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Revised Guidelines for the Clinical Management of Lynch Syndrome (HNPCC) – Recommendations by a Group of European Experts

Lynch syndrome (LS) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families. …

Question No 3

How effective is surveillance for endometrial and ovarian cancer?

Relevant Literature In LS, the risk of developing EC (endometrial cancer) is very high and equals or even exceeds the risk of CRC (colorectal cancer) in female gene carriers.[49] The overall prognosis of patients diagnosed with EC is relatively good, with a 10-year survival of approximately 80%. However, 20% of the patients will ultimately die from the disease. Moreover, a substantial proportion of patients need treatment with radiation and/or chemotherapy.

The main goal of surveillance for EC is detection and treatment of premalignant lesions (ie, endometrial hyperplasia) or EC at an early stage and thereby improving the prognosis for the patients. The World Health Organization classifies endometrial hyperplasia as simple or complex determined by the degree of architectural abnormality, and as having or not having atypia. Nieminen et al [50] studied serial specimens of normal endometrium, simple hyperplasia and complex hyperplasia with and without atypia during 10 years of surveillance. MMR deficiency was observed in 7% of normal endometrium, 40% of simple hyperplasia, 100% of complex hyperplasia without atypia and 92% of complex hyperplasia with atypia, suggesting that in LS, contrary to the traditional view, complex hyperplasia with and without atypia was equally important as precursor lesions of EC.

In 2011, Auranen and Joutsiniemi[51] performed a systematic review of all studies that addressed gynaecological cancer surveillance in women who belonged to LS families. The authors identified five studies in the literature that included a total of 647 women.[52–56] The screening methods applied in the studies varied from only transvaginal (or transabdominal) ultrasound (two studies) to a combination of transvaginal ultrasound and endometrial biopsy (two studies) and hysteroscopic endometrial biopsy (one study). The intervals between examinations varied between 1 year in three studies, 1–2 years in one study and 2–3 years in another study. In the studies that used only ultrasound as the screening tool, no EC were detected and only interval cancers occurred. However, in the studies with a protocol that also included endometrial biopsies, the detection of premalignant lesions and EC was improved.

Renkonen-Sinisalo et al [54] compared the Federation of Gynecology and Obstetrics (FIGO) stages of the screen-detected cancers with those of EC diagnosed after presentation of signs or symptoms. Although less advanced cancers were observed in the screen-detected group, the difference was not statistically significant. The main advantage of the surveillance programme seems to be the identification of precursor lesions. No benefit was shown for ovarian cancer surveillance. Auranen and Joutsiniemi[51] concluded that the available studies do not adequately allow for evidence-based clinical decisions.

Since that review, another retrospective study was published on the impact of gynaecological screening in MSH2 carriers (n=54).[57] Nine women were diagnosed with EC, five of which were within 1 year of the previous negative screening test (transvaginal ultrasound and/or endometrial biopsy) and two were at initial screening. Of the nine EC, seven were localised cancers (stage I), and one was at an advanced stage (stage III). There were no deaths due to EC. Six women had ovarian cancer, three of which were within 1 year of a previous normal screening. Two died from ovarian cancer. The authors concluded that gynaecological screening did not result in earlier detection of gynaecological cancer.

In view of the uncertain effect of the surveillance programme, it is important to consider possible disadvantages of the programme. Elmasry et al [58] assessed the patient acceptability of the available screening modalities. Transvaginal ultrasound was associated with less discomfort than hysteroscopy or Pipelle biopsy. There was no significant difference between the pain scores for hysteroscopy and Pipelle biopsy. Huang et al [59] compared a new patient-centered approach by combining endometrial biopsies and colonoscopy under sedation. This approach was much more acceptable than an endometrial biopsy as a single procedure without sedation.

Wood et al [60] evaluated the effect of gynaecological screening in LS families on psychological morbidity. The authors did not demonstrate any adverse psychological effect in the screened population, even in those with false positive screening results.

Conclusion The value of surveillance for EC is still unknown. Surveillance of the endometrium by gynaecogical examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35–40 years may lead to the detection of premalignant disease and early cancers (category of evidence III) and should be offered to mutation carriers (grade of recommendation C). The pros and cons should be discussed. Given the lack of evidence of any benefit, gynaecological surveillance should preferably be performed as part of a clinical trial.


Question No 4

What is the role of prophylactic hysterectomy with or without oophorectomy?

Relevant Literature Schmeler et al [61] have shown in a retrospective study that prophylactic hysterectomy and oophorectomy is very effective in LS: none of the patients who underwent prophylactic surgery (61 out of 315) developed endometrial or ovarian cancer, whereas 33% of patients who did not have surgery developed EC and 5.5% developed ovarian cancer.

