PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
Because of the higher incidence of hepatitis B viral infections, wider ingestion of aflatoxins from moldy peanuts, and intestinal parasites such as schistosomiasis, hepatocellular cancers are extremely common among Asians and the Bantu of Africa.
PERSPECTIVE AND PATTERNS OF SPREAD
Cancers of the major digestive glands (MDGs) remain a challenge to diagnose and treat. The 5-year survival rates have remained at 1% to 2% for decades, reflecting the advanced stages at which this disease is detected. Masquerading as nonspecific complaints such as epigastric fullness or mild distress, vague abdominal or back pain, or unexplained weight loss, it is no surprise that these neoplasms are not recognized until they have become extensive, replacing much of their organ of origin. Both cancer of the pancreas and cancer of the liver are increasing in incidence. Incidence of pancreatic cancers has tripled over the last 40 years, and they are the second-most-common tumor in the alimentary tract. By contrast, liver neoplasms are relatively uncommon in North America; however, in Southeast Asia and Africa, because of the higher incidence of hepatitis B viral infections, wider ingestion of aflatoxins from moldy peanuts, and intestinal parasites such as schistosomiasis, hepatocellular cancers are extremely common among Asians and the Bantu. In fact, the high incidence of hepatomas in China and Asia makes this tumor, by sheer size of the population involved, a common cancer globally.
Figure 25.1A | A photomicrograph of the tumor shows a trabecular pattern of malignant hepatocytes. Many cells are arranged in an acinar pattern and surround concretions of inspissated bile.
Clinical features and presentations include abdominal pain (59% to 95%), abdominal swelling (28% to 43%), and eventually severe weight loss and weakness. Hepatomegaly (54% to 98%), splenomegaly (27% to 42%), and ascites (35% to 61%) are common. With hepatic vein and inferior vena cava tumor invasion or compression, severe pitting edema accompanies ascites. Paraneoplastic syndromes are uncommon but rare enough to suggest hepatocellular carcinoma (HCC).
• Severe hypoglycemia (type B) can occur due to defective processing of precursor to insulin growth factor II (pro-IGFII).
• Polycythemia occurs in 10% of cases, and, if associated cirrhosis exists, hepatocellular cancer is a highly probable cause and is known to produce erythropoietin-like substances.
• Hypercalcemia in the absence of osteolytic metastases can be due to parathyroid hormone–related protein due to HCC.
• Sudden elevated cholesterol levels can be manifested in one third of wasted patients.
Figure 25.2 | Patterns of spread for liver cancer. A. Coronal. B. Sagittal: liver segments. Color-coded for T stage: Tis, yellow; T1, green; T2, blue; T3, purple; and T4, red. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 25.2.
• Elevation of alpha fetoprotein suggests HCC in Chinese and African populations.
• Dermatopathic lesions such as pityriasis rotunda manifest as rashes with single or multiple oval or round scaly and hyperpigmental lesions on trunk or thigh; this is an especially useful indication in black Africans as to HCC.
• If a person is infected with both hepatitis B virus (HBV) and hepatitis C virus (HCV), then HCC is three times higher than for each alone.
• Hemachromatosis and Wilson disease with alpha-1-antitrypsin deficiency increase risk of HCC.
With an annual rate over 20,000 new patients, liver cancers are becoming a major problem in the United States. Most patients succumb to either the hepatoma or the cirrhotic liver induced by hepatitis virus B and C. Liver failure is inevitable. Patterns of spread are mainly into adjacent liver lobules and then into its vasculature and major vessels, i.e., portal vein, hepatic artery, and then the surrounding viscera (Fig. 25.2; Table 25.2).
PATHOLOGY
The genome of HBV is integrated into the DNA of HCC and probably transforms liver cells into malignancy. HCC can be solitary or clusters of multiple nodules either as a function of multicentricity or metastatic spread. Vascular invasion is common in both the portal vein and hepatic vein since the majority of the circulation is venous (70% to 80%). The histologic types range widely from well, to mixed, to poorly differentiated.
• In the differentiated trabecular variety, hepatocytes grow in sheets separated by inconspicuous sinusoids.
