Panel members are listed in the
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This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.
The pathology panel of the 1st Central–Eastern European Professional Consensus Statement on Breast Cancer has based its recommendations principally on the consensus document on breast cancer diagnosis, work-up and reporting achieved at the recent 4th Hungarian Breast Cancer Consensus Conference, which itself was based on previously published national and international recommendations (
In the diagnosis of breast diseases, non-operative/preoperative diagnostics have become a key starting point for the treatment of patients. Diagnosis obtained intraoperatively has lost its previous significance; it is now accepted that diagnostic steps should be undertaken in all cases to establish the diagnosis before surgery/treatment.
Non-operative/preoperative pathological diagnostics is part of the “diagnostic triad” (clinical examination, radiology, pathology). It is important for the pathologist to know the results of other investigations, and to take these into account when giving an opinion on the case. If the pathological diagnosis is made in an isolated setting, without knowledge of clinical and radiological context, this can be a source of serious mistakes and errors. As a minimum requirement for pathological specimens, the localization of the lesion, findings from the physical examination, radiomorphology of the lesion, the radiologist’s opinion on the lesion, the method of sampling, and the relevant data in the medical history (e.g., history of malignancy of other organs, pregnancy/lactation at the time of sampling) should be included in the request form. In an optimal situation, the pathological findings, together with the results of other investigations, are placed in an appropriate diagnostic/therapeutic context within a multidisciplinary framework. If all findings are consistent, an appropriate therapeutic decision can be taken, while in the event of inconsistency, further diagnostic steps should be implemented.
It should be noted that, like all diagnostic tests, non-operative diagnostics have limitations. These limitations are reflected by the proportions of “acceptable” false negatives, false positives, non-evaluable and “suspicious” cases specified in the European Guidelines (
Recommended minimum values for selected quality characteristics, based on European directives (
Cytology | Minimum | Recommended |
---|---|---|
Positive predictive value (PPV) | >98% | >99% |
False negative rate (FNR) | <6% | <4% |
False positive rate (FPR) | <1% | <0.5% |
Inadequate rate (INAD) | <25% | <15 |
Inadequate rate for cancers | <10% | <5% |
Suspicious rate | <20% | <15% |
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Positive predictive value (PPV) | >99% | >99.5% |
False negative rate (FNR) | <0.5% | <0.1% |
(B1+B2) ratio for cancers | <15% | <10% |
Suspicious rate | <10% | <5% |
Pathological (cytological or histological) evaluation of a radiologically or clinically detected lesion raising the slightest suspicion of malignancy is always justified for clarification of the lesion; exceptions to this are very rare. For lesions considered benign, confirmation of benignity may also be a goal. Non-operative diagnosis may be established using a sample obtained by guided fine-needle aspiration or core needle biopsy with an automated gun or possibly with a vacuum-assisted biopsy device. For fine-needle aspiration, we recommend the use of European (UK) terminology (
For core needle biopsies, the B1−B5 category classification is a requirement (
Definition of non-operative diagnostic categories.
Cytological diagnostic categories | |
---|---|
United Kingdom/European Recommendation ( |
Recommendation of the International Academy of Cytology, Yokohama ( |
C1: Inadequate (quantitatively and/or qualitatively) | Inadequate (2.4–4.58%) |
C2: Benign lesion | Benign (1.2–2.3%) |
C3: Atypical, probably benign | Atypical (probably benign) (13–15.7%) |
C4: Suspicious of malignancy | Suspicious (of malignancy) (87.6–97.1%) |
C5: Malignant (both |
Malignant (99–100%) |
|
|
B1: Normal breast tissue/Uninterpretable | |
B2: Benign lesion | |
B3: A lesion with uncertain malignant potential (malignancy may be associated with ≤25% of cases in the group as a whole). | |
The followings are typically included in this category | |
– Some sclerosing lesions: radial scars, complex sclerosing lesions, sclerosing papillomas | |
– Non-malignant papillary lesions that have not been completely removed | |
– Lobular (intraepithelial) neoplasia (atypical lobular hyperplasia, classical LCIS; cf. B5a) | |
– Atypical epithelial proliferation of ductal type (this name is recommended for atypical epithelial proliferation of ductal type found in core biopsies, as quantitative criteria for atypical ductal hyperplasia (ADH) cannot be evaluated in core biopsy samples, so the diagnosis of ADH is not possible on core biopsy) | |
– Mucocele-like lesions | |
– Cellular fibroepithelial lesions | |
– Spindle cell lesions for which other classification is not possible based on the sample | |
B4: Suspicious of malignancy | |
B5: Malignant | |
B5a: |
|
B5b: invasive breast carcinoma | |
B5c: indeterminate, either an |
|
B5d: other malignant process |
Categories C2, B2 (benign) and C5, B5 (malignant) can be considered definitive diagnoses, but these should be interpreted only in a multidisciplinary environment together with imaging and clinical findings, in a “triple diagnostic system”. Diagnostic categories should not be used without a written opinion. Categories are primarily useful for statistical evaluation purposes and assist in patient management.
The use of (mainly ultrasound-) guided sampling is recommended even for palpable lessions, due to the possible differences between the palpated and the actual size of the lump or possible necrosis. With the use of image-guidance, it is also easier to establish that there is no other circumscribed lesion responsible for the palpatory finding (e.g., fat lobule), or that the palpatory finding does not match the lesion found on diagnostic imaging.
Calcifications that are suspicious for malignancy should be evaluated primarily using core needle biopsy or vacuum-assisted core biopsy. If, for some reason, such calcifications are still sampled by fine-needle aspiration, a negative result is not sufficient to rule out malignancy; the result of aspiration cytology is only acceptable if it confirms the suspicion of malignancy. Core biopsies have also become relevant in other clinical situations and should be preferred to cytology sampling; if a biomarker assay is likely to be performed when considering or planning PST, it can be performed more reliably on core needle biopsy samples than on cytological specimens (
Since atypical ductal epithelial proliferations and DCIS (ductal carcinoma
When planning a primary systemic (neoadjuvant) treatment, high-quality core needle biopsy material from the primary tumour should be preferred (exceptionally, incisional biopsy may be acceptable), and in each case, predictive factors should also be determined (as a minimum, oestrogen and progesterone receptor and HER2 status should be assessed, and, if requested, a marker to characterize proliferation, usually the Ki67 labelling index and the proportion of stromal tumour infiltrating lymphocytes (sTIL): see below for details). According to international (European Society for Medical Oncology) recommendations, a core biopsy with several (at least 2–3) tumour tissue cylinders is the expectation in such cases (
It is a generally accepted view that mastectomy cannot be performed based solely on cytological opinion, but this may be acceptable in exceptional cases involving reliable, well-synchronized teams. If the cytological and radiological opinions differ markedly, (e.g., C2/R4-5 or U 4/5 or C4-5/R1-2 and U1-2), repeated sampling and core needle biopsy should always be considered.
Efforts should be made to evaluate both histological and cytological specimens in reliable, quality-assured laboratories. Departments are expected to participate in external quality control programmes and meet compliance requirements. Pathology reporting of breast samples also requires sufficient skills, for which there are no defined criteria in most countries, but an international recommendation (EUSOMA: European Society of Breast Cancer Specialists) sets the minimum workload required for proficiency at 50 cases of early breast cancer surgical specimens, prefereably 100 (but at least 50) non-operative/preoperative samples and 25 metastatic cases per year (
Non-operative diagnosis of lymph node status will be discussed in the section on lymph nodes.
