primary liver cancer
Introduction
Introduction to primary liver cancer Primary carcinoma (the primary cancer) is one of the common malignant tumors in China. The mortality rate ranks third in the digestive system malignant tumors. China's annual death from liver cancer is about 110,000, accounting for 45% of the world's liver cancer deaths. Because of the detection of serum alpha-fetoprotein (AFP) combined with ultrasound imaging for high-risk population monitoring, liver cancer can be diagnosed in the sub-clinical stage, and the long-term effect of early resection is particularly significant. Coupled with active comprehensive treatment, the five-year survival rate of liver cancer has been significantly improved. The disease can occur at any age, up to 40 to 49 years old, and the ratio of male to female is 2 to 5:1. basic knowledge Sickness ratio: 2% Susceptible population: The disease can occur at any age, with a maximum of 40 to 49 years old, and the ratio of male to female is 2 to 5:1. Mode of infection: non-infectious Complications: hepatic encephalopathy gastrointestinal bleeding
Cause
Cause of primary liver cancer
Drug factors (10%):
Aflatoxin has a strong carcinogenic effect on rats, ducks, guinea pigs and other animals. Animal experiments have shown that aflatoxin B1 is the strongest carcinogen in liver cancer. Epidemiological investigations have found that in some areas with high incidence of liver cancer, grain oil, food (such as corn, wheat, soybeans, peanuts, etc.) are often contaminated with aflatoxin B1, but less common in low-incidence areas. These all suggest that aflatoxin may be a frequent cause of liver cancer in some areas, but so far there is no direct evidence for human liver cancer. It has recently been reported that epidemiological investigation of aflatoxin has nothing to do with liver cancer and remains to be further studied.
Chemical carcinogenic factors (10%):
Animal experiments have shown that some chemicals such as nitrosamines and azobenzene can cause liver cancer in many animals. In some soils and water sources in high-incidence areas of liver cancer, nitrates and nitrites were found to be high. Nitrite can form nitrosamines under acidic conditions in the stomach. The relationship between these chemical carcinogens and liver cancer is worthy of attention and research.
Parasitic infections (15%):
The Chinese branch of the sinus parasitizes the intrahepatic small bile duct, stimulates the proliferation of the bile duct epithelial cells, and some can develop cancerous and become cholangiocarcinoma. Because it is seen in the section from the proliferation of the bile duct epithelial cells to the various stages of cancer, it is considered Liver cancer is produced by physical or chemical stimulation of parasitic infections. However, most cholangiocarcinomas do not have liver fluke infection, so there may be other reasons. The liver cells of cirrhosis with schistosomiasis are mostly atrophied without obvious hyperplasia, so it rarely causes liver cancer.
Genetic factors (15%):
Liver cancer can sometimes have a family aggregation phenomenon, many of which live together and have blood relationship. Many scholars believe that the cause of family aggregation may be caused by the vertical transmission of mother and child of viral hepatitis. (2) The trace elements are detected from the high-incidence soil, drinking water, food, human hair and blood, respectively. The trace elements are found to be higher in copper and zinc, and the key is lower. The relationship between trace elements copper, zinc and liver cancer is noteworthy. (3) Malnutrition and Nutritional Lack of nutrition and cancer are major issues in human health in the 1990s and have received attention from all walks of life. Its role is to accelerate or slow down - cancer in the cancer-promoting phase. High-fat and pickled and smoked foods are most closely related to tumors. It is advisable to eat more vegetables, fruits and miscellaneous grains. Animal experiments have confirmed that high-fat diet, hypoproteinemia, methionine and biliary deficiency can cause hepatocyte necrosis, fatty changes, cirrhosis and liver cancer. If the feed is rich in protein, methionine and B vitamins, liver cancer delays or does not occur.
Pathogenesis
1. The general shape and classification of liver cancer
The appearance of liver cancer nodules is mostly spherical, and the boundary is not very regular. There may be "satellite nodules" around the tumor. The cancer nodules near the capsule in the peripheral part of the liver generally protrude from the surface but have no central depression. The nodules of the cancer nodules are grayish white. Some may be yellow due to steatosis or necrosis, may be green due to more bile, or reddish brown due to hemorrhage. Hemorrhagic necrosis is more common in the central part of the large nodules, and the texture of the cancer nodules is related to histological type. The solid cancer surface is homogeneous, smooth and soft; the beam-shaped cancer surface is dry and granular; the cholangiocarcinoma is dense due to the rich collagen fiber, the liver cancer volume is obviously increased, and the weight can reach 2000-3000g, without The massive liver cancer of cirrhosis is larger and weighs more than 7000g. Most liver cancers have large nodular or mixed cirrhosis, and some portal veins and hepatic veins can be seen.
(1) Eggel classification in 1901: liver cancer is roughly divided into three types: massive type, nodular type and diffuse type.
1 large block type: the cancer tissue is massive, it can be single-shot, or it can be made up of many dense small nodules. It is usually more common in the right lobe of the liver, accounting for 73%, similar to expansive growth, surrounding There may be a pseudo-envelope formation, combined with mild cirrhosis, a higher rate of surgical resection, and a better prognosis, but it has been reported that the prognosis of massive liver cancer with "satellite nodules" is poor.
2 nodular type: liver cancer is composed of many nodules of different sizes, and can also be merged into large nodules by several nodules, often accompanied by obvious cirrhosis, low surgical resection rate and poor prognosis.
3 diffuse type: the least seen, mainly distributed by many cancer nodules in the whole liver, with cirrhosis, the prognosis is very poor, this traditional classification has been used so far, mainly for the liver with larger and more advanced liver cancer .
Visual observation of primary liver cancer has not only the above-mentioned different types, but also the way in which it occurs. Therefore, some scholars believe that the occurrence of liver cancer is multi-centered, that is, cancer is produced simultaneously or successively from different centers; The occurrence of cancer is single-centered, that is, there is only one center at the beginning of the cancer, and other nodules in the liver are the result of diffusion and metastasis. From a clinical point of view, no matter how the liver cancer occurs, Obviously, nodular and diffuse liver cancer is more serious, because the malignancy of this liver cancer is very high, and the lesion has already affected the two leaves of the liver, so the prognosis is the worst.
(2) Okuda Bonon (Japan) combines the growth of liver cancer to divide liver cancer into:
1 Inflated type: The cancer has a clear boundary and a capsule formation. There are single nodules or multiple nodules, often accompanied by cirrhosis.
