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70 D. Harji and C. Taylor
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is opiate based [46]. A multimodal analgesic strategy should be employed during the perioperative period, with consideration of the inclusion of transdermal
buprenorphine patches, preperitoneal nerve catheters, intravenous lignocaine infusion and post-operative non-steroidal anti-inflammatory drugs [47]. Neuropathic
agents, such as Pregablin, should be initiated for patients with neuropathic pain,
and pre-operatively in those, underdoing a planned nerve or bony resection. This
should be appropriately dose-escalated to achieve therapeutic levels in the postoperative period. Non-pharmacological therapies should also be considered and
have been shown to be beneficial.
3.7 Stoma Care
Specialist nursing and stoma care is required for patients undergoing major exenterative surgery. In-depth, preoperative counselling and support should be provided
to inform and educate patients, whilst providing support for any physical, psychological or social adjustments to two stomas. Peer to peer support between patients
can be invaluable; hearing from others who manage to work, travel, enjoy activities
and intimacy can support decision-making. Patients with an existing gastrointestinal stoma, or those who coped well with a previous temporary ileostomy may
have improved self-efficacy and less anxiety about coping with two stomas. The
presence of two stomas imposes a significant change to overall body image and
physical function, which require a period of adjustment in their role function and
social function in the first 12 months post-operatively [48]. Patients should be
appropriately appraised of early and late stoma complications, as the number and
nature of stoma complications experienced will influence quality of life [49].
3.8 Empty Pelvis Syndrome
A substantial proportion of the post-operative morbidity following pelvic exenteration is attributed to the ‘empty pelvis syndrome’. This is an emerging phenomenon,
which develops as a sequalae of the empty pelvic cavity following total exenteration [50]. This leads to the accumulation of fluid and migration of small bowel
within the cavity, giving rise to the development of pelvic abscesses, perineal
fluid discharge with perineal wound dehiscence, prolonged ileus or recurrent bowel
obstruction and enteroperineal fistulae. To date, there have been a range of preventative strategies suggested to address the issue of the empty pelvic cavity, including
pelvic mesh reconstruction [51], Bakri balloon occlusion [52] and omentoplasty
[50]. The optimal preventative strategy for the empty pelvis syndrome remains
elusive. The impact of this on QoL and long-term survivorship has not been quantified, however, it is likely to have a significant impact on both these important
concepts.
3 Quality of Life and Survivorship in Extended Pelvic Resection for Advanced … 71
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3.9 Fatigue
Fatigue is often described as a whole-body tiredness not relieved by sleep, lasting
a few weeks or months; limiting normal activities. Fatigue following pelvic exenteration is common, and can persist for up to 36 months post-operatively, with a
gradual decline [53]. If fatigue becomes bothersome, support should be provided
to teach the principles of fatigue management: planning, prioritising and pacing.
There is also good evidence on the role of physical activity in managing fatigue.
3.10 Mobility
A rehabilitative multidisciplinary approach is needed to equip patients to live full
lives following complex pelvic surgery. The focus on mobility and function should
start preoperatively if individuals are to fulfil their full potential post-operatively.
Patients with locally advanced and recurrent rectal cancer requiring pelvic exenteration often have lower physical activity levels pre-operatively when compared
with the general population [54]. There is a period of associated physical deconditioning, which frequently develops in the intervening months of preoperative
oncological treatment. This timeframe should be maximised and appropriate prehabilitation should be offered at least six weeks prior to surgery to allow time
to reverse modifiable risk factors and build strength, stamina, and cardiovascular
fitness [55]. Multimodal prehabilitation programs involve physical activity, nutritional and psychological optimisation. These principles can be embedded into
post-operative rehabilitative pathway to improve the quality and duration of postoperative recovery. A personalised approach targeting patients with lower baseline
fitness or physical function is recommended [56]. Objective assessment of physical fitness and performance using cardiopulmonary exercise testing should be
mandated for patients being considered for major pelvic surgery. The Measurement of Exercise Tolerance before Surgery (METS) study; reported that an AT
of<11 mL/kg/min and a peak VO
erative mortality and non-cardiac complications, respectively [57]. These metrics
are essential in understanding the potential post-operative course and to aid shared
decision-making in the preoperative period.
