Cowden syndrome (CS) is an autosomal dominantly inherited multiple hamartoma syndrome characterized by an increased risk of breast, thyroid, and endometrial cancer. Germline mutations in PTEN, encoding a lipid and protein phosphatase on 10q23.3, are associated with a subset (25–80 %) of CS (Eng et al. 2003; Zhou et al. 2003a, b; Eng and Peacocke 1998; Zbuk and Eng 2007; Tan et al. 2011).

Clinical diagnosis is often a challenge, because of the protean manifestations of CS, many of which can occur in isolation in the general population. For this reason, the true incidence is not known. After identification of PTEN as the CS gene, a molecular-based study revealed the incidence to be at least 1 in 200,000 (Nelen et al. 1997, 1999), although this is likely still to be an underestimate. Because CS is underdiagnosed, the proportion of apparently sporadic cases and familial cases (two or more affected individuals) is not precisely known. As a broad estimate, perhaps 40–65 % of CS cases are familial (Marsh et al. 1998; Marsh et al. 1999; Eng, unpublished observations, 2011).

The lack of uniform diagnostic criteria for CS prior to 1995 led to the formation of the International Cowden Consortium (C. Eng, Coordinator and Chair, [email protected]), which represented a group of centers mainly in North America and Europe interested in systematically studying this syndrome to localize the susceptibility gene. The consortium arrived at a set of consensus operational diagnostic criteria based on published data and expert opinion (Nelen et al. 1996; Eng and Parsons 1998). These criteria have been revised annually in the context of new molecular-based data and are reflected in the practice guidelines of the US-based National Comprehensive Cancer Network Genetics/High-Risk Panel (NCCN 1999; Eng 2000a, b; Hobert and Eng 2009) ( for 2005 and 2006 revisions which remain the best sets of criteria) as follows:

1. Pathognomic criteria:

(a) Mucocutaneous lesions:

Trichilemmomas, facial Acral keratoses Papillomatous papules
Mucosal lesions (e.g., scrotal tongue) Lhermitte–Duclos disease (LDD)

2. Major criteria:

(a) Breast carcinoma, invasive

(b) Thyroid carcinoma, epithelial, especially follicular thyroid carcinoma and follicular variant of papillary thyroid carcinoma

(c) Macrocephaly (megalencephaly) (>97th percentile)

(d) Endometrial carcinoma


3. Minor criteria:

(a) Other anatomic thyroid lesions, e.g., adenoma, multinodular goiter, Hashimoto’s thyroiditis

(b) Developmental delay

(c) GI hamartomas (GI polyposis of any histology)

(d) Fibrocystic disease of the breast

(e) Lipomas

(f) Fibromas

(g) Genitourinary Tumours (e.g., renal cell carcinoma, uterine fibroids) or malformation (e.g., bicornuate uterus, duplicated collecting ducts)

Operational Diagnosis in an Individual:
1. Mucocutaneous lesions alone if:

(a) There are 6 or more facial papules, of which 3 or more are trichilemmomas

(b) There are cutaneous facial papules and oral mucosal


(c) There are oral mucosal papillomatosis and acral keratoses

(d) There are palmoplantar keratoses, 6 or more

  1. 2 Major criteria, but one must include macrocephaly or LDD

  2. 1 Major and 3 minor criteria

  3. 4 Minor criteria

Operational Diagnosis in a Family Where One Individual Is Diagnostic for Cowden Syndrome (by Clinical Criteria or by Gene Status):
1. Pathognomonic criterion/criteria

  1. Anyone major criterion with or without minor criteria

3. Two minor criteria

While the original intent of the International Cowden Consortium operational diagnostic criteria and the NCCN criteria were for the gene hunt (former) and for early clinical practice (both sets of criteria), the criteria would result in a dichotomous response, namely, meets criteria or does not meet criteria. Necessarily, these related two sets of operational criteria were based on retrospective data from exaggerated cases (full criteria mainly by pathognomic and major criteria) and familial cases. Recently, multiple logistic regression analysis of comprehensive PTEN mutation data from a >10-year prospective accrual of probands by a minimum of relaxed Consortium operational criteria from multiple centers, including the community, has resulted in a continuous score, the PTEN Cleveland Clinic Score (, based on key phenotypic features (Tan et al. 2011). Because the key phenotypic features present in children and adults are quite different, two sets of criteria are utilized depending on age groups. A PTEN CC score of >10 in adults, relating to a prior probability of >3 % of finding a pathogenic PTEN mutation, was selected as the clinical threshold for considering PTEN testing/referral to genetic specialists (Tan et al. 2011).

