ABOUT BREAST
In order to understand the importance of screening and early detection it is important to understand the breast.
The breast is a modified skin gland. Its sole purpose is to secrete milk for the nourishment of a newborn infant. Although the basic cellular functions are the same in all women, the overall structure of the breast varies between individuals women and an individual's own breasts, although similar, are not identical.
All breasts are composed, to varying degrees of 6 different types of tissue:
Glandular tissue (called lobules) for secreting milk. These are like clusters of hollow grapes joining at the end of a small hollow tube. Together this is called the Terminal Duct Lobular Unit (TDLU).
The duct networks that carry milk to the nipple can best be described as multiple tree-like structures whose bottoms open in the crevices in the verrucoid surface of the nipple. Each major duct is like a hollow tree whose hollow branches spread as it extends back from the nipple. The hollow branches become progressively smaller until they form the hollow terminal duct that connects with the lobule. During lactation the lobules undergo hypertrophy and secrete milk that flows through the ducts from the glandular tissues to the nipple. Each duct network defined by its major duct in the nipple appears to be independent from the other tree-like structures that form what are called the “lobes” or “segments” of the breast. The number of lobes and segments appear to vary from individual to individual and no one knows how many TDLU’s are found in any breast.
The breast is composed of various amounts of fat from very small amounts in very thin women to making up most of the breast in other women. The breast is a repository for fat so that gaining weight may increase the volume of the breast and weight loss may reduce its size.
Connective tissue supports the glandular tissues and fat and holds everything together. There are actually two forms of connective tissue in the breast. The usual form is like connective tissues throughout the body. This tough fibrous tissue holds the breast together.
The regular connective tissue, for want of a better term, is familiar to us all as "gristle", and it provides structure and support within the breast. Sir Astley Cooper first described these sheets of connective tissue that course through the breast and hold it together. As with “gristle”, these sheets of connective tissue vary in thickness and can be extremely tough. Cutting through the breast at surgery to remove abnormal tissue can be difficult. These "Cooper's Ligaments" actually attach the breast to the skin by the “retinacula cutis”. These are like elastic bands or shock absorbers suspending the breast from the skin. The loss of breast firmness that comes with aging is due to the stretching of the skin as much as anything else.
Specialized connective tissue of the lobule is distinctive in its staining characteristics. It encases that TDLU. There is increasing interest in this specialized connective tissue and its possible role in the development of breast cancers. Proliferation of the specialized connective tissue of the lobule is the well known “fibroadenoma”.
Blood vessels and lymphatics course through the breast to provide oxygen and nutrients and to remove waste products from cell metabolism. There are no blood vessels or lymphatics inside the ducts, but they are all around in the tissues surrounding the ducts.
BREAST DEVELOPMENT
Both male and female infants are born with short milk ducts just underneath their nipples. This area is termed the “subareolar” tissue. The areola is the thickened pigmented portion of the skin of the breast from which the nipple protrudes. Bumps on the areola are “Montgomery’s Tubercles and Glands”. These lubricate the nipple to help protect it during nursing.
In the female, hormones secreted by the brain, stimulate the ovaries. Breast development (Thelarche) begins around the time of puberty. The ducts grow longer and begin to push back into the soft tissues of the chest to form branches just like a tree (except the trunk and branches are hollow). These branches grow back toward the chest wall, and fat and connective tissues develop around them to form the breast mound.
Initially, the glandular tissues are incomplete. The ducts are blunt ending tubes. Over time, with increasing age, or in response to a full term pregnancy, the ducts stop elongating and branching, and at the ends of the smallest branches a cluster of small tubules form, surrounded by the different "specialized" connective tissue. These tubules are like the fingers of a glove. The wrist of the glove attaches to the end of the duct (terminal duct) and the fingers form "ductules" that come off like the spokes of a wheel, but in all directions. Each spoke is called an “acinus” of the lobule. As a group they are the “acini”. The cells that form the inner layer (luminal layer) of these ductules become the glandular cells that will secrete milk during nursing (lactation). Each glove with its fingers (acini) is called a “lobule”. Together with the small duct (the wrist) that leads to each lobule, the combination is called the “terminal duct lobular unit (TDLU)”. When the “acini” of the lobule proliferate forming large numbers of acini and the lobule begins to look like a porcupine, the pathologist calls this “adenosis”. The TDLU’s are the actual “glands” of the breast. No one has ever counted all of the lobules, but their numbers almost certainly differ from one individual to the other. There are likely hundreds in each breast.