It is essential that the tissue cylinders are placed into the block parallel to their longitudinal axis. Usually 2–3 cylinders, 1 mm in thickness and 10 mm in length are obtained for assessment. [The number of cores (tissue cylinders) will determine how representative the biopsy is and is proportional with the likelihood of establishing a correct diagnosis (
From core biopsy samples obtained before neoadjuvant treatment, tumour characteristics influencing the treatment should be determined, and in addition to predictive factors, the following should also be described, if possible: vascular invasion and presence of an
Another diagnostic modality of biopsy is vacuum-assisted biopsy (VAB; vacuum mammotomy), which is performed with a 7G to 11G needle under ultrasound (US), stereotaxis or magnetic resonance imaging (MRI) guidance. It is a minimally invasive breast biopsy that removes more tissue than traditional gun CNBs, allowing the removal of smaller lesions, making VAB a therapeutic alternative for some lesions (
For tissue biopsies taken from microcalcifications, it is advisable to indicate the approximate size of calcifications on microscopic examination since small calcifications (below 50 μm) are unlikely to be detected on mammography, unless multiple similar foci are superimposed; thus, stating the size of calcifications helps to establish a proper radiopathological correlation. If the core biopsy/vacuum-assisted core biopsy was performed because of microcalcification, specimen radiography of the sample is a requirement (this will validate sampling) and, optimally, calcified particles may also be sent separately for analysis. If microcalcificates do not appear in the first sections, deeper sections will be required. If microcalcifications cannot be confirmed by routine microscopic evaluation, polarized light may be helpful, since calcium oxalate crystals (weddellite) are refractile and polarizable but usually clear or tinged yellow in H&E sections (
Exceptionally (e.g., after multiple unsuccessful cytological or core biopsy samplings of a large, radiologically suspicious lesion; for extensively ulcerated, advanced breast tumours; in Paget’s disease; for very superficial lesions), a minimally invasive surgical intervention may also serve as a preoperative diagnostic method (incisional biopsy).
• Intraoperative examinations may be macroscopic examinations with the naked eye or microscopic examinations (analysis of imprint or scrape cytology samples or frozen sections). All of these have limitations compared to permanent section histology; it should be highlighted that the quality and evaluability of frozen sections is poorer than that of permanent sections. Intraoperative molecular tests are not performed in most central—eastern European countries. There are also examples of intraoperative immunohistochemistry in the literature, with both imprint cytology and frozen section variants increasing the sensitivity of lymph node examination; however, these generally reveal only small metastases that would not affect the outcome of surgery, therefore routine intraoperative immunohistochemistry is not justified. • For large lesions found to be • Frozen sections must not be prepared from lesions of 10 mm or less, since failure to obtain a sufficient quantity and quality of tissue from the lesion for embedding will jeopardize definitive diagnosis and also the ability to assess prognostic and predictive factors for small invasive tumours. If there is a definitive preoperative diagnosis, there is no need for intraoperative examination to confirm this diagnosis. Frozen sections should not be used merely to compensate for inadequate preoperative evaluation. • The indications for frozen section examination have become significantly limited. In exceptional cases, if attempts to obtain a preoperative diagnosis have failed, a multidisciplinary decision may be made to examine frozen sections; this may also be justified if there are insufficient or uncertain preoperative findings, in similarly very rare instances. • The aim of intraoperative examination may also be the assessment of surgical resection margins or the distance between the tumour and the tumour-free margin. These examinations can be performed as imprints (cytology), frozen sections and macroscopic measurements. (In the latter cases, the original resection surface must be marked with dye before incision!) • Intraoperative examinations may also be done to assess sentinel lymph node status. • The final decision on the nature and feasibility of an intraoperative examination is made by the pathologist. • Molecular tests, tissue banking: If the infrastructure allowing tissue samples to be frozen and stored at −80°C is available, it is recommended that a part of the tumour tissue be stored in this manner after proper orientation of the freshly resected tissue and marking of surgical surfaces (see below). Of course, tissue banking can be inititated only if this does not reduce the diagnostic possibilities; the priority should be for making the proper diagnosis and for assessing parameters influencing treatment. A key point of whole tissue biobanking is the time factor of the ischemia of the harvested tissue. According to several studies, it is recommended that the material be collected for freezing within 15–30 min after the interruption of the blood supply in order to minimize the hypoxic damage. If the specified time of ischemia is exceeded, irreversible processes could occur at the molecular level, which would impair the quality of biomolecules. As the time interval between surgical resection and freezing of the tissue is relatively short, biobanking requires a perfect interaction and cooperation of the workplaces involved, as well as experienced and trained pathologists.
• Surgical materials should be sent for pathological examination accompanied by clinical data described for non-operative diagnostics. If neoadjuvant treatment has been administered, it is essential to state this, indicating original tumour size, location, tumour data obtained from a biopsy specimen taken prior to treatment, nature of the treatment, and the clinically evaluated response to treatment. The pathologist should be informed of the type of surgery. Surgical resections (breast operations) are divided into breast conserving procedures (inclusive of excision, segmental resection, lumpectomy, quandrantectomy, segmental/sectoral or partial mastectomy … etc., with or without axillary surgery and different methods of oncoplastic surgery) and total mastectomy (simple, skin-sparing, nipple-sparing, modified radical and radical mastectomy). • The surgical specimen should be made available to the pathology department/pathologist immediately after removal (within a maximum of 30–60 min), without fixation and incision. If this is not feasible, the guidelines for sample fixation described under the section on “Special assessment of prognostic and predictive factors” are to be followed. Correct processing generally requires a preoperative mammography and specimen mammography image annotated by the radiologist and the related radiology report to be available to the pathologist at the time of the cut-up. This is essential for most breast-conserving surgeries, multifocal tumours, extensive DCIS, and surgical preparations following primary systemic treatment. It is recommended that macro-photography and/or a simple drawing be done of the slices, especially for small lesions, and that a specimen mammographic image of the slices be captured, especially for lesions with microcalcifications. • The multifocal character of the lesion is determined primarily by the radiologist and secondarily by the pathologist. Instead of conventional classification of tumours with multiple foci (multifocal or multicentric), it is advisable to mention a certain number of focal lesions or multiple tumours/tumours with multiple foci. pT classification is made based on the largest focus, with indication of multifocality, since this is associated with a worse prognosis ( • As with all measurements, both macroscopic and microscopic assessment of tumour size is approximate, but it is essential that this be recorded. At a minimum, the greatest dimension of the tumour should be given. (This may fall into a different plane than the plane of slicing, therefore requiring the assessment of tumour size in all three dimensions.) If there is a discrepancy between macroscopic and microscopic measurement, the latter shall prevail, unless the tumour is so large that it is impossible or meaningless to measure it microscopically. • Regardless of its size, the tumour should be processed in a representative manner, ideally achieved by examining the entirety of the cut surfaces in multiple planes. For large tumours, a minimum of 1 block/1 cm is recommended. • The surgical specimen should be marked in the operating room, ideally • To allow the assessment of the resection margins, staining the resection surfaces of the surgical specimen is essential: most simply with one colour, but with at least two different colours (e.g., black—anterior surface, blue—posterior surface) to facilitate subsequent orientation, and ideally with 6 colours. Our understanding of the recommended minimum tumour-free margin has changed significantly recently. For early invasive breast cancer (stage I and II), on the basis of consensus based on results from randomized trials and meta-analysis (highest level of evidence), a margin is considered positive (i.e., justifying re-excision) when dye is seen on tumour cells (invasive or • It should be clearly identified whether there are one or more abnormal masses in the parenchyma. • Blocks are sequentially numbered so that the location of each block within the original preparation can be accurately traced back based on the macroscopic description. • All areas that appear abnormal, all parenchyma fragments containing microcalcification, are sampled in a sufficiently representative manner. If mammography images or macro photos of the slices have been captured, it is advisable to indicate the location of blocks on the film/digital image or on a schematic drawing. A schematic drawing that also reflects orientation often carries more information than a block list and lengthy descriptions, which may be expressed in local jargon. For this reason, it is important to have this visual information to hand during reporting, and (for example) if an external consultation is requested, a copy of these drawings (block maps) should also be sent to the consulting professional. • Besides sampling from the tumour for histological examination, it is also essential to sample apparently intact areas around the tumour, including surgical resection surfaces. • If a marker clip has been inserted, its documentation (its absence or presence on specimen mammography) is part of the pathological assessment. • The remaining slices of the specimen are to be kept in order and stored in a way that best enables reconstruction (e.g., wrapped in gauze). • Re-excision is required if excision was not performed with negative margins; the specimen from the re-excision should also be oriented, primarily in order to establish the relationship with the previous excision. This is the only way to perform the pathological evaluation of the new resection surfaces. • When there is a discrepancy between a clinical diagnosis and the diagnosis of the surgical material, a comparison with a preoperative biopsy specimen may resolve this contradiction; therefore, if preoperative assessment was performed at another institution, it is recommended that the pathological specimen be requested and reexamined. • If uniform orientation principles are adhered to, there are few cases in which, due to uncertainty, it may be necessary for the