GALLBLADDER CARCINOMA

-mostly in the 6th or 7th decade

-female-to-male ratio is 1.77
-accounts for 51% of all cancers arising in the biliary tract in women and 28% in men.
-incidence varies geographically and in different ethnic groups

ETIOLOGY
-most important risk factors:
Genetic background
Gallstones
-present in >80% of gallbladders harbouring carcinoma but the overall incidence of gallbladder
carcinoma in patients with cholelithiasis is <0.2%
Abnormal Choledopancreatic Junction

-diffuse calcification of the gallbladder wall (porcelain gallbladder) is present in <1% of cholecystectomy
specimens and 8-10% of such resected specimens harboring a carcinoma

-some studies have suggested that selective mucosal calcification poses significant risk while diffuse
intramural calcification does not.

-a small number of patients with FAMILIAL ADENOMATOUS POLYPOSIS (FAP) will develop dysplasia and
carcinoma of the gallbladder.

-inflammatory disorders ulcerative colitis and primary sclerosing cholangitis have also been reported to be
associated with carcinoma of the gallbladder.

CLINICAL FEATURES

-close to 50% are diagnosed incidentally in cholecystectomy specimens from patient’s with symptoms
attributed only to the presence of gallstones (cholelithiasis)

-usually, presents at late stage, even when found incidentally.

-signs and symptoms are nonspecific, often like in chronic cholecystitis

-RUQ pain is common symptom

-CT Scan and ultrasonography aid in detection of neoplasm.

-less than 1% of patients present with paraneoplastic syndrome that may be the manifestation of the
neoplasm.

-adenocarcinomas are reported to be associated with ACANTHOSIS NIGRICANS, BULLOUS PEMPHYGOID-TYPE

LESIONS, THE LESTER-TRELAT SIGN, DERMATOMYOSITIS AND GBS.
MACROSCOPY

-usually forms an infiltrating grey-white mass

-some carcinomas cause diffuse thickening and induration of the entire gallbladder wall.
-the gallbladder may be distended by the tumor or collapsed owing to obstruction of the neck or cystic duct.
-can also assume an hourglass deformity when neoplasm arises in the body and constricts the lateral walls.
-carcinomas arising in association with intracystic papillary neoplasms are usually sessile and exhibit a polypoid
or cauliflower-like appearance.
-Mucinous and signet ring cell carcinomas have a mucoid or gelatinous cut surface.

ADENOCARCINOMA, BILIARY TYPE

-well- to moderately differentiated invasive adenocarcinomas of bilary type are the MOST COMMON
MALIGNANT EPITHELIAL NEOPLASMS OF THE GALLBLADDER.
-composed of short or long tubular glands lined by cells that vary in height from cuboidal to tall columnar,
superficially resembling biliary epithelium
-cytoplasmic and luminal mucin is frequently present.
-rarely, the extracellular mucin may become calcified.
-about 1/3 of well-differentiated adenocarcinomas show FOCAL INTESTINAL DIFFERENTIATION AND CONTAIN
GOBLET CELL AND NEUROENDOCRINE CELLS.
these neuroendocrine cells sometimes immunoreactive for SEROTONIN and PEPTIDE HORMONES
But a diagnosis of neuroendocrine neoplasm is not warranted.
-adenocarcinomas may contain OSTEOCLAST-LIKE GIANT CELLS or SHOW FOCAL CRIBRIFORM or
ANGIOSARCOMATOUS PATTERNS.
-may contain cyto- and synctio-trophoblast cells.
-gallbladder adenocarcinomas tend to be more poorly differentiated and show less desmoplasia that their
counterparts in the extrahepatic bile ducts.

-MOST ADENOCARCINOMAS OF THE GALLBLADDER immunoreactive with CEA, MUC1, MUC2, p53 and
kerain 7.

