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STK11 (Peutz-Jeghers) – risk management

In this document the terms ‘male’ and ‘female’ refer to sex assigned at birth. For more information about providing individualised care refer to Resources to assist in the care of transgender individuals referred to a clinical genetics service or familial cancer centre

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Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder featuring multiple gastrointestinal hamartomatous polyps and mucocutaneous pigmentation. PJS polyps have interdigitating smooth muscle bundles with characteristic arborisation. Almost all individuals with a clinical diagnosis of PJS have a pathogenic variant in the STK11 gene.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

Exclusion criteria

  • Parents and siblings (but not children) of an individual with a clinical diagnosis of PJS, no relevant family history and no pathogenic variant in the STK11 gene identified, may not be at 50% risk of PJS. These individuals should be clinically assessed for PJS, baseline screening considered and management tailored to the clinical situation.
  • Individuals with a variant of uncertain significance.
Cancer/tumour type PJS by age 20 years PJS by age 30 years PJS by age 40 years PJS by age 50 years PJS by age 60 years PJS by age 65 years PJS by age 70 years General population risk by age 70 years^
All cancersrrr  2% 4-5% 17-21% 31-47% 55-60% Increased 76-85% 23.8%
Breast (female)r     8% 13% 31% Increased 45% 8.1%
Colorectalrr     3% 5% 15-28% Increased 39% 2.5%
Gynaecologicalr   1% 3% 8% 18% Increased 18% 2.5%
Pancreasrr     2-3% 4-5% 7-11% Increased 11-26% 0.54%
Gastricr     Increased Increased Increased 29% Increased 0.40%
Small bowelr     Increased Increased Increased 13% Increased 0.14%
Testicularr Increased             0.52%

^ Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2017 data)

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

Cancer/tumour type Recommendations
Gastrointestinal Surgical
  • Risk-reducing surgery in asymptomatic individuals in not recommended
  • In the symptomatic individual, surgical management may be clinically indicated
Surveillance Age  Strategy and frequency
Starting at age 8 years
(or earlier with onset of symptoms
  • Video capsule endoscopy (VCE) or magnetic resonance endoscopy (MRE) every 3 years (or more frequently depending on polyp load)
  • Baseline gastroduodenoscopy and colonoscopy
    • if no polyps found recommence at age 18 years
    • if polyps are found screening should occur at least every 3 years (or more frequently depending on polyp load)
From age 18 years
  • Gastroduodenoscopy and colonoscopy every 3 years (or more frequently depending on polyp load)
Risk-reducing medication There is no evidence to support the utilisation of risk-reducing medication outside clinical trials
Breast (female)  Surgical Consider bilateral risk-reducing mastectomy followed by self-surveillance of the breast area
Surveillance
  • Recommend breast imaging commencing from age 30 years
  • In families with breast cancer diagnosed under age 35 years, individualised screening recommendations may apply
30-​40 years Annual MRI, +/- US
40-50 years Annual MRI, +/- MMG, +/- US
Over age 50 years Annual MMG +/- US + CBE (Consider annual MRI if dense breast tissue)
Pregnant No MRI or MMG, consider US
Risk-reducing medication
  • Consider use of medication to reduce risk of developing breast cancer:
    • Pre-menopausal women from age 35 years may consider tamoxifen
    • Post-menopausal women may consider raloxifene, aromatase inhibitors or tamoxifen
  • Requires assessment of risks and benefits for an individual woman by an experienced medical professional. See COSA - Medications to lower the risk of breast cancer: clinician guide
Gynaecological Surveillance From age 25 years Referral to a gynaecological oncologist or gynaecologist for annual pelvic examination and endocervical smear for cytologyr
Testicular Surveillance From birth to teenage years Annual clinical examination looking for:
  • gynaecomastia
  • other signs of feminisation
  • bilateral testicular enlargement

Abbreviations: US – ultrasound, CBE – clinical breast examination, MMG – mammogram (digital if available), MRI – magnetic resonance imaging.