surgeon to review the surgical material before slicing, but in such cases, it is inappropriate to omit this step. Postoperative discussions provide an excellent opportunity for verifying that the screen-detected and removed tumour was identical. • In the vast majority of cases, intraoperative specimen mammography is performed in the radiology department that previously diagnosed the lesion. Pathology departments may also perform this examination if they are properly equipped, but the captured image should always be compared with the original mammogram. During pathological processing, the presence of the original mammographic image and comparison with specimen mammography are also important. If the pathologist has any issues with the interpretation of the specimen mammogram, consultation between the two professions is warranted. Optimally, a joint evaluation in person should be carried out; this is not always possible, but it can be replaced by various alternative solutions (e.g., consultation • Preparation of megablocks/large blocks and sections is recommended, as far as possible. For a more widespread use of the method, this recommendation is strong, since larger sections (sections of 4 × 6 cm or 5 × 7 cm are most common) allow for a more accurate radiopathological correlation, and a more accurate assessment of tumour size. These large blocks and slides may be prepared in pathology laboratories containing the usual infrastructure. Significantly larger sections also exist, but a special infrastructure is required in order to make them, prepare them for storage and store them. In the absence of whole slice giant blocks, digital reconstruction following scanning of sections obtained from conventional and/or mega-cassette blocks representing the entire slice may be a bypass solution. The use of large block technique is especially recommended for diffuse processes (diffuse calcification, diffusely infiltrating lobular carcinoma) and for multifocal tumours. Small (conventional) sections can only provide information of similar accuracy to large sections if they are available in large number and with complex orientation reconstruction ( • With mastectomy, processing of the nipple and areola is recommended. • For a PST, the area originally containing the tumour (optimally, clearly marked prior to treatment in a way that is visible for the pathologist), as well as its surrounding area, should be processed in detail to determine actual regression. Radiopathological comparison (specimen mammography, specimen mammography of slices) and giant block technique are recommended. Particular attention should also be paid to the detection of multifocality. If necessary, in addition to routine HE staining, cytokeratin immunohistochemistry may be used to detect residual tumour in the event of uncertainty. Comparison with a previous core needle biopsy specimen may help the assessment of regression (
Suggestions for assessment of the regression of primary tumour (TR) and lymph node metastasis (NR) (
Primary tumour (TR) |
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1: Complete pathological regression |
a: no residual carcinoma |
b: no residual invasive carcinoma, but residual DCIS is present |
2: Partial therapeutic response |
a: minimal (<10%) residual (invasive) tumour |
b: clear response to therapy but with 10–50% residual (invasive) tumour |
c: clear response to therapy but with >50% residual (invasive) tumour |
3: No signs of regression |
|
1: No metastases, and no visible signs of regression |
2: No metastases, but visible signs of regression |
3: Metastasis with signs of regression |
4: Metastasis without signs of regression |
Lymph nodes showing multiple different therapeutic responses should be classified based on the worse response. (TR stands for primary Tumour Regression/Tumour Response, NR for Nodal Regression/Nodal Response.). (Original (i), (ii) and (iii) subcategory designations (
One of the most important prognostic factors of breast carcinomas is the size of the invasive tumour. This should always be specified based on the largest size of the largest focus, and this is the size that determines the pT category of pTNM (
Definition of cTNM and pTNM categories for stage classification of breast cancers based on the eighth edition of the TNM (2017) (
cT (T) and pT — primary tumour | |||
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Pathological T category: same as clinical T classification, but only the largest dimension (rounded to the nearest mm value) of the invasive component measured on histological section will count when stating size. For larger tumours that cannot be measured microscopically in one block, the macroscopic size is also appropriate, according to the eighth edition of the TNM. | |||
Tx | The primary tumour cannot be assessed | ||
T0 | No evidence of primary tumour | ||
Tis | Carcinoma |
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Tis (DCIS) | Ductal carcinoma |
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Tis (LCIS) | Lobular carcinoma |
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Tis (Paget) | Paget’s disease without associated |
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T1 | Invasive tumour of 2 cm or less in size | ||
T1mi | Microinvasion of 0.1 cm or less in size | ||
T1a | Tumour is larger than 0.1 cm, but does not exceed 0.5 cm. | ||
T1b | Tumour is larger than 0.5 cm, but does not exceed 1 cm | ||
T1c | Tumour is larger than 1 cm, but does not exceed 2 cm | ||
T2 | Tumour is larger than 2 cm, but does not exceed 5 cm | ||
T3 | Tumour is larger than 5 cm | ||
T4 | Tumour of any size spreading directly to the chest wall (a) or skin (b) | ||
T4a | Spread to chest wall | ||
T4b | Oedema (“peau d’orange”) or ulceration of the skin or satellite skin nodules in the same breast | ||
T4c | If criteria T4a and T4b are present at the same time | ||
T4d | Inflammatory carcinoma (primarily a clinical staging category) | ||
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cNx | Regional lymph nodes cannot be evaluated. (e.g., have been previously removed.) | ||
cN0 | No regional lymph node metastases found | ||
cN1 | Metastases in ipsilateral level I or II mobile lymph node(s) | ||
cN2 | Metastases in ipsilateral fixed/conglomerate lymph node(s) or clinically detectable |
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cN2a | Metastases to ipsilateral surrounding structures or to (a) fixed/conglomerate lymph node(s) | ||
cN2b | Clinically detectable |
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cN3 | Clinically detectable |
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cN3a | Metastases in infraclavicular lymph node(s) | ||
cN3b | Clinically detectable |
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cN3c | Ipsilateral supraclavicular lymph node metastases | ||
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At least level I dissection is required for classification and the number of lymph nodes examined should be at least 6. (TNM recommends a minimum of 6 lymph nodes, but this is for lymph node dissections and is not valid for sentinel lymph node biopsy and axillary sampling earlier performed in some United Kingdom and Scandinavian units; if there are more than 6 sentinel lymph nodes removed, the “(sn)” postscript is not applicable) | |||
pNx | pNx Regional lymph nodes cannot be assessed. (Not removed for examination or have been previously removed.) | ||
pN0 | No regional lymph node metastases | ||
pN0(i-) | No histologically detectable regional lymph node metastases, negative IHC | ||
pN0 (i+) | Histologically confirmed lymph node involvement not larger than 0.2 mm or less than 200 tumour cells. (The size of the largest contiguous group of cells, if there are more groups, while in the absence of such groups the number of cells should be the criterion.) | ||
pN0 (mol−) | No regional lymph node metastases histologically, and negative molecular biology findings (usually RT-PCR or OSNA—one step nucleic acid amplification) | ||
pN0 (mol+) | No regional lymph node metastases histologically, and positive molecular biological findings (usually RT-PCR or OSNA) | ||
pN1mi | Micrometastasis (larger than 0.2 mm, but not larger than 2.0 mm) | ||
pN1 | Metastases in 1–3 ipsilateral axillary lymph nodes and/or lymph nodes along the internal mammary artery; in the latter case, detected by sentinel lymph node assessment, but clinically not detectable | ||
pN1a | Metastases in 1–3 axillary lymph nodes | ||
pN1b | Metastases in the lymph nodes along the internal mammary artery, microscopic disease detected by sentinel lymph node examination only, not detectable by imaging studies or physical examination | ||
pN1c | Metastases in 1–3 axillary lymph nodes and in lymph nodes along the internal mammary artery, under conditions described at pN1b, for the latter | ||
pN2 | Metastases in 4–9 axillary lymph nodes, or internal mammary lymph node metastases detected by physical examination and/or imaging, without axillary lymph node metastasis | ||
pN2a | Metastases in 4–9 axillary lymph nodes | ||
pN2b | Clinically detectable metastases along the internal mammary artery without axillary lymph node metastasis | ||
pN3 | Metastases in 10 or more axillary lymph nodes or infraclavicular lymph nodes; or clinically detectable metastases in internal mammary lymph nodes in the presence of 1 or more metastatic axillary lymph nodes; or metastases in more than 3 axillary lymph nodes with clinically non-detectable microscopic metastases along the internal mammary artery, or ipsilateral supraclavicular lymph node metastases | ||
pN3a | Metastases in more than 10 axillary lymph nodes or metastases in infraclavicular lymph nodes | ||
pN3b | Clinically detectable metastases in lymph nodes along ipsilateral internal mammary artery with 1 or more metastatic axillary lymph nodes; or metastases in more than 3 axillary lymph nodes and in the lymph nodes along the internal mammary artery, the latter being detected only on sentinel lymph node examination, but not detectable clinically | ||
pN3c | Ipsilateral supraclavicular lymph node metastases. | ||
“pN1mi(mol+) and pN1(mol+)” Categories not accepted by the eighth edition of TNM but recommended by the European Working Group for Breast Screening Pathology and the International Collaboration for Cancer Reporting for labelling of metastases with a volume greater than pN0 (mol+), which are analysed (and thus identified almost exclusively) using quantitative molecular analysis ( |
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cM0 | No distant metastases | ||
cM1 | Evidence of distant metastasis. | ||
Distant metastasis is classified as pM1 only if it has undergone histological or cytological examination (i.e. metastasis has been surgically removed or sampled by biopsy); otherwise the categories are (clinical) M categories (categories Mx, pMx, pM0 are not defined). | |||
Stage classification | |||
Stage | T |
|
M |
0 | Tis | N0 | M0 |
I A | T1 |
N0 | M0 |
I B | T0, T1 |
N1mi | M0 |
II A | T0, T1 |
N1 | M0 |
T2 | N0 | M0 | |
II B | T2 | N1 | M0 |
T3 | N0 | M0 | |
III A | T0, T1 |
N2 | M0 |
T3 | N1, N2 | M0 | |
III B | T4 | N0, N1, N2 | M0 |
III C | any T | N3 | M0 |
IV | any T | any N | M1 |
Clinically detectable: structure discovered on clinical examination or imaging (excluding lymphoscintigraphy) that raises a well-founded suspicion of malignancy, or which proves to be metastatic by non-operative biopsy. The basic requirement for pN classification is pT classification after tumour removal. Consequently, if the primary tumour is not removed, only cN classification is possible, even when microscopic examination is performed on an aspiration cytology or core biopsy sample; in such cases, the suffix “(f)” refers to the microscopic examination—e.g. cN1 (f).
