Greater specificity of p40 compared with p63 in distinguishing squamous cell carcinoma from adenocarcinoma in effusion cellblocks

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Abstract

Objective:

Squamous cell carcinoma (SCC) rarely causes malignant effusions. Distinguishing between SCC and adenocarcinoma in effusion cytology can be a challenge. p63 and p40 have been frequently used to support squamous cell differentiation in both histological and cytological specimens. However, similar results in cytological preparations of effusion fluids have been rarely reported. This study was designed to assess the diagnostic value of p63 and p40 immunoreactivity for the differentiation of SCC from adenocarcinoma in malignant effusions.

Materials and Methods:

Immunocytochemical staining of p63 and p40 was performed on thirty cellblock specimens, including ten malignant effusions carrying SCC and twenty malignant effusions showing adenocarcinoma. Any degree of nuclear staining was considered positive.

Results:

Of the ten SCC cases, 100% tested positive for both p63 and p40, and most cases showed diffuse staining (>25% of tumor cells). The expression of p63 and p40 was detected in 4 (20%) and 2 (10%) of twenty adenocarcinoma cases, and the extent of staining was all focal (≤25% of tumor cells). The p63 reactivity showed 100% sensitivity, 80% specificity, 71% positive predictive value, and 100% negative predictive value for the differentiation of SCC from adenocarcinoma in malignant effusions. The sensitivity of p40 for SCC was 100%, the specificity was 90%, the positive predictive value was 83%, and the negative predictive value was 100%.

Conclusion:

Although p63 and p40 are both useful markers for the diagnosis of SCC in malignant effusions, p40 is more specific than p63 in distinguishing SCC from adenocarcinoma.

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Most cited references 21

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Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

Hisayuki Shigematsu, Li. Lin, Takao Takahashi … (2005)

Mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene in lung cancers are associated with increased sensitivity of these cancers to drugs that inhibit EGFR kinase activity. However, the role of such mutations in the pathogenesis of lung cancers is unclear. We sequenced exons 18-21 of the EGFR TK domain from genomic DNA isolated from 617 non-small-cell lung cancers (NSCLCs) and 524 normal lung tissue samples from the same patients and 36 neuroendocrine lung tumors collected from patients in Japan, Taiwan, the United States, and Australia and from 243 other epithelial cancers. Mutation status was compared with clinicopathologic features and with the presence of mutations in KRAS, a gene in the EGFR signaling pathway that is also frequently mutated in lung cancers. All statistical tests were two sided. We detected a total of 134 EGFR TK domain mutations in 130 (21%) of the 617 NSCLCs but not in any of the other carcinomas, nor in nonmalignant lung tissue from the same patients. In NSCLC patients, EGFR TK domain mutations were statistically significantly more frequent in never smokers than ever smokers (51% versus 10%), in adenocarcinomas versus cancer of other histologies (40% versus 3%), in patients of East Asian ethnicity versus other ethnicities (30% versus 8%), and in females versus males (42% versus 14%; all P < .001). EGFR TK domain mutation status was not associated with patient age at diagnosis, clinical stage, the presence of bronchioloalveolar histologic features, or overall survival. The EGFR TK domain mutations we detected were of three common types: in-frame deletions in exon 19, single missense mutations in exon 21, and in-frame duplications/insertions in exon 20. Rare missense mutations were also detected in exons 18, 20, and 21. KRAS gene mutations were present in 50 (8%) of the 617 NSCLCs but not in any tumors with an EGFR TK domain mutation. Mutations in either the EGFR TK domain or the KRAS gene can lead to lung cancer pathogenesis. EGFR TK domain mutations are the first molecular change known to occur specifically in never smokers.

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p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma.

