What is Sentinel Node Detection and its Harms?

Sentinel Node Detection: Lymphatic mapping in cancer patients dates back to the early ’50s. The historical studies aimed to detect potentially infiltrated lymph nodes by indirect visualization to determine the extent of the surgical intervention. But the results did not reach relevant clinical significance. During the 60ies and 70ies, a concept has remained developed, which remains based on the selective identification of the representative lymph node(s) of a defined lymph node region as the 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 tumour entities.

Definition

The Sentinel Node is the primary lymph node draining from a tumour. Concerning tumour infiltration, it is considered representative of the status of the adjoint lymph node region.

Technique

Two detection methods have remained developed, the blue dye technique and the radionuclide method.

The Blue dye Technique:

• Intraoperative peritumoral injection of patent blue
• 10 minutes after injection: incision and dissection along the blue trace
• selective extermination 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 Radionuclide-Method:

• Preoperative, peritumoral injection of a radio-labelled albumin-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 remain found
• Intraoperative detection of the “hot spot(s)” and probe guided, selective destruction of the marked lymph node
• Verification, if the extirpated lymph node corresponds to the “hot spot” and if there are other points of nuclide accumulation in the lymph node area
• Selective destruction of other “sentinel” lymph node

Advantage: Easy to learn, minimized surgical trauma

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

Influence of Particle Size

It is essential 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 remains stored in the lymph nodes. The colloid size shows an inverse correlation to the velocity of its vehicle along the lymphatic channels and directly correlates 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 relatively fast movement from the tumour to the lymph nodes and a relatively short 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 heterogeneous solutions of albumin 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 transport from the injection site to the lymph node is longer than for sulfur colloids. They require a more extended period between injection and surgery but offer the possibility of several preoperative y-camera pictures and constant activity during the operative procedure. For dynamic lymph flow studies requiring a high transport velocity, pure albumen solutions are used, with a 3–5 nm particle size.

The most considerable experience with the sentinel node concept exists for patients with melanoma and breast cancer. The method is clinically applicable and has already reached influence on therapeutic strategies for specific patient subgroups.

Examination of the SN

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

• Serial sectioning and H. E.-staining
• Immunohistochemical staining (anti-lock-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. The first results, however, demonstrate another different percentage of occult metastases. Long-term studies and further evaluation will 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 tumour thickness less than 0,75 mm or more than 4 mm remains unknown. The risk of metastases in the first group is shallow, whereas the incidence of systemic disease in the second group is very high so that ELND remains 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 debatable. The procedure causes remarkable morbidity and costs for negative node patients (about 80%), whereby the benefit for routine ELND in clinically node-negative patients is not clear. Nevertheless, it is of significant interest to identify the subgroup of positive node 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 patients. Early resection of infiltrated lymph nodes increases the chance of local tumour control.
• Nodal metastases are the most important prognostic factor and may select patients for systemic therapy (e. g. INF).

The sentinel node concept helps resolve the dilemma by selecting node-positive patients for ELND, precisely 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 inexperienced hands, one or more sentinel node(s) can remain detected in more than 95% of melanoma patients. The accuracy of the SN in predicting the nodal status of the lymph node region is about 98%. Several centres already rely on the SN-biopsies as an indicator for lymph node dissection.

The Current Technique of the SN-Biopsy in Melanoma

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

First, a preoperative lymphoscintigraphy with 99mTc-sulfur colloid remains performed 2 hours before. Surgery to determine the location of one or more lymph drainage basins and make an orientating skin tattoo of the SN for intraoperative orientation.

Second, blue dye is injected intradermally in the operation theatre. The afferent blue channel is somewhat distal of the tattoo and traced until the first blue node remains reached.

Clinical Application

Although recent studies demonstrate that radionuclide alone produces SN-identification rates, Similar to the combination of both methods, the BDT remains essential because it helps distinguish first draining “sentinel lymph nodes”(first-tier or first-echelon lymph nodes). From second-tier or second-echelon lymph nodes. I am 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 tumour detection in the sentinel node in the future. Interestingly, in melanoma patients who did not undergo lymph node dissection due to negative SN-biopsy. And subsequently developed local lymph node metastases. The tyrosinase RT-PCR was positive in a re-examination.

SN in Breast Cancer Patients

With the ongoing introduction of tumour prevention and the increasing sensitivity of imaging procedures, the tumour 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 tumour 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 select the positive node patients for axillary dissection.

After gaining experience with the method, a sentinel node can remain identified in 93–98% of the clinically node-negative patients with early breast cancer (tumour 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 radionuclide 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 not as pronounced as in melanoma. Therefore the phenomenon of a second-tier lymph node in breast cancer patients does not seem to require an additional blue dye staining if the radionuclide method has been successful. Nevertheless, some workgroups have recently begun to evaluate a combination of the two ways.

Internal Mammary Lymph Nodes

It has remained shown that extended radical mastectomy with dissection of the internal mammary nodes did not improve long-term survival in large groups of patients with tumours of all sizes. However, the involvement of IMN is strongly related to axillary node involvement. And its prognostic significance is the second most crucial factor for survival after axillary node status. The expected rate of IMN-positivity in axillary negative patients is about 17–20%. The risk of recurrence or death at ten 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 tumours. Underestimating the nodal status could lead to a dispense of adjuvant treatment. Resulting in decreased survival.

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