The wording used in the 8th edition of the AJCC, and UICC, sources related to stages and classifications differs (
Including T1mi. The stages described above are those included in the TNM classification issued by the UICC, and are identical with the AJCC Cancer Staging Manual defined anatomical stages, but different from prognostic stages described in the latter source, which, in addition to ER, PR, and HER2 statuses, include grade and, when available, the recurrence score based on the Oncotype Dx test. Prognostic stages may deviate from anatomical stages by up to two subcategories in either direction (
Histological type of tumours should be specified according to the WHO (World Health Organization) classification (
Histological classification of breast tumours according to the fifth edition of the WHO classification (
Tumour group | Name | ICD-0 | ICD-11 |
---|---|---|---|
EPITHELIAL TUMOURS | |||
Benign epithelial proliferations and precursors | Normal (typical) ductal hyperplasia | GB20.Y | |
Columnar cell lesions, including atypical columnar cell transformation (FEA, flat epithelial atypia) | GB20.Y | ||
Atypical ductal hyperplasia (ADH) | GB20.Y | ||
Adenosis, benign sclerosing lesions | Sclerosing adenosis | GB20.Y | |
Apocrine adenoma | 8401/0 | 2F30&XH6YZ9 | |
Microglandular adenosis | GB20.Y | ||
Radial scar/Complex sclerosing lesion | GB20.Y | ||
Adenomas | Tubular adenoma | 8211/0 | 2F30.0&XH7SYZ9 |
Lactating adenoma | 8204/0 | 2F30.1&XH0W31 | |
Ductal adenoma | 8503/0 | 2F30.2&XH4LZ4 | |
Epithelial-myoepithelial tumours | Pleomorphic adenoma | 8940/0 | 2F30.Y&XH2KC1 |
Adenomyoepithelioma NOS | 8983/0 | 2F30.Y&XH2V57 | |
Adenomyoepithelioma with carcinoma | 8983/3 | 2C6Y&XH7TL5 | |
Epithelial-myoepithelial carcinoma | 8562/3 | ||
Papillary neoplasms | Intraductal papilloma | 8503/0 | 2F30.2&XH4LZ4 |
Papillary ductal carcinoma |
8503/2 | 2E65.2&XH4V32 | |
Encapsulated papillary carcinoma | 8504/2 | 2E65.Y&XH9XV2 | |
Encapsulated papillary carcinoma with invasion | 8504/3 | 2C6Y&XH0GT6 | |
Solid papillary carcinoma |
8509/2 | 2E65.Y&XH0134 | |
Solid papillary carcinoma with invasion | 8509/3 | 2C64 | |
Invasive papillary carcinoma | 8503/3 | 2C60&XH8JR8 | |
Non-invasive lobular neoplasia | Atypical lobular hyperplasia (ALH) | ||
Lobular carcinoma |
8520/2 | 2E65.0&XH6EH0 | |
Classical LCIS | |||
Florid LCIS | |||
Pleomorphic LCIS | 8519/2 | ||
Ductal carcinoma |
Intraductal breast carcinoma, NOS | 8500/2 | 2E65.2cXH4V32 |
Invasive breast carcinoma | Invasive carcinoma, NST | 8500/3 | 2C61.0&XH7KH3 |
Microinvasive carcinoma | 2C61.0 | ||
Invasive lobular carcinoma | 8520/3 | 2C61.1&XH2XR3 | |
Tubular carcinoma | 8211/3 | 2C60&XH4TA4 | |
Cribriform carcinoma | 8201/3 | 2C60&XH1YZ3 | |
Mucinous carcinoma | 8480/3 | 2C60&XH1S75 | |
Mucinous cystadenocarcinoma | 8470/3 | 2C60&XH1390 | |
Invasive micropapillary carcinoma | 8507/3 | 2C60&XH9C56 | |
Carcinoma with apocrine differentiation | 8401/3 | 2C61&XH4GA3 | |
Metaplastic carcinoma | 8575/3 | 2C6Y&XHORD4 | |
Rare and salivary gland type tumours | Acinic cell carcinoma | 8550/3 | 2C60&XH3PG9 |
Adenoid cystic carcinoma (ACC) | 8200/3 | 2C60&XH4302 | |
Secretory carcinoma | 8502/3 | 2C60&XH44J4 | |
Mucoepidermoid carcinoma | 8430/3 | 2C60&XH1J36 | |
Polymorphic adenocarcinoma | 8525/3 | 2C60&XH5SD5 | |
Tall cell carcinoma with reversed polarity | 8509/3 | 2C6Y | |
Neuroendocrine neoplasia | Neuroendocrine tumour NOS | 8240/3 | 2C6Y&XH9LV8 |
Neuroendocrine tumour Grade 1 | 8240/3 | ||
Neuroendocrine tumour Grade 2 |
8249/3 | ||
Neuroendocrine carcinoma NOS | 8246/3 | 2C6Y&XH0U20 | |
Neuroendocrine carcinoma, small cell | 8041/3 | 2C6Y&XH9SY0 | |
Neuroendocrine carcinoma, large cell | 8013/3 | 2C6Y&XH0NL5 | |
FIBROEPITHELIAL TUMOURS, HAMARTOMAS | Hamartoma | ||
Fibroadenoma NOS | 9010/0 | 2F30.5&XH9HE2 | |
Phyllodes tumour NOS | 9020/1 | ||
Phyllodes tumour, benign | 9020/0 | 2F30.3&XH50P7 | |
Phyllodes tumour, borderline | 9020/1 | 2F75&XH5NK4 | |
Phyllodes tumour, malignant | 9020/3 | 2C63&XH8HJ7 | |
NIPPLE TUMOURS | Syringomatous tumour | 8407/0 | 2F30.Y&XH9GB7 |
Nipple adenoma | 8506/0 | 2F30.Y&XH7GN3 | |
Paget’s disease | 8540/3 | 2E65.5&XH3E21 | |
MESENCHYMAL TUMOURS | |||
Vascular tumours | Haemangioma NOS | 9120/0 | 2F30.Y&XH5AW4 |
Angiomatosis | 2E81.0Z | ||
Common angiomatosis | |||
Capillary angiomatosis | |||
Atypical vascular lesions | 9126/0 | ||
Postradiation angiosarcoma of the breast | 9120/3 | 2B56.2&XH6264 | |
Primary angiosarcoma of the breast | 9120/3 | 2B56.2&XH6264 | |
Fibroblastic/myofibroblastic tumours | Nodular fasciitis | 8828/0 | 2F30.Y&XH5LM1 |
Myofibroblastoma | 8825/0 | 2F30.Y&XH8JB0 | |
Desmoid fibromatosis | 8821/1 | 2F75&XH13Z3 | |
Inflammatory myofibroblastic tumour | 8825/1 | 2F30.Y&XH66Z0 | |
Peripheral nerve sheath tumour | Schwannoma NOS | 9560/0 | 2F30.Y&XH98Z3 |
Neurofibroma NOS | 9540/0 | 2F30.Y&XH87J5 | |
Granular cell tumour | 9580/0 | 2F30.Y&XH09A9 | |
Granular cell tumour, malignant | 9580/3 | ||
Tumours of smooth muscle origin | Leiomyoma NOS | 8890/0 | 2F30.Y&XH4CY6 |
Leiomyosarcoma NOS | 8890/3 | 2C6Y&XH7ED4 | |
