Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group Open Access

PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome caused by pathogenic germline variants in the PTEN gene located on chromosome 10q23 (1, 2). PHTS is a molecular diagnosis that encompasses various clinically heterogeneous syndromes including Cowden syndrome, Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome, regardless of clinical presentation (3). PTEN is a tumor suppressor gene that canonically functions within the cytoplasm to antagonize the PI3K/AKT/mTOR signaling pathway, which promotes cell growth, survival, and proliferation (4). PTEN also localizes to the nucleus in which it plays an essential role in maintaining genomic integrity through physical interaction with centromeres and in controlling DNA repair (5). Individuals with PHTS may experience a variety of signs and symptoms including macrocephaly, abnormal skin growths, vascular manifestations, autism spectrum disorder (ASD), and learning and developmental delays (6–9). Notably, individuals with PHTS have significantly elevated lifetime risks of both benign and malignant tumors involving the breast, colon, endometrium, thyroid, skin, and kidney (6–12).

Guidelines on the clinical management of PHTS—primarily focusing on cancer surveillance—have been published by Schultz and colleagues (pediatric guidelines), the National Comprehensive Cancer Network (NCCN) in the United States, and the European Reference Network (ERN) for Genetic Tumor Risk Syndromes (GENTURIS) in Europe (13–16).

To provide the best practices based on the latest knowledge and literature in the surveillance and management of cancer and overgrowth in individuals with PHTS, the International PHTS Cancer and Overgrowth Guidelines Working Group was established. Overgrowth in the context of this working group and these guidelines refers generally to benign tumors occurring in individuals with PHTS. The working group comprised a set of six international experts (the core group) in the diagnosis and management of PHTS, including cancer genetics and genomics, medical oncology, and various cancer specialists and experts. The core group had joint meetings with individuals with PHTS and advocates representing the PTEN Foundation, a nonprofit patient-led community for PHTS. The core group utilized a modified Delphi approach to achieve further consensus among a wider international panel of experts in cancer and overgrowth (the external panel). Our primary aim was to generate an evidence-based PHTS individual- and provider-centered resource, highlighting international consensus for the practical management of cancer and overgrowth in individuals with PHTS. Notably, because the care of individuals with PHTS is highly multidisciplinary, additional guidelines for neurologic care, dermatologic care, and vascular malformations in PHTS are in various stages of preparation by additional expert groups.

A comprehensive literature search was performed initially on September 19, 2022. An updated literature search was performed on January 4, 2023, to include articles published after the original search to capture studies not included in the initial search. We used Ovid MEDLINE and Embase databases of all articles published between 2002 and 2023. Search terms for Ovid MEDLINE and Embase are as follows (alone or in combination): “PTEN Hamartoma Tumour Syndrome,” “Cowden Syndrome,” “Bannayan-Riley-Ruvalcaba Syndrome,” “Proteus syndrome,” “Proteus-like syndrome,” “Lhermitte Duclos,” “PHTS,” “PTEN,” or “PTEN Phosphohydrolase.”

Identified articles were imported into the Covidence systematic review software, in which studies were deduplicated and screened. Studies reporting on the incidence, prevalence, morbidity, or mortality of cancer and overgrowth as it related to PHTS were included. Publications without English translation were excluded. Review articles, editorials, opinion pieces, and meeting abstracts/posters were also excluded. Cumulatively, 5,222 studies were identified between both database searches, with 1,445 duplicates that were subsequently removed. Following screening, 3,400 studies were excluded for failing to meet inclusion criteria, and 377 published articles were included for data extraction. Studies were categorized by study type (e.g., case report, case series, therapeutic trials). Elements extracted from each study included study population, study design, intervention, outcomes measured, and result summary. Core members of the International PHTS Consensus Guidelines Working Group convened regularly between 2022 and 2024 and developed guidelines based on the extracted articles.

Similar to many rare diseases, the number of peer-reviewed articles with high-level evidence available to inform these guidelines was limited. We used an evidence grading scale to balance the weight of both published evidence and expert experience and knowledge as implemented by Tischkowitz and colleagues (15). The scale is as follows: (i) strong evidence: consistent evidence with new evidence unlikely to change the recommendation and expert consensus, (ii) moderate evidence: inconsistent evidence or significant new evidence expected and expert consensus, and (iii) weak evidence: inconsistent evidence and expert consensus. Statements with limited/no evidence and limited expert agreement were classified in separate sections as expert opinion statements.

