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Genetic Mutations in FAP and Conventional or Laparoscopic Surgical Approach 337
we place the Lap-Disc in the Pfannenstiel incision
inducing pneumoperitoneum. We insert the second
10-mm trocar on the left symmetrically to the first.
We introduce the video-camera which will remain on
the right for the entire operation (the operation is
possible with both the 0 and 30° optical camera, even
if the second option offers a better view). We observe
the visceral disposition and introduce the third and
last trocar in the right hypochondrium near the rib
arcade (Fig. 6).
Tractioning the sigmoid colon with the left hand
and using a Babcock forceps through the upper tro-
car, we expose the colon mesentery starting the syn-
thesis and section of the colic vessels with the instru-
ment inserted in the left trocar. We generally use a
radiofrequency instrument (Ligasure-Atlas
TM
, Valley-
lab, CA, USA), particularly indicated for colic vessels;
but also the last generation of ultrasound instru-
ments (Ultracision®, Ethicon Endosurgery, OH, USA)
can be used. These instruments allow a reduction in
the instrument traffic which was responsible for the
increased surgical time during the first years of expe-
rience with this surgery. Thus, it is possible to per-
form the entire operation with just one instrument.
Fig. 5a Measurement of 7 cm before Pfannenstiel incision. b
Separation of ileum from ciecum, with GIA. c Separation of
sigma from rectum, with GIA
a
c
b
Fig. 6. Videolaparoscopic colectomy: right hand controlling
Ligasure-Atlas and left hand in the patient’s abdomen
through Lap Disc
338 E. Contessini-Avesani, F. Botti, A. Carrara, C. Rocha, E. Gilardoni, B. Oreggia
Fig. 7a Mobilisation of left colon. b Section of gastro-colic
ligament. c Section of the middle colic artery
a
c
b
Fig. 8a, b. Extraction of specimen through Lap Disc
ba
Genetic Mutations in FAP and Conventional or Laparoscopic Surgical Approach 339
The curved end of the Ligasure-Atlas also allows a
gentle dissection similar to that obtainable with fin-
gers. Mobilisation of the left flexure (Fig. 7), like in
open surgery, is a delicate phase of the operation that
can be carried out after separating the omentum in
the colic corner either continuing the liberation fac-
ing the spleen, or from above, after separating colon
from the stomach, sectioning the gastrocolic liga-
ment. In more complex cases either approach can be
used. In order to facilitate gestures on the right colon
and on the hepatic flexure, we rotate the patient to
the left and begin mobilising the right colon, trac-
tioning the cecum to the left with the hand. After
recognising the duodenum we complete the section
of the right colon mesentery and hepatic flexure until
we obtain the complete liberation of the colon which
can be easily removed through the Lap-Disc (Fig. 8).
The operation is carried out with a hand-sewn
end-to-end anastomosis between the terminal ileum
and the previously sectioned rectum (IRA). Prefer-
ence for a hand-sewn anastomosis, which can be
comfortably performed through the Pfannanstiel
incision, is dictated by the need to preserve as much
ileum length as possible to be able to perform an
IPAA, when necessary, with maximum guarantee of
success.
If a proctocolectomy is indicated, we proceed as
already described for the colectomy, except for the
fact that the rectum is not initially sectioned and that
the pneumoperitoneum can be maintained by
removing the colon through the Lap-Disc. This also
allows a traction on the rectum so that pelvic dissec-
tion is facilitated (Fig. 9); once the pelvic floor is
reached, the rectum is sectioned on the plane of the
elevator muscle. Rectum removal, especially in men,
is conducted following an intramesenteric plane in
order to minimise the risk of neurological damage,
unless a TME (total mesorectal excision) is indicated
by the presence of cancer. After this first proctecto-
my, restorative surgery is carried out including
mobilisation of the terminal ileum mesentery, prepa-
ration of the ileal pouch and of the ileo-anal anasto-
b
Fig. 9. Phases of rectum mobilization in laparoscopy
a
c
b
340 E. Contessini-Avesani, F. Botti, A. Carrara, C. Rocha, E. Gilardoni, B. Oreggia
mosis, both protected by a loop-ileostomy. In our
experience, this surgery is always performed using a
traditional approach using the 7-cm Pfannenstiel
incision, or enlarging it by a few centimetres, to
mobilise the terminal ileum and prepare the “S”
reservoir (three loop pouch) [38–40].