Adipose tissue tumours | Lipoma NOS | 8850/0 | 2F30.Y&XH1PL8 |
Angiolipoma NOS | 8861/0 | 2F30.Y&XH3C77 | |
Liposarcoma NOS | 8850/3 | 2C6Y&XH2J05 | |
Other mesenchymal tumours and tumour-like lesions | Pseudoangiomatous stromal hyperplasia | GB20.Y | |
HEMATOLYMPHOID TUMOURS | Lymphoma | ||
MALT lymphoma | 9699/3 | 2A85.3 | |
Follicular lymphoma (NOS) | 9690/3 | 2A80.Z | |
Diffuse large B-cell lymphoma NOS | 9680/3 | 2A81.Z | |
Burkitt lymphoma NOS/Acute leukaemia, Burkitt type | 9687/3 | 2A85.6 | |
Anaplastic large cell lymphoma associated with breast implant | 9715/3 | 2A90.B | |
MALE BREAST TUMOURS | Epithelial tumours | ||
Gynaecomastia | GB22 | ||
Carcinoma |
8500/2 | ||
DCIS | 2E65.2&XH4V32 | ||
LCIS | 2E65.0&XH6EH0 | ||
Paget’s disease of nipple | |||
Invasive carcinoma, NST | 8500/3 | 2C61.0&XH7KH3 | |
BREAST METASTASES | 2E0Y&XA12C1 | ||
GENETIC TUMOUR SYNDROMES |
|
2C65 | |
Cowden syndrome | LD2D.Y | ||
Ataxia-telangiectasia | 4A01.31 | ||
Li–Fraumeni syndrome, |
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Li–Fraumeni syndrome, |
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|
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|
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Peutz–Jeghers syndrome | LD2D.0 | ||
Neurofibromatosis type 1 | LD2D.10 | ||
Polygenic component of breast cancer susceptibility |
The term “neuroendocrine tumour (NET) Grade 3” is not included in the WHO publication, although the principle was to harmonize the classification of neuroendocrine neoplasms with that used for other organs. Breast NET grade is determined according to the Nottingham grading scheme, which is different from the NET grading system used for other organs; Grade 3 has not been defined. Breast NET is defined as a malignant tumour. Breast NET is rare, so the prognosis of tumours classified in this category is unknown. (Altogether, the classification of tumours into NET, NEC or NST carcinoma with neuroendocrine differentiation is somewhat controversial, these tumours require individual and multidisciplinary approaches to avoid improper management. NOS, not otherwise specified; NST, no special type.
For invasive epithelial tumours, differentiation is based on the Nottingham combined histologic grade system (
Combined histologic grade (Nottingham) (
Tissue characteristic | Points |
---|---|
A. Tubule formation | |
For the most part of the tumour (>75%) | 1 |
To a moderate extent (10–75%) | 2 |
To a small extent (<10%) | 3 |
B. Nuclear pleomorphism | |
Small (<1.5 × normal), regular, uniform nuclei, uniform chromatin | 1 |
Moderately larger (1.5–2 × normal) nuclei with variability in size and shape, visible nucleoli | 2 |
Large (>2 × normal) vesicular nuclei with marked variability, multiple nucleoli | 3 |
C. Mitotic index (depending on the size of the field of view) | See table below |
Number of mitoses in 10 high magnification fields of view | ||||
Field of view diameter in mm | Field of view area in mm2 | Score 1 | Score 2 | Score 3 |
0.40 | 0.126 | ≤4 | 5–8 | ≥9 |
0.41 | 0.132 | ≤4 | 5–9 | ≥10 |
0.42 | 0.138 | ≤4 | 5–9 | ≥10 |
0.43 | 0.145 | ≤4 | 5–10 | ≥11 |
0.44 | 0.152 | ≤5 | 6–10 | ≥11 |
0.45 | 0.159 | ≤5 | 6–11 | ≥12 |
0.46 | 0.166 | ≤5 | 6–11 | ≥12 |
0.47 | 0.173 | ≤5 | 6–12 | ≥13 |
0.48 | 0.181 | ≤6 | 7–12 | ≥13 |
0.49 | 0.188 | ≤6 | 7–13 | ≥14 |
0.50 | 0.196 | ≤6 | 7–13 | ≥14 |
0.51 | 0.204 | ≤6 | 7–14 | ≥15 |
0.52 | 0.212 | ≤7 | 8–14 | ≥15 |
0.53 | 0.221 | ≤7 | 8–15 | ≥16 |
0.54 | 0.229 | ≤7 | 8–16 | ≥17 |
0.55 | 0.237 | ≤8 | 9–16 | ≥17 |
0.56 | 0.246 | ≤8 | 9–17 | ≥18 |
0.57 | 0.255 | ≤8 | 9–17 | ≥18 |
0.58 | 0.264 | ≤9 | 10–18 | ≥19 |
0.59 | 0.273 | ≤9 | 10–19 | ≥20 |
0.60 | 0.283 | ≤9 | 10–19 | ≥20 |
0.61 | 0.292 | ≤9 | 10–20 | ≥21 |
0.62 | 0.302 | ≤10 | 11–21 | ≥22 |
0.63 | 0.312 | ≤10 | 11–21 | ≥22 |
0.64 | 0.322 | ≤11 | 12–22 | ≥23 |
0.65 | 0.332 | ≤11 | 12–23 | ≥24 |
0.66 | 0.342 | ≤11 | 12–24 | ≥25 |
0.67 | 0.352 | ≤12 | 13–25 | ≥26 |
0.68 | 0.363 | ≤12 | 13–25 | ≥26 |
0.69 | 0.374 | ≤12 | 13–26 | ≥27 |
0.70 | 0.385 | ≤13 | 14–27 | ≥28 |
|
||||
Well differentiated, grade I | Scores 3 to 5 | |||
Moderately differentiated, grade II | Scores 6 to 7 | |||
Poorly differentiated, grade III | Scores 8 to 9 |
Auxiliary table for assessing the score based on mitosis index according to Chapter 6 of the European Guideline for Breast Cancer Screening (Quality assurance guidelines for pathology in mammographic screening) and the WHO tumour classification (
Nottingham prognostic index (NPI) (
*No lymph nodes involved | 1 |
1–3 lymph nodes involved | 2 |
>3 lymph nodes involved | 3 |
Prognostic groups based on NPI value | |
Excellent prognostic group (EPG) | 2–2.4 |
Good prognostic group (GPG) | 2.41–3.4 |
Moderate prognostic group I (MPG-I) | 3.41–4.4 |
Moderate prognostic group II (MPG-II) | 4.41–5.4 |
Poor prognostic group (PPG) | 5.41–6.4 |
Very poor prognostic group (VPPG) | > 6.41 |
Tumour size (cm) × 0.2 + lymph node score (according to lymph node involvement, score: 1–3*) + grade score (grade I–score 1, grade II—score 2, grade III—score 3).
