Breast Cancer 21

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Development of the Sentinel

Lymph Node Concept (Initial Approaches)

There is some controversy about whether or not general axillary dissection has an influence on survival rates. In the National Surgical Adjuvant Breast and Bowel Project no. 4, it was concluded that axillary dissection was worthless in terms of any positive influence on survival rate. However, contradictory results were recorded by Dewar et al.

(1987) and Moore et al. (1996).

Veronesi et al. (1985, 1993) estimate that, according to the experience so far available, information on metastatic involvement of the parasternal lymph nodes can be obtained in 1±9% of cases by means of radiodiagnostic sentinel lymph node (SLN) investigation. The concept of (a) ªkey lymph node(s)º in incipient metastasis, the so-called sentinel lymph node(s) has been reactivated since 1993 (Mazzeo et al. 1986; Krag et al. 1993, 1998a;

Giuliano et al. 1994, 1995, 1996, 1997; Silverstein et al. 1994; Albertini et al. 1996; Statman et al. 1996;

Chadh et al. 1997; Haffty et al. 1997; Nathanson et al. 1997; Pijpers et al. 1997; Veronesi et al. 1997;

Offodile et al. 1998), when several groups tried to define the lymph node that had a direct connection to the primary.

The high proportion of patients who underwent axillary revision without any findings of metastasis into the axillary nodes intensified the search for new possibilities. This is now more urgent than ever before, because among patients whose cancer is diagnosed as the result of early cancer detection programs the rate with a node-negative status is increasing steadily.

Recent data show that in approximately 90% of cases the sentinel nodes in breast cancer are localized in the lower axilla. However, in less than 10%

[8% in the report of Krag et al. (1998)] they can be localized outside the axilla, in the lateral area of the glandular part of the breast. Whereas the so-

called Sorgius lymph node with localization in the marginal area of the breast is a well-known localization of breast drainage from lateral breast parts, the extra-axillary SLNs seem to be located further cranially or within the breast. These facts of extra- axillary and marginal mammary localization are important in planning of the surgical procedures.

This is in keeping with the advice we have long been giving: that the marginal area of lateral breast parts should also be checked for lymph nodes and, in the case of a subcutaneous mastectomy, the subcutaneous tissue should be eliminated from medial operation sites up to the marginal area of the pectoralis major muscle. The localization of hot spots at level II helps (in 4%) in operative clearance of the axilla (Krag et al. 1998) and confirms the frequency of skipmetastasis, which according to our own experience is approximately 3%.

Under these conditions SLN labeling seems to be important as a way of helping surgeons to find the first regional lymph node(s). To determine and find a direct connection with the primary is an additional goal for surgeons, because in cases with discontinuous extirpation of primary and lymph node(s), homogeneous postoperative radiation therapy may not be fully sufficient for tumor clearance. Tumor cells can then grow out of lymphatic vessels that have no connection with lymph nodes postoperatively.

Nowadays, radiodiagnostic N-staging of breast cancer is performed by ultrasonography (US) or CT. Especially in the axillary region, US has a high sensitivity, whereas the specificity, like that of CT, remains unsatisfactory. New approaches are ¹⁸F- FDG-PET (see also Chapters 5 and contributions by Avril et al. in chapters devoted to different cancer types) and the systemic application of Sinerem (see also Chapter 20) in breast cancer to evaluate all lymph nodes involved in drainage of the breast. Un- published data have shown a higher specificity than shown by the earlier diagnostic results specified above, but no definite data have yet been reported.

Breast Cancer 21

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Is SLN Biopsy Indicated in Every Case with Suspect Lesion(s) of the Breast?

Figure 1 gives a rough answer to this question.

It must be emphasized that vacuum biopsy (Mammotome, Fischer) is only indicated in the presence of moderately suspicious small lesions to exclude cancer [BI-RADS (Breast Imaging Report- ing and Data System) 3].

It should not be used in the case of highly suspicious lesions (BI-RADS 4); in such lesions primary excision seems to be much more appropriate, as this makes it possible to avoid opening blood vessels by the vacuum procedure. Fine-needle aspiration cytology (FNAC) would also be far less traumatic.

Complications After Axillary Revision ±

an Argument for Limitation to Sentinel Biopsy Alone?

It is easily understood that surgeons like to avoid performing axillary revision, in view of the different complications that can follow, such as those that can result from prolonged general anesthesia, development of postoperative seroma or bleeding, inflammatory processes with secondary abscess formation, areas of hypoesthesia, and painful neuromas; according to Larson et al. (1986) the complication rate with development of edema of the arm was 28%

when more than ten axillary lymph nodes were re- moved. However, these complications, which have also been mentioned by Headiuk et al. (1992) and Maunsell et al. (1993), can be avoided or successfully

Fig. 1.Implications of the sentinel node concept in cancer

screening and in surgical treatment of putative early cancer cases. *Further discussion of axillary revision depending on result of sentinel lymph node (SLN) investigation

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clinically treated to a high degree at least in some cases, and they do not compare with the problems of possibly incomplete operative tumor clearance after sentinel node biopsy alone and subsequent ir- reparable local and generalized tumor progression.

Therefore, when the sentinel node concept is prac- ticed, extreme care and a high quality of the work- ing procedures performed by nuclear medicine spe- cialists, surgeons, and pathologists are absolutely vital, as is good cooperation.

Skip Metastasis

The sentinel node concept is closely connected with the problem of skip metastasis. According to the literature, the rate of skipmetastasis (leaving out the first node without metastasis formation or bypassing the first node), was approximately 3%

in earlier investigations. Similar results are also published in the current literature [Koller et al.

