Cowden syndrome (CS) is an autosomal dominant disorder characterized by presence of multiple hamartomas, and other benign and malignant abnormalities of the breasts, skin, thyroid, endometrium, gastrointestinal tract, and central nervous system. Hamartomas are benign, developmentally disorganized tumors that can develop in any of the above mentioned organs. The presence of massive calcifications in the breasts in very young women is an indication to perform a breast MRI to exclude a neoplasm since, like in the current case report, presence of breast calcifications may obscure a neoplasm. Although fibrocystic disease and cooccurrence of fibrocystic disease and breast cancer are much more common than CS, the presence of massive calcifications in the breasts of very young women should elicit the possibility of an underlying genetic disease. Furthermore, breast cancer and macrocephaly are considered major criteria for the diagnosis of CS and the combination of both is enough to establish the clinical diagnosis of this entity. Fibrocystic disease of the breasts and multinodular goiter are minor criteria. Family history is also important for the diagnosis of (any) hereditary disease.
A 26-year-old woman was diagnosed with breast cancer from biopsy of an axillary lymph node. An ultrasound (Figure
Ultrasound shows multiple, ill-defined hypoechoic areas with acoustic shadowing, indicating multiple coarse calcifications within the right breast (arrows).
Transverse T2-weighted images show multiple coarse calcifications in both breasts ((a) small arrows) and a large, lobulated mass in the lower lateral quadrant of the right breast ((b) white arrow).
Contrast-enhanced (subtraction) MR images (a) and contrast-enhanced T1-weighted MR images (b) show a large, lobulated heterogeneously enhancing mass with irregular borders in the lower lateral quadrant of the right breast (arrows).
The patient underwent annual breast ultrasound because of a family history of breast cancer. In addition, she had a history of multinodular goiter. By physical examination, it was also apparent that she had a relatively large head in relation to her length (length 170 cm and head circumference 61 cm, i.e., above 97th percentile). According to the patient, macrocephaly is a common feature in her family. Family history also revealed that the patient’s mother had breast cancer at the age of 45. The patient’s identical twin is known to have breast fibrocystic disease (Figure
Patient’s sister mammography (mediolateral oblique direction shown) showed massive calcifications in multiple, well-defined masses, some of them with adipose tissue, diagnostic of hamartomas.
In Figure
Biopsy results showed that the patient had a locally advanced, invasive, well-differentiated ductal carcinoma in the right breast which was obscured on annual ultrasound due to massive calcifications by hamartomas.
The radiological images, together with the thyroid pathology and macrocephaly, suggested Cowden syndrome (CS) as most likely underlying cause, which was later confirmed by identification of a germline splice-site mutation: c.634 + 2T > C in intron 6 of the
The patient was treated with neoadjuvant chemotherapy with a partial response, followed by a modified radical mastectomy and preventive contralateral mastectomy, and by locoregional radiotherapy (because of 5 positive axillary lymph nodes) plus adjuvant endocrine therapy.
The presence of massive calcifications in the breasts in a very young woman is a plausible indication to perform an breast MRI to exclude a neoplasm since, like it was the case in our patient, the presence of breast calcifications may obscure a neoplasm. Although fibrocystic disease and co-occurrence of fibrocystic disease and breast cancer are much more common than CS (which has an estimated prevalence between 1/200,000 and 1/250,000 in the Dutch population [
Cowden syndrome, OMIM# 158350 [
The National Comprehensive Cancer Network (NCCN) has established diagnostic criteria for CS, based on combinations of features classified as pathognomonic, major, and minor [
Operational diagnosis of CS in an individual is done when the patient has any of the following: (1) presence of any pathognomonic lesion (by mucocutaneous lesions a certain number and/of combinations of these lesions are required); (2) two or more major criteria (but one has to be macrocephaly); (3) one major and three minor criteria, or (4) four minor criteria [
A mutation in
In addition to CS, germline
Breast cancer is the most frequent malignancy of CS. It occurs in 30–50% of patients, with an average age of diagnosis between 38 and 46 years, with the youngest reported case at age 14. Risk of bilateral breast cancer is estimated to be 25% [
Although breast MRI examinations, only represent a small percentage of the MRI examinations performed, its use is growing rapidly. MRI is more sensitive than mammography in detecting tumors in women with an inherited predisposition due to mutation in
In conclusion, when massive breast calcifications in mammograms of young women are observed, the diagnosis of CS has to be considered. A breast MRI is indicated in those cases to exclude a neoplasm.