Grading of
Low grade DCIS (Nuclear grade 1) | Monotonous (monomorphic) nuclei with a size of 1.5–2 RBCs or of a normal ductal epithelial cell. Chromatin is usually diffuse, finely distributed, nucleoli or mitotic forms are only rarely detected. Cells are usually located in a polarized form. (The presence of nuclei of the same size but pleomorphic character will exclude low grade). |
Intermediate grade DCIS (Nuclear grade 2) | Nuclei do not fall into either nuclear grade 1 or nuclear grade 3 category, they are classified as intermediate. |
High grade DCIS (Nuclear grade 3) | Marked pleomorphism of nuclei with a size >2.5 RBC or of a normal ductal epithelial cell. Usually vesicular nuclei, with irregular, coarse chromatin, with visible, often multiple nucleoli. Mitosis rate may be high. |
DCIS grade should be determined based on the nuclear grade. In addition, the presence and nature of necrosis (zonal/comedo or spotty), cell polarization, DCIS pattern(s) (comedo, cribriform, micropapillary, papillary, solid, other) and possible heterogeneity of grade should be reported regardless of grade.
Assessment of DCIS prognosis: University of Southern California/Van Nuys Prognostic Index (
Scoring | 1 | 2 | 3 |
---|---|---|---|
Tumour size (mm) | ≤15 | 16–40 | ≥41 |
Surgical margin (mm) | ≥10 | 1–9 | <1 |
Histological classification (grade) | Non-HG without necrosis | Non-HG with necrosis | HG |
Age | >60 | 40–60 | <40 |
With breast preservation, prognosis is good (low probability of recurrence) if the sum of scores is 4–6, moderate if it is 7–9, and poor if it is 10–12. HG: high grade (poorly differentiated). The significance of USC/VNPI, is that of an auxiliary tool for the selection of another treatment strategy after conservative surgery: cases with a high score (
For invasive tumours, the presence or absence of peritumoral lymphovascular invasion (lymphatic and/or blood vessel invasion) should be reported.
Quantification of tumour-infiltrating lymphocytes (TIL), which can be performed on core-needle biopsy for PST, and from surgical specimens otherwise, may be a predictive and also a prognostic parameter when determining the effectiveness of (primary) systemic treatment. According to an international recommendation, only mononuclear cells/“round cells” in the stroma should be considered within the borders of the invasive tumour (
Recommendation for quantification of tumour-infiltrating lymphocytes (TILs) as recommended by the International TILs/Immuno-Oncology Working Group (
0. In terms of practice, TILs can be interpreted in several localizations. Recommendation applies to a quantitative estimation of the stromal TILs (sTILs) compartment; the term TILs is used synonymously with this. The following recommendation applies to invasive breast cancers |
1. The % of TILs should be expressed as the percentage of stromal area occupied by mononuclear stromal inflammatory cells (including plasma cells and lymphocytes but excluding granulocytes) as compared to the total area of the tumour stroma. |
2. TILs should be assessed within the borders of the invasive tumour, which includes the invasive front of the tumour (a 1 mm zone at the tumour margin). |
3. Mononuclear cells a) beyond the tumour border (invasive front), b) around DCIS, c) around normal lobules, as well as areas that d) are artificially damaged, e) are necrotic, f) show regressive hyalinization and g) showing the site of the previous core needle biopsy should be excluded from evaluation |
4. Analysis of a 4–5 micron thick section per patient, examined at × 200 or ×400 magnification is sufficient. |
5. Full sections should be preferred to core needle biopsies, but only the latter can be evaluated for PST |
6. The average TILs should be assessed in a section, and not the most intensively infiltrated areas, exclusively |
7. Quantification of TILs as a continuous variable should be performed with the highest precision possible, which in daily practice means rounding to percentages, usually ending in 5 or 0 |
8. It should also be considered that lymphocytes typically do not form confluent cell groups, so small empty gaps between mononuclear inflammatory cells in the TIL-infiltrated stromal area (in the numerator of the proportion; the total intratumoural stromal area being the denominator) are acceptable, and they exist even with an upper limit of 100% for stromal TILs |
9. No formal limits have been set. In addition to the semi-quantitative value of stromal TILs, a descriptive name, such as “lymphocyte-predominant breast cancer” (LPBC) may also be used, in which the number of lymphocytes is basically greater than that of tumour cells; by definition, a population of lympho-plasmacytes exceeding 50% or (according to another definition) 60% of the stromal area of interest, can be identified within the tumour. |
Physical and ultrasound examination of the armpit is part of patients’ preoperative assessment, during which it is necessary to distinguish between patients who are clinically metastatic, i.e., node-positive (including cases confirmed by axillary ultrasound, aspiration cytology, and possibly core biopsy) and non-metastatic, i.e., node-negative patients. For this reason, targeted sampling (mostly aspiration cytology, rarely core biopsy) is part of the preoperative assessment when clinical suspicion arises. As surgical procedures change, core needle biopsy sampling is expected to become more frequent, related to (clip, magnetic or radioactive seed) marking of metastatic axillary lymph nodes before PST; however, core needle biopsy is not a prerequisite for clip insertion, since this is inserted with a separate device and may be placed after fine needle aspiration, too. In addition to establishing the diagnosis of metastasis, a sample obtained from an axillary lymph node may also be suitable for the assessment of certain prognostic/predictive factors of the tumour (ER, PR, HER2, and Ki67).
All lymph nodes should be retrieved from the axillary fat for histological examination. Lymph nodes larger than 5 mm should be embedded, preferably cut into 2 mm thick slices, while those smaller than 5 mm should be embedded as a whole. From lymph nodes that are clearly metastatic macroscopically, embedding one single representative block is sufficient. It is advisable to choose a macroscopic slice in which extracapsular spread, if present, can also be identified. When performing the above, a methodology and marking should be used that enables reporting of the number of examined and metastatic lymph nodes at the end of the examination (e.g., staining, accurate recording of the number of lymph nodes per block if more than one lymph node is included in a block).
For axillary lymph nodes removed after PST, knowledge of the pre-treatment lymph node status and communication of this to the pathologist is essential. In addition to lymph nodes, small connective tissue masses, which are often only palpable, should also be examined. Routine use of cytokeratin immunohistochemistry in patients with lesions that suggest only scarring and regression is not warranted; however, for an HE finding suggestive of a tumour, it may help to assess the presence of residual tumour.
