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com/1948-5204office World J Gastrointest Oncol 2010 April 15; 2(4): 192-196

[email protected] ISSN 1948-5204 (online)
doi:10.4251/wjgo.v2.i4.192 © 2010 Baishideng. All rights reserved.

REVIEW

Appendiceal neuroendocrine tumors: Recent insights and

clinical implications

John Griniatsos, Othon Michail

John Griniatsos, Othon Michail, 1st Department of Surgery, Cancer Care, Masaryk Memorial Cancer Insitute, Zluty kopec 7,
Medical School, University of Athens, LAIKO Hospital, 17 Agiou 656 53 Brno, Czech
Thoma street, GR 115-27, Athens, Greece
Author contributions: Griniatsos J conceived the idea, wrote Griniatsos J, Michail O. Appendiceal neuroendocrine tumors:
the “goblet cell carcinoma” section and was responsible for the Recent insights and clinical implications. World J Gastrointest
final appearance of the manuscript; Michail O wrote the “benign Oncol 2010; 2(4): 192-196 Available from: URL: http://www.
and malignant appendiceal NETs” section. wjgnet.com/1948-5204/full/v2/i4/192.htm DOI: http://dx.doi.
Correspondence to: John Griniatsos, MD, Assistant Professor, org/10.4251/wjgo.v2.i4.192
1st Department of Surgery, Medical School, University of Athens,
LAIKO Hospital, 17 Agiou Thoma street, GR 115-27, Athens,
Greece. [email protected]
Telephone: +30-210-7456855 Fax: +30-210-7771195
Received: January 26, 2010 Revised: February 6, 2010 INTRODUCTION
Accepted: February 13, 2010
In 1907, Oberndorfer[1] first introduced the term “carcinoid”
Published online: April 15, 2010
to describe “little carcinomas” of the small intestine which
were thought (by him at that time) to be probably benign.
However, the continuous knowledge which was added
by studying these tumors for nearly a century strengthen the
Abstract notion that the above term was inaccurate or inadequate to
New insights emerged last decade that enriched our describe several parameters of this heterogeneous group of
knowledge regarding the biological behavior of ap- gastrointestinal tumors (including the appendiceal one). Thus,
pendiceal neuroendocrine tumors (NETs), which range the term “carcinoid” was replaced by the term “gastroen­
from totally benign tumors less than 1cm to goblet cell teropancreatic neuroendocrine tumors, GEP-NETs”[2]. The
carcinomas which behave similarly to colorectal adeno- term “appendiceal NET” will be used hereafter.
carcinoma. The clinical implication of that knowledge re- According to the current WHO classification[3], appen­
flected to surgical strategies which also vary from simple diceal NETs are classified as: (1a) Well differentiated
appendicectomy to radical abdominal procedures based NETs with benign biological behaviour or (1b) Well diffe­
on specific clinical and histological characteristics. Since rentiated NETs with uncertain malignant potential; (2)
the diagnosis is usually established post-appendicecto- Well differentiated neuroendocrine carcinoma (with low
my, current recommendations focus on the early detec- malignant potential); and (3) Mixed exocrine-neuroendocrine
tion of: (1) the subgroup of patients who require further carcinoma. Goblet cell carcinoma (synonyms: adenocar­
therapy; (2) the recurrence based on the chromogranin cinoid, mucous adenocarcinoid) belongs to the last category.
a plasma levels; and (3) other malignancies which are
commonly developed in patients with appendiceal NETs.
Benign and malignant appendiceal
© 2010 Baishideng. All rights reserved. NETs
Key words: Appendiceal carcinoids; Neuroendocrine Epidemiology
tumors; Goblet cell carcinoma; Right hemicolectomy Although appendiceal NETs constitute an unusual and spor­
adic entity, it accounts for more than 50% of all primary
Peer reviewer: Ondrej Slaby, PhD, Department of Comprehensive tumors of the appendix[4].

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 Griniatsos J et al . Appendiceal neuroendocrine tumors

Benign appendiceal NETs represent the second commo­ Table 1 Classification and staging of appendiceal NETs
nest neuroendocrine neoplasms of the gastrointestinal according to the TNM system
tract (small bowel NETs being the commonest) and their
histological diagnosis is established, usually incidentally, Stage T N M
in 0.3%-0.9% of patients undergoing appendicectomy. Ⅰ Τ1 Ν0 Μ0
This means that the probability of a surgeon coming Ⅱ Τ1 Ν1 Μ0
Τ2 Ν0 Μ0
across an appendiceal NET is once for every 100 to 300 Ⅲ Τ2 Ν1 Μ0
appendectomies performed by him. The annual incidence Τ3 Any Ν Μ0
is about 2-3 newly diagnosed cases per million of general Ⅳ Any Τ Any Ν Μ1
population although post-mortem studies increase the
incidence to 170 cases per 100 000. The mean age of patients NETs: Neuroendocrine tumors; T1: Tumor < 2 cm; T2: Tumor ≥ 2 cm but
at the time of diagnosis is at end of the second decade of < 3 cm; T3: Tumor ≥ 3 cm; N0: No lymph node metastases; N1: Regional
lymph node metastases; M0: No metastases; M1: Distant metastases.
life with an increased incidence among females[5-8]. The last
finding probably reflects the increased use of diagnostic
laparoscopy among females for atypical lower abdominal diameter of < 1 cm, 15% have a diameter 1-2 cm and only
pain and the concomitant laparoscopic appendectomies 5% have a diameter greater than 2 cm[14]. Tumor size greater
performed[9]. than 2 cm strongly correlates both to metastatic potential[15]
Malignant appendiceal NETs represent the third com­ and to an unfavourable 5 years survival rate[16].
monest (after small bowel and rectum) malignant neuroen­ Approximately 70%-75% of the tumors are located in
docrine neoplasms of the gastrointestinal tract with an the apex, 15%-20% in the body and 5%-10% in the base
annual incidence of 0.63 cases per million of the general of the organ[14]. Although there is not enough evidence to
population and the mean age of the patients at time of the support the theory that the location of the tumor correlates
diagnosis in the 5th decade of life[8]. to the overall survival, cecum invasion or positive resection
margins should be considered for planned future therapeutic
Clinical presentation strategies[17].
Normally, appendiceal NETs remain asymptomatic. Al­ A multifocal pattern of the disease along the appendix
though accurate preoperative diagnosis using abdominal has not been described yet. However, the coexistence of
computed tomography (CT)[10] or ultrasound[11] scans has appendiceal NET with small bowel or rectal NETs[15],
been reported, the total number of the enrolled patients colorectal cancer[18], Crohn’s disease[19] and synchronous or
is extremely small (only case reports have been published) metachronous development of malignancies outside the
and thus is not suitable for definite conclusions. Therefore, gastrointestinal tract[15] are well documented.
for the vast majority of cases, the diagnosis of appendiceal The possibility of lymph node metastases from appen­
NETs is established incidentally postoperatively in the spec­ diceal NETs with vascular invasion is estimated as high as
imens of appendectomies which had been performed due 30%[7] but only 1% for tumors with appendiceal mesentery
to either acute appendicitis or recurrent, chronic, dull, non- invasion [20]. However, the prognostic significance of
specific lower right quadrant abdominal pain[6,12]. Carcinoid appendiceal mesentery invasion remains controversial
syndrome is very uncommon (< 1%). since its relationship to distant metastases development has
been reported as between 0[20] and 4.1%[15]. To date, there
Diagnosis have been no reports correlating lymph node metastases to
Since most appendiceal NETs are diagnosed posto­peratively, appendiceal serosa invasion.
any effort to be diagnosed preoperatively is practically The rate of cellular proliferation (as it expressed by the
unrealistic so the diagnostic work-up should focus on the Ki-67) does not seem to be of prognostic value.
early detection of recurrence in patients who have already
had surgery. Classification and staging
The use of plasma chromogranin-A levels as a tumor Based on the analysis of the published report from the
marker contributes to the differential diagnosis from gob­ SEER database between 1977-2004, it is suggested that
let cell carcinoma, the early detection of recurrence and the first proposed TNM classification and staging systems
the long term follow-up of metastatic disease. All patients for appendiceal NETs (which was based on the report
should be investigated 6 and 12 mo postoperatively and then from the SEER database between 1973-1999)[21] should
annually while the follow-up should be lifelong[13]. be modified[22] according to Table 1.
Especially for tumors > 2 cm, a CT scan and somatosta­
tin receptor scintigraphy (SRS) is recommended at 6 mo and Treatment
12 mo postoperatively and then annually. Colonoscopy is Current guidelines[13,22,23] propose simple appendectomy
advised for the early detection of synchronously present or as adequate and curative for the treatment of appendiceal
metachronously developed large bowel tumors[13]. NETs < 1 cm, while for tumors 1-2 cm, a simple appen­
dectomy followed by periodic postoperative follow-up for
Biological behavior 5 years is recommended.
Approximately 80% of appendiceal NETs have a maximum Right hemicolectomy (within 3 mo from the appen­