ADENOCARCINOMA, INTESTINAL TYPE

-2 morphological variants of invasive adenocarcinoma of intestinal type have been described in the
gallbladder.
-THE MOST COMMON is composed of TUBULAR GLANDS CLOSELY RESEMBLING THOSE OF COLONIC
ADENOCARCINOMAS.
 the glands are lined predominantly by columnar cells with pseudostratified ovoid or elongated
nuclei

-the 2nd variant consists of glands lined predominantly of goblet cells usually with a variable number of
neuroendocrine and Paneth cells.

-Both variants label with antibodies to CDX2, MUC2, CEA and keratin 20.
ADENOCARCINOMA, GASTRIC FOVEOLAR TYPE
-this unusual but distinctive, well-differentiated variant is composed of tall columnar cells with basally oriented
nuclei, and abundant mucin-containing cytoplasm.

-usually labels with antibodies to MUC5A.

-combined forms (adenocarcinoma or adenosquamous carcinoma with foveolar differentiation) have been
reported in the gallbladder.

ADENOSQUAMOUS CARCINOMA
-the extent of differentiation of the 2 malignant components, glandular and squamous, varies but in general
they tend to be moderately differentiated.
-Keratin pearls are often present in the squamous component, and mucin is usually demonstrate in the
neoplastic glands.

CARCINOSARCOMA
-the epithelial (carcinomatous) elements usually predominate in the form of glands but may be arranged in
cords and sheets.
-foci of squamous differentiation are reported
-sarcomatous component can include heterologous elements such as chondrosarcoma, osteosarcoma, and
rhabdymyosarcoma.
-Keratin and CEA are absent from the mesenchymal component, helping distinguish carcinosarcomas from
undifferentiated spindle and giant cell carcinomas.

CRIBRIFORM CARCINOMA
-a distinctive invasive neoplasm of the gallbladder that resembles cribriform carcinoma of the breast
-accounts <1% of all gallbladder carcinomas
-PATIENTS ARE YOUNGER THAN THOSE WITH CONVENTIONAL ADENOCARCINOMA OF THE GALLBLADDER AND
-USUALLY associated with CHOLELITHIASIS.
-typical cribriform growth
-high grade tumors have large vesicular nuclei with prominent nucleoli and show come-type necrosis.
-IN CONTRAST TO CRIBRIFORM CARCINOMAS OF THE BREAST, gallbladder carcinomas are NEGATIVE FOR ER
AND PR receptors and behave aggressively like conventional adenocarcinomas of the gallbladder

CLEAR CELL ADENOCARCINOMAS

-rare malignant neoplasm
-composed predominantly of glycogen-rich clear cells with well-defined cytoplasmic borders and central
hyperchromatic nuclei arranged in glandular or other growth patterns.
-some cells contain eosinophilic granular cytoplasm
-foci of conventional adenocarcinoma with mucin production are usually found and can distinguish primary CA
from metastatic clear cell adenocarcinomas of the kidney
-exclusion of RCC is also accomplished with PAX8
-in some clear cell adenocarcinomas, the columnar cells contain subnuclear and supranuclear vacuoles similar
to those seen in secretory endometrium
-production of ALPHA-FETOPROTEIN has been documented in CCC with or without hepatoid differentiation.
HEPATOID ADENOCARCINOMA
-exceedlingly rare neoplasm of the gallbladder
-closely mimics hepatocellular carcinoma
-FOR DIAGNOSIS, >50% of the neoplasm SHOULD BE COMPOSED OF HEPATOID CELLS USUALLY IN
TRABECULAR PATTERN.
-the neoplastic hepatoid cells label with HepPar1 antibody and rarely with alpha fetoprotein
-the biological behavior of hepatoid adenocarcinoma appears to be similar to that of conventional
adenocarcinoma

