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\begin{document}

\title{Ectopic Pancreatic Tissue (EPT) in a cholecystectomy specimen: A rare
incidental pathologic finding}



\author[1]{Anita Khalili}%
\author[1]{Nooshin Zaresharifi}%
\author[1]{Behrad Eftekhari}%
\author[2]{Hojjat Layegh}%
\affil[1]{Guilan University of Medical Sciences}%
\affil[2]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Introduction}

Ectopic pancreas tissue (EPT) or pancreatic heterotopia is a rarely
observed congenital abnormality defined as the presence of pancreatic
tissue in another organ without any anatomical or vascular connection to
the pancreas. The term consists of the two Greek words ''hetero-'' which
means ''other'' and ''-topia'' which means ''site'', pointing out the
unique location of pancreatic cells. EPT's favored sites are the
stomach, duodenum, colon, jejunum, and Meckel's diverticula (1). The
gallbladder is a highly infrequent location for EPT (2). Almost all
cases are detected incidentally during the histopathological examination
after cholecystectomy for other pathologies. The prevalence of EPT in
the gastrointestinal tract varies from 0.6\% to 13.7\% in autopsy series
and 0.2\% in laparotomies (3, 4). Although the malignant transformation
of this tissue is not frequently expected, pathologists must be aware of
it to ensure no malignant pathology is present and prevent further
misdiagnosis. In this study, we present a case of EPT that we found
incidentally during the histopathological examination of the specimen
from the gallbladder in a patient who underwent cholecystectomy due to
acute cholecystitis.

\textbf{Case} \textbf{History}

A 40-year-old male was referred to the emergency department for acute
pain in the right upper quadrant of the abdomen. The pain was constant
and initiated hours before and intensified when he had dinner. He also
reported fever, anorexia, nausea, and one involuntary vomiting episode
containing only stomach contents. Besides intellectual disability and
epilepsy, patient's medical history was unremarkable otherwise. He was
on Valproate(200mg/D), Risperidone(1mg/BD) and Clonazepam(1mg/HS). He
denied smoking and any recreational drug use. No allergies were
reported. During the clinical examination, his vitals were slightly
above normal ranges (Blood pressure: 115/70mmHg; Heart rate: 108bpm;
Respiratory rate: 19 breaths/min; Temperature: 37.9\selectlanguage{ngerman}°C; Oxygen
saturation: 99\% without supplemental oxygen). The palpation of the
abdomen revealed tenderness in the right upper quadrant and a positive
Murphy sign with no rebound tenderness or guarding. The laboratory
evaluation was within normal range except for a WBC count of 10300, ESR
of 32, and a 2+ CRP. Additionally, he underwent an ultrasonographic
evaluation of the upper abdomen, reporting a thickened wall gallbladder
containing multiple stones (measuring up to 8x10mm). The patient was
scheduled for emergency laparoscopic cholecystectomy under the diagnosis
of acute calculous cholecystitis. During surgery, the gallbladder was
found to be gangrenous. The patient had a complicated postoperative
period due to surgical wound infections and was hospitalized for a week
to receive intravenous antibiotics; however, he did not report any
delayed complications or symptoms after discharge.

\textbf{Investigations}

During pathologic examination, gallbladder measured 9cm x 4cm containing
multiple small yellowish stones. The mucosa was green, and the maximum
wall thickness was 2mm. An area of wall thickening measuring 7mm x 4mm x
3mm was noted in the neck region of the gallbladder. Microscopic
examination revealed characteristics indicative of acute gangrenous
cholecystitis. Regarding the wall thickening in the neck area described
macroscopically, histopathology confirmed the presence of heterotopic
pancreatic tissue composed of acini and ducts (exocrine pancreatic
tissue only; no islets of Langerhans were detected). There was no
evidence of malignancy or dysplasia in any of the sections examined.

