For optimal sentinel node detection the fluids used must have the following qualities.
· They must be easily resorbed into the lymphatic flow and well transported to the target node, with no resorption or at least with only minimal resorption into the bloodstream (veins and cap- illaries).
· Storage of the fluid (colloid) within the target lymph node must be long enough for clinical, i.e. intraoperative, evaluations, and the period of storage must be correlated with the tracer used.
These demands are at least partly supported by the anatomical structures and correlated physio- logical dynamics (Fig. 1).
With reference to resorption, the fundamental structural differences between the lymphatic and the arteriovenous vascular systems must be seen in the fact that lymphatics are characterized as an ªopen systemº without basement membrane for- mation, whereas arteries, veins, and also capillaries have a well-developed basement membrane. This difference is one of the main factors in the quick resorption of small amounts of fluid in the inter- stitium via the lymphatics and the very small amounts resorbed via the bloodstream. In addi- tion, with the increase in the interstitial pressure after fluid injection, the valves of the lymphatics are opened still more widely and the fluid is com- pressed within the lymphatic system. Because there is no circulation comparable to that of the blood- stream, lymphatic fluid cannot be ªback-wateredº and the lymphatic stream is directed exclusively into the vasa afferentia of the SLN.
Figure 1 demonstrates the structural differences between lymphatics and blood vessels, which are essential for rapid fluid resorption.
On the left of Fig. 1 a lymphatic vessel with a perpendicular course can be seen. On the right a vein (upper part) and a small artery (lower part) are shown. Note the gaps between the endothelia
of the lymphatic vessels, which is essential for rap- id resorption of the interstitial fluid.
Time Schedule
After interstitial injection of labeled fluids resorp- tion via the lymph vessels begins immediately.
Lymph vessels are kept open by anchoring filaments.
Valves support drainage of the fluid towards the marginal sinuses of the regional lymph node.
Early investigations on the lymphatic drainage of the mammary gland were performed by Hult- born et al. (1955). He demonstrated that in most of his patients lymphatic drainage of cancer in- volved the axillary nodes.
Lymphatic Drainage to the SLN 7
Fig. 1. Schematic illustrating the structural differences be- tween lymphatics and blood vessels. On the left a lymphatic vessel with a straight course can be seen, and on the right a vein and a small artery. Note the gaps between the endothe- lia of the lymphatic vessels, which are essential for rapid re- sorption of the interstitial fluid
These facts about special histological features are very important for the understanding of cancer cell drainage and basic to our aim of complete lo- coregional cancer clearance.
Besides the histology and physiology of the lymphatics, it is very important to be informed about the lymph flow pattern in the entire breast.
This can easily be understood with regard to our main intentions of
· Evaluation of lymphatic drainage (to axillary and/or IM nodes)
· N-Staging with the possibility of surgical, pathohistologically controlled locoregional can- cer clearance
· In cases with positive node status, improved possibility of judgment of cancer progression, connected with the indications for chemother- apy and, if appropriate, locoregional radiation therapy
All quadrants can drain into the axilla (Fig. 2a), but centrally and medially located primaries, espe- cially, can also drain to the IM node chain or to the interpectoral and subclavicular nodes (not illu- strated in Fig. 2).
Justification for subdermal injection of the labeled nanocolloids is derived from the knowl- edge that the lymphatics from the deeper parts of the breast drain primarily to superficial (subder- mal) lymphatics and then to the axillary nodes (Fig. 2).
Involvement of the Regional Lymph Nodes in Breast Cancer
Earlier studies focused on drainage of the lymph- atic fluid to regional lymph nodes fell into two types:
· Experimental, performed by using colored fluids or tracer substances and evaluation of second- ary storage after resorption
· Systematic pathohistological examinations of nodes or node groups that must be particularly considered [axilla levels I and II, parasternal (IM chain), in special cases also supra- and in- fraclavicular groups, interpectoral node group etc.)
