Elsevier

Human Pathology

Volume 34, Issue 2, February 2003, Pages 136-142
Human Pathology

Original Contributions
The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung*,☆☆

https://doi.org/10.1053/hupa.2003.8Get rights and content

Abstract

Rb protein in its hypophosphorylated form acts as a cell cycle regulator for G1 arrest. Both cyclin D1 overexpression and P16INK4 loss of protein produce persistent hyperphosphorylation of Rb with resultant evasion of cell cycle arrest. To better establish the mechanisms of loss of Rb function in neuroendocrine lung tumors, we performed an immunohistochemical analysis of the P16INK4/cyclin D1/Rb pathway in the spectrum of neuroendocrine tumors, including 34 typical carcinoids (TCs), 25 atypical carcinoids (ACs), 42 large cell neuroendocrine carcinomas (LCNECs), and 79 small cell lung carcinomas (SCLCs). Absence of Rb expression was not observed in TCs but was seen in 21% of ACs, 68% of LCNECs, and 87% of SCLCs. P16 was expressed in 91% of TCs, 77% of ACs, 78% of LCNECs, and 93% of SCLCs. Cyclin D1 was overexpressed in 6% of TCs, 20% of ACs, 9.5% of LCNECs, and 1.3% of SCLCs. There was an inverse relationship between Rb and P16 in high-grade tumors (P <0.001) and a direct relationship between cyclin D1 and Rb (P <0.001) in all tumors, demonstrating that P16 and cyclin D1 act exclusively on the Rb pathway for cell cycle regulation. Overall, the Rb pathway (Rb/P16INK4/cyclin D1) was altered more frequently in ACs than in TCs (P = 0.001) and more frequently in LCNECs than in ACs (P = 0.001). Although Rb-negative tumors had shorter survival in the overall group (P <0.001) as a result of lack of Rb in most SCLCs, cyclin D1 overexpression and P16 loss did not influence survival in any individual category. We conclude that Rb pathway of G1 arrest is consistently compromised in high-grade neuroendocrine lung tumors (92%), primarily through loss of Rb protein, and is intact in low-grade TCs. In ACs an intermediate level of alterations (59%) is seen, consistent with their less-aggressive behavior compared with high-grade tumors. The specific profile of the Rb pathway parameters might provide specific therapeutic targets in neuroendocrine lung tumors. HUM PATHOL 34:136-142. Copyright 2003, Elsevier Science (USA). All rights reserved.

Section snippets

Patients

Cases were retrieved from the consultation files of the Armed Forces Institute of Pathology and from the Laboratoire de Pathologie Cellulaire, Grenoble. The diagnoses of TC, AC, LCNEC, and SCLC were made using the current World Health Organization/International Association for the Study of Lung Cancer criteria.21 A total of 180 cases (34 TCs, 25 ACs, 42 LCNECs, and 79 SCLCs) were included in the study.

Clinical characteristics of the TC group were as follows: mean age of 49 years (±15); 18 males

Results

The staining results are summarized in Tables 1 through 4.

. Overall results of individual markers: Distribution of P16, cyclin, and Rb reactivities according to histologic type

Empty CellNP16+P16NCyclin D1+Cyclin D1NRb+Rb
TC232123423229290
AC221752552024195
LCNEC4031942438401327
SCLC7570579178771067

. Correlation study of P16 and Rb expression according to histologic classes

Empty CellRb−Rb+P
Overall group
 P16−813
 P16+90480.017
TC
 P16−02
 P16+021NS
AC
 P16−23
 P16+314NS
LCNEC
 P16−36
 P16+2470.013
SCLC
 P16−32
 P16+6360.029

. Correlation study

Discussion

NE tumors of the lung include a spectrum of tumors from low-grade TCs to intermediate-grade ACs and high-grade LCNECs and SCLCs. Our study demonstrates that the Rb pathway is consistently compromised in LCNECs and SCLCs, less frequently compromised in ACs, and essentially intact in TCs. Abnormalities of the Rb pathway, in the form of p16 loss, cyclin D1 overexpression, or Rb protein loss, were found in 13% of TCs, 59% of ACs, and 92% of both LCNECs and SCLCs. In the 2 high-grade tumors,

Acknowledgements

We thank Marylène Lorinet for typing, Christine Claraz for technical assistance, and Jean-Michel Lasserre for photographic work.

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      Therefore, clinical impact of this subgroup in the metastatic setting requires further investigation. Loss of pRb expression is frequently seen in LCNEC, but less frequent in carcinoids [17,29–31]. We noticed preserved pRb expression in 4 stage IV NEN patients with well differentiated morphology and high proliferation rate and found a relatively long survival (median 45 months) in those patients.

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    *

    Supported in part by INSERM, ARC, La Ligue Nationale contre le Cancer (E.B.).

    ☆☆

    Address correspondence and reprint requests to Professor Elisabeth Brambilla, Laboratoire de Pathologie Cellulaire, BP 217, 38043 Grenoble Cedex 9, France.

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