Most cancers of the breast originate from the epithelial cells that line the ducts and lobules of the breast. Malignant change in these epithelial cells is known as ‘malignant neoplasia,’ ‘carcinoma’ or ‘cancer.’
In 2001, the Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute (NCI) studied a series of 135,157 women with breast cancer and reported the following sub-types:
- Invasive Ductal Carcinoma (IDC) – 76 %
- Invasive Lobular Carcinoma (ILC) – 8 %
- Lobular-Ductal Carcinoma – 7 %
- Mucinous (Colloid) Carcinoma – 2.4 %
- Tubular Carcinoma – 1.5 %
- Medullary Carcinoma – 1.2 %
- Papillary Carcinoma – 1 %
- Rare Subtypes – 2.9 %
Figure 5.1 Sub-Types of Breast Cancer. (SEER, 2001).
Rare sub-types of invasive breast carcinoma account for less than 3 % of all cases.
Invasive or infiltrating ductal carcinoma (IDC) is the commonest type of breast cancer with the most histological sub-types described. This malignancy arises from the breast duct epithelium.
In view of the variety of histological appearances seen in IDC, sometimes within the same tumor, those tumors without distinctive features have been termed, invasive carcinoma ‘not otherwise specified’ (NOS).
In the 2012 revised World Health Organization (WHO) guidelines, ductal carcinoma of the breast without distinctive features is now termed breast carcinoma of ‘no special type’ (NST). But in practice, diagnostic pathology reports will still contain ‘ductal carcinoma’ as a diagnostic term.
Section 6, will include the ‘specialized’ diagnostic tests that may be done on breast tissue samples when examined by the Pathologist; these include immunohistochemistry (IHC) for cell biomarkers (including E-cadherin), estrogen-receptor (ER), progesterone receptor (PR) and HER2 testing.
5.1 Why Classify Breast Cancer?
Benign and malignant tumors have been classified on morphological microscopic appearance alone. When it became clear that different morphological types of tumor had different behavior and prognosis, morphological classification became more important and more refined.
With the development of immunohistochemistry (Section 6) to identify cell characteristics, and with molecular tumor profiling and tumor biomarker analysis, there has been further refinement in tumor classification. This interest in tumor classification continues to be an important part of the clinical process.
Detailed classification of breast tumors is justified as long as it has meaning for the treatment of patients, as an indicator of response to therapy, or as an indicator of prognosis.
5.1.1 The 2012 WHO Classification of Breast Tumors
In 2012, the World Health Organization (WHO) sought the advice of Pathologists, Physicians and Oncologists worldwide to produce the 2012 revised WHO Classification of Breast Tumors. This 4th Edition replaces the 3rd Edition of the Classification of Breast Tumors, from 2003 and is the first edition to separate breast tumors from tumors of female genital organs. It takes into account newer developments in the understanding of specific breast lesions.
For any woman who receives a diagnosis of a breast abnormality and who reads her diagnostic pathology report, the meaning is everything. The 4th Edition of the WHO classification (2012) of breast tumors has some important changes and recommendations for invasive breast cancer; these have been included for each tumor type described in this section on breast cancer.
5.1.2 Micro-invasive Breast Cancer
The sub-set of micro-invasive breast cancer is now defined as pT1 breast cancer; cells infiltrate beyond the basement membrane at 1 or more foci, but none measure more than 0.1 cm (1 mm) in greatest dimension.
When the Pathologist examines the breast tissue section under the microscope, it is possible to measure tumor invasion, tumor size and the size of excision margins using the microscope Vernier scale (Cotton, 1984).
Micro-invasive carcinoma is associated with extensive ductal carcinoma in-situ (DCIS), notably of high nuclear grade. The reason for the application of strict histological criteria for the diagnosis of a micro-invasion is in order to avoid over-diagnosis of micro-invasion. Such a diagnosis will be of great importance to any patient and to her physicians and breast surgeon.
Like ductal carcinoma in-situ (DCIS), micro-invasive carcinoma is identified more commonly in diagnostic pathology samples, due to the breast screening program. Micro-invasive breast carcinoma remains an uncommon disease, accounting for less than 1 % of all breast cancers; when it occurs, it is mainly ductal in type (Viera et al., 2010).