• In the undifferentiated variety, the cells are pleomorphic and vary in size and shape; bizarre giant cells are present.
• Moderate differentiation can appear as a mixture and appear solid, scirrhous, or clear celled.
• Fibrolamellar HCC is a unique variant that occurs in adolescents and young adults and has eosinophilic tumor cells in a lamellar pattern.
The histopathology of hepatic malignancy originates from either hepatocytes or intrahepatic duct lining cells, that is, HCC or cholangiocarcinoma, respectively (Fig. 25.1; Table 25.1). Propagation and proliferation of cancers spread within the liver, pursuing paths infiltrating low-pressure zones such as central veins or into bile ducts.
TNM STAGING CRITERIA
CLASSIFICATION AND STAGING
The only viable alternative most often is liver transplantation.
TNM STAGING CRITERIA
Hepatomas or hepatocellular cancers of the liver tend to remain localized in the liver for long periods of time. They often tend to invade various lobes of the liver, deep into its substance, entering sinusoidal channels and producing satellite lesions. Although some encapsulation occurs, it tends to be diffuse and does not respect lobar boundaries.
As the liver substance is replaced, the cancer penetrates through Glisson's capsule. It can invade other vital viscera, such as the stomach and intestine, although this is very uncommon. The size of the liver nodules and their volume have influenced the establishment of a staging system. The size of T1 cancer is solitary, >5 cm, and lacks vascular invasion. T2 are multiple nodules in aggregates >5 cm in size but with vascular invasion. T3 are multiple tumors 5 cm, or evidence of invasion of a major branch of the portal or hepatic system must be present. T4 is penetration of the visceral peritoneum or direct invasion of surrounding abdominal viscera excluding the gall-bladder (Fig. 25.3A).
Specifically, there is a direct relationship of T category advancement and stage. Stage III is divided into A/B/C: IIIA = T3, IIIB = T4, and IIIC = N1.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
There are major changes. The seventh edition AJCC includes only hepatocellular carcinomas (Fig 25.3A), and cholangiocarcinomas (Fig. 25.3B) have their own TNM criteria.
Intrahepatic bile ducts are no longer included in this staging chapter. The staging of liver cancer now includes only hepatocellular carcinoma.
T Category Changes
• In the T3 category, patients with invasion of major vessels are distinguished from patients with multiple tumors, of which any are 5 cm, but lack major vessel invasion because of the markedly different prognosis of these subgroups.
• T3a includes multiple tumors, any 5 cm.
• T3b includes tumors of any size involving a major portal vein or hepatic vein.
• T4 category is unchanged.
N Category Changes
• Inferior phrenic lymph nodes were reclassified to regional lymph nodes from distant lymph nodes
Stage Grouping Changes
• Changes in T3 classification led to changes in Stage III groupings.
• Stage IIIA now includes only T3a; patients with major vessel invasion are removed from the IIIA stage grouping.
• Stage IIIB now includes only T3b (major vessel invasion).
• T4 is shifted to Stage IIIC.
• Stage IV includes all patients with metastasis, whether nodal or distant, separated into IVA and B to permit identification of each subgroup.
• Stage IVA now includes node-positive disease (N1).
• Stage IVB now includes distant metastasis (M1).
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 25.3).
LIVER HEPATOMA
Figure 25.3A | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Liver cancers are generally advanced stages. Stage IIIA is borderline resectable (purple), stage IIIB (red) is unresectable, as is stage IV metastatic (black). Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and IV (metastatic), black. Definitions of TN on left and stage grouping on right.
INTRAHEPATIC CHOLANGIOCARCINOMA
Perspective and Patterns of Spread
Intrahepatic cholangiocarcinomas are less common than HCC and show geographic variation. Their frequency rate varies from 15% to 20% of hepatic cancers. Higher ratios are found in the Far East—Thailand, Laos, and Cambodia. Chronic infestation of the biliary tree with liver flukes is causally related. Additional risk factors include sclerosing cholangitis, biliary atresia, von Meyenburg complexes, Caroli disease, cholidochocyst, and intrahepatic cholethiasis. HBV and HCV infections and alcoholic cirrhosis are not factors. The incidence has been rising over the last two decades in Europe and North America. They occur in older patients between 50 and 65 years old; they are equal for male and female patients and peak in the ninth decade.
• Jaundice is more frequent and prominent and occurs earlier than HCC; the liver is not as large, and ascites, fever, and metastatic spread are less frequent. Hepatic bruit is absent.
• Laboratory values are raised for CA 19-9 levels and CEA as well.
• Molecular level changes are most frequently mutations of the K-ras gene and p53, p16, and p73.
• Histopathology (Fig. 25.1B) shows that Cholangiocarcinomas are composed of cubic cells arranged in duct-like and glandular configurations.
• Differential diagnosis includes metastatic liver cancers since they can form masses.
CLASSIFICATION AND STAGING
Summary of Changes Seventh Edition AJCC
• This is a novel staging system that is independent of the staging system for hepatocellular carcinoma and independent of the staging system for extrahepatic bile duct malignancy, including hilar bile duct cancers. The rare combined hepatocellular and cholangiocarcinoma (mixed hepatocholangiocarcinomas) are included with the intrahepatic bile duct cancer staging classification (Fig. 25.3B).
• The tumor category (T) is based on three major prognostic factors including tumor number, vascular invasion, and direct extrahepatic tumoral extension.
• The nodal category (N) is a binary classification based on the presence or absence of regional lymph node metastasis.
• The metastasis category (M) is a binary classification based on the presence or absence of distant disease.
• Recommend collection of preoperative or pretreatment serum CA19.9
Regional Lymph Nodes
Compared with primary hepatocellular carcinoma, regional lymph node metastases are more commonly associated with intrahepatic cholangiocarcinoma. The lymph node drainage patterns from the intrahepatic bile ducts demonstrate laterality. Tumors in the left lateral bisegment (segments 2 to 3) of the liver may preferentially drain to lymph nodes along the lesser curvature of the stomach and subsequently to the celiac nodal basin. In contrast, intrahepatic cholangiocarcinomas of the right liver (segments 5 to 8) may primarily drain to hilar lymph nodes and subsequently to caval and periaortic lymph nodes.
For right liver (segments 5 to 8) intrahepatic cholangiocarcinomas, the regional lymph nodes include the hilar (common bile duct, hepatic artery, portal vein, and cystic duct), periduodenal, and peripancreatic lymph nodes. For left liver (segment 2 to 4) intrahepatic cholangiocarcinomas, regional lymph nodes include hilar and gastrohepatic lymph nodes. For intrahepatic cholangiocarcinomas, disease spread to the celiac and/or periaortic and caval lymph nodes is considered distant metastasis (M1). Inferior phrenic nodes are considered regional, not distant nodes.
Intrahepatic bile duct carcinoma tends to involve lymph nodes more than HCC and varies depending on the location of the primary.
Right lobe segments 5 to 8 drain to hilar lymph nodes and then the paracaval and periaortic nodes.
Left lobe segments 2 to 4, after hilar nodes, tend to drain along lesser curvature stomach and celiac nodes.
Figure 25.1B | Cholangiocarcinoma. Well-differentiated neoplastic glands are embedded in a dense fibrous stroma.
INTRAHEPATIC BILE DUCT
Figure 25.3B | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Liver cancers are generally advanced stages. Stage IIIA is borderline resectable (purple), stage IIIB (red) is unresectable as is stage IV metastatic (black). Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and IV (metastatic), black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The anatomic isocenter for the liver is to right of the midline at the T10 to T12 level (Fig. 25.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views. A. Coronal, B. Sagittal, C. Transverse axial (Figure 25.5).
By virtue of its weight, the liver is the largest visceral organ in the body. When filled with cancerous nodules, it is often the greatest repository of neoplastic disease, exceeding primary tumors in the quantity of malignant cells. To understand the anatomy of the liver, it is important to be aware of its internal structure as a gland of compound tubular design. Each lobule is shaped like a cylinder or tubule, with a central vein that drains a rich anatomic sinusoidal network derived from the fine hepatic arterioles and portal vessels (Fig. 25.4). The hepatocyte elaborates both an external/exocrine secretion and an internal/endocrine secretion of enzymes into the blood. The former is referred to as bile and is collected by biliary canaliculi.