(1998): 3.6%; Sandrucci and Mussa (1998): 4.6% in T1-2N0 breast cancers].

Are Performance and Success of the SLN Biopsy Dependent on the Tumor Stage of the Primary?

In view of the uncertainty of physical examination of the axilla, the SLN concept is increasingly fa- vored by physicians. The question is: Where is the ªstarting pointº for sentinel node biopsy in early lesions and where are the limits of applicability of the concept when lesions are more extensive?

At present, the following statements can be given:

· For ductal carcinoma in situ (DCIS) cases with minor extension upto 2.5, exclusion of sentinel node involvement should be recommended, because minimal invasion not suggested by the specimens of the primary lesion is possible and an SLN examination with negative results is safer. In the case of more extensive lesions SLN examination now seems to be obligatory, especially in high-grade types.

· All investigators agree that in invasive breast cancers the accuracy of findings corresponds to the degree of extension of the primary. Accord- ing to Giuliano et al. (1997), it is highest in lesions <10 mm in size, with 100% accurate prediction, and is much higher in pT1 and early

pT2 tumors than in pT3 or pT4 cancers (Graves et al. 1996; Cox et al. 1998a,b; O'Hea et al.

1998; Reuhl et al. 1998).

The identification of tumor-involved SLN also seems to influence adjuvant therapy in patients with pT1a, pT1b, and favorable pT1c tumors. It may also change the type and dose of chemothera- peutic regimens prescribed, especially in cases with pT1c tumors (Ollila et al. 1998).

When breast cancer is staged, there is no point in SLN detection in cases with:

· Large tumors when a metastatic process must be assumed on the basis of clinical examination;

· Massive lymphangiosis carcinomatosa;

· Inflammatory cancer;

· Multicentric cancer in many cases.

Primary- and Lymph Node-detecting

Radiodiagnostic Systems Besides Mammography and Ultrasound

Value of MRI for Cancer Detection and Injection Sites of the Nanocolloid Solution

In most cases with breast cancer, the findings es- tablished by palpation or mammography, sometimes complemented by ultrasound, are sufficient for more or less exact cancer localization and determination of the tumor margins.

However, in some cases the cancer cannot be exactly located and cannot be delineated in the periphery, especially in breasts with higher density of the parenchyma. In such cases MRI is the most appropriate method to support accurate determination of the exact cancer localization and its extension and, in special cases, to confirm multifocality or multicentricity and locations of DCIS or EIC [Fischer et al. 1993, 1996a; Orel et al. 1995;

Heywang-Kæbrunner and Beck 1996; Abraham et al. 1996; German Roentgen Society 1996; Mumatz et al. 1997; Hrung et al. 1999; Heywang-Kæbrunner et al. 2001; the participating centers in the different countries (Germany, United States, United Kingdom, Sweden, The Netherlands, Belgium) are listed in Table 1].

These facts are of great importance for local subdermal or peritumoral (not intratumoral!) ad-

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ministration of the labeling solution injected for SLN(s) detection.

The international investigation project on breast MRI, concerning diagnostic parameters for contrast-enhanced MRI (Heywang-Kæbrunner et al.

2001), has yielded valuable advice about more accurate delineation of cancer and of EIC foci, etc.

Therefore, this method should be used in addition to US and mammography for more exact ªla- beling strategies.º The cited study correlated results of various examinations carried out in 519 histopathologically certified lesions and provided fundamentals for improved standardization and optimized interpretation guidelines for contrast- enhanced MRI.

The patients had standardized dynamic MRI on a Siemens 1.0- or 1.5-T appliance using the 3D fast low-angle shot (Flash 87s) technique before and five times after a standardized bolus of 0.2 mmol Gd-DTPA/kg.

The best results were obtained by combining up to five wash-in or wash-out parameters. Different weighting of false-negative versus false-positive calls allowed to define a statistical interpretation for the highest possible sensitivity (specificity 30%) for moderate (50%) or high (64±71%) specificity.

The sensitivities at the above-mentioned specificity levels were better, at 1.0 T (98%, 97%, or 96%) than at 1.5 T (96%, 93%, or 86%).

In the search for milestones along the way of future use of MRI in our diagnostic concepts concerning breast cancer, the important aim of stan- dardizing dynamic contrast-enhanced MRI was re- alized by this study. The results provide an additional fundamental basis for further clinical development of the SLN concept. This conclusion is of fundamental importance, because the contrast labeling solution needed for determination of the SLN(s) should be administered s.c. in superficially located palpable primaries, but must be injected exactly peritumorally, avoiding intratumoral injection, in the case of more deep-seated cancers. In these cases imaging systems, including MRI, are helpful in attaining precisely placed administration of the nanocolloid solution for SLN.

Table 1. Researchers and institutes involved in the Interna- tional Investigation Project on Diagnostic Parameters in Contrast-enhanced MRI of the Breast

