11. Appendices – Breast Cancer

 

(to Chapter 4.5 Pathomorphological examination)

The appendix includes excerpts from common classifications and graduation systems referred to in the guideline, as well as proposed forms for the "Begleitschein zur Einsendung" and the "Dokumentation der verachterlichen diagnostischen Begutachtung" (see Figure 8 to Figure 10). The current nomenclature of benign breast lesions is also taken into account. In addition, the appendix contains supplements for the interpretation of the hormone receptor determination. In addition, special aspects of the assessment after neoadjuvant systemic therapy are explained.

 

 

Histological classification

The nomenclature and grouping of lesions of the breast is based on the WHO classification of tumors of the breast [119] and additionally on the "European Guidelines for Quality Assurance in Pathology in Mammography Screening" [420], [428] as well as recommendations from other internationally recognized guidelines [424], [425].

In the following, only selected points are presented which are of particular importance in terms of differential diagnosis, pathological-radiological correlation or clinical significance. In addition, individual terms of the current WHO classification are explained and commented on.

 

Normal findings and benign lesions (varia)

"Normal tissue" includes minor age-related changes such as fibrosis, lobular involution, microscopic dilatation of azini and ducts, and mild microcystic adenosis. These minimal changes are usually not sufficient to explain conspicuous clinical or radiological findings.

Fibrocystic mastopathy refers to changes associated with pronounced, macroscopically visible cyst formation, apocrine metaplasia and fibrosis.

This is distinguished from the solitary cyst, which is usually larger than 1 cm and is lined by a flat or apocrine epithelium.

Periductal mastitis (ductectasia, plasma cell mastitis) affects larger and mid-sized ducts, which are usually subareolar. The chronic inflammatory reaction in the vicinity of the ducts, which is often rich in plasma cells, may contain a large number of histiocytes and have a granulomatous aspect. It can be accompanied by pronounced periductal fibrosis. Calcifications are possible.

 

Benign epithelial proliferations

The sclerosing adenosis is rather cell-rich in the early phase. The fibre content increases with time. It is recommended that sclerosing adenosis is only mentioned in the documentation of the expert opinion if it is a prominent finding [420], [425]. Calcifications may be present.
Sclerosing adenosis must be distinguished from tubular carcinoma, microglandular adenosis and radial scarring by differential diagnosis.

If neighbouring lobules are affected, a mammographically or palpationally conspicuous tumour may develop, which is called an adenosetumour.

Adenoses with pronounced apocrine metaplasia, which occupies at least 50% of the adenosis, are documented as apocrine adenoses.

In contrast to sclerosing adenosis, microglandular adenosis does not show a lobulocentric organoid pattern. The round glandular structures are lined by a single-row epithelium without atypia. Myoepithelia are missing. However, an intact basal membrane can be shown.

The radial scar consists of a central, fibro-elastoid zone with ducts proliferating radially outwards. The lesion is rarely larger than 1 cm. The epithelium is bilayered or has ductal hyperplasia. Tubules may be trapped, distorted and tilted in the central hyaline fibrosis.

The complex sclerosing lesion simulates an invasion. It has all the characteristics of the radial scar, but is larger than 1 cm and more irregularly structured, often with nodular proliferations in the periphery. The lesion may be accompanied by changes such as papillomas, apocrine metaplasia or sclerosing adenosis. The most important differential diagnosis for both radial sclerosing lesions is tubular carcinoma, in which myoepithelium and an intact basement membrane in the border of the tubules are missing.

The diagnosis of a radial scar or complex sclerosing lesion in the punch and vacuum biopsy usually means a classification of the alteration in the B3 category [420] and the indication for a surgical excision. Excluded from this are small radial scars, which are completely recorded in a vacuum biopsy and represent a histological random finding (without mammographic correlate). These do not require excision and can be classified as B2 according to the European guidelines for mammography screening.

The reason for the assignment to the B3 category is that atypical ductal hyperplasia and carcinomas (in situ and invasive) are relatively often detectable in the periphery of mammographically detected radial scars and complex sclerosing lesions, especially in lesions with a size > 0.6 cm and in women > 50 years [119]. DCIS or invasive carcinoma is present in 4-32% of excidates after punch biopsy diagnosis of a radial scar, especially if ADH has already been registered in the punch biopsy.

The changes, which are called "ductal adenoma", have a variable appearance. Characteristic is a well defined benign glandular proliferation, which at least partially expands intraductally. There is overlap with other benign changes such as the papilloma or the complex sclerosing lesion, which is why such lesions are also called sclerosing papillomas.

 

Papillomas

The papilloma can occur solitary and multiple. The solitary papilloma is usually located centrally (central papilloma), in subareolar ducts, while the multiple papillomas are found more peripherally in the area of the terminal ductulo-lobular units (TDLE) (peripheral papillomas). Peripheral papillomas are not only more common with common ductal hyperplasia (UDH), but also with atypical ductal hyperplasia (ADH), DCIS or invasive carcinoma. Therefore, the presence of this change requires extensive tissue embedding.

