HYPERPLASIA

The enlargement of normal terminal duct lobular units (TDLUs)(FIG. 1A) by hyperplastic epithelial cells is one of the most common abnormalities of growth in the adult female human breast. 

FIG 1A FIG 1B

These hyperplastic enlarged lobular units (HELUs) are often multifocal, bilateral, and up to 100-fold larger (volume and numbers of cells) than the TDLUs they evolve from, representing a major alteration of growth (Fig.1B). 

• The majority of HELUs are lined by one or two layers of crowded columnar epithelial cells, but many exhibit more diverse histological features, contributing to the complex terminology that has evolved to describe them. 
• Currently, they are most commonly referred to as columnar cell lesions (CCLs), which encompass several putative subtypes including 
• columnar cell change (CCC; 
• characterized by a generally single layer of hyperplastic columnar epithelium), 
• columnar cell hyperplasia (CCH; 
• characterized by stratified hyperplastic columnar epithelium), and 
• CCLs with cytological atypia, sometimes referred to as flat epithelial atypia (FEA), among others. 

The CCH/HELUs are 

• much more common in cancerous than noncancerous breasts, and 
• it is supported by pathological studies, 
• epidemiological studies showing that they are weak (about 1.5-fold) risk factors for developing breast cancer, and 
• they may share identical genetic abnormalities (e.g., allelic imbalances) with cancer in the same breast, 
• although the overall frequency of these abnormalities appears to be quite low. 

Wellings and Jensen proposed that CCH/HELUs (which they referred to as atypical lobules type A) are precursors of ADH primarily because of the striking gradual histological continuity between them. 

• Similar continuity is also observed between CCH/HELUs and other alterations of growth in the breast, including microcysts (often with apocrine change) and usual ductal hyperplasia (UDH). 
• However, most CCH/HELUs probably remain stable or become cystic based on the higher incidence of these lesions compared to UDH and (especially) ADH. 
• UDH has also been identified as a weak (approximately 1.5-fold) risk factor for developing breast cancer, but the absence of convincing histological continuity with cancer and recent immunohistochemical (IHC) studies suggesting that the progenitor cells in UDH may be different from CCH/HELUs and ADH suggest that UDH may be a side branch of the family tree of ductal cancers, and their risk may be due to shared ancestry with CCH/HELUs.

The underlying causes of the hyperplasia leading to CCH/HELUs are unknown. Some evidence suggests that estrogen may be involved, including the observations that CCH/HELUs are more common in premenopausal compared to postmenopausal breasts and in cancerous compared to noncancerous breasts where increased estrogen exposure is such a strong risk factor for developing cancer. 

• Several recent studies have shown highly elevated expression of ERα in the epithelial cells lining CCH/HELUs. 
• Essentially all CCH/HELUs express ERα in some cells, and 80% to 90% show very high levels in nearly all cells, which is about threefold above normal. 
• They also show a corresponding threefold increase and decrease in average proliferation (about 5%) and apoptosis (about 0.2%), respectively, although the ranges of these phenomena are quite large. 
• Since estrogen, mediated by ERα, stimulates proliferation and suppresses apoptosis in normal cells, elevated ERα in CCH/HELUs may be a fundamental alteration leading to increased growth, although the cause of the elevation is unknown. 
• A recent study in mice overexpressing ERα in normal murine breast epithelium noted the rapid development of hyperplasias, which occasionally progressed to cancer, supporting the idea that elevated ERα may be partially responsible for the development and progression of CCH/HELUs. 
• Similar to ERα, recent studies have shown that PR is also highly elevated in CCH/HELUs, which may also contribute to their growth.

Recent microarray studies have identified some of the other pathways and genes that may be involved in the development of CCH/HELUs including, especially, the erb-b tyrosine kinases (TKs). 

• For example, compared to normal epithelium, the cells lining CCH/HELUs show a prominent uniform decrease in the expression of epidermal growth factor (EGF) and increase in amphiregulin (AREG), which are important in differentiation of adult breast and embryonic breast development, respectively. 
• Interestingly, EGF and AREG are both ligands for the erb-b1 TK receptor (also referred to as the epidermal growth factor receptor). 
• However, the levels of erb-b1 do not appear to change significantly, nor do the levels of the other erb-b TK receptors, including erb-b2 (also referred to as HER2 or ERBB2), which is amplified and overexpressed in about 20% of DCIS and IBCs. 
• Certain other alterations common in DCIS and IBCs, such as mutation of the p53 tumor suppressor gene, are also rarely if ever observed in CCH/HELUs.

Because CCH/HELUs are so common in the population and share important biological characteristics such as highly elevated ERα, their beginnings seem more likely to reflect alterations of development or differentiation than genetic defects per se. 

