see also: Case Example Sentinel Lymph Node Biopsy

see also: Lymphoseek also called technetium Tc 99m tilmanocept

see discussion re: Controversy Regarding Value of SLN Biopsy (at bottom of page)

GENERAL CONSIDERATIONS

1. INDICATIONS
   1. Malignant melanoma (see TNM specific indications at: Melanoma (Evaluation and Management))
      1. Breslow depth of invasion greater than 1 mm - may consider in thinner (>0.75 mm) melanoma in high risk sites
      2. Thin melanoma <1mm if mitotic rate 1 or more or if ulceration present
      3. Melanoma with status other than Tis (melanom in situ) or T1a
      4. Currently felt that for pure desmoplastic melanoma of the head and neck,  the high incidence of negative sentinel lymph node biopsies as well as the  low incidence of neck recurrence, argues against use of sentinel lymph node biopsy for this rare subset of melanoma (Eppsteiner et al 2012, Mohebati et al 2012)
   2. Oral squamous cell carcinoma
      1. T1N0 or T2N0 (ACOSOG protocol)
   3. Merkel cell carcinoma
      1. Stage I (localized tumor)
   4. Consider use with sebaceous carcinoma
2. RATIONALE (as per McMasters, KM, et al 2001)
   1. SLNB provides important prognostic information to the physician and patient in guiding subsequent treatment options.
   2. SLNB facilitates identify patients with nodal metastasis (important prognostic factor), who then may benefit from early therapeutic lymph node dissection (TLND).
   3. SLNB identifies patients who are candidates for adjuvant treatment (see: Melanoma (Evaluation and Management)).
   4. SLNB provides the most accurate means of regional staging, which is recognized as the most important prognostic factor in melanoma.
   5. Identification of homogenous populations allows for more powerful clinical trials, and ideally, a greater likely hood of of more effective adjuvant therapies.
3. CONTRAINDICATIONS
   1. Evidence of nodal metastasis
   2. Gross bulky disease
   3. PET or FNA positive disease
4. CONSIDERATIONS
   1. Biopsy of the suspicious lesion is best done with an excision (if possible) - punch or ellipse of the thickest portion of a larger lesion.
      1. Only 1 to 2 mm margins should be obtained around the lesion in order to permit subsequent accurate lymphoscintigraphy
      2. Photography before biopsy is useful (sometimes critical) to document original location and appearance.
      3. If the biopsy shows melanoma, leave the sutures in place until the time of definitive resection for use as marker of the site.

PREOPERATIVE CONSIDERATIONS

1. Tumor Board Discussion (special twice monthly Thursday 7 am Melanoma Tumor Board)
2. Thin cut CT of the H+N with contrast prior to lymphoscintigram - most useful in the parotid region
   1. Primary goal: permit co-registration (usually done visually with surgeon present) to correlate with lymphoscintigram immediately preoperatively
   2. Useful particularly in identifying intra- and peri-parotid nodes to plan surgical access for sentinel node dissection
3. Consultation
   1. Medical oncology (Dr. Milhem at the U of Iowa)
      1. For all cases other than the most superficial (T1)
      2. Permits consideration for study purposes (including tissue repository)
      3. Ensures discussion at melanoma tumor board
   2. Other services as dictated by comorbidity and extent of disease
4. Consent for sentinel node biopsy
   1. Describe procedure including the benefits.
   2. It should be explained to the patient that a sentinel lymph node biopsy is a staging procedure, and the current standard (pending results of the multi-center selective lymphadenectomy trial-2 - aka MSLT-2) usually directs the finding of a positive SLN to a completion lymphadenectomy, possibly with the need for further surgery, immunotherapy, chemotherapy, and/or radiation therapy.
   3. Discuss the possibility of requiring a Parotidectomy with Facial Nerve Dissection
   4. Discuss the possibility of resection of more than one lymph node biopsy and creating more than one incision (removal of greater than or equal to 3 SLNs leads to lower chance of additional positive non-SLN)
   5. Explain risks and potential complications: Bleeding, infection, reaction to the anesthesia, damage to adjacent structures
   6. Depending on the site of the sentinel node, the complications may be similar to those described for neck dissection or parotidectomy:
      1. Wound infection
      2. Shoulder weakness, adhesive capsulitis, pain
      3. Chylous fistula (at risk of Level IV dissection)
      4. Cranial nerve deficits (emphasize if disease is near a particular nerve)
      5. XI: shoulder dysfunction
      6. X: hoarseness, dysphagia, aspiration
      7. IX: dysphagia
      8. XII: dysarthria, dysphagia
      9. VII: marginal mandibular branch weakness and rare total facial paralysis unless the neck disease is high in zone II.
      10. Anesthesia (numbness) of the neck skin, earlobe, and possibly the tongue
      11. Anesthetic risks (stroke, death, MI)
      12. Possibility of need for further surgery or other treatment (XRT/chemotherapy)