MUCINOUS ADENOCARCINOMA
-more common in the gallbladder than in extrahepatic bile ducts
-BY CONVENTION, >50% of the tumor contains EXTRACELLULAR MUCIN.
-should be distinguished from a benign mucocele.
-the abundant extracellular mucin present in a mucocele may be recognized grossly in the gallbladder wall as
nodules of different size.
-the mucin can extend to the serosa through the ROKITANSKY-ASCHOFF SINUSES and induce a histiocytic
response
-the histiocytes may phagocytize mucin and be confused with signet ring cells.
-IHCS for KERATIN AND CEA are POSITIVE in mucinous carcinoma and negative in mucocele.
-ruptured, mucin-containing, rokintansky-aschoff sinuses with abundant extracellular mucins having small
benign glandular and papillary structures should not be confures with mucinous carcinoma

SIGNET CELL RING CARCINOMA

-cells containing intracytoplasmic mucin displacing the nuclei toward the periphery predominates in this
variant
-variable amount of extracellular mucin is present
-lateral spread through the lamina propria is a common features
-a diffusely infiltrating linear pattern resembling linitis plastica (diffuse-type adenocarcinoma) of the stomach
has been observed

SQUAMOUS CELL CARCINOMA

-composed entirely of squamous cells with highly variable degrees of differentiation.
-keratinizing and nonkeratinizing types exist
-spindle cells predominate in some poorly differentiated SCCA which may be confused with sarcomas
-IHCS with KERATIN AND P63 may clarify the diagnosis in these spindle-cell cases
-may arise from areas of squamous metaplasia or high grade intraepithelial neoplasia.
-most gallbladder carcinomas with squamous differentiation represent adenosquamous carcinomas, and the
glandular component may be very focal

UNDIFFERENTIATED CARCINOMA
-more common in the gallbladder than in the extrahepatic bile ducts
-characteristically, glandular structures are few or absent
-there are several histologic variants: spindle cell, giant cell (including those with osteoclast-like giant cells),
small cell (non-neuroendocrine), and a nodular/lobular type that superficially resembles breast carcinoma
-the recently described benign giant cell tumour of the biliary tree, a true histiocytic neoplasm, can be
distinguished from CA with osteoclast-like giant cells with IHCS like CD163, CD68 , HAM56 and KERATIN
PRECURSOR LESIONS

(1) ADENOMA
-benign neoplasm of glandular epithelium that are typically POLYPOID, SINGLE and WELL-DEMARCATED.
-more common in WOMEN than in men
-mostly occurs in ADULTS
-found in 0.3-0.5% of gallbladders removed for cholelithiasis or chronic cholecystitis
-often small, asymptomatic, and usually discovered incidentally during cholecystectomy, but they can be
multiple, fill the lumen of the gallbladder and be symptomatic.
-occasionally adenomas of the gallbladder occur in association with PEUTZ-JEGHERS SYNDROME or GARDNER
SYNDROME
-divided into THREE TYPES ON THE BASIS OF GROWTH PATTERNS
(1) tubular
(2) papillary
(3) tubulopapillary

-cytologically, they are classified as:

(1) pyloric-gland type
(2) intestinal type
(3) foveolar type
(4) biliary type

-PYLORIC AND INTESTINAL TYPE ADENOMAS are more common in the gallbladder than in the extrahepatic
ducts
-A SMALL PROPORTION OF ADENOMAS PROGRESS TO INVASIVE CARCINOMA

-TUBULAR ADENOMA, PYLORIC-GLAND TYPE (PYLORIC GLAND-TYPE ADENOMA) is the most common variant of
gallbladder adenoma.

-composed of lobules of closely packed pyloric-type glands, some of which may be cystically dilated, often
covered by normal biliary epithelium

-squamoid morules characterized by nodular aggregates of cytologically bland spindle cells with eosinophilic
cytoplasm but no keratinization are also seen.

-paneth cells and neuroendocrine cells are often present.

-BY DEFINITION, PYLORIC-GLAND ADENOMAS HAVE AT LEAST LOW-GRADE INTRAEPITHELIAL NEOPLASIA.

