Breast Cancer Subgross Morphology Parameters Biology Essay

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Subgross morphology represents a common basis for all imaging methods. While radiological methods generate and analyze images of the breast tissue, pathology examines the tissue itself sliced and processed for microscopic assessment. In general, all the radiology methods have far less resolution capacity compared to microscopy, but it turn, they give a perfect overview of the lesion(s) and the surrounding tissue. Radiology may also generate images in different projections allowing a three-dimensional reconstruction and exact localization of the lesion(s). Furthermore, in contrast to histopathology, radiological examinations may be repeated allowing to follow the lesion(s) during their development and progression.1, 2

Histopathology, on the other hand, is still the gold standard in breast diagnostics, a method which confirms or rules out the radiological diagnosis with the exactness of microscopic analysis. In addition, histological analysis itself generates morphological prognostic parameters (first of all tumor size, histology grade and lymph node status, but also lesion distribution, disease extent and the status of the resection margins) representing the basis of current grading and staging systems. Further, special methods of histological analysis also provide parameters predictive of the tumors' response to adjuvant therapy. The best established of these parameters are estrogen and progesterone receptor status, HER-2 status, proliferative activity of the tumor cells, and most recently, genetic and immunohistochemical phenotyping of the tumor (ER positive, HER-2 positive, triple negative and basal like).3, 4

Subgross morphology represents a level half a way between the low-resolution radiological imaging methods and the high resolution microscopic analysis. It does not correspond to macroscopic (naked eye) assessment of the surgical specimen and its slices, as such an assessment is hardly more sensitive than the radiology methods. Subgross morphology is best assessed in large-format histological preparations preferably including entire cross-sections of the specimen. These large-format histology slides are of the same thickness of 3-5 microns as the traditional small slides, but are prepared without fragmentation of the specimen slices. It preserves the in vivo relation between the different components of the tumor. The same large-format slide can be viewed under the microscope or, projected as an overhead, directly compared to mammography, ultrasound or magnetic resonance images. This method opens the possibility of correlating the radiological and histological findings and in addition may evidence subtle changes and minute lesions even if they are radiologically or macroscopically occult.5-9

The subgross parameters demonstrated in large-format histological slides are the following: the individual size of the lesion(s), the shape of the tumors (circular or stellate), the distribution of the lesions (unifocal, multifocal or diffuse), the extent of the disease (the area including all the in malignant lesions detectable within the same breast) and intertumoral or intratumoral heterogeneity. In addition, the method also documents the surgical margins in one plane. These parameters are identical to those which need to be assessed during multimodality radiological work-up of the cases representing the elements of the common language of radiology and pathology. These parameters are not only diagnostic features in breast lesions, particularly in breast carcinoma, but, as mentioned previously, some of them are established morphological prognostic parameters.

In this chapter, we will review the subgross morphology of normal and pathologically altered breast tissue and will particularly focus on the association of subgross morphological details with prognostic and predictive parameters in breast carcinoma. The subgross details can be assessed in multimodality radiology approach with high sensitivity and accuracy, thus indirect association of the radiological findings with prognostic and predictive parameters will also be pointed out.

2. Normal breast tissue - aberrations / variations - benign lesions: a continuum

The fibroglandular tissue of the mammary gland develops between the superficial and deep layers of the subcutaneous fascia. During the puberty, lobes of fatty tissue appear within the immature fibroglandular area and, by pushing aside the glands and stroma, form the fibrous skeleton of the breast. Convex spherical spaces filled of fatty tissue are typical of the mature breast skeleton, as well as the so called Cooper's ligaments on the front surface representing compressed breast tissue connected to the superficial layer of the subcutaneous fascia with fibrous strands, as illustrated in Figures 1a-c. The fatty holes with their smooth convex borders and the ligaments represent the hallmarks of the breast on radiological images in most women during the reproductive period. In a minority of cases, the breast tissue is more dense and lacks the typical silhouette characterised by the holes and Copper's ligaments (Figs. 2 and 3).7, 8, 10

During and after menopause, the glandular tissue undergoes involution and becomes usually replaced with fatty tissue, or more rarely, with fibrous tissue rich in collagen. This involution may be patchy and result in peculiar tissue structure and radiological image. This pattern may be also seen in breasts with many aberrations of the lobules (ANDIs, see later in this chapter).8 Schematic drawings, radiological and corresponding subgross histological details illustrating these three ways of breast tissue involution are demonstrated in Figure 2.