A recent study documented two cases of LS patients who developed primary peritoneal cancers after prophylactic surgery.[62] A cost-effectiveness analysis of prophylactic surgery versus gynaecological screening showed that risk-reducing surgery was associated with both the lowest costs and highest number of quality-adjusted life years.[63,64]

In view of the very high risk of EC, the substantial proportion of women who will die from the disease, the morbidity associated with treatment and the effectiveness of prophylactic surgery, there is agreement that the option of prophylactic hysterectomy should be discussed with mutation carriers who have completed their family. However, there are still some important questions that should be addressed.

First, should prophylactic surgery include salpingo-oophorectomy? The risk of developing ovarian cancer in mutation carriers is approximately 9% with the highest risks in MLH1 and MSH2 mutation carriers and the lowest risk in MSH6 mutation carriers. Although the prognosis of unselected patients with ovarian cancer (and also of patients with ovarian cancer associated with BRCA1 and BRCA2 mutations) is very poor, recent studies suggested that the biology of ovarian cancer associated with LS may be different. Three studies showed that the majority of symptomatic ovarian cancers (77–81%) in LS are diagnosed at an early stage (FIGO stages I and II).[65–67] In a multicentre study, Grindedal et al [66] collected a large number (n=144) of prospectively diagnosed cases of ovarian cancer and demonstrated a very good prognosis with a 10-year survival of 81%.

Prophylactic surgery in postmenopausal women should include salpingo-oophorectomy. However, salpingo-oophorectomy in premenopausal women is associated with various adverse effects such as an immediate onset of menopause as a result of oestrogen deprivation potentially resulting in vasomotor symptoms and possible sexual dysfunction. Oestrogen deprivation may also lead to a higher risk of osteoporosis. A large study by Madalinska et al [68] in 846 carriers of a BRCA1 and BRCA2 mutations reported significantly more endocrine symptoms in the patients who underwent prophylactic oophorectomy compared to women who underwent surveillance of the ovaries. No significant differences were observed in the level of sexual activities between the two groups, but women in the prophylactic surgery group reported significantly more discomfort (vaginal dryness and dyspareunia), less pleasure and less satisfaction during sexual activities. Despite this, the study did not reveal any other differences in quality of life. Usually, hormone replacement therapy is prescribed in premenopausal women after salpingo-oophorectomy, which may partly reduce the vasomotor symptoms but has no effect on sexual discomfort.[69]

In view of the recent study that suggests a relatively good prognosis of ovarian cancer in LS, it is questionable whether the possible small gain in life expectancy outweighs the adverse effects of prophylactic salpingo-oophorectomy at a young age.

The second question is how these issues should be discussed with the patient and how the patient can be supported in their decision-making? The best approach is to inform the patient fully about all pros and cons of prophylactic surgery. As a basis for this discussion, the pros and cons are summarised in Table 6. Depending on the type of information, a gynaecologist, geneticist, clinical psychologist or other specialists should be involved. Ideally, this information should also be available in written form.

The third question is from which age surgery should be recommended. The risk of endometrial and ovarian cancer increases from the age of 40 years. The optimal timing of prophylactic surgery, therefore, would be around the age of 40 years.

Conclusion Hysterectomy and bilateral oophorectomy largely prevents the development of endometrial and ovarian cancer (category of evidence III) and is an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years (grade of recommendation C). Also, if CRC surgery is scheduled, the option of prophylactic surgery at the same time should be considered. All pros and cons of prophylactic surgery should be discussed.


Hans F A Vasen, Ignacio Blanco, Katja Aktan-Collan, Jessica P Gopie, Angel Alonso, Stefan Aretz, Inge Bernstein, Lucio Bertario, John Burn, Gabriel Capella, Chrystelle Colas, Christoph Engel, Ian M Frayling, Maurizio Genuardi, Karl Heinimann, Frederik J Hes, Shirley V Hodgson, John A Karagiannis, Fiona Lalloo, Annika Lindblom, Jukka-Pekka Mecklin, Pal Møller, Torben Myrhoj, Fokko M Nagengast, , Yann Parc, Maurizio Ponz de Leon, Laura Renkonen-Sinisalo, Julian R Sampson, Astrid Stormorken, Rolf H Sijmons, Sabine Tejpar, Huw J W Thomas, Nils Rahner, Juul T Wijnen, Heikki Juhani Järvinen, Gabriela Möslein

Full article http://www.medscape.com/viewarticle/803749_1


This entry was posted on June 3, 2013 by in Research Updates.

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