The percentage axillary lymph node involvement by breast cancer (all cases) and prevalence of in-
volved lymph node(s) (groups and chains) are summarized in Table 1.
Developments in examination of the SLN con- cept have been extended to different primaries and intensified in recent years. As evaluated in the in- dividual chapters in the second part of the book, approaches to various cancer types, including dif- ferent subtypes, have been attempted and at least some strategies based on the results of this are now in routine use.
Qualified application techniques for the tracers have already been defined, and the related lymph- atic basins have also been evaluated.
The results reported in the international litera- ture are summarized in Table 2.
The hypothesis that breast cancer has generally al- ready seeded by both lymphogenic and hematogen- ous routes by the time it is first detected has long Chapter 7 Lymphatic Drainage to the SLN
52
Fig. 2a,b. Topography of the glandular body of the breast from the aspect of lymphatic drainage to the axillary lymph nodes. aBreast parenchyma with lacteal sinuses (1), ducts (2) and lobules (3) [I, II axillary nodes levels I and II; III axillary nodes of the apex (level III)]. b Drainage of lym- phatics from deeper parts of the breast first to the superfi- cial (subdermal) and then to the axillary nodes [1 interlob- ular, 2 interductal lymphatics, 3 primary (red), 4 axillary lymph node (level 1)]
been a constant topic of discussion and has been ac- cepted as true in many hospitals in recent decades.
This assertion is misleading and has led to the ad- ministration of systemic chemotherapy even in the early stages of tumor development and for low-grade, e.g., tubular and mucinous, cancers, on the assump- tion that primary generalization of tumor spread may already have taken place and with the intention of allaying patients' fears about their survival.
However, this assumption does not seem to have been confirmed or supported by results document- ing high 10-year cure rates in N0 cases or in early stages of lymph node involvement (N1 with micro- metastases).
These high cure rates would not be possible if hematogenous spread were present in practically all cases.
The increasing number of publications reporting high cure rates of 85% in N0 cases after 8±10 years' follow-uphas convinced a steadily increasing pro- portion of doctors participating in interdisciplinary breast cancer treatment that the ªprimary systemic disease concept,º which was never accepted by most pathologists, can also no longer be accepted by clin- icians. In Germany it was Kreienberg who first de- clared, in a lecture given at the Congress of the Ger- man Senology Society, that the assumption of sys- temic disease had been an a priori error.
Table 1.Identification rates and rates of metastases in sentinel lymph nodes of breast cancer patients (data partly compiled by B.A.E. Kapteijn, The Netherlands Cancer Institute, 1997)
Author(s) year Patient
no. Injection
modality Patent blue
tracer Size of
primary Identification
rate Rate of me-
tastases (%)
Krag 1993 22 Peritumoral Tracer Not evaluated 82 39
Giuliano 1994 174 Intratumoral Blue dye (patent
blue) Tis 15 mm
T1 104 mm
>T2 55 mm
66 32
Giuliano 1995 162 Intratumoral Patent blue Median
1.5 cm 100 42
Uren 1995 34 Peritumoral Tracer + patent
blue Not evaluated 100 67
Schneebaum
1996 15 Not given Tracer + patent
blue Not evaluated 87 20
Kapteijn 1996 30 Intratumoral Patent blue Mean 2.9 cm 87 38
Meijer 1996 30 Peritumoral Tracer 18<20 mm 100 32
Albertini 1996 62 Peritumoral Tracer patent
blue Mean 22 mm 92 32
Cox et al. 1998 167 Peritumoral Blue dye: Lym- phazurin and
99mTc sulfur col- loid
Invasive breast cancer 17 DCIS cases
31.1 5.9
De Cicco et al.
1998a; for further data see De Cicco et al.
1998b
240 Peritumoral subdermal
99mTc colloid, ad- ditional blue dye in 40 cases with subdermal ad- ministration
T1=71%;
T2=19%;
T3=10%
234/240
=97.5% 45% in 38%
SLN only
Kern KA 1999 40 Subareolar Blue dye isosul-
fan Clinical stages
I±II 38
Giuliano et al.
