Invasive Ductal Carcinoma of No Special Type and Histological Grade

Epidemiology

Ductal NST is the largest group of invasive breast carcinomas, comprising 55% to 80% of cases according to published articles. This wide range is possibly due to lack of application of strict criteria for inclusion in the special-types category, and the fact that some groups do not recognize tumors with a combination of ductal NST and special-type patterns as a separate mixed category, preferring to include them in the no special type (ductal NST) group. In addition, some, but not all, authorities, including the Nottingham group, classify tumors exhibiting prominent tubule formation (but insufficient for classification as pure tubular carcinoma) as tubular mixed carcinoma. This category comprises approximately 14% of carcinomas in a symptomatic series, and such cases appear to offer an improved prognosis. In the Nottingham series (1990–1999; 2,219 cases), ductal NSTs constitute 55% of cases, whereas tubular mixed tumors constitute 17% of cases (72% in total). Tumors with mixed ductal NST and lobular types are less common, accounting for 3% to 6% of cases. In three large studies derived from the Surveillance, Epidemiology, and End Results (SEER) database that included 338,201 breast cancers, ductal NSTs constituted 73.5% to 75.6% of cases.

Ductal NST tumors, like all forms of breast cancer, are rare in patients younger than 40 years, but the proportion of tumors classified as such in young breast cancer cases is, in general, similar to that in older cases. The majority of male breast carcinomas are of the ductal NST type ( Chapter 32 ). There are no well-recognized differences in the frequency of breast cancer type and proportion of ductal NST cancers related to many of the known risk factors including geographic, cultural/lifestyle, and reproductive variables. However, some studies have shown that ductal NSTs differ from ILCs not only in histological and clinical features, global transcriptomes, and genomic profiles, but also in risk factors. Within ductal NST carcinomas, the risk factors are different based on ER expression, with the risk factors associated with ER+ ductal NST tumors different from those of ER– ductal NST tumors. Similarly, differences between ductal NST and pure tubular and mucinous carcinomas have been reported.

Carcinomas developing after the diagnosis of precursor lesions, such as atypical ductal hyperplasia (ADH) and lobular neoplasia, include a higher proportion of tumors of a specific type, specifically pure tubular and classic lobular carcinomas. Familial breast cancer cases associated with BRCA1/2 mutations are commonly of the ductal NST type (85%–100%) but are enriched with basal-like or medullary carcinoma–like features (see also Chapter 4 ).

Clinical Presentation and Clinical Imaging

Similar to other types of breast cancer, the majority of women with ductal NSTs present symptomatically. However, in countries where population-based screening is used, there has been an increase in the proportion of asymptomatic cases that are detected mammographically. Screen-detected tumors more often are smaller and have favorable histology, and as a result, screen-detected carcinomas generally have a more favorable prognosis than symptomatic masses.

The most common findings in symptomatic women are breast lumps that may or may not be associated with pain. Nipple abnormalities (discharge, retraction, distortion, or eczema) are less common, and other forms of presentation are rare. Clinical examination should be systematic and take into account the nature of the lump and, if present, any skin dimpling or change in contour of the breast as well as assessment of the axilla. Although clinical examination is an extremely useful, easy, and practical technique, its sensitivity and specificity for diagnosis are limited. Imaging should include mammography except in women younger than 35 years, where it is rarely of value unless there is strong clinical suspicion or tissue biopsy evidence of malignancy (see also Chapter 8 ). The mammographic appearances of ductal NST carcinomas are varied and include well-defined, ill-defined, and spiculate masses; parenchymal deformity; and calcification with or without a mass lesion. Approximately 50% of tumors show calcification on mammography. In a previous study of ductal NSTs compared with grade-matched/stage-matched ILCs, there was no significant difference in the frequency of a mammographic abnormality between both tumor types, as a spiculate mass was the most common feature in both groups (63% and 69%, respectively). Low-grade cancer may be associated with other low-grade precursor lesions (i.e., columnar cell change), which may facilitate its radiological detection, whereas high-grade cancers are often mass forming, associated with necrosis/calcification within the invasive or the associated in situ component. Breast abnormalities should be evaluated by triple assessment including clinical examination, imaging (mammography and ultrasound), and tissue sampling by either fine-needle aspiration (FNA) cytology or core needle biopsy (CNB).

