Intraoperative Radioisotope Injection for Sentinel Lymph Node Biopsy

Intraoperative Radioisotope Injection for Sentinel LymphNode Biopsy

Margaret Thompson, MD,1 Soheila Korourian, MD,2 Ronda Henry-Tillman, MD,1 LauraAdkins, MAP,1 Sheilah Mumford, MA,1 Maureen Smith, RNP,1

and V. Suzanne Klimberg, MD1,2

1Division of Breast Surgical Oncology, Department of Surgery, University of Arkansas for Medical Sciences, SLOT 725, Little Rock,AR 72205-7199, USA

2Department of Pathology, University of Arkansas for Medical Sciences, SLOT 517, Little Rock, AR 72205-7199, USA

Background: Preoperative injection of technetium-99 m sulfur colloid (Tc-99) in the Nu-clear Medicine Department for localizing sentinel lymph nodes (SLNs) can be extremelypainful for the patient. The difficulties in scheduling and the delay in starting surgery can befrustrating for the patient and the surgeon. We hypothesized that intraoperative injectionfacilitated by the subareolar technique would obviate the problems associated with preoper-ative injection.Methods: We performed an institutional review board-approved prospective study of pa-

tients with operable breast cancer who were candidates for an SLN biopsy from October 2002to January 2006 at our institution. After induction of general anesthesia, patients underwent asubareolar injection of 1 mCi Tc-99 unfiltered and blue dye. Data comparing preoperative costwere collected.Results: A total of 236 patients had 252 intraoperative SLN procedures. The mean patient

age was 57.3 (range, 24-88) years. The mean ± standard deviation time from injection toincision was 25.5± 16.2 minutes. Identification rate was 96%, and the number of SLNsidentified per patient was 1.6± .8. The count of SLN was 60,313± 134,692 with 20% SLNpositivity. Tumor staging distribution was standard staging terminology for an in situ cancer(Tis) = 17 with 0% (+) SLN, T1 = 115 with 11% (+) SLN, T2 = 56 with 29% (+) SLN,T3 = 19 with 37% (+) SLN, and T4 = 4 with 50% (+) SLN. Maximum exposure to thesurgeon was well below maximum, at 100 lSV/mo. Preoperative injection had an additivecharge of $1325 associated with it for imaging, injection, and interpretation of images byphysician.Conclusion: Intraoperative subareolar injection of Tc-99 localizes the SLN and avoids the

pain, vasovagal events, delays, and cost associated with preoperative procedure.

Preoperative sentinel lymph node (SLN) injectionsare painful and represent needless added stress to thebreast cancer patient. Preoperative injections can alsobe associated with pain and vasovagal events because

local anesthesia is avoided as a result of the possi-bility of impaired transit of the radioactive cursor.Topical anesthetic or the addition of lidocaine to theinjection syringe is helpful,1 but it does not com-pletely abate the pain associated with dermal, sub-dermal, subareolar (SA), or parenchymal injections.The intraoperative injection of blue dye only issometimes used to avoid the discomfort associatedwith preoperative injections with good results,2 butother studies indicate better SLN localization with

Published online September 6, 2008.Address correspondence and reprint requests to: V. Suzanne

Klimberg, MD; E-mail: [email protected]

Published by Springer Science+Business Media, LLC � 2008 The Society ofSurgical Oncology, Inc.

Annals of Surgical Oncology 15(11):3216–3221

DOI: 10.1245/s10434-008-0010-3

3216

the use of double tracers.2–4 For the patient andsurgeon alike, unavoidable delays associated withintradepartmental scheduling are linked to preoper-ative injection. Injection the day before eliminates themorning surgical delay, but at a cost of patientinconvenience and ultimately decreased SLN tracercounts. Injection in the preoperative holding areaavoids some of the scheduling delay but not theassociated pain and anxiety of the injection itself.The fast transit time of SA injection led us to

hypothesize that intraoperative injection by the SAtechnique would improve the preoperative course ofthe patient by allowing SLN injection and identifi-cation to be performed completely intraoperativelyafter induction of anesthesia. We were the first toreport this technique in a small series of patients.5

Other small series have recently also confirmed suc-cess with intraoperative injection.6,7 We now presentour expanded series of patients undergoing intraop-erative SLN injection. Further, we examine the effectof such an intraoperative SLN program on mini-mizing operative delays, costs, and safety.