Contraception

Combination oral contraceptive pill (OCP) use requires consideration of potential risks and benefits and alternative contraceptive strategies. A small increased risk of breast cancer has been reported for current OCP users (RR 1.2) and for up to 10 years after cessation of OCP use, regardless of family history.r The same result was found with newer formulations, including progesterone-containing implanted devices.r OCP cannot be used concurrently with breast cancer risk-reducing medications due to interactions. 

Gastrointestinal polyps 

Intussusception occurs in the small intestine (commonly in the jejunum) in more than 95% of cases.r Cumulative intussusception risk is 15% at age 10 years, 50% at age 20 years, 65% at age 30 years, 77% at age 40 years and 84% at age 50 years.r Polyps greater than 15mm have a higher risk of causing intussusception. Commencing 3 yearly screening for small intestinal polyps from age 8 years is in keeping with international guidelines.rr Screening reduces polyp burden and the likelihood of polyp-related complications such as intussusception.

Video capsule endoscopy (VCE) or magnetic resonance imaging (MRI) are preferred to Barium follow through (BaFT) in PJS patients as the radiation dose is considerably reduced, they detect more polyps that are less than 1cm and they are better tolerated.r 

Individuals should be advised to seek emergency medical attention if they have any symptoms suggestive of intussusception/bowel obstruction (e.g. acute onset of vomiting, severe abdominal pain with bloating). Routine haemoglobin testing in children with PJS is not recommended, however may be useful in the symptomatic setting.r

Colorectal cancer

The mechanism of carcinogenesis in PJS remains unknown. Hamartomas are currently not considered precancerous lesions. One study detected no luminal cancers in a small cohort of patients having regular surveillance and polypectomies, raising the possibility that surveillance may reduce colorectal cancer risk.r Further studies are required to evaluate the effect of GI surveillance on the development of GI cancers in PJS.

Breast cancer (female)

Surgical 

Bilateral risk reducing mastectomy can reduce breast cancer risk by at least 90% in high-risk women (including women with PJS).

Surveillance

There is no evidence to date that early detection of breast cancer is associated with better prognosis and survival in females with PJS. Therefore, breast surveillance is based on eviQ high risk breast cancer management guidelines and expert consensus.

MRI is the preferred screening technique due to its high sensitivity. MRI detects smaller tumours which are more likely to be node negative than mammography (MMG). MRI recall rate (requiring further investigation and/or biopsy) is 15% for initial screening, which decreases to less than 10% with subsequent rounds of screening. MMG screening is not recommended before age 40 years in females with PJS.

Risk-reducing medication

Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer in high risk women. However, studies have not included enough females with PJS to determine efficacy in this population. Tamoxifen use is associated with a reduction in contralateral breast cancer risk in BRCA1 and BRCA2 pathogenic variant carriers with breast cancer; such benefit is greater if ovaries are still intact.r Similar benefit might be expected in females with PJS. In view of the potential side effects associated with tamoxifen/raloxifene, risk-reducing medications should be discussed with an experienced medical professional to determine the relevant risks and benefits in an individual pathogenic variant carrier. See COSA - Medications to lower the risk of breast cancer: clinician guide.

Cervical cancer

Cervical adenocarcinoma, in particular minimal deviation adenocarcinoma (adenoma malignum), is the most frequently reported gynaecological cancer in women with PJS.r There is no evidence-based data on routine cervical screening in PJS. Expert consensus recommendations include annual endocervical smears for cytology and pelvic examination by an experienced gynaecological oncologist (preferably) or gynaecologist from age 25 years.rrr Women need specific screening for this form of cervical cancer, as it is not detected by the screening method used by the national cervical screening program (which tests for human papillomavirus). The request form should highlight the diagnosis of PJS to the reporting pathologist so that they are alerted to the possibility of adenoma malignum.

