Assessment of stromal invasion for correct histological diagnosis of early hepatocellular carcinoma

Abstract

Stromal invasion (invasive growth of tumor tissue into portal tracts and fibrous septa) is now recognized as the most important finding in the diagnosis of the well-differentiated type of early hepatocellular carcinomas (HCCs). In differentiating stromal invasion from pseudoinvasion (benign hepatic tissue in fibrous stroma), the following 5 items are useful: (1) macroscopic or panoramic views of the histological specimen, (2) the amount of fibrous components of stroma, (3) destruction of the structure of portal tracts, (4) loss of reticulin fibers around cancer cells, and (5) cytokeratin 7 immunostaining for ductular proliferation. Knowledge of stromal invasion is also useful for a better understanding of the vasculature (hypovascular HCCs) and histological features (fatty change) of early HCCs. Invasion of preexisting arteries and portal veins causes hypo-vascularity of HCCs. Further, hypovascularity causes fatty change as a hypoxic change of cancer tissues.

Figure 1

Various features of stromal invasion of hepatocellular carcinoma (HCC) and pseudo-invasion (A) Crossing type. Cancer tissue (HCC) invades across fibrous septa (f) of tumor nodule. (B) Longitudinal type. Tumor cells grow longitudinally within fibrous septa (arrowheads). (C) Irregular type. Portal areas are irregularly invaded by tumor cells (Masson trichrome stain). (D) A non-cancerous area without invasion, and a portal area and fibrous septa are clearly seen. (E) Pseudo-invasion. Benign non-cancerous cells are found in the fibrous stroma (Masson trichrome stain). (F) Macroscopic view of stromal invasion. In the non-cancerous area without invasion (area of (a)), fibrous septa are clearly seen. In the area of tumor spread (area of (b)), septa are indistinct. (G) A panoramic view of stromal invasion. In the same way as in (F), the non-cancerous area without invasion (area of (a)) shows distinct fibrous septa. The area of tumor spread (area of (b)) shows indistinct septa because stromal invasion of longitudinal type and irregular type ((B), (C)) reduced the amount of fibrous component. (H) Continuity of fibrous invasion and vascular invasion. The arrows show portal vein (p) invasion. Vascular invasion is continuous to stromal invasion of fibrous tissue of the portal “tract” and fibrous septum (Masson trichrome stain). (I) Masson trichrome staining of pseudoinvasion. (J) Silver staining of the same specimen as (I). Liver cells are clearly surrounded by reticulin fibers. (K) Masson trichrome staining of true invasion. (L) Silver staining of the same specimen as (K). Carcinoma cells are not surrounded by reticulin fibers. (M) (N) Cytokeratin (CK) 7 immunostaining in a non-cancerous area (M) and cancerous area (N). (M) Ductular reaction, confirmed by CK 7 staining, is clearly seen in a non-cancerous, non-invasive area. (N) Ductular reaction is not found in the invasive area. (N) Adapted from Y. Kondo et al. [2], F. Kondo et al. [3], and from F. Kondo [11].

Figure 1

Various features of stromal invasion of hepatocellular carcinoma (HCC) and pseudo-invasion (A) Crossing type. Cancer tissue (HCC) invades across fibrous septa (f) of tumor nodule. (B) Longitudinal type. Tumor cells grow longitudinally within fibrous septa (arrowheads). (C) Irregular type. Portal areas are irregularly invaded by tumor cells (Masson trichrome stain). (D) A non-cancerous area without invasion, and a portal area and fibrous septa are clearly seen. (E) Pseudo-invasion. Benign non-cancerous cells are found in the fibrous stroma (Masson trichrome stain). (F) Macroscopic view of stromal invasion. In the non-cancerous area without invasion (area of (a)), fibrous septa are clearly seen. In the area of tumor spread (area of (b)), septa are indistinct. (G) A panoramic view of stromal invasion. In the same way as in (F), the non-cancerous area without invasion (area of (a)) shows distinct fibrous septa. The area of tumor spread (area of (b)) shows indistinct septa because stromal invasion of longitudinal type and irregular type ((B), (C)) reduced the amount of fibrous component. (H) Continuity of fibrous invasion and vascular invasion. The arrows show portal vein (p) invasion. Vascular invasion is continuous to stromal invasion of fibrous tissue of the portal “tract” and fibrous septum (Masson trichrome stain). (I) Masson trichrome staining of pseudoinvasion. (J) Silver staining of the same specimen as (I). Liver cells are clearly surrounded by reticulin fibers. (K) Masson trichrome staining of true invasion. (L) Silver staining of the same specimen as (K). Carcinoma cells are not surrounded by reticulin fibers. (M) (N) Cytokeratin (CK) 7 immunostaining in a non-cancerous area (M) and cancerous area (N). (M) Ductular reaction, confirmed by CK 7 staining, is clearly seen in a non-cancerous, non-invasive area. (N) Ductular reaction is not found in the invasive area. (N) Adapted from Y. Kondo et al. [2], F. Kondo et al. [3], and from F. Kondo [11].

Figure 2

Histological features which make the assessment of stromal invasion difficult (a) True stromal invasion of very mild grade. The fibrous septum is almost intact except for a small area (arrow). (b) Pseudo-invasion consisting of very thin fibrous bundles within and around thick liver cell cords. This pattern was formed by dissection of liver parenchyma by very thin fibrous tissue. (c) A specimen of very poorly performed silver stain. (d) Silver stain of HCC tissue within and around a fibrous septum. Reticulin fibers circumscribing cancer tissue are seen even in the area of true invasion (yellow arrow). However, noncircumscribed tumor cells are also seen in the same fibrous septum (green arrows). This area is a “battle front” of invasion. Red arrows show ordinary tumor tissue with reticulin fibers surrounding the fibrous tissue.

Figure 3

Relationship between cancer development, vascularity, histological feature (fatty change), and stromal invasion.