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Endocrine tumors of the appendix: a pathologic review.

Digestive endocrine tumors constitute a heterogeneous group of tumors. Their clinical features, functional properties, and outcome differ according to their site of origin. Appendiceal endocrine tumors (AETs) are the second most frequently occurring digestive endocrine tumors, with a relative frequency of 25% to 30%. They are sporadic tumors and not related to familial tumor syndromes. Appendiceal endocrine tumors are usually diagnosed incidentally during appendectomy, and a more aggressive surgical therapy, such as a right hemicolectomy, may be indicated in some cases. Appendiceal endocrine tumors are separated into 2 groups: (1) classic appendiceal endocrine tumors, and (2) goblet cell carcinomas, which have a more aggressive history.

In this review article, we will discuss these 2 entities separately. The evaluation of the risk of malignancy of an endocrine tumor discovered fortuitously after appendectomy and the indications for additional surgical treatment are also developed. The recent TNM classification systems, proposed by the European Neuroendocrine Tumor Society in 2007 and by the American Joint Committee on Cancer in 2009, as well as guidelines for management of patients with AETs are presented and discussed.


Epidemiology and Symptoms

Appendiceal endocrine tumors occur with an incidence of 2 million to 3 million per year, with a 2:1 female to male ratio. (1-8) Because most AET are diagnosed incidentally during appendectomy (,1% of appendectomies), they are not related to a specific clinical presentation. (9,10) The diagnosis is associated with, but not related to, acute appendicitis because most tumors are located at the tip of the appendix and do not induce obstruction. (1,11,12) Association with a carcinoid syndrome is extremely rare and is estimated to occur in less than 1% of cases. (1)

Location and Size

Most AETs are located at the tip of the appendix (60%-75%). (1,11-13) Location at the base of the appendix is not proven to confer a less-favorable prognosis, but it may change the therapeutic decision if there is involvement of the surgical margin. (14)

The size distribution is 60% to 80% for tumors smaller than 1 cm, 4% to 37% for those between 1 and 2 cm, and 2% to 17% for those larger than 2 cm. (1,11-13) Prognosis is related to the size of the tumor, and a maximal diameter larger than 2 cm is the most important parameter for prognosis. Indeed, metastases have not been observed in tumors smaller than 1 cm, and only 10% of tumors with lymph nodes metastases are between 1 to 2 cm. (15) In contrast, Moertel et al1 reported metastatic disease in 3 of 14 patients (21%) with tumors [greater than or equal to] 2 cm but <3 cm and in 4 of 9 patients (44%) with tumors [greater than or equal to] 3 cm.

Histopathologic Diagnosis

Histology.--Tumor cells are uniform, arranged in rounded, solid nests (Figure 1, a), with some peripheral palisading infiltrating the appendiceal wall (Figure 1, b). Most AET are serotonin-producing enterochromaffin cell tumors (Figure 1, c). (17-19) A mucin stain may be used, in some cases, for the differential diagnosis with a goblet cell carcinoid (see below).


Immunohistochemistry.--Immunohistochemical analysis according to standard procedures with chromogranin A and synaptophysin antibodies is recommended to confirm the diagnosis. Tumor subtyping by immunohistochemistry is not necessary on a routine basis. (1)

Proliferation Rate.--The proliferation marker Ki-67 and the number of mitoses are very low in most AETs (Figure 1, d). (20,21) Their relevance is not as precisely defined for AETs as it is for other endocrine tumors. However, the assessment of the mitotic count (mitoses per high-power field) and the Ki-67 index is recommended, similar to the assessment for digestive endocrine tumors in all other locations, to classify the tumor according to World Health Organization (WHO) and TNM staging (see below).

Tumor Infiltration.--Appendiceal Wall Infiltration.--Malignant behavior and prognosis is related to the infiltration of tumor cells through the different layers of the appendix; however, the incidence of the serosal and mesoappendiceal involvement differs in the literature according to the series (for review, see Plockinger et al (1)), and the effect of such infiltration on survival is still controversial. (12,13,22) Interestingly, the TNM classification proposed by the European Neuroendocrine Tumor Society for AET allows distinguishing minimal ([less than or equal to] 3 mm) from deep mesoappendiceal invasion. (23) In that classification, the minimal mesoappendiceal infiltration is regarded as an equivalent to subserosal invasion (WHOof uncertain prognosis/TNM T2, see below).

Surgical Margins.--The surgical margins (R0/R1) must be reported clearly. In some cases, a frozen section examination may be required (when possible; ie, most operations are conducted on an emergency basis) for evaluation of the appendiceal margin if a tumor is suspected by the surgeon. (25,26) If the resection margin is positive for tumor cells, a more distal resection is required. However, the criteria for an additional right hemicolectomy are difficult to analyze (see below), so an analysis of the permanent sections is required to determine whether those criteria are met, and if they are, a reintervention should be performed in those cases.

Classifications.--Appendiceal endocrine tumors can be classified according to both the WHO classification and the newly proposed TNM classifications, which give complementary data results.

WHO Classification.--According to the WHO classification, endocrine tumors of the appendix are defined as (1) a well-differentiated endocrine tumor with benign behavior (confined to the appendiceal wall, with a diameter [less than or equal to] 2 cm and without angioinvasion) or uncertain behavior (confined to the subserosa or with a maximal diameter >2 cm or angioinvasion); (2) a well-differentiated endocrine carcinoma (invading the mesoappendix or beyond and/ or with metastases); or (3) goblet cell carcinoma (Table). (17)

TNM Classification.--A TNM classification and grading scheme has been proposed in 2007 by the European Neuroendocrine Tumour Society. (23) Tumors are classified according to their size and infiltration into the appendiceal wall. Tumors smaller than 1 cm that invade the submucosa or muscularis propria are classified as T1. Tumors smaller than 2 cm with minimal (<3 mm) invasion of the mesoappendix are classified as T2, whereas a diameter greater than 2 cm or more than 3 mm of mesoappendiceal invasion classifies the tumor as T3. T4 tumors invade the peritoneum or other organs. A grading system was also proposed similar to that for all endocrine tumors of the digestive system. (23) Tumors are graded according to mitotic count (2 [mm.sup.2]/10 high-power fields but evaluated in 40 high-power fields) and Ki-67 index (the percentage of 2000 tumor cells) into G1 (mitotic count, <2; Ki-67 index, [less than or equal to] 2%), G2 (mitotic count, 2-20; Ki-67 index, [less than or equal to] 3%-20%), and G3 (mitotic count, >20; Ki-67 index, >20%). The grading system proposed in the TNM classification will probably allow better assessing and standardizing of mitoses and Ki-67 counting for future reports. Another TNM classification has recently been published in 2009 by the American Joint Committee on Cancer, which is very different from the previous one for T1, T2, and T3 grouping. (24) In this classification, tumors [less than or equal to] 1 cm are classified T1a and tumors >1 cm but [less than or equal to] 2 cm are classified T1b. T2 tumors are >2 cm but [less than or equal to] 4 cm or with extension to the cecum. T3 tumors are >4 cm or with extension to the ileum.

Prognosis and Guidelines for Follow-up and Surgical Therapy

Most patients with endocrine tumors of the appendix have a favorable prognosis. (1,6,8,10) Appendiceal endocrine tumors smaller than 2 cm that are confined to the appendix wall are generally cured with complete local excision by appendectomy. As discussed above, the most important known risk factors appear to be tumor size larger than 2 cm and infiltration of the mesoappendix. However, data are still conflicting. The following treatment and follow-up may be proposed after appendectomy (1,27):

* Tumors Smaller Than 1 cm and R0 Resection.--No complementary treatment and no follow-up required