Tabár 8, 10, 11 described five different mammographic patterns of the normal breast. Pattern 1 is the most usual reproductive pattern illustrated in Figure 1 and represents a mixture of subgross appearances that are illustrated in Figure 2. Pattern 2 corresponds to breast tissue which has undergone fatty involution, pattern 3 to fatty involution with remaining glandular tissue behind the nipple. Pattern IV is characterized with the patchy appearance of either remaining islands of non-involuted breast tissue or by ANDIs, while pattern 5 with dense collagen-rich stroma.

Although the radiological patterns are few, the histological picture of the normal breast tissue is very varying; it is difficult to assess the radiological pattern with a microscopic analysis of the tissue; large section histology image and radiological - pathological correlation are essential.

The mammographic parenchymal patterns are a result of changes in glandular structures as well as in the related intralobular and interlobular stroma. The parenchyma itself is organized into lobes having a pyramidal shape with the tip within the nipple and the basis towards the pectoralis fascia. The number of such lobes in one breast varies in range 20 to 40. The size and the shape of the lobes are also very variable. The lobes represent individual units with very few, if any, connections between them.12

Microscopic magnification discovers the ductal - lobular architecture of the glandular tissue of the breast. The largest ducts called lactiferous ducts open in the nipple and ramify into smaller so called segmental and subsegmental ducts. The largest ducts have a pleated contour allowing a considerable dilatation of these ducts during lactation. All the ducts and lobules are characterized with a wall covered by two cell layers: the inner layer of the epithelial cells and the outer layer of the myoepithelial cells. Figure 8 demonstrates a lactiferous duct surrounded by bundles of smooth muscle cells of the nipple.

The smallest branches of the ductal system are designated as terminal ducts. They further branch into blindly ending finger-like acini. The acini together with their surrounding loose hormone sensitive stroma comprise a lobule, the most important functional unit of the breast tissue which produces milk during late gravidity and lactation.7, 10 A lobule together with its terminal duct are designated as terminal ductal - lobular unit, TDLU (illustrated in Figure 9). The two-layered architecture of the lobules is illustrated in Figure 10a-c.

The acini, the ducts and the hormone sensitive periductal and intralobular stroma react on hormonal stimuli. The changing levels of estrogen, progesterone and other hormones influence the morphology of the TDLUs.13 Cyclical changes related to menstrual phase can be evidenced during the reproductive period while involution (diminishing of the number of acini per lobule as well as the number of lobules and smaller ducts) takes over around and after the menopause. As mentioned previously, the radiological appearance of normal breast tissue is mostly influenced by the changes in the stroma.10

While most of the TDLUs sensitively follow the hormonal influences, some lobules are either over-sensitive or not sensitive. This results in deviations in their morphology as well as in atypical reactions to hormonal stimuli. Such lobules were designated as aberrations of normal development and involution (ANDIs).14 Such deviated TDLUs are present practically in every breast, but are more numerous in those exhibiting the radiological appearance of pattern IV. Such TDLUs usually do not undergo involution and persist during the women's lifetime. The growth of ANDIs is very slow, but they are usually larger than the normal lobules and are about 1-3 mm in size. Some common ANDIs are illustrated in Figure 11.

By further accumulation of fluid, milk, calcium, or epithelial cells within the lumina of the acini and terminal ducts and/or by accumulation of mucin, fluid, inflammatory cells, fibroblasts or other cells within the specialized lobular stroma, the ANDIs may continue to grow even in the absence of adequate hormonal stimuli. This way, an ANDI may become 5-10-20 mm large and palpable. These lesions still represent variations and aberrations of normal morphology, but are also designated with special names. The most common such lesions are fibroadenomas (Fig 12a) and cysts ( Fig 12b). A less common lesion, intracystic papilloma is illustrated in Figure 12c. As these lesions are a result of distension and distortion of the terminal units, their shape is usually regular, spherical or oval.