Historically, there have been varying diagnostic criteria for micro-invasion, and because of this, there is little data in the literature on the clinical behavior of a micro-invasive carcinoma. However, it does appear that the outcome for the patient with a micro-invasive carcinoma is good, with little difference from patients with DCIS.
As most diagnostic biopsies are performed as core needle biopsy (CNB), the pathology report may be of DCIS ‘suspicious for’ micro-invasion. It is only when the entire breast lesion is removed that the final diagnosis of micro-invasive breast carcinoma can be made. The 2012 WHO guidance recommends that the treatment for a micro-invasive carcinoma follows that for high-grade DCIS.
Figure 5.2 Micro-Invasive Ductal Carcinoma.
Photomicrograph of the histology of a mammographically
identified area of ductal carcinoma in-situ (DCIS). Thorough
sampling shows an area of micro-invasive ductal carcinoma (*).
5.1.3 Bilateral Breast Cancer
Bilateral breast cancer, found in both breasts, is termed ‘synchronous’ or ‘non-synchronous.’
‘Synchronous’ breast cancer means that there is a contralateral breast carcinoma detected simultaneously or within three months of the primary tumor.
‘Metachronous bilateral breast cancer occurs more than three months after diagnosis of the first tumor.
Bilateral breast cancer should be distinguished from metastatic cancer in the contralateral breast; this is a much more rare occurrence.
A metastatic breast cancer, from one breast to the other, can be difficult to characterize.
5.2 Invasive Ductal Carcinoma (IDC)
Invasive ductal carcinoma (IDC) is also called ‘infiltrating’ ductal carcinoma; it is the most common type of breast cancer. Approximately 80% of all breast cancers are invasive ductal carcinomas (IDC).
One of the recommended changes in the 2012 WHO guide is to the terminology for invasive ductal carcinoma (IDC) from ‘not otherwise specified’ (NOS) (2003) to invasive carcinoma of ‘no special type’ (NST) (2012).
The American Cancer Society have reported that each year more than 180,000 women in the United States learn that they have invasive breast cancer. Most of these women are diagnosed with invasive ductal carcinoma (IDC). The word, ‘invasive‘ means that the cancer has spread into the surrounding breast tissues.
Figure 5.3 Diagnosis of Invasive Ductal Carcinoma (IDC).
A. Mammographic X-ray shows a stellate opacity with
irregular edges. B. Photomicrograph of the histology
of the core needle biopsy (CNB) shows a Grade 3, poorly
differentiated ductal carcinoma. (H&E x 40)
Invasive ductal carcinoma (IDC) affects women of all ages, but it is more commonly found with increasing age. According to the American Cancer Society, 60% of women are 55 or older when they are diagnosed with an invasive breast cancer.
On gross examination, these tumors are typically hard, gray or white, gritty and with an irregular, stellate edge.
The histology of infiltrating ductal carcinoma (IDC) features cords and nests of tumor cells with varying amounts of gland formation. The tumor cells are associated with a fibrous response which results in a palpable mass and the characteristic radiologic density.
Figure 5.4 Invasive Ductal Carcinoma (IDC).
Macroscopic or ‘gross’ appearance of the surgical resection
specimen of the breast shows a white, gritty tumor; the
surrounding tissue shows fibrosis (scar tissue) and
5.2.1 Grading of Invasive Ductal Carcinoma
In 1957, Bloom and Richardson first developed a histology grading system for invasive ductal carcinoma (IDC) of the breast, based on the degree of tubule formation, cell nuclear pleomorphism and mitotic count. This system was replaced or modified in 1991 by the ‘Nottingham’ grading system’, which is still based on a ‘points’ scoring system of the histologic features of the cancer; mild, moderate or severe or Grade 1, 2 or 3 (Elston & Ellis, 1991).