NUCLEAR MEDICINE

1. Injection of the lymphoscintigraphy isotope will take place either the evening before or (more commonly) the day of surgery.
2. Patient will undergo injection of their primary site with the appropriate radiotracer by the operating surgeon (oral cavity primary) or the nuclear medicine physician (cutaneous primary).
   1. Minimum 1-2 hours before, so that the radioisotope activity builds in the nodes. The 99mTc is phagocytosed by macrophages in the lymph nodes, therefore the activity will not "wash out" of lymph nodes.
   1. Maximum delay between injection and surgery is 12-16 hours.
   2. Half life of 99mTc is 6 hours, therefore at 12 hours, 1/4th of radioactivity remains. At 24 hours, that decreases to 1/16th remaining radioactivity.
3. Lidocaine may be infiltrated prior to radiotracer injection.
4. 0.2-0.3 ml of filtered 99mTc sulfur colloid is injected intradermally in four quadrants at the edge of the lesion, or at either side of the middle of a scar if there was a previous biopsy.
5. Lymphoscintigraphy imaging is done immediately
   1. Dynamic sequence images 15-30 minutes post injection via gamma camera
   2. Changing angles of camera allows calculation of node depth
   3. Can be co-localized with SPECT-CT

NURSING CONSIDERATIONS

1. Room Setup
   1. See Basic Soft Tissue Room Setup
   2. Instrumentation and Equipment
   3. Standard
      1. Major Instrument Tray 1, Otolaryngology
      2. Major Instrument Tray 2, Otolaryngology
      3. Bipolar Forceps Trays
   4. Special
      1. Nerve stimulator control unit and instrument
      2. Cummings retractor, large and medium
      3. NIMS facial nerve monitor if preoperative scintigraphy indicates an intraparotid sentinel lymph node
      4. Handheld gamma probe
         1. Avoid unnecessary "on" time for the gamma probe. Most are battery-controlled and lose power quickly.
         2. Calibrate the gamma probe according to manual for your specific unit. Many require recalibration with every case.
         3. Set unit for detection of technetium Tc 99m, 10 second counts
         4. Be ready with a chalkboard or paper to record all 10-second counts as indicated below
2. Medications (specific to nursing)
   1. Antibiotic ointment
   2. 1% lidocaine with 1:100,000 epinephrine
   3. Blue dye
      1. Lymphazurin 1% solution
      2. Methylene blue 1% solutions
3. Prep and Drape
   1. Standard prep, 10% providone iodine
   2. Drape
   3. Head drape
      1. Place towels outlining the face, neck, and upper chest
   4. Split sheet
   5. Ioban or large 10-10 drape for facial nerve monitoring
4. Drains and Dressings
   1. Penrose drains
   2. Antibiotic ointment to suture lines

ANESTHESIA CONSIDERATIONS

1. General Anesthesia
2. Tube position: Corner of mouth contralateral to procedure
3. Paralysis: None
4. Systemic Medication
   1. Antibiotics (see Antibiotic Prophylaxis in Head and Neck Surgery protocol)
5. Positioning
   1. Supine
   2. Head turned away
   3. Bed turned 180 degrees from anesthesia
6. Estimated Blood Loss
   1. Less than 50 cc

OPERATIVE PROCEDURE

In the past we did not routinely use blue dye (1 ml of isosulfan blue dye = Lymphazurin 1%). Despite support for its use, our experience with SLN on the ACOSOG oral cavity squamous cell carcinoma SLN study (no blue dye) and subsequent success rates w/o the dye prompted our use of the gamma counter without blue dye in most cases. Rationale for not using the blue dye is based on its staining of adjacent tissue, potential of leaving a blue tattoo, potential allergic reaction and the dye recognized as not being as sensitive as the radiotracer technique. Reports have indicated that inconsistent drainage pathways in the head and neck created more difficulties in tracing blue channels to the sentinel node (Vermeeren 2011). Others have reported that sentinel nodes in the head and neck are less often stained blue than in other body regions (Chao 2003).
Use of the blue dye classically involves injection of 0.5-1 mL of 1% isosulfan blue intradermally into the tumor 10-15 minutes prior to skin incision. The technetium and the blue dye can be used together, with a marginally increased sensitivity rate – one report: 94% for technetium alone, and 98% with combination of blue dye plus technetium.
Concerns about possible allergic reactions to lymphazurin (est ~ 1-3% chance), higher cost of lymphazurin, and a recent nationwide shortage all led to increased use of methylene blue as an adjunct to the gamma probe in helping isolate SLNs (Liu et al 2008). A randomized study by Liu in comparing lymphazurin to methylene blue yielded their impression that, although the gamma probe is the most effective means of identifying a SLN, MB is at least as effective as lymphazurin. In contrast, a retrospective review by Neves et al (Neves 2010) identified a higher complication rate among patients receiving methylene blue than lymphazurin. Although complications of infection and minor skin slough occurred in patients receiving lymphazurin, skin tattooing and loss of skin graft were more common in the group receiving methylene blue. As a result of these considerations, we have resumed use of lymphazurin 1% to serve as an adjunct to the gamma probe. Additional support for use of the blue dye (despite its short-comings) arises from the recognized difficulties with perilesional activity from radioisotope tracer impairing SLN detection from high background activity despite our routine use of single photon emission computerized tomography technique (SPECT-CT) (Vermeeren 2011). Use of blue dye does not fully circumvent this problem but may be helpful. Additional consideration for careful step sectioning of the resected primary site to evaluate for metastatic disease underlying the resection (and hence not detectable in the lymphoscintigram) is warranted with submission of identified nodes for complete step sectioning and immunohistochemical analysis (Querfeld 2011).

1. Pertinent Anatomy
   1. Identify the angle of the jaw, mastoid tip, midline of the neck, anterior and posterior borders of the SCM muscle and the clavicle.
   2. Identify the area marked by the nuclear medicine physician
      1. Our practice is to examine the patient with the nuclear medicine physician after reviewing the lymphoscintigram and CT together. Secondary nodes (that may have radioactivity but not representative of the SLN) can be identified with the nuclear medicine physician in interpreting the lymphoscintigram. Unnecessary dissection and removal of nodes not representative of sentinel nodes can be avoided by this practice.
   3. Do a preliminary sweep of the region to identify "hot" spots that may yield a sentinel node
2. Ten-second counts of "hot" areas can be compared to other sites' 10-second counts
   1. High levels of interference may be noted near the primary or injection site and preclude useful scintigraphy prior to removing the primary lesion.
3. Incisions
   1. Draw an incision in the anticipation of future surgery: flap reconstruction/completion lymphadenectomy. In the H+N region, a doubly modified blair incision is usually drawn on the patient with a pen in anticipation that a completion parotidectomy may be needed. A segment of the drawn incision or a minor modification to it usually permits access to the SLN without extensive dissection. On occasion, a full parotidectomy may be required to access nodes.
   2. Incision of approximately 3 cm may be adequate in some cases - larger incisions should be used without reservation if improved exposure will diminish the risk of complication such as nerve injury.
4. Identification of the sentinel lymph node.
   1. After flap elevation, re-scanning the area with the gamma counter may yield a more precise location of the lymph node.
   2. When the lymph node is encountered, take a 10-second count over the lymph node.
      1. This is the IN VIVO count, and should be recorded by nursing.
   3. Dissect the lymph node from the surrounding tissue bed.
      1. Dissection is facilitated by grasping fascia adjacent the node (not the node itself) to use as a 'handle' to manipulate the node in the process of removing it from adjacent tissue.
      2. Take care to not crush or tear the lymph node. It is possible to leak technetium Tc 99m into the surrounding tissue and make post-excision counts inaccurate.
   4. After removal of the lymph node, take and record two more counts
      1. 10-second EX VIVO count of the lymph node. This value is typically higher than the IN VIVO reading.
      2. 10-second wound bed count. This value should be much lower (less than 10%) than the IN VIVO reading.
      3. If the post-excision count of the tumor bed is greater than 10% of the EX VIVO sentinel lymph node reading, further dissection is indicated.

