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162 P. A. Sutton and S. T. O’Dwyer
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Fig. 6.5 Operative setup for heated intraperitoneal chemotherapy using the closed technique.
Four drains are placed through the abdominal wall for inflow and outflow of a carrier solution.
The abdomen is temporarily closed with temperature probes placed internally into all four quadrants monitoring equilibration of heat. Chemotherapy is added once pressures and temperatures
throughout the circuit are stable at 41 °C
A dedicated machine drives the heated circuit, monitoring temperature and pressure throughout the abdomen through probes placed in four quadrants alongside
or within the drains. The most commonly utilised carrier solutions are normal
saline and fluid used for peritoneal dialysis [60]. The volume of liquid used is
calculated from a normogram of height and weight to ensure adequate filling of
the abdomen and thus homogenous distribution of heat and drug, while avoiding
overdistension of the abdomen and dilution. Most circuits have a working volume of approximately 3–4 L, often slightly more where a closed technique is
utilised. Once consistent hyperthermia at 42 °C and acceptable circuit pressures
are achieved then the chemotherapy can be administered. The most commonly
used drug for appendix tumours is mitomycin C [61]; in our institution this is at a
concentration of 35 mg/m
2
(max 70 mg) in three divided doses over 90 min. Other
drugs commonly utilised for HIPEC for non-appendiceal tumours such as ovary,
hepatobiliary and mesothelioma include oxaliplatin, docetaxel, cisplatin, and doxorubicin. After completion of treatment the carrier fluid is fully drained from the
abdomen and several wash cycles implemented to remove all traces of chemotherapy. All equipment utilised is disposed of using standard cytotoxic precautions.
The abdomen is carefully inspected for any immediate complications prior to any
restorative work that may need to be undertaken, for example construction of a
bowel anastomosis. This is followed by definitive closure of the abdominal wall.
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6.4.5 Multi-visceral Transplantation
In some patients complete cytoreduction is not achievable. Most commonly this
is a result of extensive distribution of disease over the small bowel, limiting the
completeness of cytoreduction due to the risk of intestinal failure. Additionally,
22–44% of patients will suffer from recurrent disease. Re-operative cytoreductive
surgery is well described, but again has the potential to be limited by extensive involvement of the small bowel [62]. Where surgical options are limited
SACT is often utilised, although as discussed, the efficacy of this approach is
unclear. Patients will inevitably suffer progressive disease, resulting in small bowel
obstruction, fistulation, and intestinal failure.
In such cases the transplantation of a modified multi-visceral graft has been
trialled with promising medium-term results [63]. Between 2013 and 2022, 15
patients with intestinal failure secondary to low grade PMP who were not suitable
for further cytoreductive surgery were transplanted by a joint team from Basingstoke and Oxford, UK. Patients underwent radical resectional surgery including
explantation of involved small bowel, and in half of the patients in the series the
duodenum, pancreas and stomach was also transplanted. For patients with enterocutaneous fistulae the multi-visceral grafts were retrieved alongside a full thickness
abdominal wall graft based on the inferior epigastric vessels. The grafts were
individually tailored to the recipient with the aim of transplanting the minimum
amount of donor tissue that still allowed complete tumour clearance.
Two of the 15 patients died within 90 days due to surgical complications,
and the series otherwise reports actuarial 1-year and 5-year survival of 79%
and 55% respectively. Whilst most patients experienced a significant improvement in quality of life after transplantation, recurrent disease was identified in
91% of patients. This approach enables a more radical approach to the surgical
management of recurrent advanced PMP where options for conventional surgery
are limited. Whilst feasibility has been demonstrated with long-term survival and
improvement in quality of life, this approach must only be considered as part of a
regulated and monitored programme.
6.4.6 Systemic Anti-cancer Therapy (SACT)
The routine use of systemic anti-cancer therapy (SACT) for patients with PMP is
not necessary if they have had a satisfactory complete or near complete cytoreduction. For patients with high grade appendiceal mucinous neoplasms (HAMN)
there is a move to offer SACT if there has been an incomplete cytoreduction or
there is evidence of early recurrence after CRS and HIPEC. Although administration of systemic mitomycin C and oral capecitabine achieved tumour response and
clinical benefit in one-third of a 40 patient cohort in a palliative setting [64], there
is a need to provide more evidence of effectiveness and long term outcomes. It is
hoped that with improved knowledge of genetic drivers in PMP, targeted treatment
could be generated for high grade and relapsing disease.
