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.2,3The 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.4 Normal levels of CA-125 and
CA 19-9 are associated with improved survival and decreased rates of
recurrence.5 CT of the chest, abdomen, and pelvis
allows evaluation of the primary tumor and assessment of metastatic
disease.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.2Risk factors that predispose locally invasive appendiceal adenocarcinoma
to intraperitoneal dissemination and metastasis have been
described.6 One study showed that T4 depth of
invasion, N2 nodal status, and mucinous tumor were associated with
peritoneal metastasis.6 Another study showed that the
incidence of lymph node metastasis was associated with both larger tumor
size and advanced T stage.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.2,3For 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.Appendiceal AdenomaAppendiceal 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.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.8Treatment for appendiceal adenoma confined to the mucosa is appendectomy
with negative margins.Low-Grade Appendiceal Mucinous NeoplasmPatients with low-grade appendiceal mucinous neoplasms (LAMN) range in
age from 20-90 years with most in the 7th decade. They
are more common in women.3 Patients present with
symptoms of appendicitis or abdominal pain, distension or an abdominal
mass. LAMNs have uncertain malignant potential.2 About
15-20% are found incidentally when undergoing surgery for an unrelated
etiology.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.2 On
histologic exam, LAMNs consist of well differentiated, glandular,
mucinous neoplastic epithelial cells.1,3 LAMNs
frequently have KRAS mutations and loss of chromosome
5q.3 Almost 100% of mucinous appendiceal neoplasms
express Keratin 20, CDX2 and MUC2.3 They are also
associated with GNAS mutations with elevated cAMP levels leading to
increased expression of MUC2 and MUC5AC and increased mucin
production.3Prognosis 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.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 acellular mucin have a low 3-7%
risk for peritoneal recurrence and generally have a good prognosis.
LAMNs with intraperitoneal spread of cellular mucin containing
neoplastic epithelium have a higher 33-78% risk of peritoneal
recurrence and overall poorer prognosis.3 Patients
with perforated LAMNs with intraperitoneal spread of acellularmucin should have routine surveillance imaging to rule out peritoneal
recurrence or disease progression.2,3 Patients with
perforated LAMNs with intraperitoneal cellular mucin containing
neoplastic epithelium should undergo a right hemicolectomy or right
hemicolectomy with cytoreductive surgery (CRS) and hyperthermic
intraperitoneal chemotherapy (HIPEC).2,3High-grade appendiceal neoplasms are histologically similar to LAMNs but
have more aggressive cytologic atypia.2AdenocarcinomaAppendiceal adenocarcinomas occur in the
5th-7th decade with mean age 60 and
are more common in men.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.3Mucinous 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 >50% of the
neoplasm.2,3Adenocarcinomas are associated with mutations of chromosome 18q,
frequently have KRAS mutations, and histologically express p53, CD44,
and CDX2.3 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.3 Signet ring cell adenocarcinomas are rare
and have a poor prognosis.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.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.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.2Pseudomyxoma PeritoneiPMP is characterized by appendiceal neoplasm perforation with
intraperitoneal accumulation of mucin resulting in gelatinous mucinous
ascites.5,9 PMP occurs in 20% of patients with
mucinous appendiceal neoplasms and more commonly in females (ratio 4:1)
between the ages of 60-70.9 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.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.8,9 The mucin in the peritoneum adheres to
but does not invade or penetrate surrounding visceral structures within
the peritoneum.5Normal 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.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.8,9 High-grade PMP
has a strong predilection for peritoneal lesions that invade visceral
structures.5There 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.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.5Right 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.2 Several studies have shown improved prognosis
and disease-free survival in patients having CRS and HIPEC for
appendiceal cancer associated with peritoneal
carcinomatosis.10, 11 Furthermore, patients who
underwent both CRS and HIPEC versus CRS alone had improved
survivability.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.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.4,13Patients 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).5Serrated Tumors of the AppendixSerrated tumors of the appendix occur in older patients and affect both
males and females equally.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).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.3Traditional 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.