As part of a comprehensive effort to develop international consensus surveillance and management guidelines for cancer and overgrowth in PHTS, the International PHTS Consensus Guidelines Working Group undertook a two-stage modified Delphi approach to achieve consensus on guideline recommendations among the core group members. There were parallel working groups focused on neurodevelopmental and neurologic features of PHTS, vascular anomalies, dermatologic features, and genetics. The core group members (n = 6) for the Cancer and Overgrowth Working Group and the Patient Advisory Group convened regularly from 2022 to 2024 to discuss and develop guideline statements informed by the literature (literature search strategy listed in the “Materials and Methods” section) and graded as strong, moderate, or weak evidence or expert opinion statements with limited evidence and limited expert agreement. The first stage involved meetings of core group members until consensus was reached—defined as 100% agreement among the core group. The second stage of our modified Delphi approach consisted of an independent external panel of experts (listed in the “Acknowledgments” section) providing feedback on draft guideline statements. This panel, selected for their clinical expertise in PHTS, participated in two rounds of standardized Delphi surveys until consensus was reached—defined as 80% agreement among the external panel of experts. For each recommendation, the external panel of experts voted whether to keep, remove, or modify the recommendation. Experts were also given the option to provide a free-text response to support their decision or to suggest changes. Responses were anonymized and reviewed after each round of the Delphi process. The core group members and patient advocates held a joint meeting after every round to discuss and amend statements based on anonymized feedback until 100% agreement was reached among the core group. The patient advocates were present at the meetings and often provided input on the psychosocial aspects as well as the practical aspects of undergoing cancer surveillance and treatment as part of PHTS. The advocates were also present at the discussions following the feedback from the modified Delphi rounds.

The data generated in this study are available within the article and its Supplementary Materials. Any additional requests or questions may be directed to the corresponding author.

The presented guideline statements apply to individuals with a germline pathogenic variant in the PTEN gene unless otherwise stated. Clinical consensus recommendations for breast, thyroid, colon, endometrial, and renal cancers in individuals with PHTS are summarized in Tables 1–7. Agreements for modified Delphi rounds 1 and 2 are presented in Supplementary Tables S1 and S2, respectively.

Individuals with pathogenic germline variants in PTEN have a predisposition to developing different cancers such as breast cancer, colon cancer, endometrial cancer, thyroid cancer, and renal cancer (6–12). In females with germline pathogenic PTEN variants, the lifetime risk for breast and endometrial cancers is reported as 67% to 91% and 19% to 48%, respectively. Similarly, there are elevated lifetime risks for colorectal (9%–20%), renal (10%–30%), and thyroid (17%–38%) cancers (2, 7–12, 17–19). The cumulative cancer risks, as reported by various studies, are potentially overestimated due to ascertainment bias and small cohorts with limited follow-up time, yet cancer risks are likely underestimated in older individuals (10). Due to the high lifetime risk of cancer, individuals diagnosed with PHTS should consult a multidisciplinary team at an experienced medical center. This team may include specialists in medical genetics, gastroenterology, endocrinology, gynecology, urology, oncology, surgery, and radiation oncology, as needed. Further, a self-reported survey of lifestyle factors in individuals with PHTS encompassing alcohol use, smoking, body mass index, and physical activity did not find statistically significant differences between those with and without breast cancer. Although limited by sample size, the observed effect sizes for lifestyle factors affecting cancer risk were similar to that of the general population, underscoring that there are no indications to deviate from lifestyle recommendations for general population in PHTS (20).

The treatment for most cases of malignant disease involves chemotherapy and/or radiotherapy. There were only a limited number of case reports in which authors speculated or suggested that individuals with PHTS developed chemotherapy- or radiotherapy-induced secondary malignancies at a rate greater than the unaffected population (18, 21–26). The rates of chemotherapy- or radiotherapy-induced secondary malignancies are not increased in individuals with PHTS in any large-scale prospective trial, and generally, it is felt that standard treatments should not be withheld from individuals with PHTS when accounting for the balance of potential risks and benefits.

Affected individuals may also require psychosocial care. Although there is strong evidence for psychosocial care and support in the cancer population, there are no specific studies addressing this in the PHTS population (27). Psychosocial supports may include psychiatry, clinical psychology, and counseling/therapy resources. Given that nearly 25% of individuals with PHTS meet diagnostic criteria for ASD and there are heterogeneous neuropsychological profiles among individuals with PHTS, psychosocial care should be tailored to meet individual needs (27). Allied health is also recommended for all individuals, as needed, and includes physical, occupational, speech therapy, social work, and child life services.

• 1.

  We recommend that individuals with PHTS undergo standard-of-care treatment for specific malignancies, as determined by the most current local guidelines (e.g., NCCN). (100% Extended Panel Delphi Agreement; Strong Evidence)

• 2.

  There is no direct evidence to suggest that individuals with PHTS are at increased risk of developing secondary malignancies due to the effects of chemotherapy and/or radiotherapy. These concerns should not preclude individuals from receiving the standard of care for organ-specific cancer treatments. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

• 3.

  Physicians should be aware of psychosocial needs and offer support, as well as adjunctive allied health, when indicated, to individuals with PHTS. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

• 4.

  All individuals with PHTS and their caregivers, regardless of age, should be counseled on minimizing or avoiding domestic and occupational exposure to known carcinogens, given the increased lifetime malignancy risk in this condition (e.g., smoking, obesity, and alcohol). (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

• 5.