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6.4.7 Surveillance and Outcomes
Serological tumour markers (including CEA, CA125 and CA19.9) and crosssectional imaging with a CT of the thorax, abdomen and pelvis captured with both
oral and intravenous contrast are normally utilised for surveillance post CRS and
HIPEC. Given the relatively indolent nature of PMP this is necessarily required for
a number of years providing the patient does not exhibit significant co-morbidity.
In the authors’ institution, following definitive surgery patients are offered surveillance investigations and clinical review at six monthly intervals for the first two
years, then annually until year five and again at years seven and ten. This same
surveillance protocol is also extrapolated to the other appendiceal tumours.
In patients with a LAMN and no evidence of disseminated disease, approximately 20% will progress to PMP during surveillance and can be offered surgery
at this time [65]. In selected patients at high risk of developing PMP, laparoscopic risk reducing surgery can be offered up front [66, 67]. The five and ten
year overall survival for patients undergoing CRS and HIPEC for PMP is 77% and
66% respectively [68]. Approximately 80% of patients undergo complete or nearcomplete cytoreduction (CC0/CC1), with the survival in this group significantly
better than the remainder (CC2/CC3). High grade histology, prior chemotherapy
and high PCI are all associated with reduced recurrence free survival [69]. Upon
recurrence, patients can be evaluated for repeat CRS and HIPEC. Good outcomes
can be achieved in selected patients, particularly where complete cytoreduction
was achieved at the index operation [62].
Despite re-operative surgery when appropriate, 25% of patients with PMP
relapse with disease unsuitable for further surgical resection and best supportive
care must be offered. The support of interventional radiology can be applied with
ultrasound guided insertion of wide bore drains to relieve mucinous distention and
gut compression alongside nutritional support.
6.5 Appendix Adenocarcinoma
6.5.1 Clinical Presentation
The incidence of appendix adenocarcinoma (AA) is estimated to be 1–2 per
million per year [70]. As with LAMNs, appendix adenocarcinoma is often diagnosed incidentally following appendicectomy for what had thought to be benign/
inflammatory pathology. In addition, some patients have been managed conservatively with an appendix abscess thought to be inflammatory with definitive
appendicectomy and delayed diagnosis. Once diagnosed, the patient and treating
team are often traumatised by the decision to delay intervention. It follows that
any persisting mass in the right iliac fossa needs surgical intervention in a timely
manner.
AA has a tendency to preferentially spread to peritoneal tissues rather than
through lymph channels and nodes [24, 70–72]. As such, in the absence of
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acute appendicitis the clinical presentation can be indolent with chronic right
sided abdominal pain. Patients will often have had investigations for non-specific
lower abdominal pain, urinary and gynaecological conditions until a CT scan is
undertaken.
6.5.2 Investigations
The classical thickening in the appendix seen on CT is frequently associated with
local serosal and peritoneal thickening along the terminal ileum, and lymph nodes
along the ileocolic vessels. Tumours can become locally advanced invading bowel,
urinary or gynaecological organs as well as the retroperitoneum, and a varying
degree of more distant peritoneal dissemination is seen. Serum tumour markers
again can be useful in outlining disease activity, response to treatment, and relapse
during surveillance. A PET scan can be helpful in non-mucinous pathologies, and
is often used for re-assessment following systemic treatments when offered.
6.5.3 Surgical Management
Where the volume and distribution of disease is amenable to complete cytoreduction, patients should be offered CRS and HIPEC as described above. There has
been much debate regarding the need for right hemicolectomy with radical node
resection, either for accurate disease staging and/or surgical clearance of nodal disease. Data suggests, however, that for AA with peritoneal seeding and otherwise
low risk pathological factors (T1, low grade, no lymphovascular invasion) that
there is no survival advantage for including right hemicolectomy over appendicectomy or partial colectomy [73–75]. There are also studies that have shown that
lymph node status is not a significant predictor of survival after CRS and HIPEC
[73, 76]. Our institution has a selective strategy for right hemicolectomy based on
tumour grade, radiological findings, and patient factors. This is appropriate, given
the 21% rate of lymph node involvement in our current cohort is consistent with
the literature.
6.5.4 Systemic Anti-cancer Therapy
Where an MDT considers that a complete cytoreduction is possible, there is debate
as to whether pre-operative neoadjuvant chemotherapy is advantageous in either
diminishing the peritoneal disease, and/or containing systemic nodal disease leading to improved outcomes. There are limited data on pathological response to
neoadjuvant chemotherapy. One prospective cohort of 34 patients with high-grade
PM from AA were treated with preoperative oxaliplatin and 5-fluorouracil (FOLFOX4) [77, 78]. Although there was no improvement in overall survival in patients
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who received preoperative chemotherapy compared to those who did not (median
51 vs. 37 months, p = 0.56), ten (29%) patients had a pathological response.
