sentinel lymph node biopsy in melanoma patients: methods...

621MEDICINA (2003) Vol. 39, No.7 - http://medicina.kmu.lt

Sentinel lymph node biopsy in melanoma patients:methods, indications, and clinical significance

Vygintas Kaikaris, Skaidra Valiukevičienė1, Rytis Rimdeika, Harald Gollnick2, Jens Ulrich2

Department of Plastic Surgery, Clinic of Surgery, Kaunas University of Medicine Hospital,1Clinic of Dermatovenerology, Kaunas University of Medicine, Lithuania,

2Department of Dermatology, Otto-von-Guericke University, Magdeburg, Germany

Key words: sentinel lymph node biopsy, melanoma, micrometastases, lymphatic mapping,hand-held gamma probe.

Summary. The incidence of melanoma in Lithuania has doubled over the last decade.Sentinel lymph node biopsy, currently becoming a standard method in the US and Europe,is a minimal invasive and highly sensitive surgical procedure. It can be used for the detectionof melanoma micrometastasis in regional lymph nodes in cases when non-invasive methodsfail to reveal them. Both disease-free survival and disease-specific survival were significantlybetter for patients with a negative sentinel lymph node biopsy. A. Breslow thickness, W. H.Clark level, and ulceration of the melanoma were strong predictors, but not as strong as thehistological status of the sentinel lymph node. The procedure for sentinel lymph node biopsyis nowadays standardized, including preoperative dynamic lymphoscintigraphy combinedwith intraoperative gamma probe guidance and blue-dye injection.

The aim of this article is to present an update of the sentinel lymph node biopsy methodand the prognostic significance of this procedure on the basis of more than 400 sentinellymph node biopsy’s carried out at the Department of Dermatology of the Otto-von-GuerickeUniversity, Magdeburg since 1997 and the results of recently published studies in theliterature.

Correspondence to V. Kaikaris, Department of Plastic Surgery, Kaunas University of Medicine Hospital, Eivenių 2,3007 Kaunas, Lithuania

IntroductionA rapid increase in the incidence of melanoma

among Caucasians has been observed in most coun-tries of the world (3). The incidence of melanoma inLithuania has doubled over the last decade, while thegeneral incidence has amounted to 5.5 cases per100,000 inhabitants per year and reflects the globalsituation on a lower level (1).

Despite several efforts in the treatment of malig-nant melanoma, surgery remains the standard of care.An excision of the primary tumor with prognosis-adapted margins is recommended worldwide as a ba-sic therapeutic approach (2).

In Lithuania UICC classification (1998) is still used(Table 1). The new American Joint Committee on Can-cer (AJCC) classification and a new melanoma stag-ing system, which became official in 2002, includesfive major changes (Table 2). (1) The level of inva-sion (Clark’s level) is replaced by tumor thickness asthe prognostic variable of primary tumor invasion thatbest predicts survival, (2) ulceration of primary tumoris incorporated into the staging system, and patients in

each T stage subgroup are upstaged, (3) the size oflymph nodes is replaced by the number of lymph nodesinvolved in the N staging, (4) patients are categorizedinto clinical and pathologic staging to incorporate lym-phatic mapping data and micrometastatic disease withinlymph nodes, and (5) subcategorization of stage IVmetastatic disease is based on anatomic site and in-clusion of an elevated serum LDH.

When the primary tumor is 1-4 mm in thickness,the probability of metastatic spread in the regional lymphnodes rises up to 20-25% (4). In the presence of high-risk primary tumor, elective lymphadenectomy (ELND)was recommended earlier. These operations resultedin a removal of 15-20 clinically unchanged regionallymph nodes that were believed to be possibly invadedby tumor metastasis. According to the data of severalretrospective studies, ELND had a significant impacton the overall survival only in subgroups of melanomapatients (6-8). In contrast, prospective randomized trialswere not able to demonstrate prolonged survival dueto received ELND (5, 9, 10). Having in mind that in80% of the patients who had undergone ELND no