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 Griniatsos J et al . Appendiceal neuroendocrine tumors

dicectomy) should be reserved for patients in whom at histochemical expression of Math1 and HD5 is observed
least one of the following criteria is present: tumor size > in GCCs but not in NETs[31] while the biological behavior
2 cm, location of the tumor at the base of the appendix, of GCCs is identical to adenocarcinomas but not to NETs.
infiltration of the cecum, positive surgical resection margins, Based on the above findings, it is proposed that GCCs
appendiceal mesentery invasion, metastatically infiltrated should constitute a distinct histological and clinical entity
mesoappendiceal lymph node, presence of undifferentiated different from the appendiceal NETs, while the classifica­
or low differentiated cells or presence of goblet cells. tion which is proposed by Wang et al[32] seems to comply
Serosal, vascular, lymphatic or perineural invasion to the biological behavior of the tumors and with the
alone does not constitute inclusion criteria for right hemi­ prognosis of the patients.
colectomy.
Clinical presentation
In the majority of cases, the disease remains asymptomatic.
Goblet Cell Carcinoma Acute appendicitis (due to luminal obstruction by the tu­
Epidemiology mor) is the main symptom followed by atypical abdominal
Goblet cell carcinomas (GCC) constitute less than 5% pain and abdominal mass. Unusual symptoms are intus­
of all primary appendiceal tumors[24] and, similar to the susception, gastrointestinal bleeding, bowel obstruction,
appendiceal NETs, their diagnosis is established usually anemia and miscellaneous urinary manifestations[26].
incidentally in 0.3%-0.9% of patients undergoing appen­ In 11% of cases the disease is already metastatic at the
dicectomy. Its annual incidence is 0.05 new cases per 100 000 time of diagnosis, mainly to the ovaries and peritoneum[23].
of general population[23] with an equal distribution between However, studies[33] propose that the ovarian metastases
the sexes and the mean age of the patients at the time of should be considered as secondary to adenocarcinoma
diagnosis in the 6th decade of life, nearly 20 years later than rather than to appendiceal GCC, further supporting the
the mean age of the diagnosis of malignant appendiceal proposed by Tang et al classification.
NETs and almost 10 years earlier than the mean age of the
diagnosis of the appendiceal adenocarcinoma[25]. Diagnosis
In fact, most appendiceal GCCs are diagnosed postope­
Histology ratively so any effort for accurate preoperative diagnosis
GCC is derived from undifferentiated stem cells which are is unrealistic. The diagnostic work-up should focus on the
completely different from the endocrine cells in the mu­ early detection of recurrence in patients who have already
cosal stroma. The degree of integration of the goblet cells had surgery.
versus APUD cells varies from pure GCC to pure carcinoid Magnetic resonance imaging is more sensitive than CT
tumor. GCC cells have two type of granules which are and CT more sensitive than SRS in the early detection of
mainly acid mucinous, are not mixed and can be recognized pulmonary, hepatic and peritoneal metastases[34]. Plasma
by different histochemical staining[26]. chromogranin-A levels have no diagnostic value while the
In their recent study, Tang et al[27] tried to answer the periodic measurement of tumor markers related to the
long-standing question: “Should GCCs be classified as mucinous characteristics of the tumor such as CEA, CA
NETs or as de novo mucous adenocarcinomas of the 19-9 and CA 125 is recommended[23]. Lifelong screening for
appendix?” Based on histological findings, they proposed synchronous or metachronous malignancies is also recom­
classification of GCCs in: (1) Typical GCC (type A); (2) mended[13].
adenocarcinoma ex GCC, signet ring cell type (Type B);
and (3) adenocarcinoma ex GCC, poorly differentiated Treatment
carcinoma type (Type C). Right hemicolectomy (usually performed after the initial
On one hand, GCCs are developed in epithelium appendectomy) is recommended as the treatment of choice
without dysplasia and this development is not related to after the histological confirmation of GCC independent
the adenoma-carcinoma sequence of carcinogenesis. The of the size of the primary tumor[13]. In female patients with
immuno-phenotype of typical GCCs is different from the GCC of the appendix, regardless of age, bilateral salpingo-
immuno-phenotype of adenocarcinoma and genetic altera­ oophorectomy is also advocated. In cases with advanced
tions of neuroendocrine origin, completely different from peritoneal dissemination, cytoreductive surgery with ad­
the genetic alterations which lead to adenocarcinoma for­ juvant intraperitoneal chemotherapy may offer prolonged
mation, are responsible for that[28]. Moreover, both NETs survival[35]. Adjuvant chemotherapy is usually not effective
and GCCs of the appendix express chromogranin-A[29]. although it can be used in patients with obvious spread of
On the other hand, the positive expression of p53 range the disease[36]. Chemotherapeutic protocols are the same as
from 0% in type A GCC to 100% in type C GCC, findings those used in the treatment of colorectal adenocarcinoma.
suggestive that for the transformation to the adenocarcino­
ma phenotype in type C, the immunohistochemical expres­
sion of Cytokeratins (CK) 7 and 20 in appendiceal NETs CONCLUSION
and GCCs disclosed that GCCs express CKs similarly to Based on new insights that emerged last decade, the
colonic adenocarcinomas, while NETs do not[30]. Immuno­ biological behavior of appendiceal NETs ranges from totally