S.H. Heywang-Kæbrunner, Department of Diagnostic Radiology,

Section Mammography, University Clinic/

Technical University, Ismaninger Street 22 81675 Munich, Germany

U. Bick, Department of Diagnostic Radiology, Westphalian Wilhelms University, Mçnster, Germany

W.G. Bradley Jr., Memorial Medical Center,

Long Beach, California, USA

B. Bon, Department of Diagnostic Radiology, Huddinge University, Stockholm, Sweden J. Casselman, Department

of Diagnostic Radiology, A.Z. St. Jan, Brugge, Belgium

A. Coulthard, Department of Diagnostic Radiology, Royal Victoria Infirmary, Newcastle, UK

U. Fischer, Department of Diagnostic Radiology, Georg August University, Gættingen, Germany

M. Mçller-Schimpfle, Department of Diagnostic Radiology, Eberhard Karl University, Tçbingen, Germany

H. Oellinger, Department of Diagnostic Radiology, Rudolph Virchow University Clinic, Charit Berlin, Germany

R. Patt, Department of Diagnostic Radiology, Georgetown University, Washington, D.C. USA

J. Teubner, Department of Diagnostic Radiology, Mannheim Clinic, Heidelberg University, Heidelberg, Germany

M. Friedrich, Department of Diagnostic Radiology, Urban Hospital Berlin, Germany

G. Newstead, Faculty Practice Radiology, New York University, New York, New York, USA

R. Holland, Department of Pathology, University Hospital Nijmegen, Nijmegen, The Netherlands A. Schauer, Department of

Pathology, Georg August University, Gættingen, Germany

E.A. Sickles, Department of Radiology, University of California, San Francisco, California, USA

L. Tabar, Falun Central

Hospital, Falun, Sweden J. Waisman, Department of Pathology, New York University,

New York, New York, USA K.D. Wernecke, Institute

of Medical Biometrics, University Charit, Berlin, Germany

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Role of PET in Breast Cancer Staging N. Avril, W. Weber, M. Schwaiger Value in the Different pT Stages

Initial studies involving patients with advanced disease found FDG-PET to be highly accurate in detecting primary breast carcinomas (Wahl et al.

1991; Adler et al. 1993). In the largest series so far, involving 185 breast tumors, Avril et al. (2000) identified primary breast cancer with a sensitivity ranging between 64.4% for conservative image reading (CIR: only definite FDG uptake regarded as positive) and 80.3% for sensitive image reading (SIR: either definite or probable FDG uptake regarded as positive) (Fig. 2a±c). The increase in sensitivity (SIR) resulted in a noticeable decrease in specificity, specifically from 94.3% (CIR) to 75.5% (SIR).

In stage pT1 (<2 cm), only 30 (68.2%) out of 44 breast carcinomas were detected, as opposed to 57 (91.9%) out of 62 in stage pT2 (2±5 cm). In the

false-negative group, invasive lobular carcinomas were overrepresented (34.8%) relative to invasive ductal carcinomas (11.3%).

This difference can be explained by the frequent primary multifocality and the diffuse often scirrhous growth pattern with abundant collageniza- tion of the cancerous region(s).

Multicentric breast cancer is an important limitation for breast-conserving therapy. Even when SIR was applied in the above study, only 9 (50%) out of 18 patients with multifocal or multicentric breast cancer were identified. Overall accuracy in detecting noninvasive breast cancer was low, with a sensitivity of 25% (CIR) and 41.7% for SIR.

Although the number of patients in this study was small, the data suggest that detection of in situ carcinomas may not be improved by PET imaging.

Only 3 out of 53 benign breast masses presented with intense tracer uptake, suggesting that FDG- PET has a high positive predictive value, with increased FDG accumulation indicating breast cancer. Only 1 out of 9 fibroadenomas showed increased tracer uptake. Moreover, dysplastic tissue,

Fig. 2a±c.Breast carcinoma. aTransaxial PET image of the upper thoracic region. There is an area of focally increased metabolic activity in the right breast, representing an invasive ductal carcinoma.bLymph node metastases in left axilla and mammaria interna region. Transaxial PET image of the axillary region. There are areas of focally increased metabolic

activity in the left axilla and the mammaria interna region, indicating breast cancer metastases.cAxillary lymph node metastases. Coronal PET image of the body. There are multiple foci of increased metabolic activity in the right axillary region, indicating lymph node metastases

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which often accounts for false-positive results in MR imaging, mostly showed little or moderate and diffuse FDG uptake.

Value of PET in Staging: Conclusions Derived from Positive and Negative Results

in Axilla Staging

All available radioimaging systems (ultrasound, MRI, PET) are incapable of detecting incipient lymph node metastasis with loosely spread cancer cells or cancer cell clusters or even micrometastases. This statement also applies to the application of FDG-PET in cases with tiny incipient metastases.However, studies performed in recent years allow the conclusion that FDG-PET provides the highest diagnostic accuracy of all noninvasive diagnostic methods in axillary lymph node staging (Smith et al. 1998; Crippa et al. 1998).

But, with view to the introductory remarks PET:

· Is no substitute for histopathologically based lymph node staging.

· Cannot give a significant answer to the question of how many lymph nodes are involved in the metastatic process.

Therefore, SLN labeling and the subsequent histopathological examination of the node(s) cannot be fully substituted by PET.

In these conditions, the demonstration of cancer infiltration of one or more regional lymph nodes by PET makes the clinical search for the SLN(s) useless.

In conclusion, in cases with positive lymph node(s) in PET staging, axillary lymph node revision can be performed immediately without following the SLN concept. Conversely, when PET- based investigations give a negative result the SLN concept can be started.

PET Screening Investigations for Sentinel Node (Axillary) and Systemic Metastasis

in Breast Cancer Patients

Only positive results have any relevance for further diagnostic procedures and for further therapeutic efforts.

This means that additional sentinel node labeling procedures involving blue stain and/or ^99mTc labeling for detection of the sentinel node(s) can be avoided and thus also that in cases with positive parasternal nodes adjuvant therapeutic regimens should be performed.

Wahl et al. (1991) investigated 12 patients with advanced breast cancer and also noted increased FDG uptake in axillary metastases.

Nieweg et al. (1993) showed metastatic lymph node involvement in the axilla in 5 out of 11 patients studied, the smallest lymph node visualized with PET being 0.8 cm in diameter. In 18 patients, Adler et al. (1993) reported a sensitivity of 90%

and a specificity of 100% for axillary PET imaging.