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Clinicial Thickness (depth) of the tumor Probability of five- stage year survival

I pT1 (≤0.75 mm and/or Clark level II) N0 M0 95–85 %.pT2 (0.76–1.5 mm and/or Clark level III) N0 M0

II pT3 (1.51–4.0 mm and/or Clark level IV) N0 M0 70 %III pT4 (>4.0 mm and/or Clark level V) N0 M0 50 %

any pT N1, N2 M0 <30 %IV any pT any N, M1 <5–10 %

pT – pathological thickness (depth) of the tumor measured in mm according to Breslow or Clark level: I –tumor spread only in the epidermis; level II – the tumor infiltrates a part of the papillary layer of the dermis;level III– the tumor invades papillary-reticular dermal interspace; level IV – the tumor invades the reticulardermis; level V – the tumor invades the subcutaneous tissue, N0 – no regional lymph node metastasis, M0 –no distant metastasis, N1 – metastasis more than 3 cm or less in the greatest dimension in any regionallymph node, N2a- metastasis more than 3 cm or less in the greatest dimension in any regional lymph node,N2b - in-transit metastasis, N2c (N2a+N2b), M1 – distant metastasis.

Table 1. Five-year survival probability of patients in relation to the clinical stage of cutaneousmelanoma (3)

Stage Clinical staging* Pathologic staging**

0 Tis, N0, M0 Tis, N0, M0IA T1a, N0, M0 T1a, N0, M0IB T1b-2a, N0, M0 T1b-2a, N0, M0IIA T2b-3a, N0, M0 T2b-3a, N0, M0IIB T3b-4a, N0, M0 T3b-4a, N0, M0IIC T4b, N0, M0 T4b, N0, M0III any T, N1-3, M0 –IIIA – T1-4a, N1a-2a, M0IIIB – T1-4a, N1b-2b, M0

T1-4b, N1a-2a, M0T1-4a/b, N2c, M0

IIIC – T1-4b, N1b/2b,M0,any T, N3

IV any T, any N, M1 any T, any N, M1

*Clinical staging includes microstaging of the primary melanoma and clinical/radiological evaluation for me-tastases. ** Pathologic staging includes microstaging of the primary melanoma and pathologic informationabout the sentinel lymph nodes and regional lymphadenectomy, except for pathologic stage 0 or stage 1Apatients. Tis – melanoma in situ. The new TNM symbols: Ta-tumor without ulceration, Tb –tumor with ulcer-ation; N1- metastasis in one lymph node, N2 – metastases in 2 - 3 lymph nodes, N3 - 4 or more metastaticlymph nodes, matted lymph nodes, or combinations of in -transit met(s)/satellite(s) and metastatic lymph node(s); Na-micrometastases are diagnosed after sentinel or elective lymphadenectomy, Nb-macrometastases aredefined as clinically detectable lymph node metastases confirmed by therapeutic lymphadenectomy or whenany lymph node metastasis exhibits gross extracapsular extension; M1-distant skin, subcutaneous, or lymphnode mets, M2-lung mets, M3-all other visceral or any distant mets (with normal or elevated serum level ofLDH; mets-metastases.

Table 2. Revised ( AJCC) TNM Classification and new stage grouping for cutaneous melnoma (4)

Vygintas Kaikaris, Skaidra Valiukevičienė, Rytis Rimdeika et al.

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regional micrometastases occurred and post-operativecomplications (e.g. secondary lymphedema) arefrequently observed, a minimal invasive surgicaltechnique appeared attractive. To minimize the surgicaldamage of the ELND, Morton and co-workersintroduced the technique of SLNB a decade ago. TheSLNB is aimed at the earliest detection ofmicrometastases of melanoma in different lymph nodesin cases when non-invasive methods (clinicalexamination or ultrasound) failed to reveal them. Ifthe histopathological or immunohistochemicalexamination of the lymph node specimen confirmsmicrometastases, the disease is classified as stage III.This entails total removal of regional lymph nodes andthe prescription of the adjuvant auxiliary treatment withinterferon-alpha.