Postoperatively, rehabilitation will be dependent on surgery performed, critical
care outcomes and baseline function. The principles of Enhanced Recovery after
Surgery (ERAS) can be applied to patients undergoing pelvic exenteration, with a
tailored strategy, based on the complexity of the procedure undertaken. Examples
of a tailored ERAS strategy include, strict positioning and mobilising protocol for
patients following perineal flap reconstruction, stepwise mobility exercises using
a range of walking aids to regain pelvic stability following a bony resection, ‘relearning’ walking techniques and the early use of ankle/foot orthotics following
a nerve resection. The feasibility of ERAS programmes in this setting has been
demonstrated, with an associated improvement in clinical outcomes, including
reduced length of stay and post-operative morbidity.
of <15 mL/kg/min are predictive of postop-
2
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3.11 Conclusion
Pelvic surgery for locally advanced and recurrent rectal cancer has a significant
impact upon QoL and survivorship, that impacts upon a broad range of constructs.
With time, most cancer survivors adjust to their post-operative QoL and maintain
good QoL overall. The trade-offs of major surgery include living with the effect of
symptoms, including managing physical changes, emotional turmoil, loss of functional independence, reduced social well-being, and financial distress. Information
and support need to be delivered at multiple touchpoints, by a multidisciplinary
team across a variety of care settings. Assessing QoL at these touchpoints using
validated, disease-specific metrics is essential in the early detection and treatment
of arising issues and for ongoing surveillance. Survivorship care initiatives should
focus on providing a patient-centred approach to care across many years.
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Lynch Syndrome
https://t.me/med1917
Penelope Edwards and Kevin J. Monahan
Abstract
Lynch syndrome, is an inherited condition characterized by a predisposition to
predominantly epithelial cancers, particularly colorectal and endometrial cancer. This chapter provides a concise summary of Lynch syndrome, highlighting
its genetic basis, clinical manifestations, associated cancers, diagnostic criteria,
and management strategies. Understanding Lynch syndrome is crucial for early
detection, risk assessment, and appropriate cancer screening and prevention
strategies in affected individuals and their families.
Keywords
Lynch syndrome•Hereditary nonpolyposis colorectal cancer (HNPCC)
Genetic predisposition•DNA mismatch repair•Microsatellite instability
Colorectal cancer•Endometrial cancer•Gastrointestinal malignancies
Hereditary cancer syndrome•Cancer screening
4
•
•
•
List of Abbreviations
ADR Adenoma detection rate
P. Ed wa r d s · K. J. Monahan (B)
Centre for Familial Instestinal Cancer, St Mark’s Hospital & Academic Institute, London, UK
e-mail: k.monahan@imperial.ac.uk
P. Ed wa r d s
e-mail: Pebs.edwards@icr.ac.uk
Imperial College University, London, UK
P. Ed wa r d s
Institute of Cancer Research, Sutton, UK
Royal Marsden NHS Trust, London, UK
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
M. Evans e t al. (eds.), Coloproctology, https://doi.org/10.1007/978-3-031-59630-8_4
77
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APC Adenomatous polyposis coli
BSG British Society of Gastroenterologists
CA125 Cancer antigen 125
cMMRD Congenital mismatch repair deficiency
cMS Coding microsatellites
COX Cyclooxygenase
CpG 5’-C-phosphate-G-3’
CRC Colorectal cancer
CTLA-4 Cytotoxic T-lymphocyte associated protein-4
CTNNB1 Catenin beta-1
DFS Disease free survival
dMMR Mismatch repair deficient
dMMR-CF Mismatch repair deficient crypt foci
EPCAM Epithelial cellular adhesion molecule
ESGE European Society of Gastrointestinal Endoscopy
FDA US Food and drug administration
FIT Faecal immunochemical testing
FSP Frameshift peptide
HFEA Human fertility embryology association
HNPCC Hereditary non polyposis colorectal cancer
ICPI Immune checkpoint inhibitor
IHC Immunohistochemistry
IMRC International mismatch repair consortium
IUD Intrauterine device
JAK2 Janus kinase 2
LS Lynch syndrome
MLH1 MutL homolog 1
MMR Mismatch repair
MSH2 MutS homolog 2
MSH6 MutS homolog 6
MSI-H Microsatellite instability high
MSI-L Microsatellite instability low
MSI Microsatellite instability
NGS Next generation sequencing
OS Overall survival
PD-1 Programmed death 1
PD-L1 Programmed death ligand 1
PFS Progression free survival
PGT Pre-implantation genetic testing
PLSD Prospective Lynch syndrome database
pMMR Mismatch repair proficient
PMS2 Post meiotic segregation increased 2
PRS Polygenic risk score
PTEN Phosphate and TENsin homolog deleted on chromosome 10
PV Per vaginal
4 Lynch Syndrome 79
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SNP Single nucleotide polymorphism
TAH BSO Total abdominal hysterectomy bilateral salpingo-oopherectomy
TAP1 Transporter 1, ATP binding cassette subfamily B member
TIL Tumour infiltrating lymphocytes
TP53 Tumour protein 53
TVUSS Transvaginal ultrasound scan
UGI Upper gastrointestinal
Key Points
•
Lynch syndrome (LS) is a common dominantly inherited cancer predisposition
syndrome affecting approximately 1 in 400 adults, causing a high lifetime risk
especially of colorectal (CRC) or endometrial cancer (EC), and also many other
cancers.