Prior to this structure becoming a mature system capable of producing milk, the TDLU is “undifferentiated”. The cells and the structures have not completed their development into a mature milk secreting gland. This is speculation on my part, but I suspect that before “terminal differentiation” to form the mature TDLU’s takes place the breast contains a large number of stem cells. These are cells that have not decided what they will be (they are “undifferentiated” or “pleuripotent” = multiple potential) and they are waiting for the directions that will make them form the TDLU. I believe that this is important because it is easier to damage a stem cell and convert it to a cancer cell than to "dedifferentiate" a cell that has already differentiated (like a skin cell) and make it become a cancer cell. This is the most likely reason that the immature breast is susceptible to carcinogenesis from radiation while the mature breast is, essentially, radioresistant. Once terminal differentiation has taken place the concentration of stem cells likely falls making it less likely that a stem cell will be damaged and become a cancer cell.
DEVELOPMENT AND AGING
The breast is a skin gland. In the developing embryo there is a collection of cells that form the "mammary ridge" that extends from what will become the axilla (armpit) down across what will become the chest, across what will become the abdomen and into what will become the groin. As the embryo develops most of the mammary ridge disappears except the part on the chest that will become the breast. The vast majority of men and women develop a left and right breast. As with all human development, it does not always go as planned. Sometimes the "ridge" persists in unexpected areas and breast tissue, and even complete breasts that secrete milk during lactation, can develop anywhere along the mammary ridge. Many women have breast tissue that extends up toward and even into the underarm that may swell and be painful prior to a period. This is referred to as the "Tail of Spence". Some women have breast tissue that is separate from the main breast, but is high in the underarm. This is called "accessory" breast tissue. Many women have accessory nipples that look like nevi (moles) along the milk line, particularly on the skin of the upper abdomen. Accessory breast tissue can also secrete milk during lactation. Persistence of parts of the mammary ridge can extend into the groin and in very rare situations can harbor a breast cancer (1).
The breast is a repository for fat. Women well know that when they gain weight their breasts often get larger, and when they lose weight their breasts may get smaller. There are varying amounts of fat in the breast. Some breasts are composed of mostly fat while others contain very little. The majority of women have breasts that have moderate amounts of fat in a heterogeneous pattern. These patterns are easily seen on mammograms since the fat allows x-rays to pass easily through the breast while the ducts, glands and fibrous connective tissues contain water which blocks some of the x-rays making shadows on the mammogram. It is the amount of the water containing tissues of the breast that make it appear “dense” on mammograms. Very young women tend to have a very high percentage of dense tissues on their mammograms. Again this is a combination of, predominantly, fibrous connective tissue, with ducts and glands (the lobules) contributing to the density of the breast. The dense tissues do not feel any different than the fat when a breast is examined either by a health care professional or the individual, herself, so that the only way to know if a breast has a lot of dense tissue is by x-ray, ultrasound, CT, or MRI imaging. "Firmness" and "density" are unrelated. A firm breast may be dense or fatty – there is no correlation (2, 3).
As women age, the percentage of fibrous connective tissue and glandular tissues decrease (4). Women also tend to gain weight with age so that the percent of dense tissues appears to decrease with increasing age as the amount of fat increases. There is a great deal of variability and, although older women tend to have more fat in their breasts, many women have extremely dense breasts into their seventies and older. The density of the breast has been linked to the risk of breast cancer. Like so many of the other issues, the analysis of this relationship has been confused by a faulty understanding of the volume of dense tissue in a breast. The risk, if any, related to breast density has been greatly overexaggerated (5). However, since breast cancers can be hidden by dense tissues, it is somewhat harder to find small cancers in women with a large amount of dense tissue. We still find many breast cancers in these women, but mammography is less “sensitive” to cancers in dense breasts. This effect has been over exaggerated by opponents of screening women ages 40-49.
INFANTS
The breast starts out in infant boys and girls as short small tubes (ducts) beneath the nipple. The glandular tissues (lobules) that will secrete milk never form in males which is why men do not form lesions of the lobule such as fibroadenomas. The ducts are incomplete in females until a full-term pregnancy or as women get older. Stimulated by the hormones of puberty (thelarche), the ducts in females begin to get longer and grow back into the soft tissues in front of the chest wall. Fibrous tissue (gristle) forms with the ducts to support them. These were first described by Cooper more than a century ago and have been called “Cooper’s Ligaments” (6). Fat begins to be deposited and the breast mound begins to form. Older age or a full term pregnancy will cause “terminal duct” differentiation which produces mature lobules that can produce milk during lactation.
BREAST CANCER
Each milk duct has an outer tube of “mesenchymal” cells (again related to gristle) that give it its “pipelike” structure. The pipe has a lining inside made up of single layer of “epithelial” cells forming a sleeve within a sleeve. At times these cells can multiple and form several layers (hyperplasia). If the hyperplastic cells begin to look abnormal this is called “atypical” hyperplasia. When the volume of atypical changes is sufficient (somewhat nonspecific) the pathologist will call the process ‘Ductal Carcinoma In Situ” (DCIS).
