The Histology of Invasive Breast Cancer
There are a great number of different types of breast cancer, and quite frequently one encounters a combination of different types of breast cancer within the same patient.
A listing of the most common types of breast cancer would probably include:-
- tubular breast carcinoma
- mucinous breast carcinoma
- medullary breast carcinoma
- papillary breast carcinoma
- apocrine breast carcinoma.
The names given to different breast cancer types quite often refer to visual/microscopic characteristics of the malignant cells and cell formations.
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Invasive Tubular Carcinoma is recognizable as small regular tubules lined with a single layer of malignant cells.
Tubular carcinoma may contain other histologic elements, but usually an excess of 75% tubular elements is required for a confirmed diagnosis. A fine-needle aspiration is insufficient to differentiate between a ‘pure‘ tubular carcinoma, or one with mixed carcinogenic types.
Biopsies done from core-samples or excisions are required to make a thorough, confirmed diagnosis. Tubular carcinonoma sub-types with mixed pathologic features generally have a much poorer prognosis, largely determined by the most aggressive histologic element.
Well-differentiated infiltrating ductal carcinoma
Infiltrating ductal carcinoma is ‘graded‘ on a composite score of three main features: the relative number and shape of tubules, uniformity of nuclei, and mitosis or ‘cell-divisions‘. Grading is categorized as:
- moderately well-differentiated
- poorly differentiated
The more the histologic features are poorly differentiated, the higher the grade and more serious the prognosis. Highly differentiated cell formations tend to look more like normal cells, while poorly differentiated formations tend to be more bizarre and random in appearance, very different from normal, healthy cells.
The lesion below features well differentiated histologic elements, indicating and earlier stage of breast cancer development. We can also see how the cancer has spread from within the duct (intraductal) to other parts of the breast (infiltrating).
Mucinous carcinoma or Collagen Carcinoma
A mucinous or colloid carminoma is one in which the tumor is comprised primarily of mucus, more than 60%. The lesion appears as a collection of ‘lakes‘ of mucin, with floating ‘islands‘ of tumor cells scattered within them. Colloid Carcinoma generally has a good prognosis as it is not as prone to metastasis as other types of inflitrating breast cancers.
It is usually considered a low to medium grade, slow-growing type of cancer, even though, from a histological perspective, colloid carcimona tends to feature cancer cells that are poorly differentiated. In this sense it is a bit of an exception.
The image below is a colloid carcinoma, showing mucin-producing malignant cells, surrounded by yellow mucus, interspersed with strands of collagen fibers.
‘Mixed’ and ‘Pure’ mucinous carcinoma
Mucinous carcinoma is often further separated into two categories: “pure” mucinous carcinoma and “mixed” mucinous carcinoma. With colloid breast cancer the mucin forming cells are plump, containing little intracellular globules of mucin. Those globules are transported to the cell surface where they rupture, spilling the mucin to the outside of the cell. When the histological analysis reveals that all the mucin has spilled outside of the malignant cells (into the surrounding ‘lakes‘) it is called ‘pure‘ or ‘purely extracellular‘ mucin production.
However, when some of the mucin is not spilled outside the cell but remains within the immedate context of the malignant cells, this is called ‘mixed‘ mucinous carcinoma, where the mucin is not exclusively extracellular. It has thought that a ‘mixed‘ mucinous carcinoma has a more aggressive growth pattern than a pure presentation. Recent studies have also suggested a correlation between ‘pure‘ mucinous carcinoma and the presence of neuro-endorcine cells.
It is also now thought that a kind of ‘alternating pattern‘ in the orientation of mucin-producing cells suggests a lower grade carcinoma. If alternate mucin-producing cells drain towards the surrounding stroma, a ‘bond‘ of sorts occurs between the tumor and the stroma. The distinctive chemistry of this particular mucin, accumulating in the stroma surrounding the colloid cancer cells, provides for a kind of ‘cell-containment‘, slowing the spread of the cells and growth of the tumor.
Statistical prevalence and treatment options for invasive mucinous carcinoma tend to suggest a positive prognosis.
Histology of Medullary Carcinoma
Medullary carcinoma gets its name on the basis of its microscopic appearance, which is similar to tissue found in the “Medulla Oblongata” region of the brain stem. Invasive medullary carcinoma usually appears in ‘sheets‘ of closely packed cells, but the margins of individual cancer cells are not clearly defined.
Malignant cells also tend to be somewhat larger than those of other breast cancers. The tumor usually pushes against the surrounding stroma, but does not infiltrate the same way most ductal carcinomas commonly do. Glandular or fatty breast tissue is normally not found within the invasive portion of the tumor.
Pathological features and defining criteria for true and atypical medullary carcinoma
The histological identification and evaluation of medullary carcinoma is somwhat inconclusive. There are certain features that one looks for, which may or may not be present, or are present in varying degrees. It is fair to say that the diagnostic criteria for medullary breast cancer continues to evolve, but the ‘classic‘ presentation of medullary carcinoma involves a syncytial growth pattern of poorly-differentiated tumor cells with a high mitotic rate.
Medullary carcinoma always presents with involvement and infiltration by lymphocytes, which are essentially white blood cells. The lymphocytes mostly collect around the well-defined perimeter of the tumor. There is some speculation among researchers that increased numbers of activated cytotoxic lymphocytes may lead to an improved prognosis with this particular carcinoma. Some pathologists suggest that the lymphocytes should cover 75% of the periphery and also be scattered diffusely throughout the tumor, in order to be called ‘true‘ medullary carcinoma.
Identification of medullary carcinoma using the Ridolfi criteria
The criteria set forth by Ridolfi and his colleagues still serves as a baseline for the grading of Medullary carcinoma.
These features must include:
- syncythial growth pattern
- microscopic circumscription
- high nuclear grade
- lymphoplasmacytic reaction
- mitotic rate
In order for the cancer to be termed ‘true‘ medullary carcinoma, all five features must be present. “Atypical” medullary carcinoma is a term often used of one or two elements are absent. Where there is poor correspondence within the five categories, the generic ‘ductal carcinoma‘ (NOS) is used.
Among pathologists there is no clear consensus as to the best diagnostic parameters for classifying medullary carcinoma. Recent amendments to the analysis have tended to focus on genetic and hormonal aspects of the tumor, rather than conventional measurements.
Mononuclear cell infiltration: monocytes
Mononuclear cell infiltration in varying degrees is also thought to be a good indicator of ‘true‘ medullary carcinoma. Monocytes, which are a type of white blood cell produced in bone marrow, will enter tissue zones to consume the debris of dead or dying cells after an infection has been fought.
Along with monocytes, pathologists look for sparse necrosis (evidence of dead or dying cells) in the order of 25% of the overall cellular profile, as a helpful indicator of true medullary carcinoma.
Hormonal and protein-related indicators of medullary breast cancer
Medullary carcinoma usually tests negative for hormone receptors and also for the protein HER2/neu. A carcinoma with positive oestrogen receptor staining is less likely to be a typical medullary carcinoma. Medullary cancer cells frequently express a protein called p53. All of these considerations are potentially useful and beneficial. If a tumor can be indentified as ‘true‘ medullary carcinoma, this tends to carry a better prognosis. And, the more that is known about a tumor, the more it may be treated strategically.
Image of Medullary Carcinoma
In the image of medullary breast cancer below, we can see examples of atypical mitosis and syncytial growth patterns. A syncytial cell is one containing many nuclei, and in this case we observe a pattern of syncytial nucleoli within a single malignant nucleus.
The atypical mitosic cells reveal a more densely stained ‘chromatin‘, indicative of an atypical growth within the nucleus. (Chromatin is a complex of nucleic acids and proteins in the cell nucleus. It stains readily with diagnostic protein-based dyes used in the histological analysis, and indicates rapid cell division is occurring in that region). We also note that many of the cytoplasmic membranes tend to be less clearly defined.
Even though we observe the more densely stained chromatin in this tumor, it is disputable as to whether or not keratin 19 staining (a commonly used dye) is useful in differentiating medullary from more generic ductal carcinoma.
Papillary breast carcinoma
Papillary carcinoma derives its name from the ‘finger-like‘ projections prevalent thoughout the tumor. It is called an ‘intracystal‘ carcinoma because it often found as a cyst, most commonly below the nipple, which results in bloody or watery discharges. The tumor may present as a soft, fluid cyst, or as a solid mass, or a combination of the two.
The histological appearance of papillary carcinoma is recognizable from the clumps of ‘bud-like‘ cancer cells which proliferate around fibro-vascular supporting tissues. The fibrovascular stroma is often visually described as being ‘frond-like‘ (similar to a leaf) or ‘arborized‘ (like branches).
In the image below we can see the arborized fibrovascular stroma with clusters of malignant papillary projections developing around them.
Watery or bloody discharges from the nipple do not necessarily indicate the presense of carcinoma. More commonly this symptom is the result of a benign ‘papilloma‘, possibly due to a viral infection or other cause. With papillary carcinoma the pathologist looks for accumulations of epithelial cells with nuclear hyperchromasia and evidence of mitosis. Hyperchromasia refers to an increased presence of chromatin, which is a complex of DNA and proteins secreted during new cell growth.