Where systemic therapy is utilised, oxaliplatin and fluoropyrimidine chemotherapy has become the preferred first-line regimen used worldwide [79–82]. Response
rates to neoadjuvant chemotherapy can be up to 58%, with up to 45% of patients
achieving stable disease [79, 81, 83]. A current summary would indicate that
patients with non-mucinous, poorly differentiated AA who are lymph node positive are most likely to derive benefit from systemic chemotherapy [84–87]. Should
neoadjuvant treatment be given, reassessment with PET CT is recommended 6–8
weeks following treatment, and if the patient is considered suitable for CRS this
should be undertaken within three months.
The role of adjuvant systemic chemotherapy following CRS and HIPEC has
been recently evaluated in a cohort of patients [88]. For AA patients with positive
nodes, systemic chemotherapy was associated with reduced risk of death compared
to no chemotherapy (p < 0.0019). A recent comprehensive review of the role of
SACT in AA provides a summary of the evidence for treatment in the perioperative
and palliative settings [89]. Studies of postoperative chemotherapy generally show
some degree of benefit, especially in high-grade disease with presence of signet
ring cells and lymph node involvement. Systemic chemotherapy agents demonstrate some activity in the treatment of unresectable disease, but it remains unclear
the optimal way to refine selection of patients who will benefit.
6.5.5 Surveillance and Outcomes
Patients with appendix adenocarcinoma are offered surveillance as described
above. In contrast to PMP, recurrence rates are higher and survival is not as
favourable. A study of 65 patients undergoing CRS and HIPEC reported five-year
overall survival and disease event-free survival of 55.5% and 36.1% respectively.
Given the limited role for chemotherapy in patients with AA, it is noteworthy that
these data represent the most favourable outcomes of the overall cohort. Multivariate analysis revealed that PCI less than seven, complete cytoreduction, and
preoperative CEA less than six were all associated with significantly better outcomes [90]. It is anticipated that with improved knowledge of the genomic profile
of AA, targeted SACT may play a more significant role in the future and improve
survival.
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6.6 Goblet Cell Adenocarcinoma
6.6.1 Clinical Presentation
Goblet cell carcinoids were first described in 1974, later described as ‘adenocarcinoids’ [91] and now as goblet cell adenocarcinoma (GCA). Almost exclusively
arising from the appendix, GCAs share pathological characteristics of both welldifferentiated NETs and adenocarcinomas, with a natural behaviour between them
in terms of aggressiveness, metastatic spread, and survival. A systematic review
reported 600 patients diagnosed with GCA, with a median age at diagnosis of 58.9
years and a similar distribution between genders [92].
Patients who presented with appendicitis were more frequently diagnosed in
early stages (stage I or II; 80%) and were more likely to have an appendiceal
perforation (80%), while 77% of patients presenting with other symptoms (most
commonly lower abdominal pain) were diagnosed in advanced stages but without
appendiceal perforation. Ironically there was a lower rate of peritoneal metastases
in patients with appendiceal perforation compared to those without perforation
(15 vs. 42%), almost certainly due to the earlier diagnosis of such patients and the
opportunity to access additional treatment strategies prior to peritoneal metastases
being established [93].
Appendiceal GCAs have an unpredictable behaviour—even in node-negative
patients, metastatic spread to the peritoneum is frequently seen. Forty per cent of
patients with GCA have peritoneal metastasis at presentation, and 77% progress
with peritoneal disease. One of the hypotheses for this phenomenon is the characteristic submucosal growth pattern, which increases the rate of localised peritoneal
metastases in the absence of lymph node spread. Moreover, this pattern of submucosal spread avoids the development of an appendiceal mass, again contributing to
delay in diagnosis [92].
Once peritoneal involvement occurs the patient will present with chronic nonspecific right sided and lower abdominal pain. Many are misdiagnosed as irritable
bowel syndrome, and it may take some years before they attend secondary care
and enter into a programme of investigations.
6.6.2 Investigations
Following appendicectomy, accurate histological diagnosis and grading is key in
determining subsequent treatments. Where the appendix is in situ, appearances on
CT are similar to AA with thickening around the base of the caecum and terminal ileum. The degree of peritoneal dissemination is variable. In more advanced
disease there is spread to the omentum and proximal small bowel loops, with evidence of serosal involvement and multilevel obstruction. Some guidelines suggest
serum CEA, Ca19.9 and CA125 may be useful biomarkers in the diagnosis and
follow-up of these patients [40].
