Diagnostics

Disease

Breast Cancer

General

The World Health Organization classifies both benign and malignant breast tumors by histologic pattern.  The majority of tumors encountered clinically arise from the epithelial cells of the breast.  In particular, invasive breast cancers tend to be epithelial tumors of ductal or lobular origin (the vast majority being ductal).  For this reason, the most commonly encountered breast lesions will be discussed here.

Ductal Carcinoma

Ductal carcinoma is the most common form of breast cancer.  It encompasses a spectrum of disease, whereby there is an evolution of the disease process, from intraductal hyperplasia, to the development of atypia, to carcinoma in situ, to the ultimate invasion of the basement membrane.  Ductal carcinoma develops in the duct system of the breast, which carries milk from the lobules to the nipple.  For the purposes of this tutorial, two histologic types of ductal carcinoma will be presented:  Ductal Carcinoma in Situ and Infiltrating Ductal Carcinoma.

Ductal Carcinoma in Situ (DCIS)

Ductal Carcinoma in Situ occurs when ductal epithelial cells undergo malignant transformation and proliferate intraluminally.  The lesion consists of a population of cells which lack the capacity to cross the basement membrane and, therefore, are incapable of distant metastasis.  For this reason, nearly 100% of women diagnosed at an early stage can be cured.

Although, by definition, they lack the ability to invade the basement membrane, these cells can spread throughout a ductal system, producing extensive lesions (even involving an entire segment of the breast).  Although a mass is rarely felt on clinical exam, microcalcifications can often been seen on mammography.  The malignant cells of DCIS eventually outstrip their blood supply and become necrotic centrally.  This necrotic debris can calcify, leading to mammographic abnormalities.

Early recognition and diagnosis of DCIS is of the utmost importance.  It is thought that many cases of low-grade DCIS and most cases of high-grade DCIS may progress to invasive carcinoma (upwards of 30-50% if left unchecked), underscoring the importance of screening mammography and yearly exams.

Although beyond the scope of this tutorial, DCIS is typically divided into 5 subtypes, based on histological architecture:  Solid, Cribiform, Papillary, Micropapillary, and Comedo.  Their histological architecture is shown here for completeness sake:

Paget's Disease of the Nipple (PD)

Paget's Disease of the Nipple is a form of ductal carcinoma in situ, that extends retrograde from the ducts of the nipple into the contiguous skin and surrounding areola.  These tumor cells are derived from luminal lactiferous ductal epithelium of the breast and possess microscopic features of glandular epithelial cells.

Approximately 1-4% of breast cancers are associated with PD, however almost 100% of cases of PD are associated with an underlying malignancy, either in DCIS (10%) or IDC (90%), making this disease entity an important clinical marker for more serious disease.

Clinically, patients with PD present with a crusted, scaly and red nipple or areola. Unilateral involvement is typically the rule, hwever bilateral PD has been reported.  The patient may experience burning, itching or notice some bloody or serosanguinous discharge from the nipple.  Nipple invagination is sometimes seen.

Prognosis is dependant on the extent of the underlying carcinoma.  If no lump can be felt in the breast tissue and the biopsy shows the growth to be in situ and not invasive, treatment for Paget's Disease is very effective.

Infiltrating Ductal Carcinoma (IDC)

Infiltrating (or Invasive) Ductal Carcinoma constitutes the majority (80-90%) of invasive breast cancers.  Like DCIS, this cancer begins in a milk duct when ductal epithelial cells malignantly transform and begin to proliferate, however, unlike DCIS, IDC invades the basement membrane, infiltrating into the fatty tissue of the breast.  This lesion has no specific histologic characteristics, other than invading the basement membrane.  Because of this ability, IDC has the potential to metastasize via the lymphatic system.  Unlike their in situ counterpart, IDC tends to exhibit a marked increase in dense, fibrous tissue stroma, producing the characteristic firm, irregular, solid mass, felt on clinical exam.  In addition, they also usually appear more well-defined on mammography.

In addition, there are other invasive carcinomas which are forms of, or associated with, IDC which deserve mention, however they account for <10% of breast cancers combined.  They are Tubular Carcinoma (1-2%), Medullary Carcinoma (1-5%), Colloid or Mucinous Carcinoma (2-3%), and Invasive Papillary Carcinoma (1%).

Because of the potential for metastasis, it is ultimately important to diagnose and treat IDC before it has time to spread to other organs.    

Lobular Carcinoma

Lobular Carcinoma arises in the milk-producing glands of the breast.  Fortunately, it is a far less common cancer than ductal carcinoma, however, it often presents itself in both breasts more often than other carcinoma subtypes.  Because of certain pathologic features (discussed below), it remains a very difficult cancer to detect, either clinically or mammographically.

Lobular Carcinoma in situ (LCIS)

Lobular Carcinoma in Situ is characterized by proliferation, in one or more terminal ducts or ductules of the breast.  Like DCIS, LCIS also arises from epithelial cells, but rather, their growth continues in a lobular pattern.  In fact, in technical terms, LCIS is not really considered a cancer, as much as it is a form of lobular neoplasia.  That said, it is classified as a precancerous growth, which begins in the milk glands, and does not penetrate through the walls of the lobules.

In contrast to DCIS, the cells of LCIS rarely develop central necrosis or calcify.  Therefore, they almost never present as a discrete mass or are palpable.  For this same reason, they are rarely seen on mammography and usually only present themselves as incidental findings in biopsy specimens performed for other reasons.  Thus, in the mammographically screened population, this carcinoma remains infrequent (1-6%).

In clinical terms, LCIS is considered more of a marker for the development of invasive cancer, than a cancer itself.  With diagnosed LCIS, the risk of subsequent breast cancer is equal for both breasts, irrespective of the biopsy site, and LCIS is often bilateral in 50-70% of cases (compare to 10-20% of patients with DCIS).  However, most incidentally detected LCIS do not progress to clinically recognized disease and most invasive cancers that do develop are infiltrating ductal, thus supporting the concept that LCIS is no a malignant lesion.  In fact, women with LCIS develop invasive disease at a frequency similar to those with untreated DCIS, the difference being that both breasts are at equal risk.

Infiltrating Lobular Carcinoma (ILC)

Infiltrating (or Invasive) Lobular Carcinoma, similar to IDC, has the potential to metastasize and spread to other parts of the body, via the lymphatics.  Like LCIS, ILC develops from epithelial cells which have undergone neoplasia in the terminal ducts or ductules, but instead, have also gained the ability to invade the basement membrane of the lobules, giving them metastatic potential.

Fortunately, infiltrating lobular carcinoma has a much lower incidence than IDC, comprising only about 10-15% of invasive breast cancers.  However, certain features make them of particular interest to the clinician.  For one thing, they tend to be bilateral much more frequently than other types of breast cancer (upwards of 20% of the time).  They also tend to be multicentric within the same breast.  Like IDC they typically metastasize to axillary lymph nodes first, however, they more frequently later metastasize to CSF, serosal surfaces, ovaries, uterus, and bone marrow more often than other types of breast cancer.  Despite this, the prognosis is comparable to ductal carcinoma.

Histologically, ILC is characterized by small cells, with scanty cytoplasm with round or oval nuclei.  They tend to arrange themselves linearly giving them the characteristic "Indian file" description.  Like their in situ counterparts, these cells rarely undergo necrosis or calcification, making their clinical or mammographic detection very difficult.