2 invasive type: the border of cancer is unclear, most of them are not associated with cirrhosis.
3 mixed type: in addition to invasive type of cancer with invasive liver cancer, also divided into single nodular and multi-nodular.
4 diffuse type: small diffuse small nodular carcinoma of the liver, nodules more than 1cm in diameter, distributed throughout the liver.
5 special type: such as pedicle exogenous type, intrahepatic portal vein tumor thrombus without parenchymal cancer, etc., the pathological manifestations of liver cancer in different regions are different, such as Japan with more swelling type, North America with infiltration type, South Africa's liver cancer often Not accompanied by cirrhosis.
(3) The current classification criteria for liver cancer in China: The National Hepatocellular Pathology Coordination Group proposed the following classifications based on the Eggel classification, namely diffuse type, block type (including monolithic, fused block, multi-block), knot Type (including single nodules, fusion nodules and multiple nodules), small cancer type.
1 diffuse type: cancer nodules are small, diffuse distribution, this type is easy to be confused with cirrhosis.
2 block type: the diameter of the cancer is >5cm, of which >10cm is a giant block type, which can be divided into 3 subtypes.
A. Monoblock type: Single cancerous block with clear or irregular boundaries and often envelope.
B. Fusion type: adjacent cancers are fused into a block, and there are scattered satellite cancer nodules in the surrounding liver tissue.
C. Multi-block type: formed by multiple monolithic or fused block cancers.
3 nodular type: cancer nodules > 5cm, can be subdivided into 3 subtypes:
A. Single nodular type: a single cancer nodule with a clear boundary and a small satellite nodule around it.
B. Fusion nodular type: irregular borders, scattered around satellite nodules.
C. Multi-nodular type: scattered throughout the liver with clear or irregular boundaries.
4 small cancer type: the diameter of a single cancer nodule is 3cm, or the sum of the diameters of two adjacent cancer nodules is 3cm, the boundary is clear, and there is often a clear envelope.
2. Organizational classification
According to the histological source of liver cancer, it is divided into 3 types:
(1) Hepatocellular carcinoma: the most common, most accompanied by cirrhosis, generally believed to be produced by parenchymal cells, accounting for 90% to 95% of liver cancer cases (91.5% in China), mainly found in males, cancer cells are polygonal, The nucleus is large and the nucleolus is obvious. The cytoplasm is granular, and it is eosinophilic. It is arranged in a cord-like or nest-like shape. Especially in the latter, sometimes bile droplets can be seen in well-differentiated cancer cells. There are abundant sinusoids, and cancer cells have a tendency to grow into the sinusoids (Fig. 1). Hepatocellular carcinoma is divided into cord-like/beam-like type, cord-like adenoid type, solid type and sclerotic type, the same case. Sometimes nodular hyperplasia can be seen. Different lesions such as adenoma and liver cancer exist at the same time, and often accompanied by cirrhosis.
(2) cholangiocarcinoma: more common in women, accounting for 30.8% of female liver cancer, according to its source can be divided into two types, one from the small bile duct, small cancer cells, clear cytoplasm, forming a gland of different sizes Cavity, interstitial and less sinusoids, this class is relatively common in the clinic, the other from the bile duct epithelium, cancer cells are large, often columnar, often forming a larger glandular cavity, this type is less common Cholangiocarcinoma does not secrete bile but secretes mucus (Fig. 2). Cholangiocarcinoma is generally classified into three types: tubular adenocarcinoma, squamous cell carcinoma, and papillary adenocarcinoma. Compared with hepatocellular carcinoma, cholangiocarcinoma cells Cancer often has no liver disease background, rarely accompanied by cirrhosis, cancerous mass is hard and no capsule, connective tissue is more, mainly lymphatic metastasis, clinical manifestations of early jaundice, fever, portal hypertension symptoms are rare, only About 20% of patients have a mild increase in AFP.
(3) Mixed type: less common, characterized by partial tissue morphology like liver cancer cells, some of which resemble cholangiocarcinoma cells. The two cellular components are separated from each other, some are mixed, and the boundary is unclear. Mixed liver cancer can be divided into Type, transitional, and hybrid subtypes.
(4) Ultrastructure: The ultrastructural features of liver cancer cells are:
1 cells are large, irregular in shape, the basement membrane of the vessel wall, the gap between the Disse is filled with glial fibers, the sinusoidal endothelial cells may be absent, the cancer cells are directly in contact with the blood, the capillary tubes are less, the structure is unclear, and the cell gap between the tubes is not The rule is widened, the relative cell membranes have microvilli of different sizes, and the widened gap can be connected to the Disse gap or the sinusoid;
2 The number and type of organelles are related to the differentiation of liver cancer. Highly differentiated cancer cells retain mitochondria, have more dilated rough endoplasmic reticulum, and more ribosomes. Sometimes the smooth endoplasmic reticulum is thread-like, called "fingerprint" or " "Myelin sheath", the cancer cells with low differentiation are reduced, the mitochondria are large and irregular, rare, sometimes with inclusion bodies, and the whole cells appear monotonous;
3 The cell nucleus is large, irregular, invaginated, the mucosa is rough, the perinuclear space is dilated, and even vesicles are formed, and the nucleolus is large, large and irregular.
Submicroscopic changes in relative characteristics:
1 pseudo-inclusion body; irregular nuclei of the nucleus, forming a capsular bag or lobulated shape, including the cytoplasm containing organelles;
2 myeloid bodies: concentric structures formed by mitochondria or endoplasmic reticulum remaining in secondary lysosomes.
In addition, some special substances can be found in liver cancer cells:
1 glycogen granules;
2 lipid droplets;
3AFP is concentrated in the rough endoplasmic reticulum;
4HBsAg is located in the smooth endoplasmic reticulum, HBcAg is located in the nucleus, and HCV-like particles are located in the nucleus.
3. Classification of hepatocellular carcinoma
There have been various clinical classification methods for primary liver cancer at home and abroad, such as Berman, which is divided into significant cancer type, acute abdomen type, fever type, occult type and metastasis type, with significant cancer type Most of them, domestic Zhong Xueli, etc., are classified into 10 types, namely hepatomegaly, liver abscess type, cirrhosis type, obstructive jaundice type, abdominal hemorrhage type, hypoglycemia type, cholecystitis and cholelithiasis type, chronic hepatitis type. Intra-abdominal cyst type and diffuse cancer type; Lin Zhaoqi and other increased leukemia-like and paraplegic type, a total of 12 types, these types of methods are based on the clinical manifestations of patients with advanced and advanced liver cancer, and It is not suitable for early patients without clinical symptoms. Therefore, due to the diversification of clinical manifestations of primary liver cancer, these patients should be asked for detailed medical history and physical examination, especially for patients with liver disease. .
