The Use Of Sentinel Lymph Node Biopsy In MElanoma Kitty Lo Queen Elizabeth Hospital

50/M Presented with a 2 x 1.5 cm irregular pigmented skin lesion over the left side of the trunk

Total body skin examination reveals no other suspicious lesions Palpation of all lymph node basins show no clinically detectable lymphadenopathy

Excisional biopsy Malignant melanoma Superficial spreading melanoma Breslow thickness 1.5mm Mitotic rate 1/mm2 Ulceration + Closest margin 1mm

Breslow thickness Depth (in mm) from the granular layer of the epidermis to the deepest part of tumour T staging in AJCC Melanoma Staging (2010)

Breslow Thickness With increasing tumour thickness, there is a significant decline in the 5 year and 10 year survival rates1 1- Balch CM, Gershenwald JE, Soong SJ, et al: Final Version of 2009 AJCC Melonoma Staging and Classification. J Clin Oncol 2009, 27:6199-6206

Mitotic Rate Powerful predictor of survival, after tumour thickness >=1/mm2 associated with decreased survival1-4 1- Balch CM, Gershenwald JE, Soong SJ, et al: Final Version of 2009 AJCC Melonoma Staging and Classification. J Clin Oncol 2009, 27:6199-6206 2- Gimotty PA, Elder DE, Fraker DL, et al: Identification of high risk patients among those diagnosed with thin cutaneous melanomas. J Clin Oncol 2007, 25:1129-1134 3- Kesmodel SB, Karakousis GC, Botbyl JD, et al: Mitotic rate as a predictor of sentinel lymp node positivity in patients with thin melanomas. Ann Surg Oncol 2005, 12:449-458 4- Fracken AB, Shaw HM, Thompson JF, et al: The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follo-up. Ann Surg Oncol 2004, 11:426-433

Ulceration Tumour ulceration is significantly associated with decrease in survival 1-3 1- Balch CM, Gershenwald JE, Soong SJ, et al: Final Version of 2009 AJCC Melonoma Staging and Classification. J Clin Oncol 2009, 27:6199-6206 2- I Koshivuo, Hernberg M, Vihinen P, et al: Sentinel lymph node biopsy and survival in elderly patients with cutaneous melanoma. British Journal of Surgery 2011 98:1400-1407 3- Jones EL, Jones TS, Pearlman NW, et al: Long term follow up and survival following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg. 2013 May; 148(5)

Margins

USG of left groin and axilla: Clinically cT2N0 No radiologically suspicious lymph nodes Clinically cT2N0 Proceeded to wide local excision + sentinel lymph node biopsy (SLNB)

What is Sentinel LympH Node Biopsy?

Sentinel LympH Node Biopsy In Melanoma The initial route of metastasis in most patients with melanoma is to regional lymph nodes Historically, clinically LN –ve patients either received elective LN dissection prophylactically, or were observed till clinically LN metastasis was evident and received therapeutic LN dissection LN dissection associated with significant morbidity

Sentinel LympH Node Biopsy Identify the first lymph node(s) receiving lymphatic drainage from the tumour SLN no malignancy unlikely that the tumour involves other nodes in the same LN basin -> no need for LN dissection SLN +ve for malignancy possible that the disease has spread into other LN in the same basin -> proceed to LN dissection

SLNB –How it’s done Radioactive tracer (99m Tc labelled colloid) injected around the primary tumour/ excisional biopsy scar subdermally 1 day before or same day of surgery Lymphoscintigraphy performed to visualize the lymphatic drainage pathways and SLN If combined with SPECT/ CT, a higher overall SLN detection rate (particularly useful in head & neck melanoma) 1-2 1- Ingo S, Christian B, Thorsten P, etc. Association between sentinel lymph node excision with or without preoperative SPECT/CT and metastatic node detection and disease free survival in melanoma. JAMA 2012; 308 (10) :1007-1014 2- Bluemel C, Herrmann K, Giammarile F, et al. EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma. Eur J Nucl Med Mol Imaging 2015; 42:1750-1766

SLNB – How it’s Done Intraoperatively guided by hand held gamma probe The most radioactive (hottest) LN removed Any LN with >=10% of the hottest LN’s radioactive count (measured ex-vivo) are removed Bluemel C, Herrmann K, Giammarile F, et al. EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma. Eur J Nucl Med Mol Imaging 2015; 42:1750-1766

