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152 P. A. Sutton and S. T. O’Dwyer
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AMNs with low grade atypia are designated low grade appendiceal mucinous
neoplasm (LAMN) and are assigned a WHO 2019 grade G1 [19] (Table 6.1)
(Fig. 6.1).
Tab le 6.1 WHO classification (2019) of appendiceal mucinous neoplasms and their histopathological features in the primary tumour and peritoneal metastasis
Tumour
grade
1 Low grade cytology with a pushing
2 High grade cytology with a
3 Signet ring cell adenocarcinoma
Histological criteria
In the appendiceal tumour In the peritoneal metastasis
margin (low grade appendiceal
mucinous neoplasm)
pushing margin (high grade
appendiceal mucinous neoplasm)
Invasive mucinous adenocarcinoma
without a signet ring cell
component
with numerous signet ring cells in
mucin pools or infiltrating stroma
• Hypocellular mucin deposits
• Neoplastic epithelial elements have low
grade cytology
• No infiltrative type invasion
• Hypercellular mucin deposits
• High grade cytological features
• Infiltrative type invasion (jagged, angulated
glands in a desmoplastic stroma OR a small
mucin pool containing clusters of neoplastic
cells)
• Mucinous tumor deposits with signet ring
cells
Fig. 6.1 WHO (2019) histological criteria for grading appendiceal mucinous neoplasms and their
peritoneal metastases: Grade 1 – Low-grade cytology with a pushing margin (low-grade appendiceal mucinous neoplasm); Grade 2 – High-grade cytology with a pushing margin (high-grade
appendiceal mucinous neoplasm or invasive mucinous adenocarcinoma); Grade 3 – Signet-ring
adenocarcinoma with signet-ring cells in mucin pools or infiltrating tissue
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Tab le 6.2 Classification of appendiceal mucinous neoplasms utilising the PSOGI (2016) consensus definitions, TNM8, and WHO (2019) classification systems
Peritoneal disease (PSOGI
2016 category)
Acellular mucin M1a
Low grade mucinous
carcinoma peritonei
High grade mucinous
carcinoma peritonei
High grade mucinous
carcinoma pertonei with signet
ring cells
TNM8 stage and WHO
(2019) grade
No grade
M1b
Mucinous carcinoma
peritonei, Grade 1
M1b
Mucinous carcinoma
peritonei, Grade 2
M1b
Mucinous carcinoma
peritonei, Grade 3
Usual primary tumour (WHO
grade)
LAMN (Grade 1)
LAMN (Grade 1)
HAMN (Grade 2)
Mucinous adenocarcinoma
(Grade 2)
Signet ring cell adenocarcinoma
(Grade 3)
Those in which high grade cytoarchitectural atypia predominates are designated high grade appendiceal mucinous neoplasm (HAMN) and assigned a WHO
2019 grade G2. AJCC UICC TNM8 stage LAMNs as pTis (when there is no
spread of the lesion’s epithelium and/or mucin beyond the appendiceal muscularis
propria), as pT3 when there is spread beyond this but the serosal surface is uninvolved/intact, as pT4a when the tumour perforates onto or involves the serosal
surface, and pT4b when adjacent structures are involved either macroscopically
and/or microscopically [20]. Given their different risk of progression to PMP, clinicopathological distinction between LAMN1 i.e. disease confined to appendiceal
lumen and LAMN 2 i.e. mucin and/or neoplastic epithelium in the appendiceal
submucosa, wall and/or peri appendiceal tissue, with or without perforation has
been made [21]. Recommendations on staging for HAMNs are currently unclear;
this may change as more data on these lesions emerge.
When AMNs metastasise to the peritoneum this is identified as pseudomyxoma
peritonei (PMP). These metastatic deposits are classified using the Peritoneal Surgical Oncology Group International (PSOGI) 2016 consensus as either acellular
mucin, low grade mucinous carcinoma peritonei (MCP), or high grade MCP [22].
Utilising TNM8, acellular mucinosis is categorised as M1a and all other metastatic
subtypes as M1b (Table 6.2).
6.2.3 Appendix Adenocarcinoma
Mucinous adenocarcinoma is characterised by infiltrative invasion with angulated
glands, desmoplastic stroma, tumour budding or a ‘small cellular mucin pool’
pattern. These sometimes appear to arise from pre-existing dysplastic serrated
lesions or AMNs. The current WHO classification (2019) provides stricter guidance for classification of primary appendiceal adenocarcinomas (AA) as mucinous
adenocarcinomas (MAC), adenocarcinomas not otherwise specified (ANOS), and
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signet-ring adenocarcinomas (SRC). Goblet cell adenocarcinomas (GCA) are classified separately [19]. This classification also incorporates the American Joint
Committee on Cancer (AJCC) tiered grading [23]. Most AA are attributed as WHO
grade 2, with the exception of SRC which is WHO grade 3. AJCC UIC TNM8
stages appendix adenocarcinoma as pT1 to pT4 in a manner similar to colorectal
adenocarcinoma [20].