      4. Record values in table as below:

         	In Vivo – Prior to Excision	In Vivo – After Exposure	Ex Vivo	Wound Bed After Removal
         Primary site
         Lymph Node 1
         Lymph Node 2

          
   5. Resweeping the area with the handheld gamma counter and careful deep dissection will delineate other area lymph nodes.
   6. For every lymph node excised, take IN VIVO, EX VIVO, and post-excision wound bed readings.
   7. Once the wound bed reading drops below 10% of EX VIVO reading, you have successfully removed the sentinel lymph node
      1. If the wound bed uptake continues to be high, check the background.
5. Closure
   1. Dependent on extend of dissection, small Penrose drain may be beneficial
   2. Platysma: 3-0 or 4-0 Vicryl
   3. Skin: 5-0 or 6-0 nylon. 4-0 Monocryl subcuticular closure may also be used.
6. Wound dressing
   1. Ointment to skin wound

6. POSTOPERATIVE CARE

1. Drain output
   1. Slow withdrawal of Penrose if large volume of serosaguinous output versus removal on postoperative day 1.
   2. Monitor for hematoma, chyle accumulation
   3. Suture Removal
      1. No prior radiation postoperative day 6 or 7
      2. Some of the faculty suggest delaying suture removal if there has been prior radiation postoperative day 10 to14
         1. My preference (HH): remove sutures on day 6 or 7 even with previous irradiation if deeper closure with absorbable sutures adequately approximates tissue.

 

Frozen section and SLN biopsy for melanoma

Frozen section can be used to evaluate SLN and if positive for metastases proceed with lymph node dissection at that time rather than having to await permanent sections and perform a separate second surgery. Potential morbidity of a second operation can then be avoided.

A concern with frozen section analysis is that it is less sensitive with false negatives and that diagnostic tissue can be consumed in preparation. Where SLN is removed at one operation and tissue is processed for permanent sections immunohistochemical staining can also be done (with S-100 and HMB-45) to improve sensitivity.

Tanis et al. (2001) recommend against using frozen section for SLN in melanoma based on their findings in 99 melanoma patients where on frozen section they were only able to detect about half of the metastases. Whereas, Aryian et al. (2004) are in favor of using frozen section analysis for SLN in melanoma and had much greater success with the technique. They were able to diagnosis 82% of melanoma metastases on frozen section and at the same operation complete the lymph node dissection. With 2/28 patients (7%) having a false negative frozen section diagnosis.

Regardless of whether frozen section is employed at the time of SLN for melanoma, the patient should be counseled preop that second lymph node dissection could be necessary based on the findings of permanent histology.

At Iowa frozen section on SLN biopsy is not routinely done. Cooperation with pathology and their protocols is necessary at your institution. As the SLN is radioactive it can make the cryostat it is cut on unusable for a period of time and handling of the specimen in the lab must follow their precautions.

Ariyan S, Ariyan C, Farber LR, Fischer DS, Flynn SD, Truini C. Reliability of identification of 655 sentinel lymph nodes in 263 consecutive patients with malignant melanoma. J Am Coll Surg. 2004 Jun;198(6):924-32.

P.J Tanis, R.P.A Boom and H.S Koops et al., Frozen section investigation of the sentinel node in malignant melanoma and breast cancer, Ann Surg Oncol 8 (2001), pp. 222--226.