Nine of 10 cases with positive results on axillary node dissection had positive PET scans. In a more recent study the authors investigated 50 patients with breast cancer prior to axillary lymph node dissection (Adler et al. 1997). The sensitivity and negative predictive value were both 95%, and the overall accuracy was 77%. The only false-negative PET scan was obtained in the largest patient, whose scan was of a low quality. However, SIR resulted in 11 false-positive PET findings with a specificity of 66%.

Similar results have been reported by Crippa et al. (1998). Avril et al. (1996) studied 51 patients by PET and found an overall sensitivity and specificity in detection of axillary lymph node metastases of 79% and 96%, respectively. When only the patients with primary breast tumors larger than 2 cm (>stage pT1) were taken into account the sensitivity of axillary PET imaging increased to 94%, with a corresponding specificity of 100%.

Lymph node metastases could not be identified in 4 out of 6 patients with small primary breast cancers (stage pT1), giving a sensitivity of only 33%

in these patients. These results indicate that the detection of micrometastases and small tumor-in- filtrated lymph nodes is currently limited by the spatial resolution of PET imaging. PET imaging did, however, provide additional information in 12 (29%) of 41 breast cancer patients, demonstrating

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axillary involvement at level III (located medial to the border of the pectoralis minor muscle), peri- clavicular and retrosternal lymph node metastases, and bone and lung metastases.

Moon et al. (1998) found whole-body PET imaging extremely accurate in patients with suspected recurrent or metastatic breast carcinoma.

By patient, sensitivity and specificity were 93%

and 79%, respectively, the corresponding positive and negative predictive values being 82% and 92%.

By lesion, the sensitivity was 85% and the specificity 79%. With bone metastases there was a significantly higher proportion of false-negative lesions than with other nonosseous malignant sites. False- positive lesions were due to muscle uptake (n=5), inflammation (n=4), blood pool activity in the great vessels (n=2), bowel uptake (n=1) and unknown causes (n=6). Lonneux et al. studied 39 women with suspected breast cancer recurrence (Lonneux et al. 2000). PET-FDG located 37 out of 39 sites in 31 out of 33 patients with recurrence, whereas conventional imaging identified sites of recurrence in only 6 out of 33 patients. PET missed 1 locoregional recurrence, and in 1 patient it failed to detect peritoneal carcinomatosis, which became clinically apparent 6 months after a negative PET scan. False-positive results corresponded to lung infection, degenerative bone disease, and reconstruction artifacts. In 75 patients with suspected recurrent or metastatic disease, FDG-PET correctly identified 16 patients with local recurrence, 28 with lymph node involvement, 15 with bone, 5 with lung, and 2 with liver metastases (Bender et al. 1997). CT/MRI identified 10 patients with local recurrences, 17 with lymph node involvement, 6 with bone, 5 with lung, and 1 with liver metastases. In addition, FDG-PET detected 6 local recurrences, 8 lymph node, and 7 bone metastases which were not visualized by CT/MRI.

In conclusion, owing to the limited sensitivity of PET in the detection of small tumors, its use in the screening of asymptomatic women for breast cancer is not advisable. Furthermore, negative PET findings in patients presenting with palpable breast masses or abnormal mammography do not necessarily exclude breast cancer. This suggests that the number of invasive procedures performed may not be significantly reduced by the currently available metabolic imaging techniques. However, in patients with advanced breast cancer, FDG-PET,

because of its high positive predictive value, is par- ticularly useful in determining the extent of disease. In this subgroupPET identifies locoregional lymph node metastases with great accuracy. Detec- tion of micrometastases and small tumor-infil- trated lymph nodes is limited by the spatial resolution of PET imaging, which should be improved in the future. Whole-body PET imaging is very accurate in detecting patients with recurrent or metastatic breast carcinoma. PET imaging has been found to be very valuable for monitoring the ef- fects of preoperative chemotherapy. Assessment and prediction of the response to therapy are possible sooner than with any other method. There- fore, even allowing for its limitations, PET imaging is still a valuable tool in the management of breast cancer patients.

Can the ACR-BI-RADS Lexicon Influence the Choice of the Most Adequate Device for Removal of the Breast Lesion?

A. Schauer, V. Schauer

Partly by analogy to pathologists scaling of prein- vasive and early invasive neoplastic breast lesions (atypical ductal hyperplasia, ductal carcinoma in situ and early invasive breast cancer), the Ameri- can College of Radiology (ACR) has tried to devel- opa Breast Imaging Reporting and DATA System (BI-RADS) lexicon based on significant features as a basis for international comparative studies.

This lexicon discriminates five categories of lesions:

· Categories 1 and 2 raise no suspicion of malignancy

· Category 3 probably benign, but malignancy cannot be definitely excluded

· Category 4 suspect abnormality

· Category 5 highly suggestive of malignancy (see Table 2)

A few impressive case reports may demonstrate the value of the BI-RADS classification for better interdisciplinary communication, especially with respect to judge the risk and plan adequate further diagnostic and surgical treatment procedures.

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Case Histories J Case 1

This 63-year-old patient (Fig. 3a±d) had no suspicious lesions on physical examination. Mammogra- phy revealed a very dense glandular body with multiple microcalcifications. These were partly sin- gular and partly grouped, but mostly roundish with the ªteacupº phenomenon. Malignant densities were not detectable. The additional ultrasound investigation depicted several cysts. In conclusion, there were no regions suggestive of malignancy;

rather investigations suggested fibrocystic disease.

The lesions were classified as BI-RADS III and a further checkup in 3±6 months was advised.