More than 90 % of individuals affected with CS are believed to manifest a CS phenotype by the age of 20 years (Nelen et al. 1996; Eng 2000b). By the end of the third decade (i.e., 29 years), 99 % of affected individuals are believed to have developed at least the mucocutaneous signs of the syndrome, although any of a number of component features can manifest as well. The most commonly reported manifestations are mucocutaneous lesions; thyroid abnormalities; fibrocystic disease and carcinoma of the breast; multiple, early-onset uterine leiomyoma; and macrocephaly (specifically, megencephaly) (Starink et al. 1986; Hanssen and Fryns 1995; Mallory 1995; Longy and Lacombe 1996; Eng 2000b; Ngeow et al. 2011).

The two most well-documented component malignancies are carcinomas of the breast and epithelial thyroid gland (Starink et al. 1986; Zbuk and Eng 2007; Hobert and Eng 2009). Historically, lifetime risks for female breast cancer are estimated to range from 25 to 50 % (Starink et al. 1986; Longy and Lacombe 1996) in contrast to 11 % in the general population. The age at diagnosis ranges between 14 and 65 years, with a mean around 40–45 years (Starink et al. 1986; Longy and Lacombe 1996). The histopathology of CS breast cancer is adenocarcinoma of the breast, both ductal and lobular (Schrager et al. 1997). Male breast cancer may be a minor component of the syndrome (Marsh et al. 1998; Fackenthal et al. 2001). In a recent prospectively accrued series of PTEN pathogenic mutation-positive CS and CSL cases, the lifetime risk for female (invasive) breast cancer was calculated to be 85 % with age- and sex-adjusted standardized incidence rates (SIR) of >25 (Table 1) (Tan et al. 2012). This is much higher than pre-gene estimates and should be duly considered during risk management. Interestingly, this series did not note an elevated PTEN-related male breast cancer risk. The lifetime risk for differentiated thyroid cancer can be as high as 10 % in males and females with CS. A recent prospective series has revealed that individuals with germline pathogenic PTEN mutations have a 35 % lifetime risk of epithelial thyroid carcinoma (1) with SIR of 50–72 (Ngeow et al. 2011; Tan et al. 2012). In this large series, follicular thyroid carcinoma (FTC) was overrepresented among adults with PTEN mutations. While papillary thyroid carcinomas (PTC) were also observed, one-third of these were the follicular variant (FvPTC). All six children (<18 years of age) who were found to have pathogenic PTEN mutations had thyroid cancer, but interestingly all were PTC (Ngeow et al. 2011). With this new series, it is now obvious that the age at diagnosis of thyroid cancers is truly earlier (mean age 37.5 years) than that in the general population, and even children can develop PTC. Interestingly, PTEN frameshift mutations were found in 31 % of those with thyroid cancer and only 17 % of those who did not (Ngeow et al. 2011).

Table 1   Lifetime risks of PTEN-related malignancies and age-related penetrance

Malignancy Lifetime risk (%) Penetrance by age 50 years (%) Comments
Breast cancer 85 40 Females at risk only
Thyroid cancer 25
Endometrial cancer 28 20 Females only
Colorectal cancer 10 1
Renal cell cancer 34 10
Melanoma 6 5

Endometrial carcinoma was also considered to be a putative component cancer of CS in the previous genotype-phenotype and case studies (Marsh et al. 1998; DeVivo et al. 2000; Eng 2000b). In a prospective series of pathogenic PTEN mutation-positive CS and CSL cases accrued from academic and community-based healthcare facilities, the SIR of endometrial cancer was > 40, with lifetime risk of 28.2 % (Table 11.1) (Tan et al. 2012). For the first time, elevated lifetime risks of renal carcinomas (34 %) and melanoma (6 %) were noted in PTEN mutation-positive individuals.

Prior to 2010, exponents believed that hamartomatous polyps were component of CS but that colorectal carcinomas were not part of the disease spectrum. However, in a recent prospective study of a series of individuals carrying pathogenic PTEN mutations, >90 % of those who received colonoscopies were found to have polyps (Heald et al. 2010). Surprisingly, polyps of all histologies and an elevated SIR (10–100) for colorectal cancers were noted, with the earliest age at diagnosis of cancer being 35 years and the oldest 50 years (Tan et al. 2012). The lifetime risk of PTEN-related colorectal cancer is almost 10 % (Tan et al. 2012). All but one person with colorectal cancer had pre-/coexisting colonic polyposis.

