-2457
Recognizing Cowden Syndrome; radiological findings to look for
Congress: ECR 2019
Poster No.: C-2457
Type: Educational Exhibit
Keywords: CNS, Thyroid / Parathyroids, Gastrointestinal tract, MR-Diffusion/Perfusion, Ultrasound, CT-Colonography, Diagnostic procedure, Connective tissue disorders, Cancer
Authors: M. Gredilla1, M. LETURIA ETXEBERRIA2, A. Serdio3, J. Elejondo Oddo4, E. Pardo Zudaire5; 1DONOSTIA/ES, 2San Sebastian, Gipuzkoa/ES, 3Donostia - San Sebastián/ES, 4San Sebastián/ES, 5San sebastian/ES
DOI:10.26044/ecr2019/C-2457

Findings and procedure details

We now describe the most common features and pathologies related to Cowden Syndrome, and a variety of radiological findings we should look for when this syndrome is suspected.

 

1.      Mucocutaneous manifestations:

 

Mucosae and skin features are present in around 90-100% of patients with Cowden Syndrome and are many times the initial finding. They begin to appear generally around the second decade of life, in earlier stages than the life-threatening malignancies.

 

The most common lesions are the facial papules, with predilection for the perioral area and oral mucosa, acral keratosis, mucocutaneous neuromas, penile pigmentation and trichilemmomas. The latter, are defined as benign cutaneous hamartomas of the sheath of the hair follicle. The presence of three or more trichilemmomas is considered pathognomonic.

 

2.      Breast cancer:

 

Breast cancer is considered a major criterion, with an estimated lifetime risk for its development of 25-50%, although i is thtought to be underestimated, and some further researches suggest an accumulate risk as high as 81-85%. It is important to emphasise that breast cancer has been reported to be the most frequent malignancy related to Cowden Syndrome, and therefore should always be taken into consideration.

 

It tends to develop in younger patients than sporadic caner, with an average age of 38-46 years. Ductal origin accounts for the majority of these cancers and they usually show an aggressive behaviour, with multifocal and bilateral lesions.

 

Encountering an aggressive, multifocal, bilateral breast cancer, in a young woman, should raise the suspicion of a possible underlying associated genetic disease, such as Cowden Syndrome.

 

Men who present PTEN mutations can also present with breast cancer, although, a clear increase in the risk has not been established.

 

There is not enough evidence to establish an increase in the incidence of benign breast conditions, such as fibroadenomas, nipple or areolar malformations or proliferative fibrocystic diseases.

 

3.      Thyroid:

 

The thyroid is one of the major organs affected in Cowden Syndrome.

 

Benign anomalies are present in 50-70% of the patients with Cowden Syndrome, being adenomas, multinodular goitre and Hashimoto thyroiditis the most frequent ones.

 

Regarding malignancy, thyroid cancer is the second most common Cowden Syndrome associated cancer, appearing exclusively as follicular and papillary carcinomas; overrepresented entities in these patients.

 

Benign anomalies and papillary thyroid cancer are included in the minor diagnostic criteria, whereas follicular thyroid cancer is considered a major one.

 

4.    Soft-tissue hamartomas:

 

Hamartomas are benign tumour-like malformations, considered a developmental error, made up of an abnormal mixture of tissues with mature characteristics and no atypia, mitosis nor necrosis. They are composed of adipose, fibro dense and/or myxoid and anomalous vascular tissues. Hamartomas related to Cowden Syndrome have an average age of appearance of 15 years.

 

The muscle is the most frequent site of appearance, followed by fascia, subcutaneous fat, dermis and rarely bone. They can be found in any body part, in decreasing order: lower limbs, upper limbs, trunk and head and neck.

 

5.      Genitourinary variations:

 

Testicular lipomatosis is a rare benign condition of the testes, characterised by the appearance of hyperechoic lesion on the ultrasound, with no posterior shadow and no vascularity on colour Doppler.

 

As for malignant lesions, renal cell carcinoma has been described, with a lifetime estimated risk of 14-34%. Histological tests have demonstrated these carcinomas to be either papillary or chromophobe. While bilateral diseased has been described, no metastatic disease has been reported.

 

Endometrium carcinoma is another kind of cancer that women with Cowden Syndrome may suffer from, with an underestimated lifetime risk that current reports suggest as high as 28%.

 

6.      Gastrointestinal:

 

Several gastric, duodenal, colonic and rectal polyps may be found, with a high prevalence and frequency. Histologically most of them will be hamartomatous or inflammatory.