  All individuals at the time of PHTS diagnosis should undergo a comprehensive physical exam, which can be performed by a primary care provider. Clinicians should provide individuals with education about the signs and symptoms of organ-specific cancers and discuss relevant surveillance recommendations for malignancy. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

Breast cancer is the most common cancer in females with PHTS (7, 9, 12, 17). Breast cancer risk in PHTS is similar to that of women with germline pathogenic variants in BRCA1/BRCA2 (15). The risk of breast cancer in individuals with PHTS increases between 25 and 30 years of age (9–11). The cumulative risk of developing breast cancer in females with PHTS has been reported as 67% to 78%, 77%, and 85% to 91% at 60, 70, and 80 years of age, respectively (2, 7, 9–12, 17). Conversely, males with PHTS have not been reported to have an increased risk for breast cancer (9). Risk estimates have varied across studies. For instance, earlier studies reported a lower lifetime cancer risk between 25% and 50%, and the NCCN guidelines state a lifetime risk of 40% to 60% (28, 29). However, evidence in this field is evolving as newer cohorts align between these estimates [e.g., Hendricks and colleagues (10) found a lifetime risk for female breast cancer of 54%–78%], but this remains to be shown in confirmatory studies. The 10-year cumulative risk of developing second primary malignant neoplasms in the contralateral breast is reported as 29% (30).

At the molecular level, truncating variants in PTEN seem to confer a higher lifetime risk of breast cancer (9). Likewise, patients with PTEN promoter variants had a relatively lower lifetime risk of breast cancer compared with those without variants in the PTEN promoter (9). Variants in the C2 domain of PTEN (amino acids 186–351) are associated with an increased risk of breast cancer in Japanese individuals (17).

Among individuals with PHTS, the sensitivity of breast MRI in detecting breast cancer has been shown to be superior to mammography (31). In a series of 39 women with PHTS undergoing a breast surveillance program with a median age of 38 years at first surveillance examination (range, 24–70 years), it was found that the sensitivity of MRI in detecting breast cancer was higher than that of mammography (100% vs. 50%; ref. 31). Breast MRI is ideally performed every 12 months, during days 5 to 12 (follicular phase) of menses in premenopausal females with regular cycles, reducing background parenchymal enhancement (32). Surveillance regimens should fit within the goals of care of each individual with PHTS and should not be overly burdensome from a time or financial perspective. As per NCCN guidelines, clinicians may counsel individuals with PHTS about breast awareness but should note that these guidelines differ with regard to the age of starting breast MRI screening (29). In PHTS, we recommend that annual breast MRI is started at age 25 years, whereas both NCCN and ERN GENTURIS guidelines recommend breast MRI to start at age 30 years (15, 29). Because the youngest age of breast cancer reported in PHTS is 26 years and the very high lifetime risk of breast cancer in PHTS, the guidelines committee agreed that beginning annual surveillance at 25 years of age was most appropriate (10, 31).

In women with germline pathogenic variants in BRCA1/BRCA2, risk-reducing mastectomy (RRM) was found to be an effective risk-reducing strategy for breast cancer prevention (33–35). In a study of 639 women with germline BRCA1/2 pathogenic variants, at a median age of 42 years at the time of RRM, RRM reduced the risk of breast cancer by 90% at 14 years of follow-up (35). A decreased risk of breast cancer has also been demonstrated following nipple-sparing mastectomy in BRCA1 and BRCA2 mutation carriers, leading to the consideration for individuals with BRCA1/2 pathogenic variants to undergo risk-reducing breast surgery between 25 and 30 years of age (33). Extrapolating these data to individuals with PHTS, who have a similar lifetime risk of breast cancer, provides a rationale for the discussion of potential RRM, as outlined below.

• 6.

  Given the high lifetime risk of female breast cancer and second primary breast cancer in individuals with PHTS and pathogenic or likely pathogenic variants in PTEN, we recommend discussing the options of surveillance versus RRM with an experienced high-risk breast clinic team.

In individuals with pathogenic or likely pathogenic variants in PTEN, RRM may be informed by the individual’s family history of breast cancer, if known. Generally, RRM should only be considered in individuals older than 25 years of age, unless otherwise clinically indicated, and counseling should include discussions relating to the degree of risk reduction, surgical risks, and reconstructive options. The individual’s life expectancy, in addition to their residual lifetime breast cancer risk, should also be taken into consideration.

In individuals for whom surveillance may be difficult to access, RRM may also be considered with the same caveats as above. The psychosocial and quality-of-life aspects of RRM must also be discussed with individuals with PHTS when this procedure is being considered. (95% Extended Panel Delphi Agreement; Moderate Evidence)

• 7.