* Tumors Larger Than 2 cm.--Right colectomy after tests searching for metastases

* Tumors Between 1 and 2 cm.--Insufficient data for a clear-cut decision, so complementary surgery (right colectomy) and/or follow-up are discussed if (1) there is deep mesoappendiceal infiltration, (2) there are positive (or unclear) margins, or (3) there is vascular tumor invasion


Goblet cell carcinoids (GCCs; synonymous terms: adenocarcinoids, goblet cell tumors) have mixed phenotypes, with partial neuroendocrine differentiation and intestinal goblet cell morphology. Goblet cell carcinoids are classified as mixed endocrine-exocrine tumors; they are considered to represent a separate clinicopathologic entity, distinct from both classic AET and appendiceal adenocarcinomas, but their histogenesis is unclear. They have a more aggressive history than classic AET and, thus, require a different diagnostic and therapeutic approach. (1,28-31)

Epidemiology and Symptoms

The incidence of GCC is estimated to be one-tenth of that for AETs. In contrast to classic AET, roughly equal numbers of men and women develop GCC. Median age at presentation is later than for AET, during the fifth decade, with a second peak at 70 years. (5,6,31-33) Goblet cell carcinoids usually manifest as abdominal pain and a palpable mass (in patients with advanced disease) or acute appendicitis. Concomitant metastases (mostly ovaries, right colon, and peritoneum) are present at diagnosis in more than half of the patients. (29)

Location and Size

Goblet cell carcinoids are usually located in the middle third of the appendix and may well cause longitudinal extension and appendiceal obstruction. They usually lack the formation of a well-defined tumor mass; thus, it is somewhat difficult to accurately assess their size. However, a recent study showed that most GCCs are larger than 2 cm in size. (29) Size correlates with survival when analyzed by the following cutoff points: smaller than 1 cm, between 1 and 2 cm, and larger than 2 cm. (32)

Histopathologic Diagnosis of GCC

Histology.--Typical GCCs have a mixed phenotype, with partial neuroendocrine differentiation and intestinal-type goblet cell morphology. Indeed, they are characterized by the presence of mucin-containing, goblet-shaped epithelial cells, arranged in round or oval clusters (Figure 2, a and b). Mucin stains (periodic acid-Schiff, periodic acid-Schiff diastase, Alcian blue) are strongly positive within goblet cells (Figure 2, c) and may underline the presence of pools of extracellular mucin. The cells exhibit minimal cytology atypia, and there are rare or no desmoplastic stroma (Figure 2, b). The clusters are oriented along the axis of the muscle fibers of the muscularis propria (Figure 2, d); they characteristically spare the mucosa. (29) A recent retrospective study (29) of a large number of GCC cases (n 5 63) has shown that the cases could be stratified into 3 morphologic groups: (1) typical GCC, as described above; (2) adenocarcinomas, signet ring cell type; and (3) adenocarcinomas, poorly differentiated. The last 2 groups contain at least a focal component typical of GCC. Interestingly, this classification correlates with patient survival. (29,34) The authors (29) suggest that GCCs display a spectrum of histologic features and possess the potential to progress to an aggressive adenocarcinomas phenotype.


Immunohistochemistry.--Immunohistochemistry with chromogranin A and synaptophysin antibodies demonstrate focal reactivity (in 5%-25% of tumor cells), in contrast to the diffuse staining in most classic AETs (Figure 2, d). MUC2 staining results are positive in GCCs, and the CK7/CK20 profile is different from classic AET. (29,20,34) Other immunohistochemical markers for malignant behavior, such as b-catenin, E-cadherin, p53, or CK19, are not required on a routine basis because their prognostic value has not been validated in GCC. (21,35-37) In addition, molecular analysis of GCC has shown a significant overlap with classic AET. (38)

Proliferation Rate.--Mitotic figures are rarely identified in GCC. Some data include the proliferation marker Ki-67 or the number of mitoses as prognostic indicators in GCC. (20,39) In a recent study, Tang et al (29) found a proliferative index at 11% (SD = 2%) in a large series of GCC. (29) Mitotic index and Ki-67 should probably be assessed, following the consensus recommendations of the TNM for digestive endocrine tumors, but their correlation with prognosis is unclear in GCCs. (23)

Tumor Infiltration.--Appendiceal Wall Infiltration.--Serosal involvement, invasion of the mesoappendix, or extension into the peritoneum or adjacent organs are prognostic factors in GCC. Mesoappendiceal involvement is frequent and was observed in 51% of cases in a recent series of 227 patients (39); lymph node metastases are detected in 34% of patients with GCC, and the pattern of extension is predominately limited to the pelvic organs with peritoneal spread. (29)

Surgical Margins.--The surgical margins (R0/R1) must be reported clearly. However, the diagnosis of GCC generally leads to a right hemicolectomy (see discussion below), even when the appendiceal margin is negative for cancer cells.

Classifications.--Goblet cell carcinoids are classified according to the WHO and to TNM staging:

WHO Classification.--In the last version of the WHO classification for endocrine tumors (Table), GCCs were classified as mixed exocrine-endocrine carcinoma along with other, low-grade, malignant tumors. (17)

TNM Classification.--The TNM classification and grading scheme proposed for digestive endocrine tumors and used for classic AETs should not be used for GCCs. The preferred TNM classification is the one used for appendiceal adenocarcinomas. (18)

Prognosis and Guidelines for Follow-up and Surgical Therapy

Goblet cell carcinoids bear a worse prognosis than classic AET (GCC 5-year survival rate, 76%; AET 5-year survival rate when all stages are included, 83%). Right hemicolectomy, to be performed after initial appendectomy, is considered the standard surgical intervention for GCC. (1) This implies that the diagnosis of GCC on frozen section examination leads to a right hemicolectomy. (26) However, some authors have shown that low-risk tumors (<1 cm; localized; without serosal, mesoappendiceal, or cecal invasion; with low proliferative index) can be better served with appendectomy alone. (12,40) Cytoreductive surgery with adjuvant chemotherapy or intraperitoneal chemotherapy may prolong survival in cases with advanced peritoneal dissemination. (29,31,41)


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Lydia Deschamps, MD; Anne Couvelard, MD, PhD

Accepted for publication October 29, 2009.

From the Department of Pathology, Centre Hospitalier Universitaire La Meynard, Fort-de-France, France (Dr Deschamps); and the Department of Pathology, Beaujon Hospital, Assistance Publique-Hopitaux de Paris and University of Paris 7, Clichy, France (Dr Couvelard).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Anne Couvelard, MD, PhD, Service d'Anatomie Pathologique, Hopital Beaujon, 100 Boulevard du General Leclerc, 92110 Clichy, France (e-mail:
World Health Organization Classification of Endocrine
Tumors of the Appendix

A. Well-differentiated endocrine tumor

1. Benign behavior

* Nonfunctioning, and

* Confined to appendiceal wall, and

* [less than or equal to] 2 cm, and

* Nonangioinvasive, and

* Ki-67 index of [less than or equal to] 2%, and

* Mitoses of [less than or equal to] 2 cells/high-power fields x 40

2. Uncertain behavior

* Nonfunctioning, and

* Confined to subserosa, or

* >2 cm, or

* Angioinvasive

B. Well-differentiated endocrine carcinoma, low-grade,

* Invading the mesoappendix or beyond, and/or

* With metastases,

* With or without a functioning (carcinoid) syndrome

C. Mixed exocrine-endocrine carcinoma

1. Low-grade, malignant, goblet cell carcinoids

Data derived from Solcia et al. (16)
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Author:Deschamps, Lydia; Couvelard, Anne
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Geographic Code:1USA
Date:Jun 1, 2010
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