MATERIALS AND METHODS

Study Population

This was an institutional review board-approved,single-institution, prospective study carried out fromOctober 2002 to January 2006. Only patients withpathologically confirmed breast cancer without priorcircumareolar or upper outer quadrant incision werecandidates for a sentinel lymph node biopsy (SLNB).

Surgical Procedure

The patients were brought to the operating room,and after induction of general anesthesia, theyunderwent an SA injection of unfiltered technetium-99 m sulfur colloid (Tc-99) as previously described indetail.5 Briefly, under general anesthesia, 1.0 mCi ofTc-99 diluted with saline to a final volume of 4.0 mLwas injected in the SA lymphatic plexus by insertingthe needle at the limbus of the areola at 45� to instilljust beneath the nipple (Fig. 1). Three surgeons par-ticipated in the surgery (V.S.K., M.T., R.H.). Lym-phoscintigraphy was not performed. Routine scrub,preparation, and drape were then completed. Bluedye (Isosulfan) was injected in the breast in the SAplexus in a similar manner, and the breast was mas-saged for 5 minutes. Radioactive counts in the axillawere recorded before the incision. A handheld gam-

ma probe (Neoprobe, Dublin, OH) was used tolocalize the radioactive hot spots. All hot, blue, orpalpable nodes were submitted for pathology asSLNs. Patients then underwent excision of the tumorvia lumpectomy or mastectomy. Dissection of theaxilla was performed if SLNs were positive, except inthe patients where only a SLNB was being performedfor staging purposes before neoadjuvant chemother-apy. SLN identification rate, mean number of SLNs,mean count of each SLN, and time to localizationwere collected.

Pathology

Intraoperative touch prep cytology was performedon the SLN, followed by routine hematoxylin andeosin staining. If an SLN was <5 mm, it was bival-ved, and if it was >5 mm, it was sectioned in 3-mmintervals along the long axis. Non-SLNs from axillarylymph node dissections were bivalved along the longaxis, and one section from each node was submittedfor hematoxylin and eosin staining. Immunohisto-chemistry was reserved for cases involving potentialmetastases from lobular carcinoma or confirmationof suspected metastases.

Radiation Safety

Before handling the technetium, all staff involvedwere required to take a radiation safety class(approximately 4 hours in length, although the lengthvaries by institution) and were required to wearradiation dosimeters that were checked monthly.Authorized staff from the breast surgery team trans-

FIG. 1. Site of needle injection, at the limbus of the areola at 45�,to instill just beneath the nipple.

INTRAOPERATIVE RADIOISOTOPE INJECTION IMPROVES SLNB 3217

Ann. Surg. Oncol. Vol. 15, No. 11, 2008

ported the dose in lead containers to the 1-dayoperating room, which was credentialed through thesame facility for transport. Only these personnel andthe surgeons were required to wear dosimetry badges.The dose to the patient is approximately that of achest X-ray, so the dose to the nursing and preoper-ative or operative staff was far less and did not re-quire personal monitoring. The disposition of thetechnetium and its container were recorded. Theoperating room, surgical table, mayo stand, instru-ments, trash, and linens were scanned with a Geigercounter after each procedure, and findings were re-corded on data sheets from the radiation safetydepartment. Any of these with a count higher thanbackground were then appropriately bagged in aradiation hazard bag and disposed of by the NuclearMedicine Department following standard protocol.

