Tuesday, August 28, 2012

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 25th ed.

4. Greenfield's Surgery, 5th Edition

5. Atlas of breast surgery

No comments: