الفهرس 
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Abstract
Papillary lesions of the breast encompass a heterogenous group of lesions that have scale from benign intraductal papilloma to frank invasive papillary carcinoma. They represent about 10% of benign lesions and less than 2% of all breast cancer. Benign IDP alone constitutes 70% to 85% of the breast papillary lesions diagnosed on core needle biopsy (CNBs).
According to the latest WHO classification 5th edition in 2019, papillary breast lesions are classified into intraductal papilloma, papillary DCIS, encapsulated papillary carcinoma, encapsulated papillary carcinoma with invasion, solid papillary carcinoma in-situ, solid-papillary carcinoma with invasion, invasive solid papillary carcinoma and invasive papillary carcinoma. Papillary lesions of the breast manifest themselves in many variable and wide clinical presentations, it has a spectrum of completely silent and accidentally discovered lesions up to a palpable mass or even metastatic complications.
Papillary neoplasms have never been studied at the molecular level in detail. Only a few studies that had been released evaluating copy number alterations (CAN) and admitted the high prevalence of (PIK3CA\AKT1) pathway mutation in benign IDP, but interestingly not in malignant lesions. IDP is the only papillary neoplasm with a continuous, readily demonstrable layer of MECs along the papillae and around the dilated duct that contains it. Although the myoepithelial layer is always present at the fronds and the periphery of the lesion, it may be inconspicuous in many cases and difficult to evaluate by pathologists.
Though the WHO classification 5th edition considers benign papilloma as a single broad entity, benign intraductal papilloma are still subdivided into solitary, multiple and sclerosing papilloma. Multiple papilloma (MPs) is defined as “more than only a single papilloma that is usually peripherally located”. On the other hand, the term papillomatosis is preserved when five or more papillomata are present and separated from each other by uninvolved mammary tissue within a localized segment of breast tissue.
The management of papillary tumors of the breast is widely variable and highly controversial and sophisticated. Different spectrums and entities of the papillary breast lesions, also the different procedures done to diagnose and treat these lesions make the management challenging. In the past, complete surgical excision was the routine procedure done for patients diagnosed with intraductal papilloma by tru cut biopsy to rule out any suspicious underlying malignancy.
Many publications and updates were released over the years, most of them were relying on evaluating upgrade rates of intraductal papilloma to in-situ or invasive cancer after the surgical excision. In IDP with atypia, the range of upgrade is 30-40 % and it reaches 70% in some studies. So, nearly all updated opinions recommend surgical excision for papillary lesions following an image-guided core needle biopsy when atypia is diagnosed. Treatment for papilloma without atypia is still controversial at this moment and no agreement has been reached, but most recommendations are that patients with intraductal papilloma without atypia shown on needle core biopsy can safely undergo active surveillance.
The definite diagnosis of papillary breast lesions is not uncommon to be challenging. Many controversial histopathologic features regarding the diagnosis of papillary lesions of the breast face the pathologists nowadays especially with the improvement of imaging and biopsy modalities. The last edition of WHO 2019 made multiple modifications in the categories and criteria of these heterogeneous group of lesions, but some obstacles are still affecting the concordance and diagnostic reproducibility of these lesions. In addition, papillary breast lesions are commonly liable to technical artifacts related to multiple factors starting from needling process, inappropriate specimen and mechanical factors. A core-needle biopsy (CNB) under image guidance is the standard procedure done for papillary breast lesions, the needling process has some difficulties either in precise diagnosis or artifactual problems. One of the significant problems of needling procedures either fine needle aspiration, needle core biopsy or wire localization is “artifactual epithelial displacement”. Displaced epithelium either clustered or single cells could be misinterpreted as invasive component.
P63 is a well-known sensitive and specific marker for the nuclei of myoepithelial cells. Importantly, it is not expressed in stromal cells including myofibroblasts and pericytes, circumventing the diagnostic pitfalls associated with smooth muscle-related myoepithelial markers such as smooth muscle myosin heavy chain, and calponin.
Although the nuclear staining (p63) does not cross react with vascular components of papillary lesions in contrast to other cytoplasmic myoepithelial markers, it may show some misinterpretation with different lesions. In many cases, staining with p63 appears dotted and discontinuous, making the interpretation of an intact myoepithelial layer difficult. p63 may show false positive reactivity with high nuclear grade of papillary carcinomas. It could give a positive result with squamous epithelial differentiation either benign squamous metaplasia or low-grade adenosquamous carcinoma. The benign apocrine lesions, including papillary ones, may lack the reactivity of p63 so they may be misjudged as malignancy.
We aimed to evaluate the interobserver agreement rates between pathologists regarding histologic diagnosis of papillary breast lesions, with and without the use of immunohistochemical staining for myoepithelial layer.
This retrospective study was carried out on 51 cases of papillary lesions of the breast. The concordance rate and interrater reliability were assessed using the Fleiss kappa scoring method and Intraclass Correlation Coefficient (ICC) among 5 certified pathologists. The first-round review was performed using hematoxylin and eosin only. 16 multiple choice questions were scored by the observers via an electronic google form. The discordant cases that calculated by statistical analysis (22 cases) had been applied for second round review using P63 immunostaining.
The assessment of the final diagnosis regarding the 51 cases had substantial agreement between the 5 observers (Fleiss kappa 0.65) and the strength of agreement was 56.9 % before IHC aids. After p63 immunostaining, the diagnostic reproducibility showed marked improvement with an overall increase of Fleiss kappa score from substantial (0.65) to excellent κ score (0.82) and increase concordance rate from moderate 56.9 % to perfect agreement 82.4%.
Regarding the assessment of each diagnostic category, benign and malignant cases had almost excellent agreement levels while atypical intraductal papilloma showed fair agreement level between the observers.
Invasive solid papillary carcinoma had perfect agreement between observers (κ score = 1).
Intraductal papilloma, invasive carcinoma with DCIS and EPC with invasion had almost perfect agreement between the observers (0.924, 0.944, 0.922 respectively).
Papillary DCIS had the least k score (0.254) as fair agreement between the observers, followed by papilloma with DCIS and papilloma with ADH; both had moderate agreement between the observers (0.605, 0.692 respectively).
Many overlapping histopathologic features regarding the papillary lesions of the breast such as the state of fibrovascular cores and degree of epithelial proliferation are still challenging. The definite extent of atypical foci in intraductal papilloma is highly debatable between the pathologists. All these challenging features are still affecting the diagnostic reproducibility of papillary lesions of the breast. Papillary DCIS and atypical IDP showed the lowest diagnostic reproducibility compared to benign and malignant ones. However, p63 staining generally improves the interobserver variability and concordance rate between the observers and its utility is recommended in challenging cases