World literature documents the easier execution
of the J pouch which can be entirely made with sta-
plers, but in our opinion there are still good reasons
to prefer a more handmade approach, with a hand-
sewn S pouch that permits personal adjustments case
by case, depending on the patient’s characteristics.
In our experience and in that of other authors [41],
the terminal ileum sectioned on the ileo-cecal valve
can reach a more distant site than the end of a J
pouch. Even after mobilisation of the terminal ileum
and section of the ileo-colic artery, which allows its
maximum length, an S pouch does not modify the
total length of the vascular arch. Moreover, the risk
of needing to drop IPAA cannot be underestimated,
even in expert hands, as it accounts for over 4% of
the cases for different reasons [39] such as difficul-
ties related to ileum vascularisation (Fig. 10).
Moreover, in our experience, as the mucosectomy
has to be carried out from the dentate line, the “S”
reservoir seems to be the most suitable. An aspect
that is still being discussed, however, concerns the
suitability of performing a mucosectomy and thus a
hand-sewn, end-to-end, ileoanal anastomosis (for
the S reservoir), removing the residual rectal mucosa
(1.5–3 cm long) from the dentate line including the
transitional epithelium between the anal and rectal
mucosa. If a mucosectomy is not performed and sta-
pling (often double stapling) is carried out, the entire
transitional zone—at a minimum—is left: more cen-
timetres of rectal mucosa may easily be left in rela-
tion to the thickness of the pelvic floor, the patient’s
sex and surgeon’s skills.
The benefits of stapling include faster operating
times, slightly better functional results and the possi-
bility of avoiding a protective ileostomy. However, a
28% risk of adenomas forming in the transition zone
and in the residual rectal mucosa exists, as demon-
strated by Remzi et al. [43]. In our opinion, the risk
Fig. 10. S pouch (section design, position in the pelvis, oper-
ative view)
Fig. 11. Mucosectomy Fig. 12. Ileo-anal hand-sewn anastomosis
Genetic Mutations in FAP and Conventional or Laparoscopic Surgical Approach 341
of cancer developing is relevant as it is not always
easy to monitor and treat polyps close to the dentate
line and malignant transformation can also occur
during endoscopic follow-up [17].
Also Ooi et al. [44], in a recent work, points out
the need for careful monitoring of the transitional
zone left In Situ for cancer risks, and reconsiders the
suitability of mucosectomy in patients with wide-
spread polyps on the rectal mucosa. In our experi-
ence, we have always carried out mucosectomy from
the dentate line and in the second case of FAP oper-
ated on in 1985, this decision was prompted by the
discovery of a stage A Dukes carcinoma in the
removed mucosa section. Once mucosectomy is car-
ried out and the reservoir is located in the pelvic
space, ileoanal hand-sewn anastomosis in one layer
is executed (Figs. 11,12 ).
From 1984 to 2005, we have operated on 40 cases
of FAP with all the techniques in our possession,
including the Kock pouch for a continent ileostomy
in a patient who could not preserve the sphincters
but wanted to reduce the problems related to defini-
tive ileostomy. In 1996, we started treating FAP
patients, when possible, with the videolaparoscopic
techniques previously described. In this period, 9
out of 17 FAP patients were treated (2 with IRA, 7
with IPAA) with VDL or HALS, without any major
complications when compared to the traditional
open technique. Only two patients needed postoper-
ative blood transfusion (one for each group) and no
one in the laparoscopic group had an infection of the
Pfannestiel incision. In our experience functional
results such as continence, urgency, number of
bowel movements and sexual functions do not differ
significantly between IRA and IPAA and in patients
operated with traditional or laparoscopic technique.
