Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients

Abstract

Background: Cancer risk and Lhermitte-Duclos disease (LDD) risk estimates for Cowden syndrome (CS) are broad and based on a small number of patients. Risk estimates are vital to the development of diagnostic criteria, genetic counseling, and cancer surveillance. To further elaborate and estimate the risks associated with CS, a large cohort of patients was evaluated.

Methods: CS patients were identified from the medical literature and the Mayo Clinic's records. All patients met accepted diagnostic criteria for CS.

Results: A total of 211 CS patients (age 44 +/- 16 years, 64% female, 46% PTEN mutation) were included (published literature 90% and Mayo Clinic series 10%). The cumulative lifetime (age 70 years) risks were 89% for any cancer diagnosis (95% confidence interval (CI) = 80%,95%), breast cancer [female] 81% (CI = 66%,90%), LDD 32% (CI = 19%,49%), thyroid cancer 21% (CI = 14%,29%), endometrial cancer 19% (CI = 10%,32%), and renal cancer 15% (CI = 6%,32%). A previously unreported increased lifetime risk for colorectal cancer was identified (16%, CI = 8%,24%). Male CS patients had fewer cancers diagnosed than female patients and often had cancers not classically associated with CS. Seven percent of breast and thyroid cancers occurred in patients who were younger than the recommended age to commence radiographic cancer screening. There was a trend for patients with a family history of CS and PTEN mutations to have a lower cancer risk than those without.

Conclusions: This study confirms CS patients are at increased risk for cancer and quantitative data is provided to guide clinical care. Based on a different tumor spectrum, separate male and female clinical CS diagnostic criteria may be indicated.

Figure 1

A clinical array of the cancer and Lhermitte-Duclos disease (LDD) diagnoses in the 136 female Cowden syndrome patients included in the study. Each column of rectangles represents an individual patient. A diagnosis is indicated by a shaded box containing a "1". Rows represent cancer or LDD diagnosis: BCA (pink) - breast cancer (n = 61 cases); BBC (magenta) - bilateral breast cancer (n = 21 cases); LDD (teal) - Lhermitte-Duclos disease (n = 24 cases); TCA (yellow) - thyroid cancer (n = 23 cases); ECA (violet) - endometrial cancer (n = 12 cases); RCA (blue) - renal cancer (n = 5 cases); SCA (green) - skin cancer (n = 8 cases); Oth (grey) - other cancers (n = 12 cases); CRC (brown) - colorectal cancer (n = 5 cases). Patients were sorted into groups and subgroups by cancer diagnosis (hierarchical sorting). This aids identification of the clustering of one cancer diagnosis with another. Patients were first sorted into those with and without breast cancer. Those with breast cancer were then sorted into those with and without bilateral breast cancer. Each of the subgroups (breast cancer, bilateral breast cancer, and no breast cancer) were then sorted into those with and without LDD and then into those with and without thyroid cancer. Figure formatting taken from Faghri and others [14].

Figure 2

A clinical array of the cancer and Lhermitte-Duclos disease (LDD) diagnoses in the 75 male Cowden syndrome patients included in the study. See the caption of Figure 1 for an explanation of figure color coding and formatting. The diagnoses were LDD n = 11 cases, thyroid cancer n = 5 cases, other cancers n = 12 cases, skin cancer n = 5 cases, colorectal cancer n = 5 cases, renal cancer n = 3 cases, and breast cancer n = 2 cases. Patients were sorted into groups and subgroups by cancer diagnosis (hierarchical sorting). Patients were first sorted into those with and without LDD. Then those with LDD were sorted into those with and without thyroid cancer. Next the subgroups were sorted into those with and without other cancers, followed by those with and without skin cancer.

Figure 3

Cumulative risk of any cancer diagnosis in female (red) and male (blue) patients with Cowden syndrome from birth to age 70 (Kaplan-Meier).

Figure 4

Cumulative risk of breast cancer diagnosis in female patients with Cowden syndrome (CS) from birth to age 70 (Kaplan-Meier). Sixty-one of 136 female CS patients and 2 of 75 male CS patients were diagnosed with breast cancer.