P16(INK4a) protein expression in endocervical, endometrial and metastatic adenocarcinomas of extra-uterine origin: diagnostic and clinical considerations.

Determining the primary site of uterine adenocarcinoma (ADC) may be problematic, especially with small specimens. This is particularly important in light of the increase of endocervical and endometrial adenocarcinoma and the decrease in incidence of squamous cell carcinoma. P16(INK4a) , a member of the INK4 family of cell cycle regulatory proteins, plays a critical role. It functions as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein retinoblastoma (pRb), which regulates the cell cycle. Its expression is variable according to the tumoral histotype and in metastasis. The aim of this study was to investigate P16(INK4a) expression in endocervical, endometrial, and metastatic ADCs of extra-uterine origin. Fifty gynaecological biopsies (cervix or endometrium) comprised the study for P16(INK4a) determination. Cases were classified as (1) diffuse positive (P), in intense nuclear immunostaining and/or cytoplasmic in > 30% of neoplastic cells; (2) focal positive (FP), in intense immunostaining in 10% to 30% in isolated cells or small groups; and (3) negative (N), in absence of immunostaining or weak, sporadic immunostaining in < 10% of neoplastic cells. Included in the study were the following: 6 endocervical ADCs, 11 endometrioid-type endometrial ADCs, 5 endometrial serous papillary ADCs, 7 ovarian ADCs, 4 large intestine ADCs, 1 breast ADC, 12 not-otherwise-specified (NOS) ADCs, and 4 endocervical biopsy without atypia (as control). Diffuse, strong positivity with P16(INK4a) suggests an endocervical rather than an endometrial or metastatic ADC. In fact, a P16(INK4a) positive immunostaining pattern was prevalent in endocervical (83%) and serous papillary ADCs of endometrial or ovarian origin, whereas endometrioid ADCs such as metastatic non-ovarian lesions generally presented only focal or negative immunostaining. 10/12 cases of ADC-NOS were reclassified using P16(INK4a) immunostaining: 2 as endocervical ADCs (2 P), 4 as endometrioid-type endometrial ADCs (2 FP, 2 N), 3 as endometrial serous papillary ADCs (3 FP), and 1 as ovarian serous papillary ADC (1 FP).