2000 133 Peritumoral
(around edges)
Vital blue dye:
lymphazurin 1% £4 cm 99 45.6
Nonetheless, there are published results that could indeed support the idea. Schlimok and Riethmçller (1990) found a high rate of cytokera- tin-positive cells in breast cancer cases when they investigated bone marrow smears. Discussion of these results is difficult, because the rate of meta- static involvement of the bone marrow was much lower in autopsy investigations carried out by Eder (1984) than in clinical investigations at the time of initial clinical tumor staging when the primary has been detected and operated on.
Two different possible explanations for this dis- crepancy have been discussed in the literature:
One is that there are cross-reactions to nonneo- plastic cells in the bone marrow, e.g., pre-stages of plasma cells.
The other assumes a balance between slow tu- mor cell growth in the bone marrow and effective immune defense over long periods.
However, neither of these assumptions is com- pletely plausible and no scientifically convincing confirmation is available for either.
In contrast to these discussions, which have not led to any really significant conclusions, a much more convincing point for a primary ªnonsystemic concept,º namely the excellent 10-year cure rates
amounting to 85±87% without any signs of tumor recurrences in breast cancer patients with tumors in early stages at the time of treatment must be emphasized. These results, which are confirmed by a number of publications from many study groups, are the most important and convincing argument against the concept of primary systemic tumor cell spread (ªsystemic diseaseº).
Direct and Secondary Hematogenous Metastasis of Breast Cancer
Besides the characteristic locoregional spread via the lymphatics, breast cancer can metastasize very quickly via the bloodstream.
Initial, direct hematogenous spread via cancer cell invasion of the veins is a well known fact to take place, and its importance has been discussed from many angles. The first organ involved in these circumstances is the lung.
In addition to this, however, the venous blood- stream can also be reached secondarily via cancer infiltration of the axillary sentinel node, with in- volvement of further nodes in the axillary pyramid Chapter 7 Lymphatic Drainage to the SLN
54
Table 2.Lymphatic regions demonstrated by lymphoscintigraphy. [From Ege (1996)]
Injection site Lymph node groups
Breast, gynecology/
surgery Mammary, periareolar Axillary, supraclavicular, upper parasternal
Dermatology Peritumoral, intracutaneous Dorsum of the foot Dorsum of the hand
Chest wall subcutaneous, subperiosteal
Superficial lymphatic at risk
Femoral, inguinal, external iliac, para-aortic Epitrochlear, axillary, supraclavicular Axillary, supraclavicular, upper parasternal Ear nose and throat Buccal mucosa
Orbit Larynx
Jugular Deep cervical
Paralaryngeal, superior/inferior jugular Gastrointestinal Lower esophagus
Gastric cardia Mid-mediastinal, celiac, upper periaortic
Celiac, upper periaortic Gynecology
Surgery Urology
Vulva Rectal
Per anal, ischiorectal fossa Intraprostatic
Inguinal, external iliac
Superior hemorrhoid, inferior mesenteric, per rectal
Internal presacral, obturator, common iliac, para-aortic
Periprostatic, internal iliac Abdominal
Surgery Subcostal posterior rectus sheath Hepatic capsule
Splenic capsule Peritoneal cavity
Diaphragmatic, parasternal, internal mam- mary Ô mediastinal
Right parasternal, mediastinal Splenic hilar
Anterior mediastinal
or primary spread to subclavian nodes. The cancer can then extend to the venous angle (confluence of left jugular and subclavian veins), with invasion of the thoracic duct and drainage into the superior vena cava. In these cases spread via the right atri- um and ventricle of the heart into the lung (Fig. 3a) and from there via the arterial blood- stream into the liver and brain (Fig. 3b) is possi- ble.That invasion of the primary lymphatic path- ways entering the thoracic duct is a preliminary stage of hematogenous metastasis is a little-known but interesting fact. With reference to this possibil- ity, it is clear that blood vessel invasion and trans- port of cancer cells cannot initially be recognized and influenced, whereas lymphatic transport, in- cluding that taking place as a precursor stage of hematogenous metastasis, can be interrupted by locoregional lymphadenectomy (axillary revision, with or without radiation therapy).