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6.6.3 Surgical Management
The predominance of peritoneal involvement as opposed to lymph node spread
should direct surgical therapy to radical treatment of the peritoneum with CRS
and HIPEC, rather than appendicectomy with right hemicolectomy alone for lymph
node harvest and staging. A meta-analysis evaluating the role of right hemicolectomy after appendicectomy for GCA was published in 2004 [94]. After analysing
13 studies and 100 patients, the authors concluded that there was no clear benefit
from completion right hemicolectomy and supported the use of appendicectomy
alone in T1-2 tumours with low grade histology. A further retrospective analysis of 57 patients published in 2006 failed to demonstrate any benefit in from
performing a completion right hemicolectomy [95]. Due to the relative rarity of
GCA, randomised trials are unlikely to be able to address this issue. The authors’
recommendation would be to undertake selective hemicolectomy where there is
evidence of nodal disease along the ileocolic or right colic vessels. An alternative
approach of node sampling to stage the disease can be taken where there are no
macroscopically suspicious nodes. As with other primary appendiceal pathologies,
the role of HIPEC has yet to be independently evaluated.
6.6.4 Systemic Anti-Cancer Therapy (SACT)
Where there is evidence of node positive disease the MDT should discuss the
options of SACT. In 2006 Pham et al. reported one of the largest series of patients
with GCA treated with chemotherapy, in which no clear benefit from treatment was
shown either in the adjuvant or the palliative setting [95]. Current practice includes
the consideration of SACT for heavily node positive patients, and those with progressive and recurrent disease not suitable for re-operative surgery. Although there
are no trials of SACT specific to GCA, most medical oncologists will offer gastrointestinal directed SACT for residual, progressive and symptomatic disease,
however use in the adjuvant setting remains debateable. In a small series of 74
patients, FOLFOX chemotherapy was used in both the adjuvant and palliative setting. The authors observed a high rate (60%) of disease control in the palliative
cohort. The estimated median OS (all patients), disease-free survival (adjuvant
patients) and progression-free survival (palliative patients) were 52.1 (95% CI
29.4–90.3), 75.9 (26.6–not reached), and 5.3 (0.6–5.7) months, respectively [93].
In a series of thirty-seven inoperable patients who received first-line oxaliplatinbased chemotherapy the overall response rate was 24%, disease control rate was
80%, and median progression free survival and overall survival were 5.8 and 22
months, respectively [96]. In an as yet unpublished series of seventy-two patients
with GCA receiving mainly oxaliplatin based SACT in the perioperative and palliative setting, the median overall survival was 49 and 22 months respectively,
perhaps reflecting better outcomes with more aggressive treatments.
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6.6.5 Surveillance and Outcomes
In a retrospective series of seventy-four patients receiving multimodal treatment
the median overall survival was 52 months, with age and stage demonstrating
significant impact on multivariate analysis [93]. The five-year disease-specific survival varies from 58 to 81% depending on the series [18, 25, 97]. Again tumour
stage has been shown to be a prognostic factor for these patients, with a shorter
5-year OS in stage III (22%) and stage IV (14%) disease when compared with
stage I (100%) and stage II (76%) disease [95].
Little has been published with respect to long-term follow up of GCA. One
characteristic that has been observed is the late presentation with peritoneal disease relapse ten or more years following definitive treatment. This raises the need
for prolonged surveillance following potential curative surgery and awareness of
indolent disease and late relapse. Patients and healthcare providers need to be alert
to this phenomenon and have a low threshold for the investigation of non-specific
abdominal symptoms in this cohort.
6.7 Referring to Specialist Services
Given the rare nature of these tumours, the care of patients with appendix neoplasms should be centralised to specialist units. For the more common NENs this
centralisation is frequently to regional units which are able to offer dedicated crosssectional imaging (i.e., gallium PET scans), specialist MDT decision making and
appropriate medical and surgical treatments. Given the necessary expertise and
infrastructure required to support the decision making and management of patients
with AMNs and other appendix cancers, including CRS and HIPEC, patients are
usually centralised to a small number of national centres, as is the case in the
UK. Centralisation of patients with these rare tumours allows for concentration
of expertise leading to consistency in diagnosis, decision making, treatment, and
outcomes. It also allows for patients to be offered the opportunity to be enrolled
into relevant clinical trials and for high quality training and education of the next
generation of appendix and peritoneal surgeons. Given the rarity of some of these
tumours, large randomised trials are unlikely to be successfully completed. Collaboration between units, both clinically and for the benefit of research, is therefore
essential.