With the HALS technique, the time needed to per-
form an IRA or IPAA is now quite similar to that
needed in the traditional open technique; postoper-
ative pain is normally lower and the patient can be
discharged earlier. Moreover, the cost-effectiveness
of laparoscopy increases with experience and patient
satisfaction is greater. At the moment, the low num-
ber of patients operated on with this technique does
not allow statistical evaluation of the risk of postop-
erative bowel occlusion and of desmoid tumour
growth at the scar site. The laparoscopic experience
obtained by treating IBD patients with HALS
showed an absence of adherences in the second stage
of the operation (proctectomy and IPAA) and this
situation seems to reduce the risk of bowel occlu-
sion. None of the nine patients treated with
laparoscopy needed readmission, while 2 out of 31
patients treated traditionally were readmitted due to
bowel occlusion and one needed surgery for adher-
ences.
Conclusions
While the possibility of choosing the correct surgical
option is certainly related to the surgeon’s skills with
all the technical solutions, the possibility of having
genetical markers predicting the severity of the dis-
ease would make the surgeon’s task easier in pro-
posing different solutions for different presentations
of the pathology. In fact we have experienced that
extra-colonic manifestations of the disease also
determine other aggravating factors and that eradi-
cation of the colorectal disease does not solve the
problem.
We have been able to observe how in our case his-
tories a non-radical choice such as IRA, when associ-
ated with a severe mutation, involved a high risk of
conversion or demolition of the anal sphincters so in
this case the choice of an IPAA seems justified. The
more radical choice becomes more difficult in cases
of severe mutation and clinical features compatible
with IRA, when a patient requests the preservation of
the rectum or when it is impossible to detect the
genetic error. In these situations, it is advisable to
evaluate the case without following a fixed scheme.
By educating the patient on the need for constant fol-
low-up, the risk of degeneration appears reduced;
moreover, as outlined by our experience and in the
literature, it is possible to convert IRA into IPAA in
the majority of the cases especially when IRA was
conducted preserving all the ileum. On the other
hand, if we consider mucosal polyps growth at the
pouch level (as recently highlighted in the literature
[14, 45]) and their possible evolution to cancer, it is
easy to see that the first surgical choice appears more
important considering that even a radical solution
such as IPAA could not completely solve the FAP
problems at the colorectal level. The laparoscopic
approach can achieve an almost complete absence of
visceral adhesions. This has been assessed at further
operations when total colectomy had been the first
surgical step of an IPAA for Ulcerative Colitis (UC).
This aspect, on one hand, involves a lower risk of
occlusive complications and, on the other, makes
conversion to IPAA more comfortable when neces-
sary. It is clear that the videolaparoscopic approach
is appealing particularly for young people due to the
reduced aesthetic damage and IRA is appealing due
to the possibility of performing a single operation
without ileostomic protection.
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Introduction
Familial adenomatous polyposis (FAP) is an inherit-
ed autosomal dominant disorder. It is characterized
by the development of hundreds to thousands of ade-
nomatous polyps in the colon and rectum, usually
beginning at puberty, with a tendency to undergo
malignant transformation by the fifth decade
[1].Therefore, surveillance and management proto-
cols have always focused primarily on early detection
and prophylactic colectomy in affected persons.
These measures have substantially reduced the risk
of colorectal adenocarcinoma which was once the
main cause of mortality, hence changing significant-
ly the natural history of this disease manifestation.
However, genotypic aberrations of the fundamental
genetic defect that causes the syndrome, a germ-line
mutation in the APC gene, may lead to additional
phenotypic expressions in which extra-colonic
organs develop neoplasms or other changes
(Table 1). There is a large diversity in the expression
and complexity of these extra-colonic manifestations
(EM). Although some appear as clinically non-signif-
icant or are only cosmetically disturbing, others are
potentially associated with high rates of morbidity
and mortality. In contrary to the relatively straight-
forward management strategy of the colonic mani-
festation of the syndrome, some EM, like involve-
ment of the upper GI tract and intra-abdominal
desmoids, may be difficult to manage. This chapter
describes the clinical significance of these manifesta-
tions and suggests management and surveillance
strategies.