Again, peritoneal metastases (PM) are recommended to be graded separately to
that of primary tumours due to the potential for discordant grading [22, 24]. The
WHO 2019 terminology for PM arising from AA has equivalence to the PSOGI
2016 consensus, categorising metastatic deposits as either high grade MCP, or high
grade MCP with signet ring cells both of which are M1b on TNM8 [22].
6.2.4 G oblet Cell Adenocarcinoma
In 2008 Tang et al. [25] published the morphological classification of GCA,
dividing these tumours into three prognostic subgroups: Tang A tumours (or
typical GCA) are characterised by well-differentiated goblet cells arranged in
clusters, with minimal atypia; Tang B tumours (adenocarcinoma ex-GCC, signet
ring cell type) include goblet cells or signet ring cells arranged in irregular clusters with significant cytologic atypia; Tang C tumours (adenocarcinoma ex-GCC,
poorly differentiated carcinoma) are characterised by focal evidence of goblet cell
morphology with a component of poorly differentiated adenocarcinoma (glandforming, confluent sheets of signet ring cells or undifferentiated carcinoma). The
5-year survival of appendix GCAs were found to follow 100%, 36%, and 0%
for Tang groups A, B and C, respectively [25]. The WHO classification (2019)
grades these tumours as GCA 1–3, and is widely considered the most relevant to
prognosis.
Discordance in pathological characteristics between the primary tumour and
metastatic deposits has been described [26, 27]. Yan et al. [27] reported a series of
26 patients where the neuroendocrine markers present in the primary tumour were
lost in the metastatic sites of nine of the patients (35%). Their results suggest that
the adenocarcinoma component, rather than the neuroendocrine component, was
responsible for the distant spread of these malignancies.
Immunohistochemical characterisation has shown high expression of carcinoembryonic antigen (CEA); 100% and high cytokeratin (CK)-20 staining (81%)
with lower rates of the neuroendocrine markers: chromogranin (44% positive,
56% weak staining) and synaptophysin (13% positive, 75% weak staining, 12%
negative) [28].
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6.3 Appendiceal Neuroendocrine Tumours
The most common tumours arising from the appendix are neuroendocrine neoplasms (NENs), accounting for approximately 25–60% of primary malignancies
[29]. The average age at diagnosis is around 30 years of age, with a slight female
preponderance. The incidence of NENs is increasing, at least in part due to better
pathological assessment, reporting, and referral [30].
6.3.1 Clinical Presentation
The majority of appendiceal NENS are diagnosed incidentally following appendicectomy, be that for acute appendicitis, chronic abdominal pain, or concurrently
at the time of other surgery, for example surgery for colorectal, urological or
gynaecological malignancy. Features of carcinoid syndrome, for example diarrhoea, facial flushing and wheeze, may be present in patients with liver metastases.
This is very uncommon in NETS, and NECs are hormonally inactive [15]. Very
large tumours can cause local symptoms of pain, anorexia and weight loss.
6.3.2 Investigations
Given the incidental presentation of most appendiceal NEN, accurate histopathological assessment is key to evaluation. In parallel to this, biochemical evaluation
with serum Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA)
should be undertaken given its association with recurrence and poor survival [31].
CgA is a protein released by NETs, however, is very non-specific and can be artificially raised with medications such as steroids and proton pump inhibitors and
in renal insufficiency. Cross sectional imaging with a contrast enhanced CT scan
is employed to identify regional and metastatic sites of disease. A more sensitive
imaging modality is positron emission tomography (PET) scanning using a tracer
specific to somatostatin receptors, mostly commonly gallium (GA-68). This is not
recommended as routine practice in either NANETS or ENETS guidelines for
appendiceal NENs, but may be helpful in the evaluation of metastatic disease and
in patients with symptoms suggestive of carcinoid syndrome. Given that NECs are
not hormonally active and are characterised by high proliferation, PET scan with
18-FDG tracer is utilised for staging [32]. Gallium PET scan is still considered as
the gold standard staging investigation however, with a sensitivity and specificity
of 100% and 90% respectively [33, 34].