The most common nonmalignant component lesions include trichilemmomas (hamartoma of the infundibulum of the hair follicle) and papillomatous papules (90–100 %), thyroid adenomas and goiter (67 %), breast fibroadenomas and fibrocystic disease (75 %), macrocephaly (>80 %), and genitourinary abnormalities (40 %) including uterine fibroids and malformations (Mester et al. 2011; Ngeow et al. 2011). A rather striking nonmalignant hamartoma is LDD or dysplastic gangliocytoma of the cerebellum (Eng et al. 1994), which usually manifests later in life, initially with subtle degrees of dysmetria on intent, progressing to frank ataxia. A small series of incident LDD cases revealed that many adult-onset LDD carried germline PTEN mutations (Zhou et al. 2003a).

CS was mapped to 10q22–q23 (Nelen et al. 1996). Germline mutations in PTEN have been found in 85 % of CS probands diagnosed by the strict International Cowden Consortium criteria when accrued by select academic centers (Marsh et al. 1998; Zhou et al. 2003b). In contrast, a large series accrued from the community revealed that ~25 % of probands meeting the strict International Cowden Consortium criteria were found to carry pathogenic PTEN mutations (Tan et al. 2011). These mutations result in loss of function, and the majority occur in exons 5, 7, and 8, which encode the phosphatase domain, although mutations can occur throughout the gene including the promoter (Zhou et al. 2003b). Germline mutations in PTEN have also been found in approximately 60 % of individuals with BRRS accrued from select academic tertiary referral centers (Marsh et al. 1997; 1999). Thus CS and BRRS are allelic. Compared to PTEN mutations in CS, mutations in BRRS tend to occur in the 3′ half of the gene (Eng et al. 2003). There is a genotype-phenotype association in CS (Marsh et al. 1998): families found to have germline PTEN mutations have an increased risk of malignancy, in particular, breast cancer. The presence of both CS and BRRS features in a single family, of glycogenic acanthosis of the esophagus, or of LDD, increases the prior probability of finding a PTEN mutation (Marsh et al. 1999; McGarrity et al. 2003; Zhou et al. 2003b).

Germline PTEN mutations have also been described in up to 20 % of Proteus syndrome and up to 50 % of Proteus-like syndrome cases (Zhou et al. 2000, 2001; Smith et al. 2002). Germline mutations in PTEN have been described in single patients with megencephaly and VATER association and with megencephaly and autism (Dasouki et al. 2001; Reardon et al. 2001).

Multiple studies of individuals with autism or autism with macrocephaly have now confirmed that PTEN mutations occur in ~10 % of those with autism spectrum disorder and macrocephaly (Butler et al. 2005; Herman et al. 2007; Varga et al. 2009).

It was puzzling that the PTEN mutation frequency in classic CS in the general population was 25 %, yet the original linkage studies suggested no genetic heterogeneity. Recently, a new gene named KLLN (encoding KILLIN) was discovered immediately upstream of PTEN, with KLLN and PTEN sharing a single bidirectional promoter. Germline epimutation (promoter methylation) of KLLN was shown to be associated with approximately one-third of CS and CS-like individuals who lacked germline PTEN mutations (Bennett et al. 2010). Interestingly, individuals with germline KLLN epimutation had a higher frequency of breast and renal cancers than those with germline pathogenic PTEN mutation (Bennett et al. 2010). The age-/sex-adjusted SIR for epithelial thyroid carcinoma for KLLN epimutation was found to be 45, but in contrast to PTEN mutation, classic PTC was overrepresented in those with KLLN epimutation (Ngeow et al. 2011). Finally, approximately 10 % of individuals with CS without germline PTEN mutations were shown to carry germline missense variants in SDHB or SDHD (Ni et al. 2008, 2012). Individuals carrying these SDH variants had a higher frequency of breast and thyroid cancers. Interestingly, individuals with germline PTEN mutations who also carry SDHx variants had a higher risk of breast cancer than those with germline PTEN mutations alone (Ni et al. 2012). Again, unlike CS with PTEN mutations, the thyroid cancers found in cases with SDH mutations were mainly classic PTC (Ngeow et al. 2011). Recently, germline AKT1 and PIK3CA mutations have been demonstrated in some cases of Cowden syndrome (Orloff et al. 2013).