Hyperchromasia is revealed by the protein-based dyes used in histological analysis, and will appear visually more ‘dense‘ than the normal surrounding cells. Intracystic papillary carcinoma will also lack the myoepithelial cell proliferation found in most papillomas.
It can be difficult for a pathologist to assertain the invasive status of papillary carcinoma. The periphery of the cyst tends to be fibrotic or ‘thickened‘, and unless the neoplasm has infiltrated into fat tissues, the extent of the carcinoma is hard to determine. This is one reason that biopsy samples for suspected papillary carcinoma are most often obtained through a large surgical excision.
Papillary carcinoma is most commonly estrogen and progesterone receptor positive, with rates of approximately 80% and 70% respectively.
Other histological characteristics of papillary carcinoma,in addition to the papillary clustering, include palisading rows of tall columnar cells, cellular atypia, hemorrhagic background (evidence of bleeding), hypercellularity (abnormal increase in the number of cells), and calcification.
Apocrine breast carcinoma: Histological features
Apocrine breast cancer is a carcinoma of the apocrine cells or sweat producing glands of the breast. Apocrine cells secrete fluids through a ‘budded-off‘ top part of the cell, which drain into the lumen above the now free-end of the cell.
Normally these secretions are expelled from the body as sweat, but with apocrine breast cancers (and other benign breast ailments) the fluid gathers as a cyst beneath the skin or within the ducts.
The cytological appearance of apocrine carcinoma is mostly characterized by the presence of large amounts of granular cytoplasm (with a nucleus to cytoplasm ratio of about 1:2) Malignant cells also tend to be on the large side and with well-defined margins, with oval or round vesicular nuclei. Macronucleoli (extra-large nuclei) are also frequently encountered.
Apocrine carcinoma is readily revealed by protein-based dyes. A common feature of apocrine tumors is the presense of ‘apocrine snouts‘, which is a build up of secreted granules in the cytoplasm about the free end of the cells.
Apocrine cytoplasm is described as ‘eosinophilic‘, which means that it reacts quite strongly with eosin dyes, giving a clear visual cue to the pathologist. In the image of intraductal apocrine carcinoma below, we can see cylindrical malignant cells containing large amounts of granular cytoplasm, and also accumlation of apical secretion (the white fluid) in a layer around the top of the cells.
Additional histological features of apocrine breast cancer include a positive HER2 status about 50% of the time, and a positive finding for androgen receptors, ranging from 55% to 100% of cases. Estrogen and progesterone receptivity tends to be negative with apocrine breast carcinoma, but there is wide variability. Overall one would have to conclude that hormonal indicators are not particularly useful in the diagnosis of apocrine breast cancer, but could play a role in treatment therapy.
Differential diagnosis: benign cystic breast disease with apocrine involvement
A diagnosis of Apocrine breast cancer is often held back until it has been cleary differentiated from ailments such as apocrine metaplasia, and gross cystic disease of the breast, often called GCDFP-15. Both of these conditions are quite common with younger, premenopausal women.
GCDFP-15, named after the ‘fluid protein 15‘ in the secretions, is a cyst that forms as a result of ‘over-production‘ of apocrine secretions, and is in itself a completley benign ailment. However, apocrine carcinomas also test highly positive for the GCDFP-15 protein, so a thorough histological evaluation must be undertaken to rule out carcinoma as the root cause. Occasionally, there is some degeneration of cells within a cyst, but carcinoma is not necessarily the source.
Apocrine metaplasia (or APMA) is a benign breast disease which features new growth of large quantities of apocrine cells. This requires a more subtle distinction, as neoplastic apocrine carcinoma cells can resemble benign apocrine metaplasia cells with a degenerative appearance.
Apocrine carcinoma may appear in various clusters and sheets, but the benign formations of apocrine metaplasia are also somewhat unpredictable as well. Key distinguishing factors for malignant apocrine carcinoma are a somewhat uniform cell population, nuclear atypia, a slightly larger nuclear diameter, and the reconizeable ‘snout‘ chromatin pattern. The lesion itself tends to be slightly smaller for apocrine metaplasia. A certain amount of cellular necrosis (dead cells) and detritus (debris and other waste products) would also suggest the presense of carcinoma.
There is some speculation that the same genetic features in the apocrine epithelium which lead to apocrine metaplasia may be connected to a higher propensity for cancer. At this time, there is insufficient evidence to support this claim. It should be noted that the mean age for the development of apocrine carcinoma is at least 20 years older than for apocrine metaplasia.
This page has fabulous information. Everything you need to know about different types of invasive carcinomas is listed above…
For further reading, I recommend you visiting this new page on Hormone Receptor Statuses.
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