Chapter 088. Hepatocellular Carcinoma (Part 4) Physical Signs Hepatomegaly is the most common physical sign, occurring in 50–90% of patients. Abdominal bruits are noted in 6–25%, and ascites occurs in 30–60% of patients. Ascites should be examined by cytology. Splenomegaly is mainly due to portal hypertension. Weight loss and muscle wasting are common, particularly with rapidly growing or large tumors. Fever is found in 10–50% of patients, from unclear cause. The signs of chronic liver disease may be present, including jaundice, dilated abdominal veins, palmar erythema, gynecomastia, testicular atrophy, and peripheral edema. Budd-Chiari syndrome can occur due to HCC invasion of the hepatic veins; it should be suspected in patients with tense ascites and a large tender liver (Chap. 302). Paraneoplastic Syndromes Most paraneoplastic syndromes in HCC are biochemical abnormalities without associated clinical consequences. They include hypoglycemia (also caused by end-stage liver failure), erythrocytosis, hypercalcemia, hypercholesterolemia, dysfibrinogenemia, carcinoid syndrome, increased thyroxin-binding globulin, changes in secondary sex characteristics (gynecomastia, testicular atrophy, and precocious puberty), and porphyria cutanea tarda. Mild hypoglycemia occurs in rapidly growing HCC as part of terminal illness, and profound hypoglycemia may occur, although the cause is unclear. Erythrocytosis occurs in 3–12% of patients, and hypercholesterolemia in 10–40%. A high percentage of patients have thrombocytopenia or leukopenia not caused by cancer infiltration of bone marrow, as in other tumor types. Staging Although the TNM (primary tumor, regional nodes, metastasis) staging system set up by the American Joint Commission for Cancers (AJCC) is sometimes used, the newer Cancer of the Liver Italian Program (CLIP) system is now popular as it takes cirrhosis into account, as does the Okuda system (Table 88-4). Other staging systems have been proposed and a consensus is needed. The best prognosis is stage I, solitary tumor <2 cm in diameter without vascular invasion. Adverse prognostic features include ascites, vascular invasion, and lymph node spread. Vascular invasion, in particular, has profound effects on prognosis and may be microscopic or macroscopic (visible on CT). Most large tumors have microscopic vascular invasion, so full staging can usually be made only after surgical resection. Stage III disease contains a mixture of lymph node– positive and –negative tumors. Stage III patients with positive lymph node disease have a poor prognosis, and few patients survive 1 year. The prognosis of stage IV is poor after either resection or transplantation, and 1-year survival is rare. A working staging system based entirely on clinical grounds that incorporates the contribution of the underlying liver disease was originally developed by Okuda et al. (Table 88-4). Patients with Okuda stage III have a dire prognosis, because they usually cannot be curatively resected and the condition of their liver typically precludes chemotherapy. Table 88- 4 Clip and Okuda Staging Systems for Hepatocellular Carcinoma CLIP Classification Points Variables 0 1 2 i. Tumor number Single Multiple — Hepatic replacement by tumor (%) a <50 <50 >50 ii. Child-Pugh score A B C iii. α-Fetoprot ein level (ng/mL) <400 ≥400 — iv. Portal vein thrombosis (CT) No Yes — CLIP stages (score = sum of points): CLIP 0, 0 points; CLIP 1, 1 point; CLIP 2, 2 points; CLIP 3, 3 points. Okuda Classification Tumor Size a Ascites Albumin (g/L) Bilirubin (mg/dL) ≥50 % <5 0 + – ≤3 > 3 ≥3 < 3 (+) (–) (+ ) ( –) (+ ) (– ) (+ ) (– ) Okuda stages: stage 1, all (–); stage 2, 1 or 2 (+); stage 3, 3 or 4 (+). a Extent of liver occupied by tumor. Note: CLIP, Cancer of the Liver Italian Program. . Chapter 088. Hepatocellular Carcinoma (Part 4) Physical Signs Hepatomegaly is the most common physical sign, occurring. liver typically precludes chemotherapy. Table 88- 4 Clip and Okuda Staging Systems for Hepatocellular Carcinoma CLIP Classification Points Variables 0 1 2 i. Tumor number Single Multiple. contribution of the underlying liver disease was originally developed by Okuda et al. (Table 88 -4). Patients with Okuda stage III have a dire prognosis, because they usually cannot be curatively