Historical background of SLNBThe term “sentinel node” to describe the first drain-

ing lymph node was coined in 1977 by Cabanas. Theinvestigator used this procedure for carcinomas of thepenis to evaluate affected regional lymph nodes in thegroin (3). Morton and colleagues have been pioneersof SLNB in melanoma patients in 1992 (11). The in-vestigators noticed that the lymph from the tumor flowsto the regional lymph nodes via several different cuta-neous lymph vessels passing through one or severallymph nodes that collect the lymph from the body sitewith the tumor. Lymph drainage was determined us-ing blue dye (11). In 1993 Krag and Alex complementedthis study by adding lymph drainage scintigraphy and,for the first time, used a hand-held gamma probe dur-ing surgery for the detection of the sentinel lymph node(SLN) (12). The investigators proved that99mTechnetium-marked human albumin is able to wellfill the sentinel lymph node within a short period oftime, and remains there for more than 24 hours with avery slight drainage to more distant lymph nodes. InLithuania, the sentinel lymph node biopsy (SLNB) wasstarted to apply in 2000 at the Oncology center inVilnius. Sentinel lymph nodes are detected using ra-dionuclide lymphography without blue dye (13).

Indications and patient selectionUp to date, there is no consensus about the tumor

thickness cut-off for performing SLNB. Patients whohad their melanoma diagnosis confirmed by inspec-tion and dermatoscopy were offered to undergo senti-nel lymph node biopsy when the primary tumor wasdeeper than 0.75 mm and there were nomicrometastases in regional lymph nodes (11, 14).Other investigators perform sentinel lymph node bi-

opsy when the tumor is thicker than 0.9-1 mm, since95% of patients with diagnosed smaller thickness mela-noma do not have micrometastases in sentinel lymphnode (15).

If preoperative determination of the tumorthickness using high frequency ultrasound (the bestoption is 20 MHz) is possible, an exploratory excisionis not necessary (16).

After the histological confirmation of the diagnosisof melanoma, a repeated wide excision and the senti-nel lymph node biopsy is performed as soon as pos-sible after the first surgery (17).

Furthermore, a limited number of clinical studiesand case reports have been published on SLNB tech-nique in cutaneous B-cell lymphoma, Merkel cell car-cinoma, squamous cell carcinoma of head and neck,thyroid cancer, cancer of the vulva, and pharyngealand laryngeal carcinomas (18-20, 38).

Technical details of SLNBPreoperative lymphoscintigraphy. On the day

prior to the excision of the tumor or on the day ofsurgery, lymphoscintigraphy is performed in the de-partment of nuclear medicine. The patients receivean intracutaneous injection of 0.1-0.2 ml of 99mTc-albumine nanocolloid per injection site (in total, 50 to250 MBq) with an equal distribution circumferentiallyaround the lesion or the scar of the excisional biopsyor re-excision at 5 mm intervals (20, 22). The numberof injections around the tumor depends on the tumorsize.

Various colloid substances are used forlymphoscintigraphy. It is important that their particlesmove fast along the lymph vessels and are accumu-lated for a long time exclusively in the sentinel lymphnode. The majority of European researchers use 99mTc-nanocolloid. The size of its particles varies from 3 to80 nm, which enables their fast movement along thelymphatic vessels. Preoperative cutaneouslymphoscintigraphy is performed in the US with 99mTcsulphur colloid, while in Australia colloidal antimonysulphide is used (21, 34).

After the injection of radionuclide markers, theplanar gamma camera is used to record the dynamiclymphoscintigram until lymph drainage from the tumorand the maximum marker accumulation in the sentinellymph node are clarified. The dynamiclymphoscintigrams show the lymphatic paths from thesite of the injection of the preparation to one or,frequently (in 41% of cases), several sentinel lymphnodes, especially in cases when the tumor is locatedin the head, nape, or trunk (21).

