Different apoptotic activity and p21(WAF1/CIP1), but not p27(Kip1), expression in serrated adenomas as compared with traditional adenomas and hyperplastic polyps of the colorectum

Abstract

Purpose: Serrated adenomas (SAs), which include a wide spectrum of lesions, can be broadly divided into two subtypes: type I, closely mimicking hyperplastic polyps (HPs), and type II, unequivocal adenomatous tumor. Our preliminary findings showed clinicopathologic differences between them. The present study was conducted to investigate apoptotic activity and expression of the cell cycle regulator proteins p21(WAF1/CIP1) and p27(Kip1) in type I and II SAs, as compared with traditional adenomas (TAs) and HPs.

Methods: Apoptotic activity was estimated in hematoxylin-eosin stained specimens, and p21(WAF1/CIP1) or p27(Kip1) immunoreactivity was determined in 62 SAs (19 type I and 43 type II), 50 TAs and 19 HPs. The numbers (percentages) of apoptotic or immunoreactive cells were counted per 1,000 epithelial cells in equally separated crypt zones (upper, middle, and lower thirds).

Results: The apoptotic activity in the middle, but not the upper or lower crypt zone was higher in type II SAs (median 0.2%, interquartile range 0.1-0.5%) than in HPs (0.1%, 0.1-0.2%, P<0.01), whereas it was lower in type I SAs (0.2%, 0.1-0.3%) than in TAs (0.5%, 0.2-0.6%, P<0.001). P21(WAF1/CIP1) expression in the lower crypt zone was higher in both type I and type II SAs (19.8%, 7.0-33.2% and 20.4%, 3.9-47.8%, P<0.0001) than in TAs (1.2%, 0.6-5.2%), and a similar tendency was also observed for the middle crypt zone. p27(Kip1) expression did not vary among the groups.

Conclusions: The differences in apoptotic activity and p21(WAF1/CIP1) expression between SAs and TAs or HPs indicate that SA should be considered as a distinct subtype of colorectal neoplasm. The two subtypes of SA do not differ in these parameters despite specific clinicopathological features.

Fig. 1.

Type I SA demonstrating dysplastic nuclei present only in the lower halves of the serrated crypts (hematoxylin and eosin; original magnification ×80)

Fig. 2.

Type II SA having dysplastic nuclei even in the upper halves of the crypts (hematoxylin and eosin; original magnification ×100)

Fig. 3.

An apoptotic body (indicated by an arrow) in an SA (hematoxylin and eosin; original magnification ×400)

Fig. 4.

Comparison of AIs for the middle crypt zones of SAs, HPs, and TAs. †, P<0.01; ‡, P<0.001; §, P<0.0001

Fig. 5.

Comparison of p21^WAF1/CIP1 labeling indices (p21 LIs) for the lower crypt zones of SAs, HPs, and TAs. ‡, P<0.001; §, P<0.0001

Fig. 6A–C.

Immunohistochemical analysis of p21^WAF1/CIP1 expression in an HP, an SA, and a TA. A HP demonstrating immunoreactive cells mostly in the upper and middle thirds of crypts (immunoperoxidase; original magnification ×160). B SA (type II) displaying p21^WAF1/CIP1 staining extending from the upper to the lower zone of the crypts (immunoperoxidase; original magnification ×80). C p21^WAF1/CIP1-positve nuclei in the TA are localized to the superficial region (immunoperoxidase; original magnification ×80)