  Women with PHTS should undergo annual breast MRI (with contrast) from age 25 years and additional surveillance with breast mammography (with digital breast tomosynthesis) starting at age 40 years until 75 to 80 years of age. After 75 to 80 years of age, we recommend an individualized approach to surveillance and risk–benefit discussion with an experienced breast clinician. Following national guidelines is recommended. (95% Extended Panel Delphi Agreement; Strong Evidence)

• 8.

  We do not recommend that males with PHTS undergo surveillance with breast MRI, mammography, or clinical breast examinations. (100% Extended Panel Delphi Agreement; Strong Evidence)

• 9.

  Depending on local practice guidelines, the following expert opinion can be considered. Although there are no specific studies examining the use of risk-reducing medication (tamoxifen, raloxifene, exemestane, or anastrozole) in individuals with pathogenic or likely pathogenic variants in PTEN, these options may be discussed. The increased risk of endometrial cancer in individuals with an intact uterus generally precludes the risk-reducing use of the selective estrogen receptor modulator tamoxifen (the only medication that can be used in the premenopausal setting; all four medications may be used in the postmenopausal setting). In many European countries, this is not compliant with current guidelines. (92% Extended Panel Delphi Agreement; Limited/Weak Evidence)

As there is no evidence on this topic and it is not compliant with current European guidelines, in the case of using risk-reducing medication (tamoxifen, raloxifene, exemestane, or anastrozole), physicians should discuss the dearth of evidence, potential risks (e.g., possible increased endometrial cancer risk with tamoxifen use), and expected benefits of chemoprophylaxis with each individual. Local practice guidelines should be followed regarding the use of hormonal therapies.

• 10.

  Transgender individuals who are assigned female at birth with remaining breast tissue should undergo surveillance as above. There are no data about testosterone supplementation and breast cancer risk to make a recommendation. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

• 11.

  There is no contraindication to receiving gender-affirming hormone therapy in transgender individuals who are assigned male at birth. We recommend beginning breast surveillance 5 years after the start of gender-affirming hormone therapy, not before 25 to 30 years of age. We recommend surveillance in these individuals with breast MRI or annual mammography with consideration of tomosynthesis. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

The lifetime thyroid cancer risks in individuals with pathogenic/likely pathogenic PTEN variants are estimated at 17% to 38% at 70 and 80 years of age, respectively (7–9, 11, 12). Thyroid cancer risk begins to increase from around 10 years of age, with the youngest age of thyroid cancer in PHTS reported as 4 years old (8, 9, 36, 37). Although there is a potential increased risk of thyroid cancer at relatively young ages in PHTS, there is weak evidence to support surveillance of individuals throughout childhood (7, 11, 12, 17, 38, 39). In a recent study, thyroid ultrasound surveillance showed differentiated thyroid carcinoma in two of 43 individuals before age 18 years (37). This evidence supports the recommendation of thyroid ultrasound surveillance in children from age 12 years (37, 38).

Further, the clinical benefit of thyroidectomy is not clear in individuals with PHTS. The balance of the surgical risk of thyroidectomy with the potential benefit of reduced thyroid cancer risk is uncertain, particularly in the setting of straightforward biochemical surveillance for thyroid cancer.

Clinically actionable thyroid nodules are defined as nodules meeting criteria for fine-needle aspiration, according to the 2015 American Thyroid Association criteria based on sonographic characteristics and nodule size (40). Thyroid nodules are common in PHTS during childhood or early adulthood (40). The prevalence of thyroid nodules in children with PHTS ranges from 44% to 51% (19, 41, 42). Individuals with PHTS and initial thyroid ultrasound without nodules are more than 90% likely to remain free of clinically actionable nodules at 3 years of follow-up and 85% at 6 years of follow-up, with no individuals developing cancer over the entire follow-up period (41). This finding supports surveillance intervals in individuals with PHTS and without nodules on ultrasound every 3 to 5 years and individuals with clinically nonactionable nodules every 2 to 3 years.

• 12.

  We do not recommend routine risk-reducing thyroidectomy for individuals with PHTS. The decision to undergo thyroidectomy is individualized and should be made in conjunction with a multidisciplinary team involving thyroid surgery, endocrinology, and medical genetics. (100% Extended Panel Delphi Agreement; Strong Evidence)

• 13.

  From age 12 years, individuals with PHTS should undergo baseline thyroid ultrasound. We recommend stratifying the surveillance interval based on ultrasound results to help minimize the burden of frequent ultrasounds, especially in young children. Thyroid stimulating hormone (TSH) may be checked starting at age 18 years if ultrasounds are unremarkable or earlier if there are abnormalities on ultrasound. (95% Extended Panel Delphi Agreement; Moderate Evidence)

• 14.

  We recommend surveillance with thyroid ultrasound every 3 to 5 years for individuals with PHTS and without nodules seen on initial thyroid ultrasound and every 2 to 3 years for individuals with clinically nonactionable nodules seen on initial thyroid ultrasound. Consider annual TSH surveillance in individuals older than 18 years of age. (100% Extended Panel Delphi Agreement; Moderate Evidence for ultrasound; Weak Evidence for TSH)

• 15.

