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Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients
© Riegert-Johnson et al; licensee BioMed Central Ltd. 2010
Received: 13 January 2010
Accepted: 17 June 2010
Published: 17 June 2010
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.
CS patients were identified from the medical literature and the Mayo Clinic's records. All patients met accepted diagnostic criteria for CS.
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.
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.
Diagnostic criteria for Cowden syndrome in individuals without a family history
Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma) Mucocutaneous features: Six or more facial papules, ≥3 must be trichilemmomas, or Cutaneous facial papules and oral mucosal papillomatosis, or Oral mucosal papillomatosis and acral keratoses, or Six or more palmo-plantar keratoses
Thyroid cancer (especially follicular)
Macrocephaly (≥ 97% percentile)
Other structural thyroid lesions (for example, multinodular goiter)
Mental retardation (IQ ≤ 75)
Fibrocystic breast disease
Genitourinary tumors (examples include, uterine fibroids and renal cell carcinoma)
Genitourinary structural malformations
Previously reported CS associated cancer risk profiles have varied and are usually illustrated with wide variations. The commonly quoted risks are 25-50% for breast cancer, 5-10% for endometrial cancer, and 3-10% for thyroid cancer . These estimates are based on a collection of case series, each often comprising a small number of patients. In addition to cancer, CS patients are at risk for LDD. LDD is the eponym for a dysplastic cerebellar gangliocytoma, which is pathognomonic for CS. The incidence of LDD in CS is unclear. LDD is usually considered to be a hamartoma and not a cancer, but may still have serious consequences and therefore was included in this study.
As there is a limited evidence base for CS cancer and LDD risks, counseling patients regarding their risks and appropriate surveillance is challenging. This study aims to clarify these issues by reporting cumulative cancer and LDD diagnoses in a large group of CS patients.
The patient cohort was derived from both the published medical literature and the records of the Mayo Clinic (Rochester, Minnesota). The Mayo Clinic Institutional Review Board (IRB) approved this study. Patients from the medical literature were identified by searching http://www.pubmed.com using the terms "Cowden's syndrome" and "Cowden syndrome." Further reports were identified by reviewing the references listed in the initial publications retrieved. Mayo Clinic CS patients were identified through a search of medical records from January 1, 1996 to June 30, 2008 for any patients with the keyword "Cowden" in their records.
Inclusion criteria required all patients to meet accepted diagnostic criteria for CS (Table 1). Patient data was entered into the study database by one author. The database was audited for accuracy by the other authors by reviewing the source information (literature or medical record) for each patient. Importantly, all cases were reviewed to determine if they had been published more than once (duplicate publication). Where the same patient had been published more than once, only the most recent report was included. In some medical literature cases, the age of cancer diagnosis was unclear (for example, "patient had thyroid cancer in their 20 s"). In these cases, the authors made a best estimate. Statistical analysis was performed with JMP 8.0 (SAS Institute, Cary, North Carolina).
A total of 211 patients were included in the final version of the study database, 90% from the literature (n = 190) and 10% from the Mayo Clinic (n = 21). Cumulative lifetime (age 70 years) risk estimates were made with 210 patients; one literature patient had to be excluded as age data was not available. The literature patients were identified from review of 99 publications. Thirty one additional publications were identified in the literature search for review but were unavailable from the Mayo Medical Library or via inter-library loan. To date, information pertaining to individuals from the Mayo Clinic series had not been published. Patient demographics revealed that the majority were female (64%, n = 136) with a mean age at most recent follow up of 44 ± 16 years.
Cumulative cancer risk by age and site in 210 patients with Cowden syndrome (95% confidence intervals)
Colon and rectum
Cowden syndrome and general population cancer risks
This study: Overall
This study: Cumulative* (95% CI)
General population lifetime risk‡
Colon and rectum
Less than half of male CS patients had a cancer or LDD diagnosis compared to the majority of females with CS (males 45% vs. females 70%). Many males with a cancer diagnosis did not have cancers usually associated with CS (i.e. LDD, breast, thyroid, and renal cancer) (Figure 2). These cancers included three cases of lung adenocarcinoma and solitary cases of carcinoid, testicular seminoma, testicular cancer, trichilemmomal carcinoma, prostate adenocarcinoma, hepatocellular carcinoma, melanoma, transitional cell carcinoma of the bladder, anal squamous cell cancer.
