The 40th Issue of “Mai Mai” Pathology Weekly Reading Notes | Immunohistochemical Markers for Aiding Diagnosis of Dysplasia and Malignant Transformation

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6 2 月, 2026

On 6 2 月, 2026

Introduction:

In the first article of this series, we mentioned that if pathology were a martial arts world, thenroutine diagnosis would be akin to basic martial arts skills, whileimmunohistochemistry could be considered as weapons or hidden weapons, highlighting the importance of immunohistochemistry in pathological diagnosis. This article is the final installment of this series. ‘Maimai’ hopes that throughCompilation of the book “Immunohistochemistry in Tumor Diagnostics”, pathologists can gain a deeper understanding of immunohistochemistry techniques and become more proficient in the rational and correct selection of immunohistochemical markers.

Read more books, read good books. Maimai looks forward to continuing to explore a wide range of books with you, seeking truth and enlightenment.

Immunohistochemical Markers for Assisting in the Diagnosis of Dysplasia and Malignant Transformation

Detailed Explanation of Some Markers

Ki-67

Ki-67 is a nonhistone nuclear protein. Its expression begins in the G1 phase of the cell cycle and continues through the S, G2, and M phases; it is undetectable during the G0 phase or the initial stage of G1 phase, as well as during DNA repair. Therefore, Ki-67 expression is significantly correlated with the degree of cell proliferation and tumor grade. In daily practice, Ki-67 is an important indicator for assessing cell proliferation and a crucial marker for tumor diagnosis (used to differentiate between benign, borderline, and malignant tumors or low-grade and high-grade tumors). Additionally, this marker is helpful in distinguishing between atrophy, cautery changes, and dysplasia. Specifically, a Ki-67 positivity rate exceeding 30% in cells throughout the layers above the basal layer in stratified squamous epithelium indicates abnormal or dysplastic epithelium. Furthermore, Ki-67 is also an important marker for distinguishing between low-grade and high-grade lymphomas.

p53

p53 is a phosphorylated protein located in the cell nucleus, encoded by the TP53 gene on 17p13, with several subtypes. p53 is a tumor suppressor protein that, upon binding to DNA, induces the synthesis of p21 protein. p21 regulates gene stability and binds to the cell division-stimulating protein CDK2. The complex of p21 and CDK hinders the cell from entering the next phase of cell division. Mutations in the TP53 gene lead to overexpression and accumulation of the mutated p53 protein. Mutated p53 cannot bind to DNA or stimulate p21 synthesis, thus failing to provide a stop signal for the cell cycle, resulting in uncontrolled proliferation of the affected cells.

Overexpression of p53 is associated with various tumors and precancerous lesions. Immunohistochemical detection of p53 can be used to differentiate between dysplastic or neoplastic lesions and reactive changes, as the former two often show mutant-type expression, while the latter typically exhibits wild-type expression. Specific examples include: distinguishing reactive urothelium from urothelial carcinoma in situ and transitional cell carcinoma; differentiating flat dysplasia in colonic mucosa and dysplasia in ulcerative colitis from reactive dysplasia; distinguishing reactive squamous epithelium in the cervix or vagina from intraepithelial neoplasia (CIN or VIN); differentiating normal pancreatic ducts from mucinous cystic neoplasms; confirming dysplasia in esophageal columnar mucosa; determining transformation of B-cell small cell lymphoma/leukemia to high-grade lymphoma (i.e., Richter syndrome); and diagnosing secondary glioblastoma. Additionally, uterine serous carcinoma shows mutant-type expression of p53.

IMP3

IMP3 has been discussed in the mesothelioma chapter. Except in the ovaries, testes, placenta, endocrine cells, and brain tissue, benign adult tissues generally do not express this marker. In daily practice, IMP3 is used to differentiate between malignant and reactive proliferative lesions: similar to GLUT1 and BAP-1, IMP3 is helpful in distinguishing mesothelioma from reactive mesothelial hyperplasia, as most benign mesothelial cells do not express IMP3.

GLUT-1

This marker is a member of the glucose transporter protein family, belonging to membrane-associated erythrocyte glucose transporters, maintaining basal glucose transport in most cells. In practical diagnosis, this marker is a potential indicator of malignant transformation and is highly expressed in many malignant epithelial and non-epithelial tumors. For example, it helps differentiate between benign and malignant pancreatic glands and assists in distinguishing reactive mesothelial hyperplasia from malignant mesothelioma.

BAP-1

BAP-1 is a nuclear ubiquitin hydrolase that functions as a transcriptional regulator and tumor suppressor, as detailed in the mesothelioma chapter. Deletions in different parts of the corresponding gene are observed in certain malignant tumors (such as mesothelioma, retinal and cutaneous malignant melanoma, renal cell carcinoma and clear cell carcinoma, lung adenocarcinoma, meningioma). In daily practice, BAP-1 helps differentiate reactive mesothelial hyperplasia and benign melanocytic lesions from malignant mesothelioma and malignant melanoma, with the former two being positive and the latter two not expressing it.

