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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Sentinel node detection

, M.D. and , M.D.

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Lymphatic mapping in cancer patients dates back to the early 50ies. The aim of the historic studies had been the detection of potentially infiltrated lymph nodes by indirect visualization in order to determine the extense of the surgical intervention. But the results did not reach relevant clinical significance. During the 60ies and 70ies a concept has been developed, which is based on the selective identification of the representative lymph node(s) of a defined lymph node region as indicator(s) for the status of the whole lymph node region. The first studies using the term “sentinel node” for this lymph node in patients with penile cancer were published by R. Cabanas 1977. Currently, the method has reached clinical application in melanoma and breast cancer patients. Additionally, ongoing studies evaluate the applicability in other tumor entities.

Definition

The Sentinel Node is the first lymph node draining from a tumor. In regard to tumor infiltration it is considered representative for the status of the adjoint lymph node region.

Technique

Two detection methods have been developed, the blue dye technique and the radionuclid method.

The blue dye technique:

  • Intraoperative peritumoral injection of patent blue
  • 10 minutes after injection: incision and dissection along the blue trace
  • selective exstirpation of the first blue stained lymph node(s) and exact examination

Advantage: Minimal technical expense, fast, cheap.

Disadvantage: Relatively extended surgical trauma, needs more experience

The radionuclid-method:

  • Preoperative, peritumoral injection of a radio-labeled albumine-solution (Tc99m) before surgery
  • Lymphoscintigraphic photo after 1 hour and just before surgery to evaluate, if there is one or more sentinel lymph node (“hot spots”) and in which area it can be found
  • Intraoperative detection of the “hot spot(s)” and probeguided, selective exstirpation of the marked lymph node
  • Verification, if the extirpated lymph node corresponds to the “hot spot” and if there are other points of nuclid accumulation in the lymph node area
  • Selective extirpation of other “sentinel” lymph node

Advantage: Easy to learn, minimized surgical trauma

Disadvantage: High technical requirements, expensive, high time expense.

Influence of particle size

It is important to know, that the size of the tracer colloid is crucial for the quality of the transport with the lymph flow and how long it is stored in the lymph nodes. The size of the colloid shows an inverse correlation to the velocity of its transport along the lymphatic channels and a direct correlation to the duration of the storage in a lymph node. There are several substances, which had been used as tracer colloids: In the USA mostly used is Tc 99m-sulfur colloid with an average particle size of about 10 to 50 nm showing a relative fast movement from the tumor to the lymph nodes and a rather fast extraction out of the lymph node along with the efferent flow due to the capability to pass through the vascular epithelial cell gaps requiring an injection time of about 2 hours before surgery. In Germany and Europe widely used are heterogenous solutions of albumine derivates (Nanocoll) with a particle size ranging from 80–200 nm. They undergo phagocytosis by macrophages, show a long storage time in the lymph nodes and the time for the transport from the injection site to the lymph node is longer as for sulfur colloids. They require a longer time period between injection and surgery but offer the possibility of several preoperative y-ca-mera pictures and a constant activity during the operative procedure. For dynamic lymph flow studies, requiring a high transport velocity, pure albumine solutions are used, with a particle size of 3–5 nm.

The largest experience with the sentinel node concept exists for patients with melanoma and breast cancer, where the method is clinically applicated and has already reached influence on therapeutic strategies for certain patient subgroups.

Examination of the SN

In contrast to the routine sectioning and H. E.-staining, that is performed in the standard examination of an axillary specimen, the single sentinel lymph node undergoes intensive histopathologic examination, that could not be performed routinely due to technical, financial and timely reasons. The sentinel lymph node examination includes:

  • Serial sectioning and H. E.-staining
  • Immunohistochemical staining (anti-ck-ab)
  • Potentially RT-PCR assays

The more intensive evaluation by serial sectioning and immunohistochemical staining leads to the detection of about 8–10% additional (“occult”) micrometastases. The effect of RT-PCR assays is not yet determined. First results, however, demonstrate another additional percentage of occult metastases. Longterm studies and further evaluation will have to show, if that kind of “super-staging” has prognostic influence or clinical impact.