Upper Gastrointestinal Polyps and Cancer
Duodenal Neoplasia
After the colon and rectum, the duodenum is the sec-
ond most commonly affected site of polyp develop-
ment in FAP [2, 3]. Duodenal adenomas can be found
in 30–70% of patients [2–4] and the lifetime risk of
these lesions approaches 100% [4–6]. Duodenal/peri-
ampullary adenocarcinoma is a leading cause of can-
cer death in FAP patients following colectomy.
Duodenal cancer is rare in the general population,
with an incidence of 0.01–0.04% [7]. Compared with
the general population, FAP patients have a 100–330-
fold higher risk of duodenal cancer [8, 9]. The esti-
mated cumulative lifetime risk of developing duode-
nal cancer in FAP range from 4 to 10% [4,10, 11]. The
median age of duodenal cancer development is
52 years (range 26–58) [4]. Therefore, although most
patients eventually develop duodenal polyps, these
lesions occur at a later age and have lower potential
for malignant change compared with colonic polyps.
Polyps can be found throughout the duodenum,
but the second and third portion and the peri-
ampullary region are the most commonly affected
sites. This pattern suggests a role for exposure of
Clinical Significance of Extra-Colonic Manifestations of
Familial Adenomatous Polyposis
Yehuda Kariv, Hagit Tulchinsky, Micha Rabau
Table 1. Extra-colonic manifestations of familial polyposis
Upper gastrointestinal tract:
Stomach: fundic gland polyps, adenomatous polyps,
cancer
Duodenum and small bowel: duodenal adenomas, peri-
ampullary cancer, small-bowel adenomas, cancer, lym-
phoid polyps of ileum
Gallbladder, bile duct, pancreas: adenomas, cancer
Desmoid tumors: abdominal wall, mesentery, retroperi-
toneum, extremities
Bone and dental abnormalities: osteomas, unerupted teeth,
supernumerary teeth, dentigerous cyst, odontomas
Cutaneous lesions: epidermoid cysts, sebaceous cysts,
fibromas and lipomas
Ocular: pigmented ocular fundus lesions (POFLs)
Other neoplasia: adrenal adenomas, nasal angiofibromas,
thyroid papillary adenocarcinoma, CNS tumors (glio-
blastoma multiforme, cerebellar medulloblastoma), hepa-
toblastoma
346 Y.Kariv, H. Tulchinsky, M. Rabau
duodenal mucosa to bile acids in duodenal carcino-
genesis [12, 13]. Data on the relationship between the
severity of duodenal polyposis and specific muta-
tions in the APC are inconsistent [14–16]. However,
most reports indicate that mutations in exon 15 of
the APC gene, particularly distal to codon 1400, give
rise to a severe duodenal phenotype [11, 17, 18–20].
The adenoma-carcinoma sequence has been also
observed in the setting of duodenal carcinogenesis in
patients with both FAP and sporadic disease. Spigel-
man et al. showed that villous histology, moderate or
severe dysplasia, and the presence of stage IV duode-
nal polyps were associated with malignant change
[21].
The most useful system for rating the severity of
duodenal polyposis was developed by Spigelman et
al. This classification describes five (0–IV) stages.
Points are accumulated for number, size, histology,
and severity of dysplasia of polyps (Table 2). Approx-
imately 70–80% of FAP patients have stage II or stage
III duodenal disease, and 20–30% have stage I or
stage IV disease [12, 22]. However, the estimated
cumulative incidence of stage IV duodenal disease is
50% at age 70 years [4, 23]. The Spigelman classifica-
tion correlates with risk of duodenal malignancy.
Stages II, III, and IV disease are associated with a 2.3,
2.4, and 36% risk of duodenal cancer, respectively
[22].