Billing Charges Comparison

Actual billing charges of SA injection preopera-tively in nuclear medicine included technetium solu-tion, act of technetium injection by the radiologistversus surgeon, lymphoscintigraphy imaging, radiol-ogist interpretation, and presence of radiologist. Thiswas compared with billing charges of SA injectionintraoperatively that included the technetium solu-tion and the act of technetium injection by the sur-geon.

Statistical Analysis

Statistical analysis was calculated by the Descrip-tive Statistics program8 to obtain the mean andstandard deviation (SD).

RESULTS

Study Population

A total of 236 patients underwent 252 intraopera-tive SLN procedures from October 2002 to January2006. The mean ± SD patient age was 57.3± 12(range, 24–88) years. SLN was performed for invasivecancer (n = 219), with 55% of those patientsundergoing lumpectomy, 32% patients undergoingmastectomy, and 13% undergoing SLNB only asstaging for neoadjuvant chemotherapy. SLNB wasalso performed in patients receiving a prophylacticmastectomy (n = 24) or a mastectomy for ductalcarcinoma-in-situ (n = 17).

Surgical Procedure

The mean ± SD time from injection to incision was25.5± 16.2 minutes, and incision to excision was19.1± 21.1 minutes. The length of time to incisionhad more to do with scrub, preparation, and drapetime than actual localization. Our identification ratewas 96%, and the number of SLNs identified perpatient was 1.6± .8. The count of SLN was60,313± 134,692 counts per 10 seconds.

Pathology

Twenty percent of patients had SLN positivity.Tumor staging distribution was: 0 of 17 standardstaging terminology for an in situ cancer (Tis) wereSLN positive, 12 (11%) of 115 T1 were SLN positive,16 (29%) of 56 T2 were SLN positive, 7 (37%) of 19T3 were SLN positive, and 2 (50%) of 4 T4 were SLNpositive (Fig. 2). All 24 SLNBs performed for pro-phylactic mastectomy were negative.

Radiation Safety

Maximum exposure to any individual surgeon asmeasured on dosimeter tags worn on the chest was100 lSV/mo. The annual whole-body exposure limitis 50,000 lSV.

Billing Charges Analysis

Preoperative injection in the Nuclear MedicineDepartment had an additive charge of $1240 associ-ated with it for imaging, interpretation of images byradiologist, and presence of radiologist (Table 1).

0%

10%

20%

30%

40%

50%

60%

Tis T1 T2 T3 T4

Rate of Lymph node Positivity According toTumor Size

FIG. 2. Rate of lymph node positivity according to tumor size.

M. THOMPSON ET AL.3218


Complication

There were no short- or long-term complicationsdirectly related to intraoperative SA injection of Tc-99.

DISCUSSION

The status of the axillary lymph node is the mostimportant prognostic variable on which therapeuticdecisions of breast cancer patients are predicated.9–11

SLNB accurately stages the axilla and for the mostpart has replaced traditional staging of axillary lymphnode dissection.12–16 Nevertheless, variations inmethodology have spawned a great deal of conster-nation regarding how, what, and when to inject toobtain optimal SLN identification and accuracy. Arecent meta-analysis of SLN procedures demon-strated a wide variation in performing the test whiletrying to reduce the complications associated withaxillary lymph node dissection in patients with low-risk breast carcinoma.17

Preoperative injection of Tc-99 in the NuclearMedicine Department for localizing SLNs is prob-lematic, the least of which is that it can be extremelypainful for the patient. Krynyckyi et al.18,19 usedEMLA cream (lidocaine 2.5% and prilocaine 2.5%;Astra Pharmaceuticals, Wayne, PA) and found iteffective in controlling local surface pain duringinjections for all but areolar-cutaneous junctioninjections. They added lidocaine to the injection syr-inge for more sensitive shallow areolar injections, butthey did not mention whether this affected localiza-tion.1 Like needle localization breast biopsies, pre-operative injection of Tc-99 can result in strongvasovagal events precipitating nausea and vomit-ing.20 In addition, difficulties in scheduling and delaysto start surgery can be frustrating for the patient andsurgeon.There are other techniques that may help to