• For pathologists, a lymph node sent by a surgeon with such designation is considered a sentinel lymph node. • Basic examination of sentinel lymph nodes is embedded histological examination. • Broadly speaking, sentinel lymph node involvement by micrometastases (see TNM staging in • Pathological processing of sentinel lymph nodes can be tailored based on clinical picture and need: if axillary lymph node dissection is not planned in the first instance for patients with clinically negative axillary status in cases of sentinel lymph node involvement (
The factors listed in this subheading are items that currently influence the treatment of breast cancer and need to be examined separately. • Fixation of the fresh specimen should start as soon as possible: immediately or, for optimal receptor determination, no later than 30–60 min after excision, in 10% formalin kept in a refrigerator at 4°C, in a minimum of 5 times the volume of the specimen ( • If predictive and prognostic factors need to be assessed from a metastasis (body cavity fluid) or, in the absence of other specimen, from a fine needle aspiration sample, only a formalin-fixed smear or cell block may be used for HER2 immunohistochemistry to avoid the high false positivity that occurs with alcohol fixation ( The optimal method for steroid hormone receptor determination is immunohistochemistry. Laboratories examining prognostic and predictive markers using immunohistochemistry are expected to participate in an external quality control programme and achieve appropriate qualification for their performance, with particular emphasis on samples sent by the quality control centre. In the context of steroid hormone receptor (oestrogen and progesterone receptors, as well as androgen receptors) testing, “oestrogen receptor” (ER) usually refers to the alpha subtype. There is still insufficient prognostic or predictive experience with oestrogen receptor beta and androgen receptors (AR) to require their assessment, although AR may be requested for triple negative tumours. Tumours with a staining rate of 1% or more are considered positive ( • In practice, assessment of HER2 status is justified for invasive cancers; the test is based partly on the degree of HER2 protein over-expression (immunohistochemistry, IHC) and partly on HER2 gene amplification ( • Of the HER2-ISH assays, fluorescence • More recently, clinical trials testing novel targeted drugs for breast cancers demonstrating a low level of HER2 expression/amplification require reconsideration of the HER2-negative vs. HER2 positive dichotomization. A category of HER2-low has been introduced for cases demonstrating IHC scores 1+ or 2+ without ISH evidence of amplification ( In addition to the mitosis rate, IHC testing of the Ki67 proliferation marker is the most common way of assessing proliferation. In such cases, the percentage of positive tumour cell nuclei relative to the total number of tumour cells should be reported, regardless of the intensity of the reaction. There are several suggestions and recommendations for quantification, as well as for limits serving to distinguish between high and low proliferation tumours. Until there are internationally accepted long-term recommendations, we recommend using an estimate with a 5% accuracy, when assessing the Ki67 labelling index for breast cancers. According to the 2015 St. Gallen recommendation on Ki67 labelling ( • In some tumours (thus far only triple-negative, metastatic breast cancers), assessment of PD-L1 has become widespread, and testing was recommended to be performed in the metastatic tumour, if possible. Based on evidence from a clinical trial (
Assessment of oestrogen and progesterone receptors by Allred quick scoring (QS) system (
Average intensity | Points |
---|---|
Negative | 0 |
Weak | 1 |
Intermediate | 2 |
Strong | 3 |
|
|
No | 0 |
<1% | 1 |
1–10% | 2 |
10%–1/3 | 3 |
1/3–2/3 | 4 |
>2/3 | 5 |
The sum of the two subscores will give the total score. Possible values: 0, 2–8. (Response to endocrine therapy is expected for a score >2, and the response is expected to increase proportionally with the score). In theory, ER (PR) status can be Allred+ (Allred QS > 2) with <1% staining (<1% 2+, Allred QS 3 or <1% 3+, Allred QS 4), these are interpreted as negative. If recurrent or metastatic tumours are examined, steroid hormone receptor assessment should be repeated. Pathology departments performing predictive immunohistochemical tests are expected to participate in an external quality assurance programme and achieve appropriate qualification. The use of an external control tissue is recommended, and it is advisable to select a block for the immunohistochemical reaction that includes an internal control.
Assessment of HER2 testsa (
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2. Group 2: |
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3. Group 3: |
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4. Group 4: |
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5. Group 5: NEGATIVE, |
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1 | Classical HER2-amplified tumour | ≥2 | ≥4 | Positive |
2 | Chromosome 17 monosomy | ≥2 | <4 | Negative (HER2-low if IHC 1+/2+; 76) unless HER2 IHC is 3+d |
3 | Co-amplification (previously chromosome 17 polysomy) | <2 | ≥6 | Negative (HER2-low if IHC 1+; 76); unless HER2 is IHC 2+ or 3+ |
4 | Borderline/uncertain | <2 | ≥4 and <6 | Negative (HER2-low, if IHC 1+/2+; 76) unless HER2 is IHC 3+ |
5 | Classical HER2 non-amplified tumour | <2 | <4 | Negative (HER2-low, if IHC 1+/2+ ( |
Summary of ASCO/CAP HER2 Professional Recommendation of 2018. | ||||
Cases rated 3+ are considered positive for targeted treatment, while those rated 2+ are considered uncertain, including cases showing strong membrane staining in <10% of cells. Cases rated 0 and 1+ should be considered negative. (F)ISH: this is mandatory in cases of uncertain HER2 status with IHC. | ||||
HER2-low category encompasses non-amplified IHC 1+ and 2+ cases, and accordingly the “non-positive” cases of ISH groups 2, 3 and 4 ( |
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aBased on the latest (2018) ASCO/CAP recommendations (ASCO/CAP). | ||||
bClearly visible at low magnification in a homogeneous, contiguous tumour cell population. | ||||
cHER2 positivity is virtually non-existent in the following tumour types: | ||||
Histological grade 1 NST carcinomas Classical lobular carcinoma, oestrogen and progesterone receptor positive Tubular carcinoma Mucinous carcinoma Cribriform carcinoma Adenoid cystic carcinomadIn the case of HER2 monosomy, there is clinical evidence, based on retrospective analysis, that these may respond to targeted treatment in the same way as HER2 positive tumours, suggesting that targeted treatment should be considered for this group (75). HER2 testing should be performed on the surgical specimen in the following cases, even if this has previously been done on the core biopsy specimen: if the core biopsy sample contained a small amount of tumour tissue or the invasive component of the tumour was visible only in the surgical specimen. if the surgical specimen shows a high grade carcinoma not seen in the core biopsy specimen, or morphological heterogeneity or a different additional tumour nodule that was not represented by the core biopsy (30). if it is suspected that a preanalytical error has occurred during the processing of the core biopsy sample. if the HER2 assessment in the core biopsy sample yielded an uncertain result if HER2 positivity in the core biopsy sample was heterogeneous in a tumour remaining after neoadjuvant treatment.For recurrent or metastatic tumours, HER2 assessment should be repeated. |
Histopathology reporting of breast cancer can be done in a free text format, but it is recommended that a standard form be used, containing information about each of the essential elements (
Over the last 2 decades, multigene tests based on molecular techniques have become more widespread. These may help in determining the nature of the oncological treatment to give (most often the need for chemotherapy or whether this can be omitted), or may be an indirect reference for choosing therapies by classifying tumours into molecular subtypes, and giving information on prognosis (recurrence). These commercially/provider-available tests examining the expression profile of specific genes are expensive, and only some of them are available with public funding, based on the recommendation of an oncology team. In some cases, when the indication for chemotherapy cannot be determined based on the conventional prognostic and predictive factors detailed above, such a test may be warranted. According to evidence resulting from the prospective randomized trial (TAILORx), OncotypeDx, based on the examination of the expression of 21 genes, is not only prognostic but also predictive of the efficacy of chemotherapy in ER+ HER2− pN0 breast cancers, and in general a recurrence score (RS) can be specified with which chemotherapy complementing endocrine therapy is not expected to have a significant effect, or above which chemotherapy has a survival benefit (
In addition to the above multigene, predominantly RNA-based assays, targeted therapies for breast cancer may require the assessment of additional DNA-based tests for gene mutations. Currently, germline BRCA1-2 mutation testing is the most common investigation for PARP (poly-ADP ribose polymerase) inhibitor treatment. Since this mutation analysis for breast cancer is performed on blood samples, a clinical geneticist should evaluate the results, and genetic counselling is required. Testing for gene mutations responsible for resistance to endocrine or CDK4/6 (cyclin-dependent kinase 4/6) inhibitor therapy either from tumour tissue or free circulating tumour DNA isolated from plasma are another group of multigene tests. Common guidelines for testing for these mutations have not yet been developed. Molecular tests are performed in specialized laboratories; our most important task is to maintain the quality of the sample by optimal fixation and processing conditions. This is particularly important in view of the fact that prognostic multigene tests are RNA-based, and RNA is more vulnerable than DNA. It is recommended that a multidisciplinary team decides whether these tests are to be run.