Sentinel lymph node biopsy in melanoma patients

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Static lymphoscintigrams can be recorded after 40minutes from the injection of the preparation (23). Thesites of the projections of the sentinel lymph nodesthat demonstrate the accumulation of radionuclide aremarked on the skin.

Lymphatic mapping using blue dye. The detec-tion of the sentinel lymph node can be performed us-ing dye that gets into the lymphatic capillaries and iscarried to the lymphatic nodes that drain the tumor.15-20 min. before the surgery, 0.5-1 ml of isosulfanblue (Patentblau V 2.5%) is injected into the skinaround the primary tumor or the post-operative scar(20). Other dyes such as methylene blue are not use-ful for dyeing the sentinel lymph node (SLN) becauseside effects like skin necrosis in the injection site havebeen observed (24). The patient who receives the bluedye must be warned that the urine within 18-24 hoursafter the operation will have a bluish color, since thesubstance is excreted through kidneys (26).

Lymphatic mapping using hand-held gammaprobe. In most cases, SLNB is performed prior to theexcision of the primary tumor. When the SLN is lo-cated in close vicinity to the primary tumor, excisingthe primary tumor first can be helpful to have betterdiscrimination between radioactivity from the primarytumor and the SLN. The site of the incision is speci-fied with the help of the gamma-probe readings. Dur-ing layer-by-layer parting of the subcutaneous tissue,aseptically sheathed radionuclide detector of thegamma probe is used to detect the marked sentinellymph nodes. Having separated them from the adja-cent fatty tissue with the help of an electrocoagulator,the blood and lymph vessel fibers of the lymph nodeare tied off in order to stop the flow of the lymph. Ifthe sentinel lymph node is removed successfully, theradioactivity level in the excision site does not exceed10% of the highest radioactivity before the removal ofthe SLN (15).

Histopathological and immunohistochemicalexamination of the SLNB. The removed sentinellymph nodes are sent for histological examination. Intheir earlier reports, Morton and co-workers describedthe detection of melanoma cells in 40 of 194 (21%)SNs during the routine examination of hematoxylin andeosin (HE)-stained slides (10). During the develop-ment phase of the SLNB technique, these authors andothers used frozen-section analysis for routine histol-ogy (11). Later, most centres moved to permanentsections to minimize the loss of diagnostic materialduring “facing up”. The interpretation is thus moreaccurate, and immunohistochemistry is optimized (27).

Immunohistochemistry in addition to HE staining isconsidered essential by most groups. The accuracy ofthe routine histology will be improved and, furthermore,a substantial number of metastatic nodes (approxi-mately 10-15%) will be missed without immunostaining(3). As an example, in the first publication on SLNB,9% of metastatic affected SLN would have been over-looked with HE staining alone (11). Thus, the sensitiv-ity of the detection of occult micrometastasis will in-crease significantly with the addition of immunohis-tochemistry.

Several mono- and polyclonal antibodies directedagainst melanoma-associated antigens (MAA) can beused for routine evaluation of paraffin-embedded speci-mens (2). The sensitivity and specificity of widely usedantibodies against MAA is illustrated in Table 3.

Polyclonal antibody to protein S-100 is expressedby virtually all benign and malignant melanocyticlesions. In addition, it recognizes other neurally derivedcells and antigen-presenting cells (i.e., interdigitatingreticular cells and Langerhans cells) (43-44). Thus,misinterpretations might occur in the examination ofSLNs with S-100 alone.

Therefore, most pathologists use a monoclonal an-tibody to HMB-45 with higher specificity for mela-noma in parallel to S-100 staining. However, evenHMB-45 may lead to misinterpretation since, for in-stance, HMB-45 positive breast carcinomas have beendescribed (45).