\textbf{Discussion}

EPT is a rare entity; however, its actual incidence in the gallbladder
is unidentified, as a lack of clinical symptoms can complicate the
diagnosis (5). It can occur anywhere, but the most common locations are
the stomach (27.5\%), duodenum (25.5\%), colon (15.9\%), jejunum, and
spleen (6). By contrast, the presence of EPT in the gallbladder, lung
mediastinum, liver, mesentery, and ileum is considered extraordinary (2,
7). EPT can be diagnosed in any age group, but most cases are between
40-60 years old. Albeit the male-to-female ratio of any other type of
EPT is 3:1, there is a female predominance, specifically for EPT in the
gallbladder, which may be due to the fact that cholecystitis-related
cholecystectomies are more prevalent in women (2, 8). The etiologies of
EPT are still unclear, but three hypotheses about its origin have been
proposed. The first theory, which is widely accepted, suggests that EPT
separates from the primitive pancreas gland during the rotation of the
gastrointestinal tract in the embryogenic period. The second theory
suggests that the longitudinal growth of the intestine from the lateral
budding of the rudimentary pancreas tissue while penetrating the
intestinal wall causes the irregular transportation of the pancreatic
tissue (9, 10). The third theory supports that abnormalities in the
notch signaling system can result in changes in different foregut
endoderm tissue during embryogenesis (11). Jean Schultz first described
the heterotropic pancreas in the 18th century; however, the first
classification was made by Von Heinrich et al. in 1909, which was later
modified by Fuentes in 1973 that consisted of four types (12):

\begin{enumerate}
\tightlist
\item
  Type \emph{one} : acini with ducts and islet-like pancreatic gland
  (normal pancreatic tissue)
\item
  Type \emph{two} : canalicular variant pancreatic duct
\item
  Type \emph{three} : exocrine pancreas with acinar tissue
\item
  Type \emph{four} : endocrine pancreas with cellular islets
\end{enumerate}

According to what is mentioned above, this case is compatible with type
three (figure1-3).

These ectopic pieces of tissue macroscopically can appear as an
exophytic mass, similar to polypoid lesions, or as a nodule with a
yellow-colored appearance with sizes varying from a few millimeters to
even 4cm (13). Still, they are generally asymptomatic and only
discovered histopathologically. However, in some cases, it can cause
various nonspecific symptoms, depending on the location. Symptoms can
include jaundice if obstructing bile ducts or biliary colic-like
symptoms (e.g., right upper quadrant pain, anorexia, nausea, and
vomiting after meals); nevertheless, such symptoms presumably result
from simultaneous lithiasic cholecystitis. Other conditions can be
derived from EPT, such as cholelithiasis, acute or chronic
cholecystitis, or carcinoma (2, 10).

As Sato et al. reported that pancreatic enzymes (amylase and lipase)
secreted from EPT in the gallbladder could impact its mucosa leading to
gallbladder dysplasia and carcinoma. Therefore, cases with EPT in the
gallbladder must undergo cholecystectomy as a definite treatment
preventing any potential malignant transformation. Moreover, EPT can
potentially cause the same pathologies as typical pancreatic tissue,
which includes cysts, pseudocysts formation, abscess, and acute or
chronic pancreatitis (14, 15).

Diagnosing EPT in the gallbladder before and during an operation is
impossible. Preoperative radiologic evaluation (ultrasound or computed
tomography scan) usually cannot detect EPT in the gallbladder; neither
this case did (16). Therefore, only a precise histopathologic
examination can provide a definite diagnosis; consequently, it's
essential for anatomical pathologists to be aware of this uncommon
presentation of EPT in gallbladder to discriminate it from a
masquerading malignancy.

\textbf{References}

1. Wla\selectlanguage{polish}ź \selectlanguage{english}J, M\selectlanguage{polish}ą\selectlanguage{english}dro A, Ka\selectlanguage{polish}ź\selectlanguage{english}mierak W, Celi\selectlanguage{polish}ń\selectlanguage{english}ski K, S\selectlanguage{polish}ł\selectlanguage{english}omka M. Pancreatic and
gastric heterotopy in the gastrointestinal tract. Advances in Hygiene
and Experimental Medicine. 2014;68:1069-75.

2. Al-Shraim M, Rabie ME, Elhakeem H, Kandeel A, Shah MT, Jamil S.
Pancreatic heterotopia in the gallbladder associated with chronic
cholecystitis: a rare combination. JOP Journal of the Pancreas.
2010;11(5):464-6.

3. Bau P, Lucchese A, Hohmann F, Da Silva V, Marcal J. Ectopic
pancreatic tissue in a gallbladder. SOJ. 2016;3(3):1-2.

4. Sanchiz Cardenas EM, Soler Humanes R, Lavado Fernandez AI, Diaz Nieto
R, Suarez Munoz MA. Ectopic pancreas in gallbladder. Clinical
significance, diagnostic and therapeutic implications. Rev Esp Enferm
Dig. 2015;107(11):701-3.

