Histological descriptions of proliferative cellular conditions found in breast cancer screening

If a woman goes for a breast cancer screening mammogram and has no clinically palpable lump, it is usually up to the mammogram to detect lesions that may be developing within the breast. But, a woman may have proliferative new cell growth (which is in most cases benign) that will not be detected on the mammogram. Unless there are microcalcifications visible on the x-ray image, proliferative cell growth in the terminal ducts would likely remain hidden.

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Proliferative cell growth, or ‘hyperplasia’

The walls of the breast ducts are made of loose connective tissue forming a basement membrane. Basically, the duct wall can be broken into two elements; the basement membrane, which is a discontinuous layer of myoepithelial cells, and built on top of the basement membrane sits a continuous layer of epithelial cells which lines the lumen (empty space) of the duct. This epithelial cell lining of the duct wall is usually a two to three cell layer. If this epithelial cell layer is thicker than two or three cells, something is going on.

 
 

‘Hyperplasia‘ simply means an unexpected increase in either myoepithelial or epithelial cells that line the ducts. Hyperplasia does not necessarily indicate the presence of breast carcinoma, but it is certainly something the pathologist will want to look into thoroughly.

Different pathologists have different ways of categorizing the ‘seriousness‘ of hyperplasia, but generally we see a progression from mild and moderate hyperplasia, to florid hyperplasia. If the cytological evaluation reveals any odd or ‘atypical‘ appearance of the newly developed cells, this becomes of far greater concern, and is termed ‘atypical ductal hyperplasia’.

Atypical Hyperplasia is often a precursor for DCIS

There is always a grey area when trying to decide if atypical hyperplasia constitutes breast carcinoma or not. Atypical ductal hyperplasia (or ADH) is sometimes defined as a lesion that has some of the features of ductal carcinoma in situ, but not all of them. Others describe ADH as a lesion with all the features of DCIS, but smaller in size; less than 2 mm, or perhaps involving only a single duct.

DCIS is breast cancer still contained within the ducts of the TDLU or ‘terminal ductal lobular unit‘. There are various scenarios for atypical hyperplasia that end up being labelled as DCIS. It is a ‘heterogeneous‘ (many-faceted) disease, and some pathologists argue that there should be two sub-categories DCIS, based on where the hyperplasia is occuring.

Atypical hyperplasia which arises ‘de novo‘ (Latin for ‘from the beginning’) in the duct tends to be of a higher nuclear grade (more abnormal looking) and with central necrosis. Higher grade nuclear variations tend to evolve into ‘poorly differentiated‘ higher grade invasive lesions. On the other hand, Hyperplasia which over time evolves into ADH and gradually moving into the ducts tends to lead to a low grade DCIS.

Low to high grading of ductal carcinoma in situ

An informal checklist is used to determine the grading of DCIS. All ducts involved with DCIS will appear distended when compared to normal ducts. Without going into too much detail, further grading tends to have to do with the nuclear cell appearance, location or ‘polarization‘ towards the duct, and necrosis.

Low grade DCIS tends to have ‘monomorphic‘ (one shape) nuclei, with no nucleoli. It also tends to have low mitotic rates (cell division), virtually no cell necrosis, and polarized growth towards the duct lumen. Growth patterns can also give a clue, with low grade DCIS tending to form solid patterns, cribiform patterns, and sometimes with micropapillary projections. (Note, micropapillary DCIS is now thought by many specialists to be a special, highly aggressive form of DCIS).

High Grade DCIS is most often characterized by ‘pleomorhpic‘ (many-shaped) nuclei, and frequent nucleoli. Mitotic rates are high. Cell necrosis is evident, and cellular growth is not polarized to any particular orientation.

High grade DCIS cells surround and encroach the lumen of the duct, and the lumen begins to show the presence of debris and necrosis, and it is on that debris that microcalcifications tend to form. High grade DCIS is more likely to develop into more aggressive, higher grade invasive carcinoma.

Calcifications associated with proliferative cell growth tend to accumulate in two places

So, a screening process which detects calcifications and microcalcifications is in some ways ‘out of sync‘ with the growth of potentially cancerous cells in the breast. Microcalcifications develop only after some hyperplastic activity has occurred, and yet atypical hyperplasia and DCIS will only be confirmed following a biopsy and histological evaluation. But, this also implies that a clinical exam has revealed no palpable mass, so any breast cancer found will be at a very early, highly manageable stage.

Microcalcifications, which are essentially mineral deposits, tend to occur either within luminal secretions (breast milk), or on the necrotic cellular debris.

Sometimes with DCIS or breast hyperplasia, breast milk can get ‘stuck‘ in a duct for a long time. The ‘liquids‘ can get resorbed, but the remaining solids more-or-less sit there for a while. Eventually they too are resorbed, but by this time calcifications may have developed.

Calcifications that develop from luminal secretions tend to be well-defined, punctate (in small dots) or round, and with variable densities. They also tend to be clustered together. DCIS associated with calcifications of luminal secretions tends to be of a low or medium grade. However, it is important for the pathologist to take an adequate sampling from other regions of the breast, because microcalcifications in luminal secretions are a bit migratory, and can be found in areas of hyperplasia only.

Calcifications that deposit on the necrotic cellular debris are fairly distinctive on a mammogram. The tend to be ‘linear‘ with irregular borders and clefts. They occur in variable densities and may be distributed regionally, segmentally, or focally, or may extend linearly toward the nipple. When microcalcification extends toward the nipple, a radiologist can give a pretty accurate estimation of the extent of the ductal carcinoma in situ.

However, no one can predict with certainty whether or not DCIS will develop into invasive carcinoma, regardless of the microcalcifications on the mammogram. It is estimated that 10% of lesions where microcalcifications strongly predict against invasion, will develop invasive status anyways. But on a more positive note, mammograms with microcalcification strongly indicative of high grade DCIS only accurately predict invasive status about 45% of the time.

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For further reading, I recommend you to visit this page with more information on Proliferative Cellular Conditions.
Below are just a few Q&A… :

• Are proliferative breast conditions cancerous? No. But they do increase the risk of breast cancer.
• What is the most common type of proliferative breast condition? The most cmomon type of proliferative breast condition is hyperplasia. There are two types of hyperplasia: usual hyperplasia (more common) and atypical hyperplasia (less common).
• What is usual hyperplasia? In usual hyperplasia, the proliferating (dividing) cells look normal under a microscope. Women with usual hyperplasia have about two times the breast cancer risk of women without a proliferative breast condition.
• What is atypical hyperplasia? In atypical hyperplasia, the proliferating (dividing) cells look abnormal. Women with atypical hyperplasia have about four to five times the breast cancer risk of women without proliferative condition. For women with this type of hyperplasia, there are special breast cancer screening recommendations. These women should have a mammogram every year, have a clinical breast exam every 6-12 months, and they should also tal with their health care providers about screening with breast MRI. Women with atypical hyperplasia may also consider taking a risk-lowering drug (tamoxifen or raloxifene) to lower the risk of developing breast cancer.
• What is a non-proliferative breast condition? Non-proliferative benign breast conditions (such as cysts) do not increase the risk of breast cancer.

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References

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