 

Glycogenic acanthosis of the oesophagus is a common benign thickening of the oesophageal squamous epithelium. Prevalence related to Cowden Syndrome is unknown, but it must always be taken into consideration when encountering it together with hamartomatous polyps, as both findings are highly suggestive of Cowden Syndrome.

 

A recent increase in the lifetime risk for developing colorectal cancer has been described, with no exact prevalence been reported. They are thought to arise from pre-existing hamartomatous and adenomatous polyps.

 

7.      Neurologic:

 

Macrocephaly is a frequent characteristic seen in children with Cowden Syndrome. Besides, these patients may present associated peculiar facial characteristics (ojival palate, aquiline nose, mandible or maxillary hypoplasia), mental and developmental retardation and autism spectrum disorders, which would support diagnosis.

 

Lhermitte-Duclos disease of the adult or dysplastic gangliocytoma of the cerebellum is a rare but benign and slow-growing cerebellar hamartomatous tumour with unique pathological features. It is considered a pathognomonic feature of Cowden Syndrome occurring in 3rd and 4rd decades of life with no definitive gender preference. It can produce progressive mass effect of the posterior fossa, causing headaches, nausea, vomits, cerebellar ataxia, obstructive hydrocephalus, papilledema and cranial nerve palsies.

 

Neuroimaging evaluation will show the following features:

 

On CT it will appear as a nonspecific hypo-attenuating posterior fossa mass and sometimes occipital bone thinning, suggesting chronicity.

 

MR will show a single and unilateral, non-enhancing cerebellar mass with a striated, thickened and enlarged folia pattern. These striated bands of folia will appear iso- or hypo-intense at T1 and iso- or hiper-intense at T2 weighed images. “Corduroy or tiger-striped” terms are used to describe this characteristic appearance. Normally it does not cause perilesional oedema and intra-lesion calcifications are rare. Vascular proliferation will appear as enhancement areas after contrast administration. Diffusion-weighted sequences will show diffusion restriction, appearing hyper-intense and hypo-intense in diffusion and ADC maps respectively. 

 

Differential diagnosis includes several and varied entities such as subacute cerebellar infarction, cerebellitis, ganglioglioma, meningeal metastasis or granulomatous disease. Regarding the treatment, conservative treatment is preferred in asymptomatic patients, with surgical resection been performed in symptomatic ones.

 

A relation has been established between other tumours; meningioma; and malformations; cavernous and venous angioma, and Cowden Syndrome, although it is difficult to estimate their real frequency.

 

Follow-up:

 

A coordinated multidisciplinary follow-up of these patients is recommended, and surveillance for early cancer detection is critical:

 

-          Thyroid: annual US

-          Mucocutaneous manifestations: annual dermatologic revision

-          Gastrointestinal: colonoscopy every 5 years starting at age 35

-          Genitourinary: Kidney US every 1 or 2 years starting at age 40

-          Breast: annual mammography or MR starting at age 30 to 35 or 5 to 10 years before a family´s earliest breast cancer diagnosis

-          Endometrium: annual transvaginal US and blind suction endometrial biopsies

-          Lhermitte-Duclos of the adult: no surveillance guidelines have been established

 

Following, we exhibit two different cases of two patients diagnosed with Cowden Syndrome in our hospital:

 

Patient 1:

 

It is a 38 year old female with personal history of macrocephaly and multinodular goitre. In the dermatologic exam and colonoscopy she manifested trichilemmomas and colonic hamartomatous polyps respectively, both histologically confirmed. Regarding neurologic findings, she was diagnosed with Lhermitte-Duclos disease of the adult (Fig. 2) (Fig. 3). Genetic and molecular testing was performed identifying PTEN gene mutation.

 

Patient 2:

 

It is a 56 year old male who underwent a complete thyroidectomy because of a papillary cancer. He exhibited multiple mucocutaneous papilloma and gastrointestinal polyps (Fig. 4) that were biopsied and proven to be hamartomatous. He also presented multiple renal cell carcinoma, biopsy confirmed to be chromophobe (Fig. 5), PTEN hamartoma of soft-tissue (Fig. 6), pulmonary hamartomas (Fig. 7), pancreatic lipomas (Fig. 8). Genetic and molecular testing for PTEN gene mutation assessment turned out to be negative, however, this patient was diagnosed with Cowden Syndrome following the diagnostic criteria.

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