Compiled and organized: HadronsThe role of p63 immunohistochemistry in the pathological diagnosis of the breast
1.Confirm the presence of normal myoepithelial cells at the epithelial-mesenchymal junction to distinguish benign, in situ lesions, and invasive breast cancers. Common diagnostic applications in this setting include: (1) differentiating radiation scars from tubular cancer; (2) the differentiation of complex sclerosing lesions from low-grade non-special types of invasive cancer; (3) differentiation of ductal carcinoma in situ involving sclerosing lesions and invasive carcinoma; (4) differentiation of ductal carcinoma in situ from ductal carcinoma-like invasive carcinoma; (5) Classification was carried out according to the presence or distribution of fibrovascular axis and myoepithelial cells around the lesion in papillary lesions.
Invasive breast cancer is generally characterized by loss of p63 staining at the epithelial-stromal junction, whereas benign or in situ lesions are generally positive staining of p63 nuclei at this junction, i.e., myoepithelial cells. However, some rare benign proliferative epithelial lesions (eg, infiltrating epitheliosis) and some benign apocrine papillary lesions may not have p63 expression at the epithelial-interstitial junction, at least focially.
Figure 3Infiltrative epithelial proliferation (A) with focal loss of p63 expression at the epithelial-interstitial junction (B) is considered to be an invasive lesion. However, there are also p63-positive myoepithelial cells in the periphery, and the negative and positive areas are gradually transitioning, which can prompt us to make an accurate diagnosis.
In addition, some proliferative lesions with squamous, myoepithelial, and spindle cell differentiation can express p63, and this result should not be confused with the normal presence of intrinsic myoepithelial cells in the vicinity of benign, orthotopic lesions. Low-grade adenosquamous cell carcinoma is an example of a malignancy that may have a peripheral p63-positive staining that resembles innate myoepithelial cells and may therefore be mistaken as an in situ lesion.
2.Confirm whether the proliferative cells in some lesions (eg, adenomyoepitheloma, pleomorphic adenoma) are luminal epithelial or myoepithelial phenotypes;
3.Confirm the epithelial nature of the spindle cell component in metaplastic breast cancer, excluding other diagnoses such as phyllodes tumors. Like high-molecular-weight CK, immunohistochemistry P63 positivity can be used in breast pathology to distinguish mild epithelial ** spindle cell lesions (e.g., fibromatosis-like carcinoma) from mesenchymal or interstitial spindle cell lesions (benign or locally aggressive), and for sarcoma to spindle cell metaplastic carcinoma.
4.Confirm the squamous nature of cells in squamous cell metaplastic carcinoma, mucinous epidermoid carcinoma, and other metaplasia with squamous cell components, as well as in benign lesions. Immunohistochemistry p63 does not help distinguish primary squamous cell carcinoma of the breast from squamous cell carcinoma or metastatic squamous cell carcinoma. Evaluation for squamous cell carcinoma of the breast needs to include the precise location of the lesion (** or breast parenchyma), the presence of carcinoma in situ, other immunohistochemical markers, and relevant clinical history.
5.To distinguish ** appendage tumors and salivary adenoid lesions with myoepithelial differentiation, such as hidradenomas and adenoid cystic carcinomas;
6.Used to distinguish primary or metastatic breast cancer involvement** from primary apocrine adenocarcinoma. Immunohistochemistry p63 positivity can be seen in 81% of apocrine carcinomas, while the positive rate of breast cancer metastasis is only 6%, indicating that p63 is a relatively specific marker for primary apocrine adenocarcinoma of the breast in this setting.
7.Aids in the diagnosis of Pagot disease by excluding squamous differentiation.
Detailed description of the application of p63 in specific diseases of breast pathology (1).
Papillary lesions.
Determining the presence or absence of myoepithelial cells at the epithelial-stromal junction is critical for the classification of papillary lesions. In classical intraductal papillomas, immunohistochemical p63 is positive for myoepithelial cells in the fibrovascular axis and also in the periphery of the lesion. In intraductal papillomas with atypical or ductal carcinoma in situ, p63 expression is absent in the affected area, but p63 expression is present in the rest of the area and around the lesion.
