Question

When can pathological biopsy diagnoses be considered clearly benign?

Recommendation

The following pathological biopsy diagnoses can be considered clearly benign: If this corresponds to clinical findings and images, then no further action is required:

  • hamartoma
  • fibroadenoma
  • tubular adenoma
  • benign ductal hyperplasia
  • sclerosing lobular hyperplasia
  • fibro-cystous changes
  • duct ectasias
  • apocrine metaplasia
  • adenosis
  • pseudoangiomatous stroma hyperplasia
  • normal or fibrous breast tissue

 

The following pathological biopsy diagnoses cannot be considered clearly benign:

  • flat epithelial atypia/cylinder cell laesions
  • atypical ductal hyperplasia
  • atypical lobular hyperplasia and lobular carcinoma in situ
  • papillary laesions
  • radial scar/ complex sclerosing laesion
  • phyllodes tumour

 

In the case of a diagnosis that is not clearly benign, the management plan must be determined in multisciplinary consultation. It must be based on:

  • the number of biopsies and how representative the results are on which the pathology report is based
  • imaging: including the extent and level of suspicion of microcalcifications, the microcalcifications on the specimen radiogram and how many microcalcifications have remained behind
  • patient factors: including age, familial burden, treatment preference, co-morbidity

 

Depending on the above, it can be decided in multidisciplinary consultation to repeat the biopsy, perform a diagnostic excision biopsy or mammographic follow-up. Routine follow-up with MRI is not indicated.

Conclusions

 

Level 1

With the biopsy diagnosis: atypical ductal hyperplasia, atypical papillomatosis or radial scar (complex sclerosing laesion), there is a clinically significant chance of simultaneous malignancy.

 

A1        Johnson 2009, Jacobs 2002

 

Level 2

The chance of concomitant malignancy with atypical ductal hyperplasia is correlated with the number and aspect of the microcalcifications on the mammogram.

 

A1        Johnson 2009

B          Burnside 2007

 

Level 2

Ample excision is necessary for complete evaluation of a phyllodes tumour. This is also necessary to prevent a recurrence.

 

A1        Johnson 2009

B          Telli 2007

Literature summary

Management plan if there is a benign or not clearly benign abnormality

After cytology, in which no specific diagnosis is obtained or in which a proliferative laesion or atypia is suspected, histology must still be performed.

The results of a histological biopsy must continually be correlated with clinical findings and imaging. If there are microcalcifications, it is a requirement that the pathologist accurately describes the microcalcifications with a fitting BI-RADS final assessment category [Burnside, 2007] and that a specimen image is made of the biopsies (see 2.2.2). The accuracy of the PA report in relation to the presence of malignancy increased in the presence of sufficient microcalcifications: a malignant diagnosis was only missed in 1% of cases with biopsies containing microcalcifications, the diagnosis was missed in 11% (p<0.001) of cases with biopsies not containing microcalcifications [Johnson, 2009].

 

There is a relationship between the percentage of false negative findings and the number of biopsies obtained. In a large retrospective cohort study, relative risks were calculated for 9,087 women with benign breast abnormalities, using a follow-up period of 15 years (median). The RR for abnormalities with atypia was 4.24 (95%CI 3.26-5.41), RR for proliferative changes without atypia was 1.88 (95%CI 1.66-2.12). Familial burden was an independent, additional risk factor; the RR for moderately elevated risk was 1.43 (95%CI 1.15-1.75%) and RR for strongly increased risk 1.98 (95%CI 1.58-2.32) [Hartmann, 2005]. If there are concordant benign findings in a woman without additional risk factors, then the risk of a missed carcinoma is therefore no greater than after diagnostic excision biopsy and not greater than in the general population.

If there is doubt about results being representative, a decision can be made to repeat the procedure, a diagnostic excision biopsy, or perform a check-up by means of mammography. The risk factors are not high enough to justify routine follow-up using MRI [Elmore, 2005]. Follow-up after 6 months is often recommended, but a drawback is that there is often insufficient compliance from patients. This was 84% for Lee (1999) and 77% for Kunju (2007).

With (a)symptomatic patients, if there is a BI-RADS 3 (probably benign), BI-RADS 4 (probably malignant) laesion or BI-RADS 5 (malignant) laesion, a punction is performed for a substantial proportion of the BI-RADS 3 and in principle for all BI-RADS 4 and 5 laesions. The number of diagnostic excision biopsies has therefore substantially decreased. The benefit is that it is not so invasive, the drawback is that the laesion is not pathologically examined in its entirety. It is therefore extremely important that the punction is representative.

 

False positive results from histological biopsies are also possible; it is therefore necessary when using these biopsies, for the management plan to be determined after multidisciplinary consultation. Whether or not histological biopsies of mammographic abnormalities with microcalcifications are representative must be checked using a specimen photo. In the case of the diagnosis DCIS in a histological biopsy, there is a substantial chance of invasive carcinoma on excision.