It is not possible to define any 'cut-off value' for calling a lesion part of the normal panorama of breast tissue or calling it a change, a disease. During screening mammography, for example, the radiologist may see cysts or fibroadenomas very often without calling the patient back to make a biopsy. These are most often clinically silent lesions and the mammography images will be categorized as 'normal findings'. On the other hand, cysts or fibroadenomas of same size and similar characteristics may cause discomfort for the patient and may become palpable. Such cases often represent clinical manifestations needing imaging and/or needle biopsy. In these cases, diagnosing the lesions as fibroadenomas or fibrocystic change is adequate.7

Sometimes many ANDIs are concentrated on a small area and being close to each other they may form a palpable mass. Such tumor forming ANDIs, usually small cysts or lobules with adenosis may simulate invasive carcinoma on mammography. Core biopsy is often needed in these cases to avoid overdiagnosis.7

Another possibility is that the luminal content in the ANDIs becomes calcified. The result may be clustered appearance of powdery or crushed stone-like calcifications on the mammogram. Figures 13a and b illustrate TDLUs with so called lactational change with accumulation of rich secretion within the lumina and calcifications within the secretions. The interpretation of the radiology image in these cases may be problematic as low-grade in situ breast carcinomas may also develop such calcifications.

Small cysts may also contain fluid which is partly calcified as illustrated in Figure 13c. In these cases, the shape of the calcification (round or tea-cup like) may help the radiologists to differentiate these from calcifications indicating malignancy.

Low and intermediate grade in situ carcinomas (Fig. 13d) usually also develop in TDLUs although they may also involve larger ducts. Distending and distorting the lobular units, they may have the same subgross morphological and radiological appearance as the ANDIs.

The sick lobe

Breast carcinoma is a lobar disease as it develops in one of the lobes of the breast in the vast majority of the cases. The sick lobe is mal-constructed already during its embryonic development as it contains an increased stem cell / progenitor cell pool compared to the other lobes of the same breast. These cells are long-lived 'immortal' cells capable of self renewal and differentiation into more mature cells. During their long life, the stem/progenitor cells are exposed to the mutagenic stimuli from the extern or intern environment which, if accumulated, may result in malignant transformation of the cells and in clones of such cells. This theory is designated the theory of the sick lobe.15-18

A large number of observations and studies support this hypothesis. Genetic alterations similar or identical to those in cancer cells have been evidenced in microscopically benign-looking and/or in microscopically totally normal breast tissue.19-21 The field of genetic alterations was shown to occupy a 4 cm area in some cases. In our view, this cancerous field corresponds to an entire sick breast lobe or parts of it. Epidemiological studies evidencing influence of prenatal and perinatal factors on the risk of getting breast carcinoma during the individuals' adult life give support to the idea of embryonic origin of the sick lobe.22 Further, imaging methods, especially magnetic resonance imaging and the special ultrasound technique of ductal echography, may also evidence lobar ("segmental") distribution of the lesions in breast carcinoma in a certain number of cases (Fig 14). Such pattern may also be evident at histological examination of breast tissue if the adequate technique of large sections is used.15, 24 In Figure 15 a case of in situ breast carcinoma is illustrated; the involved ductal system begins within the nipple, branches and spreads over a triangular lobe-like space with basis towards the pectoralis fascia and gives the impression of an involved lobe.

