Question

How to grade breast cancer?

Recommendation

Tumour size must be determined according to the TNM classification, 7th edition.

 

All invasive carcinomas must be graded using the modified Bloom and Richardson guidelines.

Literature summary

Determining the PT and tumour grade

Tumour diameter

Tumours are staged according to the TNM classification, 7th edition. The pT is the maximum diameter of the dominant invasive carcinoma foci. This measure is used for staging, determining the prognosis and therapy evaluation and also for the indication for additional therapy.

The pT is determined by measuring macroscopically recognisable tumour, preferably in the fresh sample. In the case of star-shaped radiating tumours, only the centre of the tumour should be measured. The macroscopic measure must be compared to the microscopic findings in a central cross-section of the tumour. The largest measurement should be taken as the pT. In the case of a stellate tumour, the diameter is determined by the bulk of the tumour and not by protrusions.

If there is multinodularity, the maximum diameter of the area with the nodes are measured as pT if there is confluence. If there are separate nodes that are separated by pre-existent node tissue, the diameter of the largest foci is taken as pT. Given the turning points for the indications for adjuvant therapy lie at 1, 2 and 3 cm, these measures should therefore be avoided as much as possible by exact measurements in mm.

A pT4 tumour is when there is ulceration of the skin by the tumour, a peau d’orange, oedema of the skin, an inflammatory aspect of the skin, metastases in the skin or metastasis into the chest wall. Some of the skin changes cannot be evaluated well in a mastectomy sample and should therefore be reported by the clinic. When there is metastasis into the skin but the above skin changes are not present during pathological analysis, the tumour is classified on the basis of the dimensions (T1,T2,T3). An M. Paget is not considered a pT4 in itself. When determining the metastasis into the chest wall, the pectoralis major muscle is not to be included in the calculation. When metastasis into the muscle tissue only involves the pectoralis major muscle, the pT classification is determined by the dimensions.

 

Grading

Aside from the pT, the tumour grade is also used to determine the indication for adjuvant systemic therapy with pN0. All invasive carcinomas may be graded using the modified Bloom and Richardson guidelines [Rakha, 2008]. It therefore also applies to infiltrating lobular carcinoma and special types such as medullary, tubular and mucinous carcinoma. The method consists of three components of the tumour morphology: the extent of tubule formation, the nuclear polymorphism and mitotic activity defined as the number of mitoses per 2 mm2. In doing so, the number of fields of view to be counted differs; this depends on the size of the fields of view associated with the microscope. A score of 1, 2 or 3 is assigned to each of these components. The histological grade is determined by the sum of these scores.

Grading requires paraffin setions of well-fixed tissue.

 

Level of tubule formation:        

1 = > 75 %

2 = 10-75 %

3 = < 10 %

Nuclear polymorphism:            

1 = comparable to normal epithelium

2 = enlarged, vesicular, small nucleoli

3 = polymorphic, vesicular, large nucleoli

Mitotic activity:                        

1 = 0 through to 7 mitoses per 2 mm2

2 = 8 through to 12 mitoses per 2 mm2

3 = 13 or more mitoses per 2 mm2

 

The histological grade is I for the scores 3-5, II for 6-7, and III for 8-9.

 

Tumour excision is necessary for reliable grading of carcinomas However, because neoadjuvant chemotherapy is increasingly being applied and the indication for postoperative adjuvant systemic therapy is partly dependent on the tumour grade, the pathologist is regularly expected to make a pronouncement about the grade of the tumour according to the modified Bloom and Richardson from the needle biopsy taken prior to the neoadjuvant chemotherapy. This is possible to a limited degree given tumour heterogeneity and the chance of underestimating the mitosis index. However, a high level of concordance is possible for evident high-grade and low-grade laesions [Harris, 2003; Park, 2008].

 

MAI

The cut-off points of the MAI have been converted in the same manner as that of the Bloom and Richardson grading. The mitosis index is the most important factor in the histological grade. Incorporating MAI in the compulsory items / minimum data set ensures pathologists seriously count the mitoses. However, it is not necessary for this to be reported in the conclusion.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.

 

This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Member of workgroup

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.

 

The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.

 

Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).

 

Method of development

Evidence based

Implementation

Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.

 

A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.

 

Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:

 

Classification of research results based on level of evidence

A1

Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.

A2

Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.

B

Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.

C

Non-comparative   trials

D

Opinions   of experts, such as guideline development group members

 

Conclusions

Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.

 

Classification of conclusions based on literature analysis

1

Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.

2

Based   on at least 2 independent B reviews

3

Based   on 1 level A2 of B research, or any level C research

4

Opinions   of experts, such as guideline development group members

 

Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.

 

Recommendations

The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.

 

References

An alphabetical list of literature references can be found at the end of the guideline.

 

All draft texts have been discussed by the guideline development group.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.