J Case 2

In a 50-year-old patient a microcalcification was found in the retromammillary region on left-sided digital mammography in a craniocaudal (cc) pro- jection (Fig. 3e,f). Regular mammograms showed a constant result over some years.

J Case 3

A 70-year-old woman was admitted to hospital when the onset of neurological symptoms was noted. The initial diagnostic examinations confirmed bleeding within a brain metastasis from an unknown primary (CUP).

During the search for the primary, mammo- graphic investigation of the right breast showed a dense glandular body with no suspicious densities or microcalcifications (Fig. 4a). Cutis and subcutis were not thickened. The lesion was classified as BI-RADS I.

The left breast also showed very dense retromammillary tissue. In the lower inner quadrant there were several groups of microcalcifications ar-

ranged in a roughly Y-shaped configuration along course of the ducts (Fig. 4b). They were classified as polymorphous lesions highly suggestive of DCIS and Bi-RADS IV.

The histological diagnosis was focal DCIS (large cell, high grade) with stromal invasion.

One year after breast-preserving surgery, the patient underwent mastectomy because she had an ªin-breast recurrenceº.

J Case 4

This 61-year-old patient had calcifications classified as BI-RADS IV. Left-sided digital extended mammography showed retromammillary microcalcifications (Fig. 4c,d). Histological examination led to a diagnosis of DCIS.

J Case 5

A 54-year-old woman came into the out-patient clinic for screening. Inspection and palpation of the breasts did not disclose any suspicious lesions.

Mammography revealed a roundish density in the left upper outer quadrant, with a mostly sharp shape except at the lower lateral side (Fig. 5a). Lit- tle irregularity was seen. In the additional ultrasound investigation the lesion was unequivocally identified as a cyst. The classification was BI- RADS II.

On the right side the tissue was very dense. In the upper middle part there was a group of micro- and macrocalcifications, some of which were roundish and others rather long and thin (Fig. 5b). The classification was BI-RADS IV.

After needle marking of the right upper middle region and operation the histological examination led to a diagnosis of fibrocystic disease with microcalcifications.

Table 2.Discordance between BI-RADS and histological result with regard to categories 4and 5 and to device used for tissue sampling

BI-RADS category Frequency of cancer Discordance between imaging and histopathology

Discordance between 11-G vacuum biopsy and other devices

Discordance rates not significant for masses

5 43.8% 4.8% 1.7% vs 6.8% 3.78% vs 2.7%

413.7% 2.6% (P<0.001) P =0.44

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Fig. 3. a±dMammography pictures recorded in a 63-year-old woman with a dense glandular body and multiple, mostly roundish microcalcifications suggestive of fibrocystic disease (BI- RADS III).e,fMicrocalcifications categorized as BI-RADS III in a 50-year-old patient, which gave a constant result on repeated mammographies over many years:eMicrocalcification in the retromammillary region seen in left-sided mammography in a craniocaudal pro- jection;fWith zoom activated regional arrangement of monomorphous calcifications is shown more precisely (e,fsee p. 186)

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Fig. 3e,f(Legend see page 185)

Fig. 4. a,bDense glandular tissue on the right side without any suspicious focal lesions (BI-RADS I) in a 70-year-old woman. In the lower interior quadrant of the left breast several polymorphous microcalcifications were seen, some of them in groups (BI-RADS IV). Histological investigation revealed high-grade ductal carcinoma in situ (DCIS) with mi-

croinvasion.c, dCalcifications categorized as BI-RADS IV in a 61-year-old patient. c Left-sided digital extended mammography showing microcalcifications in a central retromammillary region. dWith zoom activated a more precise analysis of the segmentally arranged polymorphous calcifications is possible. Histological examination revealed DCIS

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Fig. 4c,d(Legend see page 186)

Fig. 5a,b.Mammography of a 54-year-old woman with cys- tic density in the left upper exterior quadrant (BI-RADS II).

In the upper middle part of the right side line-like micro-

calcifications are seen (BI-RADS IV). Histological investigation showed fibrocystic disease with microcalcifications

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In training programs tested in the Ukraine (Leh- man et al. 2001) the initial mean baseline sensitivity, specificity and positive predictive values were 50%, 77%, and 43%, respectively. In conclusion, the authors stressed that the ACR-B1-RADS lexicon provides a systematic and efficient method of training radiologists to improve their interpreta- tional skills in the evaluation of screening mammograms.

Liberman et al. (2000), at Sloan±Kettering Can- cer Center, tried to evaluate the significance of BI- RADS in routine clinical work. The results of their studies are summarized in Table 2. The average imaging±histology discordance amounted to 3.1%.

In discordant cases the authors recommend surgical excision because there is a high cancer risk (24%) in such cases.

Wedegartner et al. (2001), using the ABBI system, had a cancer rate of approximately 22% in their series, while the positive predictive value (PPV) for BI-RADS-based indications for surgical excision in categories 4and 5 was 31%.

The authors conclude from their results that the use of BI-RADS should be mandatory in mammo- graphic evaluation. This is an important point, not least with regard to the choice of the most suitable biopsy system for the individually adapted diagnostic procedure.

Kim et al. (2001) analyzed 82 patients, 68 of whom had carcinoma. According to the BI-RADS lexicon, 61% of their lesions were classed as category 5, 35% as category 4and 4% as category 3; this means that 93% of the cases with malignancies were classified as highly suggestive of malignancy.

When Obenauer et al. (2001) evaluated vacuum biopsy specimens from 86 cases with BI-RADS category 3 lesions they found the spectrum of entities detailed in Table 3.

Sentinel Node Localization in the Different Node Groups

The distribution of lymph node metastases in the different node groups and their frequencies relative to each other had already been intensively investigated by many clinical research groups many years before sentinel node research started.

