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COLON 291
and still others may not be able to aord the test because of a lack
of insurance coverage. Whatever the reason, in these instances the
clinician is forced to make management decisions without a certain diagnosis. Evidence of MMR deciency is a hallmark of Lynch
syndrome tumors, and although MMR deciency more commonly
results from epigenetic silencing of MLH1, the likelihood of Lynch
syndrome can be estimated using tumor testing and clinical acumen.
For patients with both an MMR decient/MSI-H tumor and a family
history that meets Amsterdam criteria, Lynch syndrome is likely, and
all at-risk relatives are managed as if they are gene mutation carriers.
More modern tumor testing, including screening for BRAF mutation and testing for MLH1 methylation, will help exclude CpG island
methylator phenotype cancers. When doubt exists, the presence of
Lynch syndrome should be assumed so that cancers are not missed as
a result of inadequate screening.
Tumor Lynch
When a CRC is MMR decient and there is no evidence of MLH1
methylation but a germline mutation is not identied with genetic
testing, the situation can be called “tumor Lynch” (i.e., the tumor has
the genetic characteristics typical of Lynch syndrome, reecting an
MMR deciency, and no evidence exists that this is due to promoter
methylation of MLH1). e following explanations are possible: (1)
e patient has an undetected germline MMR gene mutation or a
dierent genetic alteration or epigenetic change (e.g., methylation)
that reduces gene expression critically enough to cause the syndrome,
or (2) biallelic somatic mutations (possibly causing 50% of cases of
tumor Lynch) or genetic mosaicism are present. Tumor testing (at
specialized laboratories) for biallelic loss may be performed to conrm sporadic mutations as the cause of the cancer. Making this distinction is clinically valuable because it means that relatives of the
proband do not need Lynch syndrome screening. If Lynch syndrome
cannot be eliminated from the diagnosis, these patients are managed
as if they had Lynch syndrome.
SUMMARY
In summary, HNPCC is a syndrome dened by clinical criteria and
marked by multiple cancers within multiple members of a family, with
some cancers occurring at a young age. Lynch syndrome is an autosomal-dominant disorder dened by mutations in MMR genes and
represents the most common cause for hereditary syndromic CRC. A
detailed family history and a high index of suspicion are necessary to
identify patients and families who are aected, while universal tumor
testing for evidence of MMR deciency allows recognition of cases
that may not fulll clinical criteria. Genetic counseling and testing
should be performed to conrm the diagnosis, which can be applied
to the entire family and then dictates screening and management
strategies for both colorectal and extracolonic cancers. Colonoscopy screening and polypectomy reduces risk of CRC development
and death from cancer. For patients with Lynch syndrome who have
CRC, extended resection is warranted because the risk of metachronous CRC is signicant. Both the clinical and genetic understanding
of Lynch syndrome continues to evolve, and management guidelines
will continue to become more precise.
S u g g e S t e d R e a d i n g
Bonadona V, Bonaiti B, Olschwang S, etal. Cancer risks associated with ger-
mline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome.
JAMA. 2011;305:2304–2310.
Burn J, Gerdes AM, Macrae F, etal. Long-term eect of aspirin on cancer risk
in carriers of hereditary colorectal cancer: an analysis from the CAPP2
randomised controlled trial. Lancet. 2011;378:2081–2087.
Chen S, Wang W, Lee S, et al. Colon Cancer Family Registry. Prediction
of germline mutations and cancer risk in the Lynch syndrome. JAMA.
2006;296:1479–1487.
Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evalua-
tion and management of Lynch syndrome: a consensus statement by the
US Multi-Society Task Force on Colorectal Cancer. Dis Colon Rectum.
2014;57:1025–1048.
Haanstra JF, de Vos Tot Nederveen Cappel WH, Gopie JP, etal. Quality of life
aer surgery for colon cancer in patients with Lynch syndrome: partial
versus subtotal colectomy. Dis Colon Rectum. 2012;55:653–659.
Hampel H, Frankel WL, Martin E, etal. Feasibility of screening for Lynch
syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:
5783–5788.
Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syn-
drome (hereditary nonpolyposis colorectal cancer). N Engl J Med.
2005;352(18):1851–1860.
Jarvinen HJ, Aarnio M, Mustonen H, etal. Controlled 15-year trial on screen-
ing for colorectal cancer in families with hereditary nonpolyposis colorec-
tal cancer. Gastroenterology. 2000;118:829–834.
Kalady MF, Lipman J, McGannon E, Church JM. Risk of colonic neoplasia
aer proctectomy for rectal cancer in hereditary nonpolyposis colorectal
cancer. Ann Surg. 2012;255:1121–1125.
Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in
Amsterdam-I criteria families without mismatch repair deciency: famil-
ial colorectal cancer type X. JAMA. 2005;293:1979–1985.
Lynch HT, Shaw MW, Magnuson CW, etal. Hereditary factors in cancer.
Study of two large Midwestern kindreds. Arch Intern Med. 1966;117:
206–212.
Mensenkamp AR, Vogelaar IP, van Zelst-Stams WA, etal. Somatic mutations
in MLH1 and MSH2 are a frequent cause of mismatch-repair deciency in
Lynch syndrome-like tumors. Gastroenterology. 2014;146:643.
