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142 G. L. Beets
https://t.me/med1917
pathological response was observed in 95% of patients, with a complete response
in 67%. Only 3 patients of the entire group received adjuvant chemotherapy. The
median follow-up of 12 months it is too early to make observations on the 3 yr
DFS, but it is encouraging that so far not a single patient experienced a recurrence,
whereas in this group of patients with 77% of high-risk stage III disease one would
have expected 5–10% of recurrences at this follow up timeframe.
Although both the studies on dMMR/MSI rectal cancer and on colon cancer
still require longer follow for more definitive conclusions, the spectacular first
results are beyond expectation, and provide a strong support for the biological
rationale to use ICI in dMMR/MSI colorectal tumours with the primary tumour
still in situ. (Fig. 5.3) There are a number of remaining questions such as on
the optimal duration of ICI, single or double agent, optimal timing of surgery,
how to monitor response, whether or not to combine ICI with chemotherapy or
radiotherapy which is being addressed in many ongoing studies.
One of the more intriguing questions is if these patients are still going to require
a resection. In rectal cancer the concept of organ preservation after a good response
to neoadjuvant therapy is well established, and the small study of Cercek et al. that
Fig. 5.3 54-year-old man with a change of bowel habits and anaemia was diagnosed with a tumour
of ascending colon. Analysis showed a dMMR adenocarcinoma, with MLH1 promotor hypermethylation. No relevant familial history. A1: baseline CT showing thickened wall ascending colon
(small arrow) with adjacent abscess extending into abdominal wall, staged cT4N0M0. A2: baseline
endoscopic image of an ulcerating tumour of the ascending colon. After three courses of pembrolizumab there was a good response (images not shown) and immunotherapy was continued. B1:
CT after six courses shows no abscess, only some residual infiltration of the fat and a small residual thickening of colonic wall. B2: endoscopic image shows no tumour, only redness and irritation
of mucosa with some distortion of mucosal folds (arrow). C1 and C2: after 10 courses further normalization on CT and endoscopy with only some minor irritation (arrow). A biopsy showed only
reactive changes. The patient had no complaints and no side effects of the immunotherapy, and
in a shared decision process it was agreed not to perform a resection but rather to continue the
immunotherapy for two years and then to continue with follow up
5 Neoadjuvant Therapy in Colon Cancer 143
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is described above definitely will push organ preservation with ICI in dMMR/MSI
rectal cancer forward. For colon cancer, and especially right-sided colon cancer,
there are however notable differences. Firstly, the surgical treatment of a colon
cancer has much less impact on long term quality of life, with a much smaller
risk for a definitive colostomy or anorectal dysfunction. Secondly, whereas the
follow up in organ preservation in rectal cancer is fairly established with digital
rectal examination, flexible endoscopy and MRI, this is not yet established and
more cumbersome for colon cancer. There are some patient groups where organ
preservation in colon cancer could move forward more easily, like patients with
an increased operative risk, and patients with sigmoid tumours where the follow
up is quite similar to rectal tumours.
For the larger group of pMMR tumours, that were generally considered as
nonresponsive to ICI in the metastatic setting, the exploratory NICHE-1 trial
intriguingly showed a response in four out of fifteen patients with a complete
response in two patients. This again lends support to the biological rationale of a
better immune response in the non-metastasized setting with the primary tumour
still in situ. Ongoing translational research is focused on trying to improve the
responses in pMMR/MSS tumours and to characterize those who respond.
5.7 Conclusions
In patients with large and borderline resectable or unresectable tumours, neoadjuvant chemotherapy increases the chances of resectability and tumour free margins.
In this setting it is customary to start with 2–3 courses of chemotherapy, and to
continue to a total of 4–8 courses when there is a good response.
For the patients with a resectable colon tumour where chemotherapy is targeting undetected micrometastatic disease, there probably is a small benefit in
disease recurrence from moving at least a part of the total of 3 months of adjuvant chemotherapy to the neoadjuvant setting. The evidence mostly comes from a
single large randomized study where 6 weeks of neoadjuvant chemotherapy was
tested. Ongoing studies are awaited to support this finding, and to establish the
value of different regimens. The downside of neoadjuvant therapy that it further
increases the inherent risk of overtreatment of patients who do not benefit from
chemotherapy, because of the inherent inaccuracy of CT assessment of stage. One
of the approaches to address this is to find a better way to select patients at highest
risk of metastases with a combination of imaging and molecular markers.
