gallbladder



OVERVIEW

Definition

Gallbladder cancer refers to a malignant tumor that develops in the epithelium of the gallbladder.

It can occur anywhere in the gallbladder, including the base of the gallbladder, the body, the neck, and the cystic duct. It is prone to infiltrative metastasis to the hilar and hepatic parenchyma.

Staging and Classification

Broad types

It can be categorized into three types.

Infiltrative type: the most common, accounting for about 80%, can be divided into localized infiltrative type and diffuse infiltrative type.

Intraluminal growth type: also known as exophytic type, accounting for about 15%; the tumor may be polypoid, cauliflower-like or nodular protruding into the gallbladder cavity, with little peripheral infiltration.

Mixed type: manifested as thickening, rigidity and atrophy of the gallbladder wall, which may invade the surrounding tissues and organs and at the same time grow into the gallbladder cavity to form a mass.

Histopathologic classification

According to the WHO 2010 edition of the histopathologic types of gallbladder cancer, it can be classified as follows:

The most common pathologic type is adenocarcinoma. Others include adenosquamous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, tumors of neuroendocrine origin and tumors of mesenchymal tissue origin.

Although some tumors are benign lesions, their biological behavior is between benign and malignant, and they need to be closely followed up after surgery.

Clinical classification

In clinic, according to the origin site of gallbladder cancer, it can be divided into gallbladder cancer at the base of gallbladder, body and neck, with the proportion of 60%, 30% and 10% respectively.

There are differences in the organs and tissue structures invaded by the tumor and the prognosis of progressive gallbladder cancer in different tumor sites, and the surgical methods and scope should be adjusted accordingly to the tumor sites.

Incidence situation

The incidence of gallbladder cancer in China is as follows:

It accounts for 0.4%-3.8% of biliary tract diseases in the same period.

It ranks 6th among digestive tract tumors.

Etiology

Causes

Risk factors

About 85% of gallbladder cancer patients are combined with gallbladder stones.

The risk of gallbladder cancer in patients with gallbladder stones is 13.7 times higher than that in people without gallbladder stones.

The diameter and number of gallbladder stones are positively correlated with the development of gallbladder cancer.

The risk was higher for cholesterol and mixed cholesterol gallbladder stones.

Gallbladder polyps with malignant tendency have the following characteristics:

≥10 mm in diameter;

Combination of gallbladder stones and cholecystitis;

Solitary polyps or non-tipped polyps with rapid polyp growth (>3 mm in 6 months);

Adenomatous polyps.

Chronic inflammation of the gallbladder accompanied by heterogeneous calcification or punctate calcification within the mucosal glands is considered precancerous.

Calcification of the gallbladder wall may result in the formation of porcelain gallbladders, which are highly associated with gallbladder carcinogenesis in approximately 25% of cases.

After “biliary lithotripsy”, the risk factors for stone formation and gallbladder inflammation are not eliminated, and the stones are prone to recurrence, again with the possibility of cancer.

Possible risk factors

Abnormal confluence of pancreatic and biliary ducts is a kind of congenital abnormality, pancreatic fluid flows backward into the gallbladder, and long-term chronic inflammation stimulation causes repeated regeneration and repair of the mucosa, which ultimately leads to malignant transformation of the gallbladder.

About 10% of patients with gallbladder cancer combine with pancreaticobiliary duct confluence variant.

About 6% of patients with adenomyosis of gallbladder combined with gallbladder cancer.

Early surgery is recommended when gallbladder adenomyosis is combined with gallbladder stones or when preoperative imaging cannot determine whether gallbladder adenomyosis is cancerous, especially when the gallbladder wall thickness is >10 mm.

Chronic infection of the biliary system increases the risk of gallbladder cancer. Common causative organisms are Salmonella and Helicobacter pylori, and the pathogenesis may be related to the degradation of bile acids and metabolites induced by persistent inflammation caused by the bacteria.

Metabolic syndrome due to obesity can increase the risk of gallbladder cancer. Diabetes mellitus is a risk factor for the formation of gallbladder stones, and the synergistic effect of diabetes mellitus and stones promotes the development of gallbladder cancer.

The incidence of gallbladder cancer tends to increase with age.

The incidence of gallbladder cancer in women is two to six times higher than that in men.

Women with early menarche, late menopause, and multiple pregnancies have an increased risk of gallbladder cancer, which may be related to estrogen promoting cholestasis and stone formation.

Patients with primary sclerosing cholangitis combined with gallbladder stones, cholecystitis, and gallbladder polyps have increased risk of gallbladder cancer.

Those with a family history of gallbladder cancer have an increased risk of developing gallbladder cancer; those with a family history of gallbladder stones also have an increased risk of developing gallbladder cancer.