SN in melanoma patients

Elective lymph node dissection (ELND) for melanoma patients with a tumor thickness less than 0,75 mm or more than 4 mm is not indicated. The risk of metastases in the first group is very low, whereas the incidence of systemic disease in the second group is very high, so that ELND is not expected to be of value for both groups. In contrast, ELND for patients with intermediate thickness melanoma (0,76 mm to 4,0 mm) is still under debate. The procedure causes remarkable morbidity and costs for node negative patients (about 80%), whereby the benefit for routine ELND in clinically node negative patients is not clear. Nevertheless, it is of major interest to identify the subgroup of node positive patients for the following reasons:

  • The early resection of occult micrometastases may decrease the chance of systemic spread, because there is strong evidence, that the lymphatic spread of melanoma is strongly sequential in most of the patients. Early resection of infiltrated lymph nodes increases the chance of local tumor control.
  • Nodal metastases is by far the most important prognostic factor and may select patients for systemic therapy (e. g. INF).

The sentinel node concept helps to resolve the dilemma by selecting node positive patients for ELND very specifically without causing morbidity.

Since the first study in melanoma patients (Morton et al. 1992), which was the “rebirth” of the SN-concept, it has been shown that in experienced hands, one or more sentinel node(s) can be detected in more than 95% of melanoma patients and the accuracy of the SN in predicting the nodal status of the lymph node region is about 98%. Several centers already rely on the SN-biopsie as indicator for the lymph node dissection.

Current technique of the SN-biopsy in melanoma

Since the first studies the blue dye technique (BDT) has been used in melanoma patients. Recently the combination of the radionuclid method and blue dye technique is becoming the procedure of choice.

  • First, a preoperative lymphscintigraphy with 99mTc-sulfur colloid is performed 2 hours before surgery to determine the location of one or more lymph drainage basins and to make an orientating skin tatoo of the SN for intraoperative orientation.
  • Second, blue dye is injected intradermally in the operation theatre and the afferent blue channel is identified somewhat distal of the tattoo and traced until the first blue node is reached.

Clinical application

Although recent studies demonstrate, that the radionuclid alone produces SN-identification rates similar to the combination of both methods, the BDT remains important, because it helps to distinguish first draining “sentinel lymph nodes” (first-tier or first-echelon lymph nodes) from second-tier or second-echelon lymph nodes receiving the tracer from other lymph nodes.

Recent studies described promising results with the tyrosinase RT-PCR, which seems to be very specific for melanoma and is likely to increase the sensitivity of the tumor detection in the sentinel node in the future. Interestingly, in melanoma patients, who did not undergo lymph node dissection due to negative SN-biopsie and subsequently developed local lymph node metastases (classified as “false negative”), the tyrosinase RT-PCR were positive in a re-examination.

SN in breast cancer patients

With the ongoing introduction of tumor prevention and the increasing sensitivity of imaging procedures, the tumor size at the time of diagnosis has decreased dramatically in the last years. Equally, the rate of nodal negative axillary dissections increased to 70–80% in clinically node negative patients with a tumor diameter between 1 and 3 cm. The sentinel node concept is currently in evaluation to avoid costs and morbidity for this group of patients and to select very specifically the node positive patients for axillary dissection.

After having gained experience with the method, a sentinel node can be identified in 93–98% of the clinically node negative patients with early breast cancer (tumor diameter 0,5–3 cm) and predict the nodal status correctly in 95–99%. Whereas some study groups in the USA (Giuliano et al.) still use the blue dye technique, the radionuclid method, as described above, is the method of choice for most of the study groups in Europe.

In breast cancer “the passthrough” effect in the draining lymph nodes is obviously not as pronounced as it is in melanoma, therefore the phenomenon of second-tier lymph node in breast cancer patients does not seem to require an additional blue dye staining, if the radionuclid method has been successful. Nevertheless, some work groups have recently begun to evaluate a combination of the two methods.

