European Review for Medical and Pharmacological Sciences

2014; 18: 1591-1594

Goblet cells carcinoid with mucinous
adenocarcinoma of the vermiform appendix: a step
towards the unitary intestinal stem cell theory?
G. GRAVANTE, S. YAHIA, K. GOPALAKRISHNAN1, G. MATHEW
Department of Surgery, and 1Department of Histopathology, George Eliot Hospital, Nuneaton,
United Kingdom

Abstract. – Associations of various histotypes in appendiceal neoplasms may help elucidate the histogenesis of such uncommon tumors. We present the fourth published case ofGoblet Cell Carcinoid (GCC) associated withmucinous adenocarcinoma of the appendix.
This association has been described only for
GCC and not for classic appendix carcinoids
which are thought to originate from neuroendocrine-committed cells. The GCC-mucinous
association adds more towards the theory of apluripotent intestinal stem cell with amphicrine
possibilities of differentiation.
Key Words:
Goblet cell carcinoid, Mucinous adenocarcinoma,Appendix.

Introduction
Appendiceal tumors are important neoplasms
which can be encountered in both district general
hospitals and tertiary referral centres. They are
frequently discovered incidentally on appendicectomy specimens (0.1-0.8%)1, but can alsopresent with acute appendicitis caused by luminal obstruction from the tumor mass, or withmore severe symptoms due to local widespreaddissemination (pseudomyxoma peritonei in casesof mucinous types or peritoneal carcinomatosis
for adenocarcinomas)2-4. Historically five histotypes have been described3: mucinous adenocarcinomas represent the most common type of appendiceal tumors (37%), followed by colonictype adenocarcinomas (25%), carcinoids (20%),
goblet cell carcinoids (GCC – 14%), and signet
ring cell carcinomas (4%)5. Carcinoids are associated with the best prognosis and signet ring cellcarcinomas with the worst5.
Among all appendiceal tumors mucinous adenocarcinomas and GCC are those that pose nu-

merous controversial issues currently under debate. Uncertainties about their malignant behaviour are reflected in the number of classifications
available and in the use of terms such as “uncertain malignant potential” or “low malignant potential” to describe histologic grading between
the classic progression adenoma-carcinoma4,6,7.
“Low-grade” mucinous neoplasms can spread tothe peritoneum and the ovaries without local invasion of the appendix4. Therefore, pseudomyxoma peritonei is associated with mucinous neoplasms of low malignant potential despite it represents a disseminated disease4. The clinical significance of localised pseudomyxoma peritonei(i.e. during ruptured mucinous neoplasms) is also
uncertain, although many of the local recurrences
are determined by malignant cells in the periappendiceal mucin pool4,8.
Differently from mucinous adenocarcinomas,
globet cell carcinoids are amphicrine tumors of
the appendix. Amphicrine tumors are neoplasmsthat contain cells with both exocrine and endocrine features9 and, therefore, not easily classifiable. These rare neoplasms can be found in numerous organs of the respiratory and gastrointestinal tract, glands (thyroid, breast, prostate)
and epithelia (ear, skin, cervix, vulva)9. In thecase of appendiceal tumors, goblet cells containboth histological and immunohystochemical features of colonic adenocarcinomas (CK 20 positivity, IGA staining) and classic carcinoids (minimal atypia, rare mitotic figures), suggesting acommon origin from an undifferentiated pluripotent intestinal stem cell with divergent differentiation10,11. This cell type is not present in the appendiceal mucosa and is thought to be generated
from an epithelial metaplasia12.
The debate about the histologic origins of appendiceal tumors is one of the most fascinating
controversies. In the present article we present arare case of appendiceal neoplasm in which bothCorresponding Author: Gianpiero Gravante, MD; e-mail: ggravante@hotmail.com

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G. Gravante, S. Yahia, K. Gopalakrishnan, G. MathewFigure 1. Upper panel: adenocarcinoma with abundant extracellular mucin and floating glandular elements (10x).
Lower quadrant: abundant extracellular mucin and floating
glandular elements (40x).

GCC and mucinous adenocarcinoma coexisted in
the same specimen. The significance of this report adds towards the unifying theory of a single
totipotent intestinal stem cell that could originate
most appendiceal neoplasms.

Case Report
A 62-year-old female patient presented to theEmergency Department with a 48-hour history ofright iliac fossa pain. Symptoms were previously
managed by the family doctor as urinary tract infection with oral antibiotics without improvement. The past medical history included hypertension, previous laparoscopic cholecystectomy
and hysterectomy. On admission she was febrileand tachycardic with tenderness to palpation over
McBurney’s point. Routine blood analysis revealed raised inflammatory markers (White Cell1592

Count – WCC 15.2 and C-Reactive Protein –CRP 147). A working diagnosis of appendicitis
was assigned and immediate treatment with IV
antibiotics was commenced. The following morning a Computed Tomography scan of the abdomen demonstrated a mixed density mass (7x6cm) in the right iliac fossa extending in the pelvis
with surrounding inflammatory changes. Differential diagnosis at this stage included appendicular mass, inflammatory bowel disease or malignancy. General clinical conditions and blood
analysis improved progressively. Therefore, thedecision was to continue the conservative management and request a colonoscopy as an outpatient. The patient was discharged home 6 days after the admission and the outpatient colonoscopy
showed only evidence of diverticulosis in the sigmoid and descending colon.
Three months later the patient presented again
to the Emergency Department complaining oflower abdominal pain, occasional rectal bleeding
and raised inflammatory markers (WCC 12.2,CRP 28). A provisional diagnosis of acute diverticulitis was made and intravenous antibiotic treatment commenced. The mass in the right iliac fossa was again noted and a repeat CT scan showedinflammatory changes associated with the cecalpole. However, compared to the previous study
the inflammatory appearances were less severe.
Repeated blood tests the following day showed
continued derangement of the inflammatory
markers (WCC 10, CRP 112) and, therefore, thepatient was offered a surgical approach. Intraoperative findings consisted of an ileocaecal mass
wrapped in the omentum and tightly adherent to
the right lateral pelvic wall and the right ovary.
En-bloc resection was performed and the specimen sent for analysis. Recovery was characterisedby a postoperative ileus that spontaneously resolved with conservative treatment, and a wound
infection treated with regular change of dressings.
The histology diagnosed a mixed GCC and mucinous adenocarcinoma of appendicular origin (Figures 1 and 2), with one node positive out of 13 examined (staging pT3 pN1 Dukes C1). The patientunderwent adjuvant chemotherapy with Oxaliplatin and Capecitabine and at present does notshow any signs of local or systemic recurrence.

Discussion
Amphicrine tumors are interesting variants of themore common exocrine or endocrine counterparts.

Combined appendiceal tumors

Histological features, and quite often their clinicalbehaviour, lie between these two extremes. A morphological classification divides them into thosewith separation of the two components at a cellularlevel (cells contain either exocrine or endocrinegranules) but intermixed in the tumor mass; thosewhere the two components are separated at a cellular level and in the mass (juxtaposed – collision tumors)13; those in which the two components are intermixed within the cell, further subdivided if exocrine granules are in separated cytoplasmic areasfrom endocrine or are mixed with them14.
GCC are peculiar amphicrine tumors that almost exclusively present in the appendix15. Theircells contain both endocrine and exocrine features
and their histogenesis is still under debate. GCC
could be a variant of the neuroendocrine carcinoid with exocrine differentiation or a subtype of
adenocarcinoma with neuroendocrine differentiation15. A more unifying theory sees the GCC ori-gin from a “single undifferentiated pluripotent intestinal epithelial crypt base progenitor stem cellwith divergent neuroendocrine and mucinous
glandular differentiation” (unitary intestinal stem
cell theory)12,15. This theory is confirmed by thepresence in rare case reports of the association between GCC and mucinous neoplasms10,13,16, neverfound in classical carcinoids. For this reason classic carcinoids would originate from dedicatedneuroendocrine stem cells that lack the possibilityof an exocrine phenotype while GCC would originate from an earlier precursor that can still produce exocrine features15. Typical GCCs have also
been described in association with signet ring or
poorly differentiated carcinomas of the appendix
which would suggest, similarly for the association
with mucinous neoplasm, a common origin froman early histogenetic precursor (unitary intestinal
stem cell theory)12,15.
In our case the coexistence of GCC with mucinous adenocarcinoma adds to the current literature of cases described with such association. The
importance of our case report is that it is, to thebest of our knowledge, the fourth reported casetowards the unitary intestinal stem cell theory.

Conclusions
The debate about the origin of appendiceal
neoplasms is far from being solved and every day
new pieces of information are gathered by casereports and small series due to the rarity of thesediseases. Different from classic carcinoids andcolonic-type adenocarcinomas, for which theoriginating stem cells have already been found,
GCC, mucinous adenocarcinomas and signet ringcell carcinomas have still not been offered such apossibility. However, the co-existence of GCC
and mucinous neoplasms in the same specimen
increase the likelihood of a common precursor
that could differentiate towards both histotypes
during the proliferative pathway. Although ourreport represents only a single patient, its importance lies in the fact that is the fourth reported in
the literature of such association, therefore,
adding more probabilities towards the unitary intestinal stem cell theory.

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Figure 2. Upper panel: goblet cell carcinoid characterisedby nests of goblet cells (10x). Lower panel: goblet cell clusters with occasional Paneth cells (40x).

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