Pyloric gland adenoma of the cystic duct with malignant transformation: report of a case with a review of the literature
© Schaefer et al.; licensee BioMed Central Ltd. 2012
Received: 22 September 2012
Accepted: 29 November 2012
Published: 4 December 2012
Pyloric gland adenoma consists of closely packed pyloric-type glands lined by mucus-secreting cells. To date, approximately 230 cases have been reported, mostly of gastric localization with a tumour size up to 3.5 cm and a mean age of occurrence around 70 years. Adenocarcinoma develops in about 40% of cases and may be difficult to detect due to relatively mild nuclear atypia.
We present the first case of a pyloric gland adenoma of the cystic duct in a 62-year-old male patient and demonstrate the clinicopathologic characteristics, including radiographic, molecular, and cytogenetic findings. The 2 cm-tumour developed in the cystic duct and protruded into the hepatic and common bile duct. On microscopic examination, it displayed closely packed pyloric-type glands, and focal architectural distortion with mild nuclear atypia. Immunohistochemically, it expressed MUC1, MUC5AC, MUC6 and p53, but not MUC2 and CD10. The Ki67-proliferation index was 25%. Furthermore, high-grade intraepithelial neoplasia was observed in the surrounding bile duct. We detected chromosomal gains at 7p, 7q11q21, 15q, 16p, 20, losses at 6p23pter, 6q, 18, and amplifications at 1q and 6p21p22 in the pyloric gland adenoma by comparative genomic hybridization. A KRAS codon 12 mutation (c.35G>T; p.G12V) was detected in the pyloric gland adenoma and in the adjacent dysplasia by sequencing analysis. The diagnosis of pyloric gland adenoma was established with transition into well-differentiated adenocarcinoma and high-grade biliary intraepithelial neoplasia.
Pyloric gland adenoma evolving in the cystic duct is a rare differential diagnosis of obstructive bile duct tumours. Other premalignant bile duct lesions may be associated. Due to the risk of developing adenocarcinoma, surgical resection should be performed.
KeywordsPyloric gland adenoma Adenocarcinoma Cystic duct Comparative genomic hybridization (CGH) KRAS mutation
Pyloric gland adenoma was first described in 1976 by Kurt Elster. At that time, a neoplasm was not recognized, but since 1990 pyloric gland adenoma has been categorized as a distinct neoplastic entity in the WHO classification of gastric tumours [1–3]. In the approximately 230 previously reported cases, the lesion was mostly localized in the stomach (69%), followed by gallbladder (14%), duodenum (12%), esophagus, gastroesophageal junction, bile duct, pancreatic duct, and rectum (together <5%) [2–15]. In the stomach, the pyloric gland adenoma accounts for <3% of gastric polyps . Extra-gastric cases are even rarer and their incidence is not known . However, pyloric gland adenoma is reported to be the most common type of benign epithelial neoplasm of the gallbladder, although it rarely occurs in the extrahepatic bile ducts . The lesion occurs in patients with a mean age of approximately 70 years, with a reported mean tumour size of 0.6-3.5 cm, and a slight female predominance [2–15]. It harbors the risk of malignant transition into adenocarcinoma, occurring in up to 47% of cases of all locations . The diagnosis of pyloric gland adenoma can be established according to the histological criteria proposed by Watanabe et al.: closely packed pyloric-type glands, lined by cuboidal or columnar mucus-secreting cells with round or oval, relatively small, hyperchromatic nuclei with a parabasal location; so-called lateral expansion or fusion of neighboring foveolae indicate adenocarcinoma .
Three cases of pyloric gland adenoma of the common bile duct have up to now been reported . Here, we present the first reported case of pyloric gland adenoma evolving in the cystic duct, with transition into well-differentiated adenocarcinoma, and associated high-grade intraepithelial neoplasia of the adjacent bile duct. The clinico-pathologic characteristics, including radiologic as well as molecular and cytogenetic findings, will be demonstrated with a review of the literature.
After a four-week interval for weight reduction, ERCP was re-performed and the stent was removed. Fluoroscopic guidance with contrast application revealed the tumour in the middle part of the common bile duct. After obtaining biopsies from the tumour, a stent was inserted again for drainage until the operation. Endosonography located the tumour in the common bile duct (Figure 1D) and the cystic duct, protruding into the infundibulum of the gallbladder. A suspect lymph node was detected between bile duct and cystic duct.
Histopathological examination revealed tubulo-papillary neoplastic proliferations and closely packed glandular structures with eosinophilic cytoplasm, round to oval nuclei and inconspicuous nucleoli. At the surface, small papillary proliferations were observed. Focally, marked architectural distortion with nuclear atypia, hyperchromatic nuclei with prominent nucleoli, and a back-to-back formation of stellar glands were present. Squamous morules were not observed. The diagnosis of a pyloric gland adenoma with possible transition into well-differentiated adenocarcinoma was established and confirmed by reference pathology.
In the meantime the patient developed a thrombosis of the right cephalic vein after catheter infection and a non-ST-elevation myocardial infarction, which were treated non-interventionally with antibiotics and heparin for prolongation of the prothrombin time. Two weeks later, resection of the extrahepatic bile ducts including gallbladder with biliodigestive anastomosis was performed.