Smoking is an independent risk factor for gallbladder cancer, with a linear positive correlation with dose and duration of smoking.

The levels of aflatoxin and heavy metals (nickel, cadmium, chromium, etc.) in the peripheral blood of patients with gallbladder cancer are higher than those of healthy people, which may be related to the release of β-glucuronidase by bacteria or chemical free toxins that directly

may be related to the release of β-glucuronidase or chemical free toxins by bacteria that directly contact the gallbladder mucosa, inducing carcinogenesis.

Pathogenesis

At present, the pathogenesis of gallbladder cancer is not fully understood, and it is mostly believed to be related to environmental and genetic factors.

The time from gallbladder stones to the occurrence of gallbladder cancer is 10-15 years or even longer, which indicates that gallbladder stones cause gallbladder cancer as a result of long-term physical stimulation.

Symptoms

Common symptoms

Early gallbladder cancer has no specific symptoms, some of which may include abdominal discomfort, loss of appetite or weight loss, etc., but they are often concealed by cholecystitis, gallbladder stones and their complications.

Symptoms in middle and late stages

Once gallbladder cancer develops obvious symptoms, it is mostly in middle or late stage, which can be manifested as jaundice, fever and abdominal pain, etc. Physical examination can find jaundice and right side of the right side of the gallbladder.

Physical examination may find jaundice and right upper abdomen mass.

Consultation

Department of Medicine

Gastroenterology

Gastroenterology is the department of choice when symptoms such as abdominal discomfort, loss of appetite or weight loss occur.

General Surgery

If ultrasound or other tests indicate that you have gallbladder stones, gallbladder polyps, or gallbladder space, we recommend that you visit the Department of Hepatobiliary Surgery or the Department of General Surgery.

Oncology

If you are diagnosed with this disease, you can also go to the Department of Oncology or Medical Oncology.

Preparation for medical treatment

Preparation for medical consultation: registration, preparation of documents, common problems

Tips for the doctor

The doctor will usually conduct a physical examination. It is recommended to choose loose and suitable clothes for the examination.

Preparation Checklist

Pay particular attention to the time of onset of symptoms and special manifestations.

Any pain or discomfort in the upper abdomen? Any nausea, loss of appetite, etc.?

Is there any change in the color of urine or stool?

Are there any black stools or blood in the stool?

Any recent unexplained weight loss, fever or fatigue?

Is there any family history of gallbladder cancer or other malignant tumors?

Do you have gallstones, choledochal cysts, cholangitis, hepatitis, etc.?

Are there any other associated diseases?

Are there any drug or food allergies?

Test results in the last six months, which can be brought to the doctor’s office

Specialized examination: Tumor marker report.

Imaging examination: abdominal ultrasound, endoscopic ultrasound, CT, magnetic resonance imaging (MRI) and other imaging examination reports.

Routine examination: blood routine report, biochemical examination report, etc.

Other examinations: PET-CT, etc.

Diagnosis

Diagnosis is based on

Medical history

History of gallbladder stones.

Chronic inflammation of the gallbladder.

History of polypoid lesions of the gallbladder, etc.

Clinical manifestations

Patients may present with abdominal discomfort, loss of appetite or weight loss.

In patients with intermediate to advanced stages, they may present with jaundice, fever and abdominal pain.

Physical examination may reveal jaundice and a mass in the right upper abdomen, with pressure pain under the rib margin and percussion pain in the liver area.

Examination

Elevated serum CA19-9 and/or carcinoembryonic antigen (CEA) are commonly used tumor markers for diagnosing gallbladder cancer.

CA125, CA724, CA153, etc. are also tumor markers to assist in the diagnosis of gallbladder cancer.

Ultrasonography is the examination method of choice for initial screening and dynamic follow-up observation of gallbladder diseases, and uneven thickening of the gallbladder wall and intracystic masses are the most common imaging manifestations.

Endoscopic ultrasonography can accurately show the mass in the gallbladder lumen, the structure and depth of the infiltrating cystic wall, and the invasion of the liver and biliary tract.

Endoscopic ultrasound-guided cytologic puncture pathology biopsy can identify the benign and malignant nature of gallbladder lesions.

Multi-slice spiral CT examination has a diagnostic accuracy of about 90% and can show the extent of gallbladder wall invasion, whether adjacent organs are involved and lymph node metastasis.

Magnetic resonance imaging (MRI) examination has an overall accuracy of about 90%.

Magnetic resonance cholangiopancreatic imaging can clearly show the anatomical relationship between the pancreatic and biliary ducts, and the sensitivity of showing bile duct obstruction is close to 100%, with an accuracy of more than 90%.

Dynamic enhancement MRI combined with angiography can clarify the size of the tumor, the degree of liver invasion, vascular invasion, abdominal lymph node metastasis and distant metastasis.