Internal mammary lymph nodes

It has been shown, that extended radical mastectomy with dissection of the internal mammary nodes did not improve longterm survival in large groups of patients with tumors of all sizes. Involvement of IMN, however, is strongly related to axillary node involvement and its prognostic significance is the second most important factor for survival after axillary node status. The expected rate of IMN-positivity in axillary negative patients is about 17–20% and the risk of recurrence or death at 10 years is twofold greater, if the patients receive no adjuvant therapy. Thus, for a certain percentage of IMN-positive/axillary node negative patients with small tumors, the underestimation of the nodal status could lead to a dispense of adjuvant therapy, resulting in a decrease of survival.

For no one would claim the indication for a systematic parasternal dissection in small, axillary node negative tumors, the problem of the IMN-status remained unresolved up to now. CT/MRT or the historic method of indirect lymph scintigraphy were not sufficiently reliable, newer methods like PETscan remain to be evaluated. Even for this problem the SN-concept seems to be a striking logic concept. The experience with these group of lymph nodes is generally low, but previous data showed, that SN-biopsy in this region is feasible. The detection rate, however, is for unknown reasons lower, than expected subsequent to historic studies. Further investigation has to be undertaken in this subject.

Clinical application

After a lot of reproducible, very successful tests of the method, currently, several prospective clinical trials in patients with small tumors up to 1,5 cm are carried out in the USA and Central Europe. Figure 1 shows a clinically applicable algorithm of the SN-biopsy.

Figure 1. Algorithm for the application of the SN-biopsy (IHC: immunohistochemistry).

Figure 1

Algorithm for the application of the SN-biopsy (IHC: immunohistochemistry).

In contrast to melanoma, no reliable, sufficiently specific mRNA markers for RT-PCR assays for superselective staging of the SN have been found yet. Ongoing studies are searching for a multimarker panel.

Further application of the SN-concept

After the promising results of the method in melanoma and breast cancer patients several attempts have been made to transfer the principle into other organ systems. Theoretically all lymph node regions draining from any tumor could be examined for metastatic invasion by the sentinel node concept. Thus, the method may be useful in every cancer where the indication and radicality of the dissection of a lymph node region is indetermined. Beside the studies on penile cancer patients of R. Cabanas in the 70ies, which introduced the term “sentinel node”, preliminary study results have been published in patients with head and neck cancer, thyroid cancer, colorectal cancer, vulvar and endometrium cancer.

Most of these studies used the blue dye technique with intraoperative injection of patent blue around the tumor and visualization of the lymph channels. The feasibility to visualize lymphatic passways intraoperatively could be demonstrated in all the mentioned subgroups of tumor patients, but any subsequent clinically relevant information remains to be demonstrated. The application of the radionuclid method in other than breast cancer and melanoma patients is still limited. It has been published in patients with vulvar cancer and -recently- head and neck cancer patients. In vulvar cancer a clinical application seems to be possible in regard to the indication of lymph node dissection of the groin, whereas the application in head and neck cancer seems to be rather difficult.

Beside this, the use of the yprobe intraoperatively, following preoperative CEA-immunoscintigraphy in patients with colorectal cancer has recently been reported describing an improvement of the staging by detection of distant lymph node metastasis.

Conclusion

The sentinel node is defined as the first lymph node draining directly from a tumor. In regard to tumor infiltration it is considered representative for the status of the adjoint lymph node region. For the SN-detection two techniques are currently carried out: The blue dye technique and the radionuclid method. In experienced hands both methods show very high SN detection rates and an equally high accuracy in the prediction of the nodal status of a lymph node region. In contrast to the blue dye, preoperative lymphscintigraphy provides information about additional or aberrant lymph flow passways, especially important for patients with trunc melanoma and breast cancer patients with infiltration of intramammary lymph nodes. Therefore the radionucleid method alone or in combination with the blue dye technique has become the method of choice up to now. Facing very low false negative rates, the intensive histopathological examination of the SN provides a super-selective staging with an additional 6–10% percent of occult metastases of unknown clinical and prognostic impact. Clinical application of the method under control of prospective studies have been successfully carried out in melanoma patients for several years, and have recently been initiated for patients with early breast cancer (tumor diameter up to 3 cm), too. Ongoing studies are currently evaluating the applicability of the SN-concept in patients with other tumors, for example cancer of the head and neck, thyroid, vulvar and endometrial cancer and colorectal carcinoma.

References

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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6977

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