• This idea is supported by the microarray evidence of suppressed differentiation and reactivated embryonic developmental pathways and by the generally low frequency of genetic alterations identified so far.
• Regardless, the end result is increased growth, creating fertile soil for accumulating random genetic defects, leading to diversity and progression to other types of lesions, including more committed breast cancer precursors such as ADH.

Reference :     

1. Diseases of the Breast, 4th Edition

2. Atlas_of_breast_surgery

3. Bailey Love’s short practice of surgery     25^th ed.

4. Greenfield's Surgery, 5th Edition

5. Pathophysiology of Disease

Premalignant Breast Disease

Premalignant Breast Disease

Pathology and Biological Features

The human breast is capable of producing a very large number histologically defined abnormalities of growth. However, only a handful appear to have any significance as risk factors or precursors of breast cancer.

• One of the first attempts to incorporate these premalignant lesions into a comprehensive model of breast cancer evolution was published by Wellings and Jensen over 30 years ago.
• The model was based primarily on the evidence of gradual histological continuity and proposed that the cellular origin of breast cancers occurs in the normal terminal duct lobular unit (TDLU) and that the putative precursors represent a nonobligatory series of increasingly abnormal stages that progress to cancer over long periods of time, probably decades in most cases.

The key stages in the model are generically referred to as

• hyperplasias,
• atypical hyperplasias,
• in situ carcinomas, and
• invasive carcinomas,

but there are multiple lineages and subtypes.

In the largest so-called ductal lineage (representing about 80% of all breast cancers), the terminology of hyperplasias is diverse and still evolving, while the other stages are referred to as

• atypical ductal hyperplasia (ADH),
•  ductal carcinoma in situ (DCIS), and
• invasive ductal carcinoma (IDC).

IDCs are also referred to as no-special-type or not-otherwise-specified invasive breast cancers (IBCs) to distinguish them from the major so-called special histological subtypes, which include invasive tubular, mucinous, medullary, and lobular carcinomas.

All of the special subtypes except lobular carcinomas can be considered as subtypes of IDC in the sense that they appear to evolve from the same precursors.

The progression of the lobular lineage (representing the remaining 20% of carcinomas) is histologically relatively distinct, and the key precursors in this setting are referred to as

• atypical lobular hyperplasia (ALH) and
• lobular carcinoma in situ (LCIS).

However, the practice of referring to breast cancers as ductal or lobular implies that they originate and reside in ducts and lobules, respectively, which is a historical misconception in the sense that both lineages are thought to arise from progenitor cells in normal TDLUs and both can occupy ducts and lobules (4).

Furthermore, many IBCs show complex combinations of ductal (including special subtypes) and lobular features, emphasizing that these histology-based classifications, while very useful, oversimplify enormous diversity.

Epidemiological studies have shown that women with a history of these lesions in a previous biopsy are at increased relative risk for developing breast cancer, ranging from about

• 1.5-fold for hyperplasias, to
• 5-fold for ADH and ALH, to
• 10-fold or higher for DCIS and LCIS, and precursors must also be risk factors, although the opposite is not always true.

Some studies suggest that the elevated risks associated with ADH, ALH, and LCIS are equal in both breasts, implying that they are only risk factors.

However, these lesions (especially ALH and LCIS) are often multifocal and bilateral (2,3,6), so it is possible for them to be both risk factors and precursors, and their wide distribution suggests that they may be initiated during early breast development.

Recent comprehensive studies of ALH and LCIS place the majority of the risk in the ipsilateral breast, supporting a precursor role, although the apparently equal bilateral risk associated with ADH remains an enigma.

DCIS is usually a localized disease with a predominately ipsilateral risk for developing IBC, consistent with the notion that DCIS is a relatively advanced and committed precursor.

Some of the most compelling evidence comes from recent laboratory studies showing that the putative precursors share identical genetic abnormalities with breast cancers, especially when they occur in the same breasts as well as histological and biological similarities with genetically engineered mouse models.

There are important general characteristics that distinguish one stage from the next in the Wellings-Jensen model that accumulate and increase with progression.

• The transition from TDLUs to hyperplasias is characterized by increased growth due to epithelial hyperplasia.
• Alterations of cell adhesion and polarity distinguish ADH from hyperplasias as the epithelium begins to pile up and distend acini.
• DCIS is characterized by further growth and the appearance of enormously increased histological and biological diversity compared to earlier precursors.
• Invasion into surrounding stroma defines the transition of DCIS to IBC.

Reference : 
  
1. Pathophysiology of Disease of Disease

2. Diseases of the Breast, 4th Edition

3. Bailey Love’s short practice of surgery 25^th ed.

4. Greenfield's Surgery, 5th Edition

5. Atlas of breast surgery