Gross Pathology

Because ductal NST is a diagnosis of exclusion, there are no specific morphological features, and a variety of appearances may be seen. Tumors vary considerably in size, with a range from 0.2 cm up to 10 cm or more in advanced cases. They frequently have an irregular, stellate outline or nodular configuration. The tumor edge is usually moderately or ill-defined and lacks sharp circumscription. The latter feature characterizes medullary, mucinous, papillary, and some basal-like tumors. The majority are firm or hard in consistency (hence, the former designation of scirrhous carcinoma) and may feel gritty on incision. However, consistency is related to the stromal/malignant cell mass ratio and the nature of associated stromal elements (fibroblastic, loose/inflammatory, or fibrotic/hyalinized). Compared with ductal NST carcinomas, women with lobular, mixed ductal and lobular, and papillary carcinomas are more likely to be diagnosed with larger tumors (≥5.0 cm), whereas pure tubular and pure mucinous carcinomas are likely to be smaller. Ductal NST cancer is more frequently associated with positive lymph nodes than pure low-grade mucinous, pure tubular, medullary, or papillary carcinomas, but less frequently than lobular, invasive micropapillary, and inflammatory carcinomas. There is a slightly higher frequency in the left breast, with a reported left-to-right ratio of approximately 1.07:1. Although the location of the tumor in the breast is not associated with histological subtype, between 40% and 50% of ductal NSTs occur in the upper outer quadrant of the breast, and there is a decreasing order of frequency in the other quadrants from the central, upper inner, lower outer, to the lower inner quadrant, which matches the amount of breast parenchyma in each quadrant.

Microscopic Pathology

There is considerable variation in the histological appearances of ductal NSTs, depending in part on the interplay between the epithelial and stromal components, and it is not possible to be prescriptive about the features used for its classification (see Fig. 23.1 ). Architecturally, the tumor cells may be arranged in cords and trabeculae, whereas some tumors are characterized by a predominantly solid or syncytial growth pattern with little associated stroma or can be diffusely infiltrative. In a proportion of cases, glandular differentiation may be apparent as poorly formed tubular structures with central lumina in tumor cell groups, contrasting the open oval or angulated well-formed tubules of tubular carcinoma. Occasionally, areas with single-file infiltration or targetoid features are seen, but these lack the cytomorphological characteristics of ILC ( Fig. 23.2 ). The carcinoma cells also have a variable appearance ( Fig. 23.3 ). The cytoplasm is often abundant and eosinophilic. Nuclei may be highly pleomorphic or regular, and glandular structures extensive or absent. The stromal component is extremely variable ( Fig. 23.4 ). There may be a highly cellular desmoplastic fibroblastic proliferation, a scanty connective tissue element, or marked hyalinization. Foci of elastosis may also be present, especially in low-grade tumors, with a periductal or perivenous distribution. Focal necrosis may be present (seen in ∼60% of cases) ( Fig. 23.5 ), and this is occasionally extensive, especially in high-grade tumors. Lymphoplasmacytoid infiltrates can be identified, and in general, the higher the grade or tumor mutational burden, the higher the number of lymphoplasmacytoid infiltrates present ( Fig. 23.6 ).

Ductal NST carcinomas include tumors that express, in part, one or more characteristics of the special types of breast carcinoma but do not constitute a pure example of individual tumors. Ductal NSTs may have microscopic foci of tubular, medullary papillary, or mucinous differentiation ( Fig. 23.7 ).

Occasionally, ductal NSTs show small areas of metaplasia, such as squamous metaplasia and clear cell metaplasia. Some cases of ductal NST carcinoma may show prominent cytoplasmic lipofuscin deposition, which must be distinguished from tumors showing melanocytic differentiation that usually represents metastatic malignant melanoma. However, the presence of melanin in breast cancer cells can occur when breast cancers invade the skin and involve the dermal–epidermal junction. Although patients with ductal NST carcinoma may have elevated levels of serum β human chorionic gonadotropins (β-hCGs), histological evidence of choriocarcinomatous differentiation is exceptionally rare. High-grade ductal NST carcinoma may show occasional pleomorphic cells; however, the rare variant pleomorphic carcinoma is characterized by proliferation of pleomorphic and bizarre tumor giant cells comprising more than 50% of the tumor cells ( Fig. 23.8 ) in a background of adenocarcinoma or adenocarcinoma with spindle and squamous differentiation.