It is fairly clear that breast cancers are due to alterations in the control mechanisms of these epithelial cells. A cancer occurs when these altered cells, that line the milk ducts, multiply without stopping. They grow for a time inside the duct as DCIS filling up the duct like a clog in a pipe. Ultimately, the cells break through the wall of the pipe and "invade" or "infiltrate" from inside the duct into the surrounding tissue outside the duct (like a leak in a pipe) where they can then get into the blood vessels and/or lymphatic systems that are found outside the ducts. The mechanism for this “invasion” is unknown. Originally it was believed that there were DNA changes that created invasive cells from “in situ” cells”, but this, apparently, is not the case. No one has identified major differences in the DNA of these cells.
Obviously the blood vessels carry blood around the body. Most people don't know that there are other tubes that also go all over our bodies that collect fluid that we leak all the time into our soft tissues. These are called "lymphatics" and they collect the leaked fluid and conduct it back to the blood (vascular system) through a connecting pipe in the chest called the "thoracic duct".
When cancer cells get into these tubes (blood vessels and lymphatics) they can spread to other organs in the body. Like seeds in a field, some find sites in other organs where the cancer cells can multiply. Not all cells that float to other organs are able to survive and become established. It is when some cells are “successful” in “rooting” and growing in other parts of the body that the cancer is said to be “metastatic”. It is this “metastatic spread” to other organs where the cancer cells crowd out and destroy the normal cells that causes breast cancer to become lethal. If enough normal cells are killed and the organ (liver, lung, bone marrow, brain, etc.) can no longer perform the functions needed to support life, then this causes the death of the individual. At this point in time, although therapy can delay deaths, once a breast cancer is “successfully” metastatic, it cannot be cured. Newer therapies can help to delay death, but if the woman does not die from some other cause, she will, ultimately, be killed by her metastatic breast cancer. The goal of screening is to detect cancers and eliminate them before they can successfully spread to other organs and become incurable.
STEM CELLS AND CANCER
As noted earlier, some investigators think that cancers originate from stem cells. This is also pure speculation on my part, but I suspect that there are likely a large number of undifferentiated stem cells around before the breast has become fully "differentiated". When there are a large number of these undifferentiated cells, exposure to a carcinogen (in the water, air, food???) may lead to damaging one of the stem cells and the subsequent development of a cancer. This may be the reason that women who are exposed to radiation during this period in their lives (when they are teenagers), prior to differentiation, are at higher risk of developing breast cancer. As they age, the susceptibility of the breast to radiation drops dramatically. For example, teenage girls who are treated with high doses of radiation to the central chest to treat Hodgkin’s Lymphoma, exposing their breast tissue to a lot of radiation, have a very high risk of developing breast cancer (30% over the next 20 years) (7). I suspect that the higher the concentration of undifferentiated stem cells, the greater the chance that one will get damaged from a carcinogen like radiation, and, instead of becoming a normal breast cell, it may develop into a cancer. Protecting the breast from carcinogens in teenagers and young women before “terminal differentiation” has taken place is probably a good idea.
EXPOSURE TO ONES OWN HORMONES
Another factor in developing breast cancers is a woman’s exposure to her own hormones. It has been known for years that early menarche and late menopause are risk factors for breast cancer. With every menstrual cycle, the breast prepares for a possible pregnancy. The cells of the breast proliferate. If there is no pregnancy some of the cells undergo apoptosis until the next cycle leads once again to proliferation and the cycle repeats every month. In order for cell proliferation, the DNA needs to be copied. If the breast is exposed to a carcinogen at this time it may interfere with having DNA copied accurately. Cell mechanisms generally correct minor errors in copying, but it is likely that some errors do not get corrected. I suspect that these usually lead to the cell dying (apoptosis) so that the damage is not preserved, but it is likely that some cells are not repaired (BRCA genes are abnormal repair genes which is likely why women have such a high risk of breast and ovarian cancers) and the cell does not commit suicide and the damage is preserved. Perhaps at a later date there is more damage that is not repaired, and the cell survives ultimately to become a cancer cell. Early menarche and late menopause are risks for developing breast cancer.
REFERENCES
1. Piura B, Gemer O, Rabinovich A, Yanai-Inbar I. Eur J Gynaecol Oncol. Primary breast carcinoma of the vulva: case report and review of literature.2002;23(1):21-4.
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3. Boren WL, Hunter TB, Bjelland JC, et al. Comparison of breast consistency at palpation with breast density at mammography. Invest Radiol 1990;25:1010–1011.
4. Prechtel K. Mastopathic und Altersabbangige Brustdrusen Verandernagen. Fortschr Med 1971;89:1312–1315.
5. Kopans DB.Basic physics and doubts about relationship between mammographically determined tissue density and breast cancer risk. Radiology. 2008;246:348-53.
6. Cooper A. The Anatomy and Diseases of the Breast. Philadelphia, Lea and Blanchard 1845.
7. Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, Meadows AT. Breast Cancer and Other Second Neoplasms After Childhood Hodgkin's Disease. J Engl J Med 1996;334:745-751.