Figure 4Some intraductal papillomas involved by ductal carcinoma in situ (black arrows) with regional immunohistochemical p63 focal loss of neoplastic hyperplasia; P63 is also stained around the lesion and in benign areas. Immunohistochemistry of ER and basal CK confirmed the clonality of the lesion.
In papillary ductal carcinoma in situ, p63 is not expressed in the nipple, but is still expressed in the periphery; In encapsulated and solid papillary carcinomas, p63 is not expressed within the lesion, but the degree of expression around the lesion is unequal, or it is absent.
Figure 5intraductal papillary lesions, coarse needle aspiration biopsy, histologic partial involvement of ductal carcinoma in situ with low-grade nuclei; Immunohistochemistry p63 showed the presence of myoepithelial cells at the epithelial and mesenchymal junctions in the residual benign or proliferative papillary components.
Figure 6Crude needle aspiration biopsy specimens are morphologically solid papillary carcinoma with no peripheral myoepithelial cells and no staining of immunohistochemical p63, making it difficult to distinguish between non-invasive and invasive carcinomas, especially if there are irregular nested multinodular manifestations.
An important pitfall of immunohistochemistry p63 in the evaluation of papillary lesions is that some hyperplastic epithelial cells may be p63 positive. This may be focal myoepithelial cells or early squamous differentiation that can occur in some papillary tumors. Among the papillary lesions with overlapping morphological characteristics with pleomorphic adenomas, squamous differentiation and myoepithelial cell differentiation are generally more pronounced.
Figure 7In encapsulated papillary carcinoma, there is significant p63 staining in the surrounding focal areas and lesions, which may be focal myoepithelial cells or early squamous differentiation, which can indeed be seen in some papillary tumors.
Figure 8Solid papillary carcinoma, with squamous metaplasia in some areas, that is, the corresponding immunohistochemistry P63 positive area in the lesion.
P63 can also be used in coarse needle aspiration biopsy specimens and sometimes in excision specimens to distinguish papillomas from hidradenomas: proliferative cells in hidradenomas are diffuse, strongly positive for P63 (and ER-negative), whereas papillomas are generally found only in cells lining the fibrovascular axis and surrounding lesions.
Non-specific type of invasive breast cancer.
P63 positivity has been reported in non-specific invasive breast cancers, but based on the experience of the authors of this article, this positive staining is uncommon and, if present, is generally focal and weakly positive. Possible explanations for the occasional p63 positivity in non-specific types of invasive breast cancer are: tumor progression with new expression of p63 (neoexpression), abnormal differentiation of malignant epithelial cells and reprogramming of other cell lineages** differentiation (e.g., differentiation into squamous cells or myoepithelial cells) with phenotypic remodeling including p63 positivity, heterologous differentiation in the early stages of tumor evolution leading to biphasic morphology (eg, adenocarcinoma cells with squamous cells or spindle cells, or both epithelioid tumor cells and myoepithelioid tumor cells proliferate).
On full evaluation, these p63-positive tumors are most commonly found to have focal squamous features in HE sections and are generally high molecular weight CK positive. These tumors should not be confused with "basal-like" breast cancer, which mainly expresses vimentin, basal CK (eg, CK5 6, CK14, CK17), EGFR, P-cadherin, and occasionally myogenic markers (eg, SMA, SMMHC), but P63 is not expressed or is weakly positively expressed.
Some non-specific types of invasive breast cancer also express S100, and some cancers (e.g., secretory cancer) are diffuse and strongly positive. S100 expression in these tumors may not be a response to the myoepithelial phenotype, and these tumors are generally p63-negative.
The expression of p63 in non-specific types of invasive cancer may also reflect the differences in antibodies, detection methods, and interpretation standards. It is well known that different antibodies against the same target protein can have significant differences in binding characteristics, and changes in detection protocols can have a significant impact on the proportion of cases in which a particular protein is considered "positive".
——To be continued——
Previous review: immunohistochemistry p63 in breast pathology (I).
Immunohistochemistry p63 in breast pathology (II).