As previously discussed, the majority of patients with appendix neoplasms are
diagnosed after appendicectomy. In these circumstances, once the pathology has
been identified the findings should be communicated to the patient who should
then be referred to a specialist centre. Recent cross-sectional imaging (CT of the
thorax, abdomen and pelvis with both oral and intravenous contrast) will facilitate
prompt specialist MDT review. In parallel to this, given the significance of the
pathological assessment to both treatment and prognosis, most centres also undertake further histological assessment by a pathologist with a dedicated interest in
appendix neoplasms.
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In circumstances where the appendix neoplasm is identified during diagnostic
work-up for symptoms, there is an opportunity to discuss that patient’s management with a specialist centre. In cases which are equivocal, for example
an abnormal appendix or unruptured mucocoele on CT, performing an appendicectomy allows for accurate histopathological assessment and laparoscopic
assessment of the abdomen prior to referral. If proceeding to appendicectomy,
right hemicolectomy should be avoided unless operatively required to perform safe
appendicectomy. Where the appendix abnormality is clearly associated with evidence of peritoneal disease, patients should be referred to a specialist centre prior
to undertaking surgery. Where patients present acutely, for example with perforation or obstruction, decision making should be guided by the patient’s physiology.
Operative management should be restricted to the management of the presenting
problem, however the opportunity to take tissue for histology and make a thorough assessment of the abdomen and pelvis should also be taken to help inform
future decision making. By engaging with specialist centres, opportunities to support research into these rare conditions will ultimately benefit patients and improve
outcomes.
6.8 Current Research and Future Directions
Due to the rarity of appendiceal neoplasms there is a lack of interest from pharma
sponsored research to investigate potential therapeutic targets in these disease
types. However, in line with the expansion of genetic interrogation of gastrointestinal tumours with generation of targeted treatments, interest in determining the
genetic drivers in appendix pathologies has been raised.
Perhaps not surprisingly most information has been generated for appendix
adenocarcinoma where KRAS mutations have been identified: In a series of 53
patients 55% demonstrated KRAS mutations, the highest variant being G12D
in 24% raising the opportunity to offer KRAS
patients [98]. Paradoxically, KRAS wild type individuals who received anti-EGFR
agents had worse outcomes than with chemotherapy alone.
In 2020 a pan European initiative to accelerate knowledge and explore new
therapeutic opportunities for PMP was created. This collaboration is exploring
biomarkers in LAMNs and HAMNs and their associated peritoneal metastases.
Early results indicate that there are differences in expression of collagen and
mucin associated genes in high grade and low grade disease. The PMP Accelerator Group has generated organoids from PMP cells allowing in vitro testing
of gene targeted agents. Identification of proteins unique to the appendix, and in
plasma from patients with PMP may allow liquid biopsy as a tool for surveillance
following treatment.
Over the last five years a number of groups have explored new directions in
the understanding of cellular processes and the extracellular matrix in PMP. These
programmes have included a Phase 1 study using the intraperitoneal application of
an anti-mucin agent Bromelain to modify the mucinosis in advanced disease [99].
G12C
inhibitors for these selected
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A further initiative has explored the potential of exploiting the immune response
in PMP and developing a potential vaccine directed toward GNAS expression
and immune check point modulation [100]. It is anticipated that such advances
will open opportunities for less invasive diagnosis, treatment, and surveillance of
patients with appendix neoplasia over the next decade.
6.9 Conclusion
Appendix tumours are most commonly identified as incidental findings on the
histological examination of appendicectomy specimens from patients presenting
as an emergency with acute appendicitis. A much smaller proportion of patients
present with symptoms of either a locally advanced appendix mass or disseminated peritoneal disease. Most neuro-endocrine tumours are treated adequately
with appendicectomy alone. There is some evidence to support right hemicolectomy and lymphadenectomy for higher risk tumours, most commonly categorised
by a size greater than 2 cm. Appendiceal mucinous neoplasms, appendix adenocarcinoma and goblet cell adenocarcinoma cover a broad spectrum of pathologies
from low grade PMP to extensive peritoneal carcinomatosis with signet ring
cells. Whilst these pathologies have common treatments, specifically cytoreductive surgery and HIPEC, outcomes vary significantly between these disease states.
Patients with advanced disease and aggressive tumour types are at risk of bowel
obstruction and fistulation, often suffering from intestinal failure. With limited
surgical options these patients are increasingly being treated with systemic anticancer therapy, although efficacy remains limited and patient selection challenging.
Patients with these rare tumours should be referred to specialist centres for management, where advances in surgical technique, understanding of tumour biology,
and the development of novel agents will hopefully continue to improve outcomes.
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