p53

p53 is a tumor suppressor protein encoded by the TP53 gene on chromosome 17. Upon detecting DNA damage, p53 binds to DNA and temporarily arrests the cell cycle to facilitate repair. If the damage cannot be repaired, p53 initiates apoptosis.

 Mutations in the TP53 gene impair the tumor suppressor function of p53 and such mutations are observed in approximately 50% of all malignancies.

In the absence of mutations, p53 exhibits a wild-type pattern, characterized by tumor cells showing a heterogeneous nuclear staining reaction that is typically weak to moderate in intensity.

p53 immunohistochemical (IHC) patterns indicative of underlying TP53 mutations:

p53 overexpression pattern: uniform, strong nuclear staining reaction.

Specific subtypes of overexpression show a basal-to-surface gradient, with staining intensity decreasing from strong to weak/negative, which may reflect cells permanently exiting the cell cycle:

-Basal overexpression: uniform, strong nuclear staining reaction in basal cells, without significant parabasal reaction in squamous epithelium.

-Terminal differentiation: staining decreases to absent towards the surface, in glandular epithelium. 

p53 absence pattern: complete lack of staining reaction in tumor cells, while background stromal cells, lymphocytes and endothelial cells show the normal wild-type pattern.

p53 cytoplasmic pattern: cytoplasmic staining with no nuclear staining reaction in tumor cells.

p53 IHC pattern indicative of HPV infection:

p53 basal-sparing pattern- complete lack of staining reaction in basal cells with heterogenous nuclear staining reaction in the mid portion of epithelium, associated with HPV infection and related to p53 inactivation by the E6 oncoprotein. 

• Ovarian serous neoplasms: p53 IHC helps distinguish high-grade serous carcinomas (p53 mutation pattern) from low-grade serous carcinomas (p53 wild-type).
• Ovarian high-grade serous carcinoma vs. grade 3 endometrioid carcinoma: p53 mutation pattern and WT1 positivity help distinguish high-grade serous carcinoma, as endometrioid carcinoma exhibits this profile in only 1% of cases. Endometrioid carcinomas with a p53 mutation pattern have a worse prognosis than wild-type cases.
• Precursor lesions of high-grade serous carcinomas: p53 IHC helps distinguish precursor lesions, such as serous tubal intraepithelial carcinoma (p53 mutation pattern), from the background uninvolved fallopian tube epithelium (p53 wild-type).
• Ovarian mucinous neoplasms: p53 IHC aids in distinguishing mucinous borderline tumors (p53 wild-type) from mucinous carcinomas (p53 mutation pattern), as TP53 mutations are significantly more common in mucinous carcinomas. 
• Endometrial carcinomas: p53 mutation pattern is characteristic of serous carcinomas but is also observed in ~25% of grade 3 endometrioid carcinomas. TP53 status is the strongest molecular predictor of prognosis, with the TP53-abnormal subtype having the worst outcomes, guiding treatment decisions. Subclonal p53 mutations, often linked to POLE mutations or MMR deficiency, are associated with a better prognosis than primary TP53-mutated carcinomas.
• Uterine mesenchymal neoplasms: Leiomyosarcomas and undifferentiated uterine sarcomas (pleomorphic-type) frequently show a mutation-type p53 immunostaining pattern. This finding can help distinguish them from other uterine mesenchymal tumors, which usually show a wild-type p53 pattern.
• Vulvar squamous cell carcinomas: Vulvar squamous cell carcinomas are classified as HPV-associated, HPV-independent with TP53 mutation and HPV-independent with normal p53. Accurate assessment of p53 status is important for subclassifying HPV-independent type, as TP53-mutated tumors show more aggressive behavior.
• Vulvar intraepithelial neoplasi (VIN): p53 IHC in combination with p16 helps distinguish differentiated VIN (p53 mutation pattern, sometimes presenting as basal overexpression, no p16 overexpression) from HPV-related VIN (p53 wild-type or basal sparing, p16 overexpression) and reactive squamous mucosa (p53 wild-type, no p16 overexpression).
• Barrets esophagus indefinite for dysplasia: In cases where dysplasia is indefinite, p53 IHC can help refine the diagnosis and form follow-up strategies, as the presence of a p53 mutation pattern is strongly linked to a higher risk of disease progression.
• Neuroendocrine neoplasmas: p53 IHC can aid in the differential diagnosis of neuroendocrine carcinoma (NEC) vs. grade 3 neuroendocrine tumor (NET). Biallelic inactivation of TP53 and RB1, immunohistochemically characterized by a p53 mutation pattern and Rb loss, is a defining feature of small cell lung cancer but is also frequently observed in extrapulmonary visceral and large cell NEC. In contrast, NETs rarely exhibit this pattern and when present, it is likely associated with clinical progression/ prior chemo- or radiotherapy.
• Hematologic malignancies: TP53 mutations are linked to various hematologic malignancies, contributing to the transformation of low-grade B-cell lymphomas into high-grade forms and correlating with poor prognosis in mantle cell lymphoma, large B-cell lymphoma, myelodysplastic syndrome and acute myeloid leukemia. 
• Low-grade astrocytoma vs gliosis: p53 immunohistochemistry, combined with IDH and ATRX testing, can help differentiate astrocytomas (p53 mutation pattern, ATRX-lost, IDH-positive) from reactive gliosis (p53-wild type, ATRX-intact, IDH-negative).

Tonsil and appendix are the recommended external positive and negative tissue controls. 

More than 50% of germinal center B-cells in the tonsil should exhibit weak to moderate nuclear staining reaction, while less than 50% of mantle zone B-cells should show a nuclear staining reaction. 

In the appendix, dispersed epithelial cells in the basal parts of the crypts should demonstrate weak to moderate nuclear staining reaction, whereas virtually all luminal epithelial cells must remain negative.

It is important that stromal cells, lymphocytes and endothelial cells in clinical samples serve as internal positive tissue controls.