•
LS is genetically defined by the presence of pathogenic variants in mismatch repair
(MMR) genes (MLH1, MSH2, MSH6, PMS2 and deletion of a gene adjacent to
MSH2 known as EPCAM) leading to defective DNA repair causing an accumulation of mutations and the development of mismatch repair deficient (dMMR)
tumours.
•
The lifetime risk of CRC in people with LS is between 15 and 82% depending on
the specific LS gene affected.
•
Colonoscopic surveillance is recommended every 2 years: with a gene-dependent
starting age: 25 years (MLH1 and MSH2), or 35 years (MSH6 and PMS2).
Other preventative strategies improving outcomes for patients include aspirin
chemoprophylaxis and prophylactic gynaecological surgery.
•
Followinggenetic diagnosis, cascade testing is recommended for family members.
•
CRC in people with LS is not easily clinically distinguished from sporadic CRC,
although it may be characterised by flat, non-polypoid or submucosal lesions.
Therefore, all colorectal and endometrial tumours diagnosed in the UK should
undergo universal molecular testing for LS regardless of age.
•
LS diagnosis can facilitate therapeutic personalisation for cancer patients. Medical treatment options include immunotherapy via immune checkpoint inhibitors
and surgical options may include extended colectomy, which may improve
oncological outcomes.
•
Optimisation of clinical management including the interval for colonoscopy
surveillance and vaccine design and efficacy are subject to ongoing research.
4.1 Introduction
The lifetime risk of LS-related cancers is increased compared to the general population and can lead to early-age onset cancers, which may be the ‘herald’ diagnosis
of cancer susceptibility in families (Fig. 4.1). Cancer risk is dependent on the
specific gene affected in combination with lifestyle and polygenic factors (other
genetic variants contributing to cancer risk) and can vary from between 10 and
80 P. Edwards and K. J. Monahan
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Fig. 4.1 Lifetime risks of organ specific cancers in Lynch syndrome (LS) as per PLSD database
accessed 1st September 2023. Specific LS genes convey different % risks. Created with BioRender.com [2, 3]
90% over a patient’s lifetime. In the UK, LS accounts for 3.3% of CRCs and is
the most common familial cause of CRC [1].
CRC in the context of LS is usually not distinguishable from CRC in nonLS patients (Figs. 4.2 and 4.3). However, they are more likely to be proximal in
location, may be morphologically ‘flat’ (as with LS precursor lesions) and may
present at a younger age [4]. They often have pathological features of poor differentiation with mucinous features, signet ring cells and medullary pattern [4,
5], and may have an associated lymphocytic infiltration due to immune activation
[6]. The lymphocyte infiltration is associated with improved prognosis stage-bystage compared to non-LS CRC, likely related to immune regulation [7]. They
are therefore less likely to metastasise, can become locally advanced and invasive without metastasis, necessitating broader surgical resection margins without
neoadjuvant therapy. Recent approval of funding for immunotherapy with checkpoint inhibitors for locally advanced disease [8, 9] [see section on immunotherapy]
or use of chemotherapy can reduce disease bulk and may be an effective strategy
to enhance surgical options.
LS is defined by the presence of a constitutional pathogenic germline variant
within one of the mismatch repair (MMR) genes which includes mutL homolog 1
(MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and post meiotic segregation increased 2 (PMS2) as well as deletions of the epithelial cellular adhesion
molecule (EPCAM) gene (which regulates MSH2 expression). In healthy individuals, these proteins repair errors, or potential mutations, during DNA replication
[more in Biology].
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