  In individuals with PHTS and clinically actionable nodules, we recommend appropriate intervention in accordance with the American Thyroid Association or similar local guidelines. In the case of benign findings on cytologic examination, continued surveillance in 1 to 2 years is reasonable. (100% Extended Panel Delphi Agreement; Moderate Evidence)

Gastrointestinal (GI) polyps, typically occurring as hamartomas, are common and can occur anywhere along the GI tract of individuals with PHTS (43). Upper GI and lower GI polyps with mixed histologic types have shown an increased risk of colorectal cancer in individuals with PHTS (43–47). The lifetime risk of colon cancer in individuals with PHTS is estimated to be 9% to 20% (7–9, 11, 12, 17). The risk of colon cancer in individuals with pathogenic/likely pathogenic PTEN variants or truncating variants begins to increase in the early 20s; the youngest age of colorectal cancer diagnosis is 21 years of age (9). Individuals with PHTS also have an approximately sixfold increase in developing second primary colorectal malignancies (30).

Multiple polyps are common in individuals with PHTS with a high prevalence of colonic adenomas and adenocarcinoma (48, 49). Serrated polyps and adenomas were found in 38% and 36% of individuals at index colonoscopy and 42% and 31% in individuals less than 50 years (50). Colorectal and gastric polyps were also found in 73% to 98% of individuals, with 73% of individuals having between one and 50 polyps (12, 17). Individuals with PHTS and colorectal cancer generally had more than 50 polyps (43, 46). Case series provide low-level evidence suggesting that individuals with PHTS may be at an increased risk of gastric cancer (46, 50). However, it is difficult to draw conclusions as in each series, only a single subject with gastric cancer was presented. One case of small bowel carcinoid tumor was reported in an individual with PHTS and colorectal cancer among a series of 156 individuals with PHTS (51). Notably, hamartomatous polyps are common in individuals with PHTS, reported in the large bowel in up to 85% of patients, with a diverse set of stromal components (lipomatous, ganglioneuromatous, and fibrous components all reported, most with at least two components; ref. 52). Further, hamartomatous polyps in PHTS were associated with serrated polyps or conventional adenomas in nearly half of patients in one series, affirming the need for gastroenterologist-directed endoscopic surveillance in this subset of patients (52).

Pathogenic/likely pathogenic PTEN variants are associated with GI polyps in children; there is also now emerging evidence that upper GI polyps are more common in children with PHTS who do not have PHTS-associated ASD (49, 53). The most prevalent GI features in children with PHTS are constipation and feeding issues (including dysphagia, food aversion, and aspiration; ref. 49). Children with PHTS and GI symptoms may benefit from an evaluation for polyposis and may require colonoscopy. Adult individuals with PHTS have been reported to present with colorectal cancer prior to the diagnosis of PHTS between the ages of 41 and 71 years (38). Colonoscopy is not recommended in asymptomatic individuals younger than 35 to 40 years of age as only younger individuals with PHTS with symptoms should undergo evaluation.

Although mTOR inhibitors have been shown to reduce the risk of colectomy and improve protein-losing enteropathy and chronic GI bleeding in juvenile polyposis of infancy with germline PTEN variant without adverse effects, mTOR inhibitors are not recommended for the chemoprophylaxis of colon cancer or management of polyps in individuals without juvenile polyposis of infancy and PHTS. Individuals with PHTS treated with sirolimus demonstrate regression of GI lesions (54, 55). No strong evidence supports the use of COX-1/COX-2 inhibitors (e.g., acetylsalicylic acid [ASA]) in the chemoprevention of polyposis and colon cancer in PHTS. Chemoprevention trials in hereditary colorectal cancer syndromes have been conducted in familial adenomatous polyposis individuals, but just one trial has achieved the primary outcome of reduced duodenal polyp burden (56).

• 16.

  We do not recommend the use of mTOR inhibitors for the chemoprophylaxis of colon cancer or management of polyps in individuals with PHTS. (100% Extended Panel Delphi Agreement; Moderate Evidence)

• 17.

  We do not recommend the use of COX-1/COX-2 inhibitors (e.g., ASA) in the chemoprevention of polyposis and colon cancer in PHTS. (100% Extended Panel Delphi Agreement; Weak Evidence)

• 18.

  We do not recommend risk-reducing colectomy in individuals with PHTS and polyposis. (100% Extended Panel Delphi Agreement; Weak Evidence)

• 19.

  We recommend that all individuals with PHTS undergo a baseline colonoscopy at 35 to 40 years. We do not recommend routine colonoscopy in individuals younger than 35 to 40 years old. (100% Extended Panel Delphi Agreement; Moderate Evidence)

• 20.

  Individuals with PHTS and a high colon polyp burden (five or more tubular adenomas) or polyps greater than or equal to 1 cm in diameter or with high-grade dysplasia should undergo colonoscopy at a 1- to 3-year interval, as directed by their gastroenterologist. (95% Extended Panel Delphi Agreement; Moderate Evidence)

• 21.