Ages to initiate screening to capture 95 and 100% of reported cancer cases by site
95% of cases (yrs)
100% of cases (yrs)
Colon and rectum
A family history or a possible family history of CS was noted in 53% (n = 111). A PTEN mutation was identified in 46% of patients overall and in 92% of those that had PTEN testing (97 of 105 were mutation positive). The spectrum of PTEN mutations reported was nonsense (41%, n = 40), missense (14%, n = 14), splice site and other (12%, n = 12), and mutation found but type not noted (32%, n = 31). In patients who had PTEN testing, one of four patients without an identifiable mutation had breast cancer compared to 24 of 64 with an identifiable mutation being diagnosed with breast cancer (25% vs. 38%, p = 0.5 Fisher's exact test).
There was no obvious association of the diagnosis of one cancer with the diagnosis of another cancer (as an example, patients who were diagnosed with breast cancer were no more likely to be diagnosed with thyroid cancer than patients who did not have breast cancer) (Figures 1 and 2). Family history of CS or a reported PTEN mutation were less likely to occur in the cancer group, but this trend was not statistically significant (family history odds ratio (OR) 0.6 95% confidence interval (CI) = 0.4, 1.1; PTEN mutation OR 0.7, 95% CI = 0.4, 1.1).
We report that cumulative lifetime CS cancer risks are higher than those previously published. Previously reported risks were overall estimates from small groups of patients. The large cohort of patients studied in this report made it possible to determine cumulative risks with adjustment for the number of patients at risk at a particular age (Kaplan-Meier estimation). The presented findings highlight the importance of determining cumulative lifetime risks in hereditary cancer syndromes.
Ascertainment and publication biases both may have artificially elevated the risks reported here. Evidence of publication bias includes that the proportion of patients with LDD was much higher in the medical literature than the unpublished Mayo Clinic series. As cases of LDD are rare, they are more likely to be published as case reports. Ascertainment and publication bias can be corrected for by excluding probands from the analysis. This approach would have left only 23 patients; a number too small for meaningful analysis.
Cancer surveillance guidelines for Cowden syndrome
Physical examination beginning at age 18 or 5 years before the diagnosis of breast or thyroid cancer in the family.
Baseline ultrasound thyroid examination at age 18 and consider yearly thereafter.
Annual dermatologic exam.
For those without a family history of breast cancer, self breast examination and clinical breast examination are recommended to commence at ages 18 and 25, respectively. Also, mammography and breast magnetic resonance imaging are recommended to begin at ages 30 to 35. Consider prophylactic mastectomy.
Educate on symptoms and consider enrollment in a clinical trial.
CS patients often have colorectal polyps, and it has been unclear if these polyps place such patients at increased risk for colorectal cancer (CRC) [6, 11]. Current recommendations are that CS patients should have average risk CRC screening with colonoscopy beginning at 50 years of age [9, 12]. The elevated CRC risk identified here would support earlier and more intense screening. The authors recommend colonoscopy beginning at age 45 and every 5 years thereafter.
This study did not identify any risk factors for cancer in CS patients. This is consistent with the findings from most other hereditary cancer syndromes. The patients who had a family history consistent with CS had a trend for lower cancer risk than those without a family history. The most likely reason for this is, ascertainment bias; patients with a family history were more likely to be identified by non-malignant CS signs such as skin findings rather than cancer. There was also a trend for lower cancer risk in those with a PTEN mutation. This is possibly the result of individuals suspected to have CS but who do not have a cancer diagnosis having PTEN testing to confirm the diagnosis.
An association between an identified PTEN mutation and breast cancer diagnosis in CS has been reported . Our study does not support this association. The utility of a detailed genotype/phenotype analysis of this study's database is limited and was not performed for several reasons. These include that only half of patients had PTEN testing and of those with a mutation identified most had a nonsense mutation limiting the diversity of mutation types.
Cancer and LDD are critical components to recognizing and diagnosing CS and the current CS diagnostic criteria includes LDD, breast, thyroid, renal and endometrial cancers. Most males did not have cancer and many that did had cancers that are not usually associated with CS. Developers of the clinical criteria for CS diagnosis should consider separate criteria for male and female patients with the male criteria having a decreased emphasis on cancer diagnosis and inclusion of cancers not usually associated with CS. Regardless of the diagnostic criteria used, clinicians should maintain a high degree of suspicion for the often subtle signs of CS.
There was no extramural funding.
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