Partly with orientation on Veronesi's results (1993) and partly on the basis of our own results and those reported in the international literature, the rates of involvement in possible metastatic spread are summarized in Table 4.

Figure 6 illustrates the various possible localizations of the SLN(s): the most frequent is within level I of the axillary node group, while a location among the lateral paraglandular nodes is rare; a further possibility is among the parasternal nodes. The po- sition of the sentinel node(s) can be detected by the methods already described. The nodes are excised and investigated histologically and immunohisto- chemically in serial sections. Only parasternally localized sentinel nodes are generally not excised.

However, when these are found to be the sentinels, this node group is irradiated postoperatively.

Table 3. Lesions described histologically and diagnosed in vacuum biopsies

Fibrocystic disease 67 cases 78%

Papillomas 4cases 4.7%

Fibroadenomas 4cases 4.7%

Atypical ductal hyperplasia

(ADH) 4cases 4.7%

Ductal carcinoma in situ

(DCIS) 3 cases 3.5% (one

minimally invasive)

Table 4.Distribution of lymph node metastases in breast cancer cases (all pT stages) in the different basins Axillary

nodes levels Iand II

Paraglandu-

lar nodes Parasternal

(mammaria interna) nodes (according to literature)

Mammaria interna nodes as basin according to labeling with^99mTc nanocolloid^a

Interpector-

al nodes Two basins

75% 6±8% 20±28% 9%^a 2% 7%

aThe frequency of labeling marks only the basin, and does not indicate metastatic involvement in comparison with the percentages in the other columns

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Four Regions of Interest for Lymph Node Investigation Using Different Cartridges in MRI Evaluation

To achieve the best possible investigation of the different node groups, especially in MRI imaging, separate cartridges are necessary.

The fields for separate investigations be clearly delineated, as demonstrated in Fig. 7.

Confirmation of Breast Cancer Diagnosis Before Sentinel Node Labeling and Extirpation for Analysis Together with the Primary

According to our present state of knowledge it is clear that before the sentinel node labeling procedure is started, the diagnosis of breast cancer for the primary should be confirmed. Otherwise, the complicated sentinel node detection procedures would have to be regarded critically in view of the stress they impose on the patient with the injection of blue dye stains and a radioactive substance.

Because of these facts, and also because of the high personnel and pharmaceutical costs involved, these new procedures cannot be seen in the same light as operations on mammographically unclear lesions with the cancer detection rates ranging from 4:1 to 2:1 seen 10 or 15 years ago.

Therefore, the preoperative diagnostic programs using different radio-imaging systems and histo- and/or cytopathological methods that do not harm the local structures must give a clear-cut diagnosis of malignant epithelial cancer of the breast. This means that the diagnosis can only be made by aspiration or needle biopsy in smears or very small biopsy cylinders (see also Chapter 16).

The main point in this connection is that the cancers and the peritumoral structures should not be harmed. These statements are in keeping with the recommendation that if possible no attempt should be made to label sentinel nodes by peritumoral application of the labeling solution after surgical excision of the primary. In contrast subdermal application seems to be possible.

In DCIS, it is difficult to make a decision in fa- vor of sentinel lymph node examination. It de- pends on many factors.

· DCIS cannot be detected with a high degree of certainty by mammography in the early stages.

In contrast, in a retrospective analysis published by Viehweg et al. (2000), the majority (96%) of DCIS lesions showed contrast enhancement in MRI, with a 50% rate of so-called typical enhancement behavior.

· Because there is no infiltrative cancer, it is difficult to obtain significant material by fine needle aspiration cytology preoperatively.

Fig. 6.Demonstration of the different possible localizations of the SLN(s).

The most frequent is within level I (1) of the axillary node group. Occasion- ally they are among the lateral paraglandular nodes (2). They can also be in parasternal nodes (3)

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· As a rule, at least, it is not possible to exclude the presence of invasion.

In these circumstances, it must be stated that the radio-imaging systems (mammography, MRI) and their results are the strongest indication available that we have to suppose DCIS is present.

The question of whether or not SLN(s) should be excised in DCIS cases is more or less an individual therapeutic problem and must therefore be discussed with the patient (informed consent).

A rough rule can be accepted as a guideline for discussion:

· If histological examination of the primary lesions leads to the diagnosis of DCIS without any signs of invasion and the lesion is micropapillary and low grade, and if the process does not extend to more than 2.5 cm and the margins are free, lymph node excision can be avoided.

± However, a higher degree of safety can be achieved by removal and histological examination of the sentinel node(s). This has to be pointed out, because in rare cases lymphatic spread has been observed already to have taken place even in this category.

± When in sentinel node-positive cases no invasion has been found in serial sections of the primary DCIS lesion, it is necessary to exclude multifocality or multicentricity.

· When the histopathological diagnosis is DCIS (large cell) with high-grade malignancy, what- ever the extension the SLN (s) should be excised and subjected to histopathological examination as described in Chapter 10.

± In discussions with the patient it must be made clear that such solutions are compro- mises and it is impossible ever be absolutely certain about phase-shifted multicentricity;

recurrences can still occur later and develop into invasive cancers before being detected.

Sentinel Node Labeling in Microcarcinomas or DCIS Not Ascertained Preoperatively

There are two main options:

· In microcarcinomas or cases of less extensive DCIS one option would be to label the sentinel nodes before excision, by subdermal or peritumoral administration of the ^99mTc-nanocolloid solution, and to excise the suspect lesion and the sentinel node in a single operative session.