Duodenal polyposis slowly progresses in size,
number, and histology, and eventually in Spigelman
stage [24]. Heiskanen et al. reported worsening poly-
posis in 73% of 71 FAP patients followed for 11 years
[5]. The median interval for progression by one stage
was 4–11 years. The risk of developing stage III or IV
disease exponentially increases after 40 years of age
[25]. Endoscopic surveillance of the upper gastroin-
testinal tract for the development of neoplasia is rec-
ommended by most authorities. Screening for upper
gastrointestinal disease should start at the time of
FAP diagnosis [26
]. The guidelines for continued
endoscopic surveillance after baseline examination
are according to the Spigelman stage (Table 3) [6,
22].
Treatment
Endoscopic treatment options for duodenal lesions
include snare excision, thermal ablation, argon plas-
ma coagulation, and photodynamic therapy (PDT).
Most reports of endoscopic therapy use snare exci-
sion. However, endoscopic treatment is usually
insufficient in guaranteeing a polyp-free duodenum
and might cause complications. Recurrence rates of
adenomatous tissue in the duodenum of FAP
patients treated endoscopically range from 50 to
100% [26, 27–29]. Surgical procedures to treat duo-
denal polyposis include local excision (duodenotomy
with polypectomy and/or ampullectomy), pancreas
preserving duodenectomy, and pancreaticoduo-
denectomy. There are no randomized studies pub-
lished to help guide surgical selection.
Local surgical treatment with duodenotomy has
proven insufficient in guaranteeing a polyp-free duo-
denum, with most studies reporting high recurrence
rates in patients with severe duodenal adenomatosis
[5, 26–28, 30–33]. Farnell and colleagues found a
lower recurrence rate of duodenal polyps of 32 and
43% at 5 and 10 years of follow up, respectively [34].
Nevertheless, duodenotomy may be indicated in
patients with one or two dominant worrisome duo-
denal lesions in otherwise uninvolved or minimally
involved intestine.
More radical surgery, in the form of pancreatico-
duodenectomy, or pancreas preserving duodenecto-
my, has been indicated for patients with severe poly-
posis (stage III–IV), failed endoscopic or local surgi-
cal treatment, and carcinoma. [26–28, 31–39]. Low
recurrence rates of polyposis have been reported
with these procedures.
Pharmacological Treatment. Duodenal adenomas
seem less responsive to chemoprevention with
NSAIDs than colonic counterparts. The results of
NSAID, COX 2 inhibitors and other compounds on
regression or prevention of duodenal adenomas in
FAP appear disappointing [40–42]. The response of
Table 2. Spigelman classification for duodenal polyposis in
familial adenomatous polyposis
Points 12 3
Polyp number 1–45–20 >20
Polyp size (mm) 1–45–10 >10
Histology Tubular Tubulovillous Villous
Dysplasia Mild Moderate Severe
Stage 0, 0 points; stage I, 1–4 points; stage II, 5–6 points; stage III,
7–8 points; stage IV, 9–12 points
Table 3. Recommendations for management of duodenal
polyposis in familial adenomatous polyposis adjusted to
the Spigelman stage of duodenal polyposis [6]
Spigelman Endoscopic Chemo- Surgery
stage frequency prevention
04years No No
I 2–3 years No No
II 2–3 years Yes/no No
III 6–12 months Yes/no Yes/no
IV 6–12 months Yes/no Yes
Clinical Significance of Extra-Colonic Manifestation of Familial Adenomatous Polyposis 347
earlier Spigelman stages might be better [43]. Sug-
gested guidelines for chemoprevention are presented
in Table 3.
Gastric Neoplasia
Gastric polyps occur in 23–100% of FAP patients
[44–46]. Fundic gland polyps (FGP) are the most
common gastric polyps in FAP. They usually appear
in the gastric fundus and body, and have traditional-
ly been regarded as non-neoplastic, possibly hamar-
tomatous lesions. Similar polyps, although fewer in
number, are sometimes observed in the general pop-
ulation and possibly associated with chronic use of
proton pump inhibitors [47]. These polyps are con-
sidered to have little or no potential for malignant
transformation; however, recent studies have report-
ed that dysplasia and malignant transformation
occur more frequently than previously believed (48,
49). Histologically, these polyps consist of simple
hyperplasia of the fundic glands with microcytes.