6.3.3 M anagement
In patients who are diagnosed following appendicectomy, the need for further surgical treatment is determined by tumour size and the presence of other high risk
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features i.e. mesoappendiceal invasion > 3 mm, positive margins, lymphovascular
invasion, and high Ki67 proliferation rate. The incidence of metastasis is associated with size of the primary tumour, with lesions 2 cm or greater associated with
positive ileocolic lymph nodes in 33%, and metastases in 12% [35].
Consensus based guidelines from both NANETS and ENETS recommend that
appendicectomy alone is sufficient treatment for any lesion smaller than 1 cm, and
for those between 1 and 2 cm without high risk features [36, 37]. Right hemicolectomy is recommended for lesions larger than 2 cm in most guidelines. The optimal
surgical approach for appendix NENs between 1 and 2 cm with high risk features
remains controversial [38], and therefore a multidisciplinary approach is essential
to discuss high-risk pathological features, lesion site (base vs. tip), patient age,
comorbidities, and the potential for surgical complications (Fig. 6.2). If surgery
is to be considered, endoscopic examination of the colon to exclude synchronous
pathology should be performed [36]. A number of retrospective studies have suggested that the NANETs and ENETS guidelines risk overtreatment, and therefore
careful discussion with the patient is needed.
Fig. 6.2 Therapeutic algorithm for appendiceal neuroendocrine tumours. Taken with permission
from: Lamarca A, Nonaka D, Lopez Escola C, Hubner RA, O’Dwyer S, Chakrabarty B, et al.
Appendiceal Goblet Cell Carcinoids: Management Considerations from a Reference Peritoneal
Tumour Service Centre and ENETS Centre of Excellence. Neuroendocrinology. 2016;103(5):500–
17. Permission needed
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6.3.4 Surveillance and Outcomes
Patients with small low risk appendix NENs (less than 1 cm with no adverse
histopathological features) who have been treated by appendicectomy with clear
margins (R0) do not require surveillance [39, 40]. The only exception to this would
be in the case of patients who have biochemically demonstrable hormone secretion or who had symptoms suggestive of this. Surveillance is also not required for
patients with tumours 1–2 cm in size who have undergone right hemicolectomy
with no residual disease on histology. For those with residual disease following
right hemicolectomy, incomplete resection not proceeding to right hemicolectomy,
lymph node involvement, lymphovascular invasion, and/or G2–3 tumours, consensus guidelines from ENETS would recommend surveillance with biochemistry and
cross-sectional imaging. Biochemical surveillance is most commonly performed
with CgA with the same cautions regarding its lack of specificity. Plasma or
twenty-four hour urinary 5HIAA is helpful in those patients with serotonin producing tumours and in those with signs and symptoms suggestive of carcinoid
syndrome. Cross sectional imaging can be performed with a standard contrast
enhanced CT or MRI on an annual basis, with no evidence for the routine use
of PET scanning in surveillance. These surveillance recommendations also apply
to all larger (> 2 cm) appendix NENs.
The rationale for right hemicolectomy for appendiceal NENs greater than 2 cm
or with high risk features is to undertake lymphadenectomy of involved regional
lymph nodes, reducing the risk of distant metastasis and ultimately to improve
overall survival. A number of studies however have failed to show any survival
benefit with this approach [41]. Furthermore, studies have shown no differences
in the rate of regional lymph node positivity, metastatic disease, and overall survival between small and larger tumours [38]. Ten year disease-specific survival
in a recent meta-analysis is not significantly different between patients with and
without lymph node involvement (95.6% vs. 99.2% OR: 0.2, 95% CI: 0.02–2.4)
[42].
6.4 Appendiceal Mucinous Neoplasms
6.4.1 Clinical Presentation
In the majority of cases, an appendiceal mucinous neoplasm (AMN) is diagnosed
following appendicectomy for incidental appendicitis. At operation the appendix
may appear swollen and bulbous, which raises suspicion, but most tumours are
diagnosed coincidentally following histopathological examination. If the appendix
is felt to be abnormal at the time of surgery, care should be taken to remove the
likely tumour in totality and without rupture. Evidence of an appendix mucocele
with or without perforation, extra-appendiceal mucin or other peritoneal disease
noted at operation must be carefully documented to assist with future management
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Fig. 6.3 CT image of a large appendix mucocoele (left), and in a second case an intra-operative
image (right) demonstrating a smaller mucocoele with extra-appendiceal mucin
(Fig. 6.3). In men, incidental presentation of mucin in a hernial sac while undergoing hernia repair is often the indicator of an occult appendix neoplasm [43].