The term "papillomatosis" should be avoided, as it has been used for both UDH and multiple papillomas.

Papillomas with atypical ductal hyperplasia (ADH) or ductal carcinoma in si-tu (DCIS), low-grade, are characterized by the occurrence of a focal proliferation of uniform cells with the cytological and architectural features of a low-grade neoplasia [119] Myopithelia may be reduced. Epithelial proliferation usually does not express basal cytokeratins and is homogeneously ER-positive. In the past, both the extent and the proportion of atypical epithelial proliferation have been used as quantitative criteria to distinguish between a papilloma with ADH and a DCIS in the papilloma. On the one hand, atypical epithelial proliferations of less than 3 mm in size were classified as ADH [1635], on the other hand, atypical epithelial proliferations that occupy less than 30% or 90% of the papilloma cross-section [361], [1636]. Flocks above this were classified as DCIS in a papilloma.

For pragmatic reasons, the WHO expert group recommends the use of the size criterion (limit value 3 mm) to differentiate between a papilloma with ADH and a low-grade DCIS in the papilloma and also points out that in the case of epithelial proliferation with intermediate or high core degree, the diagnosis of a DCIS in the papilloma should be made independent of the extent [119].

The B classification of papillary lesions is based on the epithelial component. Since the epithelial changes within the papillary lesion can be heterogeneous and the punch biopsy usually does not completely capture the lesion, most papillary lesions fall into the B3 category (uncertain biological potential). This excludes small papillomas which have been extensively sampled and are presumably completely removed by the punch/vacuum biopsy. These can be classified as B2. A higher B category is appropriate if the epithelial proliferates have atypia that justify either the suspicion of malignancy (B4) or the reliable diagnosis of a DCIS in the papilloma or an intraductal papillary carcinoma (B5).

 

Myoepithelial lesions

While myoepitheliosis is a mostly multifocal, microscopic process, adenomyoepitheliomas impress as circumscribed nodal formations, which can be multilobulated. They are characterized by their biphasic cellular differentiation: The myoepithelial, partly clear cell compartment usually surrounds the tubular component with a luminal epithelial lining. There are essentially 3 different morphological variants: lobulated, tubular and spindle cell/myoid. The differential diagnosis includes not only papilloma and adenosis (each with a fluid transition) but also the tubular adenoma (sharply defined in contrast to the tubular variant of adenomyoepithelioma) and the invasive carcinoma (no biphasic cellular structure).

The majority of adenomyoepitheliomas behave benignly. However, they are considered to have a low malignant potential and should therefore be classified as B3 in the punch/vacuum biopsy and a complete excision is recommended.

Significantly less frequent than benign adenomyoepithelioma are malignant forms (malignant adenomyoepitheliomas) in which the epithelial and/or myoepithelial component may be degenerated.

 

Fibroepithelial tumours

Fibroadenomas are benign biphasic tumours that are mostly diagnosed in women of childbearing age. Epithelial (ductal) hyperplasia is not unusual in fibroadenoma. In any case, ADH or DCIS in a fibroadenoma must be reported separately. In this case, when punch biopsy is used for diagnosis, the B category is increased from B2 to B3, B4 or B5 depending on the degree and extent of the atypia.

The fibroadenoma must be distinguished from the phylloides tumour, which has a stroma richer in cells. For its dignity assessment on the resected tissue, a sufficient number of tissue sections is necessary (rule of thumb: 1 tissue block per cm tumor diameter) to representatively record the characteristic stromal features (cellularity, pleomorphy, mitotic activity, distribution pattern) and the relationship to the surrounding tissue.

In principle, fibroepithelial tumors that suggest the presence of a phylloidal tumor (PT) in the punch or vacuum biopsy due to their cell-rich stroma, the predominance of the stromal component or an increased mitotic activity of the stromal cells are classified as B3. Cell-rich fibroepithelial lesions in which a phylloides tumour cannot be excluded should also be classified as B3.

 

Intraductal proliferative lesions

In the current WHO classification [119], this group includes various int-raductal proliferations that have a common point of origin: the terminal ductulo-lobular unit (TDLUs). They are associated with an increased risk for the development of invasive breast carcinoma, although to a significantly different extent.

The common ductal hyperplasia (UDH) comprises all cases of intraluminal epithelial proliferation without atypia. A colorful, flowing cell picture is common. If secondary lumina are formed, they are slit-shaped, rounded and irregularly shaped with tangential alignment of the nuclei in the limiting epithelial cells. One of the most important indicators of UDH is the presence of a mixture of at least 2 cell types (luminal and basal/myoepithelial and/or metaplastic apocrine cells). It is associated with only a very slightly increased risk (1.5-fold) of developing breast cancer. It is usually accompanied by diffuse or mosaic-like expression of the basal cytokeratins (including CK5, CK14).