According to the degree of differentiation of cancer cells, hepatocellular carcinoma is divided into four grades I, II, III and IV, of which grade I is highly differentiated, grades II and III are moderately differentiated, grade IV is poorly differentiated, and moderately differentiated. Hepatocellular carcinoma is most common.
Grade I: The morphology of cancer cells is similar to that of normal hepatocytes. It is generally arranged in a strip shape. The cytoplasm is eosinophilic, the nucleus is round, the size is regular, and nuclear division is rare.
Grade II: The morphology of cancer cells is slightly deformed, arranged in a strip or nest, the proportion of nucleoplasm is obviously increased, the cytoplasm is mildly basophilic, and bile droplets are often seen, and nuclear fission is increased.
Grade III: The cancer cells are obviously deformed, arranged in a nest, the proportion of nucleoplasm is increased, the cytoplasm is stained with eosinophilic, the bile droplets are rare, the size of the nucleus is irregular, the mitosis is common, and sometimes the cancerous giant cells are seen.
Grade IV: The cancer cells are obviously shaped, and the spindle cells and multinucleated giant cells are seen. The cytoplasm is less and the nucleus is deeply stained, the mitosis is more, the cells are arranged in disorder, and there are often no bile droplets.
4. TNM staging of hepatocellular carcinoma
UICC The TNM classification of primary liver cancer in 1987 is as follows:
The primary tumor of Tx is unknown, and T0 has no evidence of primary cancer.
T1: Single nodule 2cm, no vascular invasion.
T2: single nodule 2cm, invading blood vessels, or multiple confined one leaf, 2cm, not invading blood vessels; or single, > 2cm, not invading blood vessels.
T3: single nodule, > 2 cm, invading blood vessels; or multiple, limited to one leaf, 2 cm, invading blood vessels; or multiple, one leaf, > 2 cm, with or without vascular invasion.
T4: multiple nodules, one leaf beyond; or invasion of the main branch of the portal vein or hepatic vein.
N0: There is no metastasis in the local lymph nodes.
N1: There is local lymph node metastasis.
M0: No distant transfer.
Ml: There is a distant transfer.
On the basis of TNM classification, Japan divides liver cancer into 4 stages, stage I is T1N1M0; stage II is T2N0M0; stage III is T3N0M0 or T1~3N1M0; stage IVa is T4N0~1M0, stage IVb is T1~4N0Ml.
Studies have shown that I, II, III, IVa, IVb surgical resection rates were 100%, 82.7%, 76.3%, 51.4% and 50.0%, respectively; radical resection rate was 88.9%, 60.2%, 32.6%, 7.6% and 6.3%; the three-year survival rate after treatment was 88.2% in stage I, 60.0% in stage II, 28.0% in stage III, and 12.1% in stage IVa.
5. Special types of liver cancer
(1) Fibrous melanoma: Fibrola memellar carcinoma of liver is a special type of hepatocellular carcinoma discovered and recognized in recent years. It has many characteristics different from HCC:
More common in the youth;
2 few HBY infection backgrounds;
3 less associated with cirrhosis;
4AFP is often negative;
5 tumors are often single;
6 tumor growth is slow;
7 high surgical resection rate;
8 The prognosis was good regardless of resection or not, the median survival time HCC was 6 months, and the fibrolat type liver cancer was 32 to 68 months. The median survival time of surgically resected HCC was 22 months. For 50 months, the pathological diagnostic criteria for fibrolamellar liver cancer are:
1 strong eosinophilic granular cancer cell slurry;
2 There are a large number of parallel lamellar fibrous matrix in the nest of cancer cells. This type of liver cancer has a high proportion in liver cancer in western countries, but it is rare in China, Japan, Africa, etc. It has recently been found that its collagen matrix mainly contains collagen. I, III, V, cancer cells often express transforming growth factor 1 (TGF-1), while stromal cells express interleukin-6 (IL-6). Overexpression of these cytokines may be related to changes in collagen gene expression.
(2) Small liver cancer: Liver cancer with a single cancer nodule diameter or a diameter of two adjacent cancer nodules less than 3 cm is called small liver cancer. Compared with large liver cancer, small liver cancer has pathological features:
1 often a single nodule, it has been reported that only 3% of small liver cancers have satellite nodules, and the incidence of satellite nodules is often positively correlated with tumor size;
2 often forms a capsule, especially for swelling growth. If the tumor is less than 1cm, the capsule often does not form, because the liver cancer capsule is often formed when the tumor is about 1.5cm in diameter; the invasive growth is dominant, the tumor boundary Irregular and often without envelope formation;
3 The degree of differentiation is better, mostly Ed-mondson I to II. The degree of differentiation of cancer cells is often positively correlated with the size of the mass. As the mass increases, the degree of malignancy gradually increases.
4 flow cytometry suggests that small liver cancer DNA is often diploid, and grows to polyploid with increasing volume;
The prognosis of patients with small hepatocellular carcinoma after surgical resection was significantly better than that of non-surgical patients. The survival rates of one, two, three and four years after surgical resection of small hepatocellular carcinoma were 75%, 46.7%, 45.5% and 40%, respectively. 34.9%, 32.1%, 15.8% and 7.7%;
6 small hepatocarcinoma cells are of liver cancer cell type, the cell morphology and differentiation are extremely consistent, and there is very little hemorrhage and necrosis;
7 Intravascular thrombosis is rare in the naked eye, but intravascular thrombous tumors are common. Most of them are small clusters of liver cancer cells floating in the portal vein.
6. Liver disease background of liver cancer
Liver cirrhosis often occurs in China with liver cirrhosis. According to the data, HCC with cirrhosis is as high as 84.65%, cirrhosis with liver cancer is about 49.9%; among them, the incidence of massive nodular cirrhosis with liver cancer is as high as 73%, small nodular cirrhosis The incidence of liver cancer is 34.1%, so some people with large nodular cirrhosis are called liver cirrhosis related to liver cancer. Most of these cirrhosis comes from cirrhosis after hepatitis.