6.4.2 Pseudomyxoma Peritonei
Adenomatous lesions of the appendix generate mucinous distention, compression
of the wall, and perforation of the appendix. In the absence of appendicitis this
perforation often seals having released cells into the peritoneal cavity. Over a
number of years, the implanted cells will generate mucinous implants and the
condition known as Pseudomyxoma Peritonei (PMP). PMP is characterised by
abundant production of mucinous ascites, and if left untreated or is unrecognised
and misdiagnosed, gross abdominal distension, loss of peripheral lean body mass
secondary to limited nutritional intake and compression of the gastrointestinal tract
will develop (Fig. 6.4). In these situations, many patients have been erroneously
treated: women commonly for ovarian cancer and men for occult gastrointestinal
cancer or categorised as cancer of unknown primary (CUP).
Following the pioneering work of Professor Sugarbaker from Washington, DC
over the latter decades of the twenty-first century, it is now accepted that in the vast
majority of cases PMP develops secondary to an epithelial adenomatous tumour
of the appendix, most commonly a low grade appendiceal mucinous neoplasm
(LAMN) [44]. It has been estimated that PMP has an incidence approximating
two per million of the population per year in developed countries. It follows that
LAMNs must occur more frequently as when they are confined to the appendix
and removed without perforation, PMP does not develop [45]. The spectrum of
disease ranges from abundant production of mucin with very scant or no epithelial
cell proliferation, through to peritoneal mucinous carcinoma peritonei (MCP).
The unique feature of PMP is the ability to develop surface peritoneal implants
without progressing to parenchymal or lymph node metastases. Recent evaluation
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Fig. 6.4 Advanced pseudomyxoma peritonei. CT scan (left) shows large volume mucinous ascites
compressing the small bowel resulting in nutritional compromise and gross abdominal distension
(right)
of adhesion molecules in PMP and colorectal cancer has demonstrated a distinct
profile that may explain the pattern of disease and offer potential for molecular targeting to prevent invasion [46]. Many patients with PMP present to non-specialist
centres and are misdiagnosed as having ovarian pathology [43]. Some are treated
with repeated laparotomies, debulking of the tumour or removal of the mucin,
while others receive systemic chemotherapy with minimal response. It is recognised that repeat laparotomy is unlikely to achieve cure and the recommended
treatment is an attempt at complete cytoreduction and administration of heated
intraoperative intraperitoneal chemotherapy [47].
Due to the rarity of these tumours and the devastating effect of misdiagnosis
and treatment, in the UK, two centres have been designated for the treatment of
tumours of appendiceal origin: North Hampshire Hospital, Basingstoke, and The
Christie Hospital, Manchester. This approach is supported by the UK National
Institute for Health and Care Excellence (NICE) whose recommendations for PMP
treatment were published in 2004 [48]. The concentration of patients to specialist
treatment centres has allowed the two teams to gain experience in the radical
approach of cytoreductive surgery and heated intraperitoneal chemotherapy leading
to good outcomes and long-term survival [49, 50].
6.4.3 Investigations
Investigation of patients with known or suspected PMP arising from an AMN
include CT, which often demonstrates classical features of disease in the right and
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left upper quadrants, described as scalloping of the liver and spleen. Other common
sites of disease often visible on CT include the ovaries, omentum, gall bladder and
porta hepatis, right iliac fossa and pouch of Douglas. To optimise assessment of
the small bowel and mesentery, a CT scan with oral and intravenous contrast will
offer discrimination of bowel gas and mucinous implants. In recent years, MRI of
the small bowel has assisted in determining the extent of small bowel involvement
and can be a useful tool particularly if considering re-operative surgery. Serum
tumour markers (CEA, CA 125 and CA19.9) are helpful in determining disease
activity, response to treatment, and relapse during follow up [51].
6.4.4 Surgical Management
Unfortunately, some patients have severely advanced disease at presentation such
that the more radical treatment cannot be offered. Palliative debulking has a place
in these patients and allows determination of peritoneal pathology, particularly
when the appendix had previously been removed. Where there is abundance of
mucin causing compression of the bowel but also of the inferior vena cava, a
debulking procedure to remove the primary tumour and mucin can allow sufficient
recovery prior to undertaking definitive cytoreduction.