The term flat epithelial atypia (FEA) was introduced into the WHO classification in 2003. This rather descriptive category includes lesions that are neoplastic by current standards and are also known as "clinging carcinoma" of the monomorphic type, atypical cystic lobules, atypical lobules type A, columnar cell metaplasia with atypia or columnar cell hyperplasia with atypia. Characteristic is the replacement of the original epithelium by a single layer of a slightly atypical epithelium, which often shows apical "snouts" or 3-5 layers of a monotonously atypical cell population of prismatic cells or columnar cells. The cell nuclei are round, relatively uniform and contain small nucleoli. Micropapillae or more complex structures like arcades are missing. The affected extended lobules often contain secreted material and microcalcifications.

If an FEA is diagnosed in the punch or vacuum biopsy, this change must be assigned to category B3 (see also Chapter 4.3.3 Risk lesions).

As described above, FEA is usually a columnar cell alteration with or without hyperplasia, with low to moderate cytological atypia. This should be distinguished from columnar cell hyperplasia with architectural atypia, in which micropapillae or bridges are preferably formed, with only slight cytological atypia. These changes are now classified as ADH or low-grade DCIS depending on the type and extent of the cytological and structural atypias.

It should also be noted that columnar cell proliferations are homogeneously ER-positive and usually CK5-negative. Immunohistochemical imaging of basal cytokeratins is often not helpful in the differential diagnostic differentiation between columnar cell hyperplasia without and with atypia, since the characteristic mosaic-like reaction pattern of UDH in columnar cell hyperplasia without atypia may be absent.

Atypical ductal hyperplasia (ADH) is also considered neoplastic intraductal epithelial proliferation. It is characterized by an intraductal proliferation of evenly distributed, uniform cells which can form micropapillae, arches, solid or cribriform patterns [119]. Roundish, rigid secondary lumina appear together with irregularly shaped ones. Cytologically, the cells of an ADH thus correspond to a low-grade DCIS. However, in an ADH the characteristic cells mix with non-uniform cells within a TDLU (s) or only a limited number of corridors of a TDLU are colonized.

In individual cases, the differentiation between ADH and low-grade DCIS can be difficult. Immunohistochemical imaging of basal cytokeratins does not help in differential diagnosis, since the proliferating epithelia in both lesions do not express them.

Nowadays, quantitative criteria are primarily used to distinguish ADH from low-grade DCIS. The most commonly used quantitative criteria are those that are used to diagnose a low-grade DCIS when at least two duct structures are completely and homogeneously colonized by neoplastic epithelial proliferation or the lesion is > 2 mm. The expert group of the current WHO classification was not in a position to favor either of the two criteria [119]. It was rather pointed out that these quantitative criteria are primarily helpful to avoid overtherapy of very small neoplastic lesions by not diagnosing these lesions as DCIS. Therefore, a conservative approach is recommended in the differential diagnosis between ADH and low-grade DCIS, especially in punch and vacuum biopsies. The diagnosis of ADH or an atypical intraductal proliferative lesion should be sufficient to induce surgical excision of the change. Depending on the degree of atypia and the extent of the lesion, the result is a B3 or B4 category.

The final diagnostic classification is then made on the surgical specimen (see also Chapter 4.3.3 Risk lesions).

Lobular neoplasia (LN)

According to the current WHO classification [119], the term lobular neoplasia (LN) is used to describe the entire spectrum of atypical epithelial proliferations originating from TDLUs and characterized by the proliferation of mostly small and non-cohesive cells - with or without pagetoid involvement of the terminal ducts. The terms atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) reflect the extent of the change. A classic LCIS is diagnosed when more than half of the azini of a TDLU are colonized and dilated by the characteristic neoplastic proliferation. A less pronounced infestation corresponds to an ALH. The determination of the extension and thus the differentiation between ALH and LCIS is usually only possible on surgical specimens but not on punch biopsies.

As a special feature of the LN, its frequent multicentric (46-85 %) and bilateral occurrence (30-67 %) must be noted. In principle, the LN is, according to current opinion, an indicator lesion for an increased carcinoma risk. The relative risk of a patient is bilaterally increased by a factor of 4-12 after the diagnosis of an LN, whereas the risk after the diagnosis of ALH is half as high as after an LCIS.

According to the WHO, different variants of the LCIS are increasingly frequently diagnosed due to their association with microcalcification:

• Classical LCIS with comedonecroses
• Pleomorphic LCIS with/without apocrine properties and comedonecroses

Even though individual reports suggest that these variants may have a different course than the classic LCIS, the clinical significance and adequate therapy is not yet clear [119].