Overview of multigene expression-based/molecular prognostic tests (
Test | Methods | Number of genes/proteins tested | Role of patient group/test | ASCO/NCCN recommendation |
---|---|---|---|---|
OncotypeDX Tumour RNA | RT-PCR | 21 genes (16 genes + 5 references genes) | ER/PR+, HER2-, pN0 ER/PR+, HER2-, pN1/Estimation of the recurrence risk, assessment of the need for chemotherapy (predictive and prognostic) | strong |
MammaPrint Tumour RNA | Microarray | 70 genes | ER/PR+, HER2-, pN0 ER/PR+, HER2-, pN1/Estimation of the recurrence risk, assessment of the need for chemotherapy (prognostic) | strong |
Prosigna (PAM50) Tumour RNA | Microarray | 50 genes + 5 references genes | ER/PR+, HER2-, pN0 | intermediate |
EndoPredict Tumour RNA | RT-PCR | 12 genes (8 genes + 3 RNA references genes + 1 DNA references gene) | ER/PR+, HER2-, pN0 Assessing the need for chemotherapy, prolonged hormone therapy | intermediate |
Germ cell mutation testing Non-tumour-derived DNA from blood | Sanger sequencing or NGS | BRCA1-2 | Screening for hereditary breast cancer: Patients under the age of 40 years, significant family history of breast cancer, triple-negative breast carcinoma, history of ovarian cancer, susceptibility to PARP inhibitor therapy | strong |
Gene panel test: hotspot mutations, amplifications, fusions; microsatellite instability (tumour DNA, RNA) | NGS, PCR, FISH, IHC | ESR1, PIK3CA, RB1, FGFR1, NTRK, microsatellite markers, MLH1, MSH2, MSH6, PMS2 | Hormone therapy resistance, CDK4/6 inhibitor resistance… | Indication depending on clinical picture |
Multigene testing methods (comprehensive genomic analysis) in which a potential resistance mechanism and/or therapeutic target is sought based on tumour-specific abnormalities may also be used, although these methods are used rarely because of the versatility of therapeutic options in breast cancer (
Use of tissue markers (the old-fashioned method to insert foreign tissues, generally from cadavers or benign surgeries, for either identification or orientation purposes) endangers the effectiveness of molecular tests, and therefore this traditional way of identifying and orienting the sample “in the 21st century era of targeted molecular diagnostics and modern patient rights, is a completely obsolete and unacceptable practice and should therefore be abandoned” (
Liquid biopsies are suitable for targeting circulating tumor cells (CTC) or circulating tumor DNA (ctDNA). Fields of application include 1) initial detection of oncogenic and targetable mutations, 2) response monitoring: under successful therapy, decrease of cell-free DNA (cfDNA) and ctDNA levels in blood; 3) identification of (actionable) resistance mutations in patients under therapy. One of the possible mechanisms for resistance in ER+HER2-cancers might be due to the dysregulation of phosphoinositide 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signalling pathway (
Since molecular subtypes of breast cancer were first described, there has been a growing need for pathologists to classify tumours, based on the pattern of immunohistochemical stains used in the everyday diagnosis of breast cancer, into surrogate subtypes that approximately reflect molecular subtypes. According to the recommendations of the St. Gallen Consensus Conference in 2015 (
Immunohistochemistry classification for therapeutic classification of breast cancers based on the recommendations of the St. Gallen Consensus Conference of 2015 (
Clinical classification | Notes |
---|---|
Triple negative | ER−/PR−/HER2− |
Hormone receptor negative, HER2-positive | See criteria above |
Hormone receptor positive, HER2-positive | See criteria above |
Hormone receptor positive, HER2-negative: spectrum of luminal tumours | |
Strong hormone receptor positivity, low proliferation, low tumour mass (luminal A-like) | Strong hormone receptor expression, low Ki67 labelling index. pN0-pN1, pT1-pT2 |
Intermediate | |
Less hormone receptor positive, increased proliferation, high tumour mass (luminal B-like) | Lower hormone receptor expression, high Ki67 labelling index, ≥pN2, histological grade 3, extensive lymphovascular invasion, ≥pT3 |
Notes. ER positivity between 1% and 9% was considered uncertain by the St. Gallen consensus conference, rare tumors with this range of positivity have generally worse prognosis than those with higher range of ER positivity. The assessment of the Ki67 labelling index should be based on the average Ki67 values of each laboratory: e.g., if the median Ki67 labelling index is 20%, then a value below 10% is clearly low, a value of 30% or above is certainly high. As an update to this approach, the 2021 StGallen/Vienna Consensus proposed values >30% as an indication for chemotherapy in ER-positive tumours (
With the acceleration of targeted drug development, more and more patients are being treated in clinical trials, in which tumours are most often re-examined, or a target molecule or biomarker needed for treatment is assessed in a central laboratory. In such cases, cooperation with the pathologist diagnosing the tumour is required. A prerequisite for cooperation is that the pathologist is involved in the clinical trial, as the specialist creating the report serving as the basis for enrolment; as such, they should be informed of the details and objectives of the trial and their participation should be part of the contract. Preferably, the pathology department should be contracted by the study sponsors, to inform the participating pathologists about trial goals and material requirements as well as to ensure proper reimbursement of trial-related procedures. The specimen specified in the protocol must be released by the pathologist under the specified conditions and the delivery/dispatch of the block (or the requested specimen) should be documented. A similar situation may arise with regard to sample selection for multigene expression tests. For a limited amount of tumour tissue, division of the sample should also be considered.
The diagnosis and treatment of breast cancer is a multidisciplinary collaboration between different medical and paramedical professionals. As mentioned before, the diagnosis of breast cancer and its differential diagnosis requires radiopathological and clinicopatholgical correlation. Adjuvant, neoadjuvant and palliative therapy related decisions are founded on prognostic and predictive markers, identified target molecules determined by pathologists. The interpretation of these results is not always straight forward, and communication by solely reports may lead to misunderstanding and harm to the patient. This is why it is expected that pathologists present their findings at the multidisciplinary tumor boards, interpret any limitations and take part in the decision-making process.
As a conclusion to the text on pathology, here are some of the recommendations proposed by the expert panel, the implementation of which requires policy support, but which may contribute to a higher standard and better quality of professional practice, performed under better circumstances.
In the recommendations above, quality assurance is mentioned in two aspects, namely: an endeavour for cytology laboratories establishing the diagnosis; and a requirement for pathology laboratories involved in predictive immunohistochemistry. In the future, it seems to be a realistic goal that all pathology units involved in the screening and diagnosis of breast cancer should certify their professional competence using external quality control. Generally speaking, however, pathology laboratories should be prepared to achieve a higher level of quality, the elements of which are included in the requirements of ISO 15189 ( • In addition to the technological external quality control indicated above, there is justification for setting up a centrally organized diagnostic (and reporting) programme for pathological units involved in breast cancer screening and diagnosis, in order to improve and ensure compliance, with the necessary infrastructure and financial resources. • It would be appropriate to install specimen mammography devices in high throughput breast diagnostic pathology departments (the EUSOMA recommendation of 150 cases/year may be relevant here, see under “Non-operative diagnostics (preoperative or pretreatment biopsy diagnosis)”. • In line with the panel of radiology experts, we recommend that if an expert is involved in the diagnosis or false diagnosis of breast cancer in case of suspected error (e.g., legal dispute, claim for compensation, etc.), the expert should be a person with documentable experience in this field. Non-pathologists and general pathologists who examine small numbers (<100 per year) of cases and have no experience in evaluating samples obtained from screening should not be accepted as experts. In order to give an opinion, an expert must simulate a real-life situation (they should not analyse the appropriateness of preoperative diagnosis and therapeutic decision retrospectively, with the knowledge of the detailed results of all investigations and surgical-histological reports). It is recommended that the expert form an opinion only on the basis of the information available at the time of the decision(s) contested in the dispute/lawsuit, evaluating the case in question together with several similar, anonymised cases. • Development and investment in the field of digital pathology are also necessary. The possibilities of these developments are multifold and include teaching, quality control, consultation, morphometry, image analysis; and digital material is the
This is part 2 of a series of 6 publications on the 1st Central-Eastern European Professional Consensus Statements on Breast Cancer covering imaging diagnosis and screening (
The consensus document contains product placement without the intention of advertising. Each complex molecular test is unique, and although these can be described without indicating their name (for example with the number of genes tested), not everyone will necessarily understand what this refers to. For this reason, and adopting the practice used in some of the source works, the tests are listed under their trade name.
GC drafted the manuscript. All authors have complemented this with parts related to their field of expertise, the final content was discussed at the 1st Central and Eastern European Academy of Oncology organized consensus conference. All authors have reviewed the manuscript, taken part in its revisions and approved the final version submitted.
The 1st Central-Eastern European Professional Consensus Statements on Breast Cancer were initiated, organized and granted by the Central-Eastern European Academy of Oncology (CEEAO), the National Institute of Oncology, Hungary and the Bács-Kiskun County Teaching Hospital. This regional oncological project was supported by Prof. Miklós Kásler, founder of CEEAO, Minister of Human Capacities, the Government of Hungary.
Author BJ was employed by the company Medserv Kft.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at: