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Through pathological examination of excised tumours it is possible to reach a prognosis for an individual patient although there are many aspects that can help to decide this. By far the most important in breast cancer is the stage, or extent of spread of a tumour. Standard staging is from I to IV, which encompasses tumour size and extent of local, regional or distant spread. The higher the stage, the worse the prognosis (table 1.1).

Stage Description 5 year survival

I Tumour < 2cm with no direct

extension or nodal métastasés 84%

n Tumour 2 to 5cm, with or without _{nodal métastasés} 71%

m Tumour > 5cm, or fixed to pectoralis _{muscle or fixed nodes} 48%

IV

Any tumour fixed to chest wall (ribs or intercostal muscles) or involving skin, or distant métastasés

18%

Table 1.1 - Simplified staging based on TNM classification where T= tumour size, N= presence o f axillary nodes and M= presence o f métastasés. [Miller et al., 1994]

There have been many attempts at producing a more accurate prognosis through incorporation of other factors such as histological grade, oestrogen receptor status, proliferative capacity, and lymphatic or vascular invasion. The best validated of these is the Nottingham prognostic index which uses a scoring system for histological grade, oestrogen receptor status, site of initial metastasis (SIMD) and disease-free interval [Robertson et al., 1992]. More recently, there has been much interest in identifying certain genetic abnormalities that have a bearing on tumour growth, such as C-erb B2 (Her-2), epidermal growth factor receptor (EGRF) or p53.

Histological grade is however more widely accepted and understood, and is a measure of the differentiation of a tumour i.e. its resemblance to the original cell type. It is based on quantification of three factors: (1) the degree of glandular differentiation, (2) the degree of nuclear atypia and (3) the mitotic index [Elston, 1987]. Each is scored out of three and the sum of which gives an overall grade where 3 to 5 is well differentiated, 6 to 7 is moderate, and 8 to 9 is poorly differentiated. In general, the more undifferentiated, the more aggressive the tumour, and hence the worse the prognosis.

As pathological analysis becomes ever more sophisticated, further subtyping of tumours is set to continue. Prognostic indicators are undoubtedly interesting from an academic point of view, and are sometimes helpful in directing treatments. However, percentage survival figures for an individual patient based on her tumour characteristics often become meaningless as ultimately at present, survival time depends on good luck rather than any other factor.

1.6 Se n t i n e l No d e s

It has been well validated that the presence of axillary lymph node métastasés is the single most important prognostic factor in women with breast cancer with the overall incidence of axillary metastatic disease approaching 50% [Carter et al., 1989]. This incidence has however been shown to be directly related to the size of the tumour [Walls et al., 1993]. The optimal treatment of axillary disease has always been controversial but through large randomised trials such as NSABP-B04, delayed treatment has been shown to have no effect on overall survival [Fisher et al., 1985].

It is therefore now accepted by most, that surgical removal of non-clinically apparent metastatic nodes is purely for prognostic purposes only.

Axillary lymph node clearance has been the mainstay of surgical treatment for breast cancer until relatively recently. Unfortunately it carries significant morbidity especially when combined with radiotherapy. Such complications range from the relatively minor, such as haematoma, stiff shoulder or parasthesia, to the more debilitating arm lymphoedema. There has therefore been a move to try and avoid such surgery for the 50%+ of patients who are lymph node negative. Initially an effort to achieve this was through lymph node sampling, where only a few lymph nodes were removed (usually 4 or more) from the lower axilla to achieve staging [Steele et al., 1985]. The proponents of this technique demonstrated it to be reliable both for initial assessment of the axilla and also for controlling local disease through the addition of axillary radiotherapy when lymph node métastasés were found [Forrest et al., 1995]. Even more recently however, interest has been directed towards sentinel lymph node biopsy, which aims to detect, remove and histopathologically assess the first node to which a particular breast cancer is most likely to metastasise.

The concept of the sentinel lymph node (SLN) was first introduced by Cabanas in 1977 for the management of penile cancer [Cabanas, 1977] and later by Morton for melanoma [Morton et al., 1992]. The theory is that the first lymph node to receive lymphatic drainage from a tumour should be the first site of lymphatic spread and therefore removal of this node alone should serve as an indicator of lymph node status. Only relatively recently has research been directed into its use for the management of breast cancer. Three main techniques for identifying the SLN in breast cancer have been described:

• Injection of visible dye such as patent blue or isosulphan blue to outline the lymphatic vessels and lymph nodes during surgery.

• Lymphoscintigraphy following local injection of radionuclide (usually technetium-99m-labelled antimony sulphate or colloidal albumin) to pre- operatively map lymphatic drainage.

• Local injection of radionuclide and use of a hand held gamma probe during surgery to help direct dissection.

The main concerns with sentinel lymph node biopsy (SLNB) are the possibilities of failed detection of the correct lymph node and therefore false negative biopsies i.e. the sentinel node is negative but other axillary nodes are positive. It also cannot be assumed that the if the sentinel node is negative, the remainder of the nodes will be negative, as the presence of ‘skip lesions’ have been well documented [Roche et al., 1997] i.e. normal level 1 nodes but metastatic level 2 or 3 nodes. This may simply be due to abnormal lymphatic pathways. Such aberrant drainage channels may become better understood as experience in lymphoscintigraphy accrues. To test the efficacy of each method of detection, initial study designs included routine axillary dissection following SLNB. Some investigators have suggested that using a combination of both blue dye and radioisotope can increase the yield and accuracy [Hill et al., 1999]. A recent review of various trials however, suggested that scintigraphy and/or use of a gamma probe was much more accurate than blue dye alone. The optimum method however was a combination of dye and radioisotope techniques [McIntosh and Purushotham, 1998]. Numbers of patients however were generally smaller than in the Hill study. The findings of this review are summarised in table 1.2. Experience of all of these techniques is still fairly limited and it is clear that there is a definite learning curve for the surgeons involved, but undoubtedly with further experience, these figures can only improve further.

Further support for SLNB lies within the ability to target the most important nodes for thorough histological analysis. Detection of lymph node métastasés has until recently relied mainly on standard single sectioning and H&E staining. It is clear however that multi-sectioning and the addition of immunohistochemistry techniques can identify otherwise occult métastasés. The importance of such micrometastases has been hotly debated but a recent review article concluded that conventional techniques will underestimate nodal involvement and patients with micrometastases have a reduced overall survival [Dowlatshahi et al., 1997]. As these techniques are expensive and laborious, it is impractical to assess every excised axillary lymph node in this way. SLNB therefore offers the chance to focus valuable resources at

thorough assessment of one or two nodes only. The small false negative rate of SLNB may therefore be compensated for by the increased detection of otherwise occult disease. Technique Number o f studies Detection rate (mean) False negative rate (mean)

Blue dye alone 5 66-92% (73.8%) 0-17% (11.4%)

Gamma probe alone 2 82-98% (90%) 0% (0%)

Scintigraphy and gamma probe 4 69-98% (88.3%) 0-5% (2.8%)

Scintigraphy and/or gamma probe + dye

6 92-100% (93.7%) 0-15% (4%)

Table 1.2 - summary o f SLNB studies

At present, no centres in the United Kingdom are routinely using SLNB. However, a substantial number of breast surgeons have gained enough experience in the technique to progress past the learning curve, with detection rates approaching 100% and 1% or less false negative rates. The next stage therefore is to test the safety of treating patients on the basis of SLNB alone. To this end, randomised trials are shortly about to commence where adjuvant treatment will be based either on SLNB or standard axillary node dissection. Providing there is no difference in disease free or overall survival between the two groups, SLNB will undoubtedly become routine, especially as the morbidity from this procedure should be considerably less when compared to a full axillary dissection.