Most invasive ductal carcinomas form solid masses with ill-defined margins and infiltrative edges (Fig. 12.6) or are round and circumscribed with pushing margins (Fig. 12.7). Some tumours have contours with a mixture of these patterns (Fig. 12.8). The consistency and colour of the lesion vary based on the amount of stroma present within the tumour. Invasive carcinomas with an abundant stromal component appear more grey-white and tend to be firm on palpation. In contrast, tumours with less stroma appear tan or yellow and are softer (Fig. 12.9). Certain tumours appear red-brown, not only because of dense cellularity but also because of other morphologic features such as papillary growth pattern and intratumoural haemorrhage (Fig. 12.10). These tumours typically have a concave cut surface as a distinguishing feature, in contrast to benign lesions such as fibroadenomas, which have convex, bulging cut sections (Fig. 12.11). Cystic change can rarely be present and is usually due to tumour necrosis (Figs. 12.12 and 12.13).

Because the tumour size is an important prognostic factor of breast cancer, macroscopic evaluation of tumour size is essential, with careful measurement expressed in three dimensions. Dimensions of smaller tumours are confirmed microscopically. Satellite tumour nodules may be present (Fig. 12.14).

The microscopic appearance of invasive ductal carcinoma is highly variable [1–3]. The degree of tumour cellularity, growth pattern, extent of associated in situ carcinoma component, degree of cytologic atypia, mitotic activity, amount of stroma, presence or absence of necrosis, and the presence and amount of lymphocytic infiltrate in the stroma and among tumour cells all vary significantly in different tumours. Some of these features may even differ in different areas of the same tumour [10–13]. Tumour cells may show varying degrees of gland formation (Fig. 12.15); may form nests, cords, or trabeculae; or may grow in solid sheets. Necrosis may be present and can be extensive, potentially leading to pseudocyst formation. The appearance of malignant cells varies significantly. Some tumours have minimal cellular atypia and pleomorphism; the tumour cells are small and uniform, similar to the cells of normal duct epithelium. In other tumours, there can be marked cellular atypia and pleomorphism, with tumour cells that have enlarged, hyperchromatic nuclei (Fig. 12.16). The degree of mitotic activity varies significantly, from abundant and easily identified to almost none. Focal mucin production (both intracellular and extracellular) can sometimes be seen. Squamoid, clear-cell, and apocrine differentiation are other histologic findings that can be observed. Similar to tumour cells, the stroma may display marked variation in its amount, composition, and distribution. The amount of stroma can range from none to abundant (Fig. 12.17). Some tumours have large amounts of dense, hyalinised stroma resulting in a very firm consistency, termed scirrhous carcinoma. In some tumours, the stroma consists of only collagen, whereas others are cellular and include fibroblasts and myofibroblasts (Fig. 12.18). Elastosis can be present. Stromal distribution throughout the tumour is also variable. Tumour cells may proliferate around the central sclerotic stromal component, but in other tumours, the stroma is uniformly distributed (Figs. 12.19 and 12.20). Calcifications can be detected in more than half of the cases. Additionally, the amount of lymphoplasmacytic infiltrate in tumour and stroma varies considerably, from moderate or marked to none (Fig. 12.21). Recent studies have suggested that the amount of lymphoplasmacytic infiltrate may have a prognostic and potentially predictive value, particularly in triple-negative and c-erbB-2-overexpressing breast cancers [14]. Osteoclast-like giant cells or giant-cell granulomas are rarely seen in the stroma. With adequate sampling of the tumour, an in situ carcinoma component can be identified in most cases of invasive ductal carcinomas (Fig. 12.22). The in situ component is most often ductal, but rarely it can be lobular. When ductal carcinoma in situ (DCIS) is identified, its grade is usually similar to that of the invasive component. The presence of lymphovascular invasion should be carefully evaluated in all invasive ductal carcinomas, preferably at the peripheral aspect of the tumour (Fig. 12.23) [15, 16]. Retraction artefacts that are commonly seen around clusters of tumour should not be confused with true lymphovascular space invasion. Unless a tumour embolus is identified in a large blood vessel, it is not recommended to try to distinguish small capillaries from lymphatics. Perineural invasion occasionally may be seen, but this finding is not of prognostic significance (Fig. 12.24) [17].

Tubular carcinoma is a well-differentiated invasive carcinoma composed almost completely of tubules, which are lined by a single layer of low-grade tumour cells and have open lumens.

Tubular carcinoma accounts for 2–10 % of all invasive breast cancers in published series. The wide range of reported incidence reflects variations of histologic criteria (percentage of tubules required) to establish this diagnosis and inclusion of patients’ data from screening programmes, in which the incidence of tubular carcinoma is much higher. Tubular carcinoma accounts for up to 25 % of carcinomas detected by mammographic screening, whereas it is less than 5 % of breast cancers in unscreened populations [43, 44].

Although tubular carcinoma has been reported in a wide age range (25–80 years), the average age is 60 years, which is slightly older than that of invasive ductal carcinoma. Most patients present with either a palpable mass or mammographic abnormality [44, 45]. Tubular carcinoma has also been documented in males. About 10–20 % of patients have been reported with multifocal tubular carcinomas growing as separate foci in one or more quadrants.

Most tubular carcinomas present as irregularly shaped masses with spiculated margins and central density (Fig. 12.27a). In most cases, the spicules are longer than the diameter of the central lesion. Microcalcifications are present in half of the cases. Mammographic findings may overlap with radial scar. Sonography reveals ill-defined and hypoechoic masses, with posterior acoustic shadowing seen in the majority of cases [45].

The differential diagnosis includes benign, small, glandular proliferations of the breast, and invasive carcinomas with tubular growth pattern. The absence of myoepithelial cells in tubules is the hallmark of tubular carcinoma, in contrast to benign small glandular proliferations (Fig. 12.33). Myoepithelial cells may be highlighted by immunohistochemical markers such as smooth muscle actin, smooth muscle myosin, or p63. (For detailed discussion, see Chap. 5). Microglandular adenosis is another benign lesion that may mimic tubular carcinoma (Fig. 12.34). Although the lack of a myoepithelial layer in microglandular adenosis glands is a major pitfall, their small and round shapes, in contrast to the angulated and irregular shapes of tubular carcinoma glands, are helpful in distinguishing the two entities. Cells lining microglandular adenosis glands are positive for S100 and negative for oestrogen and progesterone receptors and for epithelial membrane antigen (EMA); tubular carcinoma cells are almost always positive for hormone receptors and EMA. Other malignant tumours that mimic tubular carcinoma include well-differentiated invasive ductal carcinoma and low-grade adenosquamous carcinoma. Tubular carcinoma is not synonymous with invasive ductal carcinoma grade 1. Well-differentiated invasive ductal carcinomas have tubules lined by multiple cell layers, display areas of non-tubular growth pattern, and can have more nuclear atypia. Low-grade adenosquamous carcinoma may have well-formed tubules lined by low-grade tumour cells mimicking tubular carcinoma, but when sampled adequately, these tumours show solid nests and squamous differentiation even if they are focal. Adenosquamous carcinoma cells are typically negative for oestrogen and progesterone receptors; this negativity can assist in the differential diagnosis.

Tubular carcinoma generally has a low incidence of metastases to axillary lymph nodes and low recurrence rates, leading to a favourable prognosis [48, 49]. The prognosis of mixed tumours is worse than that of pure tubular carcinoma. The incidence of axillary metastases in tubular carcinoma ranges from 0 to 10 % in reported series, and the most important predictor of metastases is tumour size. In patients whose tubular carcinoma is less than 1 cm, the incidence of axillary metastasis is so low that some authors have suggested that axillary lymph node surgery can be omitted, but other authors have shown that axillary lymph node metastases can occur even with tumours less than 1 cm in size. In most cases, metastases also show a tubular carcinoma growth pattern, and only one to three lymph nodes are involved in almost all cases. The standard therapy protocol is segmental resection with sentinel lymph node dissection, followed by radiation therapy. Because the great majority of tubular carcinomas are positive for oestrogen and progesterone receptors, adjuvant hormonal therapy can be administered.