Ovarian cancer (sex cord tumours)

Females are at increased risk of sex cord tumours of the ovary (SCTAT), which may be benign or malignant. These tumours can occur from infancy but are most common in the fourth and fifth decades. Hyperoestrogenism may occur. Recommendations for annual abdominal examination to assess for abdominal mass are based on low level evidence.rr There is no evidence for routine abdominal imaging or CA125 testing.

Pancreatic cancer

Individuals with PJS have an increased lifetime risk of pancreatic cancer, however there is no strong evidence that pancreatic cancer screening is beneficial. Pancreatic cancer screening should only be performed as part of a clinical research protocol.r

Testicular cancer

Males may be at increased risk of large cell calcifying Sertoli cell tumours (LCCSCTs) of the testis. These most commonly present in childhood and may present with feminisation.r Annual clinical assessment should include testicular examination, growth and height velocity, and signs of feminisation including gynaecomastia. There is no evidence to support routine testicular ultrasound. If signs of LCCSCTs are identified, refer to a paediatric endocrinologist.r

Lung cancer

There may be an increased risk of lung cancer, especially for males. Advice should be given about the benefits of avoiding cigarette smoking.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Bibliography

Beggs, A. D., A. R. Latchford, H. F. Vasen, et al. 2010. "Peutz-Jeghers syndrome: a systematic review and recommendations for management." Gut 59(7):975-986.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Burke, C. A., J. Santisi, J. Church, et al. 2005. "The utility of capsule endoscopy small bowel surveillance in patients with polyposis." Am J Gastroenterol. 100(7):1498-1502.

BACKGROUND: Small intestinal (SI) surveillance is recommended for polyposis patients. The utility and safety of capsule endoscopy (CE) for surveillance of SI neoplasia in patients with familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS) is unknown. METHODS: CE was offered to consecutive FAP and PJS patients due for routine upper endoscopic surveillance. The prevalence, location (jejunum, ileum), size (1-5 mm, 6-10 mm, >10 mm) and number (1-5, 6-12, >20) of polyps detected by CE was assessed. RESULTS: 19 subjects (15 FAP/4 PJS) with a mean age of 43 were included. All subjects had previous intestinal surgery. No complications occurred with CE. CE in FAP: 9/15 (60%) of subjects with FAP had SI polyps. The prevalence of SI polyps was related to the duodenal polyposis stage and subject age. The location, size and number of polyps progressed as duodenal polyposis stage advanced. CE in PJS: 3/4 (75%) of subjects with PJS had SI polyps. The polyps were diffuse in 2/4 and only in the ileum in one subject. CE findings led to laparotomy with intra-operative endoscopic polypectomy in two PJS patients. CONCLUSION: SI polyps are common in FAP but their importance is unknown. CE should be performed in FAP patients with stage III and IV duodenal disease. Clinically significant polyps are commonly detected by CE in PJS and lead to change in management in 50% of PJS subjects. CE should replace radiographic SI surveillance for PJS patients. CE is safe in polyposis patients who have undergone major intestinal surgery

Domchek, S. M., T. M. Friebel, C. F. Singer, et al. 2010. "Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality." JAMA 304(9):967-975

CONTEXT: Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer. OBJECTIVE: To estimate risk and mortality reduction stratified by mutation and prior cancer status. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009. MAIN OUTCOMES MEASURES: Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality. RESULTS: No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer-specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer-specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]). CONCLUSIONS: Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer-specific mortality, and ovarian cancer-specific mortality.

Evans, DG, Gaarenstroom KN, Stirling D, et al. 2009. "Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers." J Med Genet. 46(9):593-597. Epub 2008 Apr 2015.

AIM: To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk. Patients and METHODS: A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement. RESULTS: 64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant. CONCLUSION: Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

Gaarenstroom, K. N., B. van der Hiel, et al. (2006). "Efficacy of screening women at high risk of hereditary ovarian cancer: results of an 11-year cohort study." Int J Gynecol Cancer 16 Suppl 1: 54-9.