If a classic LN is diagnosed in the punch or vacuum biopsy as part of mammography screening, this corresponds to a B3 category. If it is not possible to decide on the punch or vacuum biopsy material whether small cell epithelial proliferation in TDLUs and/or ducts should be classified as LN or DCIS, a higher B category: B4 or B5 is recommended. The variants of the LN (especially pleomorphic variant and classical LN with comedonecroses) are classified as B5a. With regard to the management of the LN, see also Chapter 4.3.3 Risk lesions.

 

Ductal carcinoma in situ (DCIS)

In the current WHO classification, ductal carcinoma in situ (DCIS) is defined as a neoplastic intraductal lesion characterized by subtle to severe cellular atypia and an inherent but not necessarily obligatory tendency to progression to invasive carcinoma [119]. In small low-grade or non-high-grade DCIS a differentiation from ADH is necessary (see above).

Artefacts at the preparation margin, the retrograde expansion of a DCIS into terminal ductulo-lobular units (so-called lobular carcinoma) or a ductal sclerosis with inclusion of atypical epithelial complexes must not be misinterpreted as microinvasion (pseudoinvasion). The preparation of additional incisions and the use of immunohistochemistry to visualize the epithelial-stroma boundary often allow clarification of the diagnosis. Markers for the detection of myoepithelia (especially p63) and basement membrane components (e.g. type IV collagen) have proven to be particularly helpful.

With regard to clinical, risk and management aspects see chapter 4.3.2 DCIS

Grading and classification

(see also chapter 4.5.2.6)

For correlation with imaging and further therapy planning, the grading of DCIS should be performed not only on the excidate but also on the punch or vacuum biopsy material. However, grading may vary between punch/vacuum biopsy and the final surgical preparation due to intratumoral heterogeneity.

The core grading should follow the recommendations of the "Consensus Conference on the Classification of DCIS in Philadelphia, 1997" [453] (see Table 22).

 

 

Determination of hormone receptor expression

The evaluation and interpretation of immunohistochemistry is based on the guidelines for invasive breast cancer (see below).

Invasive breast carcinomas

Histological typing

(see also Statement 4.26.)

For all invasive breast carcinomas a histological typing according to the current WHO classification must be performed (see Table 24 [119] ). In the case of preoperative diagnostics, this should be done on the punch or vacuum biopsy material. This serves both for correlation with imaging and for therapy planning. As a result of intratumoral heterogeneity there can rarely be deviations between the punch/vacuum biopsy and the surgical specimen. The findings on the surgical specimen are decisive for the final assignment of the histological type. Some special histological types take a demonstrably more favourable course. These include the tubular, invasive cribriform, mucinous and adenoid-cystic carcinoma. Some authors also include the well differentiated mucinous, tubulo-lobular and papillary carcinoma in this group. In addition to these usually ER-positive carcinomas, certain carcinomas also show a favourable course, which are triple-negative, i.e. ER-, PR- and HER2-negative. These include the adenoid-cystic carcinoma and the low grade fibromatosis-like metaplastic carcinoma. These carcinomas usually grow locally aggressively and have a low tendency to (systemic) metastasis.

 

 

Prognostically relevant is the differentiation of carcinomas of a "pure" special type from mixed types.

According to the WHO classification, a carcinoma is classified as a "pure" type if at least 90% of the tumour shows the characteristic pattern (e.g. tubular carcinoma). A mixed-type carcinoma is defined as a carcinoma where the proportion of a particular type exceeds 50% but 10-49% of the tumour has no specialised pattern; i.e. mixed invasive carcinoma NST (no particular type) and particular type (e.g. mucinous, lobular).

In the following, only certain histological types will be explained in more detail, which are either particularly frequent or for which strict adherence to diagnostic criteria is of particular relevance for correct typing, as this determines the estimation of the prognosis (see also [1637]).

Invasive carcinoma, no special type (NST) is by far the most common type of tumour, accounting for 50-80 % of all tumours. It comprises a heterogeneous group of tumours that do not have sufficient characteristics to be assigned to a specific histological type (e.g. lobular or tubular carcinoma). In order to be classified as invasive carcinoma NST, a tumour must, after careful examination of representative sections, show a non-specialised pattern in more than 50 % of its mass (to distinguish "pure" invasive ductal carcinoma from mixed forms, see also above).

The prognosis of invasive carcinoma NST is equal or slightly worse compared to the prognosis of the total group of all breast cancers. The prognosis is mainly influenced by the established parameters: nodal status, tumor size, grading, etc. Therapeutically relevant is the steroid hormone receptor expression in about 70-80% of invasive ductal carcinomas. HER2 overexpression or amplification is present in about 15 % of cases.

