Cowden’s syndrome is named after Rachel Cowden, the first patient who was described as having many of the characteristic changes found in this patient group (10). Cowden’s syndrome is rare. A Dutch clinical epidemiological study from 1999 estimated its prevalence to be between 1 : 200 000 and 1 : 250 000 (11), but as the syndrome has a variable clinical presentation and is often difficult to recognise, this is believed to be an underestimation (9). Increased possibilities for genetic testing may help to determine the prevalence of the disease, also in subjects who do not meet the classical clinical criteria. It is estimated that 10 – 47 % of persons with PTEN mutation have a de novo mutation (12), i.e., neither of the patient’s parents has the mutation.
The great variation in clinical expression of Cowden’s syndrome makes diagnosing it a challenge. Not all patients found to have a defective PTEN gene meet the clinical criteria for the syndrome. Similarly, there may be patients who meet the clinical criteria for Cowden’s syndrome, but who do not have a detectable PTEN gene mutation (13). Many features of Cowden’s syndrome are subtle and occur frequently in the general population. Clinical findings in various organs such as the skin, thyroid, breast, bowel, central nervous system and soft tissue, including the vascular and urogenital systems, result in patients being attended to by a variety of medical specialists, with a risk of the overall picture not being seen. Dermatologists are often the first to meet patients with the syndrome (14, 15). Detection of a PTEN mutation makes it possible to treat premalignant conditions and thereby improve survival. The patient’s relatives (parents, siblings and children) should be offered genetic testing. In rare cases, children with PTEN gene defects may develop cancer in addition to benign nodules in the thyroid gland (8). It is therefore permissible to test children for this defect. In the event of findings of multiple mucocutaneous papules in young patients, Cowden’s syndrome should be ruled out. Breast and endocrine surgeons who treat breast and thyroid lesions should also have Cowden's syndrome in mind as a possible diagnosis.
Pathologists have a key and vital part to play in detecting the syndrome (16). New and improved pathology databases with an overview of all specimens submitted for testing from each patient have given pathologists an important diagnostic means of identifying patients who should be tested for PTEN mutation. From a histopathological point of view, findings of a large number of tightly packed follicular adenomas and adenomatous colloid nodules should result in a remark in the results urging clinicians to consider referral for genetic study with Cowden's syndrome in mind. Follow-up is recommended for patients in whom PTEN mutation is detected with a view to preventing malignant neoplasms or detecting neoplasms at an early stage. Guidelines for follow-up have changed over time, and vary somewhat across institutions. As a result, we have established guidelines during the past few years (8, 13) (Box 2).
The box is modified from Tan et al. and Gammon et al. (8, 13)
Annual thyroid ultrasound is seldom relevant before the age of ten. Prophylactic thyroidectomy can be considered if it is difficult to assess the gland because of multiple nodules.
Annual mammography and MRI scan of the breasts from the age of 25. Prophylactic mastectomy should be considered.
Annual uterine screening with ultrasound and possibly endometrial cytology tests from the age of 30.
Basic cutaneous examination after genetic testing. Follow-up as needed or about every fifth year.
Annual renal ultrasound from the age of 40.
Colonoscopy every five years from the age of 40.
The patient presented in this case history had a complex of clinical symptoms and findings for several years without their arousing suspicion of a genetic connection. The pathologists reacted to the histological appearance of the thyroid specimen, as a result of which the patient was referred for genetic study. Knowledge of, and focus on Cowden’s syndrome has been increasing both in Norway and internationally over the past ten years, not least as a result of steadily improved multidisciplinary cooperation. The patient in this case history developed her first symptoms many years before diagnostic criteria and follow-up for this rare disease had been established. Cowden’s syndrome was not mentioned in the patient’s therapy programmes from the period when she was diagnosed with breast cancer. According to today’s breast cancer treatment programme, the patient should have been referred for genetic study. Since histological findings for this patient led to genetic testing and detection of a PTEN mutation, several patients with a PTEN mutation have been found at the Department of Pathology, Oslo University Hospital, following findings of characteristic histological features in thyroid specimens.
When the patient in question was referred for genetic study 12 – 13 years earlier because of her family history, she had not yet been found to have cancer. This, coupled with the fact that the testing options were limited at that time, meant that there was no indication for further genetic study. In the case of this patient, early suspicion of Cowden’s syndrome on the part of one or more of the clinicians who treated the patient and subsequent genetic testing might have led to prevention or early diagnosis of her mammary carcinomas.
This case study shows that interdisciplinary cooperation on patients with a complex of symptoms and findings is important. Multidisciplinary meetings at which medical history, symptoms, and clinical, radiological and pathological findings are presented and discussed could contribute to syndromes like Cowden’s being detected so early that prophylactic measures can be implemented.