The initial phase of breast cancer development is the so called in situ phase during which a clone or clones of malignant cells appear and gradually replace the normal layer of the epithelium in TDLUs and/or in ducts. The normal breast tissue is characterized by a delicately regulated continuous renewal of the epithelial and myoepithelial cells, the basement membrane and the cells of stroma. In in situ carcinomas, this process is slightly deregulated, the malignant epithelial cells proliferate but the balance between them and the other components is maintained. Thus, during the in situ phase, the malignant process is able to maintain the lobular - ductal architecture of the breast, although the lobules and the small ducts are distended, dilated, distorted if compared to the normal state. The myoepithelium and the basement membrane are also maintained and represent diagnostic criteria in delineating the in situ phase of carcinoma from its invasive phase.17, 25

Further accumulation of genetic alterations results in deregulation of the balance between the epithelial and stromal elements. The cancer cell clone(s) looses the ability of maintaining the myoepithelial layer and the basement membrane. Stromal remodelling takes place with appearance of myofibroblasts and accumulation of collagen. The cancer cells may also mimic stromal elements during their epithelial-mesenchymal transition and to move from the luminal breast compartment into the stroma and into vessels. This way, the malignant process becomes invasive.

The invasive phase represents a late, a more advanced stadium of the malignant process within the breast. Sometimes the process is detected during the in situ phase and becomes stopped with surgical intervention. These cases are designated as purely in situ carcinomas. In some cases, the original in situ component of the tumor becomes destroyed during the progression of the process or is not detected during histological work-up. Such cases are rare and represent purely invasive tumors. The vast majority of breast carcinomas, however, comprise of both in situ and invasive tumor components. Such a tumor is illustrated in Figure 16. The percentages of cases belonging to these three categories of tumors in our material are presented in Figure 17.

The malignant transformation of the cells within the sick lobe takes place decades after the embryonic initiation of the process. Obviously, this very slow process may involve either the ducts or the lobules or both structures within the breast, sometimes simultaneously at the same time, more often asynchronously, with time difference of several months, years or decades, dependent of the number on replications needed for complete malignant transformation of the progenitor cells. As the biological timing of this transformation varies, the morphology of the resulting malignant process is also very variable. Three basic morphological patterns (and many variations of these) seem to exist. Sometimes the malignant transformation happens approximately at the same time affecting the majority of the progenitor cells which are dispersed over the entire lobe; this we designate the 'lobar' pattern which is characteristic of the diffuse in situ carcinomas involving TDLUs and ducts, including also the largest ducts. Sometimes the malignant transformation is restricted to a branch of the largest ducts and to the TDLUs belonging to this duct. This situation is designated as 'segmental' pattern. More often, the larger ducts are not involved at all, the process is restricted to TDLUs, usually to several of them distant to each other. This is the characteristic of the 'peripheral' pattern.

Breast carcinoma in its in situ phase is mostly (in about 75% of the cases) detected because of the appearance of microcalcifications on the mammogram. The type and distribution of mammographic calcifications reflect the basic patterns of malignant transformation within the sick lobe. Localization of the process within the TDLUs results in clustering of microcalcifications, usually in form of multiple clusters. Localization of the malignant process within the larger ducts results in long branching calcifications.7, 8

Histologically, two main types of calcifications can be distinguished: the psammoma-body-like and the amorphous types. While the psammoma-body-like calcifications are regular round particles with concentric rings and represent an early phenomenon in cancer development (crystallization of calcium salts within a calcium-rich secretion), the amorphous calcifications are irregular, appear later during the process and represent dystrophic accumulation of calcium within necrotic debris.1, 2

4. Malignant transformation within the sick lobe

4.1 The peripheral pattern

The peripheral pattern of malignant transformation within the sick lobe is associated with appearance of microcalcifications within the involved lobules in about quarter of the cases. Low-grade in situ carcinomas are usually associated with psammoma-body-like calcification (Figs 18 and 19).7, 8, 26 On the mammogram, these calcifications are like a powder and often are seen at multiple sites. Consequently, appearance of multiple powdery calcifications on the mammogram indicates a low-grade malignant process involving the TDLUs in a peripheral pattern. This observation also has an immediate prognostic relevance, as the mortality in cases of carcinomas associated with powdery microcalcifications is extremely low (Fig. 20).

Importantly, however, psammoma-body-like calcifications may appear not only in low-grade in situ carcinomas, but also in a series of benign processes, including ANDIs, fibrocystic change, involution. Calcifications of this type may be presenting in benign or in malignant structures or in both of them within the same diseased area, and mammographic examination cannot distinguish between these localizations.