Liver cancer often has a background of HBV infection. According to statistical investigations, 90% of liver cancer patients in China have HBV infection background, and 10% have a history of HCV infection.
7. Liver cancer precancerous lesions
Precancerous lesions refer to a type of lesion that has a tendency to become cancerous, but does not necessarily evolve into cancer. Currently, precancerous lesions of liver cancer include hepatic dysplasia (DLC), adenomatous hyperplasia and cirrhosis.
The occurrence of tumors generally occurs in three stages of initiation, promotion and evolution. During the process of experimental hepatocarcinogenesis in rats, it is found that hepatocytes undergo gene mutation under the action of external carcinogenic factors, which is at the initiation stage of liver cancer, and occurs in liver cancer related genes. Abnormal activation and overexpression of early genes such as IGF-II, under the continuous action of carcinogenic factors, such cells develop into single-cell clones, which continue to multiply, at this time precancerous lesions, but the gene expression is basically stable and in the promotion phase; Subsequently, the precancerous lesions showed nuclear instability and gradually formed hyperplasia. The cells overexpressed protooncogene proteins such as G-myc, which evolved into liver cancer.
(1) Atypical hyperplasia of hepatocytes: Compared with normal cells, DLC has a significantly increased volume, about 2 to 3 times that of normal hepatocytes, and is closely arranged. The formed cell cord is thick, the cytoplasm is rich, and the nucleus is large and slightly Irregular, hematoxylin staining is deep, nuclear membrane is thick, chromatin distribution is uneven, nucleoli are large and obvious, and sometimes dual-nuclear, using flow cytometry, scanning microspectrophotometer, image analysis technology, etc. to determine intracellular DNA content, Staining protoploid analysis, nuclear area, nuclear irregularity index, etc. also found that DLC converges to liver cancer cells. Analysis of gene expression products revealed that GTPase and ATPase were significantly reduced or disappeared in DLC, oncogene products ras, myc, IGF-II Compared with normal liver cells, compared with liver cancer cells, DLC cytoplasmic eosin, nucleoplasm ratio is close to normal, no mitotic figures, nucleolar organizer silver staining protein is mostly in the normal range.
Watanabe divides DLC into two types: large cell and small cell, and small cell atypical hyperplasia tends to precancerous lesions. Its characteristics are mainly:
1 cytoplasm reduction;
2 cell bodies are smaller than normal liver cells;
3 The core is moderately increased and the nuclear/plasma ratio is increased.
In animal experiments of chemical carcinogenesis, it was found that there is an oval cell in the liver portal area, which is a kind of stem cell with multi-directional differentiation potential. Under normal circumstances, it can be transformed into hepatocytes and biliary epithelial cells, causing carcinogenic factors. It can be transformed into various types of cancer cells, stimulated oval cells with chemical carcinogens, and transduced ras gene, and then inoculated into mice, which can induce compound cancer, liver cancer, cholangiocarcinoma, epithelial-interstitial Various types of tumors such as cutaneous mixed tumors have demonstrated the differentiation potential of oval cells. Similar morphological oval cells have been found in human adjacent liver tissues and chronic active hepatitis tissues, but the mechanism of their outcome or transformation is still For further study.
(2) Cirrhosis: Many studies suggest that cirrhosis is closely related to the occurrence of liver cancer. Epidemiological data show that about 40% of liver cirrhosis with liver cancer in China, and liver cancer with liver cirrhosis up to 85%, especially large nodular liver Hardening combined with liver cancer up to 73%, the vast majority of liver cancer occurred on the basis of large nodular cirrhosis, from the molecular basis, liver cirrhosis and liver cancer have a certain degree of consistency, liver cancer The expression levels of IGF-I, IGF-II and its receptors were significantly increased in tissues, and other genes such as C-myc, N-ras, and ets-2 were overexpressed similarly to liver cancer cells, but different from normal hepatocytes. It is proved that the frequency of atypical hyperplasia in the lobes of cirrhosis is high. It is possible that the process of liver cancer cirrhosis is formed by the malignant evolution of DLC.
(3) adenomatous hyperplasia: the pathological feature of adenomatous hyperplasia is diffuse nodular changes in the liver, the liver can be normal, increase or decrease, using chemical carcinogens such as AFB1, diethylnitrosamine to induce cancer The liver may have adenoma-like hyperplasia. In the adenomatous hyperplasia liver tissue, atypical hyperplasia hepatocytes can be found. The follow-up investigation of patients with adenomatoid hyperplasia proves that some patients can develop liver cancer.
8. The malignant biological characteristics of liver cancer
Liver cancer cells are active, invasive, and rich in peripheral sinusoids. They are easy to invade the capsule and blood vessels, leading to local spread and distant metastasis. The incidence of liver cancer metastasis and disease progression, the biological characteristics of the tumor and the immunity of the body. The functions and other factors are closely related. There are intrahepatic metastasis and extrahepatic metastasis. The pathways of metastasis include hematogenous dissemination, lymphatic metastasis, direct infiltration and implant metastasis. The iatrogenic metastasis is related to the operation. The rupture of liver cancer can lead to a wide range of abdominal cavity. Metastasis, many cases can be transferred to the liver or other organs through the portal vein tumor thrombus at an early stage. The rate of intravascular tumor thrombosis in small liver cancer is 30%, so intrahepatic metastasis is the most common metastasis pathway for liver cancer. Cancer metastasis is not uncommon, and the transfer rate is about 40% to 71.6%.
(1) The metastasis pathway of liver cancer: The metastasis of liver cancer can be transferred to other organs or tissues through bloodways, lymphatics, direct dissemination, and local spread.
1 Hematogenous metastasis: Invasion of the liver into the portal vein is very common in the liver. It is more common in the sinusoids, fibrous tissue is scarce, and liver tissue without cirrhosis is more obvious. Therefore, multiple "satellite nodules" are often formed. The main organ of metastasis is the lung. The lung metastasis of liver cancer accounts for about 90% of the extrahepatic metastasis. The small tumor thrombus in the blood vessels enters the blood circulation and retains the lung to form metastatic cancer. The diameter of the metastatic nodules in the lung cancer is <1cm, and the dispersion is distributed. In the lobes of the lungs, it is often spherical, and the cut surface is grayish white. There may be bleeding and necrosis in the center. The bone metastasis of liver cancer is also common. The data reported in different places are inconsistent, ranging from 3% to 16.2%. The common sites are vertebrae, ribs and sternum, followed by pelvis. , the skull and the upper end of the femur, bone metastases can lead to pathological fractures, a small number of liver cancer can be transferred to the adrenal gland, kidney and brain.