Invasive lobular carcinomas account for about 5-15% of invasive breast carcinomas. The classic appearance of invasive lobular carcinoma is mainly characterized by its small cell size, its dissociated infiltrating growth. From the classic type, different morphological variants are distinguished (solid, alveolar, pleomorphic, tubulo-lobular and mixed) with a partly better (alveolar and tubulo-lobular variants), partly worse prognosis (solid and pleomorphic). The classic form of invasive lobular carcinoma is in most cases associated with lobular neoplasia, but occasionally also with DCIS or carcinoma in situ with ductal and lobular phenotype.

A comparison of the long-term prognosis of ILC and NST carcinomas shows a lower risk of progression of ILC in the first years, but an overlap of the survival curves after about 10 years with a worse long-term survival of ILC. However, invasive lobular carcinomas are characterized by multifocality (9-31%), bilateralism (5-19%) and a different pattern of metastasis. Bones, meninges, gastrointestinal tract and peritoneum are more frequently affected by distant metastases. Lung metastases, on the other hand, are observed less frequently than in the ductal type.

The invasive lobular carcinomas usually express steroid hormone receptors. Among the variants, the ER-positivity rate is highest for the alveolar variant and lowest for the pleomorphic variant. HER2 overexpression or amplification is very rare in classic invasive lobular carcinoma. The pleomorphic variant (G3) is more likely to show HER2 overexpression and gene amplification.

The tubular carcinoma is characterized by the presence of neoplastic rounded-oval tubules with a single-row cubic epithelial lining in a dense collagenous connective tissue. The tubules may be angled or folded with a drop-like shape. The epithelium often exhibits "apical snouts". The nuclei are slightly hyperchromatic and should have only small inconspicuous nucleoli. Mitoses are rare. The diagnosis of a (pure) tubular carcinoma requires that the tumour consists of > 90% tubular structures with the described structural and cytological criteria. The (pure) tubular carcinoma accounts for about 2% of all breast carcinomas, but seems to be found more frequently with subtle radiological diagnosis. Its proportion of tumours less than 1 cm in diameter is at least 8%, in pure screening populations even 8-27%.

Strict adherence to the above criteria is crucial for the assessment of the prognosis. Pure tubular carcinoma has an excellent prognosis. The disease-free 10-year survival rate is well over 90%. Even the rare presence of axillary lymph node metastases (6-19%) has no influence on the survival rate.

The tubular carcinomas are usually ER- and PR-positive and HER2-negative.

In mucinous carcinomas, islands of relatively uniform cells lie in lakes of extracellular mucus. The classification as (pure) mucinous carcinoma requires, as with the other special types, that the characteristic morphology is developed in > 90% of the tumour. This applies to max. 2% of invasive breast carcinomas. Here, too, strict adherence to diagnostic criteria serves the purpose of identifying tumours with a favourable prognosis, especially those occurring in older patients. The 10-year survival rate is 80-100 %.

Mucinous carcinomas are usually ER- and PR-positive. HER2 overexpression or gene amplification is very unusual.

In the current WHO classification, it is recommended to leave the terms "medullary carcinoma", "atypical medullary carcinoma" and "invasive carcinoma NST with medullary characteristics" and instead to group tumours with all or some of the following characteristics in the category of "carcinomas with medullary characteristics": sharp limitation, synzytial growth pattern, high-grade nuclei and prominent lymphoid cell infiltrate. The background is the insufficient reproducibility of the criteria for distinguishing the classic medullary carcinoma, which accounts for less than 1% of all breast carcinomas, from the other tumours with medullary characteristics. However, a superordinate ICD-O code is missing so far, so that a tumour has to be assigned to one of the older categories for ICD-O coding after all.

Patients diagnosed with a carcinoma with medullary characteristics are on average younger (45-52 years) than those diagnosed with other invasive carcinomas. As these tumours are usually relatively well-defined, low stroma tumours, they can be clinically and imaging benign. Carcinomas of this group are mostly ER-, PgR- and HER2-negative (triple-negative). Basal cytokeratins (CK5/6, CK14), sm-actin, EGFR1, P-cadherin, p53 and caveolin-1 are variably expressed.

The majority of breast carcinomas with medullary characteristics show a basal-like gene expression profile. A common feature is also genomic instability associated with p53 mutations in about 2/3 of the tumors. Remarkably, patients with germline mutations of the BRCA1 gene are more likely to have carcinomas with medullary characteristics.

In the findings report, therefore, the possibility of a hereditary background should be pointed out in the presence of a triple-negative invasive G3 carcinoma with medullary characteristics (see Statement 3.16.).

The classic medullary carcinoma has a more favourable prognosis than a low differentiated NST carcinoma. The relatively favourable prognosis of these tumours is attributed to the presence of the prominent lympho-plasmacellular infiltrate or, at the molecular level, to a B-cell/plasmacell metagen. However, when the overall group of BRCA1-associated breast carcinomas is considered, they show a similar prognosis to sporadic breast carcinomas.