All individuals with or suspected of having CS or any PTEN-related disorder should be referred to cancer genetic professionals. PTEN mutation analysis is a useful molecular diagnostic test and, in families with a known PTEN mutation, is a good predictive test. With the recent independent validation of germline SDHx variants in CS/CSL individuals (Ni et al. 2012), SDHx testing should also be seriously considered. Once the KLLN epimutation data are validated in independent series, KLLN should be considered in the armamentarium of CS testing.

Until now, surveillance recommendations are based on expert opinion, governed by the component neoplasia, breast carcinoma, epithelial thyroid carcinoma and adenocarcinoma of the endometrium, and now colonic polyps and cancer (Eng 2000b; Pilarski and Eng 2004; Heald et al. 2007; Hobert and Eng 2009) ( Because of a recent prospective series of CS/CSL individuals, we suggest consideration of new potential surveillance recommendations based on the prospective risk data as outlined in Table 11.2 (Tan et al. 2012), although the cancer risk estimates are subject to ascertainment bias and may be overestimated in some series. For example, clinicians should consider thyroid examination and baseline ultrasound at diagnosis of CS or upon finding a mutation defining CS, even in children (Ngeow et al. 2011). Females should begin annual clinical breast examination and breast self-examination around the age of 25 years. Annual breast imaging (mammography, breast MRI) should begin at 30 years. Because of accumulating data on PTEN-related colonic polyposis and cancer, colonoscopic surveillance could begin by 35–40 years or 5 years younger than the youngest age at diagnosis of colon cancer in the family (Heald et al. 2010; Levi et al. 2011) (Table 2). The optimal interval for colonoscopies is currently unknown but could be modified by polyp load. In the past, the recommendation was for the endometrium to be screened clinically beginning at the age of 35–40 years or 5 years younger than the earliest age of endometrial cancer diagnosis in the family: annual blind repeal biopsies prior to menopause and transabdominal ultrasound after menopause. The NCCN in its recent (2009 onwards) revisions has removed endometrial screening because no formal evaluation studies have been completed. However, in view of the new prospective data which have yielded a much higher lifetime risk of endometrial cancer than previously believed, endometrial surveillance could be reconsidered (Table 11.2) (Tan et al. 2012). Clinicians who look after CS patients should be mindful to note any other seemingly non-component neoplasias, which might be overrepresented in a particular family as well.

Table 2   Recommendations for diagnostic workup and cancer surveillance in patients with   PTEN mutations

Pediatric (<18 years) Adult male Adult female
Baseline workup Targeted history and physical examination Targeted history and physical examination Targeted history and physical  examination
Baseline thyroid ultrasound Baseline thyroid ultrasound Baseline thyroid ultrasound
Dermatological examination Dermatological examination Dermatological examination
Formal neurological and psychological testing
Cancer surveillance
From diagnosis Annual thyroid ultrasound and skin examination Annual thyroid ultrasound and skin examination Annual thyroid ultrasound and skin  examination
From age      As per adult

30a               recommendations

Annual mammogram (for consideration of breast MRI instead of mammography if dense  breasts)
Annual endometrial sampling or transvaginal ultrasound (or from 5 years before age of earliest endometrial cancer in family)
From age      As per adult

40a               recommendations

Biannual colonoscopyb Biennial colonoscopyb
Biannual renal ultrasound/MRI Biennial renal ultrasound/MRI
Prophylactic surgery Nil Nil Individual discussion of prophylactic mastectomy or hysterectomy

aSurveillance may begin 5 years before the earliest onset of specific cancer in the family, but not later than the recommended age cutoff bThe presence of multiple nonmalignant polyps in patients with PTEN mutations may complicate noninvasive methods of colon evaluation. More frequent colonoscopy should be considered for patients with a heavy poly burden

With the elucidation of the PTEN-AKT-mTOR signaling pathway, targeted therapeutics hold great promise. mTOR inhibitors are being used in clinical trials for Cowden syndrome patients, specifically PTEN hamartoma Tumours syndrome, and efficacy has been demonstrated in a related phakomatosis, tuberous sclerosis complex, and in the somatic setting in malignancies where upregulation of mTOR signaling is evident.

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