The promising current developments in ctDNA provide another approach to
minimize overtreatment. It provides the opportunity to base the choice for systemic
therapy more on actual presence of metastatic disease after the resection, than on
an estimated risk.
A potential future policy that combines all of the above would be to identify
patients with a high risk for metastases or an incomplete resection, and to offer
these patients neoadjuvant chemotherapy. A consideration in these patients is to
give the entire schedule upfront, and potentially an intensification. For all other
144 G. L. Beets
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patients with a lower risk for metastases the decision to offer systemic therapy can
be based on ctDNA testing after the resection.
Because of the profound impact on the choices of systemic therapy, testing for
dMMR/MSI will become a standard procedure in the workup of colorectal cancer
patients. Although the exact role and best regimen still has to be defined, with
the spectacular response rates of immunotherapy in dMMR/MSI tumours in the
neoadjuvant setting it should not take too long to become a standard option for
these patients.
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Appendix Neoplasms
https://t.me/med1917
Paul A. Sutton and Sarah T. O’Dwyer
Abstract
Pathology of the vermiform appendix is commonly encountered by surgeons,
most frequently in patients presenting with acute appendicitis. After surgical
removal of the appendix, a very small proportion (1%) will contain a tumour.
Occasionally patients present with chronic symptoms, by which time the disease process is usually well established. The most common tumours found in the
appendix are neuroendocrine tumours. Whilst most are treated adequately with
appendicectomy alone, a proportion of these tumours are at higher risk of both
lymph node and distant metastases, justifying a more radical surgical approach.
Appendiceal mucinous neoplasms and adenocarcinoma of the appendix are rare
tumours, the management of which is undertaken in centralised services. Rather
than metastasising through lymphatic or haematogenous routes, these tumours
have a greater propensity for seeding and spread throughout the peritoneal cavity. When this occurs from an appendiceal mucinous neoplasm, the condition is
known as pseudomxyoma peritonei. Given the route of metastasis, treatment is
focussed on the peritoneal cavity with cytoreductive surgery entailing removal
of all macroscopic tumour deposits and heated intraperitoneal chemotherapy.
The role of chemotherapy is currently limited but evolving as the understanding of the biology of these rare tumours grows. Whilst aggressive forms of
these tumours do exist, prognosis for many is good with the disease process
6
P. A. S u t t o n (B)
Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK
e-mail: Paul.sutton1@nhs.net
S. T. O’Dwyer
Division of Cancer Sciences, University of Manchester, Manchester, 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_6
147
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often following an indolent course. Knowledge of these conditions is essential
to ensure recognition and appropriate referral to specialist centres.
Keywords
Appendix•Appendicitis•Adenocarcinoma•Neuroendocrine tumour
•
Pseudomyxoma peritonei•Cytoreductive surgery•Heated intraperitoneal
chemotherapy
Key Points
•
Appendiceal mucinous neoplasms and adenocarcinoma of the appendix are rare
tumours.
•
Neuroendocrine neoplasms, appendiceal mucinous neoplasms and adenocarcinomas are the most common.
•
Neuroendocrine tumours are commonly diagnosed after incidental appendicectomy and only need further treatment based on stage/size.
•
Management of mucinous neoplasms and adenocaricinomas should be undertaken
in specialised centres.
•
These tumours have the propensity for seeding and spread throughout the
peritoneal cavity.
•
Treatment is focussed on the peritoneal cavity with cytoreductive surgery and
heated intraperitoneal chemotherapy.
6.1 The Normal Appendix
The vermiform appendix is an organ of significant interest to surgeons given the
variety of clinical presentations that manifest from pathology within, both acutely
and electively. This chapter explores the structure and function of the appendix
and the spectrum of neoplastic processes that can arise, focussing on their clinical
management and outcomes.