  We do not recommend routine upper GI endoscopic surveillance with small bowel follow-through in individuals with PHTS. (100% Extended Panel Delphi Agreement; Moderate Evidence)

An increased risk of endometrial cancer is reported in individuals with PHTS, with estimates of cumulative risk of 19% to 33% and 48% at ages 60 and 80 years, respectively (7–9, 11, 17). The youngest reported age of endometrial cancer in PHTS is 14 years (57).

Endometrial cancer can be detected at an early stage and suspected in the presence of symptoms such as abnormal uterine bleeding. In a series of 25 adult individuals with PHTS in the Netherlands undergoing endometrial cancer surveillance, seven women reported abnormal uterine bleeding (58). Endometrial hyperplasia, diffuse thickening of the endometrium, is also a known premalignant sign of endometrial cancer, aiding in its early detection. Endometrial hyperplasia with or without atypia was detected in seven individuals with PHTS on endometrial biopsy and transvaginal ultrasound (TVUS), of whom six individuals had asymptomatic hyperplasia and one individual had hyperplasia with atypia (58).

TVUS surveillance for endometrial cancer in premenopausal individuals is not sensitive or specific in PHTS but may be considered at the clinician’s discretion (59). TVUS alone is less sensitive than endometrial biopsy for the diagnosis of endometrial hyperplasia in individuals with PHTS. The addition of endometrial biopsy to TVUS aids in cancer prevention by improving the detection of asymptomatic premalignancies, such as hyperplasia with and without atypia (58).

Discussions with a multidisciplinary team about reducing endometrial cancer risk may involve consideration of hysterectomy with ovary-sparing approaches, given that current knowledge indicates that the ovarian cancer risk in PHTS is not greater than that of the general population. Factors such as age, desire for future fertility, and overall health status should be carefully considered.

• 22.

  We do not recommend routine hysterectomy for endometrial cancer risk reduction in PHTS individuals with a uterus. The decision to undergo hysterectomy is individualized and should be made in discussion with a multidisciplinary team involving obstetrics/gynecology, reproductive health, and medical genetics. (100% Extended Panel Delphi Agreement; Weak Evidence)

• 23.

  For individuals with PHTS who have been diagnosed with uterine leiomyomas or endometrial hyperplasia with atypia, treatment options may include risk-reducing hysterectomy, hysteroscopy with endometrial curettage, and/or placement of a progestin-releasing intrauterine device. Treatment decisions should be individualized and made in discussion with a multidisciplinary team involving obstetrics/gynecology, reproductive health, and medical genetics. (95% Extended Panel Delphi Agreement; Weak Evidence)

• 24.

  At the time of PHTS diagnosis or at 30 to 35 years of age, we encourage individual education and prompt response to abnormal uterine bleeding or postmenopausal bleeding. (100% Extended Panel Delphi Agreement; Weak Evidence)

• 25.

  In individuals older than 30 to 35 years of age with PHTS and unexplained or irregular vaginal bleeding, we recommend evaluation with both TVUS and endometrial biopsy. (100% Extended Panel Delphi Agreement; Weak Evidence)

• 26.

  There is limited evidence about routine endometrial cancer surveillance in PHTS. If the decision to offer surveillance for endometrial cancer is made, this should be part of a clinical trial. (90% Extended Panel Delphi Agreement; Weak Evidence)

Renal cancer was found in a worldwide PHTS population with an estimated lifetime risk of 10% to 30% and a median age of onset of 50 years (9). In a series of 455 individuals, 372 of whom had prospective follow-up for a median of 6 years, the cumulative risk of renal cancer was less than 10% at 60 years (10). In a case series of 24 individuals, papillary renal cancer and chromophobe renal cell carcinoma were seen at a higher rate in individuals with PHTS compared with clear-cell renal cell carcinoma, which is more common in the general population (60). There is no evidence related to the benefit of MRI over ultrasound in surveillance for renal cell carcinoma. Moreover, urine cytospin for red blood cells has not been validated in individuals with PHTS as a surveillance modality.

• 27.

  Starting at the age of 35 to 40 years, a surveillance ultrasound every 2 years for renal cell carcinoma may be considered in individuals with PHTS. MRI of the kidneys may also be considered. (100% Extended Panel Delphi Agreement; Limited/Weak Evidence)

The clinical management of individuals with pathogenic or likely pathogenic germline PTEN variants is complex and remains challenging due to variable expressivity, a dearth of clinical evidence, and age-related specificities. In this study, we present international consensus guidelines for the surveillance and management of cancer and overgrowths associated with PHTS, excluding the management of skin cancers, aimed at standardizing and improving care for affected individuals and families. These guidelines have been developed by an internationally recognized panel of core experts and further affirmed through a modified Delphi process with an external panel of experts and patient advocates. As with all medical evidence, this is an evolving document and will be periodically reviewed and updated as new data emerge. The management of skin cancers and dermatologic findings in PHTS will be covered in a dermatology-specific guidelines statement.