A more aggressive malignant process, an intermediate or high-grade in situ carcinoma, distends and distorts the involved TDLUs more rapidly and fills the lumina of the acini with tumor cells and necrotic debris. Amorphous calcium accumulates in this debris in about a quarter of the cases. The shape of individual calcium particles is usually triangular or pyramidal following the shape of the dilated acini.26, 27 A cluster or multiple clusters of such microcalcifications on the mammogram indicates presence of a non-low-grade in situ carcinoma. The pattern of malignant transformation within the sick lobe is still peripheral; the prognosis is relatively good (see Figures 21 and 22).

Microcalcifications of triangular shape may also appear in some benign lesions representing differential diagnostic options. These are illustrated in Figures 22b and 24a-c. The most common of them are fibrocystic change, fibroadenomas and papillomas. It is difficult to distinguish these benign lesions from in situ carcinoma at radiologic examination, but core biopsy is helpful. Histological characterizations of papillary lesions on core biopsy may still be problematic.

4.2 The segmental and lobar patterns

The segmental and the lobar patterns of malignant transformation within the sick lobe are characterized with involvement of the larger ducts. In the segmental pattern, a segmental duct and its branches, in the lobar pattern, the largest ducts including often a single lactiferous duct, are involved. The ducts are dilated because of the accumulation of cancer cells and necrotic debris within the lumen. Calcifications appear in about half of such cases. These calcification represent castings of the ducts, consequently they are long and branching (Figs. 25a-d). These calcifications represent a radiological prognostic parameter indicating decreased overall survival of the patients if associated with invasive carcinoma compared to those lacking calcifications or having calcifications of other types.28, 29

As described previously in this chapter, in situ carcinoma cells involving the TDLUs have the capacity to rebuild the seemingly normal architecture of the breast and to form new, cancerous TDLUs.17 In situ carcinomas involving the ductal tree also have the capacity of maintaining ductal architecture, but only the most aggressive subtypes of the tumor have the potential to form new large ducts. This phenomenon is called neoductgenesis and can be traced both radiologically and histologically.29 The hallmark of neoductgenesis is presence of a large number of ducts, much more then anatomically expected, in a volume unit of the breast tissue. Additionally, at histological examination, the newly formed ducts may be surrounded by lymphocytic infiltration (Fig 26). Accumulation of tenascin c (Fig 27) is characteristic of structures in formation and is seen around the embryonic ducts as well as around the ducts in a duct-neogenetic process. Tenascin is also regularly overexpressed in the stroma of invasive carcinomas.

The prognostic power of the type and distribution of mammographic calcifications is a reflection of the grade and distribution of the underlying pathological process. If only a single TDLU or a group of neighbouring TDLUs are involved, the process should be designated as 'unifocal'. This corresponds to some peripheral and some segmental pattern cases. If the process involves several TDLUs distant to each other with uninvolved breast tissue in between these TDLUs, the process is designated as 'multifocal' (corresponding mostly to peripheral pattern cases). If the in situ process mainly involves the larger ducts, we use the term 'diffuse' to underline the difficulties in delineating and measuring such a process (otherwise corresponding to some segmental and all lobar pattern cases).17, 30

The proportion of cases by distribution of the in situ component is demonstrated in Figure 28. In about one third of breast cancer cases, the process is unifocal in its in situ phase, one third are multifocal already at the beginning, and in about a quarter of the cases, large ducts are also involved (diffuse cases).

As illustrated in Figure 29, purely in situ carcinoma and those having both in situ and invasive components are relatively infrequently associated with calcifications detectable on the mammogram. Only 20% of the unifocal and 27% of the multifocal cases are calcified, compared to 51% of diffuse cases. Thus, the majority of in situ structures within a breast carcinoma remains not calcified and is detected and characterized at histological examination of the biopsied or operated tissue.