The Nottingham Grading System for Invasive Ductal Carcinoma:
- >10% 1 point
- 10% to 75% 2 points
- <75% 3 points
Cell nuclear pleomorphism:
- Small, regular uniform cells 1 point
- Moderate increase insize and variability 2 points
- Marked Variation 3 points
- Dependent on microscope field area 1-3 points
Tumor grading is based upon the tumor cell cytology, the degree of glandular differentiation and the mitotic count, seen histologically.Using these criteria, invasive ductal carcinoma (IDC) is divided in to three grades:
- Grade 1 – well-differentiated;
- Grade 2 – moderately differentiated and
- Grade 3 – poorly-differentiated.
Figure 5.5 Moderately Differentiated Invasive Ductal
Carcinoma (IDC) with micro-calcification.
Photomicrograph of the histology of this tumor shows areas
of ductal carcinoma in-situ (DCIS) and IDC with
micro-calcifications C. (H&E x 60)
Figure 5.6 Grading of Invasive Ductal Carcinoma (IDC).
1. Grade 1 carcinoma cells are disorganized, with enlarged cell nuclei (blue)
some with nucleoli (dots in the nuclei); there are few mitoses. 2. Grade 2
carcinoma cells have larger cell nuclei in proportion to the amount of
cytoplasm; the nuclei are vesicular or ‘bubbly’ and ‘folded’. 3. Grade 3
carcinoma cells are more irregularly shaped with varying enlarged nuclei;
the nuclei are enlarged, vesicular and there are atypical nuclear mitoses.
Figure 5.7 Grading of Ductal Carcinoma in Fine
Needle Aspiration Cytology (FNAC).
1. Grade 1 carcinoma cells are loosely cohesive, with enlarged cell nuclei (dark blue);
there are few mitoses. 2. Grade 2 carcinoma cells lack cohesion and have larger cell
nuclei in proportion to the amount of cytoplasm; nucleoli are present. 3. Grade 3
carcinoma cells lack cohesion and are more irregularly shaped with varying enlarged
nuclei with multiple nucleoli. (H&E x100) (PAP & Giemsa x 60 & 100)
5.2.2 Pleomorphic Carcinoma
Pleomorphic breast carcinoma has a characteristic histology; more than 50 % of the malignant cells show six or more varieties of cell morphology (cytology).
Pleomorphic breast carcinoma is now considered to be a distinct sub-type of breast tumor in the new WHO classification scheme and is a rare, high-grade variant of invasive ductal carcinoma (IDC). Pleomorphic carcinoma has a poorer prognosis, in keeping with its high-grade (poorly-differentiated) characteristics.
Pleomorphism in malignancy may cause diagnostic difficulties. In the case of pleomorphic carcinoma of the breast, the differential diagnosis will include metastatic breast tumors, such as metastatic sarcoma or carcinoma with osteoclast giant cells.
‘Pleomorphic breast cancer’ has not previously been well-recognized; it is now considered to be a distinct breast cancer phenotype.
Figure 5.8 Pleomorphic Carcinoma.
Photomicrograph of the histology of a high-grade carcinoma
associated with areas of necrosis, inflammation and necrosis.
In this field there are spindle cells, small round cells, large
cells with nucleoli and giant cells. (H&E x20)
5.2.3 Metaplastic Carcinoma
The word ‘metaplasia’ means the replacement of one differentiated cells type by another differentiated cell type. Cancer cells lack the restraints in behavior seen by benign cells; many cancers ‘de-differentiate,’ particularly when they are more poorly-differentiated. Breast cancers can also incite a metaplastic response in the normal breast tissues that they invade.
The most common variants of ‘metaplastic carcinoma’ include those with melanotic features, choriocarcinoma and osteoclast giant cells.
Figure 5.9 Metaplastic Breast Carcinoma.
Photomicrographs of the histology from metaplastic tumors.
A. with melanotic features. B. with choriocarcinoma.
C. with osteoclast giant cells.
5.2.4 Carcinoma of Mixed Type
Carcinomas of mixed type are defined as having 50% of a specialized pattern, and a non-specialized pattern of between 10% and 49%. These tumors are classified as ‘mixed invasive NST,’ ‘special type’ or ‘mixed invasive NST and lobular carcinoma.’
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