2 lymphatic metastasis: about 30% of liver cancer cells and 70% of cholangiocarcinoma cells are metastasized by lymphatics, most of which are first transferred to the hilar lymph nodes, and a few can also be transferred to the peripancreatic, para-aortic, retroperitoneal, mediastinal and supraclavicular Lymph nodes.
3 disseminated metastasis: generally appear in the advanced stage of liver cancer, especially in the liver surface near the surface of the liver, often destroy the liver capsule, followed by implant metastasis, the most common is peritoneal metastasis.
4 local diffusion: liver cancer cells can directly invade and infiltrate the surrounding liver capsule, and the cancer nodules near the liver capsule can also infiltrate adjacent organs and tissues, such as diaphragm, stomach, colon, right chest.
(2) There are many factors affecting the metastasis of liver cancer, mainly including:
1 patient age: metastasis is more common under 30 years old, and occurs early and extensive.
2 degree of differentiation and invasiveness of liver cancer cells: those with low degree of differentiation are prone to metastasis.
3 Whether combined with cirrhosis: patients with cirrhosis are prone to metastasis, the metastasis rate is 84%, and the rate of metastasis without cirrhosis is 60%.
In recent years, it has been found from molecular level analysis that 67% of MMP-2 mRNA is significantly increased in invasive liver cancer, and MMP-2 is also expressed in different degrees. However, only 20% of MMP-2 mRNA is expressed in intact hepatoma cells. 30% MMP-2 expression was positive; MMP-2 positive rate of liver cancer with tumor thrombosis or metastasis (83.3%) was significantly higher than that of non-metastatic liver cancer (37.5%) (P<0.01), and microvessels of cancer tissue with intrahepatic metastasis Density (MDV), PCNA was significantly higher than those without intrahepatic metastasis. In addition, the expression levels of nm23, MDV, MMP-2, and PCNA in hepatocellular carcinoma cells were related to the metastasis of hepatocellular carcinoma, which could be used as a reference for progression, treatment options, and prognosis. index.
Prevention
Primary liver cancer prevention
prevention
Active prevention and treatment of viral hepatitis is of great significance in reducing the incidence of liver cancer. The preventive injection of hepatitis B virus inactivated vaccine not only has an effect on the prevention and treatment of hepatitis, but also plays a certain role in the prevention of liver cancer. Avoid unnecessary blood transfusions and blood products. Preventing mildew from food, improving the quality of drinking water, and refraining from drinking alcohol are also important measures to prevent liver cancer. When primary prevention of liver cancer is not yet perfected, early detection, early diagnosis, and early treatment of liver cancer are called "secondary prevention" in oncology. Since the implementation of liver cancer screening, the diagnosis of primary liver cancer has entered the subclinical level, the proportion of early liver cancer is increasing, and the 5-year survival rate is also significantly improved. Since the 1980s, high-risk subjects with liver cancer (history of chronic hepatitis or HBsAg over 35 years old) have been screened by detection of AFP and ultrasound, and many early liver cancers have been detected. After early diagnosis and early treatment, they have been effectively reduced. The mortality rate of liver cancer.
Population prevention
Liver cancer is one of the most common malignant tumors in China. There are about 110,000 new cases each year, accounting for about 40% of the world's cases. Control the incidence of liver cancer, reduce mortality, the current prevention and treatment of liver cancer has been included in China's prevention focus. Population prevention for liver cancer is focused on primary prevention and census or screening.
1. Primary prevention of liver cancer
It is aimed at preventing the occurrence of liver cancer, which is to prevent people from being exposed to known carcinogenic factors and risk factors. According to the research on the etiology of liver cancer, China has adopted the strategic measures of pipe water, tube food, and hepatitis prevention in areas with high incidence of liver cancer, or implemented control of hepatitis, control of grain and mildew, appropriate amount of selenium supplement, and improved drinking water. Primary prevention. details as follows:
(1) Treatment of water pipes and improvement of drinking water hygiene
Organic matter pollution in drinking water is related to the occurrence of liver cancer. Studies suggest that drinking highly contaminated surface water, chlorinated water, and high concentrations of chloroform water increase the risk of cancer, which may come from a variety of carcinogens that have additive and synergistic effects in drinking water contamination. There are also studies suggesting that drinking water and HBV carrying status have a significant synergistic effect on the onset of liver cancer.
At present, it has been found that drinking water in high-incidence areas of liver cancer contains various carcinogens. Although the individual carcinogenic content of these polluted water bodies is very small, the concentration of all carcinogens can reach the threshold of carcinogenesis after long-term small intake, so many scholars It is believed that changing water, water, and improving drinking water hygiene may help reduce the incidence of liver cancer. In recent years, residents of Qidong County have strengthened drinking water management. Most residents have changed the drinking water quality to meet the health standards. The survey shows that the incidence of liver cancer has dropped significantly. Fusui County combined with farmland water conservancy construction, the county has improved drinking water in a large area, and most of the residents drink deep well water and water, and have received good results.
(2) Strengthening the anti-mold and detoxification of grain, oil and food
Reduce aflatoxin intake, block or inhibit the carcinogenic effects of aflatoxin. In areas with high incidence of liver cancer, the incidence of liver cancer is positively correlated with grain mildew, especially aflatoxin contamination of corn. In view of the fact that the grain mildew is mainly in the field harvesting period and the post-harvest processing period and storage period, many scholars believe that it is extremely important to strengthen the anti-mildew measures in these links. In addition, changing the cultivation habits, replacing rice with rice, and promoting rice consumption are also one of the ways to reduce the intake of aflatoxin.
For cereals and oils that have been mildewed and cannot be discarded, it is also possible to remove certain toxins by selecting mildew and processing subtraction.
(3) Block HBV infection and actively prevent and treat hepatitis
Hepatitis B virus infection is currently a serious public health problem. In the high incidence area of liver cancer, the hepatitis B virus carrying rate is also high, and 80% of liver cancer patients have hepatitis B virus infection. In liver cancer patients, hepatitis B virus DNA was found to be integrated into the DNA of liver cells. Therefore, blocking HBV infection is an important way to prevent primary liver cancer, and vaccination against hepatitis B is the most fundamental and effective measure to control hepatitis B. The WHO noted that vaccines should be used selectively in low-population areas of HBV. In the mid-high endemic areas, all babies should be vaccinated, and the application of hepatitis B vaccine should be included in the expanded planned immunization. Practice has proved that hepatitis B vaccination is given to newborns, especially those with HBsAg-positive and/or HBeAg-positive mothers, and the immune effect is reliable. In Qidong City, by the end of 1990, 41,417 newborns had been vaccinated, the vaccination rate was 98.6%, and the anti-HBS positive rate was 82% at the age of 5, and the trend of chronic hepatitis has been observed. The long-term effect of vaccination against hepatitis B vaccine to prevent liver cancer needs further observation.
(4) Drug prevention for high-risk groups of liver cancer
Studies at home and abroad suggest that increasing selenium levels may help reduce the incidence of liver cancer. New Zealand used sodium selenite granules on low-selenium farms and Denmark to spray selenium on the land, which changed the local phenomenon of selenium deficiency. In Qidong County, China, a preventive test was conducted in 380,000 people in low-selenium areas. By spraying selenium fertilizer on crops, the selenium levels of corn and barley were increased by 6 times, and the blood selenium level of residents was also greatly improved. Animal experiments suggest that selenium can significantly inhibit hepatitis and precancerous lesions. The anti-cancer effect of selenium is mainly manifested in the early stage of inhibiting the formation of hyperplasia, and inhibiting the carcinogenesis of hyperplasia in the late stage. Recently, the intervention experiment between Sino-US cooperation in the on-site residents of Qidong County shows that the selenium salt (15mg/kg) and selenium yeast preparations in the past 4 years, the standardization rate of liver cancer in the population has dropped from 42/100,000 to 30/100,000. The incidence rate of the group did not decrease, and the difference between the two was significant. Practice has proved that it is safe and feasible to supplement selenium in the high discovery field of liver cancer. Shows the value and significance of selenium in preventing liver cancer.
The chemical drugs that have been reported to prevent liver cancer at home and abroad include levamisole, vitamin A and vitamin C. Chinese traditional medicine and natural foods are abundant. It is worthwhile to develop this treasure house to prevent liver cancer. Recently, more research has been done on green tea. Studies have shown that green tea has a significant inhibitory effect on aflatoxin B1-induced liver cancer in rats, and it has also been observed that green tea extract can inhibit the pre-cancerous lesions of rat liver induced by diethylnitrosamine. The epidemiology of high incidence areas of liver cancer also suggests that green tea may have a certain preventive effect. In addition, some Chinese medicines for treating hepatitis, such as salvia miltiorrhiza, schisandra, lentinan, and Yunzhi polysaccharide, have been shown to antagonize the formation of liver cancer in rats induced by aflatoxin.
(5) Health promotion education and implementation of relevant administrative regulations
Primary prevention is a social work for large-scale people. It has a wide range, high cost, and high resistance. It is difficult to show results in a short period of time. It is difficult to implement, so it is planned, organized, and targeted to implement health education. Increasing public awareness of cancer prevention is an important condition for ensuring the implementation of primary prevention measures for liver cancer. Relevant administrative measures and regulations should be adopted when necessary.
2. Secondary prevention of liver cancer
Primary prevention of liver cancer is important and has great potential for reducing liver cancer, but it is still important to emphasize level II prevention with practical effects. In the prevention of population, the implementation of liver cancer screening or screening, early detection of liver cancer is an important aspect of secondary prevention.
1 Target of the census: Before the 1980s, there was a big contradiction in the census of liver cancer in China, that is, the contradiction between cost and benefit. In the natural population census, even in the high-incidence area of liver cancer such as Shanghai, the detection rate is only 14.7/100,000, which is costly and not effective. Since the 1980s, according to the results of epidemiological investigations, the high-risk groups of liver cancer have been divided. Therefore, the screening of liver cancer has changed from the general survey of natural populations to the survey of high-risk groups. The detection rate has been greatly improved, and the cost and benefit have been well solved. The contradiction, this concept is also accepted by the majority of medical workers. High-risk groups are generally considered to be over 40 years old, hepatitis B surface antigen positive and chronic hepatitis history for more than 5 years (referring to those who had hepatitis 5 years ago), especially males and family history.
2 census method: For the large-scale population census, a simple method, high sensitivity, accurate and reliable detection method must be adopted. The hemagglutination method of alpha-fetoprotein (AFP) roughly meets this requirement. The positive limit of AFP hemagglutination method was 40g/L, and the false positive rate was 30%. For each case of positive AFP hemagglutination method, radioimmunoassay should be performed. Those who do have an AFP increase should be advised to go to a specialist clinic.
The positive rate of AFP detection in patients with primary liver cancer in China is about 70%, that is, about one-third of patients are difficult to obtain early detection by AFP. Other liver cancer markers other than AFP are not suitable for census for various reasons. The clinical application of B-ultrasound has been proved to be a simple, accurate and reliable imaging diagnosis method, which has been gradually included in the work of liver cancer screening in recent years. The combined detection of B-ultrasound and AFP did solve the problem of early detection of liver cancer in AFP-negative cases.
3 Intervals of census: Regarding the interval between censuses, the reports of the scholars are basically the same. It is generally considered that for high-risk groups, the census is at least once every 6 months.
4 Organization of census work: The knowledge of cancer prevention and prevention and the importance of early detection of cancer should be widely publicized through various channels. The publicity work for high-risk groups should pay special attention to both serious treatment, regular inspection and unnecessary avoidance. tension.
In order to do a good job in census work, we must mobilize the enthusiasm of medical staff in grassroots health organizations such as factories and mines, do a good job in mobilizing and inspecting the organization of objects, and regularly check and closely follow up on AFP cases.
Complication
Primary liver cancer complications Complications, hepatic encephalopathy, gastrointestinal bleeding
Complications can be caused by liver cancer itself or coexisting cirrhosis, which is common in the late stages of the disease, so it is often the cause of death.
Complications of primary liver cancer can be caused by liver cancer itself or coexisting cirrhosis. These complications are often the cause of or contribute to the death of a patient.
1. Liver cancer nodule rupture
Spontaneous rupture of liver cancer is one of the most common complications of liver cancer, and the incidence rate is about 5.46% to 19.8%. The clinical manifestation of rupture of liver cancer is upper abdominal pain. Those with larger bleeding volume may have hypotension, shock, ascites and other manifestations in a short period of time; if the bleeding is slow, the clinical symptoms may not be obvious, only the symptoms of anemia are not found until imaging examination or abdominal puncture. A considerable number of patients, with abdominal pain and other clinical manifestations of acute abdomen as the first symptoms, many of which have occurred liver cancer nodules rupture, so clinically encountered a history of chronic liver disease, sudden abdominal pain without obvious causes, abdominal cavity Puncture and withdrawal of non-coagulated blood can exclude other visceral hemorrhage, and the possibility of hepatocellular nodule rupture and bleeding should be considered. For patients with liver cancer who have been diagnosed clearly, it is not difficult to diagnose. Imaging examinations such as B-ultrasound and CT can provide direct evidence of rupture of liver cancer.
Patients with hepatic rupture and hemorrhage often suffer from coagulopathy, and non-surgical treatment is difficult to stop bleeding. The mortality rate is almost 100%. Therefore, as long as the patient can tolerate surgery in general, he should actively seek surgical exploration and hemostasis treatment.
(1) surgical indications:
1 Diagnosis of clear liver cancer spontaneous rupture with shock or rapid decline in hemoglobin in the short term. 2 It is estimated that patients with liver cancer resection or other effective treatment can be performed. 3 can not rule out visceral bleeding for other reasons. 4 liver function compensation is good, no hepatic encephalopathy, massive ascites or other important organ dysfunction.
(2) The surgical methods are:
1 partial tamponade. 2 hepatic artery ligation. 3 hepatic artery embolization. 4 microwave high temperature curing hemostasis method. 5 hepatic lobe or segmentectomy.
2. Hepatic encephalopathy
Hepatic encephalopathy is a manifestation of decompensation due to severe liver damage in advanced liver cancer. It is a common serious complication of liver cancer and one of the important causes of liver cancer death. The clinical manifestations of hepatic encephalopathy mainly include two aspects: one is the manifestation of liver damage and the other is the manifestation of encephalopathy. The manifestations of encephalopathy can be classified into two categories: one is mental disorder, such as ambiguity, silence, low mood, slow speech, slurred speech, decreased orientation and comprehension, writing errors, unable to complete simple calculations and intellectual actions, sleep changes In the later stage, there may be stupor, lethargy, and eventually coma. Some patients have euphoria and naive behavior, which resembles schizophrenia. The second type is abnormal behavior, often showing exercise, mutual aid, balance and dissonance. The tremor is the most characteristic. EEG examination showed abnormal brain waves.
Hepatic encephalopathy is divided into four phases according to the patient's clinical manifestations.
Stage I is a prodromal period and patients have mild personality changes.
Stage II is pre-coma, with mental confusion, confusion, increased muscle tone, hyperreflexia, flapping tremors, and waves in EEG.
Stage III is a sleepy period. The patient is mainly slumber, and there may be flapping tremors. EEG shows obvious waves and three-phase slow waves.
Stage IV is a coma, the patient is in a coma, the reflex disappears, and the EK wave appears on the EEG.
According to their clinical process, they are divided into three types, namely acute type, chronic type and intermediate type. Most of the brain diseases caused by liver cancer are intermediate types.
Hepatic encephalopathy is produced on the basis of liver failure. Therefore, patients with liver cancer should pay attention to liver protection, avoid using drugs that damage the liver, maintain water and electrolyte balance, and prevent infection and gastrointestinal bleeding. Treatment should eliminate the cause of hepatic encephalopathy, control infection, reduce ammonia intake and body formation, promote ammonia excretion, improve liver function, promote liver cell regeneration, use branched-chain amino acids, broad-spectrum antibiotics and symptomatic supportive treatment.
3. Gastrointestinal bleeding
Most of the portal hypertension caused by cirrhosis or cancer thrombus causes bleeding of the esophagus and gastric varices. Patients often die from hemorrhagic shock or induced hepatic encephalopathy. In addition, patients with advanced liver cancer may also suffer from extensive oozing due to gastrointestinal mucosal erosion, ulceration and coagulopathy. The causes of liver cancer patients with gastrointestinal bleeding are:
(1) esophagogastric varices: liver cancer patients often have cirrhosis, cirrhosis patients often due to portal hypertension caused by esophageal varices, and liver cancer and portal vein tumor thrombus can aggravate portal hypertension, causing esophageal varices rupture Bleeding.
(2) portal hypertensive gastropathy: due to portal hypertension, gastric mucosal blood flow is reduced, submucosal edema is extensive, mucosal ischemia, hypoxia, metabolic disorders, and gastric mucosal barrier impaired function.
(3) coagulation dysfunction: liver function in patients with liver cancer leads to decreased synthesis of coagulation factors, increased fibrinolytic properties and abnormal platelet mass, leading to coagulopathy. Once gastrointestinal bleeding occurs, it is often difficult to stop by itself.
(4) Hepatic nodules rupture and hemorrhage, blood can flow out from the biliary system and drain into the intestine.
(5) liver cancer metastasis, direct infiltration of gastrointestinal mucosal blood vessels, causing gastrointestinal bleeding.
The treatment of liver cancer combined with gastrointestinal bleeding is mainly due to blood and anti-shock, including hemostatic drugs, rest, and infusion of fresh blood. Different hemostasis measures can be used for bleeding depending on the cause. Esophageal varices bleeding can be used to stop bleeding with three-chamber two-capsule tube, sclerotherapy multi-point injection or snare ligation to stop bleeding; portal hypertensive gastration oral or intravenous injection of proton pump inhibitors and mucosal protective agents. Surgical hemostasis can be considered when conservative treatment is ineffective. Since this type of patient is often unable to tolerate hepatectomy, local tumor treatment is used as much as possible during surgery.
4. Bloody chest and ascites
Liver cancer can be directly infiltrated or caused by blood flow or lymphatic metastasis, which is common on the right side.
5. Secondary infection
Due to the long-term consumption of cancer, the resistance is weakened, especially in patients with decreased white blood cells after radiation and chemotherapy, and various infections such as pneumonia, intestinal infection, and fungal infection are easily caused.