Due to the rarity of PHTS, the evidence base in these guidelines is limited. The paucity of published studies constrained our ability to make recommendations on conditions that may be potentially associated with PHTS based on our clinical observations. Importantly, these guidelines have differences between published recommendations by the NCCN and ERN GENTURIS committees (15, 29). Specifically, the guidelines presented in this work do not recommend self-examination and clinical examination of breast and, in contrast to both the ERN and NCCN guidelines, recommend surveillance starting at age 25 years with annual breast MRI, as opposed to 30 years of age. ERN guidelines also recommend annual thyroid ultrasound starting at age 18 years, whereas NCCN guidelines recommend starting annual thyroid ultrasound at age 7 years, and the guidelines presented in this work recommend thyroid ultrasound starting at age 12 years, at a reduced frequency dictated by ultrasound findings. Notably, our recommendation for beginning thyroid surveillance at age 12 years is consistent with the recent guideline for pediatric cancer surveillance in PHTS published by Schultz and colleagues (16). Colon cancer and renal cancer surveillance guidelines are equivalent between the three guideline organizations, and none of the guidelines recommend routine surveillance for uterine cancers.

There is also a relative dearth of prospective natural history studies, constraining our understanding of the trajectory and disease progression of cancer in PHTS. Natural history and deep phenotyping studies in PHTS are underway with the hope of improving anticipatory guidance by clinicians and genetic counselors and a better understanding of the optimal timing and specificity of interventions. Genotype–phenotype associations between PTEN variants and cancer risk are also limited, and at this time, it is not felt that genotype-specific recommendations could be made for individuals with PHTS, but future iterations of these guidelines may incorporate this as evidence emerges.

There are limited studies in several areas of concern in individuals with PHTS. Further investigations about increased risk of secondary malignancies due to chemo-/radiotherapy and the nature of metastatic disease or recurrent malignancy in individuals with and without germline PTEN variants are needed. This is important while ascertaining the risk–benefit ratio for intensive surveillance regimens. Moreover, it is not clear if individuals with PHTS experience increased or distinct toxicities to systemic cancer treatments. Further randomized controlled trials are also required to determine the efficacy of mTOR/AKT inhibitors in the treatment of PHTS-related malignancies, and we note that a phase II trial investigating AKT inhibitors treating advanced solid tumors in individuals with PHTS was terminated due to insufficient accrual (61). Two cases have been recently published of individuals with PHTS and breast cancer with durable responses to capivasertib, an inhibitor of AKT (62). A pilot study of 18 adult individuals with PHTS treated with sirolimus demonstrated regression of skin and benign GI lesions (55). There are several case reports of individuals with germline PTEN variants with severe manifestations that experience partially successful and/or successful treatment of soft tissue masses/hamartomas/vascular malformations (63, 64).

Several PHTS surveillance articles show conventional imaging approaches, reviewed at expert centers, were able to identify early-stage PHTS with a high level of sensitivity. For instance, annual breast cancer surveillance with MRI enables detection of early-stage breast cancers with a 100% overall sensitivity (31). Research should additionally focus on the effectiveness of other imaging modalities (e.g., whole-body MRI, low-dose fluorodeoxyglucose PET) on surveillance of cancer, as well as identifying reliable predictive biomarkers for cancer risk and determining whether the lifetime cancer risks vary among individuals with PHTS of different ancestries. Notably, recent work examining the sensitivity of unbiased multicancer detection by identification of circulating tumor DNA has shown relatively low sensitivities for early-stage disease, with 16.8% sensitivity [95% confidence interval (CI), 14.5%–19.5%] reported for stage I cancers, as would be desirable in PHTS (65). It is also important to explore whether there are disparities (e.g., genetics, comorbidities, social determinants of health) in clinical outcomes across subgroups of individuals with PHTS. Furthermore, the extent of financial and time toxicity that cancer treatment has on individuals with PHTS, acknowledging their increased healthcare interaction and increased risk for neurodevelopmental disabilities, remains to be studied (66, 67). To this point, we note that although time and financial toxicity are often commented upon, there are very few follow-up studies rigorously examining their impact, and this remains a key gap for future work.

Despite the advancements in studying PHTS-related cancer and overgrowth organ systems, there are key details that are yet to be determined. For instance, the precise age for starting thyroid surveillance in individuals with PHTS is not firmly delineated (68). In addition, there is no sufficient evidence for volumetric follow-up in the detection of growing thyroid nodules that may need workup. Further research is needed to better understand the frequency and nature of GI tract cancers, as well as the morbidity and clinical outcomes associated with colon polyposis (subtotal/total colectomy vs. polypectomy). Lastly, further research is required to resolve the optimal surveillance frequency and modality for renal cancers in individuals with PHTS while working on determining the optimal surveillance interval for recurrence or second malignancies.