Histological grading

(see also statement 4.27.)

For all invasive breast carcinomas a grading has to be performed [119]. In the case of preoperative diagnostics, this should already be done on the punch or vacuum biopsy material.

 

 

The histological grading is performed after a modification of the grading proposed by Bloom and Richardson according to Elston and Ellis [510]. Histological grading should generally be performed on primarily fixed and paraffin-embedded material. The histo- and cytological criteria that are assessed semi-quantitatively are tubule formation, nuclear pleomorphy and mitosis rate (see Table 25).

When quantifying the mitosis rate, the individual visual field size must be taken into account in order to avoid blurring (see Table 26). It is determined in 10 consecutive high power fields (= 400-fold magnification in the microscope) in the area of the highest mitotic activity of the tumour. Only distinct mitotic figures are counted.

 

 

If the detected tumor area in the punch and vacuum biopsies is less than 10 HPFs, the mitosis rate can be approximately determined by counting the total number of mitoses in the available HPFs. The number obtained is divided by the number of HPFs evaluated and multiplied by a factor of 10.

An overview of the evaluation criteria with image examples for the assessment of nuclear pleomorphism and a table for the allocation of the mitosis score in relation to the individual visual field size is provided by a poster of the NHS Cancer Screening Programme, UK (Appendix I in [1638]).

 

Nottingham-Prognose-Index

Ergänzend wird hier noch der Nottingham-Prognose-Index (vgl. Tabelle 27) für invasive Karzinome angeführt, der Tumorgröße, Grading und Lymphknotenstatus einbezieht und als prognostisch sehr aussagekräftig gilt [1639], [D'Eredita, G. et al. 2001], [1641]. Seine Angabe ist optional.

 

Special additional examinations

(see also Statements 4.28. with text)

In the case of invasive breast cancer, the estrogen and progesterone receptor status and the HER2 status must be determined in the primary diagnosis, preferably already on the punch biopsies [185], [265], [421], [426].

Hormone receptor status: allred score and immunoreactive score

For the immunohistochemical determination of the estrogen and progesterone receptor status, the percentage of positive tumor cell nuclei and the average staining intensity must be indicated in each case. The evaluation as ER- or PR-positive requires at least 1% positive tumor cell nuclei.

In addition, scores can be given that take into account the percentage of positive cells and the staining intensity: Allred-Score [479] or the immunoreactive score (IRS) according to Remmele and Stegner [480]. Their calculation bases are shown in Table 28.

 

 

Further special examinations

Fresh material for additional molecular investigations or for tissue agerivation in a tumour bank can only be taken if it is ensured that sufficient and representative material is available for an adequate histopathological examination. The removal of fresh material from surgical specimens for such examinations is exclusively under the control of the pathologist (see Statement 4.24. and text).

 

 

Special aspects in the processing and reporting of surgical specimens after primary (neoadjuvant) chemotherapy

The pathomorphological examination of surgical preparations after neoadjuvant chemotherapy (NACT) provides objective information on the effect of the therapy and the prognosis. The recommendations of an international working group, which emerged from the cooperation of the Breast International Group (BIG) and the North American Breast Cancer Group (NABCG) [1643], provide support for the standardization of the pathological processing and characterization of tumor residuals.

For histological diagnosis the following information should be sent from the clinic to the pathologist:

• The information that a NACT has occurred
• Whether this was done in a study and whether a specific grading system is recommended in the study for the response to therapy
• Results of a pre-therapeutic punch biopsy, especially if it was performed externally
• Lymph node status pre-NACT and method of determination
• The localization of the tumor/tumor bed, whether a clip marker was used
• The clinically determined size of the tumor pretherapeutic and posttherapeutic

The processing of the surgical specimens is essentially analogous to the procedure for primary surgical therapy (see sections 4.5.6-4.5.8). Special features result from the varying degrees of tumor regression during cutting and the assessment of the size of the residual tumor and the resection margins.

In the case of a tumour that can be clearly delimited macroscopically, the embedding is carried out in the same way as for palpable tumours in primary surgical therapy.

If macroscopically no clear tumor focus or tumor bed can be delimited, a systematic examination of the former tumor bed should be performed to document the response to preoperative chemotherapy. For this purpose, the extent and location/quadrant of the original tumor should be clinically indicated or marked. If the tumor bed is then recognizable as a blurred fibrosis area in this clinically indicated area, the extent of the cut is based on the clinically indicated preoperative tumor size. At least one cross-section of the largest tumour diameter should be embedded, taking into account the resection margins (as a guideline, at least one block per cm of the pretherapeutic tumour size). In addition, fibrosed areas suspected of being tumour-suspicious should be examined from the vicinity of the tumour bed and from the area of the resection edges.