Fig. 7.Demonstration of the four regions of interest for preoperative radiodiagnosis. The anatomical delineation of the different groups allows the development of specific cartridges for: (a) The most frequently involved axillary node

groups (levels I±III); (b) the paraglandular group; (c) the interpectoral group (the target group in rare cases of deep, prefascial localized cancers; (d) the parasternal nodes, involvement mostly in central or medical localized primaries

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· A second option would be to excise the focus that is suggestive of microcarcinoma or DCIS in order to confirm the diagnosis histologically and control the margins, and then to label the sentinel nodes by subdermal or subareolar injection using^99mTc-nanocolloid-solutions prepa- ratory to their excision in a second operative session. This option seems to be correct for primary lesions with locations that are not too deep.

Cytological Examination of Nipple Secretion Can Confirm a Diagnosis of Ductal Cancer (Support for Prelabeling Cancer Diagnosis)

It must be recommended that every mammillary secretion is cytologically evaluated. Even the ap- pearance of the secretion can give information about its origin and quality. In the case of bleeding the most important differential diagnoses are papillary lesions, such as a papilloma, or papillary intraductal cancer or cancer that is already invasive.

If cancer cells are detected further diagnostic procedures are indicated and must be instituted immediately without fail.

In brownish yellow secretions cytopathologists often find vital or necrotic cancer cells as part of a ductal, especially comedocarcinoma or a papillary cancer. A clear or white secretion is not very rare and is associated with secretory stimulation, but cancer cannot be excluded (cytopathological examination of the smears).

Factors that Influence the Frequency of Lymphatic Metastasis and Block Lymphatic Drainage

Breast cancer diagnosis and further developments in the SLN concept must be seen in relation to the pTNM system and the most important prognostic parameters, such as tumor size, degree of malignancy and lymph node status.

The tumor size (pT) in well delineated cancers is determined by measurement of the native cancer tissue, the longest diameter being measured.

In diffuse and growing cancers that are not well delineated, slices of the suspect areas are investigated histologically, which is an opportunity to measure the most widely extended tumor forma-

tions plus 10%, to allow for shrinkage processes caused by formalin fixation. Note that diffuse, often scirrhous, growing cancers or primarily multi- focally developed lobular cancers with confluence of the disseminated foci must be emphatically delineated from so-called diffuse growing inflammatory cancers, because different therapeutic regimens are obligatory, and because

· There is a high prevalence of hematogenous metastasis in inflammatory cancers.

· Lymphatic metastasis cannot be definitely evaluated, because of the low significance and wide extension of the lesion, blockade of the subdermal lymphatics by cancer cells, and inflammation.

Inflammatory cancers are rare, so that the problems associated with it have a secondary role in daily routine work. More importance in daily work attaches to the question of the implications of the pT values and the dependence of the search for sentinel node(s) on pT stage.

Two questions are of interest with regard to the search for sentinel node(s):

a) The increasing frequency of lymphatic metastases with rising pT value

b) The increasing blockade rate with increasing pT value.

Ad a) The frequency of regional lymph node metastasis increases from pT1a to pT3 from approx.

20% to approx. 70%. The rates related to the different stages are listed in Table 5.

Ad b) The rate of blockade of lymphatic drainage and the pattern of the preferred new drainage pathways is largely unknown, but it must be concluded that when the drainage to the parasternal nodes is blocked, drainage to the subclavicular and interpectoral nodes increases.

Histopathological, Immunohistochemical, and Molecular Biological Examination of the Primaries ±

Significance for the Sentinel Node Concept

It is important and necessary for cancer subtyping to precede application of the sentinel node approach. E.R. Fisher (personal discussion) was one of the first authors to express very clearly that

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some subtypes of breast cancer have an excellent prognosis.

In life-tables of a collective of 1500 patients, those with the following subtypes had a near-90%

survival rate:

· Tubular type of breast cancer (Fig. 8)

· Mucinous subtype (Fig. 9a,b)

· Invasive (micro)papillary subtype (see Fig. 10) These subtypes are demonstrated in Figs. 8±10.

Tubular cancers show far reaching isomorphism of the cancer cell nuclei, so that partly difficulties ex-

ist at first view to delineate these cancers from adenosis. They are nearly always grade I cancers and not connected with unfavorable prognostic factors like c-erbB2 overexpression, expression of mutated p53, vimentin coexpression etc.

In our studies (German Breast Cancer Study Group) of low-risk cancers the rate of tubular cancers was 12-fold that found in an unselected pT1N0M0 collection.

Mucinous cancers are conspicuous by their mucus formation, which is sometimes difficult to as- sess in frozen sections but is easily detectable when stained with PAS reaction or Alcian Blue.

From the aspect of nuclear grading they mostly give the impression of being grade I or II cancers, but biologically they behave mostly in the same way as grade I tumors (Fig. 9 a,b).

Cancers with Unfavorable or Incalculable Prognosis Large-cell high-grade types of breast cancer (often invasive ductal cancers, comedo type, with c-erb B2-(p185) overexpression (Fig. 11) and diffuse infiltrating scirrhous cancers (Fig. 12), some with intensively developed lymphangiosis carcinomatosa, show fast cancer progression with hematogenous metastasis or locoregional cancer infiltration (breast wall, pleura etc.), respectively.

Therefore, this subtype is mostly not suitable for a SLN search, because

· Subdermal or peritumoral labeling, as usual, is hardly possible because there is no peripheral delineation.

