Gallbladder carcinoma

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Introduction0:00–0:42

. With gallbladder carcinoma, gallbladder refers to the small pear-shaped organ that stores bile beneath the liver, while carcinoma refers to a malignant tumor arising from epithelial cells.
In fact, most gallbladder carcinomas are adenocarcinomas, meaning the cancer develops from the glandular epithelial cells that line the gallbladder.
Overall, gallbladder carcinoma is the most common malignancy of the extra hepatic biliary tract. Now, to understand gallbladder carcinoma, first, let's look at the gallbladder.
The gallbladder is a small pear-shaped organ that stores the digestive fluid called bile produced by the liver. The bile contains bile acids, phospholipids, cholesterol, and bilirubin, and its main function is to digest fats in the intestine.

Pathophysiology and symptoms0:42–3:29

Now, the gallbladder is lined by simple columnar glandular epithelial cells that help concentrate bile and secrete protective mucus.
Normally, this epithelium regenerates itself in an orderly fashion. Surface cells shed into the lumen while new ones migrate upward to replace them.
This process is tightly regulated by genes controlling cell growth and death. Now, when something tips the tightly controlled regeneration of the mucosal layer, the glandular epithelial cells begin dividing uncontrollably.
The result is gallbladder carcinoma, most often adenocarcinoma, which typically arises in the gallbladder fundus. Gallbladder adenocarcinoma is more common in biological females and often occurs in the 7th decade of life.
Now there are several reasons why this might occur, but the biggest risk factor is gallstones, which are present in most cases.
However, keep in mind that although gallstones are common, only a tiny fraction of people with gallstones develop carcinoma.
The problem is not the stones themselves, it's the constant irritation they cause as they rub against the gallbladder wall, they trigger chronic inflammation, which is the key driver of mutations that lead to carcinoma.
In addition to mechanical irritation from gallstones, chemical irritation from bile acids can damage DNA, adding to the risk of mutations that lead to cancer.
Over time, chronic inflammation can cause calcium to deposit in the gallbladder wall, forming a porcelain gallbladder, which significantly increases the risk.
Other risk factors include bacterial or parasitic infections and primary sclerosing cholangitis, a condition causing inflammation and scarring of bile ducts.
One thing ties all these risk factors together, and that's chronic inflammation. Repeated injury and repair make the mucosal cells more likely to accumulate mutations.
But this process does not happen overnight. Instead, gallbladder carcinoma arises from precursor lesions.
First, there's intestinal metaplasia, where chronic inflammation causes normal gallbladder cells to change into more resilient intestinal type cells.
Next, we have flat lesions with dysplasia, where the cells become progressively abnormal and disorganized. Finally, there's intracholecystic papillary tubular neoplasm, where cells organize to create a mass lesion that can progress to invasive cancer.

Treatment3:29–9:34

As they accumulate more mutations, any of these lesions can progress to carcinoma. When speaking about mutations, there's actually a mix of mutations that push cells to grow out of control.
One major player is the EGF receptor family, including HER2, which sits on the cell's surface and acts as a sensor. When it detects growth signals, it passes the message inside the cell and activates downstream messengers like RAS proteins.
These proteins carry a message to the nucleus which then turns on genes that tell the cell to divide and grow. When there are gain of function mutations in genes that encode HER2 and RAS proteins, the cell produces faulty proteins that keep signaling the cell to divide.
It's like the gas pedal is stuck down. On the other hand, the tumor suppressor gene TP53 normally acts as a brake, stopping cell division when things go wrong.
With loss of function mutations in the TP53 gene, the brake pedal fails, allowing damaged cells to multiply. That's why many cancers, including gallbladder carcinoma, show anuploidy, meaning abnormal numbers of chromosomes.
Under the microscope, gallbladder adenocarcinomas show gland-like structures buried in the dense fibrous tissue known as desmoplastic stroma.
The cells themselves look abnormal with irregular dark staining nuclei, which is a feature known as cystologic atypia. Now as the cells invade surrounding tissue, they can grow in two main patterns.
First, we have the infiltrating type, which is more common. In this case, the cells spread diffusely through the wall, making the gallbladder thick, firm, and poorly defined.
The second one is the exophytic type, which is less common. Here the cells grow into the lumen, creating an irregular cauliflower-like mass that can block the cystic duct.
In both cases, cells can spread through the gallbladder wall and invade the liver, surrounding organs, and peritoneum. Also, they can spread along the bile ducts or to the lymph nodes of the portahepatis.
Now in the early stages, most individuals are asymptomatic. However, as carcinoma grows, it can start causing symptoms that look a lot like gallstones.
These include right upper quadrant abdominal pain, jaundice, nausea, vomiting, and malaise. Unlike the occasional sharp pain from gallstones after meals, the pain in gallbladder carcinoma tends to hang around and slowly get worse.
Sometimes it can mimic cholecystitis or inflammation of the gallbladder with fever and tenderness. In later stages, individuals often lose their appetite and report unintentional weight loss.
Finally, on physical exam, you might notice a palpable, painless gallbladder in the presence of jaundice, which is known as the Corsier sign.
As far as diagnosis goes, gallbladder carcinoma can be tricky to spot. Labs often reveal elevated alkaline phosphatase and bilirubin, which suggest bile duct obstruction and injury.
Also, tumor markers like cancer antigen 199 and carcinoembryonic antigen can be elevated, but they are not specific enough to confirm the diagnosis.
That's why imaging is the key. Ultrasound might reveal a thickened gallbladder wall, calcifications, gallbladder polyps, or a protruding mass.
In some cases, widespread calcifications might be seen throughout the gallbladder wall, which is a classic finding known as porcelain gallbladder.
Additionally, a CT scan can provide a clearer picture showing how far the tumor has spread. However, CT scans can miss distant spots and metastases, and that's where the PET scan comes into action.
Since the early stages are silent, gallbladder carcinoma can also be found incidentally, for example, during surgery for gallstones.
If caught early before it spreads, surgical resection can help and potentially cure a person. Unfortunately, most of the time, gallbladder carcinoma is diagnosed late when the cancer has already spread.
In these cases, treatment primarily relies on symptom relief and chemotherapy, which can help slow down the progression.
Alright, as a quick recap, most gallbladder carcinomas are adenocarcinomas, meaning they arise from glandular epithelial cells.
Gallbladder adenocarcinoma is typically found in the fundus and represents the most common extrahepatic biliary tract malignancy.
The key driver is chronic inflammation, usually from gallstones, which repeatedly injures the mucosa and promotes mutations.
Microscopically, adenocarcinomas show gland-like structures buried in the desmoplastic stroma with cytologic atypia. Macroscopically, they can be infiltrating, spreading diffusely through the wall, making the gallbladder thick or exophytic, forming a protruding cauliflower-like