At the porta hepatis, the bile ducts coalesce into a right and a left main duct via the common hepatic duct to the gallbladder and the cystic ducts below, as common bile duct courses toward the second portion of the duodenum, where it fuses with the pancreatic duct at the ampulla of Vater. The gallbladder and its cystic duct are to the right and below the porta hepatis.
The liver sits under and is virtually surrounded by the diaphragm superiorly, most of which is covered by peritoneum. Inferiorly, it is partially attached to the retroperitoneum. Abdominal viscera are in contact with its undersurface.
There are two major vascular systems in the liver. The major blood supply to the organ consists of the hepatic artery and vein. The portal system results from a fusion of the splenic vein with the superior mesenteric vein to form a portal vein that also enters the liver parenchyma via the porta hepatis. This brings the products of the intestine for detoxification and metabolic activation. The lymphatics follow the hepatic and portal veins and drain into the high para-aortic nodes, particularly around the celiac axis.
The new anatomic terminology refined by Couinaud is based on dividing the liver into four sectors by virtual/oblique planes referred to as scissura. The sectors are divided by a horizontal scissura, thereby increasing the number of liver segments to eight. The eight segments are numbered clockwise in the frontal plane (Fig. 25.5).
• Coronal: The liver is divided into a right and a left half, if one judges by its blood supply, for both the hepatic artery and portal veins bifurcate at the porta hepatis. The left side usually includes the quadrate and caudate lobes of the liver.
• Sagittal: The new anatomic terminology refined by Couinaud is based on dividing the liver into four sectors by virtual/oblique planes referred to as scissura. The sectors are divided by a horizontal scissura, thereby increasing the number of liver segments to eight. The eight segments are numbered in a clockwise manner in the frontal plane and are based on hepatic vein branching, and determine portal liver resections.
• Transverse: There is an H-shaped group of fissures and fossae that describe these aforementioned lobes on either side of the H, with other lobes positioned on the right and left sides. The porta hepatis represents the letter's crossbar, where the hepatic artery, portal vein, and major bile ducts enter, as well as nerves and lymphatics. The falciform ligament holds the liver in its position anteriorly and is attached to the superior and anterior surfaces as well as the dome of the diaphragm. The stomach and bowel are in contact on its inferior surface.
Figure 25.4 | Orientation and overview of oncoanatomy. The anatomic isocenter of the three-planar anatomy is placed to the right in the epigastrium and between T11 and T12 posteriorly. A. Coronal. B. Sagittal. *This only applies to hepatocellular carcinomas.
Figure 25.5 | T-oncoanatomy. Connecting the DOTS: structures are color coded for cancer stage progression. The color code for the anatomic sites correlates with the color code for the stage group (Fig. 25.3) and patterns of spread (Fig. 25.2) and SIMLAP tables (Table 25.2). Connecting the dots in similar colors will provide an appreciation for the 3D oncoanatomy.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
The lymphatics follow the hepatic and portal veins and drain into the para-aortic or paracaval nodes, particularly around the celiac axis (Fig. 25.6A; Table 25.4).
Regional Lymph Nodes
The regional lymph nodes are the hilar, hepatoduodenal ligament, inferior phrenic, and caval lymph nodes, among which the most prominent are the hepatic artery and portal vein lymph nodes. Nodal involvement should be coded as N1. Nodal involvement is now considered stage IV disease.
M-ONCOANATOMY
The entire portal circulation should be considered as a unit with regard to the venous anatomy of the gastrointestinal tract below the diaphragm (see Fig. 25.6B). The two major trunks are the inferior mesenteric and superior mesenteric veins. The inferior mesenteric vein drains the left colon and sigmoid colon tributaries, which cover the vascular drainage to the left of the midline originating from the superior rectal veins. On the right side, the superior mesenteric vein originates from the tributaries draining the ileum, the jejunum, and the ileocolic and right and middle colic veins. The inferior mesenteric vein usually joins the splenic vein, which coalesces with the superior mesenteric vein and forms the portal vein. The splenic vein, which is a major tributary of the portal system, also drains much of the stomach along its greater curvature and includes the short gastric veins and left and right gastric epiploic veins. The right gastroepiploic also flows into the superior mesenteric vein. The entire drainage of the lesser curvature of the stomach, including the left and right gastric veins, drains directly into the portal vein. Because the portal vein then drains directly into the liver, it is the target metastatic organ and the most commonly involved organ in a hematogenous spread pattern from the venous system of the gastrointestinal tract, as compared with other parts of the body, where the drainage is directly into the lung by way of the caval system.
Figure 25.6 | A. N-oncoanatomy. Sentinel nodes of the liver include the paracaval and para-aortic nodes. B. M-oncoanatomy. Both hepatomas and cholangiocarcinomas tend to spread directly into the liver or can be multifocal, similar to metastatic spread. Since the liver drains into the central vein, which in turn drains into the inferior vena cava, spread of metastases will be into the lung as well.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Imaging is essential for clinical staging of HCC. Because the liver is diseased due to hepatitis B and C infection and its associated cirrhosis, it is a challenge to uncover dysplastic nodules believed to be precursors to HCC. Computed tomography is favored to determine tumor size and if vascular invasion is present. Only 10% to 20% of HCC patients are surgically resected, preferably with T1 nodules, preferably 2 cm and not >5 cm. Numerous additional adverse factors can be found to contraindicate surgery, namely, presence of nodules in other lobes, lymphadenopathy, or major vessel invasion (Table 25.5; Fig. 25.7).
Pathologic Staging
The surgically resected liver segments and associated lymph nodes removed are assessed. Tumor extension and location of both primary and nodes should be documented. Complete surgical staging consists of evaluation of primary tumor and underlying associated liver disease as severity of fibrosis/cirrhosis (F0 = Ishak score 0–4; F1 = Ishak score 5–6) for better versus worse prognosis. Histologic grade and lymph node, if any, are recorded. If surgical margins are not released, total hepatectomy and liver transplantation are required for survival.
Oncoimaging Annotations
• HCC nodules receive blood via hepatic artery versus dysplastic nodules supplied by portal veins.
• HCC is classified on imaging as nodular, massive, and diffuse.
Figure 25.7 | Axial CTs of T11 and T12 level correlate with the T-oncoanatomy transverse section (Figure 25.5C). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. 1. Main portal vein. 2. Splenic vein. 4. Pancreas (body) 5. Caudate lobe of liver. 7. Inferior vena cava A, abdominal aorta; Spl, spleen; Stom, stomach.
PROGNOSIS AND CANCER SURVIVAL
PROGNOSIS
The limited number of prognostic factors are listed in Tables 25.6A and Table 25.6B.
CANCER STATISTICS AND SURVIVAL
The digestive system or gastrointestinal tract, which includes MDGs, accounts for 255,640 new patients annually, with colon and rectum responsible for >50%, or about 147,000 new diagnoses annually. Approximately half of these patients eventually die of these cancers. MDG cancers as a group are more lethal; only a handful of patients become long-term survivors. Fortunately, colon and rectal cancers are the most common, with the majority of patients becoming 5-year survivors (63%) responding to chemoradiation programs often with the sparing of the rectal sphincter with conservative surgery. Anal cancers are the most responsive to chemoradiation (5-fluorouracil and cisplatin), eliminating the need for surgery, and 5-year survival is >90%, with anal sphincter preservation. This regimen has been proven to be very effective in clinical trials and to result in more long-term survivors, which is currently reflected in the literature. Liver, bile duct, and pancreatic cancers are among the poorest in the terms of survival, often measured in months rather than years.
Specifically, the liver accounted for 24,120 new cancer cases and 18,910 cancer deaths (88%), with a 5-year survival rate improvement over the last three decades of 10%. Currently, relative 5-year survival for all stages is 14%, but, when localized, it improves to 16.3% (see Table 24.5).
Overall survival at 5 years has steadily improved with total hepatectomy and liver transplantation, from 30% survival in 1988 to 57% today. For all liver transplantations in the United States, a 74% 5-year survival is reported (Fig. 25.8).
Figure 25.8 | Five-year survival for liver cancer and intrahepatic bile ducts. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)