-larger adenomas may have HIGH-GRADE INTRAEPITHELIAL NEOPLASIA or may be associated with foci of
invasive carcinoma.
-as they enlarge, some develop a pedicle and project into the lumen
-rarely, they extend into or arise from ROKITANSKY-ASCHOFF SINUSES, a finidng that should not be mistaken
for invasive carcinoma.
INTESTINAL-TYPE ADENOMA
-rare benign neoplasm composed of dysplastic tubular glands lined by cells with an intestinal phenotype,
which closely resembles colonic adenomas.

FOVEOLAR-TYPE ADENOMA
-has a tubulopapillary architecture and consists of tall columnar with small basal hyperchromatic nuclei with
abundant mucin-containing cytoplasm.
-rarely arise from epithelial invaginations of adenomyomatous hyperplasia
-label with antibodies to MUC5AC and occasionally MUC6

-there is also exceedingly rare BILIARY TYPE ADENOMA lined by cytologically normal-appearing biliary
epithelium.

BILIARY INTRAEPITHELIAL NEOPLASIA

-characterized by atypical epithelial cells with multilayering of nuclei and micropapillary projections into the
gallbladder lumen
-the atypical cells have an increased nucleus-to-cytoplasm ratio, partial loss of nuclear polarity, and nuclear
hyperchromasia.
-BIN-1 and BIN-2 correspond to low grade and intermediate grade lesions and BIN-3 corresponds to high grade
lesions.

-the incidence of BIN-3 parallels that of invasive carcinoma and it prevalence is higher in countries in which
gallbladder carcinoma is endemic than in countries in which it is sporadic.

-The incidence of BIN-3 in gallbladders with lithiasis varies from 0.5-0.3%. This variation in the incidence of
BIN3 is partially attributable to a lack of uniformity in morphological criteria and sampling methods

-in addition to cholelithiasis, BIN3 occurs in the mucosa adjacent to most invasive carcinoma and can be found
in patients with FAP, sclerosing cholangitis and pancreatobiliary reflux

-BIN is usually NOT RECOGNIZED ON MACROSCOPIC EXAMINATION because it often occurs in association with
chronic cholecystitis.
-the mucosa may be granular, nodular, plaque-like, or trabeculated.

-BIN1 and 2 of the gallbladder is characterized by mild cytoarchitectural atypia including enlargement of cells,
pseudostratification of nuclei and hyperchromatism.

-typically detected incidentally and is of no established clinical significance.

-BIN3 usullay arises in the background of pyloric and intestinal metaplasia.

-occasional goblet cells are found in 1/3 cases
-abrupt transition between columnar cells of normal appearance and dysplastic cells is seen in NEARLY OF ALL
CASES.
-five cell phenotypes are recognized: BILIARY, INTESTINAL, ONCOCYTIC, SQUAMOUS, AND SIGNET RING CELL
-when associated with invasive cancer, the morphological type of BIN3 does not always correspond with that
of the carcinoma.
-may arise from or extend into ROKITANSKY ASCHOFF SINUSES, a feature that should not be considered with
stromal invasion.
-if BIN3 is present, multiple sections should be take to exclude invasive cancer.
-the dysplastic cells are positive for CEA, S100 A4, CA19-9 and p53.
-CHOLECYSTECTOMY WITH NEGATIVE MARGINS IS A CURATIVE SURGICAL PROCEDURE FOR PATIENTS WITH
BIN3 OR WITH INVASIVE CARCINOMA LIMITED TO THE LAMINA PROPRIA.

-BIN is often encountered in the setting of chronic cholecystitis and may coexist with reactive epithelial
changes.
-In contrast to BIN, these changes (atypia of repair) involve a heterogenous cell population containing
columnar mucous secreting cells, low cuboidal cells, atrophic appearing epithelium and pencil-like cells.
-reactive changes show gradual transition between cellular abnormalities, in contrast to abrupt transition in
BIN3