The outcome of screening and prophylactic surgery in 269 women at high risk of hereditary ovarian cancer is reported. Screening was performed using transvaginal ultrasound and serum CA125 testing. Mean follow-up was 26 months (583 person-years). A total of 113 (42%) of 269 women had a pathogenic BRCA1 or BRCA2 mutation, and 127 (47%) of 269 women underwent salpingo-oophorectomy. No occult cancers were found. In eight women having both elevated CA125 levels and abnormal ultrasound findings, a malignancy was found. Four of these cancers (one borderline, one stage Ia, one stage IIIb, and one stage IIIc ovarian or peritoneal cancer) were detected at the first screening visit. One stage IIIb and one stage IIIc cancer were detected at the second screening visit after 12 months, and two interval stage IIIc and IV cancers were detected 8 and 10 months after the first screening visit. No peritoneal carcinoma was found among those 114 women who underwent bilateral salpingo-oophorectomy with normal or benign pathology results, after a mean follow-up of 16 months (152 person-years). We conclude that the efficacy of screening women at high risk of ovarian cancer seems poor because the majority of cancers were detected at an advanced stage.

Pennazio, M. (2006). "Capsule endoscopy: where are we after 6 years of clinical use?" Dig Liver Dis 38(12): 867-78.

Capsule endoscopy has revolutionised the management of digestive tract diseases by providing a new non-invasive way to view the entire small bowel mucosa directly. Obscure gastrointestinal bleeding is the primary and best validated indication to capsule endoscopy, which when used as first-line exploration is the most efficient strategy as regards diagnosis. In these patients, the technique is also helpful for effective decision-making concerning subsequent treatments. There is significant uncertainty regarding the role of capsule endoscopy in patients with Crohn's disease. Although it is clearly more sensitive than conventional imaging modalities, the implications of the lesions identified with this technique are not fully understood. Further prospective studies are required to identify the clinical settings where capsule endoscopy is most effective in these patients. Capsule endoscopy may potentially lead to diagnosis of small bowel tumours earlier in their course; it should be used as first-line surveillance procedure in patients with Peutz-Jeghers syndrome, and it may be of clinical value in selected patients with familial adenomatous polyposis. Although preliminary results are promising, additional research is necessary to determine its role in the diagnosis and management of coeliac disease, as well as for the diagnosis of oesophageal and large bowel disorders. Well-designed studies are also needed to better define the impact of capsule endoscopy on health care use and clinical outcome of patients with intestinal diseases.

Rebbeck, T. R., T. Friebel, H. T. Lynch, et al. 2004. "Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group." J Clin Oncol 22(6):1055-1062.

PURPOSE: Data on the efficacy of bilateral prophylactic mastectomy for breast cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations are limited, despite the clinical use of this risk-management strategy. Thus, we estimated the degree of breast cancer risk reduction after surgery in women who carry these mutations. PATIENTS AND METHODS: Four hundred eighty-three women with disease-associated germline BRCA1/2 mutations were studied for the occurrence of breast cancer. Cases were mutation carriers who underwent bilateral prophylactic mastectomy and who were followed prospectively from the time of their center ascertainment and their surgery, with analyses performed for both follow-up periods. Controls were BRCA1/2 mutation carriers with no history of bilateral prophylactic mastectomy matched to cases on gene, center, and year of birth. Both cases and controls were excluded for previous or concurrent diagnosis of breast cancer. Analyses were adjusted for duration of endogenous ovarian hormone exposure, including age at bilateral prophylactic oophorectomy if applicable. RESULTS: Breast cancer was diagnosed in two (1.9%) of 105 women who had bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have the procedure, with a mean follow-up of 6.4 years. Bilateral prophylactic mastectomy reduced the risk of breast cancer by approximately 95% in women with prior or concurrent bilateral prophylactic oophorectomy and by approximately 90% in women with intact ovaries. CONCLUSION: Bilateral prophylactic mastectomy reduces the risk of breast cancer in women with BRCA1/2 mutations by approximately 90%.