Endoscopically, these are multiple sessile lesions, 1–5
mm in diameter, that are the same color with the sur-
rounding mucosa. They vary considerably in size and
number. The polyps are sometimes numerous, and
coalesce, forming an irregular matted surface
mucosa. These polyps rarely cause symptoms and
have been observed as early as 8 years of age.
Adenomatous polyps occur in the stomach of
about 10% of patients with FAP. Most often, they are
confined to the antrum but occasionally found in the
body and fundus (44, 50]. The lifetime risk for gastric
cancer in FAP is about 0.6%, believed in large part to
arise from adenomatous polyps. Interestingly, Japan-
ese and Korean FAP patients have a 3–4 times higher
risk of gastric cancer compared with the general pop-
ulation [51, 52], whereas no increased risk has been
found in Western countries [9].
Small-Bowel Neoplasia
Clinically significant small-bowel adenomas distal to
the duodenum are uncommon in patients with FAP.
Adenomas may occur throughout the small bowel
but are concentrated for the most part in the proxi-
mal jejunum and the distal ileum. Studies using the
capsule camera showed ileal polyps in 5% of FAP
patients. Malignancy is unusual. In patients with FAP
after restorative proctocolectomy, the incidence of
neoplasia in the ileal pouch increases. The incidence
of adenomas within the ileal pouch ranges between
20 and 62% and depends on duration of follow-up
[53–56]. Parc et al. [57] found that the risk of devel-
oping adenomas at 5, 10, and 15 years was 7, 35, and
75%, respectively. The risk of cancer development in
such adenomas has not been established, although
three cases of pouch cancer have been reported [58].
Therefore, for all patients with FAP who have under-
gone restorative proctocolectomy, periodic endo-
scopic examination is indicated. Adenomas also
occur in the terminal ileum of patients who have an
ileostomy or Kock pouch after proctocolectomy
without restoration. In addition, the risk of ileostomy
carcinoma in these patients appears to be increased
compared to the very low incidence of primary
small-bowel carcinoma. By 2005, 11 ileostomy carci-
nomas were reported [59]. Other small bowel lesions
include prominent lymphoid polyps that may occur
in the terminal ileum of younger patients with FAP
and should be differentiated from adenomas by biop-
sy [60].
Desmoid Tumors
Desmoid tumors (DTs) are benign fibrous growths
which do not metastasize, but tend to invade locally.
Although rare in the general population, DTs are not
rare in FAP. They may arise in musculoaponeurotic
structures throughout the body, but are most com-
mon in the abdomen. Desmoid tumors (DTs) affect
between 4 and 20% of FAP patients. Within 10 years
after colectomy, the cumulative risk of developing
DTs is 16% [61], and the cumulative lifetime risk is
21% [62]. The peak incidence is between 28 and
31 years, although they may occur at any age [61, 63,
64].
Bertario et al. [65] described independent predic-
tors of DTs in FAP patients: APC mutations beyond
codon 1444, family history of desmoids, female gen-
der, and the presence of osteomas. The female-to-
male ratio of DTs in FAP is 1.4 [62, 63, 66]. In first-
degree relatives of FAP patients with DTs, the relative
risk of developing DTs is 2.5, when compared to FAP
kindreds with no family history of DTs [61, 63].
Eleven to thirteen percent of patients are diagnosed
with DTs before diagnosis of FAP, while 8–19% have
a simultaneous diagnosis, and 68–82 % develop DTs
after the diagnosis of FAP [63, 67].
Desmoid tumors (DTs) in FAP seem to occur on
the basis of APC gene inactivation and accumulation
of β-catenin in the cells. There is evidence to suggest
that a mutation near or beyond codon 1444 may
influence the process [68, 69].
A model of DT development has been suggested
that is analogous to the adenoma-carcinoma
sequence: mesenteric plaque-like precursor lesions
progress to mesenteric fibromatosis that can give rise
to desmoid tumors [70]. Desmoid tumors often
develop in surgical scars, leading to the theory that
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