If macroscopically no clear tumor bed can be identified even when taking into account the clinical information, it is advisable to embed smaller diagnostic excidates primarily completely. In the case of larger resectates, an orienting cut from fibrosed areas should be made first. The extent of the cutting depends on the pre-therapeutic tumor size and the size of the preparation. As a rule of thumb it is recommended to take at least one block per 2 cm of the largest preparation diameter as well as samples from the resection margins (at least one block per dimension). In the case of microscopic detection of residual tumours or inflammatory/regressive changes, tissue from this area should then be examined in an expanded section, taking into account the resection margins, and if necessary the entire former tumour bed.

In the case of a pronounced resorptive inflammatory reaction, the differentiation between regressively altered tumor cells and histiocytes can be difficult. This is where immunohistological examinations with pancytokeratin antibodies help.

In order to be able to diagnose pathological complete remission (pCR) with sufficient certainty, it is recommended to embed one complete cross-section of the tumour bed per cm of the former tumour size or, in the case of very large tumours, 5 representative blocks of a cross-section per 1-2 cm of the former tumour size (max. 25 blocks) [1643].

In the pTNM classification after primary systemic therapy the prefix y should be prefixed [429].

The determination of residual tumor size post-NACT is often difficult. Tumor residuals can be scattered as small tumor foci in the area of the former tumor bed. Since the 7th edition of the TNM Classification (AJCC/UICC), the ypT classification should be based on the largest coherent tumor focus without inclusion of fibrosis areas. If several tumor foci are present, this is indicated by the suffix "m" (e.g. ypT1b(m)). However, it is also pointed out by the BIG-NABCG working group that this recommendation of the AJCC/UICC leads to a systematic artifactual downgrading of those tumors that respond to therapy with tumor thinning and multifocal scattered tumor residuals. In the view of the experts of the BIG-NABCG working group, the largest extension of tumor residuals (including possible intermediate fibrosis areas) is a better indicator of tumor response than the largest diameter of a contiguous tumor focus and should therefore also be reported in the findings report.

Various histopathological classification systems are under discussion for the graduation of tumor regression. The system recommended by the BIG-NABCG working group for quantification of the residual tumor burden, the Residual Cancer Burden (RCB) System, takes into account not only the maximum tumor extent (2-dimensional) but also the tumor cellularity as well as the DCIS fraction and the number and maximum size of lymph node metastases [1644]. A calculator for the calculation of the 4-stage RCB system is freely available on the Internet on the website of the MD Anderson Cancer Center: http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3

In various studies, the CPS+EG score [1645], [1646], [1647] has also proven to be prognostically relevant in the meantime. This takes into account the clinical stage (according to AJCC) before NACT (CS), the post-therapeutic pathological stage (PS) as well as the oestrogen receptor status (E) and the core grading (G) at the pre-therapeutic biopsy (see Table 29). The level of the resulting score correlates with the disease-specific survival of patients after neoadjuvant therapy. It is therefore recommended to document the pre- and post-therapeutic relevant pathomorphological parameters in the findings report.

 

 

(8th ed. [D'Eredita, G. et al. 2001], [1650],[1651], [1652], [1653], [1654])

Rules for classification

The classification only applies to carcinomas of both the male and female breast.

In case of multiple simultaneous breast tumours, the tumour with the highest T-category is classified. Simultaneous bilateral breast carcinomas should be classified separately in order to allow for the possible assignment of tumors to different histological types.

 

TNM: Clinical classification

T-primary tumor

TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
Tis (DCIS)	Ductal carcinoma in situ
Tis (LCIS)	Lobular carcinoma in situ
Tis (Paget)	M. Paget's nipple without detectable tumor

 

Note:

Tis (Paget) is not combined with an invasive carcinoma and/or DCIS or LCIS Breast carcinomas combined with Paget's disease are classified according to the size and characteristics of the carcinoma in the mammary parenchyma, but the presence of Paget's disease of the nipple should be noted.

The AJCC does not include Tis of type LCIS [517].

 

T1	Tumour maximum 2 cm in the largest diameter
T1mi	Microinvasion 0,1 cm or less in the largest diameter
T1a	exceeding 0,1 cm up to a maximum of 0,5 cm in the largest diameter
T1b	greater than 0,5 cm to a maximum of 1 cm in the largest diameter
T1c	greater than 1 cm to a maximum of 2 cm in the largest diameter
T2	Tumour larger than 2 cm up to a maximum of 5 cm in the largest diameter
T3	Tumour larger than 5 cm in the largest diameter
T4	Tumour of any size with direct extension to the chest wall or skin, as described under T4a-T4d
T4a	Extension to chest wall (ribs, intercostal muscles, anterior serratus muscle, but not pectoralis muscles)
T4b	Oedema (including 'peau d'orange') or ulceration of the skin of the breast or satellite nodules of the skin of the same breast
T4c	Criteria 4a and 4b
T4d	Inflammatory (inflammatory) carcinoma

 

Remarks:

Microinvasion is understood to be the penetration of carcinoma cells beyond the basement membrane into the adjacent tissue. No point of invasion may measure more than 0.1 cm in the largest extension. If multiple microinvasion foci are present, only the extent of the largest foci is used for classification. A sum of the size of all micro-invasion foci must not be calculated. The presence of multiple micro-invasion foci should be recorded in the same way as for multiple larger carcinomas (e.g. pT1mi (m), pT2 (m)). The size indications of the T-classification are applied.