In most cases (≤80%), foci of associated DCIS are present, and some authorities recognize a subtype with an extensive in situ component. The growth pattern of a coexisting DCIS component is usually reflected in the structure of the invasive carcinomas, and there is a significant association between grade of DCIS and invasive carcinomas that have both components. Grade 1 ductal NST is usually associated with low- or intermediate-grade DCIS of cribriform and micropapillary patterns, whereas in grade 3 tumors, associated DCIS is often of a high-grade type with comedonecrosis, but all other patterns may be seen. Moreover, some ductal NST tumors mimic solid or cribriform DCIS, which may be of clinical relevance in cases of assessment of invasion on CNB and estimation of tumor size in excision specimens. Immunohistochemistry (IHC) for myoepithelial markers may be helpful in such cases.

Immunohistochemistry

Ductal NST carcinomas show reactivity to low molecular weight (luminal) cytokeratins (CKs) in a majority of cases, and in almost all cases if multiple CKs are used. CK7, CK8, and CK18 are reliable IHC markers for ductal NST carcinoma. Other luminal CKs used in clinical practice include CK19 and AE1/AE3. Ductal NST tumors are usually positive for epithelial membrane antigen (EMA) and ECAD, 70% are positive for lactalbumin, milk fat globule membrane, and 20% to 50% are positive for gross cystic disease fluid protein-15 (GCDFP-15); the latter three markers are more breast specific. Approximately 60% to 80% of ductal NSTs are positive for ERs and androgen receptors (ARs), a slightly lower percentage (55%–70%) are positive for PgR, and 12% to 20% are positive for HER2 or show HER2 gene amplification. Basal-associated markers such as CK5, CK5/6, CK14, CK17, vimentin, p-cadherin, and laminin are expressed in a small proportion of cases (5%–20%) (see also Chapter 9, Chapter 11 ).

Approximately 5% to 40% of ductal NST tumors are positive for epidermal growth factor receptor (EGFR; HER1) and p53, whereas 80% to 90% are positive for HER3, HER4, and FHT proteins. Expression of smooth muscle actin (SMA) is reported in 15% of cases. Unlike metaplastic carcinomas, very few cases of ductal NST carcinoma express p63. Less than 10% of ductal NSTs express neuroendocrine markers (synaptophysin and chromogranin-A). Breast carcinoma of NST is usually negative for PAX8, WT1, TTF1, CDX2, and CK20, but focal reactivity for WT1 may be seen in mucinous carcinoma, and focal TTF-1 may occasionally be seen.

Genetics

The genetic variation seen in breast cancer as a whole is similarly reflected in ductal NST tumors and has, until recently, proved difficult to analyze or explain. The genetic profiles of ductal NST are mainly related to histological grade and expression of ER and HER2. High-grade tumors are genetically different from low-grade ER+ tumors and are markedly different from ER– cancers. Similarly, the genetic profile of HER2+ ductal NST tumors is different from HER2– tumors. The observation that specific genetic lesions or regions of alteration are associated with the histological type of cancer or are related to grade and ER expression in the large ductal NST group does not support the hypothesis of a linear progression model in breast carcinoma. It implies that breast cancer of ductal NST includes a number of tumors of unrelated genetic evolutionary pathways and that these tumors show fundamental differences when compared with some special-type tumors, including lobular and tubular carcinoma. It is now well recognized that ductal NST tumors comprise a heterogeneous group of tumors not only at the morphological level but also at the molecular level. Global gene expression profiling of breast cancer has demonstrated that ductal NST tumors can be classified into subtypes on the basis of expression patterns (see also Chapter 10, Chapter 20 ). At least three main molecular classes have been identified: the luminal/ER+ (60%–85%), HER2+ (15%–20%), and basal-like/triple-negative (ER–, PgR–, and HER2–; 15%–20%) classes. The luminal and triple-negative classes have been further subdivided into subclasses based on differences in the expression of other biomarkers. This molecular heterogeneity of ductal NSTs has also been demonstrated at the DNA level and at protein levels. Multiple independent studies have demonstrated an association between these molecular classes of ductal NST and their distinct behavior and response to systemic therapy. These observations are consistent with the morphological spectrum of ductal NST tumors, which, unlike special types, show wide variation in grade and histological features.

In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic, and epigenetic variability, supporting the existence of intratumor genetic heterogeneity in breast cancers. Ductal NSTs are more likely to have intratumor heterogeneity than special tumor types.