Table 5. Increasing rates of lymph node metastasis referred to the different pT-stages of breast cancers.^a (SEER data from NCI [Survival in Epidemiology and End-Results pro- gram, 1989])

Stage Diameter Percentages of

axillary node involvement pT value

pT1a <0.5 cm 20.6%

pT1b 0.5±0.9 cm 20.6%

pT1c 1±1.9 cm 33.2%

pT2 2±2.9 cm 44.9%

3±3.9 cm 52.1%

4±4.9 cm 60%

pT3 >5 cm 70.1%

aIn an overview of the literature, Witt et al. (2002) stated that the frequency of axillary involvement in the pT1a stage given in the literature varies from zero to 28%

Figs. 8, 9.Breast cancer types with excellent prognosis, in which the SLN search helps to avoid extended axillary revision (levels I and II)

Fig. 8.Tubular cancer: in most cases grade I, very low mitotic activity, nearly regularly homogeneous hor- mone receptor equipment. In nearly all cases there is no axillary lymph node metastasis. Therefore, search for and investigation of SLN are highly valuable

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Fig. 9a, b.Mucinous breast cancer.

aMostly a cancer of the elderly, this type is sharply delineated, so that on mammography it can be misinterpreted as a fibroadenoma.bHistopathology of mucinous cancer: Tubular or solid cancer cell formations swim in secreted mucus (Alcian blue stained) (AFIP pic- ture). In most cases grade I±II with low mitotic activity and positive for steroid receptors; search for SLN therefore highly valuable

Fig. 10.Micropapillary low-grade breast cancer showing gracile intraductal papillary cancer cell proliferation with only low to moderate nuclear polymorphism and a low rate of mitosis. The invasive parts of the cancer show identical cellu- larity

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· In extensive cancers mastectomy must generally be performed.

· Because of breakout through the lymph vessels and nodes full axillary revision is generally indicated.

Tumor Typing by Different Pathologists

We have to realize that primaries with diameters of 1±2 cm have already undergone a relatively high number of spontaneous mutations based on genetic instabilities, leading to subclones with different phe- notypes. However, as a rule these changes do not change the fundamental subtype, which is related not only to growth pattern but also to nuclear struc-

ture, cell size and other criteria. Accordingly, the classification of breast cancers according to the WHO (1982) seems to be absolutely practicable.

It must be emphasized that the main type, namely the ductal invasive cancer with mostly solid growth pattern, also termed as type ªnot otherwise specifiedº (NOS), can generally easily be confirmed, even when parts of the tumor show adenoid structures, because these have nothing to do with a tubular cancer as a specific subentity of breast cancer, which is nearly always a grade I cancer (Fig. 8).

In addition, grading of solid ductal cancers is also not influenced by the existence of adenoid (tubular) structures, because in multivariate analysis of the individual grading criteria: polymorph- Fig. 11.Infiltrating large-cell breast cancer (grade III) with high degree of cancer cell dissociation. Simultaneous immunohistochemical double staining:

(a) for Ki67 (MIB I): more than 50% of the cancer cells are in the proliferative compartment (brown-stained cancer cell nuclei) and (b) for p185 transmembrane protein [=oncoprotein of c-erbB2 (HER/

neu) (red-stained cancer cell mem- branes, arrows)

Fig. 12.Scirrhous structures in cancer (subtype of solid ductal, sometimes also lobular, cancers) can often hardly be delineated in the periphery of cancer growth. These cancers often infiltrate the subepidermal structures (peau d 'or- ange) and frequently metastasize early to the regional lymph nodes

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ism, mitotic activity, tubule formation, both polymorphism and mitosis rate, have been found to be of much higher significance than gland formation.

Medullary cancer is a special entity with regard to:± Radioimaging (mammography, MRI)

± Histopathology and

± Biological behavior.

Medullary cancers are well delineated in the periphery and can therefore awake the impression of fibroadenomas on mammography and MRI. Histo- pathologically, they show a solid growth pattern al- most without exception, and as a rule they develop in a prelobular site. Cytological examination re- veals large nuclei with central large nucleoli; the mitotic activity is generally high. Therefore, most of these cancers are graded as grade-III tumors.

Lymphocytic infiltration can have developed and may be intensive, but is also sometimes absent (Fig. 13).

Biologically, in the first 5 years after surgery, in spite of the high mitotic activity medullary cancers have a similar or slightly better outcome than the main groupof ductal invasive cancers (NOS). After 5 years, however, their survival rates are somewhat worse. These patients' lesions enhance strongly on MRI. See also subsection ªDuctal Carcinoma In Situº by V. Schauer and A. Schauer in this chapter.

Lobular Breast Cancers: Care Multifocality, Multicentricity, Bilaterality and Wide Variability in Biological Behavior in Relation to the Sentinel Node Concept

Lobular cancers mostly account for 10±14% of all breast cancers in the different statistics published (Schauer 1981).

They become apparent as destructive processes in the lobular fields of the pre-existing glandular structures (deletion). This deletion process with preserved innocent-seeming ducts in the tumor areas already gives a first hint indicating the right direction to go in to reach the correct diagnosis.

An ªIndian fileº pattern of tumor growth is a second important feature, but solid and tubuloalveo- lar growth patterns are also possible.

In this connection, it must be pointed out that the ªball-likeº growth pattern, especially, is quite helpful in the diagnosis, as well as the Indian file pattern.

Because of the isomorphism of the cancer cells, which is sometimes far reaching, some tumors are classed as grade I cancers, but basically these cancers are known mostly to behave in a similar way to grade II cancers.

Fig. 13.Invasive medullary cancer with large nuclei, prominent nucleoli, and pale nuclei. Note intensive lymphocyte infiltration of the cancer. In sentinel node labeling procedures no special re- strictions are necessary. Subdermal labeling is possible, but so also is distinct peritumoral labeling with an optimal distance of 4±5 mm from the mostly sharpdelineated cancer nodule