Postgraduate Medicine

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Appendiceal Carcinoma: A Diagnostic and

Therapeutic Challenge

Deepthi Subramanya MD, Petros D. Grivas MD & Michael Styler MD

To cite this article: Deepthi Subramanya MD, Petros D. Grivas MD & Michael Styler MD (2008)
Appendiceal Carcinoma: A Diagnostic and Therapeutic Challenge, Postgraduate Medicine, 120:4,
95-100, DOI: 10.3810/pgm.2008.11.1944

To link to this article: http://dx.doi.org/10.3810/pgm.2008.11.1944

Published online: 30 Jun 2015.

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Appendiceal Carcinoma: A Diagnostic
and Therapeutic Challenge
Deepthi Subramanya, MD 1
Petros D. Grivas, MD 1
Michael Styler, MD 2
'Department of Internal Medicine,
Drexel University College
of Medicine, Hahnemann University
Hospital, Philadelphia, PA;
2
Department of Hematology/
Oncology, Drexel University College
of Medicine, Hahnemann University
Hospital, Philadelphia, PA
Correspondence: Petros Grivas, MD
Drexel University College of Medicine,
Department of Internal Medicine, 245 N.
15th Street, Mail Stop 427, PA-191 02.
Tel: 215-762-7916
Fax:215-762-7765
E-mail: petros.grivas@drexelmed.edu
© Postgraduate Medicine, Volume 120, Issue 4, November 2008, ISSN - 0032-5481, e-ISSN - 1941-9260
CLINICAL FEATURES
Abstract: Appendiceal carcinoma is a very rare clinical entity, constituting I% of all colorectal
malignancies and 1% of all appendectomy specimens. Appendiceal malignancies often present
atypically, thus creating diagnostic challenges. We present a patient with mucinous carcinoma
of the appendix who presented with hematuria and abdominal pain. Similar case reports are
extremely rare in the literature, while typical presentations of appendiceal carcinoma include
abdominal pain, abdominal mass, early satiety, nausea, and iron-deficiency anemia. Initially,
the diagnostic investigation in our patient was focused on urinary tract disorders, but ultimately
resulted in finding a mucinous appendiceal carcinoma. The carcinoma had invaded the urinary
bladder and was disseminated in the peritoneal cavity. Aggressive cytoreductive surgery is
the most common therapeutic approach for disseminated tumors, often followed by intraperi-
toneal chemotherapy. However, treatment should be individualized based on patient-specific
parameters, such as the presence of comorbidities, performance status, as well as the presence
of metastatic disease. Our patient had optimal cytoreduction with subsequent systemic therapy
with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab, a monoclonal antibody directed
against vascular endothelial growth factor. She completed her treatment regimen without com-
plications and is currently being restaged. An integrative approach is required in the diagnostic
investigation and management of appendiceal malignancies.
Keywords: appendiceal cancer; mucinous carcinoma; cytoreductive surgery; intraperitoneal
chemotherapy; systemic chemotherapy
Introduction
Appendiceal carcinoma is a very rare entity and accounts for about 1% of all colorectal
malignancies. 1 Epithelial tumors of the appendix have been divided into 4 distinct his-
tologic types: carcinoid, mucinous adenocarcinoma (mucinous cystadenocarcinoma/
malignant mucocele), colonic-type adenocarcinoma, and adenocarcinoid (with a
dual-cell origin). Carcinoids account for 85% of the epithelial appendiceal tumors,
followed by mucinous adenocarcinoma (8% ), colonic-type adenocarcinoma (4% ), and
the adenocarcinoid type (2%).2 The variability of clinical presentation often results
in late diagnosis, rendering appendiceal carcinoma a great diagnostic and therapeutic
challenge. We report a rare case of mucinous appendiceal carcinoma presenting with
hematuria as acute on chronic cystitis, discussing at the same time the typical presenta-
tion, diagnostic approach, and management of appendiceal cancer.
Case Report
A 44-year-old black woman with a history of uterine fibroids presented with right
lower-quadrant pain and bloody urine for a period of 6 weeks. Her family history
was not pertinent, she drank socially, and she had never smoked. The review of
95
Subramanya et al
her symptoms was negative for fever, chills, night sweats,
weight loss, and decreased appetite. She also denied any
change in the pattern of bowel habits, in stool color or
caliber, and she did not complain of nausea, vomiting,
weakness, or fatigue. The physical examination did not
reveal any abnormal findings, with the exception oftender-
ness on palpation of the right lower abdomen, without any
associated guarding or rebound tenderness. Urine analysis
showed the presence of red blood cells (RBC), without
protein or casts. The complete blood count (CBC) was
consistent with hypochromic, microcytic anemia, with a
normal white blood cell (WBC) count and platelets. No
electrolyte abnormalities were detected and renal function
was completely preserved.
An abdominal ultrasound indicated the presence of
multiple small hepatic and splenic cysts, but did not reveal
any structural abnormality of the urinary tract. A subsequent
cystoscopy showed marked epithelial hyperplasia consistent
with acute exacerbation of chronic cystitis. This was followed
by a computed tomography (CT) urogram which revealed
extrinsic compression of the posterosuperior aspect of the
urinary bladder by a soft tissue density in the right pelvis. No
synchronous disseminated peritoneal deposits were observed
on the abdominal CT. A normal neurological examination
and a thoracic CT scan excluded the presence of extra-
abdominal dissemination of the disease.
An exploratory and diagnostic laparotomy was performed
with the purpose of visual assessment of the mass, its origin
and local extent, adequate tissue obtainment, and potential
complete resection. The laparoscopy revealed a bulky tumor
arising from the appendix which was adherent to the right
pelvic sidewall, right ovary, and urinary bladder, as well
as regional lymphadenopathy. Frozen section analysis of
the surgical specimen was consistent with the diagnosis of
invasive mucinous carcinoma of appendiceal origin.
Extensive cytoreductive surgery was performed, aim-
ing at the optimal removal of macroscopic disease. Spe-
cifically, a right hemicolectomy, extensive mesenteric
resection, and lymphadenectomy (14 lymph nodes) were
performed along with partial cystectomy and right salpingo-
oophorectomy. There are 3 possible outcomes after such
cytoreductive procedure: RO resection, which corresponds
with no residual disease; R1 resection, which corresponds
with microscopic residual disease; and R2 resection, which
corresponds with macroscopic residual disease. The resection
in our patient was considered RO, without any evidence
of microscopic residual disease in the tissue examination
(free surgical margins).
96 © Postgraduate Medicine, Volume 120,1ssue 4, November 2008, ISSN - 0032-5481, e-ISSN - 1941-9260
The final pathology report confirmed the diagnosis and
showed evidence of significant destruction of the appendiceal
architecture with perforation, involvement of cecum at the
base of the appendix, as well as areas oftubulovillous for-
mation and signet-ring cell features. It was also consistent
with lymphovascular and perineural invasion. Three out of
the 14 resected lymph nodes were positive. The pathology
report was not based on the Ronnet criteria, which are often
used for the histopathologic identification of appendiceal
carcinoma!pseudomyxoma peritonei (PMP). 3 This set of
criteria is not universally accepted, but the rational for its
use is based on the potential heterogeneous pathology and
biologic behavior ofPMP.
Since the resection was regarded as optimal, there was no
expected additional benefit from peritoneal chemotherapy.
However, since there was lymph node involvement and
angiolymphatic invasion, the patient was treate.d with sys-
temic therapy (5-fluorouracil, leucovorin, and oxaliplatin
combined with bevacizurnab) for 6 cycles. She tolerated the
regimen well, with the exception of mild dysuria and neuro-
sensory symptoms, and did not require dose adjustment. The
patient completed the planned 6 cycles of systemic treatment
and is currently being restaged.
The results of the restaging are significant for subsequent
management. If there is evidence of recurrent peritoneal
disease after chemotherapy, this will indicate a more aggres-
sive tumor which may require more intense second-line
chemotherapy and/or referral to a center for intraperitoneal
chemotherapy.
Discussion
Carcinoma of the appendix is a rare gastrointestinal malig-
nancy accounting for 0.4% of all gastrointestinal and 1% of
all colorectal malignancies. 1 Approximately 10% are muci-
nous carcinomas, which constitute distinct clinical entities
since they are often metastasized in the peritoneal cavity
at the time of diagnosis (ie, PMP), mimicking the clinical
and biological behavior of ovarian adenocarcinoma. I-J The
atypical nature of the presentation, along with the presence
of nonspecific symptoms, often renders early diagnosis a
difficult endeavor.
In contrast to our case, appendiceal carcinomas usu-
ally present as acute appendicitis or an abdominal mass. 4
Moreover, they commonly represent an incidental finding
on a CT scan of the abdomen performed for an unrelated
reason. Alternatively, an appendiceal tumor might be
the incidental finding of an appendectomy specimen.
The differential diagnosis includes appendicitis, right-

sided diverticulitis, right colon adenocarcinoma, ovarian
adenocarcinoma, primary peritoneal carcinoma, abdomi-
nal sarcomatosis, gastric cancer, peritoneal mesothelioma
and, rarely, Meckel's diverticulum and intussuception.4-5
More atypical presentations include large bowel and/or
ureteral obstruction, mass in the neck, vaginal bleeding,
visceral fistula, and hematuria.6-8 Pseudomyxoma peritonei
is the manifestation of ruptured appendiceal carcinomas
(mucinous), but more rarely develops after the rupture of
other types of adenocarcinomas, usually ovarian. 5 It usually
presents with progressive abdominal distention, increasing
abdominal girth, pain, nausea, and early satiety second to the
development of malignant ascites. 9 Patients are individual-
ized to have either disseminated peritoneal adenomucinosis
(DPAM) or peritoneal mucinous carcinomatosis (PMC),
depending on the histolopathological characteristics of the
primary tumor. Disseminated peritoneal adenomucinosis
results from large-volume extracellular mucin, produced by
focal areas of nonmalignant mucin-producing cells on the
peritoneum. Peritoneal mucinous carcinomatosis originates
from malignant mucin-producing cells on the peritoneum.
The differential diagnosis has prognostic implications, since
the 5-year survival rates for DPAM and PMC are 84% and
6.7%, respectively, while tumors with intermediate histo-
logical features are associated with a 5-year survival rate
of 37.6%_HHJ
Our patient presented with vague lower abdominal dis-
comfort and macroscopic hematuria, which were not initially
suggestive of colorectal cancer, despite the extensive involve-
ment of the terminal ileum, cecum, and ascending colon.
There have been case reports of similar clinical presentations,
which could be attributed to the early invasion of the blad-
der wall by the tumor, probably secondary to the anatomical
proximity to the appendix. 6-s There should be a high index of
suspicion for the presence of extraurinary tumors in patients
with otherwise unexplained hematuria.
Hematuria is a commonly reported symptom in the gen-
eral population. The evaluation of hematuria should begin
with a thorough history pertinent to the various potential
causes, followed by a detailed physical examination, both in
the primary care and inpatient settings. Subsequently, urine
analysis should be performed since the results direct the next
diagnostic step. The role of imaging studies, such as ultra-
sound and/or CT is well established in the investigation of
the presence of structural urinary tract disease (Figure 1). The
presence of extraurinary tumors, including appendiceal carci-
nomas, should be considered when the etiology ofhematuria
is still unclear despite a thorough evaluation. In our patient,
© Postgraduate Medicine, Volume 120,1ssue 4, November 2008,1SSN - 0032-5481, e-ISSN - 1941-9260
Appendiceal Carcinoma
hematuria was found to be caused by an appendiceal carci-
noma with urinary bladder and peritoneal invasion.
Typical symptoms of appendiceal carcinoma, such as
right lower abdominal discomfort or a new abdominal
mass, as well as the diagnosis of new-onset iron deficiency
anemia, should alert the primary care physician for the pres-
ence of a right colonic tumor. A fecal occult blood test, or
preferably a total-length colonoscopy, should be offered
to the patient based on the current recommendations for
colorectal cancer screening (Table 1). 12- 13 Data on screening
and diagnostic work-up are inevitably extrapolated from
colorectal cancer. Finally, the definite diagnosis requires
a tissue biopsy performed either during colonoscopy,
percutaneously (palpated lymph nodes), or during a surgi-
cal procedure, as in this case. The tissue examination and
pathology assessment should be performed by an experi-
enced pathologist, as the report has critical impact on the
subsequent therapeutic decisions.
Once the diagnosis of appendiceal cancer is made, further
work-up should include an abdominal and thoracic CT scan,
measurement of carcinoembryonic antigen (CEA), as well
as a thorough physical examination for the accurate disease
staging. At this point, the intemist should try to identify the
extent of the disease and refer the patient to a specialized
cancer center for further management. The significance of
a multidisciplinary approach for both diagnosis and treat-
ment is considered paramount. The components of such a
multidisciplinary approach include surgery, chemotherapy
(intraperitoneal and systemic), irradiation, and systemic-
targeted biologic therapy.
The major treatment modality for all appendiceal tumors
is surgery. The extent of resection is determined by the
tumor size, histologic type, grade of differentiation, pres-
ence of appendiceal perforation/rupture, angiolymphatic
invasion, peritoneal involvement, and intraperitoneal organ
and regional lymph node infiltration.
Appendectomy alone is reserved for carcinoid tumors and
adenomas < 2 cm without any evidence oflocal invasion. 1•14
Right hemicolectomy is performed for all the other tumor
types including carcinoids > 2 cm, adenocarcinoids regard-
less of size, large adenomas, and all adeno- and mucinous
carcinomas with high-risk features. 1 The standard of care
for appendiceal epithelial neoplasms without peritoneal
involvement is right hemicolectomy with regional lymph-
adenectomy, which has been shown to double the survival
rates. 15 This is important for both staging and better local
tumor control.
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Subramanya et al

Figure I. Algorithm for the Evaluation of Hematuria.

If red blood cells (RBC) are not If RBC are present:

present consider: • Check UA for pyuria,
• Urine hemoglobin bacteriuria, proteinuria
• Urine myoglobin
• Medications

If pyuria and/or bacteriuria

consider:
• Urine culture for infection
• Hansel stain for allergic
interstitial nephritis

Not present

Continue evaluation with:

Consider glomerular disease
• Complete blood count (CBC)
(RBC casts may be present)
• Prothrombin time (PT)
• Partial thromboplastin time (PTI)
• Hemoglobin (Hb) electrophoresis if
necessary

If etiology still unclear, evaluate for neoplasms and other .structural disease
with ultrasound, CT scan, cystoscopy, or exploratory laparotomy

In patients with peritoneal dissemination, the most widely
practiced modality is cytoreductive surgery (CRS), target-
ing the removal of all macroscopic disease. This is usually
followed by hyperthermic intraperitoneal chemotherapy
(HIPEC), which usually involves administration of intrap-
eritoneal mitomycin, fluoropyrimidine or irinotecan, admin-
istered either pre-, intra-, or postoperatively depending on
disease extent. 16 This modality still remains a controversial
therapy and is not universally accepted as standard of care,
as there are no randomized clinical trials to support its use. 17
Early postoperative intraperitoneal chemotherapy can also be
used for better disease control. Only a certain proportion of
patients are eligible for CRS and HIPEC, and careful patient
selection is necessary for optimal outcome. 15- 17
Tumor grade, histologic type, and stage (peritoneal dis-
semination and lymph node status), as well as quality of

98 © Postgraduate Medicine, Volume 120, Issue 4, November 2008, ISSN - 0032-5481, e-ISSN - 1941-9260

Table I. Options for Colorectal Cancer Screening
• Fecal occult blood test
• Fecal DNA test
• Flexible sigmoidoscopy and barium enema
• Total-length colonoscopy
• CT colonography
CRS and length of HIPEC are the principal determinants
of peritoneal disease recurrence and long-term survival. 18
Signet-ring morphology is associated with a more dismal
outcome. 19 Regarding neoplasms with mucinous character-
istics, there have been data commenting on the prognostic
significance of localized extra-appendiceal mucin deposi-
tion. 20 Tumors with acellular periappendiceal mucin are less
likely to develop recurrent disease. 20 However, microscopic
examination of the entire appendix is necessary, because
lesions with extra-appendiceal epithelial cells are more
likely to develop disseminated disease, associated with a
dismal outcome. 20
A retrospective study evaluating factors associated with
recurrence after surgery and the role of possible adjuvant
locoregional radiation therapy in reducing recurrence rates
was conducted. 21 This study suggested a beneficial role of
adjuvant radiation therapy in preventing local recurrence as
well as providing a slight survival advantage compared with
surgery alone. Nevertheless, this study is limited as it encom-
passed a small patient population. Postoperative irradiation is
limited to patients with intraperitoneal disease, and without
any evidence of extraperitoneal metastases. 21
For. patients ineligible for CRS and/or HIPEC, either
because of poor performance status, major comorbidities, or
extraperitoneal metastatic disease, systemic chemotherapy is
a reasonable alternative. Due to the rare nature of this disease,
most of the data regarding systemic chemotherapy come from
retrospective studies. 22 •23 Prospective trials do not exist, and
the exact role of systemic chemotherapy has not been defined.
Risks and benefits of systemic chemotherapy should be evalu-
ated on an individualized basis, and patients' preferences
should always be considered. Patients with a more aggressive
histologic type (ie, signet-ring adenocarcinoma) may benefit
from a combination approach with systemic chemotherapy
administered first followed by CRS/HIPEC. More data are
required to confirm such a hypothesis.
Our patient had optimal cytoreduction and was sub-
sequently given systemic therapy with 5-fluorouracil,
leucovorin, oxaliplatin, and bevacizumab. Intraperitoneal
chemotherapy was not used in our patient because of
© Postgraduate Medicine, Volume 120,1ssue 4, November 2008,1SSN - 0032-5481, e-ISSN - 1941-9260
Appendiceal Carcinoma
prolonged postoperative recovery period associated with a
high risk of impaired wound healing. The lack of intraperi-
toneal (lP) access is often the reason why eligible patients
do not receive intraperitoneal chemotherapy. Postoperative
intraperitoneal chemotherapy is expected to provide optimal
outcomes if administered early, when the tumor burden is
minimaP 4 The basic chemotherapeutic regimen for the man-
agement of colorectal cancer includes 5-ftuorouracil, which
is an antimetabolite inhibiting the synthesis of pyrimidines,
and thus DNA in cancer cells. The use ofleucovorin aims to
increase treatment efficacy, as it exhibits synergistic activ-
ity with 5-ftuorouracil. The major adverse events with the
use of 5-ftuorouracil include diarrhea, mucositis, and bone
marrow suppression. Capecitabine is an oral 5-ftuorouracil
analogue that does not require intravenous pump infusions.
The most common dose-limiting adverse effects associated
with this compound are hyperbilirubinemia, diarrhea, and
hand-foot syndrome. 25 Oxaliplatin is a new platinum-derived
chemotherapeutic agent that also inhibits DNA synthesis.
The median patient survival is significantly increased with
the addition of oxaliplatin to the previous standard treat-
ment regimens. 26 The most common side effects observed
with the use of oxaliplatin include neuropathy, fatigue,
nausea, vomiting, diarrhea, and bone marrow suppression. 26
Irinotecan is a topoisomerase-1 inhibitor which is often
implemented in the management of colorectal cancer, with
diarrhea being its most common adverse event. Since there
is no prospective data clarifYing the role of these agents in
appendiceal cancer, its efficacy is extrapolated based on data
in colorectal cancer.
Since the survival benefit from conventional chemotherapy
reached a plateau, biologic-targeted therapeutic strategies have
been developed. Such strategies require the identification of
molecular biomarkers, which are selectively/mainly overex-
pressed in the tumor microenvironment, having a significant
role in cancer cell survival, thus being appropriate targets. Such
critical biomarke,rs are the epidermal growth factor receptor
(EGFR) and the vascular endothelial growth factor (VEGF), a
molecule that mediates turnor angiogenesis, which is a process
associated with turnor invasion and metastasis. 27 •28 Cetuximab
and panitumumab are monoclonal antibodies targeting EGFR,
being used in the treatment of metastatic colorectal cancer.
Bevacizumab is a humanized monoclonal antibody that inhib-
its the biological activities of VEGF and blocks the binding
ofVEGF to its receptor on vascular endothelium. Recent data
reveal the abundance of VEGF expression in appendiceal
carcinomas, illustrating the role of angiogenesis in the spread
of this disease. 29 Despite the fact that VEGF expression has
99
Subramanya et al
not been shown to be a reliable marker oftumor response to
bevacizumab, its intense expression in appendiceal carcino-
mas might justify the use of the antibody in this setting. Apart
from the association of its use with impaired wound healing,
bevacizumab can also cause hypertension, thrombotic events,
bleeding, and proteinuriaP
Conclusion
Mucinous appendiceal tumors constitute a diagnostic and
therapeutic challenge. They comprise distinct clinical entities
and often present with a variety of npnspecific symptoms,
leading to delayed or erroneous diagnosis. Therapeutic
modalities include appendectomy, right hemicolectomy,
extensive cytoreductive surgery, and intraperitoneal and
systemic chemotherapy. The intemist should implement
an integrative approach in the diagnostic investigation and
management of such malignancies.
Conflict of Interest Statement
Deepthi Subramanya, MD discloses no conflict of inter-
est. Petros D. Grivas, MD discloses no conflict of interest.
Michael Styler, MD discloses no conflict of interest.
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