5. Koukourakis IM, Perente Memet MS, Kouroupi M, Simopoulos K. Ectopic
pancreatic tissue adherent to the external gallbladder wall. Case
Reports in Gastroenterology. 2018;12(1):170-5.

6. Dolan RV, ReMine WH, Dockerty MB. The fate of heterotopic pancreatic
tissue: a study of 212 cases. Archives of Surgery. 1974;109(6):762-5.

7. Filip R, Walczak E, Huk J, Radzki RP, Bie\selectlanguage{polish}ń\selectlanguage{english}ko M. Heterotopic
pancreatic tissue in the gastric cardia: a case report and literature
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8. Aborajooh E, Ghayada IKK, Lafi YMI. Heterotopic pancreas in the
gallbladder: case report and literature review. Case Reports in
Medicine. 2021;2021.

9. Pilloni L, Cois A, Uccheddu A, Ambu R, Coni P, Faa G. Complete
pancreatic heterotopia of gallbladder with hypertrophic duct simulating
an adenomyoma. World Journal of Gastroenterology: WJG. 2006;12(11):1786.

10. Elpek G\selectlanguage{ngerman}Ö, Bozova S, Küpesiz GY, Ö\selectlanguage{polish}ğ\selectlanguage{ngerman}ü\selectlanguage{polish}ş \selectlanguage{english}M. An unusual cause of
cholecystitis: heterotopic pancreatic tissue in the gallbladder. World
Journal of Gastroenterology: WJG. 2007;13(2):313.

11. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate
control and signal integration in development. Science.
1999;284(5415):770-6.

12. Trifan A, T\selectlanguage{ngerman}ârcoveanu E, Danciu M, Hu\selectlanguage{polish}ţ\selectlanguage{english}ana\selectlanguage{polish}ş\selectlanguage{english}u C, Cojocariu C, Stanciu
C. Gastric heterotopic pancreas: an unusual case and review of the
literature. J Gastrointestin Liver Dis. 2012;21(2):209-12.

13. Klimis T, Roukounakis N, Kafetzis I, Mouziouras V, Karantonis I,
Andromanakos N. Heterotopic pancreas of the gallbladder associated with
chronic cholecystitis and high levels of amylasuria. JOP Journal of the
Pancreas. 2011;12(5):458-60.

14. Sato A, Hashimoto M, Sasaki K, Matsuda M, Watanabe G. Elevation of
pancreatic enzymes in gallbladder bile associated with heterotopic
pancreas. A case report and review of the literature. JOP Journal of the
Pancreas. 2012;13(2):235-8.

15. Rezvani M, Menias C, Sandrasegaran K, Olpin JD, Elsayes KM, Shaaban
AM. Heterotopic pancreas: histopathologic features, imaging findings,
and complications. Radiographics. 2017;37(2):484-99.

16. Kondi-Paphiti A, Antoniou A, Kotsis T, Polimeneas G. Aberrant
pancreas in the gallbladder wall. European radiology. 1997;7:1064-6.

\textbf{Figures' legend:}

Figure1. \emph{(x10, a)} and \emph{(x40, b)} Heterotopic pancreatic
islands consists of exocrine pancreas with acinar glands \emph{arrow
heads} and pancreatic ducts \emph{arrows.}

Figure2. Small pancreatic ducts \emph{arrows} with adjacent atrophic
gallbladder mucosa \emph{asterisk (x10)}

\textbf{Hosted file}

\verb`fig 1a.docx`  available at \url{https://authorea.com/users/638731/articles/654405-ectopic-pancreatic-tissue-ept-in-a-cholecystectomy-specimen-a-rare-incidental-pathologic-finding}

\textbf{Hosted file}

\verb`fig 1b.docx`  available at \url{https://authorea.com/users/638731/articles/654405-ectopic-pancreatic-tissue-ept-in-a-cholecystectomy-specimen-a-rare-incidental-pathologic-finding}

\textbf{Hosted file}

\verb`fig 2.docx`  available at \url{https://authorea.com/users/638731/articles/654405-ectopic-pancreatic-tissue-ept-in-a-cholecystectomy-specimen-a-rare-incidental-pathologic-finding}

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