 

Clearly benign PA diagnosis

If a clearly benign PA diagnosis correlates with clinical findings and imaging, additional diagnostics or follow-up is not necessary. Clearly benign PA diagnosis are: hamartoma, fibroadenoma, tubular adenoma, benign hyperplasia, sclerosing lobular hyperplasia, fibro-cystous changes, duct ectasias, apocrine metaplasia, pseudoangiomatous stromahyperplasia, normal or fibrous breast tissue [Jacobs, 2006; Johnson, 2009; Hargaden, 2008].

 

Not clearly benign PA diagnosis

In addition, there are PA abnormalities that are risk factors for development of a malignancy (see 1.3.1) and PA abnormalities that may accompany DCIS in the direct proximity of the obtained biopsy, so that the biopsy may therefore be deemed non-representative for the entire abnormality. These 2 categories overlap and the extent of the risk is difficult to determine, because the published series are all small and retrospective. Determining the management plan is the most difficult if there is a BI-RADS 4 abnormality or BI-RADS 4 microcalcifications. The below information is largely based on Elston (2000), van de Vijver (2003), Jacobs (2006), Johnson (2009), Lopez-Garcia (2010) and Jain (2011). The literature mentioned makes it clear that not in all cases regarding the classification of particular laesions and the clinical consequences of a pathology diagnosis (that is not clearly benign) is there international consensus.

 

  • Atypical ductal hyperplasia (ADH)

Because a common criterion for ADH is based on the size of the abnormality, it is not possible in a strict sense to make the diagnosis ADH on the basis of a needle biopsy. Furthermore, there is substantial interobserver variation when diagnosing ADH and the abnormalities found in ADH fully correspond with those of DCIS grade I. Studies that have made use of the diagnosis ADH on the basis of a biopsy, have found percentages of additional DCIS of 18-87% with the use of 14G needles and 10-39% with the use of 9-11G needles. Invasive carcinoma has also been seen in approximately a quarter of these. There is a clear relationship between the mammographic image of the microcalcifications and pathology. If so-called ADH was found in biopsies in which all microcalcifications were removed, the underestimate rate (the chance of missing a DCIS with possible invasive component) was negligibly small. If ADH was diagnosed with less than 2 foci or with incomplete removal of an area smaller than 21 mm, the underestimate rate was 4%. With more than 2 foci and incomplete removal, the underestimate rate was 38%. If there were 4 foci or more, an underestimate rate of 87% was reported.

  • Cylinder cell laesions

These laesions may be encountered in biopsies of microcalcifications. Especially if there is cell atypia, the laesion may be associated with low-grade DCIS. The risk is comparable with atypical lobular hyperplasia and ADH.

  • Ductal Carcinoma in Situ

This is a malignant diagnosis, the underestimate rate in relation to invasive growth is 10-38%. The chance increased with high-grade DCIS, if comedo necrosis is seen or if the abnormalities is accompanied with a solid or palpable component. The chance of invasive carcinoma with low-grade DCIS is comparable to an LCIS found by accident.

  • Lobular neoplasia (Atypical Lobular Hyperplasia and Lobular Carcinoma in Situ)

These abnormalities usually do not have a radiological substrate and can therefore be considered chance findings. As a marker for increased risk of breast cancer, they do not need to be excised; mammographic follow-up is sufficient.

Exceptions, for when excision should take place:

  • If they occur in combination with ADH (underestimate rate for DCIS and IDC increasing to 67%)
  • If they occur with macroacinar and pleomorphic morphology
  • If they occur in combination with microcalcifications that are highly suspect on a mammogram
  • Papillary laesions

There is an increased frequency in ADH and malignancy in both solitary papillomas and multiple papillomas or atypical papillomatosis. Frequencies are higher with multiple papillomas and atypical papillomatosis. The risk with a solitary papilloma may be underestimated because the core biopsies are difficult to evaluate due to the fragmented tissue and there may be sampling error. If the papilloma causes nipple discharge, there is a therapeutic reason for excision.

  • Radial scar/complex sclerosing laesions

The diagnosis radial scar may be made using histological biopsies. This abnormality is known to be associated with invasive (tubular) carcinoma or in situ carcinoma, especially with elderly patients and larger laesions. The underestimate rate varies from 0-12% and decreases with increasing number of biopsies (12 biopsies or more).

  • Fibroepithelial laesions

In rare cases, an LCIS, DCIS and even invasive carcinoma is described in a fibroadenoma [Kuijper, 2001]. Given the rarity, this does not have any consequences for the management plan for a typical fibroadenoma with concordant imaging. The laesions with suspected phyllodes tumour form a separate group. These fibroepithelial tumours have histological characteristics that fit with benign, borderline or malignant tumours. These characteristics play a role in the risk of recurrence, which is 15% on average. A malignant phyllodes tumour has a favourable prognosis. The primary treatment consists of ample excision [Telli, 2007].

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

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