The vermiform (worm-shaped) appendix is a cylindrical appendage of the caecum, located approximately 2 cm from the ileocaecal valve and most commonly
sited on the postero-medial aspect of the bowel wall. There is considerable variation in both the diameter and length of a normal appendix as well as its position.
The most commonly recognised sites of the appendix are retrocaecal, pelvic, postileal, subcaecal, pre-ileal, and paracaecal [1]. Embryologically the appendix arises
from the midgut, and becomes visible by week nine of foetal development. Whilst
it is normally located in the right iliac fossa, its anatomical relationship with the
caecum means that in cases where the caecum is aberrantly located, for example in situs inversus and midgut malrotation, it may be located anywhere in the
abdomino-pelvic cavity [2].
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Blood supply to the appendix is from the appendiceal artery, a branch of the
ileocolic artery which in turn is a branch of the superior mesenteric artery. Venous
drainage is achieved through the ileocolic vein, which drains into the superior
mesenteric vein and ultimately the portal venous system. Lymphatic drainage is
through the ileocolic nodes, and the appendix receives its innervation from the
vagus nerve and the superior mesenteric plexus. The appendix is surrounded by a
fatty mesentery—the mesoappendix. This mesoappendix carries the small terminal
blood vessels to the appendix and occasionally a small number of lymph nodes.
Its primary purpose is to anchor the appendix [3].
6.1.1 Histopathology
Histolopathologically the appendix is comparable to the colon, comprising: serosa,
subserosa, muscularis propria, submucosa, mucosa and epithelium. In keeping
with the colon, the muscularis propria contains complete longitudinal and circular
muscular layers, with frequent and prominent ganglion cells. The key difference
between the appendix and the remainder of the large bowel is the rich layers
of lymphoid tissue in the mucosa and submucosa [1]. These lymphoid aggregates can disrupt the mucosa and distort the architecture of the normal appendix.
The mucosa is a prominent layer, with crypt forming epithelia interspersed with
enteroendocrine cells. The epithelium also contains Paneth cells at the crypt bases.
These cells are specialised secretory epithelial cells, producing antimicrobial and
immunomodulating proteins, the function of which is to regulate the intestinal
flora. Whilst eosinophils are commonly found in the normal appendix, the presence
of neutrophils is not typical and suggests an inflammatory process.
6.1.2 Function
The appendix is widely considered to be a vestigial structure, however there is
evidence to suggest it does have an immunological function and is a site of B
cell maturation during childhood [4]. Recent research has suggested it may be an
important part of the gastrointestinal immune response [5, 6]. Furthermore, studies have also shown an association between the appendix and previously unlinked
diseases. An increased risk of new-onset type II diabetes within three years of
appendicectomy has been observed [7], in contrast to a protective effect of appendicectomy on the development of ulcerative colitis [8]. With regards to the latter,
appendicectomy in patients with ulcerative colitis appears to result in improvement
of inflammation in the colon [9]. In addition, the removal of the appendix has been
associated with reduced risk of both developing Parkinson’s disease and delaying
the onset of symptoms should it occur. These findings are often explained by the
pathogenic forms of α-synuclein in the normal human appendix that may affect
the risk of developing Parkinson’s disease [10]. However patients with appendicitis who undergo appendicectomy were more likely to develop Alzheimer’s disease
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and dementia, with an earlier onset of dementia compared with controls [11].
These associations suggest an immunological link between the appendix and these
diseases.
A recent study has quantified those proteins expressed within the normal human
appendix and identified those which appear to be exclusive to it when compared
to the small intestine and colon. The most abundant exclusive proteins identified
are involved in immune, cell adhesion and calcium binding processes. Notably,
receptor tyrosine kinases were exclusively identified in the appendix, and influx
transporters were significantly more abundant in the appendix. Such receptors
could serve as agents for targeted treatment in appendiceal disease [12].
6.1.3 Appearances on Imaging
On ultrasound, the appendix is a blind ending tubular structure contiguous with
the caecum, compressible, and filled with a combination of faeces, fluid and air.
Computed tomography (CT) again demonstrates a thin walled tubular structure
adjacent to the caecum which may contain gas or oral contrast. On magnetic resonance imaging the appendix demonstrates the above features with a hypointense
wall on both T1 and T2 weighted images. On all imaging modalities it is not
uncommon for the appendix to be unidentifiable [13].
6.2 Pathology of Appendix Tumours
The principal tumour types arising in the appendix are neuroendocrine neoplasms
(NEN), appendiceal mucinous neoplasms (AMN), adenocarcinomas and rarer
pathologies including gastrointestinal stromal tumours, mesenchymal tumours, and
metastatic tumours of colorectal origin and rarely melanomas. On analysis of
appendicectomy specimens removed largely for the presentation of appendicitis,
< 1% are found to have tumours and only one-tenth of these are primary malignant tumours [14]. Overall, 30–55% of tumours prove to be NEN tumours, 15%
AMNs, 10% primary adenocarcinomas and 15% secondary malignancy, half of
which were adenocarcinomas in patients with colorectal cancer. It is notable that
in patients with appendiceal tumours of all histological types there is a high incidence of synchronous and metachronous colorectal cancer: NEN tumours 10%,
adenomas 33%, and secondary malignancy 55% [15]. Further support for an association between epithelial appendiceal tumours and colorectal cancer is provided
from the observation of a 4% incidence of such tumours in appendices removed
electively in patients undergoing rectal and colonic cancer surgery [16].
There are a number of benign pathologies of the appendix which often mimic
appendiceal neoplasms. A simple mucocoele, retention cyst, or diverticulum of
the appendix is associated with degenerative changes due to obstruction and distension of the appendix, however contain no hyperplasia or neoplasia. Serrated
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polyps of the appendix which may have dysplastic changes within them resemble lesions of the colon and rectum, and as such are often associated with other
colonic pathology.
6.2.1 Neuroendocrine Neoplasms
The 2019 World Health Organisation (WHO) classification of appendix neuroendocrine neoplasms includes well-differentiated neuroendocrine tumours (NETS),
poorly differentiated neuroendocrine cancers (NECS) with large and small cell
types, and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) which
contain a population of both neuroendocrine neoplasm and adenocarcinoma [17].
NETS, formerly referred to as carcinoid tumours account for 75% of these
tumours, and are further divided by Ki67 proliferation index into G1, G2, or G3.
Grade 1 tumours are more indolent than Grade 2 and 3 tumours, and poorly differentiated NECs can be aggressive tumours, frequently with metastatic disease
at presentation [18]. MiNENs have varying differentiation and grades, with survival outcomes lower than NETs but better than NECs. Appendix NENs are most
commonly identified at the tip of the appendix, followed by the body, and rarely
at the base. Regional and metastatic disease are seen in 28% and 12% respectively. For NETS the 5-year survival rate decreases as the tumour increases in
size, with regional lymph node involvement and distant metastatic disease uncommon in tumours less than 2 cm in size [18]. These data have informed the TNM
staging used for these tumours.
6.2.2 Appendiceal Mucinous Neoplasms
Appendiceal mucinous neoplasms (AMNs) are characterised by a mucinous neoplastic epithelial proliferation, villous, undulating or flattened pattern that show
expansile or diverticular pushing margins and extension into the appendiceal
submucosa or beyond. These are associated with extracellular mucin that may
also dissect the appendiceal wall. These tumours are distinguished from invasive
mucinous adenocarcinomas by the absence of destructive stromal invasion. The
appendiceal wall is often densely fibrotic, can frequently become thinned and
may also be calcified. Cytological atypia of the proliferating neoplastic epithelium is usually minimal and does not exceed that seen in low-grade adenomas
of the colorectum; however, occasionally higher grade cytoarchitectural atypia is
admixed or predominates. This is characterised by nuclear pleomorphism, high
nuclear/cytoplasmic ratio, loss of nuclear polarity with full-thickness pseudo stratification of nuclei, frequent or atypical mitoses, occasionally a cribriform pattern,
and by pseudo papillary structures composed of cells with hyperchromatic nuclei
and numerous apoptotic bodies. Despite these features, pushing margins are still
retained.
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