Invasive cribriform carcinoma is an invasive, well-differentiated carcinoma with a cribriform growth pattern similar to that of cribriform ductal carcinoma in situ (DCIS).

Invasive cribriform carcinoma is rare, representing 0.8–3.5 % of all invasive cancers. This tumour is closely related to tubular carcinoma, and a mixed tubular and invasive cribriform pattern is commonly seen. Because both tumours are associated with excellent prognosis, distinguishing these two components is less critical than verifying that invasive carcinoma not otherwise specified is not present [50]. To be designated as an invasive cribriform carcinoma, more than 90 % of the tumour must display a cribriform pattern. If an invasive carcinoma displays only tubules and cribriform islands, classification as either tubular or invasive cribriform carcinoma depends on which pattern predominates. Invasive cribriform carcinoma has been reported in a wide age range (20–90 years), with the average age in the mid-50s in most reported series [50, 51].

Mammographic features of invasive cribriform carcinomas are similar to those of other invasive breast cancers. Most lesions present as spiculated masses, with or without microcalcifications. Not uncommonly, they can also present as fairly well-circumscribed masses with a regular shape. Multifocal tumours have been reported in up to 20 % of cases in some series.

Invasive cribriform carcinoma should be differentiated from cribriform DCIS and other invasive carcinomas such as invasive ductal carcinoma and adenoid cystic carcinoma.

Although both in situ and invasive cribriform carcinomas have the same cribriform growth pattern, the nests of invasive cribriform carcinoma show more infiltrative edges. If the infiltrative edge is not present on a small biopsy specimen, the invasive nature of cribriform nests in invasive cribriform carcinoma can be confirmed by the absence of surrounding myoepithelial cells on immunohistochemistry. Invasive ductal carcinomas may have areas of cribriform growth pattern mimicking invasive cribriform carcinoma, but the tumour should almost totally show a cribriform pattern in order to be classified as invasive cribriform carcinoma.

Adenoid cystic carcinoma can be differentiated from invasive cribriform carcinoma on the basis of its typical dual cell proliferation (Fig. 12.41). Cribriform spaces of adenoid cystic carcinoma characteristically contain material resembling basement membrane, whereas spaces in invasive cribriform carcinoma are often empty. Furthermore, immunohistochemical staining for oestrogen and progesterone receptors will be helpful in this differential diagnosis. Adenoid cystic carcinomas are positive for cKIT and p63 and negative for oestrogen and progesterone receptors; invasive cribriform carcinomas are almost always positive for oestrogen receptor and negative for cKIT and p63 (Fig. 12.42) [52].

Collagenous spherulosis may superficially resemble invasive cribriform carcinoma, but this is usually a focal lesion with a lobulocentric growth pattern. Typically, the cribriform spaces contain basement membrane-like material (Fig. 12.43).

The clinical behaviour of invasive cribriform carcinoma is very similar to that of tubular carcinoma, with a lower incidence of nodal metastases than for invasive ductal carcinoma [50]. Segmental resection with or without radiotherapy and sentinel lymph node sampling are considered standard treatment. Patients with small, pure invasive cribriform carcinomas have an excellent prognosis, and some authors question the need for radiation therapy after complete excision.

As the histological characteristics of classic medullary carcinoma are difficult to reproducibly define and recognise, the WHO Working Group recommends classifying these tumours as carcinomas with medullary features, a term that incorporates tumours previously categorised as medullary carcinoma, atypical medullary carcinoma, and invasive carcinoma with medullary features [53].

Classic medullary carcinomas account for less than 1 % of breast carcinomas. Studies that report higher rates likely included atypical forms and invasive carcinomas with medullary features. Patients tend to be younger and may present with palpable lumps. Some tumours are mammographically detected.

These tumours are often circumscribed and may radiologically mimic a benign lesion (Fig. 12.44). Intralesional cystic components due to tumour necrosis may be seen.