The inflammatory carcinoma of the breast is characterized by a diffuse brown induration of the skin with an erysipelas-like border, usually without a palpable tumor mass underneath. If the skin biopsy is negative and no localised measurable primary tumour is found, this corresponds to clinical inflammatory carcinoma (T4d), in the pathological classification pTX.

Retraction of the skin or nipple or other skin lesions other than those listed under T4b and T4d may occur in T1, T2 or T3 without affecting the T classification.

 

 

pTNM: Pathological Classification

pT primary tumor

The pathological classification requires the examination of the primary tumor without macroscopically recognizable tumor at the resection margins. A case can be classified according to pT if only histological tumor is detected at the resection margins.

The pT categories correspond to the T categories. In the pT classification, only the invasive component is measured to determine the tumor size.

 

pN-regional lymph nodes

The pN classification requires the resection and examination of at least the lower axillary lymph nodes (level I). Usually 6 or more lymph nodes are histologically examined.

If the lymph nodes examined are tumour-free, but the number of lymph nodes normally examined is not reached, pN0 should be classified and the number of lymph nodes examined should be added in brackets

pNX Regional lymph nodes cannot be assessed (not removed for examination or removed earlier)

pN0 No regional lymph node metastases

Note:

Cases with isolated tumor cells (ITC) in regional lymph nodes are classified as pN0. Isolated tumor cells are defined as single tumor cells or small clusters of cells not larger than 0.2 mm in the largest dimension, which can usually be detected by immunohistochemical or molecular methods and sometimes verified in HE staining. As an additional criterion it has been proposed to include a cluster of less than 200 cells (in a histological section). Lymph nodes containing only isolated tumor cells are not considered in the counting of lymph node metastases. However, they should be included in the counting of the total lymph nodes examined.

pN1	Micrometastases; metastasis(s) in 1-3 ipsilateral lymph nodes and/or microscopic metastases in sentinel lymph nodes along the ipsilateral A. mammaria interna (not clinically detectable)
pN1mi	Micrometastasis(s) (> 0,2 mm and/or more than 200 tumour cells, but not exceeding 0,2 cm)
pN1a	1-3 axillary lymph node metastasis(s), at least one > 2 mm
pN1b	Lymph nodes along the A. mammaria interna with microscopic metastasis(s)
pN1c	Metastases in 1-3 axillary lymph nodes and lymph nodes along the A. mammaria interna
pN2	Metastasis(s) in 4-9 ipsilateral axillary lymph nodes or in clinically recognizable lymph nodes along the internal mammary artery without axillary lymph node metastases
pN2a	Metastases in 4-9 axillary lymph nodes, including at least one > 2 mm
pN2b	Metastases in clinically recognizable lymph nodes along the A. mammaria interna without axillary lymph node metastases
pN3	metastases as described below:
pN3a	Metastasis(s) in ≥10 ipsilateral axillary lymph nodes (at least one > 2 mm) or in ipsilateral infraclavicular lymph nodes
pN3b	Metastasis(s) in clinically recognizable lymph nodes along internal mammary artery with at least one axillary lymph node metastasis or lymph node metastases in more than 3 axillary lymph nodes and in lymph nodes along internal mammary artery, as determined by examination of the sentinel lymph node(s), but not clinically recognizable
pN3c	Metastasis(s) in ipsilateral supraclavicular lymph nodes

ypN nach Behandlung

Der Zusatz „sn“ wird nur dann verwendet, wenn eine Sentinellymphknotenuntersuchung nach der Behandlung vorgenommen wurde. Wenn kein Zusatz angegeben ist, ist davon auszugehen, dass die Untersuchung der axillären Lymphknoten an durch Dissektion entfernten Lymphknoten vorgenommen wurde.

Der Zusatz „X“ wird dann verwendet (ypNX) wenn nach der Behandlung keine Untersuchung des Sentinellymphknotens oder eines Axilladissektates erfolgte.

pM-Fernmetastasen

pM1 Fernmetastasen mikroskopisch bestätigt

Anmerkung:

pM0 und pMX sind keine anwendbaren Kategorien. Die Kategorie pM1 kann in gleicher Weise wie M1 weiter spezifiziert werden (z. B. pM1(PUL) für mikroskopisch nachgewiesene Lungenmetastase).