Breast Cancer

After a general learning period of nearly a decade, there is already an important knowledge base about the fundamental primary techniques for managing sentinel lymph node (SLN) detection in the best way.

The international literature makes it clear that early experience was gained in the treatment of breast cancer and malignant melanoma, whereas experience of SLN diagnosis of other primaries is still limited.

Three routes of contrast solution injection (subdermal, peritumoral, intratumoral) have been compared for SLN detection in breast cancer cases, and the intratumoral route, initially used and propagated by Giuliano et al. (1995), Kapteijn (1996), and Nieweg et al. 1997 has now been generally rul ed out by most investigators because of the very real danger of tumor spread that it entails.

Nonetheless, there are still no very precise indications as to how to choose between the subdermal and peritumoral injection routes (see also Chapter 7). Roughly, it seems to be clear that in the case of more superficially located primaries subdermal injection is best, while for those in deeper locations peritumoral injection is more appropriate (see Figs. 1, 2).

This still leaves some questions open, one of these being that of the best method in cancers that cannot be precisely delineated. This requires further experience (see below in this section).

A further question is that of particle size and the quality of the colloid used (see also Chapter 8).

It is clear that the use of very small particles can lead to "spillover" into the lymph nodes downstream of the SLN in the lymphatic stream,

Fig. 1. a Most frequent localization of the primary (upper lateral quadrant). The "mTc-nanocolloid is given in a single subdermal injection. b In cases with deeper localization of the primary the labeling solution is injected in four portions (at the 3, 6, 9, and 12 o clock positions) or as shown in b with the bulk of it directed the same way as the putative lymph flow; that means, most of the tracer solution is injected toward the axilla a few millimeters away from the primary. A second portion can mark the lymphathic flow to the parasternal nodes

Fig. 1. a Most frequent localization of the primary (upper lateral quadrant). The "mTc-nanocolloid is given in a single subdermal injection. b In cases with deeper localization of the primary the labeling solution is injected in four portions (at the 3, 6, 9, and 12 o clock positions) or as shown in b with the bulk of it directed the same way as the putative lymph flow; that means, most of the tracer solution is injected toward the axilla a few millimeters away from the primary. A second portion can mark the lymphathic flow to the parasternal nodes

Fig. 2. Injection profiles differ for various cancers in different organs. For breast cancer the tracer fluid is usually given by the subcutaneous or peritumoral route injection, depending on the depth at which the tumor is located. Most of the tracer fluid should be injected in the suspected direction of flow to the sentinel node(s). This figure shows peri-tumoral labeling in a deeply located primary (four-spot labeling). a The cancer drains exclusively into the axillary lymph nodes. b Left breast with drainage to axillary and mammaria interna (parasternal) lymph nodes. c All four peritumorally located spots of labeled solutions drain to the axillary nodes (cf. a). Arrow subdermal injection over a superficially located primary

Fig. 2. Injection profiles differ for various cancers in different organs. For breast cancer the tracer fluid is usually given by the subcutaneous or peritumoral route injection, depending on the depth at which the tumor is located. Most of the tracer fluid should be injected in the suspected direction of flow to the sentinel node(s). This figure shows peri-tumoral labeling in a deeply located primary (four-spot labeling). a The cancer drains exclusively into the axillary lymph nodes. b Left breast with drainage to axillary and mammaria interna (parasternal) lymph nodes. c All four peritumorally located spots of labeled solutions drain to the axillary nodes (cf. a). Arrow subdermal injection over a superficially located primary whereas bigger particles are held back and are first seen to be stored in the marginal sinuses (Fig. 3). However, when the particles have rather large diameters (>200 mm), the amount of colloid resorbed and transported may be too small. In such cases the sentinels cannot be detected.

Because parasternal lymph node involvement has always been a critical and also an important point, the problem of the subdermal versus the peritumoral injection modality has also been tested in this connection. It has been shown that after subdermal injection much lower parasternal detection rates are obtained than after peritumoral injection. These differences make it clear that we need an individual, case-adapted approach in order to obtain the most helpful results for optimal therapy planning in every single case.

Palpable and Nonpalpable Cancers

It is clear that when the SLN concept is applied it would not be "good practice" first to investigate the excised cancer histologically and not to start the SLN detection program until after the diagnosis has been confirmed. Therefore, the complicated, but meanwhile technically improved, "triple diagnosis" (palpable lesion, high level of suspicion on radiological examination, and cancer cells revealed by cytological investigation) is coming into its own again. With reference to safety, it must be pointed out that radiological methods have vastly improved in both sensitivity and specificity. The additional use of MRI has also improved the success rate.

Analogous progress has been attained in cyto-and histological examinations of smears and minibiopsies of cancers.

Fig. 3. Differences in node labeling when too-small particles are used ("spillover") and normal situation, which is helpful in accurate detection of the sentinel lymph node (SLN)

Therefore, triple diagnosis is a far-reaching and reliable diagnostic instrument, which can also ethically be used to decide whether SLN detection procedures are indicated. This opinion is supported by the fact that this primarily diagnostic principle is still not seen as the basis for a serious operative process such as mastectomy, because decisions in favor of such operations are then based on further histological diagnosis of the primary, following its excision for definitive examinations of the pT value, for example.

The exclusion criteria for performance of the SLN investigation based on triple diagnosis are easy to understand and apply in cases of current or recent pregnancy, mostly when

• Multifocal or multicentric primaries are present.

• Axillary nodes are clinically already positive and immobilized.

• Operations have already been performed on the breast or in the axilla and been followed by extensive scar formation.

In contrast, earlier operations that were not extensive and have been followed by only very focal scar formation or none at all in a quadrant not currently involved seem not to constitute an exclusion criterion for SLN investigations.

Injection in Nonpalpable Breast Cancers

No uniform concept can be established for non-palpable cancers, because quite different biological entities belong to this group.

These cancers can be divided into the following categories:

• Microcarcinomas up to 5 mm or slightly more in diameter

• Intraductal carcinomas with no or with incipient early stromal invasion

• Diffusely growing cancers, mostly small-cell lobular cancers with a high degree of tumor cell dissociation

Figure 4 summarizes important entities classed as nonpalpable breast cancer. All three categories (Fig. 4) can be nonpalpable lesions. As is well known, palpation of such cancers is particularly difficult in the presence of fibrocystic disease, when multiple indurated fibrous nodules can be palpated in so-called shotty breasts.

It must be made quite clear that type A and type B lesions (Fig. 4) are the ones that are most suitable for treatment with sentinel node biopsy, because, as a rule, these are "early cancers." As progress continues to be made in the detection of breast cancer in its early stages by screening programs using mammography and in special cases

Retromammary cancer in the dense tissue, impalpable even microcarcinoma in early stromal invasion

Retromammary cancer in the dense tissue, impalpable even microcarcinoma in early stromal invasion

peripheral partly multifocal lobular cancer

Type A Type 8 Type C

Fig. 4. Important entities classed as impalpable breast cancer. Type A: Microcarcinoma 5 mm or a few millimeters more in size, within fibrocystic disease, especially in a shotty breast. Type B: Retromamillary cancer intraductal peripheral partly multifocal lobular cancer

Type A Type 8 Type C

Fig. 4. Important entities classed as impalpable breast cancer. Type A: Microcarcinoma 5 mm or a few millimeters more in size, within fibrocystic disease, especially in a shotty breast. Type B: Retromamillary cancer intraductal breast cancer or intraductal breast cancer in smaller peripheral ducts, with or without early stromal invasion. Type C: Diffuse invasive lobular cancer with a high degree of tumor cell dissociation (scirrhus)

also MRI the recorded incidence of such lesions is increasing steadily.

Problems in Confirming a Breast Cancer Diagnosis in the Primary Lesions Before SLN Evaluation

The histologically/cytologically confirmed cancer diagnosis and the exact localization of the lesion must be reliably known before a patient is considered for SLN biopsy.

In addition to mammographic and ultrasound investigations for exact localization of the breast cancers, MRI is also very helpful (Heywang-Ko-brunner et al. 2001). In particular, MRI is very helpful in detecting very small tumor foci, sometimes even revealing foci only 3 mm in diameter.

Such small lesions can then be evaluated by ultrasound-guided puncture for cytological investigations and by Tru-Cut biopsies, which are used to obtain coherent tissue cylinders for histological diagnosis (see also Chapters 15 and 20).

In this context, it must be mentioned that classic ductal cancers can be reliably recognized in smears gained by the fine-needle aspiration technique, whereas low-grade breast cancers, especially those belonging to the group of tubular cancers, cannot be definitely differentiated from benign adenosis. In such cases needle biopsies, which allow investigation of the histological pattern, are more useful for confirmation of the malignant invasive process.

In addition, intraductal centrally localized cancers drain cancer cells via the ductal system to the retromamillary milk sinuses. From there, these cells are secreted via the mammilla. These cells or cell aggregates can then be found in smears of the secreted material.

The methods described are generally helpful in cancer diagnosis when the tumors are not palpable (types A and B), but they are perhaps not helpful in type C (Fig. 4), in which the tumor grows quite diffusely with a high degree of dissociation. In these cases, in some of which there is associated lymphangiosis carcinomatosa, sentinel node detection seems not to be an optimal or even a particularly good solution, because these tumors often develop satellite foci and their lymph drainage to lymphatic basins can involve different node chains (axillary, parasternal, interpectoral, sub- and su-praclavicular). The result is that open biopsy and histopathological examination using the frozen section technique during surgery gives us an overview and allows selection of further procedures, which then consist mostly in axillary revision (levels I and II).

Reasons Why the Dermal Injection Procedure is the Most Frequently Used

This is the most frequently used method; problems in cases with deep-seated or medially located primaries are discussed above.

That the subdermal injection method can be used in most cases is confirmed by the fundamental investigations of Grant et al. (1959), who stud ied the lymphatic network of the breast, the subar-eolar circle and the main streams of the lymphatics to the axillary nodes, and also the development of the breast from the predestined cellular potential of the epidermis.

The development of the subareolar plexus of the lymphatics is basic to our understanding that the lymphatic network grows downward as the ductal and peripheral lobular structures develop.

The diffuse anastomosing branches of the network combine into two main lymphatic vessels, one collecting the lymph from the upper lateral and some of the medial parts and the other that from the caudal, lateral, and medial parts of the breast. Both these main strands drain into the axillary lymph nodes. Because of existing anastomosis in many parts, drainage to the parasternal (mam-maria interna) nodes is also possible.

These observations have lately been confirmed by means of lymphangiographic methods. In addition, results recorded in practice are now increasingly confirming the described important anatomical structures that have been investigated and their significance.

It is an important indicator of the significance attaching to the statement that dermal injection is also appropriate for slightly more deeply localized tumor nodes that it has repeatedly been confirmed that the superficial lymphatic network communicates with the deeper lymphatics and that the lymphatic stream from deeper regions goes to the superficial central parts of the breast, because the lymph stream runs parallel to the radial sector and ends in the subareolar lymph circle and then at a conical angle. In this region many factors, including scars, can be responsible for the direction of lymphatic flow, i.e., whether it goes into the axilla and/or into the parasternal node group.

The technique of labeling is as follows:

An injection of 10-15 MBq of "mTc-labeled colloid solution in 0.2 ml is given into the dermal region over the primary.

The syringe is held at an angle of 10-20° to the skin. After the injection, pressing on the injection site with cotton wool is helpful to avoid reflux. In addition, any good adhesive plaster is applied over the injection site.

Peritumoral injection is practiced mainly in the case of deep-seated cancers. The tracer solution is injected into four peritumoral regions: apical, caudal, medial, lateral.

The reduced resorption rate is compensated for by the large volumes of the solution. With 1-2 ml per focal application, the total amount injected amounts to 4-8 ml.

In the peritumoral injection technique quantity is important. Larger volumes extend the anchoring filaments and in this way open the lymphatic vessels at the junction points of the lymphatic en-dothelia (see also Chapter 7).