 

Errors in performing SLN bx: FALSE NEGATIVE RATE

1. Definition of 'false negative' varies. - largest study to evaluate false negative rate to date: Sunbelt Melanoma Trial - 79 centers in the US and Canada. 2,451 patients with melanoma thickness >1.0 mm had median follow-up of 61 months. (ref Scoggins et al 2010)
   Definition of a False Negative = sentinel lymph node negative with subsequent appearance of regional metastasis.
   1. False Negative Rate: 3% = 59/1,965 patients with original tumor-negative sentinel node
      1. alternatively - False negative rate = 10.8% when calculated as the proportion of node positive patients who had a tumor negative sentinel node biopsy (59 false negative/(486 true positive + 59 false negative) x 100 = 10.8%
      2. alternatively - False negative rate = 7.6% if patients with local/in transit recurrences are excluded (reasonable to perform this manipulation in that there is no failure in technique in identifying nodal disease because the subsequent metastasis came from the local recurrence. False negative rate 7.6% = []
      3. True Positive: 486 patients (19.8%)
   2. True Negative: 1,906 patients (77.8%) (sentinel lymph node negative, no regional recurrence)
2. Sunbelt Melanoma Trial SLN processing (ref Scoggins et al 2010)
   1. Serial section each SLN and process with H&E staining at multiple levels
      1. At least 5 sections per block
      2. 2 additional random sections for S-100 immunohistochemistry
   2. In Sunbelt study, a small portion of each SLN was taken for PCR study

 

Controversy re: Value of SLN biopsy for melanoma

(editorial comment by H Hoffman 12-28-2014 updated 2017)

Recent discussion regarding the merits of sentinel lymph node biopsy for melanoma have called these recommendations into question. The standard recommendation favoring liberal use of SLN biopsy (for clinically N0 melanoma other than T1a) has never been based on statistically proven survival benefit. Recent study has also failed to document survival benefit from inclusion of SLN biopsy compared to treatment without SLN biopsy (Sperry et al 2014). The Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) - a randomized controlled study comparing SLNB with observation in 1270 patients with intermediate Breslow depth (17% with head and neck primaries) - also failed to identify a significant difference in melanoma disease specific survival (Morton et al 2014). This study (similar to Sperry et al) identified a non-significant trend toward reduced risk of death from melanoma when SLNB was done - and has resulted in robust discussion of the value of SLN bx - highlighted by further subset analysis of the MSLT-1 study. Decision-making as to how to present SLN biopsy as an option to patients is now more complicated in view of published recommendations that are conflicting.

The 7th Edition AJCC Cancer Staging Manual (Melanoma, p 328) published in 2010 'strongly recommends that sentinel lymph node biopsy be required as an entry criterion for all melanoma patients presenting with clinical Stage IB or II disease (including T1a patients with melanoma = 1.00 mm) before entry into clinical trials involving new surgical techniques or adjuvant therapy". More contemporary NCCN guidelines (accessed 12-28-2014) identify that although SLNB is important in staging, the impact of SLNB on overall survival is unclear". The AJCC Staging Manual (2010) reports that SLNB 'should be used (or discussed with the patient) in defining occult Stage III disease among patients who present with clinical Stage IB or II melanoma". This discussion should include the concept that "decision not to perform SLNB may be based on significant patient comorbidities, patient preference, or other factors" (NCCN guidelines accessed 12-28-2014). Among the 'other factors' that warrant consideration include the location of the melanoma. Potential morbidity from a sentinel node biopsy of a superficial suboccipital node (see: Case Example Sentinel Lymph Node Biopsy) is less than from an intra-parotid node adjacent the facial nerve (as per: Parotidectomy with Facial Nerve Dissection). The need for a general anesthetic to perform sentinel node biopsy may induce additional morbidity that is not an issue if the lesion can be removed and reconstructed under local anesthesia.

A thoughtful analysis of cancer screening by Saini et al (2014) introduces a tailored approach to screening for cancer. Simulation modelling - incorporating cancer risk, life expectancy and screening efficacy - has been recently introduced as a tool for individualized cancer screening that possibly be exploited to help in decisions regarding use of sentinel node biopsy for patients with melanoma.