Rebbeck, T. R., N. D. Kauff and S. M. Domchek. 2009. "Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers." J Natl Cancer Inst 101(2):80-87.

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not. METHODS: All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis. RESULTS: Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers. CONCLUSION: The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Resta N, Pierannunzio D, Lenato GM, et al. 2013. "Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study. Dig Liver Dis 45(7):606-611.

BACKGROUND: Germline mutations in the STK11/LKB1 gene cause Peutz-Jeghers syndrome, an autosomal-dominantly inherited condition characterized by mucocutaneous pigmentation, hamartomatous gastrointestinal polyposis, and an increased risk for various malignancies. We here report the results of the first Italian collaborative study on Peutz-Jeghers syndrome.

AIMS: To assess cancer risks in a large homogenous cohort of patients with Peutz-Jeghers syndrome, carrying, in large majority, an identified STK11/LKB1 mutation.

METHODS: One-hundred and nineteen patients with Peutz-Jeghers syndrome, ascertained in sixteen different Italian centres, were enrolled in a retrospective cohort study. Relative and cumulative cancer risks and genotype-phenotype correlations were evaluated.

RESULTS: 36 malignant tumours were found in 31/119 (29 STK11/LKB1 mutation carriers) patients. The mean age at first cancer diagnosis was 41 years. The relative overall cancer risk was 15.1 with a significantly higher risk (p < 0.001) in females (22.0) than in males (8.6). Highly increased relative risks were present for gastrointestinal (126.2) and gynaecological cancers (27.7), in particular for pancreatic (139.7) and cervical cancer (55.6). The Kaplan-Meier estimates for overall cumulative cancer risks were 20%, 43%, 71%, and 89%, at age 40, 50, 60 and 65 years, respectively.

CONCLUSION: Peutz-Jeghers syndrome entails markedly elevated cancer risks, mainly for pancreatic and cervical cancers. This study provides a helpful reference for improving current surveillance protocols.

Schulmann, K., S. Hollerbach, et al. (2005). "Feasibility and diagnostic utility of video capsule endoscopy for the detection of small bowel polyps in patients with hereditary polyposis syndromes." Am J Gastroenterol. 100(1): 27-37.

OBJECTIVES: At present, surveillance of premalignant small bowel polyps in hereditary polyposis syndromes has a number of limitations. Capsule endoscopy (CE) is a promising new method to endoscopically assess the entire length of the small bowel. METHODS: We prospectively examined 40 patients with hereditary polyposis syndromes (29 familial adenomatous polyposis (FAP), 11 Peutz-Jeghers syndrome (PJS)). Results were compared with push-enteroscopy (PE) results in FAP and with esophagogastroduodenoscopy, PE, (MR)-enteroclysis, and surgical specimen in PJS patients. RESULTS: A total of 76% of the patients with FAP with duodenal adenomas (n = 21) had additional adenomas in the proximal jejunum that could be detected by CE and PE. Moreover, 24% of these FAP patients had further polyps in the distal jejunum or ileum that could only be detected by CE. In contrast, in FAP patients without duodenal polyps (n = 8), jejunal or ileal polyps occurred rarely (12%). CE detected polyps in 10 of 11 patients with PJS, a rate superior to all other reference procedures employed. Importantly, the findings of CE had immediate impact on further clinical management in all PJS patients. CONCLUSIONS: Our results suggest that CE may be of clinical value in selected patients with FAP, whereas in PJS, CE could be used as first line surveillance procedure

Woodward, E. R., H. V. Sleightholme, et al. (2007). "Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective." Bjog 114(12): 1500-9.