Krag et al. found that lymphatic uptake increased from 96% to 100% when the volume of solution injected was increased from 4 to 8 ml.

The intratumoral injection route, viewed with some doubt even initially, has now been abandoned as a routine method.

Dermal Injection of Radioactive Colloid in Preference to Peritumoral Administration?

In a multicenter breast cancer study published by McMasters et al. (2001), 229 surgeons were involved in searching for the SLNs; patients with stage T1-2 N0 were eligible.

In all, 2,206 patients, 1,074 of whom received peritumoral injections of tracer, 274 subdermal and 511 dermal injections, were evaluated for detection of the SLNs. In 94% of the patients, peritu-moral injections of blue dye were given in addition to the injections of radioactive colloid. The SLN identification rates were better after dermal injection than after subdermal or peritumoral injection of the radioactive colloid.

Clinically, the most important end-points for comparison were the false-negative rates, which were:

• 8.3% for peritumoral injection

• 7.8% for subdermal injection

For detection of the SLN(s), using the gamma probe five- to seven-fold radioactivity after dermal injection has been found and is interpreted as an advantage in node detection. When we concentrate on SLN detection in the axillary basin and disregard other possible locations (parasternal nodes in central or medial located primaries, or interpectoral nodes in deep-seated cancers), dermal injection gives a significantly better axillary detection rate than peritumoral or subdermal injection.

Table 1. Results of sentinel lymph node biopsy based on injection technique. From McMasters et al. (2001) (SLN ID sentinel lymph node identification)

Injection technique SLN ID SLN ID ratea True positives False negatives False-negative ratef

Radioactive colloid

Peritumoral 965/1,074 89.9% 311 28 8.3%

Subdermal 283/297 95.3%c 94 8 7.8%

Blue dye alone 208/239 87.0%b 63 8 11.3%

a p <0.0001, significant difference among peritumoral, subdermal, dermal and blue dye alone groups, Chi-square; bp = 0.20 vs peritumoral injection, Chi-square; cp = 0.0037 vs peritumoral injection, Chi-square; d p <0.0001 vs peritumoral injection, Chi-square; e p = 0.026 vs subdermal injection, Chi-square; fNo significant differences among peritumoral, subdermal, dermal and blue dye alone groups, Chi-square

Table 2. Summary of radioactive colloid injection techniques from all published literature. From McMasters et al. (2001)

Injection technique

SLN ID rate

False-negative rate

Blue dye alone

79.3%

9.3%

Peritumoral radioactive colloid (with or without blue dye)

88.2%

8.0%

Subdermal radioactive colloid (with or without blue dye)

96.3%

6.4%

Dermal radioactive colloid (present study, 94% with peritumoral blue dye)

98.0%

6.5%

These results are ideal in one way, but on the other hand the reduced frequency or loss of parasternal SLN detection also means there is no further evaluation of these nodes and, depending on the result, leads to the loss of the facultative indication for regional radiotherapy.

In view of the much higher radioactivity in the SLNs after dermal injection, McMasters et al. (2001) calculate that the learning process can be shortened when the dermal injection modality is given preference.

McMasters et al. (2001) summarized their results in a table with their focus on false-negative rates, which helps their readers by providing a quick overview. It is therefore reproduced below. The differences among peritumoral, subdermal, dermal and blue dye alone groups are obvious, but are not significant in Chi-square tests.

In addition, the authors summarized the results of solitary and combined injection modalities using blue dye and/or radioactive colloid published so far in the world literature. This table is reproduced here so that readers can use it as an aide to develop their own optimal strategies for SLN detection in breast cancer patients (Table 2)

The authors' main conclusion, on the basis of their own study results and those recorded in the world literature, is that additive dermal radioactive colloid injection and peritumoral blue dye administration have lower false-negative rates than peritumoral administration of labeling solutions alone.

How To Reduce Acne Scarring

How To Reduce Acne Scarring

Acne is a name that is famous in its own right, but for all of the wrong reasons. Most teenagers know, and dread, the very word, as it so prevalently wrecks havoc on their faces throughout their adolescent years.

Get My Free Ebook


Post a comment