Recently, Jarrett et al. reported on a comparativeimmunohistochemistry study in SLNs from melanomapatients. Antibodies to S-100 and NKI/C3, both wellestablished with a high sensitivity, were compared withtwo new markers. Antibodies to Melan-A and tyrosi-nase, useful in paraffin-embedded tissue from lymphnodes, were investigated. Melan-A, as a product ofthe MART-1 gene and a melanocytic differentiation

Table 3. Sensitivity and specificity of markersagainst melanoma-associated antigens

detectable in sentinel nodes:+++ 90-100% ++ 60-90%; + <60% (3)

Antigen/marker Sensitivity SpecificityS-100 +++ moderateHMB-45 ++ moderateNKI/C3 +++ moderateMART 1/Melan-A ++ highTirosinase ++

ahigh

MAGE3 + high



a- weak staining of melanoma cells; unspecific backgroundstaining expression pattern in melanoma

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antigen and tyrosinase, an enzyme of the melanin pro-duction pathway, did not produce additional informa-tion compared to S-100 and NKI/C3 alone. WhereasMelan-A demonstrated clean and effective staining,tyrosinase was less helpful, with weaker staining ofmelanoma cell deposits. Furthermore, a significant,unspecific background staining was present (46).

An immunohistological study using the monoclonalantibody 57 B, specifically detecting MAGE-3 geneprotein, showed a high expression in melanoma sec-tions resulting in a high specificity of 100% but, unfor-tunately, a low sensitivity of only 44% (Table 3).

In conclusion, S-100 and HMB-45 remain standardmarkers for immunohistology, but NKI/C3 and Melan-A are further attractive candidates for the detectionof melanoma cells in paraffin-embedded specimensof sentinel lymph node.

Molecular examination of the SLNB. Minimalresidual metastatic disease detection is of great clinicalinterest, because it allows for insights into the biology

of metastasis and would ideally implicate clinicaldecisions (i.e., adjuvant treatment). A sensitivepolymerase chain reaction (PCR) – based techniqueis able to detect isolated tumor cells. Numerous studieson the detection of tyrosinase mRNA identified byreverse transcriptase (RT-PCR) were performed inperipheral blood from melanoma patients. Tyrosinase,as the key enzyme of melanin biosynthesis, isexclusively expressed by melanocytes and theirmalignant variant, melanoma cells (27-28). More con-sistent results were reported from trials focusing onthe detection of melanoma-associated antigens throughRT–PCR in SLNs. Tyrosinase-RT–PCR (49% posi-tivity) significantly increased the number of patientswho histochemically expressed S–100 B and/or HMB–45 in sentinel lymph nodes (18%) (47). The relativelyhigh number of RT–PCR positive cells in SLN (ap-proximately 50%) in patients with primary melanomais surprising. In accordance with the individual distri-bution pattern of known risk factors in different stud-

Table 4. Survey of the methods and results of sentinel lymph node (SLN) biopsy in melanomapatients

No. Researchers Year Methods Number Frequency Frequency Cut-off forof study of studied of SLN of metastases performing

patients determination in SLN, SLNBduring confirmed bysurgery morphological

(%) studies(%)

1. D. L. Morton et al. 1992 LS+BD 194 81.6 20.6 not indicated2. R. Pijpers et al. 1997 LS+GP+BD 135 100 21.5 >0.45 mm3. S. Mraz-Gernhard et al. 1998 LS+GP+BD 215 100 21.4 >1 mm4. J. E. Gershenwald et al. 1999 LS+GP+BD 612 94.7 15 ≥1 mm5. C. P. Karakousis et al. 1999 BD 84 93 not indicated ≥1 mm

LS+GP+BD 58 98.5 not indicated142 95 25

(in total) (in total) (in total)6. D. L. Morton et al. 1999 LS+GP+BD 554 99.1 not indicated 0.75 mm

(multicenter study) BD 551 95,2 not indicated ≤pT≤0.75 mm7. M. G. Statius-Muller et al. 2001 LS+GP+BD 348 99 18.4 ≥0.5 mm8. S. P. Harlow et al. 2001 LS+GP+BD 336 97.9 11,9 0.75 mm

≤pT≤0.75 mm9. M. Doting et al. 2002 LS+GP 200 99 24 >1 mm

BD (in total) 87 (in total)10. J. Ulrich et al. 2002 LS+GP+BD 358 97 10 0.75 mm

≤pT≤0.75 mm

BD – blue dye, LS - lymphoscintigraphy, GP – gamma probe.pT – tumor thickness according to Breslow.