This guideline provides the most up-to-date distilled evidence for healthcare providers evaluating individuals with PHTS to perform an adequate assessment and make initial management recommendations. The development of these international consensus guidelines represents the most up-to-date standard of care for cancer and overgrowth for individuals with PHTS, regardless of geographic location. Moving forward, it is essential to engage with the wider PHTS community to ensure dissemination and implementation of these recommendations. We recognize that various obstacles often exist for individuals, whether at the individual, regional, or national levels, that limit availability or access to the recommendations made here. In such circumstances, local healthcare professionals may need to adapt specific recommendations to ensure the provision of high-quality care. Concurrently, it is imperative that healthcare professionals and institutions, patient advocacy organizations, and local and national policymakers collaborate and advocate to minimize barriers to care. Such collective efforts are essential to ensure that these guidelines can be effectively put into practice and that all individuals with PHTS receive the highest-quality care.

J. Ngeow reports that she serves on the scientific advisory board of the PTEN Foundation. No disclosures were reported by the other authors.

A. Dhawan: Conceptualization, resources, data curation, formal analysis, validation, methodology, writing–original draft, project administration, writing–review and editing. S. Baitamouni: Data curation, writing–original draft. D. Liu: Data curation, writing–original draft, writing–review and editing. L. Yehia: Methodology, project administration. K. Anthony: Methodology, project administration. A. McCarther: Methodology, project administration. M. Tischkowitz: Formal analysis, supervision, writing–review and editing. S.P. MacFarland: Formal analysis, supervision, writing–review and editing. J. Ngeow: Formal analysis, supervision, writing–review and editing. N. Hoogerbrugge: Formal analysis, supervision, methodology, writing–review and editing. C. Eng: Conceptualization, resources, formal analysis, funding acquisition, methodology, project administration, writing–review and editing.

This work has been funded, in part, by PTEN Research, a charity governed by English law (charity number 117358) to A. Dhawan and C. Eng under grant numbers CCF-18-001 and CCF-21-001. The core expert panel and all authors would like to thank PTEN Research for their continued support. The authors also express gratitude to the PTEN Foundation, United States, as well as patients with PHTS and their and families, for their continued advocacy in PHTS. The core expert panel and all authors also express immense gratitude to the following independent reviewers for the guideline statements participating in the expanded expert panel modified Delphi process: Claudio Ales, Patient Advocate, PTEN Foundation President, PTEN Foundation, Italy; Maria Piccione, MD, PhD, Medical Geneticist, Palermo, Italy; Giuseppe Novelli, MD, PhD, Medical Geneticist, Rome, Italy; Francesca Mercadante, MD, Medical Geneticist, Palermo, Italy; Holly J. Pederson, MD, General Surgeon, Cleveland, Ohio, United States; Andrew J. Bauer, MD, Pediatric Endocrinologist, Pennsylvania, United States; Chad M. Michener, MD, Gynecologic Oncologist, Cleveland, Ohio, United States; Steven C. Campbell, MD, PhD, Urologic Oncologist, Cleveland, Ohio, United States; Joyce J. Shin, MD, General Surgery Specialist, Cleveland, Ohio, United States; Carole Macaron, MD, Gastroenterologist, Cleveland, Ohio, United States; Petar Mamula, MD, Pediatric Gastroenterologist, Pennsylvania, United States; Pauline Funchain, MD, Oncologist, California, United States; Katherine Lachlan, MD, Clinical Geneticist, Southampton, United Kingdom; Angie Brady, MD, PhD, Clinical Geneticist, PHTS Expert, London, United Kingdom; Kelly Kearley, Patient Advocate, the PTEN United Kingdom and Ireland Patient Group; Robert K. Semple, MD, PhD, Geneticist and Cardiovascular Scientist, Edinburgh, United Kingdom; Andrew Latchford, MD, Gastroenterologist, London, United Kingdom; Chrystelle Colas, MD, PhD, Clinical Geneticist, Paris, France; Patrick Benusiglio, MD, PhD, Clinical Geneticist, Paris, France; Chella van der Post, MD, Gastrointestinal Pathologist, Nijmegen, Netherlands; Martin Gotthart, MD, PhD, Radiologist, Nijmegen, Netherlands; Tanya Bisseling, MD, Gastroenterologist and Hepatologist, Nijmegen, Netherlands; Joanne de Hulu, MD, Gynecologist Oncologist, Nijmegen, Netherlands; Jolanda Schieving, MD, Pediatric Neurologist, Nijmegen, Netherlands; and Verena Steinke-lange, MD, Clinical Geneticist, Munich, Germany.

A. Dhawan and C. Eng also acknowledge support from The Developmental Synaptopathies Consortium. The Developmental Synaptopathies Consortium (U54NS092090) is part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN) and is supported by the RDCRN Data Management and Coordinating Center (DMCC) (U2CTR002818).  RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS), Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD) and National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH).