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\begin{document}

\title{Locally Advanced Perforated Appendiceal Cancer: Case Report and Review}



\author[1]{Samik Patel}%
\author[1]{John Eggenberger}%
\author[1]{Beth-Ann Shanker}%
\author[1]{Robert Cleary}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Appendiceal cancers may be difficult to diagnose even after
comprehensive investigation. This report of locally advanced perforated
appendiceal adenocarcinoma attached to the terminal ileum, cecum, and
rectosigmoid illustrates the management challenges that require
comprehensive knowledge of pathologic variations and range from simple
appendectomy to cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

The incidence of appendiceal neoplasms is 1.2 cases per 100,000 persons
per year in the United States and 1-2\% of
appendectomies.\textsuperscript{1} Management of appendiceal neoplasms
is challenging partly due to classification complexity. Following SCARE
criteria \textsuperscript{2}, we present a patient with locally advanced
and perforated appendiceal adenocarcinoma with no signs of peritoneal,
solid organ or nodal metastases and without evidence of pseudomyxoma
peritonei. To address pathologic variations and treatment algorithm
inconsistencies, we also review epithelial appendiceal neoplasms based
on the World Health Organization classification, current nomenclature,
clinical presentations, and provide a proposed algorithm for management.

\section*{Case Report}

{\label{case-report}}

A 58-year-old healthy man with no family history of colorectal cancer or
inflammatory bowel disease presented to our colorectal clinic with a
6-month history of bilateral lower abdominal pain radiating to the back,
5-pound weight loss, and irregular watery bowel movements. He has one
alcoholic drink per day and denied tobacco and recreational drug use.
There was no nausea, vomiting, melena, hematochezia, shortness of
breath, chest pain, dysuria or previous abdominal surgeries. On
presentation his vitals were normal. Physical exam revealed no abdominal
tenderness, distention, or palpable masses.\emph{Diagnosis}Prior to the
colorectal surgery clinic visit, a stool DNA test was ordered by his
primary care physician and was negative. Laboratory studies were
remarkable only for a carcinoembryonic antigen (CEA) level of 5.9 ng/mL
He was initially diagnosed with irritable bowel syndrome. Colonoscopy
performed by the gastroenterologist revealed a long rectosigmoid
stricture that required a gastroscope to negotiate. The cecum and
appendiceal orifice appeared normal. Biopsies of the rectosigmoid
stenosis showed no significant pathologic abnormality and was
non-diagnostic. Computed tomography (CT) imaging of the abdomen and
pelvis demonstrated an irregular rim-enhancing heterogeneous mass
measuring 6.7 cm x 2.8cm, originating from the base of the cecum and
extending across the midline and tethered to the rectosigmoid junction
without evidence of fistula (Figure 1). CT-guided fine needle aspiration
was unsuccessful. The patient was then referred to the colorectal
surgery clinic for further evaluation.\emph{Differential
Diagnosis}Considering patient symptoms, CT imaging, and endoscopic
findings, the differential diagnosis included possible colorectal
malignancy, perforated appendix with pelvic abscess formation with
involvement of the rectosigmoid junction, perforated colon cancer with
abscess formation, or inflammatory bowel disease with fistula and
abscess formation.\emph{Treatment}The patient underwent an exploratory
laparotomy for concern of possible malignancy and near- obstructing
rectosigmoid stricture. An abscess cavity involving the terminal ileum,
distal sigmoid and proximal rectum was identified. Mobilization of the
right colon revealed a pocket of purulent material posterior to the
proximal ascending colon. En-bloc resection of the terminal ileum, right
colon, sigmoid and proximal rectum was performed with two primary
anastomoses (ileocolic and colorectal) without
stomas.\emph{Outcome}Intraoperative pelvic fluid cultures grew
Streptococcus viridans and the patient was treated with appropriate
antibiotics. Pathology showed perforated appendiceal moderately
differentiated adenocarcinoma with abscess formation and direct invasion
of the rectum without lymph node involvement (Stage IIC T4bN0Mx, 0/34
lymph nodes). Postoperative course was unremarkable and the patient was
discharged home without complications and meeting discharge criteria.
The patient was presented at the multidisciplinary tumor board and 6-12
cycles of systemic FOLFOX chemotherapy was recommended because of
high-risk features that included T4 depth of invasion, perforation and
adherence to the rectosigmoid, concern for micrometastasis, and
lymphovascular invasion. However, the patient refused chemotherapy and
instead opted for routine surveillance with CEA levels and CT imaging.
Postoperative CEA level one month after surgery was 1.7 (from 5.9 and
currently 4.3). CT of the chest/abdomen/pelvis 6 months after surgery
showed no evidence of recurrence or metastasis. The patient is now 12
months since surgery without evidence of recurrent disease and training
for a half marathon.

\section*{Discussion}

{\label{discussion}}

The World Health Organization classification scheme divides appendiceal
neoplasms into epithelial tumors, mesenchymal tumors, lymphomas, and
secondary tumors. The epithelial tumors include premalignant lesions
(adenomas and serrated lesions), carcinomas (mucinous adenocarcinoma,
low-grade appendiceal mucinous neoplasm (LAMN), signet ring cell
carcinoma, undifferentiated carcinoma) and neuroendocrine
neoplasms.\textsuperscript{2,3}The diagnosis of appendiceal neoplasm may
be challenging and requires thorough history and physical examination,
laboratory studies, imaging (CT/ MRI), endoscopy and diagnostic tumor
biopsy or surgery. Serum carcinoembryonic antigen (CEA) levels should be
obtained as for colorectal cancers. Colonoscopy may show an appendiceal
orifice mass. Tumor markers CA-125 and CA 19-9 may be elevated in
patients with appendiceal primary tumors and peritoneal
disease.\textsuperscript{4} Normal levels of CA-125 and CA 19-9 are
associated with improved survival and decreased rates of
recurrence.\textsuperscript{5} CT of the chest, abdomen, and pelvis
allows evaluation of the primary tumor and assessment of metastatic
disease.\textsuperscript{5} The diagnosis is often unknown prior to
operative intervention for presumed appendicitis. Malignant neoplasia is
identified in 2.3-12.0\% of patients having appendectomy for
appendicitis. Risk factors for appendiceal cancer in this appendicitis
group are older age and periappendiceal abscess.\textsuperscript{2}Risk
factors that predispose locally invasive appendiceal adenocarcinoma to
intraperitoneal dissemination and metastasis have been
described.\textsuperscript{6} One study showed that T4 depth of
invasion, N2 nodal status, and mucinous tumor were associated with
peritoneal metastasis.\textsuperscript{6} Another study showed that the
incidence of lymph node metastasis was associated with both larger tumor
size and advanced T stage.\textsuperscript{7} The patient described in
this case report had a T4b neoplasm but had no lymph node metastases and
has no evidence of metastatic disease to date. Management of appendiceal
neoplasms varies depending on the pathology. For appendiceal
adenocarcinoma, treatment depends on whether the neoplasm has perforated
and led to intraperitoneal dissemination. There is extensive literature
describing ruptured appendiceal adenocarcinoma with widespread
intra-peritoneal mucinous ascites leading to pseudomyxoma peritonei
(PMP) and peritoneal carcinomatosis. However, there are currently no
standard guidelines for management of locally invasive perforated
appendiceal adenocarcinoma without PMP or intra-peritoneal
dissemination.\textsuperscript{2,3}For patients like the one presented
in this case report with locally advanced perforated appendiceal
adenocarcinoma without PMP or carcinomatous, en-bloc R0 resection, when
possible, with postoperative systemic chemotherapy would likely be the
best option. The lack of standardized nomenclature for appendiceal
neoplasms contributes to treatment algorithm inconsistencies. The
following is the most recent update in pathologic terminology and
management recommendations for the most common appendiceal neoplasms.
The proposed algorithm for management is shown in Figure
2.\emph{Appendiceal Adenoma}Appendiceal adenomas are benign polyps of
the mucosa like adenomas elsewhere in the colon and rectum. Most do not
have presenting symptoms and are found incidentally but some patients
may have symptoms of appendicitis.\textsuperscript{3} Histologic exam
resembles colonic tubular, villous, or tubulovillous adenomas. There is
cellular crowding and often low-grade dysplastic changes of nuclear
elongation and stratification, pleomorphism, and increased mitotic
figures. Adenomas are associated with KRAS mutations and loss of
chromosome 5q. The majority of adenomas are microsatellite stable and
lack BRAF mutations. Like colonic adenomas, appendiceal adenomas are
premalignant and follow the adenoma-carcinoma
sequence.\textsuperscript{8}Treatment for appendiceal adenoma confined
to the mucosa is appendectomy with negative margins.\emph{Low-Grade
Appendiceal Mucinous Neoplasm}Patients with low-grade appendiceal
mucinous neoplasms (LAMN) range in age from 20-90 years with most in the
7\textsuperscript{th} decade. They are more common in
women.\textsuperscript{3} Patients present with symptoms of appendicitis
or abdominal pain, distension or an abdominal mass. LAMNs have uncertain
malignant potential.\textsuperscript{2} About 15-20\% are found
incidentally when undergoing surgery for an unrelated
etiology.\textsuperscript{3} Grossly, the appendix appears normal but
may be dilated due to intraluminal mucin accumulation. They may also
present with appendiceal perforation, mucin within the appendiceal wall,
or acellular mucin outside of the appendix.\textsuperscript{2} On
histologic exam, LAMNs consist of well differentiated, glandular,
mucinous neoplastic epithelial cells.\textsuperscript{1,3} LAMNs
frequently have KRAS mutations and loss of chromosome
5q.\textsuperscript{3} Almost 100\% of mucinous appendiceal neoplasms
express Keratin 20, CDX2 and MUC2.\textsuperscript{3} They are also
associated with GNAS mutations with elevated cAMP levels leading to
increased expression of MUC2 and MUC5AC and increased mucin
production.\textsuperscript{3}Prognosis depends on LAMN perforation and
the presence of mucinous neoplastic epithelium outside the appendix.
LAMNs confined to the appendix with no extra-appendiceal perforation are
treated by appendectomy with negative margins. This may require a
partial cecectomy if the tumor involves the base of the
appendix.\textsuperscript{2,5} The specimen should be placed in a
retrieval bag when done by the laparoscopic approach to decrease the
risk for mucin spillage. When the risk for mucin spillage is considered
high, an open approach should be considered. LAMNs with
extra-appendiceal \emph{acellular} mucin have a low 3-7\% risk for
peritoneal recurrence and generally have a good prognosis. LAMNs with
intraperitoneal spread of \emph{cellular} mucin containing neoplastic
epithelium have a higher 33-78\% risk of peritoneal recurrence and
overall poorer prognosis.\textsuperscript{3} Patients with perforated
LAMNs with intraperitoneal spread of \emph{acellular}mucin should have
routine surveillance imaging to rule out peritoneal recurrence or
disease progression.\textsuperscript{2,3} Patients with perforated LAMNs
with intraperitoneal \emph{cellular} mucin containing neoplastic
epithelium should undergo a right hemicolectomy or right hemicolectomy
with cytoreductive surgery (CRS) and hyperthermic intraperitoneal
chemotherapy (HIPEC).\textsuperscript{2,3}High-grade appendiceal
neoplasms are histologically similar to LAMNs but have more aggressive
cytologic atypia.\textsuperscript{2}\emph{Adenocarcinoma}Appendiceal
adenocarcinomas occur in the 5\textsuperscript{th}-7\textsuperscript{th}
decade with mean age 60 and are more common in men.\textsuperscript{1}
Patients may present with signs and symptoms of acute appendicitis.
Adenocarcinomas may be mucinous or nonmucinous and are subclassified
into adenocarcinoma not otherwise specified, mucinous adenocarcinoma,
signet ring cell adenocarcinoma and undifferentiated
carcinoma.\textsuperscript{3}Mucinous adenocarcinoma is the most common
adenocarcinoma of the appendix - about 40\% of all adenocarcinomas. They
consist of malignant glandular mucinous epithelium within the wall of
the appendix with infiltrative destructive invasion, high- grade
cytologic atypia and extracellular mucin in \textgreater{}50\% of the
neoplasm.\textsuperscript{2,3}Adenocarcinomas are associated with
mutations of chromosome 18q, frequently have KRAS mutations, and
histologically express p53, CD44, and CDX2.\textsuperscript{3}
Intraperitoneal dissemination of mucinous adenocarcinoma is similar to
LAMN except that the malignant epithelium contains high-grade cytologic
atypia and the mucin is more cellular.\textsuperscript{3} Signet ring
cell adenocarcinomas are rare and have a poor
prognosis.\textsuperscript{5} Non-mucinous adenocarcinomas, like that
presented in this case report, behave like colonic adenocarcinomas.
Patients with invasive mucinous or nonmucinous adenocarcinomas and
signet ring cell adenocarcinomas should undergo a right hemicolectomy
with lymphadenectomy due to 20-67\% risk of lymph node
metastases.\textsuperscript{1} These patients require oncologic
resection that includes high ligation of mesenteric vessels, removal of
the associated lymph node basin, and grossly negative 5-cm margins.
Patients with mucinous adenocarcinoma with widespread intraperitoneal
deposits should undergo CRS and HIPEC. There is no advantage to right
hemicolectomy over appendectomy when peritoneal metastases are present
unless it is necessary to achieve complete
cytoreduction.\textsuperscript{2,3} Systemic chemotherapy should be
administered to patients with lymph node or distant organ metastases.
Goblet cell carcinoid tumors are mixed adeno-neuroendocrine carcinomas
with neuroendocrine tumor features such as positive chromogranin A
staining. They are clinically more aggressive than neuroendocrine tumors
and treatment is the same as for appendiceal
adenocarcinomas.\textsuperscript{2}\emph{Pseudomyxoma Peritonei}PMP is
characterized by appendiceal neoplasm perforation with intraperitoneal
accumulation of mucin resulting in gelatinous mucinous
ascites.\textsuperscript{5,9} PMP occurs in 20\% of patients with
mucinous appendiceal neoplasms and more commonly in females (ratio 4:1)
between the ages of 60-70.\textsuperscript{9} In 2010, the American
Joint Committee on Cancer (AJCC) and World Health Organization (WHO)
classified PMP into 2 groups: low-grade PMP and high-grade
PMP.\textsuperscript{5,8,9} Low-grade PMP, also known as diffuse
peritoneal adenomucinosis (DPAM), is associated with LAMN and is
characterized by intraperitoneal spread of acellular or cellular mucin
with low-grade cytology and no significant mitotic
activity.\textsuperscript{8,9} The mucin in the peritoneum adheres to
but does not invade or penetrate surrounding visceral structures within
the peritoneum.\textsuperscript{5}Normal baseline CA-125 and CEA
returning to normal after surgery are associated with the ability to
achieve complete cytoreduction in this patient population. Elevated
baseline CA19-9 is associated with worse progression-free
survival.\textsuperscript{2} High-grade PMP, also known as peritoneal
mucinous carcinomatosis (PMCA), is associated with mucinous
adenocarcinoma and is characterized by intraperitoneal spread of mucin
containing high-grade malignant neoplastic epithelium with moderate to
severe cytologic atypia.\textsuperscript{8,9} High-grade PMP has a
strong predilection for peritoneal lesions that invade visceral
structures.\textsuperscript{5}There is considerable debate over the
management of PMP and the treatment algorithm has not been standardized.
Prior to CRS, treatment was surgical debulking. Sugarbaker introduced
and popularized the use of CRS and HIPEC for patients with
PMP.\textsuperscript{5,9} CRS removes all visible macroscopic disease
and HIPEC is used to provide directed highly concentrated
intraperitoneal chemotherapy to penetrate any remaining microscopic
disease.\textsuperscript{5}Right hemicolectomy with cytoreductive
surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is
currently recommended for appendiceal adenocarcinoma with peritoneal
carcinomatosis or PMP. HIPEC most commonly includes Mitomycin C or
platinum chemotherapy agents.\textsuperscript{2} Several studies have
shown improved prognosis and disease-free survival in patients having
CRS and HIPEC for appendiceal cancer associated with peritoneal
carcinomatosis.\textsuperscript{10, 11} Furthermore, patients who
underwent both CRS and HIPEC versus CRS alone had improved
survivability.\textsuperscript{10} Five- and ten-year survival rates for
low-grade PMP are 75\% and 68\% respectively. Five- and ten-year
survival rates for high-grade PMP are 14\% and 3\% respectively. Several
studies have shown no clear disease-free survival or overall survival
advantage for patients who underwent preoperative chemotherapy prior to
CRS and HIPEC.\textsuperscript{12} The use of early postoperative
intraperitoneal chemotherapy (EPIC) has been shown to improve survival
in patients with appendiceal adenocarcinoma with peritoneal
carcinomatosis compared with HIPEC alone without increasing
postoperative morbidity and mortality.\textsuperscript{4,13}Patients who
undergo CRS and HIPEC require routine surveillance for recurrence that
includes physical examination, CT imaging of the chest, abdomen and
pelvis and tumor markers (CEA, CA-125, CA 19-9) every 6 months for the
first 2 years, and then yearly for at least 3 years. MRI may be superior
to CT for postoperative surveillance after (CRS) and
(HIPEC).\textsuperscript{5}\emph{Serrated Tumors of the
Appendix}Serrated tumors of the appendix occur in older patients and
affect both males and females equally.\textsuperscript{3} They are found
incidentally or in patients who present with signs and symptoms of
appendicitis. They are classified into hyperplastic polyps, sessile
serrated adenoma/polyps (+/- cytologic dysplasia), and traditional
serrated adenoma/polyps (+/- cytologic dysplasia).\textsuperscript{11}
Hyperplastic polyps are benign and have low risk for malignant
transformation. Sessile serrated polyps consist of serrated, dysplastic
epithelium in the basal crypts with increased mitotic figures and mild
nuclear atypia.\textsuperscript{3}Traditional serrated adenomas have
villous growth pattern with complex serration. Due to the risk of
malignant transformation, serrated neoplasms confined to the appendix
without involvement of the adjacent cecum are treated by appendectomy
with negative margins. Right hemicolectomy with regional lymphadenectomy
is the preferred option for patients with large serrated lesions
suspicious for malignant degeneration or those that involve the cecum or
other organs. This case report adds to current literature by providing
an unusual presentation of appendiceal adenocarcinoma, by providing a
review of classification schemes and pathologic variations, and by
providing a proposed treatment algorithm.

\section*{\texorpdfstring{Legends \emph{(All Figures will need to be in
color for
print)}}{Legends (All Figures will need to be in color for print)}}

{\label{legends-all-figures-will-need-to-be-in-color-for-print}}

Figure 1. CT imaging of irregular pelvic mass arising from cecum with
extension to the rectosigmoid junction Figure 2. Classification and
Management of Appendix Epithelial Neoplasms

\section*{Data Availability}

{\label{data-availability}}

All of the data is included in this report.

\section*{Conflict of Interest}

{\label{conflict-of-interest}}

Samik H. Patel MD has no conflict of interest to report. John C.
Eggenberger MD has no conflict of interest to report. Beth-Ann Shanker
MD has no conflict of interest to report. Robert K. Cleary has no
conflict of interest to report related to this research. He has received
honoraria from Intuitive Surgical, Inc. for educational speaking.

\textbf{Authorship}

Samik H Patel MD: Substantial contributions to the design of the work
and analysis and interpretation of data for the work; Drafting the work
or revising it critically for important intellectual content; Final
approval of the version to be published; Agreement to be accountable for
all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately
investigated and resolved.

John C Eggenberger MD: Substantial contributions to the design of the
work; Drafting the work or revising it critically for important
intellectual content; Final approval of the version to be published;
Agreement to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.

Beth-Ann Shanker MD: Substantial contributions to the design of the
work; Drafting the work or revising it critically for important
intellectual content; Final approval of the version to be published;
Agreement to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved.

Robert K Cleary MD: Substantial contributions to the design of the work
and analysis and interpretation of data for the work; Drafting the work
or revising it critically for important intellectual content; Final
approval of the version to be published; Agreement to be accountable for
all aspects of the work in ensuring that questions related to the
accuracy or integrity of any part of the work are appropriately
investigated and resolved.

\section*{Funding Statement}

{\label{funding-statement}}

No funding was received for this research.\textbf{Acknowledgments}There
are no other acknowledgments.

\section*{References}

{\label{references}}

\begin{enumerate}
\tightlist
\item
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\item
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\item
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\item
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\item
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\begin{enumerate}
\tightlist
\item
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\end{enumerate}

Figure 1. CT imaging of irregular pelvic mass arising from cecum with
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Figure 2. Classification and Management of Appendicular Epithelial
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