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Grading and Staging

Grading of Breast Cancer


Assessing lymphatic/vascular invasion


Classifying lymph node metastases using TNM6

Grading of Breast Cancer



Scoring system



Acini
> 75% - Score 1
10 - 75% - Score 2
<10% - Score 3


Nuclear atypia/pleomorphism
Small nuclei very similar in size to benign ductal/acinar epithelial cells
Minimal pleomorphism and even chromatin pattern
Nucleoli very inconspicuous
This score is applied uncommonly
Score 1
Larger nuclei with mild to moderate pleomorphism
Nucleoli visible but small and inconspicuous
Score 2
Vesicular nuclei often with prominent nucleoli
Marked variation in size and shape
Score 3


Mitoses
figures below refer to a high power field (hpf) diameter = 0.50mm
(see note below)
< or = to 7 per 10 hpf Score 1
8-14 per 10 hpf Score 2
> 15 per 10 hpf Score 3


When assessing mitotic count it is essential to calibrate your microscope so that you know the diameter of your (x40) hpf. Readers are referred to the calibration table in the UK breast screening guidelines2.

A minimum a 10 hpfs should be counted at the periphery of the lesion and an attempt made to seek out mitoses. The illustrations below show examples of what are and more importantly what are not mitoses. It is especially important not to count apoptitic bodies and other dark nuclear blobs.

The following score groupings are used to define the Grade of a cancer. When reporting the Grade it is good practice to give the individual score components as well as the calculated grade. This allows for possible audits in the future and also allows for immediate comment on comparisons with core grade (if its score components have also been recorded).


Scores and equivalent Grades
Total score 3 - 5 = Grade 1
Total score 6 or 7 = Grade 2
Total score 8 or 9 = Grade 3



It is worthwhile when trying to assess tumour grade identifying those elements about which you have no doubt and then looking at the remaining scoring element(s) which may or may not be critical depending whether the two most likely scoring options push the grade one higher or one lower. In the following example the final element may or may not be non-critical depending on whether the scoring decision is between 1 & 2 or between 2 & 3. Obviously we do not want to encourage sloppy practice, on the contrary, simply a more robust approach to the practicalities of grading:




The following examples further illustrate this point:




  • Tubule score unequivocally 2
  • Mitotic score unequivocally 2
  • Nuclear score (1 v 2) critical for deciding between grade 1 and grade 2


Examples of Tubule Formation


When assessing tubule formation, having initially assessed the tumour at scanning power examine some representative fields more closely picking out ten epithelial units at a time and estimating how many are solid and how many have a glandular space. Very quickly you will have a very good idea whether it is < 10% or > 75%.



Tubule score = 1 (>75% tubules)
The overwhelming bulk of this carcinoma shows tubular differentiation. It is morphologically of NST type and NOT a Tubular Carcinoma Medium power view of >75% tubule formation

Tubule score = 2 (10 - 75% tubules)
This cancer shows < 75% tubule formation - Tubule score=2 This medium power view allows critical evaluation of those structures forming tubules and those that are solid

Tubule score = 3 (< 10% tubules)
This carcinoma shows no tubule formation whatsoever - Tubule score = 3 A single acinar structure is seen in the top left hand corner (arrow). Overall, tubule formation is well under 10% - Tubule score = 3

Examples of the three nuclear grades


NOTE - All the nuclear grading photographs have been taken at identical magnification for ease of comparison


Four examples of Nuclear score = 1
Small very regular nuclei with inconspicuous nucleoli Tumour acinus on left and normal duct on right - note similarity of nuclear size
Nuclear score 1 Nuclear score 1

Two examples of a mixture of Score 1 and Score 2 nuclei (see arrows) - this is predominantly nuclear score = 1 however the higher nuclear grade always applies when there is a mixed population
Mixture of nuclear scores 1 & 2 Mixture of nuclear scores 1 & 2

Two examples of Score 2 nuclei - lower end of the range on the left, the higher end on the right
Nuclear score 2 Nuclear score 2


Four examples of Score 3 nuclei from the lower end of the range (top left) to the higher end (bottom right)
Nuclear score 3 (lower end) Nuclear score 3
Nuclear score 3 Nuclear score 3 (higher end)


An example of nuclear score 3 at the severely pleomorphic end of the range. Note the normal duct in the centre of the image for comparison. Original magnification x 40; 75% enlargement in comparison to series of images above.
Nuclear score 3 with normal duct for comparison

Examples of mitoses (Y) and not mitoses (N)


The following examples are from a selection of nuclear grade 3 carcinomas which show brisk mitotic activity. Various nuclear changes have been marked as to whether the author believes them to be (Y) or not to be (N) mitoses. It is inevitable that different pathologists will argue over some of these!




Lymphatic/vascular invasion


  • Best assessed around periphery of tumour
  • Difficulty distinguishing from shrinkage artefact in section - do not overdiagnose!
  • Lymphatics tend to accompany small veins arteries and nerves - if seen improves confidence in diagnosis
  • Tumour in vessels tends to be 'stuck' to the sides and may be accompanied by red cells
  • An independent prognostic factor so do not diagnose just because the nodes are positive!!

Examples of lymphatic/vascular invasion
Two foci of lymphatic invasion by carcinoma - the focus on the right is close to a venous channel
Vascular bundle with lymphatic invasion by carcinoma
Venous invasion by carcinoma - note adjacent small artery Invasion of dermal lymphatics and dermal connective tissue by recurrent carcinoma of breast

The images below are from the same case.
On the left the arrow points to a possible focus of lymphatic invasion; on the right lymphatic invasion is unequivocal.
The diagnosis is made considerably more secure by confirming the presence of a lymphatic "in company" with a vein and small artery in the right hand image. Pass the mouse over these images to change the view.
Low and medium power views of intermediate grade DCIS with adjacent invasion (circled). Low and hgh power views of lymphatic invasion - note adjacent artery & vein

An example of probable retraction artefact and NOT lymphatic/vascular invasion
This focus was regarded as NOT being diagnostic of lymphatic invasion but more likely to be simply retraction artefact of surrounding tissues

Nodal metastases


  • Identification of nodal metastatic disease is the most important task facing the pathologist examining an operative lymph node specimen in a case of breast cancer
  • Microscopic assesment should include the size of the largest metastasis, extranodal extension & invasion of adjacent lymphatics if present
  • Node metastases are subclassified into - replacement type, micrometastases and isolated tumour cells (ITCs)according to TNM 6 - see below

Subclassification of nodal metastases (TNM6)
Replacement metastases > 2mm
Micrometastases 0.2mm-2mm
Isolated tumour cells < 0.2mm


Replacement Metastases


Two examples of replacement metastases in axillary nodes. Note extra-capsular spread into adjacent fat in the images on the right
Low power view of replacement metastasis. Tumour acini infiltrating perinodal fat
Low power view of replacement matastasis - extension into perinodal fat can be seen at this magnification. Medium power view showing infitration of perinodal fat by metastatic carcinoma.


Micrometastases

Subcapsular micrometastasis - this deposit is < 2mm on the H&E but the immuno stain for pan CK was on a section taken after cutting into the block further and measures just over 0.2mm qualifying as a micrometastasis


Isolated Tumour Cells and Micrometastases


Two subtle subcapsular deposits (arrows) of metastatic carcinoma in an axillary node sample - the sentinel node was negative in this case.
The deposit in the upper left quadrant measures <0.2mm and on its own would be recorded as "isolated tumour cells" (N0)
The deposit in the lower right hand quadrant measures 0.27mm and therefore qualifies as a micrometastasis (N1)


The enlarged photomicrograph below shows more detail of the metastatic foci when you move the mouse over those areas



References


1. Elston CW and Ellis IO. Pathological prognostic factors in breast cancer I. The value of histological grade in breast cancer: experience from a large study with long-term follow up. Histopathology, 1991, 19:403-10

2. Pathology Reporting of Breast Disease. NHS Cancer Screening Programmes/Royal College of Pathologists. NHS BSP Publication No 58, 2005.LINK


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