TP53 Staining in Tissue Samples of Chronic Lymphocytic Lymphoma Cases: An Immunohistochemical Survey of 51 Cases

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Abstract

Objective:

Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disease in adults. The aim of this study is to find out if the extent of proliferation centers or the immunohistochemical expression of p53 is related to disease prognosis.

Materials and Methods:

In the scope of this study, 54 biopsy specimens from 51 patients (50 of lymph nodes; the others of spleen, tonsil, orbit, and liver) diagnosed with CLL at the Hacettepe University Department of Pathology in 2000-2013 were reevaluated. The clinical and demographic data of the patients were obtained from our patient database. Biopsy samples were assessed semi-quantitatively for the percentage of proliferation center/total biopsy area (PC/TBA) and an immunohistochemical study was performed on representative blocks of tissues for p53 expression.

Results:

When the patients were divided into two categories according to Rai stage as high and low (stages 0, 1, and 2 vs. stages 3 and 4), it was seen that patients with low Rai stage had a better prognosis than those with high stages (p=0.030). However, there was no statistically significant correlation between overall survival and PC/TBA ratio or p53 expression levels.

Conclusion:

In our cohort, PC/TBA ratio and immunopositivity of p53 did not show correlations with overall survival.

Translated abstract

Amaç:

Kronik lenfositik lösemi (KLL) erişkin bireylerde en sık görülen lenfoproliferatif hastalıktır. Bu çalışmanın amacı KLL tanısı almış hastaların doku örneklerindeki proliferasyon merkezlerinin yaygınlığı ve p53 ekspresyonu ile prognozları arasında bağlantı olup olmadığını araştırmaktır.

Gereç ve Yöntemler:

Bu çalışma kapsamında Hacettepe Üniversitesi Tıp Fakültesi Hastanesi Patoloji Anabilim Dalı’nda 2000-2013 yılları arasında KLL tanısı almış 51 hastanın 54 biyopsi örneği yeniden değerlendirilmiştir. Hastaların klinik ve demografik verileri hasta veri tabanından elde edilmiştir. Yapılan incelemede biyopsi örneklerinde proliferasyon merkezlerinin tüm biyopsi alanına oranı (PM/TBA) yarı niceleyici olarak değerlendirilmiş ve seçilen temsili bloklardan elde edilen kesitlerde immünohistokimyasal yöntemle p53 ekspresyonuna bakılmıştır.

Bulgular:

Hastalar Rai evrelerine göre düşük ve yüksek olmak üzere iki gruba ayrıldığında düşük evreli hastaların genel sağkalım sürelerinin yüksek evreli hastalara göre daha uzun olduğu görülmüştür (p=0,030). Ancak, proliferasyon merkezi oranı veya p53 ekspresyon düzeyleri arasında istatistiksel olarak anlamlı ilişki gösterilememiştir.

Sonuç:

Çalışmamıza dahil edilen hasta grubunda PM/TBA oranı ve p53 immünpozitifliginin sağkalım ile ilişkisi olmadığı görülmüştür.

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Most cited references 21

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Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis.

Anna Yemelyanova, Russell Vang, Malti Kshirsagar … (2011)

Immunohistochemical staining for p53 is used as a surrogate for mutational analysis in the diagnostic workup of carcinomas of multiple sites including ovarian cancers. Strong and diffuse immunoexpression of p53 is generally interpreted as likely indicating a TP53 gene mutation. The immunoprofile that correlates with wild-type TP53, however, is not as clear. In particular, the significance of completely negative immunostaining is controversial. The aim of this study was to clarify the relationship of the immunohistochemical expression of p53 with the mutational status of the TP53 gene in ovarian cancer. A total of 57 ovarian carcinomas (43 high-grade serous ovarian/peritoneal carcinomas, 2 malignant mesodermal mixed tumors (carcinosarcomas), 2 low-grade serous carcinomas, 4 clear cell carcinomas, 1 well-differentiated endometrioid carcinoma, and 5 carcinomas with mixed epithelial differentiation) were analyzed for TP53 mutations by nucleotide sequencing (exons 4-9), and subjected to immunohistochemical analysis of p53 expression. Thirty six tumors contained functional mutations and 13 had wild type TP53. Five tumors were found to harbor known TP53 polymorphism and changes in the intron region were detected in three. Tumors with wild-type TP53 displayed a wide range of immunolabeling patterns, with the most common pattern showing ≤10% of positive cells in 6 cases (46%). Mutant TP53 was associated with 60-100% positive cells in 23 cases (64% of cases). This pattern of staining was also seen in three cases with wild-type TP53. Tumors that were completely negative (0% cells staining) had a mutation of TP53 in 65% of cases and wild-type TP53 in 11%. Combining two immunohistochemical labeling patterns associated with TP53 mutations (0% and 60-100% positive cells), correctly identified a mutation in 94% of cases (P<0.001). Immunohistochemical analysis can be used as a robust method for inferring the presence of a TP53 mutation in ovarian carcinomas. In addition to a strong and diffuse pattern of p53 expression (in greater than 60% of cells), complete absence of p53 immunoexpression is commonly associated with a TP53 mutation. Accordingly, this latter pattern, unlike low-level expression (10-50% cells), should not be construed as indicative of wild-type TP53.