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 Griniatsos J et al . Appendiceal neuroendocrine tumors

Table 2 Recommended surgical strategies for appendiceal NETs based on specific clinical and histological characteristics

Indications Type of operation

Tumor size < 1 cm Appendicectomy
Tumor size 1-2 cm Appendicectomy + Regular F/Up for 5 years
Tumor size > 2 cm Right hemicolectomy
Location of the tumor at the base of the appendix Right hemicolectomy
Infiltration of the cecum Right hemicolectomy
Positive surgical resection margins Right hemicolectomy
Appendiceal mesentery invasion Right hemicolectomy
Metastatically infiltrated mesoappendiceal lymph node Right hemicolectomy
Presence of undifferentiated or low differentiated cells Right hemicolectomy
Presence of goblet cells
Goblet cell carcinoma in males Right hemicolectomy
Goblet cell carcinoma in females (regardless of age) Right hemicolectomy + Bilateral salpingo-oophorectomy
Peritoneal dissemination from goblet cell carcinoma Cytoreductive surgery + Adjuvant intraperitoneal chemotherapy

benign tumors less than 1 cm to goblet cell carcinomas Christ E, de Herder WW, Gross D, Knapp WH, Knigge UP,
which behave similarly to colorectal adenocarcinoma. Depen­ Kulke MH, Pape UF. Consensus guidelines for the management
of patients with digestive neuroendocrine tumours: well-
ding on specific clinical and histological characteristics, differentiated tumour/carcinoma of the appendix and goblet
surgical strategies also vary from simple appendicectomy to cell carcinoma. Neuroendocrinology 2008; 87: 20-30
radical abdominal procedures (Table 2). Since, in the vast 14 Debnath D, Rees J, Myint F. Are we missing diagnostic oppor­
majority of cases, the diagnosis is usually established post- tunities in cases of carcinoid tumours of the appendix? Surgeon
appendicectomy, it is crucial for clinicians to identify the 2008; 6: 266-272
15 Moertel CG, Weiland LH, Nagorney DM, Dockerty MB.
subgroup of patients who require further therapy, to detect Carcinoid tumor of the appendix: treatment and prognosis. N
early the recurrence based on the chromogranin A plasma Engl J Med 1987; 317: 1699-1701
levels and to detect early other malignancies which are 16 McGory ML, Maggard MA, Kang H, O'Connell JB, Ko CY.
commonly developed in patients with appendiceal NETs. Malignancies of the appendix: beyond case series reports. Dis
Colon Rectum 2005; 48: 2264-2271
17 Safioleas MC, Moulakakis KG, Kontzoglou K, Stamoulis J,
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S- Editor Li LF L- Editor Roemmele A E- Editor Yang C

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