Paganelli and his group, in Milan (see Albertini et al. 1996, De Cicco et al. 1998a,b), were the first to conduct extensive investigations into:
· The probability of SLN labeling in breast cancer patients
· The dependence of adequate labeling on the size of nanocolloid particles
· The possibility of labeling nonaxillary lymph nodes, e.g., those in the IM group(different ba- sins)
These important facts can be derived from Fig. 4 a±c, which summarizes the results of these investigation programs.
Is Intraoperative SLN Staging Possible in Breast Cancer Cases?
As long ago as in the 1970s, our groupdeveloped our system of intraoperative axillary node staging in breast cancer cases by staining frozen sections of the nodes and simultaneously investigating im- print cytologies taken from the cut surface of each node (Schauer 1977, 1981). The correspondence between histology and cytology results was 98%.
This method was immediately adopted by numer- ous national and international cooperative groups.
The disadvantage of this strategy (one aim of which is to avoid two sessions of surgery) was that for each case we needed one pathologist, one cyto-
pathologist, and three technicians (two to prepare the histopathological sections and one to stain the imprints).
Fig. 3. aLymphatic spread from the primary (1) to the axil- lary (2) or infraclavicular (3) lymph nodes and from there to the venous angle (4). Spread to the parenchyma of the lung follows (5) with a secondary liver metastasis forming via primary spread into the lung (6).b Cancer cells from a lung metastasis (1) or cancer cells that have flowed through the lung can be transported via the left heart (2) into the brain (3) or the liver (4)
It is interesting to read that the Milan group (Galimberti et al. 2000) has lately tried taking 60 sections from the sentinel node(s) and staining them intraoperatively with the aim of obtaining
immediate knowledge of the sentinel status so as to be able to continue with axillary revision at once in positive cases.
Chapter 7 Lymphatic Drainage to the SLN 56
Fig. 4 a±c.The scale of the three figures demonstrates very clearly:athe classic result of lymph node labeling;bspill- over when the particle size of the colloid is too small;cla- beling of lymph node chains of the basis and the possibility of also labeling sentinel nodes of the mammaria interna group.a Classic case with labeling of a SLN belonging to the axillary node groupon level I in a case with a primary
located in the central part of the breast above the areolar region.bThe number of SLN labeled depends to a high de- gree on the size of the nanocolloid particles. c Note that SLN localization in the internal mammary chain is not only possible in cases with medial primaries, but also in cancers located in the lateral quadrants. (Kindly supplied by Profes- sor Paganelli, Milan)
Their sentinel node detection rate was 98.7%.
Comparison with complete axillary node dissec- tion showed that the sentinel node predicted the axillary status in 96.8% of cases. However, when the intraoperative frozen section method was used the axillary status was correctly predicted in only 86.5%.
The lower rate cannot be tolerated; it can be un- derstood as the result of the Milan group's use, so far, of H-E staining only.
It could be that the introduction of ultrarapid immunohistochemistry (see chapter 17) in the Mi- lan scheme will bring about a considerable im- provement in these results. Technical developments directed at avoiding loss of tissue parts by cutting the tissue to obtain frozen sections and staining a large number of sections immunohistochemically, use of the ultrarapid staining techniques (see Nåh- rig et al. in this book, Chap. 17) and the introduc- tion of scanning methods for fast evaluation of a large number of sections could theoretically help to avoid subjecting patients to two diagnostic op- erations. Even now, however, it seems clear that in- traoperative sentinel node staging will only be- come possible with considerable improvements of the techniques and the introduction of adequate pathological and cytological investigation tech- niques.