Parry S, Win AK, Parry B, etal. Metachronous colorectal cancer risk for mis-
match repair gene mutation carriers: the advantage of more extensive co-
lon surgery. Gut. 2011;60:950–957.
Schmeler KM, Lynch HT, Chen LM, etal. Prophylactic surgery to reduce
the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med.
2006;354:261–269.
Umar A, Boland CR, Terdiman JP, etal. Revised Bethesda Guidelines for he-
reditary nonpolyposis colorectal cancer (Lynch syndrome) and microsat-
ellite instability. J Natl Cancer Inst. 2004;96:261–268.
Vasen HF, Abdirahman M, Brohet R, etal. One to 2-year surveillance inter-
vals reduce risk of colorectal cancer in families with Lynch syndrome.
Gastroenterology. 2010;138:2300–2306.
Vasen HF, Blanco I, Aktan-Collan K, etal. Revised guidelines for the clinical
management of Lynch syndrome (HNPCC): recommendations by a group
of European experts. Gut. 2013;62:812–823.
Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for heredi-
tary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed
by the International Collaborative group on HNPCC. Gastroenterology.
1999;116:1453–1456.
You YN, Chua HK, Nelson H, etal. Segmental vs. extended colectomy: meas-
urable dierences in morbidity, function, and quality of life. Dis Colon
Rectum. 2008;51:1036–1043.
C
A
P
P S
Paul H. Sugarbaker
INTRODUCTION
Malignant tumors of the appendix are rare, making up approximately
0.4% of all intestinal neoplasms. About 1% of all large bowel cancers
arise from the appendix. e histopathology of appendiceal malignancy has been confusing, and the approach to therapy is complex.
Many of the tumors have perforated at the time of denitive surgical treatment, and thus the physician is required to manage both the
primary tumor and its peritoneal surface dissemination. Despite the
oen widespread peritoneal metastases present at the time of initial
diagnosis, liver and lymph node metastases are seldom present. Such
patients oen can be saved, and what once was regarded as a uniformly
lethal condition (the spread of tumor on peritoneal surfaces) can be
successfully treated. In this chapter I will describe the surgical treatment of patients with cancer of the appendix and the condition that
arises from its perforation and spread—pseudomyxoma peritonei.
PATHOLOGY OF APPENDICEAL MALIGNANT TUMORS
e two most commonly occurring malignant tumors of the appendix are carcinoid and adenocarcinoma. Approximately two thirds of
appendiceal malignancies are carcinoid tumors, and the other third
are variations of adenocarcinoma (Table 60-1).
Carcinoid Tumors
By far the most common tumor within the appendix is the carcinoid
tumor. is lesion is usually found incidentally at appendectomy. It is
a small, hard, yellow tumor mass in the distal portion of the appendix. e appendix is the site of 45% of all gastrointestinal carcinoid
tumors. e incidence in females is higher than in males, probably
because of the greater number of incidental appendectomies performed in women undergoing hysterectomy and cholecystectomy.
Although 90% of appendiceal carcinoids are incidental, approximately 10% are associated with acute appendicitis. e carcinoid syndrome is rarely the presenting feature of appendiceal carcinoids, but
if it does occur, it usually heralds metastases to the liver.
e selection of treatment options for a carcinoid tumor depends
on its size and, in large tumors, on the extent of local spread. It is
extremely important to determine these clinical features at the time
of exploration because the histopathologic features of aggressive
tumors are the same as those with no malignant potential.
Adenocarcinoid Tumors of the Appendix (Goblet
Cell Carcinoid)
In a small percentage of carcinoid tumors, malignant epithelial cells
producing abundant mucus are scattered among the carcinoid tumor
292
cells. Usually these tumors have dissecting mucus diusely inltrating the wall of the appendix. In contrast, nonmucinous carcinoid
tumors present as an innocuous occurrence at the tip of the organ.
Adenocarcinoid tumors present as acute appendicitis more frequently than do carcinoid tumors. e 5-year survival rate of such
patients is greatly reduced compared with patients with carcinoid
tumors because patients with adenocarcinoid tumors usually have
peritoneal metastases at initial diagnosis. ese patients have dissecting mucus produced in large quantity by the cancer. e wide distribution on peritoneal surfaces results in a grim prognosis unless they
receive special treatments for peritoneal surface malignancy.
Epithelial (Noncarcinoid) Tumors of the Appendix
Mucinous Adenoma and Adenocarcinoma
e most common varieties of epithelial malignancy within the
appendix are mucinous adenomas or mucinous adenocarcinomas.
In the appendix, these mucinous appendiceal neoplasms are many
times more common than the intestinal type of adenocarcinoma. In
the colon, only approximately 15% of colonic adenocarcinomas are
mucinous. is preponderance of mucinous tumors in the appendix
is probably related to the high proportion of goblet cells within its
epithelium (Table 60-2).
On gross examination, it may be dicult or impossible to distinguish a mucinous tumor of the appendix from a benign mucocele.
Both benign and malignant tumors of the appendix are likely to cause
appendicitis, and mucin collections may be present within the right
lower quadrant or throughout the abdominopelvic space. Two histologic features should be sought that will separate tumors that are
inconsequential with complete removal from those capable of causing death from progressive pseudomyxoma peritonei syndrome:
1. Invasion through the appendiceal wall by neoplastic glands
2. Epithelial cells found within the extra-appendiceal mucin
If either of these clinical features occurs, special follow-up and
aggressive treatments are required.
e most common clinical entity arising from an appendiceal
mucinous neoplasm is pseudomyxoma peritonei. is clinical entity
has a perforated appendiceal adenoma or villous adenoma as its
primary site. Hyperplastic polyps, adenomatous polyps, and villous
polyps within the appendix that have resulted in an appendiceal perforation are implicated in the pseudomyxoma peritonei syndrome.
e mucus accumulations that are distributed in a characteristic
fashion around the peritoneal cavity are referred to as adenomucinosis. Histologically, epithelial cells in single layers are surrounded
by lakes of mucin. ese epithelial cells show little atypia and absent
mitosis and result in mucinous tumor accumulations that follow the
ow of peritoneal uid within the abdomen and pelvis.
Ronnett and colleagues, in their histologic description of the
mucinous appendiceal tumors, found a small proportion of patients
TABLE 60-1: Survey of Appendiceal Tumors*
Feature Carcinoid Adenocarcinoid
Approximate
incidence
66% Rare 20% Rare 10%
Pseudomyxoma
Peritonei
COLON 293
Mucinous
Adenocarcinoma Adenocarcinoma
Location Tip of appendix Diuse along
appendix
Major symptom Incidental nding Expanding abdomen,
ovarian mass
Middle to tip of
appendix
Expanding abdomen,
ovarian mass, her-
Diuse along
Base of appendix
appendix
Appendicitis Appendicitis
nia, appendicitis
Prognosis <1 cm 100% cure
Poor Localized 100% cure
>2 cm 50% cure
Histopathology of
peritoneal surface
implants
Carcinoid Carcinoid plus muci-
nous adenocarcinoma
Clinical syndromes Carcinoid Mucinous peritoneal
carcinomatosis
Treatment <1 cm appendectomy
only
>2 cm right colecto-
my + cytoreductive
surgery
Appendectomy only
or cytoreductive surgery +
intraperitoneal
chemotherapy
84% cure at 5 yr if
Adenomucinosis 90%
cure at 5 yr
unperforated;
30% cure at 5 yr if
perforated
Adenomucinosis Mucinous carcino-
matosis
Pseudomyxoma
peritonei
Appendectomy + cy-
toreductive surgery
+ intraperitoneal
Mucinous peritoneal
carcinomatosis
Cytoreductive sur-
gery + intraperitoneal chemotherapy
chemotherapy
Follows Duke stages
A-80% cure
B-50% cure
C-20% cure
Intestinal type
(nonmucinous)
adenocarcinoma
Peritoneal carcino-
matosis
Right colectomy +
cytoreductive
surgery +
intraperitoneal
chemotherapy if
peritoneal implants
*In separating pseudomyxoma peritonei, mucinous adenocarcinoma, and adenocarcinoma, it must be remembered that these represent a spectrum of disease
and are probably not distinct clinical entities. Benign mucocele is not included as an appendiceal tumor but rather is a cystic process. A perforated mucocele
resulting from an appendiceal adenoma may progress into pseudomyxoma peritonei. Tumors that histologically are between adenomucinosis and mucinous
adenocarcinoma are designated as hybrid type.
TABLE 60-2: Comparison of Colorectal and
Appendiceal Malignant Tumors
Feature Colon Appendix
Adenocarcinoma incidence 85% 10%
Carcinoid incidence <1% 70%
Mucinous adenocarcinoma 10%-15% 20%
Signet ring adenocarcinoma 1/1000 1/10
Adenocarcinoid Not reported Rare
Dierentiation of adenocarcinoma
Well-dierentiated 20% 60%
Moderately dierentiated 60% 20%
Poorly dierentiated 20% 20%
Associated malignancy Unusual Common
with pseudomyxoma peritonei syndrome who had small foci of mucinous adenocarcinoma within the large volume of adenomucinosis.
ese tumors presented with the typical pseudomyxoma peritonei
syndrome but had a poorer prognosis, similar to that of patients with
mucinous carcinomatosis. Tumors with a predominant histologic
type of adenomucinosis but foci (less than 5% of elds) of mucinous
adenocarcinoma are referred to as a hybrid histologic type.
Nonmucinous Adenocarcinoma
A less common histologic type of appendiceal adenocarcinoma is the
intestinal type of tumor, oen referred to as the nonmucinous type. is
cancer is usually located at the base of the appendix and resembles colonic
adenocarcinoma in its histopathologic appearance. It is locally invasive
and results in peritoneal metastases proximal to the appendix, usually in
the right paracolic sulcus and pelvis, especially in the cul-de-sac.
A third histologic type of appendiceal adenocarcinoma is the
classical mucinous adenocarcinoma. is more invasive tumor type
tends to involve the appendix diusely. Yan and colleagues described
three dierent variants as well, moderately, and poorly dierentiated.
e poorly dierentiated histologic type contains signet ring cells.
DIAGNOSIS OF APPENDICEAL MALIGNANT TUMORS
Carcinoid
Ninety percent of carcinoid tumors are found as incidental ndings
upon removal of an otherwise normal appendix. Approximately 10%
of patients with carcinoid tumors have appendicitis, and only rarely
does a patient present with the carcinoid syndrome. In patients who
have the malignant carcinoid syndrome, elevated urine levels of
CanCer of the appendix and pseudomyxoma peritonei syndrome294
5-hydroxyindoleacetic acid and high levels of serum serotonin are routinely found. ese patients almost invariably have liver metastasis.
Adenocarcinoma and Mucinous Adenocarcinoma
e preoperative diagnosis in patients with adenocarcinoma of the
appendix is usually appendicitis, a right lower quadrant abscess, or a
tumor mass (Table 60-3). Mucinous appendiceal cancer has usually
perforated prior to diagnosis. is perforation results in tumor spread
to the ovaries, or the tumor may present as peritoneal metastases
within a hernia sac. An aggressive mucinous adenocarcinoma may
invade the retroperitoneum and appear as a mucus accumulation in
the buttock or thigh. Also, abdominal wall invasion with an enterocutaneous stula or bladder invasion with an enterovesical stula may
occur. Obstruction of the right ureter by a mucus- containing mass or
invasion into the urinary bladder has also been reported.
Pseudomyxoma Peritonei Syndrome
Pseudomyxoma peritonei syndrome features minimally invasive appendiceal tumors that have a high propensity for spread to
TABLE 60-3: Preoperative Diagnosis of Appendix
Cancer at Time of Initial Laparotomy in 296 Case
Reports
Diagnosis No. of Patients Percent
Acute appendicitis 139 47
peritoneal surfaces but are unlikely to metastasize to lymph nodes
or liver. In a study of 501 patients, Gonzalez-Moreno and Sugarbaker
reported lymph node metastases in 2% and liver metastases in 2%.
Aer the appendiceal tumor ruptures, adenomucinosis may progress
for months or even years without causing other symptoms (Fig. 60-1).
When this occurs, the resulting clinical syndrome is termed pseudo-
myxoma peritonei. e peritoneal cavity becomes lled with mucinous tumor and mucinous ascites in a characteristic manner. e
greater omentum is thickened (omental cake) and extensively inltrated by tumor (Fig. 60-2). All dependent parts of the abdomen that
tend to entrap malignant cells are also lled by tumor.
Ruptured appendix with/
53 18
without abscess
Intra-abdominal cancer or right lower
30 10
quadrant mass
Inguinal hernia or chronic
17 5
appendicitis
Incidental operations except for
14 —
cholecystitis*
†
Cholecystitis (acute and chronic)
10 —
Ovarian tumor or cyst 10 —
Small bowel obstruction 8 —
Right-sided groin mass or stula 6 —
Acute abdomen 4 —
Appendiceal carcinoma 3 —
Hydronephrosis 2 —
Tota l 296
Autopsy nding
*Preoperative diagnosis include gynecologic cases (eight) and one each of
incisional hernia, gastric, esophageal, and sigmoid cancer, duodenal ulcer,
and torsion of the small bowel.
†
Not listed as incidental because the present symptom complex may have
been related to appendiceal disease in some cases.
‡
Some patients died with postmortem diagnosis of metastatic malignancy.
Modied from Lyss AP. Appendiceal malignancies. Semin Oncol. 1988;15:
129-137.
‡
10
FIGURE 60-1 The distal appendix has ruptured from mucin within the
mucocele. Adenomatous epithelial cells become widely distributed on
peritoneal surfaces. The silk suture is on the base of the appendix.
FIGURE 60-2 A thickened omentum (omental cake) is characteristi-
cally present in patients with pseudomyxoma peritonei.
COLON 295
is process involves the undersurface of the right and le hemidiaphragms, the right subhepatic space, the splenic hilus, the right
and le abdominal gutters, and especially the pelvis and cul-de-sac.
An important clinical feature of pseudomyxoma peritonei is the relative sparing of the small bowel by this process (Fig. 60-3). Because the
small bowel is spared by tumor involvement, removal of the involved
parietal and visceral peritoneal surfaces by peritonectomy procedures
combined with intraperitoneal chemotherapy may provide long-term
disease-free survival in more than 80% of patients.
Preoperative diagnosis of pseudomyxoma peritonei is quite dierent from appendiceal adenocarcinoma. e most common symptom
in both men and women with pseudomyxoma peritonei syndrome is
a gradually increasing abdominal girth. In women, the second most
common symptom is an ovarian mass, usually on the right side and
frequently diagnosed at the time of a routine gynecologic examination.
In men, the second most common symptom is a new-onset hernia.
e hernia sac is found to be lled with mucinous tumor. In both men
and women, the third most common presenting feature is appendicitis.
Appendicitis is the clinical manifestation of rupture of an appendiceal
mucocele that contains intestinal bacteria. e symptoms and signs of
pseudomyxoma peritonei syndrome are listed in Table 60-4.
A caveat should be mentioned regarding the surgical management of a “benign mucocele” of the appendix. If a mucocele of the
appendix is found at the time of a planned laparoscopic appendectomy, extreme caution should be used to prevent disruption of the
FIGURE 60-3 When the omentum is elevated, sparing of small bowel
is common in pseudomyxoma peritonei.
specimen. Conversion to an open appendectomy should be considered. Laparoscopic resection of a mucocele is likely to cause rupture
of that structure, and pseudomyxoma peritonei syndrome may then
result within months or years. Resection of the appendiceal mass
without traumatic rupture and without tumor spillage results in a
complete eradication of the disease process.
When a patient presents with increasing abdominal girth as a result
of presumed malignant ascites, a paracentesis or laparoscopy with biopsy
is usually performed to establish a diagnosis. In many female patients,
an ovarian neoplasm may be found. In others, a perforated adenocarcinoma from the colon, stomach, gallbladder, or appendix will be found.
e remainder of these patients will have a peritoneal surface tumor such
as a peritoneal mesothelioma or papillary serous adenocarcinoma. In all
instances, paracentesis or laparoscopy with a biopsy should be performed
directly within the midline and through the linea alba. ese sites can be
excised as part of a midline abdominal incision. No lateral puncture sites
or port sites should be used because incision in these areas will seed the
abdominal wall with tumor and greatly interfere with disease eradication. Cytoreductive surgery and intraperitoneal chemotherapy are not
eective for tumors within the abdominal wall.
TREATMENT OF APPENDICEAL
TUMORS
Carcinoid Tumors
e prognosis of the tumor depends on the stage at which it is diagnosed and the skill and experience of the surgeon and the team. Fortunately, for 90% of carcinoid tumors, the disease is asymptomatic
and cure is expected in nearly 100% of cases (Fig. 60-4). e prognosis depends on the size of the lesion and its capacity to invade locally.
In patients with tumors 1 cm or smaller, a simple appendectomy is
all that is required. In this situation, the prognosis is extremely good.
In patients with tumors 2 cm or larger, the likelihood of lymphatic or
hepatic metastases is greater. erefore, if the tumor is greater than
2 cm in size, if lymph nodes are involved, or if the tumor has invaded
out of the appendix into the mesoappendix or nearby small bowel,
an en bloc right hemicolectomy with peritonectomy of the periappendiceal surfaces is advised. Sometimes extensive spread of the
tumor into the ileocolic mesentery is present. Even in this situation,
a vigorous attempt is made to radically excise all tumor and involved
adjacent organs en bloc.
In some patients an advanced local carcinoid tumor will occur
with hepatic metastases. Often these patients have the carcinoid
syndrome. If the local tumor can be excised even with minimal
TABLE 60-4: Symptoms and Signs of Patients Presenting with Pseudomyxoma Peritonei Syndrome
Symptoms/Signs No. of Patients (%) No. of Men (%) No. of Women (%)
Appendicitis 58 (27) 36 (34) 22 (20)
Increased abdominal girth 49 (23) 28 (27) 21 (19)
Ovarian mass 44 (20) — 44 (39)
Hernia 30 (14) 26 (25) 4 (4)
Ascites 9 (4) 5 (5) 4 (4)
Abdominal pain 8 (4) 5 (5) 3 (3)
Other 19 (9) 5 (5) 14 (12)
TO TAL 217 (100) 105 (48) 112 (52)
From Esquivel J, Sugarbaker PH. Clinical presentation of the pseudomyxoma peritonei syndrome. Br J Surg. 2000;87:1414-1418.
CanCer of the appendix and pseudomyxoma peritonei syndrome296
APPENDICEAL TUMOR
Mucocele Carcinoid Epithelial tumor
Enbloc excision
<1 cm >2 cm
Appendectomy
only
Appendectomy
only
Locally advanced
Right
colectomy
PerforatedNonperforated PerforatedNonperforated
Appendectomy +
HIPEC
Right colectomy +
cytoreductive surgery
Perforated with
pseudomyxoma
peritonei syndrome
Appendectomy +
cytoreductive
surgery + HIPEC
Locally advanced
+ liver metastases
Right colectomy +
cytoreductive surgery +
hepatic resection
Right
colectomy
Pseudomyxoma Adenocarcinoma
Perforated with
peritoneal
carcinomatosis
Right colectomy +
HIPEC
Right colectomy +
cytoreductive
surgery +
HIPEC + Adjuvent
FOLFOX x 6 cycles
FIGURE 60-4 Algorithm for treatment of appendiceal malignancy. HIPEC, Hyperthermic perioperative chemotherapy.
margins of resection, one should undertake its removal, along
with resection of hepatic metastases. Occasionally, several repeat
hepatic resections may be required. A segmental approach or a
metastasectomy procedure is preferred compared with a right or
left hepatectomy. Whatever liver surgery is required to remove all
visible deposits of tumor should be performed to gain maximal
long-term palliation.
Appendiceal Adenocarcinoma
In patients with adenocarcinoma of the appendix, a right hemicolectomy is standard. Certainly, when the surgeon performing an
appendectomy nds that the appendix is inltrated by an aggressive malignant process, emergency frozen sectioning should be performed. If a diagnosis of adenocarcinoma can be made denitively,
one should proceed with a right hemicolectomy without hesitation.
Management of Appendiceal Neoplasms with Peritoneal Dissemination
Most patients with mucinous tumors of the appendix show perforation of the appendix at the time of exploration. In most of
these patients, peritoneal metastases or pseudomyxoma peritonei is found at the time of appendectomy. In the past, this condition was always fatal. Recently, peritonectomy procedures and
visceral resections combined with intraperitoneal chemotherapy
have been used for the treatment of peritoneal dissemination of
appendiceal neoplasms. The essential features of this approach
are diagrammed in Figure 60-5. The surgeon is responsible for
the resection of all visible tumor from peritoneal surfaces. This
removal is accomplished by using a cytoreductive procedure in
patients who have gross spread of tumor around the peritoneal
cavity. This procedure involves a greater and lesser omentectomy
and splenectomy, followed by peritonectomy procedures to strip
Second-look
surgery
Peritoneal
dissemination of
perforated
appendiceal
malignancy
Cytoreductive
surgery
Heated
intraoperative
intraperitoneal
chemotherapy with
mitomycin C
Early
postoperative
intraperitoneal 5-
fluorouracil
COLON 297
FIGURE 60-6 Coliseum technique for using intraperitoneal chemo-
therapy. The skin edges are suspended on a self-retaining retractor.
Warmed (41°C to 42°C) chemotherapy solution fills the peritoneal
space while being manually distributed throughout the abdomen and
pelvis.
Follow-up CT
every 6 months,
CEA & CA 19-9
tumor markers
every 3 months
Recurrence
No evidence of
disease
FIGURE 60-5 Approach to the treatment of peritoneal metastases
from appendix cancer. CEA, Carcinoembryonic antigen; C T, computed
tomography.
tumor from the abdominal gutters, pelvis, right subhepatic space,
and right and left subphrenic spaces. The primary appendiceal
tumor should be cleared by appendectomy only unless the margins are positive or lymph nodes are positive and a right colectomy is necessary. Rectosigmoid colon resection is necessary in
50% of patients.
Perioperative Chemotherapy
After the resection, and with the abdomen open, the peritoneal
space is extensively washed by the surgeon’s hand using heated
mitomycin C chemotherapy (Fig. 60-6). Also, a window of time
exists in which all intraperitoneal surfaces are available for intraperitoneal chemotherapy utilizing 5-fluorouracil in the early postoperative period. Uniformity of treatment with intraperitoneal
chemotherapy to all peritoneal surfaces, including the surfaces
dissected by the surgeon, can be achieved if the intraperitoneal
chemotherapy is used during the first postoperative week. As the
chemotherapy is dwelling, distribution is facilitated by turning the
patient alternately onto the right and left sides, as well as into the
prone position.
is perioperative intraperitoneal chemotherapy (a combination of heated intraoperative mitomycin C and early postoperative
5-uorouracil) has been used in more than 1000 patients and has
not been associated with an increased incidence of anastomotic disruptions. In patients who have had extensive prior surgical procedures and who require many hours of lysis of adhesions, great care
is taken to prevent an increased incidence of postoperative bowel
perforation. is outcome is presumably a result of the combined
eects of damage to the small bowel from electrosurgical dissection
of adhesions (seromuscular damage) and systemic eects of intraperitoneal chemotherapy on the intestine (mucosa and submucosa
damage). In patients who have high-grade appendiceal mucinous
peritoneal carcinomatosis, adjuvant intravenous chemotherapy is
recommended.
In approximately one fourth of patients, a second-look surgery
is required approximately 9 months aer the cytoreduction with
perioperative chemotherapy because of localized disease recurrence
detected on follow-up. If at the reoperative procedure small tumor
foci are found in peritoneal ssures in the abdomen or pelvis, a nal
intraperitoneal chemotherapy treatment is performed.
Serial Debulking
It is important that denitive treatment of peritoneal metastases or
pseudomyxoma peritonei be instituted early. Each nondenitive
(debulking) operation makes potentially curative cytoreductive surgery more dicult. e relative sparing of the small bowel is seen
only early on in the natural history of peritoneal metastases and
pseudomyxoma peritonei. Aer several procedures, the brous adhesions that inevitably result become inltrated by tumor, which leads
to extensive involvement of the small bowel. Eventually it becomes
CanCer of the appendix and pseudomyxoma peritonei syndrome298
Survivor probability
Product-limit survival estimates
A
Product-limit survival estimates
0
B
1.0
0.8
0.6
0.4
0.2
0.0
1 397 353 311 264 215 167 127 89 52 34 14 5 3 2 2 0
2 58 41 28 19 14 13 11 8 3 3 2 1 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360
FIGURE 60-7 Survival of patients with mucinous appendiceal neoplasms by completeness of cytoreduction score. A, Adenomucinosis patients; the
blue line (n = 397) indicates patients with complete cytoreduction, and the red line (n = 58) indicates incomplete cytoreduction. B, Impact of com-
plete versus incomplete cytoreduction for patients with a mucinous carcinoma. The blue line indicates complete cytoreduction (n = 263), and the
red line indicates incomplete cytoreduction (n = 226).
impossible to cytoreduce the tumor safely, and the eects of the intraperitoneal chemotherapy by itself are not adequate to keep the patient
disease free.
With number of subjects at risk
Months follow-up
+ Censored
Log rank P <.0001
1.0
0.8
0.6
0.4
Survivor probability
0.2
0.0
1 263 219 164 120 87 65 35 24 18 11 3 2 1 0
2 226 93 30 27 18 9 7 1 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 36
as a cystadenoma. Hybrid malignancies showed adenomucinosis
combined with isolated foci of mucinous adenocarcinomas (less
than 5%). Mucinous adenocarcinoma showed an atypical histologic
With number of subjects at risk
+ Censored
Log rank P <.0001
Months follow-up
appearance. Oen a signet ring structure and poor dierentiation
was observed.
CYTOREDUCTIVE SURGERY AND PERIOPERATIVE CHEMOTHERAPY
e results of these treatments for peritoneal surface dissemination of
appendiceal malignancies are unexpectedly good. Recently, the results of
treatment of 1000 patients with prolonged follow-up have been reported.
Figure 60-8 shows the survival distribution of these patients with
appendix malignancy by histologic type. e survival dierences
between patients with adenomucinosis and those with hybrid or
mucinous adenocarcinoma were signicant. A noninvasive histopathologic appearance is extremely important in selecting patients
who are most likely to benet from this treatment strategy. No signicant dierences were found between patients with hybrid and mucinous adenocarcinoma histology.
Survival by Completeness of Cytoreduction
e mean follow-up of this group of 1000 patients with appendix
malignancy was 10 years. Aer completion of the cytoreductive
surgery, the abdomen was inspected for the presence or absence of
residual disease in all these patients. A completeness of cytoreduction
(CC) score was obtained for all patients. e CC score was based on
the size of individual tumor nodules remaining unresected. A CC-0
score indicated no visible tumor remaining aer surgery. A CC-1
score indicated tumor nodules measuring less than 2.5 mm. A CC-2
score indicated tumor nodules between 2.5 mm and 2.5 cm. A CC-3
score indicated tumor nodules greater than 2.5 cm or a conuence of
implants at any site. In Figure 60-7, the survival of patients who had
a complete cytoreduction (CC-O and CC-1) is compared with those
who had an incomplete cytoreduction (CC-2 and CC-3). Survival
dierences were signicant; patients who le the operating room
aer cytoreductive surgery with tumor nodules less than 2.5 mm in
diameter remaining were much more likely to survive long term than
were those with an incomplete cytoreduction. No signicant dierences in survival were found between patients with CC-2 and CC-3
cytoreductions (data not shown).
Survival by Prior Surgical Score
When the previous operative notes on these patients were reviewed, a
judgment was made regarding the anatomic sites of previous surgical dissections. e summation of these dissections was recorded on a diagram
of the abdominopelvic regions. is review allowed an assessment of the
anatomic locations in which previous surgery had been performed. In
patients with a prior surgical score (PSS) of 0, diagnosis of peritoneal
carcinomatosis was obtained through biopsy only or by laparoscopy plus
biopsy. PSS-1 indicated only a previous exploratory laparotomy. PSS-2
indicated exploratory laparotomy with some resections; usually this was
a greater omentectomy or a greater omentectomy plus a right colectomy.
PSS-3 indicated that patients had undergone a prior attempt at a complete cytoreduction. is procedure was usually a greater omentectomy,
right colectomy, hysterectomy, and bilateral salpingo-oophorectomy,
with the possibility of other resections from both abdominal organs or
parietal peritoneal regions. e survival distribution by previous surgical
score is shown in Figure 60-9. Patients with PSS scores of 0 through 2 had
an improved survival compared with those with a PSS of 3.
Survival by Histologic Assessment
At the time of cytoreductive surgery and whenever possible from a
review of the primary appendiceal malignancy, a histologic assessment was made using designations of adenomucinosis, hybrid,
and mucinous adenocarcinoma. Adenomucinosis included minimally aggressive peritoneal tumors that produced large volumes
of mucous ascites. e primary appendiceal tumor was described
Treatment of Adenocarcinoid Appendiceal
Malignancy
In the database at the Washington Cancer Institute, 42 patients had a
diagnosis of adenocarcinoid of the appendix. All patients had peritoneal seeding, and most patients had a high peritoneal carcinomatosis
index. All patients underwent exploration, and cytoreduction was
attempted. If the cytoreduction was complete, perioperative and early
COLON 299
Survivor probability
Product-limit survival estimates
Months follow-up
A
Product-limit survival estimates
Months follow-up
B
Survivor probability
Product-limit survival estimates
Months follow-up
A
Product-limit survival estimates
Months follow-up
B
1.0
0.8
0.6
0.4
0.2
0.0
1 455 394 339 283 229 180 138 97 55 37 16 6 3 2 2 0
2 492 314 215 148 106 75 43 26 18 11 3 2 1
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360
FIGURE 60-8 Survival of patients with mucinous appendiceal neoplasms by histopathology. A, All patients. The blue line (n = 455) indicates patients
With number of subjects at risk
+ Censored
Log rank P <.0001
1.0
0.8
0.6
0.4
Survivor probability
0.2
0.0
1 402 356 317 120 221 172 132 94 52 35 15 6 3 2 2 0
2 272 226 170 126 94 72 42 26 18 11 3 2 1 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360
With number of subjects at risk
+ Censored
Log rank P <.0001
with adenomucinosis. The red line (n = 492) indicates patients with mucinous adenocarcinoma and includes patients with intermediate type histology.
B, Patients with a complete cytoreduction; 402 patients had adenomucinosis (blue line), and 272 patients had a mucinous adenocarcinoma (red line).
1.0
0.8
0.6
With number of subjects at risk
+ Censored
Log rank P <.0001
1.0
0.8
0.6
With number of subjects at risk
+ Censored
Log rank P <.0001
0.4
0.2
0.0
FIGURE 60-9 Survival of patients with mucinous appendiceal neoplasms by prior surgical score (PSS). A, Survival in patients with adenomucinosis
of PSS 0-2 (blue line, n = 348) versus PSS 3 (red line, n = 92). B, The impact of PSS on survival of patients with mucinous peritoneal carcinomatosis,
PSS 0-2 (blue line, n = 341) versus PSS 3 (red line, n = 123).
postoperative intraperitoneal chemotherapy was used. e survival
distribution of patients having surgical removal of adenocarcinoid is
shown in Figure 60-10. In selected patients, an attempt at complete
cancer resection is warranted, but the prognosis is guarded. If a debulking results in gross residual disease, only palliative surgical eorts
associated with low morbidity and mortality are indicated because
survival is limited. Systemic chemotherapy with the FOLFOX regimen is considered to be benecial.
Morbidity and Mortality Rates
e extensive cytoreductive surgery combined with perioperative
chemotherapy is very traumatic. Nevertheless, the mortality rate
remains at 0.6%. An anastomotic leak and stula formation (4.0%)
were the major causes for a return to the operating room, but anastomotic leaks were no more common in this group of patients than
in a routine general surgical setting. e overall grade IV morbidity was 12%. Mortality was not directly associated with the intraperitoneal chemotherapy administration. Rather, the incidence
of complications depended on the extent of the surgery, number
1 348 307 267 220 174 135 103 67 35 25 10 3 0
2 92 77 64 53 48 38 28 24 16 9 4 1 1 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360
0.4
Survivor probability
0.2
0.0
1 341 224 159 113 77 58 32 21 14 8 2 1 1 0
2 123 76 52 34 28 17 11 5 4 3 1 1 0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360
of peritonectomy procedures, and time required to complete the
cytoreduction.
SUMMARY OF TREATMENT STRATEGIES FOR PERITONEAL METASTASES
FROM APPENDICEAL MALIGNANCY
Peritonectomy
In the peritonectomy treatment strategy for patients with peritoneal carcinomatosis from appendiceal malignancy, several distinct
changes have occurred in the techniques used for surgery and methods of chemotherapy administration. Surgery was more extensive
and more meticulous than in other cytoreductive protocols. Because
of the very limited penetration of tumor nodules by chemotherapy,
the cytoreduction attempted to reduce the cancer within the abdomen and pelvis to its smallest volume. is goal required the use of
peritoneal stripping procedures, now commonly referred to as peritonectomy procedures. ese procedures oen required many hours
Survival probability
Product-limit survival estimates
0
Survival in months
1.0
0.8
0.6
0.4
0.2
0.0
FIGURE 60-10 Results of treatment of 43 patients with peritoneal
metastases from adenocarcinoid of the appendix. The graph compares
the survival of patients with complete (CC-0/1) versus incomplete
(CC-2/3) cytoreduction. All patients were treated hyperthermic
perioperative chemotherapy and systemic chemotherapy.
TABLE 60-5: Suggested Changes in the Use of
Chemotherapy for Peritoneal Metastases from
Gastrointestinal Cancer
Chemotherapy Application Change
Route Intraperitoneal vs intravenous
Timing Perioperative vs systemic adjuvant
Patient selection Minimal residual peritoneal surface
Target Peritoneal metastases vs liver or
Surgical approach Peritonectomies vs debulking
Results Improved survival
in the operating room. Frequently, the abdomen was le without
peritoneal surfaces except that which was found on the small bowel.
is approach represents a departure from the previous conservative
surgical approach to peritoneal carcinomatosis.
Perioperative Chemotherapy
Several changes occurred in the use of chemotherapy in this
patient population. First, the route of chemotherapy administration was changed from intravenous to intraperitoneal. Maximal
doses of intraoperative intraperitoneal mitomycin C and early
postoperative intraperitoneal 5-fluorouracil were used for the
first 5 postoperative days. This chemotherapy was instilled perioperatively in order to contact all the abdominal and pelvic surfaces before the onset of wound healing. Once fibrinous deposits
became organized, the chemotherapy would be unable to reach
the residual tumors, and local recurrence would occur where the
surfaces were adherent (Table 60-5).
CanCer of the appendix and pseudomyxoma peritonei syndrome300
+ Censored
CC 0/1 2/3
0 20 40 60 80 100 12
disease vs gross peritoneal
implants
systemic disease
e timing of chemotherapy administration also was changed.
Chemotherapy was used in the perioperative period rather than 4 to
6 weeks aer surgery in an adjuvant setting. Perhaps most important
to the long-term favorable results, the selection of patients for treatment was changed. Patients with minimal peritoneal surface residual
disease were treated more successfully. Patients with large-volume
residual disease in the abdomen aer cytoreduction did not achieve
a complete response. e target of these therapies was not metastases
that were present at distant sites such as the liver, bone marrow, or
lungs; rather, the target for these therapies was macroscopic residual disease on both the parietal and visceral surfaces. Patients with
metastases that could not be resected or with gross residual peritoneal surface malignancy aer completion of the cytoreductive surgery were excluded from these treatments.
It has been demonstrated that with these changes in chemotherapy and changes in surgical approach, patients with peritoneal metastases can do well. e previous failures of palliative chemotherapy
for peritoneal metastases and pseudomyxoma peritonei can be converted to success with this new combination of surgery plus regional
chemotherapy.
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