Positron emission tomography (PET) is highly sensitive to gallbladder cancer and can detect early stage lesions of gallbladder cancer, such as metastatic lymph nodes and metastatic foci with a maximum diameter of less than 1.0 cm.

When there are suspicious findings in CT or MRI, PET-CT is generally recommended.

Staging

TNM staging

Currently, TNM staging of gallbladder cancer is a staging system jointly developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC), which is mainly based on the four elements of T, N, M and G. The staging system is based on the four elements of T, N, M and G:

T: represents the extent of the primary tumor, mainly referring to the size of the primary tumor foci and the degree of extravasation.

N: represents the situation of regional lymph node metastasis, the regional extent of metastasis.

M: represents the situation of distant metastasis.

G: represents the grading of the tumor, which is related to the differentiation, nuclear division and necrosis of the tumor.

Tis: carcinoma in situ.

T1a: invasion of the lamina propria.

T1b: invasion of the muscularis propria.

T2a: abdominal side of the tumor invades the perimuscular connective tissue without going beyond the plasma membrane.

T2b: hepatic side of the tumor invades the perimuscular connective tissue without invading the liver.

T3: penetration of the plasma membrane and/or direct invasion of the liver and/or an adjacent organ or structure.

T4: invasion of the portal vein or hepatic artery trunk, or direct invasion of two or more extrahepatic organs or structures.

N0: no regional lymph node metastasis.

N1: 1 to 3 regional lymph node metastases.

N2: ≥4 regional lymph node metastases.

M0: no distant metastasis.

M1: distant metastasis.

Special reminder: TNM and G will be followed by Arabic numerals 1-4, etc. The larger the number, the more serious the disease.

Overall staging

Based on the different TNM stages, a final overall stage (prognostic grouping) is determined for the total number of patients, which is indicated by the Roman letters Ⅰ, Ⅱ, Ⅲ and Ⅳ stage.

According to the combination of TNM stages, gallbladder cancer can be categorized into the following stages:

Stage IIB

T2b, N0, M0

Stage IIIA T3, N0, M0

Stage IIIA

T3, N0, M0

IIIB stage T1-3, N1, M0

Stage IIIB

T1～3、N1、M0

Stage IVA T4, N0～1, M0

Stage IVA

T4、N0～1、M0

Stage IVB any T, any N, M1

Stage IVB

Any T, any N, M1

Differential Diagnosis

Gallbladder cancer may need to be differentiated from yellow granulomatous cholecystitis, hepatocellular carcinoma invading the gallbladder, hepatoportal cholangiocarcinoma with atrophic cholecystitis, and other diseases before the diagnosis is confirmed.

Special reminder: It is difficult to differentiate the above diseases by clinical manifestations, and imaging or pathologic examination is usually needed for further diagnosis.

Treatment

Surgical treatment

Radical resection

Radical resection surgery is the only possible cure for gallbladder cancer.

The specific surgical method needs to be considered according to the tumor stage and the patient’s physical condition.

Generally, patients with Tis or T1a stage can undergo simple cholecystectomy. For patients with other stages, combined liver resection may be needed, and the specific plan needs to be determined according to the patient’s own condition.

T4 stage gallbladder cancer combined with distant metastasis (i.e., M1 stage) generally cannot undergo radical surgery.

Palliative surgical treatment

For patients with advanced gallbladder cancer, the most important thing is to improve patients’ quality of life and prolong survival time.

Palliative tumor reduction surgery is generally not performed, while surgical and interventional treatments are limited to relieving biliary obstruction and gastrointestinal obstruction.

Chemotherapy

Preoperative neoadjuvant chemotherapy

At present, neoadjuvant chemotherapy for gallbladder cancer is still in the exploratory research stage. The aim is to downstage after chemotherapy in order to increase the surgical resection rate.

Suitable cases:

Neoadjuvant chemotherapy is recommended before secondary surgery for gallbladder cancer diagnosed after surgery when the lymph nodes of the cystic duct are positive.

For locally progressive gallbladder cancer [invasion of liver and/or lymphatic metastasis], neoadjuvant chemotherapy may be considered.

Postoperative adjuvant chemotherapy

In general, patients with stage T2 or above, positive lymph nodes or R1 resection can benefit from adjuvant chemotherapy.

The following regimens are recommended in the Guidelines for the Diagnosis and Treatment of Gallbladder Cancer (2019 Edition):

Capecitabine monotherapy.

Gemcitabine combined with oxaliplatin.

Gemcitabine combined with Tegretol, etc.

Effectiveness of chemotherapy

The results of several prospective randomized controlled clinical studies have confirmed that chemotherapy prolongs survival in unresectable gallbladder cancer.

