All invasive carcinomas (NST and special types) are morphologically subdivided according to their degree of differentiation which reflects how closely they resemble normal breast epithelium. To objectively assess the histological grade, the original methods by Patey & Scarff [35] and Bloom & Richardson [36], have been modified by Elston & Ellis [37]. According to this method, the following three tumor features are evaluated to assess the histological grade: tubule formation, as expression of glandular differentiation; nuclear pleomorphism; and mitotic counts. A numerical scoring system of 1 to 3 is used to separately evaluate each feature. Table 2.2 shows how to assign each score to each feature in order to determine the final grading by summing all the scores. Moreover, Table 2.3 shows some score thresholds for mitotic counts with the corresponding diameters of the high power field (HPF) of the microscope. It is necessary to determine the diameter of a HPF, because it varies with the different oculars of the microscope. The three values obtained with the evaluation of each feature are added together to produce scores of 3 to 9, to which the histological grade is assigned as follows: 3–5 points, well differentiated (grade 1); 6–7 points, moderately differentiated (grade 2); 8–9 points, poorly differentiated (grade 3). To obtain an optimal evaluation of histological grade, a high quality of tissue preservation and of histological section, in terms of cutting and staining, is required. Histological grade is a powerful prognostic factor. In unselected breast cancer series, the overall survival is significantly better in patients with grade 1 tumors (about 75% of patients alive after more than 20 years from the diagnosis), than in those with grade 2 or grade 3 tumors (about 55% and 45% of patients alive after more than 20 years from the diagnosis, respectively). For these reasons, histological grade should be included as a component of the minimum dataset for histological reporting of early invasive breast cancer.

Tumor size is indispensable to determine the pathological “T” in TNM system published by American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), which is the most widely used system for staging breast cancer [15]. For this purpose, the evaluation of tumor size is performed on the gross and microscopic examination. T classification depends on the maximum size of invasive carcinoma; concomitant DCIS should not be considered. If multiple areas of invasion are present, T classification is based on the largest focus. A small cancer and some special types of breast carcinomas, such as the classical variant of ILC, are often best evaluated by measuring size on glass slides. Increasing tumor size is independently associated with a worsening survival, with a 10-years cumulative survival of 0.9 in tumors less than 1 cm in maximum diameter, against a 10-years cumulative survival of 0.5 in tumors more than 2.5 cm in maximum diameter [38]. For these reasons, the size of invasive carcinoma should always be specified in the histological report of early invasive breast cancer.

Lymph node status is the most important single prognostic factor for all except a small group of breast cancers that appear to metastasize hematogenously without the involvement of nodes. For example, basal-like carcinomas, a molecular subtype with a poor prognosis, is rarely associated with an extensive nodal involvement; for the patients affected by this cancer, other prognostic markers are more important than nodal staging. Nodal metastases are strongly correlated with tumor size and the number of invasive carcinomas [38]. According to the TNM system, a lymph node can be macrometastatic (presence of a metastatic deposit > 0.2 cm in size: N1), micrometastatic (> 0.02 cm, up to 0.2 cm; or > 200 cells in a single nodal cross-section: N1(mi)), or can show isolated tumor cell clusters (ITCs, no larger than 0.02 cm, or < 200 cells in a single nodal cross sections: N0(i+)) [15]. While the presence of macrometastatic lymph nodes and the number of positive nodes are strongly related to prognosis, the presence of micrometastases or ITCs seem to have actually a limited impact on prognosis, estimable in less than 3% at 5 and 10 years when compared with node-negative women [39]. Moreover, positive nodes are a marker of distant dissemination and surgical removal of lymph nodes does not appear to have a major effect on survival [40]. Finally, even if negative nodes are a favorable prognostic factor, 10–30% of patients will eventually develop distant metastases.

Lymphovascular invasion (LVI) can be present in up to 50% of invasive breast carcinomas, even if in medical literature, the percentages of breast cancer with LVI are different, principally due to differences in stringency of diagnosis. With this argument, it is necessary to underline that the application of strict criteria for determination of the presence of LVI is advisable. The assessment of LVI should be concentrated on breast parenchyma around the tumor and not within it. LVI is microscopically seen as small groups of neoplastic cells within clear spaces lined by endothelium. Sometimes fixation shrinkage artifact may mimic LVI, especially when spaces arise around nests of neoplastic cells; moreover, DCIS extending outside the infiltrating tumor could be mistaken for LVI. In all these cases, the immunohistochemistry may be helpful by staining endothelial (CD31 and D2–40) and myoepithelial (calponin, p63, etc.) cells. LVI is generally correlated to locoregional lymph node involvement, and it is also an important independent prognostic factor, very useful especially in node-negative patients [41]. Moreover, LVI can also predict local recurrence following breast conservation surgery, as well as flap recurrence after mastectomy. Finally, LVI in the dermis is a particularly poor prognostic factor, being strongly associated with local recurrence and distant metastases. The presence/absence of LVI should be included as a component of the minimum dataset for histological reporting of early invasive breast cancer.

ER is a nuclear transcription factor that, when activated by the hormone estrogen, stimulates the growth of normal breast epithelial cells [42]. PR is regulated by ER, so its presence indicates that the estrogen-ER pathway is intact and functional. If expressed, PR is activated by the hormone progesterone, which also stimulates the cellular growth. Invasive breast carcinomas frequently (65–80%) express ER and PR, especially if they are grade 1 or 2 [43]; in women affected by these carcinomas, the hormone estrogen, which binds ER present in the nuclei of neoplastic cells, can stimulate their proliferation; this phenomenon, of course, is detrimental. ER and PR tests are performed by immunohistochemistry which is a sensitive, specific, and inexpensive method that can be performed on formalin-fixed paraffin embedded tissue sections [43

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