OBJECTIVE: To assess the efficacy of annual CA125 and transvaginal ultrasound (TVU) scan as surveillance for ovarian cancer. DESIGN: Retrospective audit. SETTING: NHS Trust. POPULATION: Three hundred and forty-one asymptomatic women enrolled for ovarian cancer screening: 179 were in a high-risk group ( >10% lifetime risk of developing ovarian cancer), 77 in a moderate risk group (4-10% lifetime risk of developing ovarian cancer) and 71 in a near population risk group ( <4% lifetime risk). METHODS: Retrospective audit of case records, laboratory CA125 results, radiology reports, histology records and local cancer registry data. MAIN OUTCOME MEASURES: Ovarian cancers occurring in study population. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU, and CA125 as a screening tool for ovarian cancer. RESULTS: Four ovarian cancers and one endometrial cancer occurred. One ovarian cancer was detected at surveillance, three occurred in women who presented symptomatically between screenings. Thirty women underwent exploratory surgery because of abnormal findings at surveillance. Two women had cancer (PPV = 6.7%); one had ovarian cancer and the other endometrial cancer. Twenty-eight women (93.3%) had no malignancy. Sensitivity, specificity, PPV and NPV for TVU in the whole cohort were 33.3, 85.8, 0.6 and 99.8%, respectively. For high-risk individuals, the figures for TVU were 33.3, 84.5, 1.1 and 99.6, respectively. Combining both modalities for the whole cohort, the sensitivity, specificity, PPV and NPV were 66.7, 82.9, 1.5 and 99.8% and 50.0, 82.8, 1.3 and 99.7%, respectively, for the high-risk group alone. CONCLUSIONS: Ovarian screening by annual TVU and CA125 is inefficient at detecting early-stage ovarian cancers.

Version 10

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.10.

Version 9

Date Summary of changes
13/02/2023

The following sections of the document were updated to align with the new eviQ cancer genetics risk management template:

  • Target population:
    • Added to exclusion criteria "Individuals with a variant of uncertain significance".
  • Cancer/tumour risk management guidelines:
    • Template sentence updated. 
    • Lifestyle factors sentence moved above table.
  • Management of associated health problems:
    • Accordion title changed to "Management of associated health issues".
    • Subheading "Contraception and fertility" changed to "Contraception".

Version number increased to V.2.

Version 8

Date Summary of changes
05/07/2022

Protocol reviewed at March 2022 cancer genetics reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made: 

  • Summary and Target group: minor wording changes
  • Lifetime risk of cancer/tumour: general population risk updated to AIHW 2017 data
  • Cancer/tumour risk management guidelines: 
    • Gastrointestinal - Surveillance: 
      • Gastrointestinal polyps surveillance information moved from non-cancer risk management section and combined into this table
      • Recommendation for 'annual haemoglobin' removed
    • Breast (female) - Surveillance: minor wording changes
    • Breast (female) - Risk-reducing medication: changed to standard eviQ breast cancer risk-reducing medication information block
    • Gynaecological - Surveillance: 
      • Removed 'Annual abdominal examination from childhood (no evidence for imaging)'
      • 'endocervical smear annually from 18 years of age' changed to 'endocervical smear for cytology from age 25 years'
  • Management of associated health problems: section added
  • Evidence for risk management guidelines: reviewed and updated

Version number increased to V.8. Review in 2 years

Version 7

Date Summary of changes
09/10/2019

Protocol reviewed at May 2019 reference committee meeting. Discussions continued via email. Approved for publication with the following changes made:

  • Summary - wording updated
  • Target group - exclusion criteria wording amended
  • Lifetime risk of cancer table - data updated. Testicular cancer added to table
  • Cancer risk management guidelines
    • Gastrointestinal cancer surveillance - "Barium follow through (BaFT) at least every 3 years" removed from recommendations 
    • Testicular cancer surveillance - recommendations added
  • Evidence for risk management guidelines - reviewed and updated
  • References - reviewed and updated
  • New template changes applied
  • "Mutation" changed to "pathogenic variant" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. Definition of "pathogenic variant" added as a pop-up.