alleviate some of these problems. Anan et al.21

demonstrated double mapping with SA blue dye andperitumoral green dye injections. This technique notonly decreased the false-negative rate of dye-onlySLN for early breast cancer, but also avoided pre-operative delay because the dyes were injected intra-operatively. However, use of color dyes from twosites have the same problems with localization as theuse of a single dye. Another study assessed the use ofI-125 methylene blue.22 This phase 1/2 trial involvedintraoperative injection of radiolabeled blue dye.Cundiff et al.22 demonstrated that this method elim-inated painful preoperative injection, was associatedwith low radiation exposures, and avoided schedulingdelays. We recently reported a new procedure,axillary reverse mapping, that uses blue dye to mapand preserve the lymphatics draining the arm duringa Tc-99-driven SLNB and thus prevent lymphedema.It is now our opinion that blue dye should be reservedfor this purpose rather than localization of theSLN.23

Klimberg et al.24 first described SA injection oftechnetium and demonstrated that it drained to thesame lymph node as a peritumoral injection of bluedye. We as well as others have demonstrated SAaccuracy25 even with multiple breast cancers, becausecancers from different quadrants of the breast arelikely to drain to the same SLN.26 In particular, thenotable fast transit time of SA injections led us tohypothesize that intraoperative injection by the SAtechnique would improve the preoperative course ofthe patient by allowing SLN injection and identifi-cation to be performed completely intraoperatively.27

The present study demonstrated that intraopera-tive SA injection can provide rapid and accuratelocalization (95%) of the SLN, obviating the com-mensurate pain and vasovagal events associated withpreoperative injection. These data include the learn-ing curve for this technique and therefore imply thatthis technique is easy to master and overcomes theimaging needed for peritumoral injection of nonpal-pable lesions. Further, the developed procedureavoids surgical delay and costs associated with pre-operative injection in the radiology department. Theprocedure is safe, with the maximum exposure to anyone personnel being approximately 1/50 of the annualwhole-body exposure limit of 50,000 lSV. Finally,there were no complications associated with theprocedure.The downside of such an intraoperative SLN pro-

gram is the radiation safety component. All personnelmust complete a radiation safety course and be cer-tified to pick up and handle the radioactive material.The onus of the disposition of the material is on the

TABLE 1. Billing charges analysis

ChargeNuclear medicine

department cost (US$)Intraoperativecost (US$)

Tc-99 109 109Act of sentinel lymphnode injection

85 85

Imaging 823 n/aPhysician presence 260 n/aReading of images 157 n/aTotal 1434 194Difference +1240



surgeon and radiation safety staff. After the case isfinished, all materials from the case must be scanned,and any bags from the case having a higher countthan background (200 cpm) must be appropriatelydisposed. Arguably, the loss of preoperative lym-phoscintigraphy may represent a deterrent to some.28

McMasters et al.,29 as well as others, have demon-strated that preoperative lymphoscintigraphy is notnecessary for the identification of axillary SLNs inbreast cancer because it does not improve the abilityto identify the axillary SLN during surgery and doesnot decrease the false-negative rate.Intraoperative SA injection of Tc-99 rapidly

localizes the SLN and avoids the pain, vasovagalevents, delays, and cost associated with preoperativeinjection for SLN identification, with the majortrade-off being a greater awareness of radiation safetyissues. For surgeons wanting to incorporate intra-operative SLNB in their practice, we recommendbeginning by taking a radiation safety course, thendeveloping a relationship with radiation safety and anuclear medicine physician. This team will then worktogether to provide this option as a best-care practicefor the patient.

ACKNOWLEDGMENT

Dr. Margaret Thompson was supported by theSusan G. Komen Breast Cancer InterdisciplinaryFellowship (M.T.) and the Fashion Footwear asso-ciation of New York/QVC.

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Intraoperative Radioisotope Injection for Sentinel Lymph Node Biopsy

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