Figure 30 demonstrates a clear association between subgross lesion distribution and grade of the in situ component of breast carcinomas. Diffuse in situ carcinomas tend to be of high grade (and associated of casting type microcalcifications on the mammogram) while unifocal and multifocal in situ lesions are more frequently of low or intermediate grade (and tend to be associated with crushed stone- like or powdery calcifications).

Thus, the patterns of malignant transformation of the cells within the sick lobe (peripheral, segmental and lobar) parallel with the subgross morphological distribution of the lesions in the in situ phase of the tumor (unifocal, multifocal or diffuse), which in turn is associated with the type and distribution of the microcalcifications in the calcified cases (powdery, crushed stone-like or casting type). These are only different approaches in characterization of the same malignant process in its initial phase. Such characterization is essential as these subgross patterns are closely related to survival (Figs 20 and 31).

5. Subgross morphological parameters in invasive breast carcinomas

5.1 Tumor shape

As mentioned previously in this chapter, most of breast carcinomas are detected in their invasive phase. Invasion is a complex biological process resulting in interaction of the stroma and the tumor cells. If the stromal reaction is relatively weak, the tumor cells may invade in all directions which results in a spherical (oval) invasive lesion. Such a case is illustrated in Figures 32 a-c.

A more intensive stromal reaction, especially if associated with collagen formation (so called desmoplastic reaction) may prevent invasion of the tumor cells in some directions, while it may allow less limited spreading in other directions. At the same time, retraction of the collagen may distort the normal architecture in the immediate surroundings of the tumor focus. This is the way of developing stellate lesions (a spiculated masses). Such a case is illustrated in Figures 33a-c.

Both spherical lesions and stellate lesions are mass lesions well seen with mammography, at ultrasound examination or at magnetic resonance imaging. In a minority of cases, however, no such mass lesions are present and the carcinoma is detected based on architectural distortion or other radiological or clinical signs. A small proportion of breast carcinomas remain radiologically silent (Fig. 34).

The radiological manifestation of the invasive tumor component in breast carcinoma is also a reflection of the tumor's subgross morphology, like in case of the in situ component. Circular masses on the mammogram may represent not only cancers but also many benign lesions. In fact, among the cases operated for a spherical mass, benign lesions represent a considerable proportion (about one third of the cases in our material). The most common spherical benign lesions are cysts and fibroadenomas (see Fig. 12). On contrary, operated stellate masses are regularly invasive carcinomas (more than 90% of the cases). The only differential diagnostic options are radial scars or postoperative scars (and some extremely rare other lesions) which also may manifest as stellate lesions on the mammogram.

A detailed analysis of the radiological appearance of the mass lesions helps the radiologist in distinguishing benign from malignant masses. The malignant stellate mass regularly has a tumor body ("white star"), may be palpable and show typical shadowing on ultrasound as well as malignant type enhancement on magnetic resonance imaging. Radial scars are often not palpable and typically lack a central tumor mass ("black stars"). The malignant spherical lesions are less circumscribed, usually denser and lack the halo signs contrary to their benign counterparts.

The shape of malignant mass lesions is associated with histopathological tumor characteristics. Medullary breast carcinomas are regularly spherical, like the most examples of mucinous and high-grade ductal carcinomas.1 The more recently delineated so called "basal-like" carcinomas are also spherical in most cases. Their typical appearance is that of a spherical tumor mass with central necrosis / sclerosis. These tumors exhibit a special immunohistochemical phenotype (and genetic construction) expressing antigens typical of myoepithelial cells in the normal breast.31-33 Such a case is illustrated in Figure 35 a-d. Tubular and lobular carcinomas are rarely spherical. On the other hand, metastatic tumors in the breast, and some non-epithelial tumors (sarcomas, lymphomas) are also often spherical.

Stellate masses on the other hand represent most often low-grade ductal, tubular and lobular carcinomas.1 Mucinous, medullary, metaplastic and basal-like carcinomas are rarely stellate.

Figures 36 and 37 demonstrates clear association between the radiological (and subgross morphological) shape of the breast tumor and histological / immunohistological tumor characteristics. The circular (spherical) masses are more frequently high-grade than the stellate tumors.

