Pathological Diagnosis of Hepatocellular Cellular Adenoma according to the Clinical Context

Abstract

In Europe and North America, hepatocellular adenomas (HCA) occur, classically, in middle-aged woman taking oral contraceptives. Twenty percent of women, however, are not exposed to oral contraceptives; HCA can more rarely occur in men, children, and women over 65 years. HCA have been observed in many pathological conditions such as glycogenosis, familial adenomatous polyposis, MODY3, after male hormone administration, and in vascular diseases. Obesity is frequent particularly in inflammatory HCA. The background liver is often normal, but steatosis is a frequent finding particularly in inflammatory HCA. The diagnosis of HCA is more difficult when the background liver is fibrotic, notably in vascular diseases. HCA can be solitary, or multiple or in great number (adenomatosis). When nodules are multiple, they are usually of the same subtype. HNF1 α -inactivated HCA occur almost exclusively in woman. The most important point of the classification is the identification of β -catenin mutated HCA, a strong argument to identify patients at risk of malignant transformation. Some HCA already present criteria indicating malignant transformation. When the whole nodule is a hepatocellular carcinoma, it is extremely difficult to prove that it is the consequence of a former HCA. It is occasionally difficult to identify HCA remodeled by necrosis or hemorrhage.

Figure 1

b-IHCA (with discovery of an HCC 12 years later). A woman born in 1959. Discovery of a nodule 17 cm. Oral contraceptives 4 years, BMI 21.5. Surgery 1984: right hepatectomy but incomplete resection. Followup refused by the patient: 2 pregnancies. Patient seen 12 years later with numerous liver nodules of a well-differentiated HCC. Death occurred few months later. (a) H&E—proliferation of hepatocytes with some atypia (not visible at this magnification) and numerous dilated vessels; no arguments for overt malignancy; inset: a few inflammatory infiltrates (arrows). (b) Moderate expression of SAA by adenomatous hepatocytes. (c) Heterogenous, patchy expression of GS; inset: aberrant expression of a few hepatocytic nuclei (arrows).

Figure 2

b-IHCA in the context of a FAP. A man born in 1966. Familial adenomatous polyposis (surgery in 1990 and 1996). Liver nodule discovered by chance, 9 cm. BMI 32.3. Segmentectomies V and VI. (a) H&E: HCA with ill-defined border (arrows). (b) Strong and diffuse expression of GS, contrasting with normal GS staining limited to a few centrolobular hepatocytes in the nontumoral liver (NT). (c) Diffuse expression of SAA in adenomatous hepatocytes with sharp demarcation from the surrounding NT.

Figure 3

HCA on the background of NASH. (a) A woman born in 1956. Several nodules in the liver, largest 8 cm. Oral contraceptives for 31 years; BMI 24.6. Surgery in 2007 (several tumorectomies and segmentectomies). H&E: IHCA (typical expression of SAA and CRP—not shown), very mild steatosis, contrasting with highly steatotic (60%) nontumoral liver (NT): NASH with mild activity, without fibrosis. (b-c) Woman born in 1973, metabolic syndrome (noninsulin-dependant diabetes, hypercholesterolemia, hypertriglyceridemia). Oral contraceptives 15 years, BMI 31.6. Two liver nodules, largest 26 mm in segment IV. Segmentectomy IVB plus radio frequency of the other nodule (1 cm) in segment VIII. (b) H&E: nonsteatotic HCA (without immunohistochemical characteristics), classified as UHCA; its limit contrast with severe steatotic non tumoral liver (NT). (c) H&E: nontumoral liver: NASH with severe steatosis (80%), mild activity, and septal fibrosis (stage 3).

Figure 4

H-HCA associated with polycystic disease. Woman born in 1954. In 1991: kidney transplantation for polycystic kidney disease. In 2000: left hepatectomy for a 11 cm liver nodule. On oral contraceptives for 2 years, BMI 21.2. LFABP immunostaining: numerous biliary cysts with some areas of liver normally expressing LFABP (asterisk), contrasting with a portion of the H-HCA (upper) where LFABP is sharply decreased.

Figure 5

FNH associated with H-HCA. Woman born in 1966. Three FNH, largest 10 cm. Surgery in 2008 (segments V and VI). Discovery on the resected specimen of several small H-HCA. (a) Fresh specimen: typical FNH closed to a small yellow nodule (arrow). (b) Masson's trichrome: typical aspect of FNH, nearby a small steatotic nodule (asterisk). (c) GS staining is negative in the nodule, contrasting with map-like positivity in FNH. (d) LFABP is lacking in the small nodule, whereas it is normally expressed in FNH (as in nontumoral liver, not shown).

Figure 6

H-HCA and IHCA. Woman born in 1965. Abnormal liver function tests. Hypertriglyceridemia. Multiple nodules largest 9.5 cm. BMI 21.5. 18-year oral contraceptives. Left hepatectomy in 2011. (a) Fresh specimen—the large reddish nodule is not well limited (black arrows), associated with numerous yellowish small nodules in the surrounding resected parenchyma, sometimes visible under the Glisson's capsule (white arrows). (b) The small nodules are steatotic. (c) LFABP is lacking in all the small nodules (H-HCA), contrasting with normal expression in the nearby IHCA. (d) CRP is strongly expressed in IHCA, whereas it is negative in the small nodule of H-HCA.

Figure 7

Rare, misleading cytological findings. (a) Woman born in 1964. Abnormal liver tests and anemia. No oral contraceptives, BMI 40.4. Alcohol (30 to 40 g per day), hypercholesterolemia, and type 2 diabetes. Biopsy: IHCA. Right hepatectomy 2006: IHCA. The anemia corrected several months after surgery. Perls staining: positivity in sinusoidal cells of the IHCA. (b) Woman born in 1936. Oral contraceptives 21 years. Several liver nodules. Tumorectomies in 1989. H&E: numerous epithelioid granulomas are widespread within the IHCA. (c-d): Woman born in 1947. Massive bleeding. No oral contraceptives, BMI 21.5. Right hepatectomy 2000. Massive liver necrosis. Pathological diagnosis: IHCA. H&E: areas with cytological abnormalities: dystrophic nuclei (irregular, hyperchromatic), nearby necrotic/hemorrhagic zones of the IHCA.

Figure 8

HCA looking like FNH. Same as patient 7A. (a) Fresh specimen: large subcapsular reddish tumor, with a white stellate area of loose fibrosis in the center. (b) CK7 is expressed at the border of fibrotic bands delineating nodules. (c) H&E (αSMA insert). The overall aspect is in favor of an IHCA. (d) Ductular reaction around inflammatory pseudo-portal tracts. (e) CRP is diffusely expressed in the nodule. The diagnosis of IHCA was reinforced by the disappearance of the chronic anemia after resection of the nodule.

Figure 9

H-HCA size increment. Woman born in 1952. Abnormal liver function tests. Oral contraceptives 13 years, BMI 25.4 MRI adenomatosis, largest nodule 6 cm. Segmentectomies IV and VI 2001. Follow-up: increase size of one nodule Segmentectomy III, 2010. (a–c) Phased-opposed T1 weighted MR images in 2001 (a), 2007 (b), and 2010 (c) showing multiple hepatocellular adenomas showing hypointense because of the massive fat component. The nodule located in segment II (arrow) gradually increases in diameter between 2001 and 2010. As the 13 mm nodule located in segment VIII (asterisk), other nodules did not change their size.