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Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.

Natali Pflug, Jasmin Bahlo, Tait Shanafelt … (2014)

In addition to clinical staging, a number of biomarkers predicting overall survival (OS) have been identified in chronic lymphocytic leukemia (CLL). The multiplicity of markers, limited information on their independent prognostic value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We therefore performed an analysis of 23 prognostic markers based on prospectively collected data from 1948 CLL patients participating in phase 3 trials of the German CLL Study Group to develop a comprehensive prognostic index. A multivariable Cox regression model identified 8 independent predictors of OS: sex, age, ECOG status, del(17p), del(11q), IGHV mutation status, serum β2-microglobulin, and serum thymidine kinase. Using a weighted grading system, a prognostic index was derived that separated 4 risk categories with 5-year OS ranging from 18.7% to 95.2% and having a C-statistic of 0.75. The index stratified OS within all analyzed subgroups, including all Rai/Binet stages. The validity of the index was externally confirmed in a series of 676 newly diagnosed CLL patients from Mayo Clinic. Using this multistep process including external validation, we developed a comprehensive prognostic index with high discriminatory power and prognostic significance on the individual patient level. The studies were registered as follows: CLL1 trial (NCT00262782, http://clinicaltrials.gov), CLL4 trial (ISRCTN 75653261, http://www.controlled-trials.com), and CLL8 trial (NCT00281918, http://clinicaltrials.gov).

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Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial.

David Oscier, Sarah Hockley, S. Richards … (2011)

TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

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Author and article information

Journal

Journal ID (nlm-ta): Turk J Haematol

Journal ID (iso-abbrev): Turk J Haematol

Journal ID (publisher-id): TJH

Title: Turkish Journal of Hematology

Publisher: Galenos Publishing

ISSN (Print): 1300-7777

ISSN (Electronic): 1308-5263

Publication date (Print): March 2017

Publication date (Electronic): 1 March 2017

Volume: 34

Issue: 1

Pages: 34-39

Affiliations

[1 ] Hacettepe University Faculty of Medicine, Department of Pathology, Ankara, Turkey

[2 ] Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Oncology, Drug Resistance Laboratory, Ankara, Turkey

[3 ] Hacettepe University Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ankara, Turkey

[4 ] Author is currently appointed at Johns Hopkins University Faculty of Medicine, Baltimore, USA

Author notes

* Address for Correspondence: Johns Hopkins University Faculty of Medicine, Baltimore, USA Phone: +1 410 502 7354 E-mail: dribrahimkulac@ 123456gmail.com

Article

Publisher ID: 1958

DOI: 10.4274/tjh.2016.0115

PMC ID: 5451686

PubMed ID: 27174363

SO-VID: c50f1c35-ebd8-413d-a964-f2c22fd5260d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

TP53 Staining in Tissue Samples of Chronic Lymphocytic Lymphoma Cases: An Immunohistochemical Survey of 51 Cases Translated title: Kronik Lenfositik Lenfoma Hastalarının Doku Örneklerinde TP53 Boyaması: Elli Bir Hastanın İmmünohistokimya ile Değerlendirilmesi

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Abstract

Objective:

Materials and Methods:

Results:

Conclusion:

Translated abstract

Related collections

Karger: Oncology

Most cited references 21

Immunohistochemical staining patterns of p53 can serve as a surrogate marker for TP53 mutations in ovarian carcinoma: an immunohistochemical and nucleotide sequencing analysis.

Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.

Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial.

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