Stellate masses are very infrequently negative for estrogen receptors and even more infrequently triple-negative (negative for estrogen, progesterone as well as HER-2 receptors). Most of triple negative tumors and basal-like tumors are of spherical shape. Thus, radiological and subgross tumor shape has a prognostic and predictive power indicating the tumors' receptor status and predicting their sensitivity to hormonal therapy.

5.2 Tumor size: early and advanced breast carcinoma

The most powerful subgross morphologic prognostic parameter is the size of the tumor. It is defined as being equal to the largest dimension of the largest invasive focus. Assessment of the size of the tumor is relatively easy in case of invasive foci of spherical shape, but is less reproducible in stellate tumors, and especially in tumors manifesting as architectural distortion. Modern radiology methods, especially ultrasound and magnetic resonance imaging, provide more exact size measurement in several projections. Importantly, only the central body of the tumor should be measured, the extensions in case of a spiculated mass should not be included. Radiological - pathological correlation is essential in assessing the size of the tumor: histological tumor size in a large section taken at the level of largest diameter represents the ideal documentation of the size of the tumor. The frequency of peritumoral vascular invasion as well as the rate of lymph node metastasis increases parallel with the increasing size of the tumor. Figure 38 illustrates an early breast carcinoma while Figures 39 and 40 more advanced tumors.

5.2.1 Early breast cancer

We define early breast carcinoma as purely in situ carcinomas and those with invasive component less than 15 mm.17, 34 Such tumors comprise about 50% of the cases in a population of countries with ongoing regular screening. Among those women who attend screening, this proportion is much higher, about 70%. Patients with such tumors have excellent prognosis, over 90% cumulative 10-year survival. The distribution of the cases with fatal outcome in our material is illustrated in Figure 41.

5.3 Tumor multifocality

In a minority of cases, more than one sick lobe may exist in the same breast. In these cases real multicentric carcinomas may develop asynchronously or at the same time. Much more frequently the tumor develops as multifocal, defined as development of several individual tumor foci within the same sick lobe. Multifocality of the in situ component is a result of involvement of several distant terminal units within the same lobe. The invasive component may also develop as unifocal or multifocal or diffuse.

There are two different mechanism of developing multifocal invasive breast carcinomas. Multiple foci may develop independently from each other from different foci of in situ carcinoma distant to each other, or, similarly, on different sites of a diffuse in situ carcinoma involving large parts of the ductal tree of the sick lobe. In this situation, the rests of in situ component is regularly demonstrable within the invasive areas. Another way of developing multiple invasive foci is a kind of intramammary metastatic spread through the prelymphatic35 and lymphatic channels. In this case, some of the invasive foci lack any in situ component. Hypothetically, this type of multifocality as an expression of intramammary cancer spreading may represent a more advanced disease than developing multiple invasive foci each from an in situ component. Multifocal invasive carcinomas are illustrated in Figures 42 and 43.

Tumors with multifocal invasive component may have a central dominant tumor mass and small "satellite" invasive foci in the near surrounding tissue, but the majority of multifocal tumors lack such a dominant mass and comprise of widespread invasive foci of approximately equal size. Multifocality of the invasive component is associated with increased (approximately doubled) frequency of vascular invasion compared to that in their unifocal counterparts. Likewise, lymph node metastases appear twice as often in patients with multifocal (and diffuse) invasive tumors than in those with unifocal cancers.30 Figure 43 illustrates a case of multifocal invasive breast carcinoma with evident vascular invasion and lymph node metastasis. In Figure 44 we report our results regarding lymph node macrometastases in unifocal, multifocal and diffusely infiltrating breast carcinomas.

5.4. Diffuse invasive growth

Absence of stromal reaction in some invasive carcinomas may result in unlimited invasion of the cancer cells in any direction. The tumor cells permeate the normal structures of the breast without causing obvious distortion of the tissue architecture and without forming a well-defined tumor mass. In such cases, the tumor grows much like a spider's web and is difficult to detect on radiological examination. Such tumors often reach a large size before they become detectable. These tumors are designated "diffuse invasive" breast carcinomas. Invasive lobular carcinomas comprise two-thirds of diffuse invasive tumors. Two such cases are illustrated in Figures 45 and 46.