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ies carried out so far, a rate of about 30% progressivepatients would have been expected.

Whether solitary melanoma cells can be consideredas “micrometastasis” is questioned. Since the definitionof metastasis includes the capacity for angiogenesis andproliferation, the detection of tumor cells alone, withoutknowledge of the particular biology of these cells, isunsatisfactory. The term “disseminated tumor cells”,instead of “micrometastasis”, should be preferred un-less the biology of melanoma cells becomes clearer.

Thus, interpretation of clinical studies on RT–PCRdiagnosis should be considered with some caution. Itappears too early to draw therapeutic decisions (i.e.,radical lymphadenectomy of the entire basin) based onRT–PCR findings alone (3).

In summary, the conclusion to introduce RT–PCRin routine examinations of SLNs in general appears tobe too early. However, this experimental tool can con-tribute to a significantly better knowledge and under-standing of tumor biology and the metastatic cascade.

Review of the methods and the results of thestudy

The majority of researchers use a triple technique ofthe study for the detection of the SLN. The performanceof lymphoscintigraphy prior to surgery and the injectionof blue dye during surgery together with the observationof acoustic signal and radioactivity with the help of theportable gamma probe allow for the successful detectionof sentinel lymph nodes in 97-100% of patients (Table 4).

Since ca. 13% of sentinel lymph nodes are locatedin several lymphatic basins, their more precise detec-tion is facilitated by radionuclide studies, according tothe data obtained by C. P. Karakousis et al. (31). Inorder to mark all regional lymphatic basins to which thelymph from the primary tumor is drained, high quality ofdynamic lymphoscintigraphy is of great importance. Insome sites of the body, e.g. the hollow of the knee orthe bend of the elbow (in 5% of patients), the sentinellymph node can be detected using staticlymphoscintigrams (35).

According to the data obtained by various research-ers (Table 4), using blue dye alone sentinel lymph nodesare detected in 81.6-95.2% of patients. It has been no-ticed that, using the double technique, i.e. both radionu-clide and blue dye, the sentinel lymph node is not dyedin 13% of cases (34).

According to some researchers, radionuclide andgamma probe study is fully sufficient for the detectionof the sentinel lymph node, and blue dye can be usedadditionally in cases where sentinel lymph nodes aresearched in the head and the nape or in deeper subcu-taneous layers in the armpit (21). According to the dataobtained by B. M. Gogel and colleagues, after a wideexcision of melanoma, lymphoscintigraphy and gammaprobe can detect the sentinel lymph node better thanblue dye (22). The injection of radioactive colloid aroundan 8 or 12 centimeter-long scar formed after the exci-sion of primary melanoma on the trunk allows for de-tecting the actual sentinel lymph node (22).

Fig. 1. Injection of radioactive colloid around the primary tumor and shifts of radioactivity in thechain of lymph nodes (37)

A. Primary tumor.B. Sentinel lymph node with highest radioactivity (4000–8000 impulses in a time unit).



Po 20 min. Po 3,5 val.

B B

Limfamazgių

A A

after 20 min. after 3.5 hours

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1%3%

24%

31%

0%2%

12%

40%

0%

28%

67%

14%

0%

10%

20%

30%

40%

50%

60%

70%

80%

0.74 0.75-1.50 1.51-3.99 4.00Thickness of melanoma in mm

Harlow S.P. et al. (n=336) Carcoforo C. et al. (n=110) Paipers R. et al. (n=135)

Radionuclide-marked colloids differ in the speed oftraveling through lymph vessels and the accumulationin the second- or third-rank lymph nodes. For this rea-son, sentinel lymph node biopsy is advised not later than4 hours after the injection of radionuclide, before it fillsthe more remote lymph nodes, or after 16 or 24 hours,when the radioactive colloid is removed from these lymphnodes (Fig. 1).

According to the data of multi-center studies, radio-actively “hot” are considered to be the lymph nodes whoseradioactivity is at least two times higher than in the sur-rounding tissue. The number of radioactively “hot” nodesdepends on the substance used for the radiological study,and the time passed from the injection of this substancearound the tumor prior to the operation. Flowing throughthe lymph node chain, radioactive colloid at first fills thesentinel lymph node, and therefore, when the study isperformed instantly after the injection of the preparation,only the sentinel lymph node should be “hot”. Later theradioactive colloid disperses along the lymph node chainresulting in the appearance of more “hot” lymph nodes(Fig. 1). Since not all the “hot” lymph nodes are sentinelnodes, a surgeon who uses the radioactive colloid alonemay not be able to identify the sentinel lymph nodes amongthe removed nodes.

No multi-center study confirmed that the sentinellymph node can be detected using radionuclide alone,since most researchers used blue dye as well (Table 4).According to D. L. Morton and his colleagues, all thedyed lymph nodes really are sentinel nodes, although8% of them are not radioactive. For this reason, theseresearchers propose to qualify the radiocolloid study asauxiliary, leaving the blue dye method as a “golden stan-dard” (37). C. P. Karakousis and colleagues argue thatblue dye helps in a more precise detection of the senti-nel lymph node when melanoma is located in the ex-tremities (31).

The use of the portable gamma probe during theoperation is necessary irrespective of the location ofmelanoma in order to specify the site of the incision andthe direction of the parting of tissues during the searchfor sentinel lymph nodes. This apparatus decreases theduration of the operation and helps to locate other sentinellymph nodes when radioactivity in the surrounding tissueremains high after the removal of the most radioactivelymph node (21).

The study data on whether it is expedient to per-form sentinel lymph node biopsy after a wide excisionof melanoma are controversial. According to G. Marianiet al., this operation may damage lymph vessels, and

Fig. 2. The frequency of micrometastases in sentinel lymph nodes (%) in relation to melanomathickness measured according to Breslow

≤ ≥



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therefore sentinel lymph node biopsy should not be per-formed, since the lymph will flow not into the actualsentinel lymph node (25). Other authors do not performsentinel lymph node biopsy if the excision of melanomawas wider than 2 cm from the border, or the damagedtissue after surgery covered with rotational flaps ofadjacent tissue. If the site of melanoma excision wassutured with the primary stitch or autodermoplasty wasperformed, sentinel lymph node biopsy is recommended(39).

So far there has been no consensus reached as towhat thickness of melanoma necessitates the searchfor sentinel lymph node. Some researchers performsentinel lymph node biopsy when the thickness of thetumor (determined with the help of ultrasound or histo-logical examination) is 0.75 mm or more (Table 4). USAUnited Cancer Committee proposes sentinel lymph nodebiopsy when melanoma is 1 mm or thicker (4).

According to the data obtained by various research-ers, the frequency of the determination of morphologi-cally confirmed micrometastases in the sentinel lymphnode depends on the thickness of melanoma and variesbetween 10% and 25% (Table 4). When the thicknessof melanoma does not reach 0.75 mm, micrometastasesare detected in less than 1% of patients, when the thick-ness is 0.75-1.5 mm – in ca. 6% of patients, when thethickness is 1.5-4 mm – in ca. 21% of patients, andwhen the tumor is thicker than 4 mm, micrometastasesare found in 46% of patients (Fig. 2).

During the histological examination, in addition to thetumor thickness according to Breslow, the penetrationdepth according to Clark is measured (Table 1). If thedepth of the penetration of the tumor according to Clarkis bigger than stage III, sentinel lymph node biopsy hasto be performed (32, 36).