References
Albertini JJ, Lyman GH, Cox C Yeatman T, Balducci L, Ku N, Shivers S, Berman C, Wells K, Rapaport D, Shons A, Hor- ton J, Greenberg H, Nicosia S, Clark R, Cantor A, Reintgen DS (1996) Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA 276:1818±1822 Cox CE, Bass SS, Ku NN, Berman C, Shons AR, Yeatman TJ,
Reintgen DS (1998) Sentinel lymphadenectomy: a safe answer to less axillary surgery? Recent Results Cancer Res 152:170±9
De Cicco C, Cremonesi M, Luini A, Bartolomei M, Grana CH, Prisco G, Galimberti V, Calza P, Viale G, Veronesi U, Paganelli G (1998a) Lymphoscintigraphy and radio- guided biopsy of the sentinel axillary node in breast can- cer. J Nucl Med 39:2080±2084
De Cicco C, Chinol M, Paganelli G (1998b) Intraoperative localization of the sentinel node in breast cancer: techni- cal aspects of lymphoscintigraphic methods. Semin Surg Oncol 15(4):268±271
De Cicco C, Sideri M, Bartolomei M, Grana C, Cremonesi M, Fiorenza M, Maggioni A, Bocciolone L, Mangioni C, Colombo N, Paganelli G (2000) Sentinel node biopsy in early vulvar cancer. Br J Cancer 82(2):295±299
Eder M (1984) Die Metastasierung: Fakten und Probleme aus human-pathologischer Sicht (Metastasis: facts and problems in human pathology). Verh Dtsch Ges Pathol 68:1±11
Ege GN (1996) Lymphoscintigraphy in oncology: lymphatic regions demonstrated by lymphoscintigraphy. In: Henkin RE, et al (eds) Nuklearmedizin, vol II. Mosby, St. Louis, pp 1505±1523
Galimberti V, Zurrida S, Intra M, Monti S, Arnone P, Pru- neri G, De Cicco C (2000) Sentinel node biopsy interpre- tation: the Milan experience. Breast J 6(5):306±309 Giuliano AE, Haigh PI, Brennan MB, Hansen NM, Kelley
MC, Ye W, Glass EC, Turner RR (2000) Prospective ob- servational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node negative breast cancer. J Clin Oncol 18(13):2553±2559 Hultborn Larsson L-G, Ragnhult I (1995) The lymph drai-
nage from the breast to the axillary and parasternal lymph nodes, studied with the aid of colloidal AU198.
Acta Radiol 43:52±64
Kern KA (1999) Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg 189(6):539±545
Krag DN, Weaver DL, Alex JC, Fairband JT (1993) Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol 2:335±340
Kreienberg R (1997) Der aktuelle Stand der Brustkrebsbe- handlung. Lecture given at the Congress of German So- ciety of Senology, Berlin, 1997
Paganelli G, De Cicco C, Cremonesi M, Prisco G, Calza P, Luini A, Zucali P, Veronesi U (1998) Optimised sentinel node scintigraphy in breast cancer. Q J Nucl Med 42:49±
Paganelli G, De Cicco C, Chinol M (2000) Sentinel node lo-53 calization by lymphoscintigraphy: a reliable technique with widespread applications. Recent Results Cancer Res 157:121±129
Schauer A (1981) Mammacarcinom. Pathologische Anato- mie in Chirurgie der Gegenwart. Urban und Schwarzen- berg, Munich Vienna Baltimore, pp 6±39
Schauer A, Droese M, Rahlf G (1977) Pathologische Anato- mie des Mammacarcinoms. Langenbecks Arch Chir 345:39±44
Schlimok G, Riethmçller G (1990) Detection, characteriza- tion and tumorigenicity of disseminated tumor cells in human bone marrow. Semin Cancer Biol 1:207±215 Uren RF, Howman-Giles RB, Thompson JF, Malouf D, Ram-
sey-Stewart G, Niesche FW, Renwick SM (1995) Mam- mary lymphoscintigraphy in breast cancer. J Nucl Med 36:1775±1780