6. Other complications
Primary liver cancer is prone to various infections due to long-term consumption, weakened body resistance or prolonged bed rest, especially in the case of leukopenia caused by chemotherapy or radiotherapy, which is more prone to complications such as pneumonia, sepsis, intestinal and fungal infections. . Liver cancer close to the face can be directly infiltrated, or bloody pleural effusion can be caused by lymphatic and blood transfer. Bloody ascites may also occur due to cancer rupture or direct infiltration and dissemination into the abdominal cavity. In addition, cases of successful ablation of right atrial tumor thrombus due to hepatic venous tumor thrombus have also been reported. Ehrich reported an acute right atrial tumor thrombus obstruction. The surgically removed tumor thrombus was approximately 8 cm × 6 cm × 10 cm. The pathological report was metastatic tumor thrombosis in primary hepatocellular carcinoma.
Symptom
Symptoms of primary liver cancer Common symptoms Increased transaminase abnormality Liver metastasis Liver cancerous fever Abdominal pain Liver function impairment Dull pain Liver enlargement Weak nosebleed
The clinical signs of primary liver cancer are extremely atypical, and the symptoms are generally not obvious, especially in the early stage of the disease. Generally, about 70% of small liver cancers below 5 cm are asymptomatic, and about 70% of asymptomatic subclinical liver cancers are small liver cancers.
Once the symptoms appear, the tumors are already large, and the progress of the disease is generally very rapid. Usually, the cachexia is present within a few weeks, often failing within a few months to one year.
Clinical signs are mainly two aspects of the disease:
1 manifestations of cirrhosis, such as ascites, collateral circulation, hematemesis and limb edema.
2 symptoms caused by the tumor itself, such as weight loss, weakness, liver pain and liver enlargement. After the development of liver cancer to a certain stage, there may be some clinical symptoms that are easily confused with hepatitis, cirrhosis, gastrointestinal tract, pancreas and biliary system diseases. The onset is often hidden, and more often in the liver disease follow-up or physical examination census using AFP and B-type ultra-examination to find liver cancer, the patient is asymptomatic, physical examination and lack of the tumor itself, this period is called subclinical liver cancer. In the event of a symptom, the patient's course of disease has mostly entered the middle and late stages. The clinical manifestations of liver cancer at different stages are significantly different.
1. The main clinical symptoms
There are pain in the liver area, bloating, fatigue, anorexia, weight loss, fever, jaundice and progressive enlargement of the liver or upper abdominal mass.
(1) Pain in the liver area
It is the most common and most important clinical symptom. Most of the pain is persistent dull pain, dull pain, pain or tingling, which is obvious at night or after exertion. Pain in the liver area is caused by a rapid increase in the tumor, an increase in the tension of the liver capsule, or a rupture of the subcapsular cancer nodules, or a hemorrhage of the liver cancer nodules. The pain area in the liver area is closely related to the lesion. The lesion is located in the right lobe of the liver and can be expressed as pain in the right quarter of the rib; in the left lobe of the liver, it is manifested as stomach cramps; in the posterior part of the dome, the pain can be radiated to the shoulders and lower back. Such as sudden onset of severe pain, accompanied by shock and other performance, mostly due to massive hemorrhage of cancer nodules.
(2) Anorexia, nausea, vomiting
Often due to liver damage, tumor compression of the gastrointestinal tract, which is a common symptom of anorexia, the more serious the condition, the more obvious the symptoms.
(3) bloating
Due to huge tumors, ascites and liver dysfunction. Abdominal swelling above the abdomen is obvious, especially after eating and in the afternoon, abdominal distension is aggravated. Patients often reduce their own food to reduce symptoms, and they are often mistaken for indigestion without paying attention and delaying diagnosis and treatment.
(4) fatigue, weight loss
Caused by the metabolism, excessive consumption and less food intake of malignant tumors. Early may not be obvious, as the disease develops more and more, the weight is also gradually decreasing, and the extreme is extremely thin, anemia, and exhaustion, showing cachexia. A small number of liver cancer patients with slower development of the disease may also experience temporary weight gain after rest and supportive treatment.
(5) Diarrhea
Mainly due to the diminished digestion and absorption capacity caused by different degrees of liver function damage, can also be caused by the metastasis of liver cancer cells to form portal vein tumor thrombus. Although this symptom is not very common, it can sometimes be used as the first symptom of liver cancer, which is often misunderstood as a gastrointestinal infection. Diarrhea can be accompanied by abdominal pain, usually after eating, that is, diarrhea, stool is mostly indigestible food residue, often no pus and blood, anti-inflammatory drugs can not be controlled. When the condition is serious, more than ten stools a day can make the condition deteriorate rapidly.
(6) fever
Due to tumor tissue necrosis, increased metabolites and tumor compression bile duct combined with cholangitis. Non-infected people are called cancer fever, and many are not accompanied by chills. Unexplained low fever is a common symptom of liver cancer, body temperature is generally between 37.5 ° C ~ 38 ° C, but inflammatory diffuse liver cancer has high fever, body temperature can reach more than 39 ° C, easily misdiagnosed as liver abscess, antibiotic treatment is often ineffective And with indomethacin (indomethacin) can be fever.
(7) hematemesis, black stool
Mainly due to hematemesis, mainly due to liver cancer with cirrhosis, portal hypertension caused by rupture of the lower esophagus-gastric varices and acute gastric mucosal lesions. Most people with black stools are caused by portal hypertensive gastropathy or peptic ulcer. Due to liver damage, gastrointestinal bleeding caused by decreased coagulation is rare.
(8) metastatic symptoms
Liver cancer can be transferred to the lungs, bones, pleura, gastrointestinal and lymph nodes. According to the site of metastasis, the corresponding symptoms can be caused. For example, chest metastases can cause chest pain, hemoptysis, etc., and bone metastases can cause local pain and pathological fractures.
In addition, a few clinically misdiagnosed symptoms can occur. Some patients have small liver, and the clinical manifestations of subcutaneous subcapsular cancer nodules are similar to cholecystitis. There are also small ruptures of right hepatic nodules, and a small amount of blood slowly flows to the right lower abdomen and is misdiagnosed as appendicitis.
Other symptoms still have bleeding tendency, such as gums and nose bleeding, which are related to impaired liver function, coagulation mechanism, and hypersplenism.
2. Signs
Progressive hepatomegaly, splenomegaly, jaundice, ascites, edema, and common signs such as liver palm, spider mites, and abdominal wall varices often occur in advanced stages.
(1) Progressive hepatomegaly
It is the most common sign of liver cancer. When the liver protrudes under the right rib or under the xiphoid process, the upper abdomen may be limited or full, the liver is hard, the surface is uneven, there are nodules or large pieces of different sizes, and the edges are blunt. Not neat, often with varying degrees of tenderness.;;()
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