Cytoreductive surgery is demanding, of long duration and carries a risk of blood
loss and significant fluid shifts, hence careful patient preparation and physiological optimisation is required pre-operatively. Surgery begins with careful placement
on the operating table in the lithotomy position with the legs abducted to allow
access to the perineum; a nasogastric drain and indwelling urinary catheter is
placed. Ureteric stents are placed selectively to facilitate ureteric identification
intra-operatively where recurrent or radical pelvic surgery is anticipated. A midline incision from xiphisternum to pubis allows complete access to the abdominal
and pelvic compartments, facilitated by a retraction system. Complete adhesiolysis
is performed to allow thorough exploration and assessment of both the volume and
distribution of disease which is formally recorded using the peritoneal carcinoma
index (PCI) score [52]. The abdomen and pelvis are divided into nine regions and
the entire length of the small bowel divided into a further four regions. These 13
regions are scored from 0 to 3 (0: no tumour; 1: tumour < 0.5 cm; 2: tumour
< 5 cm; 3: tumour > 5 cm) giving a maximum score of 39. Visceral resections
of the colon and rectum, uterus, ovaries, gallbladder, spleen, and less commonly
stomach are performed as necessary to remove the mucinous tumour deposits.
Peritonectomy of the pelvic, parietal and diaphragmatic peritoneum are performed
as necessary, although in appendix pathologies a full diaphragmatic strip is often
necessary to clear the disease over the right hemidiaphragm. In more penetrative
disease there may be full thickness involvement of the diaphragm, in which case a
section can be excised and the diaphragm closed prior to instillation of chemotherapy. Complete infracolic and supracolic radical greater omentectomy is essential,
and the lesser omentum is removed for disease clearance and to allow free flow
of the HIPEC after cytoreduction. In removing the lesser omentum, care must be
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taken to preserve the lesser curve vascular arcade and vagus nerve to protect the
neurovascular supply to the stomach. Mobilisation of the liver is usually necessary
if there is disease affecting the diaphragm, and also allows safe access to Morrison’s pouch, the caudate lobe, and the porta hepatis. High power electrofulguration
of Glisson’s capsule allows for disease clearance involving the liver surface. Smoke
extraction is necessary for this given the carbonisation of tissue, and cooling of
the surrounding parenchymal tissue is also performed. The extent of small bowel
involvement is often the factor which limits the radicality of surgery. Small bowel
resection(s) can be performed, as can peritonectomy of the small bowel mesentery.
Small deposits on the mesentery may also be treated with electrofulguration [53].
After completing the cytoreductive component of the procedure, an assessment of
the completeness of cytoreduction (CC score) is made: CC-0: no disease; CC-1:
residual disease with size < 2.5 mm; CC-2: residual disease with size 2.5 mm–
2.5 cm; CC-3: residual disease with size > 2.5 cm or confluent disease [54]. The
maximum penetration of the chemotherapeutic agent is 2.5mm hence CC-0 and
CC-1 are deemed optimal and considered as complete cytoreduction, whilst CC-2
and CC-3 are by definition incomplete cytoreduction.
After cytoreduction, patients are treated with heated intraperitoneal chemotherapy (HIPEC). Exposing the peritoneal cavity to chemotherapy in this manner
overcomes many of the challenges of systemic treatment which fail to adequately penetrate the peritoneal-plasma barrier [55]. Many of the drugs used are
hydrophilic and have a high molecular mass, increasing their activity within the
peritoneal cavity through reduced peritoneal clearance. Distribution across the
cavity is also more consistent with intraperitoneal chemotherapy than with systemic administration. The rationale for hyperthermia is a combination of the direct
cytotoxic effect of heat, and increasing the penetration of cytotoxic drugs into
tumour and peritoneal tissue to achieve greater intracellular levels [56]. Other
advantages include a reduction in intracellular drug metabolism, a reduction in
cell proliferation, and an increase in apoptosis [57]. The tissue response to hyperthermia, including a reduction in pH, glucose, and oxygen levels also leads to a
microenvironment more susceptible to the effects of chemotherapy [58].
Both open and closed (abdomen) techniques for delivering HIPEC have been
described, with a recent evaluation concluding no short term differences in morbidity [59]. In the open technique, the skin edges of the laparotomy wound are
secured or suspended in order to create a basin in which the carrier fluid can sit—
traditionally described as the coliseum technique by Sugarbaker. The surgeon may
choose to manipulate the abdominal contents to ensure adequate distribution of the
carrier fluid and therefore both heat and drug, although currently most teams take
advantage of the controlled mechanical flow delivered with commercial perfusion
machines. With the open technique, a smoke evacuator is used to clear any drug
particles released during the operation. In the closed technique, the skin edges of
the wound are temporarily closed with a continuous suture (Fig. 6.5).
For both techniques, four drains are placed into the abdominal cavity, two to
deliver the carrier fluid and two to complete the circuit and drain the abdomen.
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