Protocol version number increased to V.7. Review in 2 years
18/12/2020 The following sections of the protocol were updated to align with the revised eviQ cancer genetics risk management template:
  • Lifetime risk of cancer table:
    • Heading changed to "Lifetime risk of cancer/tumour"
    • Risk for general population updated to include AIHW 2016 data
  • Cancer risk management guidelines:
    • Sentence added above table "The choice of risk management strategy should take into account current age, other health issues and residual cancer risk." 
    • Surveillance: "Age to begin" changed to "Age" 
    • Updated link to "COSA - Medications to lower the risk of breast cancer: clinician guide" (also updated in evidence section)
    • Other table formatting changes
  • Support and information: template wording updated
  • Website resources: added link to "COSA - Medications to lower the risk of breast cancer: clinician guide" and "COSA - Medications to lower the chance of breast cancer: information for women".

Version 6

Date Summary of changes
21/12/2010 Approved.
08/08/2013 Discussed at August 2012 reference committee, discussion continued by email and the following changes made: 
  • Opening paragraph updated.
  • Target group - updated.
  • Exclusion criteria - updated.
  • Cancer risk management guidelines:  
    • Upper and lower gastrointestinal and small bowel changed to gastrointestinal - surgical and surveillance updated. Chemoprevention title updated to risk-reducing medication. 
    • Female breast- surgical and surveillance updated. Chemoprevention title updated to risk-reducing medication.
    • Gynaecological - surgical deleted, surveillance updated.
    • Pancreas - deleted.
    • Testicular - deleted.
  • Non-cancer risk management guidelines table added.
  • Evidence for risk management guidelines - all sections reviewed and updated.
  • Reference list reviewed and updated.
  • Review second yearly. 
09/07/2014 Lifetime risk of cancer table - General population by age 75 yrs - pancreas changed to 0.7% as previously shown as 0.01%.
03/02/2014

Following previous reference committee discussion (October 30, 2013 meeting) regarding risk management protocol for unaffected female BRCA1 mutation carrier the following changes have been made:

Evidence for cancer risk management guidelines - Female Breast

  • Surgical and risk-reducing medication - evidence updated.
  • Additional references placed in history tab.
31/07/2015 Link to AGSA changed to Genetic Alliance Australia.
07/01/2016 Sentence added to Risk Management template: "The impact of lifestyle on cancer risk should be discussed."
14/04/2016 Sentence added to Risk Management template: "This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour.  The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow up."
24/01/2017

Protocol reviewed at the Oct 2015 RC meeting and review finalised over email with the following changes:

  • Exclusion criteria - updated
  • Lifetime risk of cancer table - updated
  • Non-cancer risk management guidelines table - updated
  • Cancer risk management guidelines table - update
  • Evidence for risk management guidelines - updated 
  • Support and Information - Hereditary cancer registry 
  • References - updated
  • Next review in 2 years.
31/05/2017 Transferred to new eviQ website. Version number changed to V.4.
29/01/2019
  • Link changed from Cancer Australia Risk-reducing medication resource to COSA medication to lower the risk of breast cancer: clinician guide as per consensus at November 2018 RCM.
  • Table caption in cancer risk management guidelines section amended to include 'and avoid excessive sun exposure.'
  • Formatting of table caption in cancer risk management guidelines section amended.
  • Version kept at V.4.
19/03/2019

Minor review undertaken to bring breast surveillance recommendations in line with BRCA1/2 recommendations. Reviewed and approved with the following changes made:

  • Summary: Sentence changed from 'PJS polyps are characterised by arborisation with the presence of smooth muscle essential for diagnosis' to 'PJS polyps have characteristic histopathology; smooth muscle bundles with arborising (branching tree) appearance are essential for diagnosis'
  •  Cancer risk management guidelines: Breast (female) - Surveillance updated.
  • Evidence for risk management guidelines: Female breast - surveillance: MRI+/-MMG changed to MRI. Sentence added at end of first paragraph: 'Mammography screening is not recommended before age 40 years in females with PJS.'

Version number has been increased to V.5. Review dates kept same for next major review. 
28/08/2019 Protocol title changed from 'Risk management for Peutz-Jeghers syndrome' to 'STK11 (Peutz-Jeghers) – risk management' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.6.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/395

10 Sep 2024