Number of cases
Malignancy developing in PGA
MUC6 (= M2)
Pancreas (main duct)
Heterotopic gastric corpus mucosa
PAS, negative: Alcian blue, chromogranin, serotonin, somatostatin, gastrin
KRAS exon 1 (p.G12R; c.34G>C)
Heterotopic gastric corpus mucosa
MUC5AC (= M1), MUC6 (= M2)
Pancreas (main duct)
PCS, HIK1083, negative: neuroendocrine markers, hormones
KRAS exon 1, codon 12
Pancreas (branch duct)
PAS, negative: Alcian blue
73/F:M = 3:1
Stomach (n =77 ), duodenal bulb (n = 7), duodenum (n = 1), common bile duct (n = 3), gallbladder (n = 2)
Gastritis (A-, B-, and C-type) (20-34%), tubular adenoma (n = 1), carcinoid tumour (n = 1), adenocarcinoma (n = 1)
Heterotopic gastric corpus mucosa
MUC6, MUC5AC, negative: MUC2, CD10
CGH: losses at 2p24p25.2, 2q14.1pter, 5q31.3q32, 6q23q24, 8q23q24.2,11q22.3q24, 18q21.1q22
41 tumours, 36 patients
73/F:M = 25:11
Stomach (19), duodenum (19), gastroesophageal junction (2), pancreas (1)
Gastritis (A-type) (40%), intestinal metaplasia (60%)
MUC6, MUC5AC, negative: CDX2, MUC2
Intestinal metaplasia (34.4%), squamous morules (24.1%)
MUC6, MUC5AC, M-GGMC-1, morules: CDX2, beta-catenin
MUC6, MUC5AC (MUC2, CD10), p53 and Ki67 in malignant transition
MUC6, MUC5AC, negative: MUC2
MUC5AC, MUC6, VEGF, p53, p21, Ki67, (MUC1, p16), negative: MUC2, CD10, CDX2
KRAS exon 1 (p.G12V; c.35G>T); CGH: gains at 1q, 6p11p22, 7p, 15q, 20p, and losses at 6p23pter, 6q14qter, 11q12q13, 18
Histopathological differential diagnoses of polypous intraductal bile duct lesions include adenomas of the gallbladder and extrahepatic bile ducts. They can be divided into a tubular, papillary, and tubulopapillary type based on their growth pattern, and cytologically into a pyloric-gland, intestinal, foveolar, and biliary type . IPN of gastric, pancreatobiliary, intestinal or oncocytic phenotype, and mucinous cystic neoplasms should also be considered . Furthermore, concomitant intraductal papillary mucinous neoplasms (IPMN) [5, 13] have been observed in cases of pancreatic pyloric gland adenomas. In the pancreas, gastric-type IPMN are usually located as small cystic lesions in branching ducts, harboring only mild/low-grade atypia and immunohistochemically expressing MUC5AC, but not MUC1, MUC2 or CDX2. They are associated with a rather favorable clinical prognosis compared to the other subtypes of IPMN ; adenocarcinoma occurs in 10-15% . Invasive adenocarcinoma may also develop in IPN of the bile duct . BilIN of the gallbladder and extrahepatic bile ducts are associated with lithiasis in up to 3%, familial adenomatous polyposis coli, sclerosing cholangitis, and pancreatobiliary reflux . Additionally, BilIN-3 usually arises in a association with pyloric and intestinal metaplasia, as observed in the present case, with an abrupt transition between normal and atypical columnar cells . As reported, BilIN immunohistochemically also expresses p53 .
KRAS codon 12 mutations have been previously reported in two cases of pyloric gland adenoma of the main pancreatic duct, and probably support the neoplastic nature of this tumour [4, 5]. KRAS (13-100%) and TP53 (50%) mutations have been described for IPMN of the pancreas before . Also in the present case, the pyloric gland adenoma and the BilIN-3 harbored a KRAS codon 12 mutation, indicating a possible metaplasia-dysplasia-carcinoma sequence with a common tumourigenesis.
Previous CGH results of a pyloric gland adenoma of the esophagus revealed chromosomal aberrations which overlapped with findings in Barrett’s dysplasia and adenocarcinoma as well as gastric cardia adenocarcinoma . In pyloric gland adenomas of the stomach, previous CGH analyses revealed chromosomal abnormalities common to invasive gastric adenocarcinoma, including -5q (50%), -6 (40%), -4q, +17pq and +20 [18, 20]. Additional gains were observed at 1, 3q, 5q, 7, 9q, 11q, 12q, 13q, 15q, 17 and 22q, and losses at 1p, 2q, 4, 9p, 10, 12q 13q, 14q, 16, 18q, 20q, and 21 . Of these aberrations, gains at 7p and 15q, and losses at 6q, and 18q were also detected in the present case. Interestingly, losses at 6q and 18q have been demonstrated in pancreatic IPMN, before . Furthermore, the amplicon at 6p21p22 harbors the VEGF (VEGF-A) gene at 6p21.1 (MIM ID *192240) which was shown to be expressed by the pyloric gland adenoma by immunohistochemical staining, suggesting VEGF upregulation. VEGF plays a crucial role in angiogenesis of normal tissues and several types of tumours . Altogether, the relatively high number of chromosomal imbalances in the present case of pyloric gland adenoma of the cystic duct suggests an instable karyotype and underlines the risk of malignant transformation.
In conclusion, a pyloric gland adenoma evolving in the cystic duct is very rare, but may sometimes be overlooked and therefore should be considered as a differential diagnosis for obstructive bile duct tumours. An association with other premalignant bile duct lesions such as BilIN may be observed. ERCP-guided biopsy with histopathological examination is necessary to establish the diagnosis. Due to the high risk of evolving adenocarcinoma, surgical resection should be performed whenever possible.
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Series Editor of this journal.
The authors thank Sabine Schäfer, Radiology group practice Göttingen, Germany, for providing radiographic images.
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