In some studies, in order to determine “false nega-tive” sentinel lymph nodes, i.e. a missed metastasis,sentinel lymph node biopsy was performed and all re-gional lymph nodes were removed. The histological stud-

ies of the removed lymph nodes showed that less than2% of patients without changes in sentinel lymph nodeshad metastases in other regional lymph nodes (14, 36).In such cases, the immunohistochemical examinationof the “false negative” sentinel lymph nodes showedthe presence of micrometastases in 19%-27% of pa-tients (32, 40). This shows that it is necessary to equal-ize the methods of the morphological studies of sentinellymph nodes.

The incidence of surgical complications after senti-nel lymph node biopsy does not exceed 2%. The mostcommon complications after sentinel lymph node biopsyare seromas or hematomas that later disappear by them-selves; slight lymphedema of limbs is less common (41).

ConclusionsSLNB becomes accepted as a standard care for

melanoma patients. The results of the sentinel lymphnode biopsy help to make the patient’s survival progno-sis and to select patients who need the removal of allregional lymph nodes or supportive treatment with in-terferon-alpha. Summarizing the conclusions made bya number of researchers, one can state that a precisedetermination and detection of the sentinel lymph nodeduring surgery requires three methods of examination– lymphoscintigraphy, blue dye and a gamma probe.

Carefully conducted examinations of the SLNs us-ing conventional histology (HE staining) and immuno-histology (S–100, HMB–45) are necessary to avoid themissing of melanoma cells in SLN. The mRNA detec-tion of melanoma-associated antigens (tyrosinase,MART–1, gp 100, and others) remains experimentalunless conclusive results on its clinical value are avail-able.

At present, studies are being performed in order todetermine whether sentinel lymph node biopsy may havea beneficial effect and prolong the patients’ survival.This question will be answered by the results of thecompleted multi-center prospective studies (42).



Sarginio limfamazgio biopsijos metodai, indikacijos ir tyrimo reikšmė odosmelanomos atvejais

Vygintas Kaikaris, Skaidra Valiukevičienė1, Rytis Rimdeika, Harald Gollnick2, Jens Ulrich2

Kauno medicinos universiteto klinikų Chirurgijos klinikos Plastinės chirurgijos skyrius,1Kauno medicinos universiteto Odos ir venerinių ligų klinika,

2Otto-von-Guericke universiteto Dermatologijos klinika, Magdeburgas, Vokietija

Raktažodžiai: sarginio limfamazgio biopsija, melanoma, mikrometastazės, limfografija, rankinis radiometras.

Santrauka. Per pastarąjį dešimtmetį sergamumas melanomomis Lietuvoje padidėjo du kartus. Tyrimais

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įrodyta, kad sergančiųjų melanoma išgyvenamumas, kai nėra sisteminių metastazių, tiesiogiai priklauso nuonaviko gylio, išmatuoto pagal A. Breslow, naviko įsiskverbimo į odą pagal W. H. Clark, naviko išopėjimo irmikrometastazių buvimo sarginiame limfamazgyje. Sarginio (angl. sentinel) limfamazgio biopsija, prieš melanomosoperaciją atliekant netiesioginę limfoscintigrafiją, kartu su rankiniu radiometru ir audinių dažu per operaciją – taistandartinė chirurginė intervencija, taikoma JAV ir Europoje. Tai mažai invazinis ir labai jautrus chirurginistyrimas. Juo galima nustatyti melanomos mikrometastazes sritiniuose limfamazgiuose. Tiriant neinvaziniaismetodais, jų nematyti. Šio straipsnio tikslas – remiantis naujausiais literatūros duomenimis ir daugiau kaip 400pacientų sarginių limfamazgių biopsijų, atliktų Vokietijos Magdeburgo universiteto klinikoje, duomenimis, pateiktinaujausią informaciją apie šio tyrimo atlikimo galimybes, jo reikšmę melanomų prognozei bei šio tyrimoperspektyvas.

Adresas susirašinėjimui: V. Kaikaris, KMUK Chirurgijos klinikos Plastinės chirurgijos skyrius, Eivenių 2, 3007 Kaunas

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stage melanoma: a multicenter trial. Ann Surg 1999;230:453-63.

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Received 9 April 2003, accepted 14 May 2003



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