Diffuse invasive carcinomas are associated with elevated risk of lymph node metastases. The metastatic tumors often exhibit a diffuse growth pattern similar to the primary tumors within the breast (Fig 47a). Although diffuse invasive carcinomas only represent less than 5% of all breast cancers, such cases are overrepresented among those with fatal outcome (Fig. 48).36 It has to be underlined that distribution of the invasive foci (unifocal, multifocal or diffuse) is closely related to prognosis.

5.5. Intratumoral and intertumoral heterogeneity

Breast cancer may originate from different clones of progenitor cells within the sick lobe. Also, during tumor development and progression, new malignant cell clones may appear as a result of additional genetic changes. This may result in presence of genetically, phenotypically and morphologically different cell populations within the same tumor focus, a phenomenon called intratumoral heterogeneity. One such case representing a mixed ductal - lobular carcinoma is demonstrated in Figures 49a and b.

The multiple tumor foci within the same tumor are neither necessarily identical. They may differ in their size, shape, grade, histological type and immunohistological as well as genetic characteristics. This phenomenon is designated as intertumoral heterogeneity and is one of the less studied subgross morphological parameters. Consequently, little is known about its clinical significance but there is a belief that the worst component of the tumor (the largest in size, that of the highest grade or that lacking hormone receptors) determine the prognosis in the individual case. This rule is certainly not without exception. There are studies indicating that summing up the characteristics is more reliable in predicting prognosis. For example, aggregate tumor size (the sum of all the sizes of the invasive tumor foci present) may better correlate with lymph node status and survival that the single size of the largest invasive focus.37 A case of multifocal breast carcinoma showing intertumoral heterogeneity is demonstrated in Figure 50a-c.

5.6 The extent of the disease

As discussed in this chapter, the vast majority of breast carcinomas is complex tumors and contains multiple invasive foci and an in situ component having varying growth pattern. The size of the tumor is a parameter characterizing the largest invasive focus. To better characterize the entire complex process, another parameter is needed called the extent of the disease, defined as the area (volume) of the breast tissue containing all the in situ and invasive malignant tumor foci as well as the intravascular tumor cell groups. This parameter is not identical to the sick lobe, as often only part of the lobe has undergone malignant transformation. Further, already at early stage of tumor development, cancer cells distend and distort parts of the involved sick lobe increasing its original dimensions. In case of a unifocal carcinoma having in situ component only within the invasive area, the extent of the disease is equal to the size of the tumor, however it is a rather uncommon situation. Diffuse invasive breast carcinomas, on the other hand, are easier to characterize with their extent, rather than size.

The extent of the disease is an important parameter determining the type of the required surgical intervention. Tumors of limited extent are proper candidates for breast conserving surgery in contrast to extensive tumors. Definition of the cut-off value is, however, varying in different studies. Faverly et al.38 defined breast carcinoma with limited extent as tumors in which the distance between the individual tumor foci is less than 1 cm. We defined tumor of limited extent as breast carcinoma occupying an area (or volume) 40 mm or less in largest dimension. Such tumors are associated with lower local recurrence rates after breast conserving surgery compared to extensive carcinomas. The extent of the disease is also associated with overall survival of the patients.39, 40 A breast carcinoma of limited extent is illustrated in Figure 51 a and b. Extensive carcinomas are illustrated in Figures 52 a and b, 53 and 54.

6 Conclusions

To properly characterize a case of breast carcinoma, the following morphological parameters should be assessed: the size of the tumor, the distribution of the in situ and invasive components (unifocal, multifocal or diffuse), the extent of the disease and presence of intratumoral and intertumoral heterogeneity. These parameters can and should be adequately assessed with multimodality radiologic examination preoperatively. Adequate histological work-up of the surgical specimen will confirm or modify the preoperative results. Radiological - pathological correlation is essential. All these subgross morphological parameters have prognostic relevance and are clearly related to predictive parameters.