CEA

Carcinoembryonic antigen (CEA) is normally expressed in the mucosa of fetal colon and to a lesser extent in adult colonic mucosa. Various types of adenocarcinomas in different organs show high expression of CEA. Overexpression of CEA in adenomas or precancerous lesions is related to the grade of dysplasia and can serve as an indication of malignant transformation.

CD24

CD24 is a glycoprotein that functions as a cell adhesion molecule, expressed on the surface of most B lymphocytes and mature granulocytes, squamous epithelium, renal tubular epithelium, neuroblasts, and regenerative tissues. Overexpression of CD24 detected by immunohistochemistry on paraffin-embedded sections is speculated to be a marker for dysplasia in oral and cervical mucosa. Overexpression of CD24 is found in various tumors, such as colorectal cancer, cholangiocarcinoma, breast cancer, prostate cancer, and cervical cancer. For neoplastic lesions, CD24 is an important regulator of proliferation and invasion. Generally, overexpression of CD24 within tumors is associated with aggressive biological behavior and poor prognosis.

p16

p16 protein is a cyclin-dependent kinase inhibitor A2 encoded by the CDKN2A gene, playing a crucial role in preventing cells from transitioning from G1 phase to S phase, thus acting as a tumor suppressor. Various mutations or deletions in the CDKN2A gene are observed in multiple epithelial and mesenchymal tumors. p16 is overexpressed in HPV-related intraepithelial neoplasia and squamous cell carcinomas at different sites (such as vulva, vagina, cervix) and laryngeal cancer. Additionally, p16 is very helpful in distinguishing benign lipomas (p16 negative) from well-differentiated liposarcomas (p16 positive).

Conclusion: Considerations for the Application of Immunohistochemistry in Tumor Diagnosis

Immunohistochemistry has become an extremely powerful diagnostic tool in tumor diagnosis, but its practical application requires professional theoretical knowledge and practical experience. Accurate tumor diagnosis, regardless of the measures taken, must start with appropriate and reasonable specimen handling; specifically for immunohistochemistry, it also involves the standardization of related techniques, rational selection of antibodies, and accurate interpretation of results. Therefore, at the end of this series of compiled articles, we offer the following recommendations:

First and foremost, remember that careful morphological evaluation combined with clinical information remains the foundation of pathological diagnosis; the purpose of immunohistochemical testing is to support or rule out possible diagnoses;
The work of an immunohistochemistry laboratory includes several aspects: well-trained pathologists; highly specialized testing methods and immunohistochemistry techniques; staff must understand morphology and be able to accurately interpret immunohistochemical staining results;
Single-marker immunohistochemical testing is the most common cause of errors in tumor diagnosis immunohistochemistry. No single marker result can be entirely relied upon! Necessary marker combinations help avoid misdiagnosis; and when confirming or ruling out a diagnosis, always select two or more markers;
Understanding the nature of the antigen to be detected is crucial for result interpretation. Specifically, consider the following questions:

1) Antigen expression pattern: nuclear, cytoplasmic, membranous, extracellular?

2) Stability of the antigen during tissue processing: standardized specimen fixation and processing, as well as good section quality, are critical for immunohistochemistry results;

3) Tumors are composed of various cell types, and even within the tumor component, there is genetic and phenotypic heterogeneity. Atypical antigen expression patterns may be due to tumor biological heterogeneity or issues with the antigen used.
The properties of new antibodies must be carefully studied. Specifically, consider the following questions:

1) Antibody type: polyclonal or monoclonal? If monoclonal, note the clone number;

2) Sensitivity and specificity, recommended dilution ratio;

3) Be particularly cautious when using newly developed antibodies. New antibodies generally have strong specificity initially, but specificity often decreases after a period of use or upon validation with tissue microarrays;

4) Sensitivity and specificity of the detection system used.
Standardization of immunohistochemistry methods is an important part of accurate result interpretation; positive and negative controls are meaningful for result interpretation;
Interpretation and reporting of immunohistochemistry results must also be standardized. Simply judging staining results as positive or negative is insufficient; staining quality, intensity, and pattern should also be considered and recorded, and conflicting results must be analyzed and explained. Standardized reporting is very helpful for accurate diagnosis;
Although immunohistochemistry has high sensitivity and a large number of antibodies available, this method also has its own limitations. Do not force a diagnosis based on ambiguous or non-specific results. Some cases must be confirmed by other methods.

Maimai Recommends: “A correct choice is worth more than a hundred times the effort of a wrong one! This issue, Maimai recommends the following products for you!””

Antibody Name	Clone Number	Positive Control	Cellular Localization
CEA*	MX068	Lung adenocarcinoma, appendix	Cytoplasmic
^GLUT-1	SPM498	Placenta, colon adenocarcinoma	Membranous
IMP3	EP286	Pancreatic cancer, colon adenocarcinoma	Membranous/Cytoplasmic
^Ki-67*	MXR002	Tonsil, breast cancer	Nuclear
p16*	MX007	Cervical squamous cell carcinoma, tonsil	Nuclear/Cytoplasmic
^p53*	MX008	Gastric cancer, ovarian serous carcinoma	Nuclear

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