A recent (January 2016 Wat et al) multicenter review identified further stratification in the interpretation of mitotic rate as an indicator to perform SLN. These investigators that, using current methods, their study did not support use of mitotic rate to predict SLN positivity in thin melanoma. They identified the mitotic rate may help select patients with intermediate-thickness melanomas for SLNB - but was not useful in melanomas with thickness less than 1 mm. They identified the mitotic rate was also difficult to discriminate from Breslow thickness as an independent predictive variable for SLN positivity in that almost all (92%) of melamonas >2 mm in thickness had a mitotic rate >0. The identified the same rationale for tumors larger than 4.0 mm who have a mitotic rate >0 in 94.3%)

References

Morton DL, Thompson JF, Cochran AJ et al: Sentinel-Node Biopsy or Nodal Observation in Melanoma. N Engl J Med 2006;355:1307-17 (includes access to video by Dr. Morton: http://content.nejm.org/content/vol355/issue13/images/data/1307/DC1/NEJM...\]

The management of head and neck melanoma. Schmalbach CE, Johnson TM, Bradford CR. Curr Probl Surg. 2006 Nov;43(11):781-835. Review.

Merkel Cell Carcinoma. Swann, MH; Yoon,J; Semin Oncol 34:51-56

McMasters, KM, et al: Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 2001 Jun 1;19(11):2851-5

Scoggins CR, Martin RCG et al: Factors Associated with False-Negative Sentinel Lymph Node Biopsy in Melanoma Patients. Ann Surg Oncol (2010) 17:709-71

Meharany K, Otley CC, Weenig RH, Phillips PK, Roenigk RK, Nguyen TH: A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma.  Dermatol Surg. 2002 Feb;28(2):113-7; discusion 117

Neves RI, Reynolds BQ, Hazard SW, Saunders B, and Mackay DR:Increased Post-Operative Complications with Methylene Blue Versus Lymphazurin in Sentinel Lymph Node Biopsies for Skin Cancers. J Surg. Onc 2010 (epub)

Liu Y, Truini C, and Ariyan S: A Randomized Study Comparing the Effectiveness of Methylene Blue Dye with Lymphazuirn Blue Dye in Sentienl Lymph Node Biopsy for the Treatment of Cutaneous Melanoma. Annals of Surgical Oncology 15(9):2412-2417

Querfeld C, Wayne JD, Wei J-J, Abdul-Nabi Anmaar, and Gerami: Local Lymph Node Micrometastis in a Patientw ith Negative Sentianel Lymph Node Biopsies After Lymphatic Mapping With Wide Local Excision of Primary melanoma on the Hea/Neck Area. Am J Dermatopathol Vol 33, Number 7, October 2011

Vermeeren L, Valdes Olmos RA, Klop WM, et al SPECT-CT for sentinel lymph node mapping in head and neck melanoma. Head Neck 2011;33:1-6

Chao C, Wong SL, Edwards MJ et al. Sentienl lymph node biopsy for head and neck melanomas. Ann Surg Oncol 2003;10:21-26.

Mohebati A, Ganly I, Busam KJ, Coit D, Kraus DH, Shah JP, Patel SG: The Role of sentienl lymph node biopsy in the management of head and neck dsmoplastic melanoma. Ann Surg Oncol. 2012 Dec;19(13):4307-13  

Eppsteiner RW, Swick BL, Milhem MM, Hoffman HT and Pagedar NA: Sentinel node biopsy for head and neck desmoplastic melanoma: not a given. Otolaryngology Head Neck Sur. 2012 Aug:147(2):271-4

Sperry SM, Charlton ME, Pagedar NA: Association of Sentienl Lymph Node Biopsy With Survival for Head and Neck Melanoma: Survival Analysis Using the SEER Database.  JAMA Otolaryngol Head Neck Surg. 2014 Dec 1; 140 (12): 1101-9

Morton DL, Thompson JF, Cochran AJ, et al: MSLT Group. Final trial report of sentienl-node biopsy versus nodal observation in melanoma. N Eng J Med. 2014;370(7):599-609

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines (R)) version 1.2015 accessed 12-28-104 (http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf)

AJCC Cancer Staging Manual 7th Edition (2010) - Chapter 31 Melanoma of the Skin pp 325-344

Saini SD, van Hees, F and Vijan S: Smarter Screening for Cancer Possibilities and Challenges of Personalization. JAMA Dec 3, 2014 Vol 312 No21 pp 2211-2212

Wat H, Ambikaipakan S, Salopek TG: A retrospective, multicenter analysis of the predictive value of mitotic rate for sentinel lymph node (SLN) positivity in thin melanomas. Mournal of the American Academy of Dermatology Volume 74, Issue 1, January 2016, pp 94-101