Giuseppe Pelosi, Gail Bishop, James W Travis … (2012)

Immunohistochemistry has recently emerged as a powerful ancillary tool for differentiating lung adenocarcinoma and squamous cell carcinoma-a distinction with important therapeutic implications. Although the most frequently recommended squamous marker p63 is extremely sensitive, it suffers from low specificity due to its reactivity in a substantial proportion of lung adenocarcinomas and other tumor types, particularly lymphomas. p40 is a relatively unknown antibody that recognizes ΔNp63-a p63 isoform suggested to be highly specific for squamous/basal cells. Here we compared the standard p63 antibody (4A4) and p40 in a series of 470 tumors from the archives of Memorial Sloan-Kettering Cancer Center and The Johns Hopkins Hospital, which included lung squamous cell carcinomas (n=81), adenocarcinomas (n=237), and large cell lymphomas (n=152). The p63 was positive in 100% of squamous cell carcinomas, 31% of adenocarcinomas, and 54% of large cell lymphomas (sensitivity 100%, specificity 60%). In contrast, although p40 was also positive in 100% of squamous cell carcinomas, only 3% of adenocarcinomas, and none of large cell lymphomas had p40 labeling (sensitivity 100%, specificity 98%). The mean percentage of p63 versus p40-immunoreactive cells in squamous cell carcinomas was equivalent (97 vs 96%, respectively, P=0.73). Rare adenocarcinomas with p40 labeling had reactivity in no more than 5% of tumor cells, whereas the mean (range) of p63-positive cells in adenocarcinomas and lymphomas was 26% (1-90%) and 48% (2-100%), respectively. In summary, p40 is equivalent to p63 in sensitivity for squamous cell carcinoma, but it is markedly superior to p63 in specificity, which eliminates a potential pitfall of misinterpreting a p63-positive adenocarcinoma or unsuspected lymphoma as squamous cell carcinoma. These findings strongly support the routine use of p40 in place of p63 for the diagnosis of pulmonary squamous cell carcinoma.

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Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer.

Stephen Shepherd, Giorgio Scagliotti, Christian Manegold … (2011)

Recently, histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer (NSCLC). These analyses evaluate whether the differential efficacy of pemetrexed by NSCLC histology is reproducible and consistent across three registration studies of different lines of therapy (first-line/second-line and maintenance settings). The reported studies for patients with advanced NSCLC were pemetrexed versus docetaxel in previously treated patients (N = 571), cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (N = 1725), and maintenance pemetrexed plus best supportive care versus placebo plus best supportive care (N = 663). Cox models of overall survival (OS) and progression-free survival (PFS) were used to test for a significant treatment-by-histology interaction (THI). A significant THI indicates that the efficacy benefit for pemetrexed relative to the control arm is greater in patients with nonsquamous histology than in those with squamous histology. Subsequent Cox models were used to estimate hazard ratios for OS and PFS according to histology. Histology was well balanced between treatment arms in each study. Across all three studies, no clinically relevant differences were observed for the safety profile of pemetrexed among histologic groups. THIs were statistically significant in all three studies for OS (p = 0.001, 0.002, and 0.033, respectively) and PFS (p = 0.004, 0.002, and 0.036, respectively). These analyses demonstrate a statistically significant interaction between treatment effect and NSCLC histology, indicating superior efficacy of pemetrexed in nonsquamous patients compared with other standard treatment options. Thus, histology is consistently predictive of the improved efficacy of pemetrexed in patients with nonsquamous NSCLC.

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Author and article information

Journal

Journal ID (nlm-ta): Cytojournal

Journal ID (iso-abbrev): Cytojournal

Journal ID (publisher-id): Cytojournal

Title: CytoJournal

Publisher: Scientific Scholar

ISSN (Print): 0974-5963

ISSN (Electronic): 1742-6413

Publication date (Electronic): 08 June 2020

Publication date Collection: 2020

Volume: 17

Electronic Location Identifier: 13

Affiliations

[1 ]Department of Pathology , Chonnam National University Medical School, Gwangju, Republic of Korea.

Author notes

[* ] Corresponding author: Ji Shin Lee, MD, PhD Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea. jshinlee@ 123456hanmail.net

Article

Publisher ID: Cytojournal-17-13

DOI: 10.25259/Cytojournal_78_2019

PMC ID: 7332517

SO-VID: a4a22b0f-c31a-416f-81e4-0c375d8fdc18

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial- Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Greater specificity of p40 compared with p63 in distinguishing squamous cell carcinoma from adenocarcinoma in effusion cellblocks

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Abstract

Objective:

Materials and Methods:

Results:

Conclusion:

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Journal of Circulating Biomarkers

Most cited references 21

Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers.

p40 (ΔNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma.

Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer.

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