Gemcitabine combined with Tegio regimen has an overall efficacy rate of 30% and a tumor control rate of 70% in advanced gallbladder cancer. However, adverse reactions such as nausea, vomiting and bone marrow suppression are mild.

The efficacy of gemcitabine combined with cisplatin regimen was similar to that of the combined Tegio regimen. For those with abdominal cavity and abdominal wall metastasis, peritoneal heat infusion chemotherapy is effective in controlling extensive tumor metastasis and carcinomatous ascites.

Radiotherapy

Preoperative radiotherapy

It is suitable for the following situations:

Patients with deeper tumor sites, larger tumors, and difficulty in simple surgical resection.

Although the tumor is not big, it has obvious infiltration and adhesion to the surrounding tissues, and there are local lymph node metastases, which are difficult to be radically resected by surgery alone.

Intraoperative radiotherapy

It can well protect normal tissues, isolate normal organs under direct vision, and perform radiotherapy only for the operation field of radical gallbladder cancer resection, which can achieve radical effect.

Postoperative radiotherapy

It is applicable to the following situations:

People with high risk of recurrence after radical resection of gallbladder cancer with T2 stage or above, R1 resection or positive lymph nodes.

Patients after palliative surgical treatment for gallbladder cancer and tumor recurrence.

Palliative radiotherapy

Through palliative radiotherapy, some patients can relieve the symptoms and prolong the survival period.

It is mainly applied to patients whose gallbladder cancer is large in scope and cannot be radically resected, or whose disease stage is late and the possibility of cure is small.

Immunotherapy

Current studies show that in patients with unresectable or recurrent gallbladder cancer, some patients may benefit from treatment with the immune checkpoint inhibitors karelizumab or navulizumab.

Prognosis

Survival

The prognosis of gallbladder cancer is related to clinical stage.

The majority of gallbladder cancers have a poor prognosis, with an overall 5-year survival rate of no more than 5% and 80% of patients surviving no longer than 1 year after surgery for gallbladder cancer.

Only the early gallbladder cancer confined to mucosa and submucosa has a better outcome after surgery, nevertheless, the 5-year survival rate after surgery is only 40%~60%.

Special reminder] The overall survival time of cancer patients can be roughly predicted by 5-year survival rate, which refers to the proportion of patients who survive for more than 5 years after various comprehensive treatments for their tumors.

Prognostic factors

The prognosis of gallbladder cancer is related to the differentiation of the tumor, location, invasion range (size of tumor volume), stage, age, whether the diagnosis is early or not, whether the treatment is timely and reasonable, the effect of chemotherapy and other factors.

Metastasis

75% of gallbladder cancer can directly invade the surrounding organs, and the frequency of occurrence is liver, bile duct, pancreas, stomach, duodenum, omentum and colon in order.

60% have lymphatic metastasis, about 15% have distant metastasis, and less than 20% have peritoneal metastasis.

Spreading along nerve sheath is one of the characteristics of hepatobiliary system cancer, and nerve invasion occurs in nearly 90% of patients with progressive gallbladder cancer, which is the main cause of pain caused by this disease.

Daily

Daily management

Mindfulness and emotional adjustment

Good emotion and mindset cannot be replaced by drugs.

After diagnosis, the patient may develop a sense of fear and may be afraid of pain, abandonment and death. Family members should pay attention to listen to the patient’s heart, improve the patient’s mental ability and relieve anxiety symptoms.

Encourage the patient’s family to give support so that the patient can face the surgery and other treatments positively with a good mindset.

During the period between treatments and after treatments, family members encourage the patient to do work and household chores that are within his/her ability to reintegrate into his/her social roles.

Dietary regulation

The dietary structure is balanced, with diversified and nutritious food types.

Pickled, fried and deep-fried foods should be avoided.

Eat more vitamin-rich vegetables and fruits, such as broccoli, tomatoes, celery, lettuce, kiwi, apples and bananas.

Eat more protein-rich foods, such as eggs, milk, lean meat and fish. It is recommended not to eat foods that stimulate the secretion of gastric acid, such as foods that are too sweet and spicy.

Follow-up review

After radical resection of T1N0M0 stage gallbladder cancer patients, it is recommended to review every 3 months within 1 year and every 6 months after 1 year. Other stages of gallbladder cancer should be reviewed every 3 months.

After radical resection of gallbladder cancer, patients who need adjuvant treatment or palliative treatment for gallbladder cancer should receive treatment and follow-up according to the treatment cycle.

Special reminder: The above recommendations are for reference only, please strictly follow the doctor’s instructions for the specific time of review, and consult the doctor at any time if there is any discomfort.

Prevention

General preventive measures

Eat a light diet and less food with high fat content, e.g. no fatty meat and fried food.