To the Editor:
With interest, we recognized the response of Dr. Herrington (1) to our previous study about the expression of cell cycle regulatory proteins in small cell neuroendocrine carcinoma (SmCC) of the cervix uteri (2). Regarding their previous results (3,4), Dr. Herrington stressed the very interesting hypothesis that early integration events of high-risk human papillomavirus DNA with consecutive related high-level E7 expression in SmCC, in conjunction with the absence of cyclin D1 expression (2), are related to a disruption of the retinoblastoma protein (pRb) pathway. This idea has been supported by in vitro (5) and in vivo results on cervical intraepithelial neoplasia lesions (4) and in several human malignancies (for review, see (6)). Concerning this hypothesis, and the suggestion of Herrington (1) for completing the data on SmCC of the uterine cervix, we have evaluated pRb-1 expression in the SmCC of our previous study (2) and in 1 additional case using a monoclonal pRb-1 antibody (clone Rb-10, catalogue no. R 6878, 1:500, pretreatment: cooking in a microwave oven for 20 minutes at pH6; Sigma-Aldrich Inc, St Louis, MO). Nine of the 10 tested SmCC showed negative staining results (90%). However, all tumors, inclusive of the additional one, were positive for p16 and high-risk human papillomavirus.
It has been found that pRb was phosphorylated in synchrony with the cell cycle (7). These data suggested that pRb may be a general cell cycle regulator. This hypothesis was initially supported by the observations that exogenous unphosphorylated pRb could arrest cells in the G1 phase of the cell cycle (8) and that depletion of pRb led to an accelerated G1/S transition (9), improving cellular proliferation and tumor growth.
In conclusion, the available data on SmCC of the uterine cervix show a marked overexpression of p16 in all cases but a loss of cyclin D1 and pRb1 in most cases, which might indicate a widespread disruption of the Rb pathway. These alterations are not completely understood at time but might be responsible for the very aggressive behavior of SmCC of the cervix uteri.
Lars-Christian Horn, M.D., Ph.D.
Division of Gynecopathology
Institute of Pathology
University of Leipzig
Steffen Hauptmann, M.D., Ph.D.
Martin-Luther-University of Halle-Wittenberg
Institute of Pathology
Cornelia Leo, M.D.
Department of Obstetrics and Gynecology
1. Herrington CS. p16, p14, p53, and Cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix by Horn et al. Int J Gynecol Pathol
2. Horn LC, Lindner K, Szepankiewicz G, et al. p16, p14, p53, and cyclin D1 expression and HPV analysis in small cell carcinomas of the uterine cervix. Int J Gynecol Pathol
3. Herrington CS, Graham D, Southern SA, et al. Loss of retinoblastoma protein expression is frequent in small cell neuroendocrine carcinoma of the cervix and is unrelated to HPV type. Hum Pathol
4. Southern SA, Herrington CS. Differential cell cycle regulation by low- and high-risk human papillomaviruses in low-grade squamous intraepithelial lesions of the cervix. Cancer Res
5. Lukas J, Muller H, Bartkova J, et al. DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol
6. Goodrich DW. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene
7. Buchkovich K, Duffy LA, Harlow E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell
8. Connell-Crowley L, Harper JW, Goodrich DW. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell
9. Herrera RE, Sah VP, Williams BO, et al. Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts. Mol Cell Biol