SLNB – How It’s Done Some surgeons will also inject patent blue/ isosulphan blue intradermally around the tumour/ biopsy site at the beginning of the operation Dissect the blue draining vessels until it drains into a blue SLN Bluemel C, Herrmann K, Giammarile F, et al. EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma. Eur J Nucl Med Mol Imaging 2015; 42:1750-1766

SLNB – How It’s Done Any palpable LN (even if non-hot & non-blue) should also be removed 13% SLN are only radioactive (hot), 1% only blue, 86% both hot and blue 1 1- Estourgie SH, Nieweg OE, Valdes Olmos RA, et al. Review and evaluation of sentinel lymph node procedures in 250 melanoma patients with a median follow up of 6 years. Ann Surg Oncol 1998; 5: 517-21

How IT All STarted Published in the Archives of Surgery, 1992

223 patients with localized, clinically node –ve melanoma All patients had WLE + SLNB + immediate lymph node dissection 82% SLN identification rate SLN +ve in 18% False omission rate 1% -see if SLNB was feasible, and whether the SLN status could accurately predict the presence of occult metastasis in the regional LN

SLNB can identify with a high degree of accuracy patients with subclinical LN metastases who are likely to benefit from LN dissection

Multicentre Selective Lymphadenectomy Trial -1 Final trial report published 2014

Multicentre Selective Lymphadenectomy Trial -1 18 centres in Europe, Australia and US 2001 patients with primary cutaneous melanoma (1994- 2002) Randomized in a 4:6 ratio to WLE + observation, with LND for clinically evident nodal relapse vs WLE + SLNB, with completion LND for +ve SLNB Stratified by Breslow thickness Intermediate 1.2- 3.5mm Thick >3.5mm Followed up for 10 years Phase 3 RCT Main focus was on intermediate thickness group as prelim studies show that SLNB was most likely to benefit those with intermediate thickness Few patients with thin melanoma so this subgroup was not analyzed Included patients with breslow thickness >=1mm + clark level III, or clark level IV/ V with any thickness

SLN status was the strongest predictor of disease recurrence or death from melanoma

Overall 10 year Melanoma Specific Survival No significant difference between treatment groups for both intermediate and thick melanomas

Overall 10 year Disease Free Survival Significantly higher in the biopsy group for both Intermediate and Thick melanoma

Looking at the subgroup with nodal metastasis SLN +ve with immediate completion LND versus observation till clinically evident LN metastasis then therapeutic LND SLNB significantly prolongs melanoma specific survival & distant disease free survival in intermediate thickness melanoma Similar benefit was not seen for thick melanomas Still significant effect even after including patients with false –ve SLNB with subsequent LN recurrence into the biopsy group

Conclusion SLNB provides important prognostic information For all patients, biopsy based management prolongs disease free survival For patients with nodal metastasis from intermediate thickness melanomas, SLNB also prolongs melanoma specific survival and distant disease free survival

SLN status incorporated into n staging Latest AJCC guidelines in 2010 Prognostic significance of SLN validated by many studies

Management pathway of Melanoma Pathology Report: Breslow thickness Ulceration status Mitotic rate Deep and peripheral margin status Presence of microsatellitosis Clark level (for lesions <=1mm) Excisional biopsy (1-3mm margins) preferred; or full thickness incisional biopsy at clinically thickest portion Complete skin examination + Locoregional lymph node examination Suspicious pigmented lesion 1- Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Joint Clinical Practice Guideline. J Clin Oncol. 2012;30:2912-18. 2- NCCN Guidelines Version 3.2016 Melanoma

Management pathway of Melanoma Breslow thickness <=0.75mm Wide Local Excision Breslow thickness 0.76- 1mm, no ulceration, mitotic rate 0/mm2 Wide local excision + Consider SLNB Clinically node negative SLN -ve Observe SLN +ve Completion LN dissection Wide local excision + SLNB Breslow thickness 0.76-1mm, with ulceration, or mitotic rate >=1/mm2 OR Breslow thickness >1mm 1- Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Joint Clinical Practice Guideline. J Clin Oncol. 2012;30:2912-18. 2- NCCN Guidelines Version 3.2016 Melanoma

The Future?

Can LN dissection be avoided in most patients with +ve SLN? Only 10-20% of patients with +ve SLN have tumour +ve non SLN identified in completion LN dissection 1 If nodal metastases are limited to one or two sentinel nodes, then SLNB might be therapeutic as well as diagnostic Can LN dissection be avoided in most patients with +ve SLN? (12% in MSLT-I trial) 1- Lee JH, Essner R, Torisu-Itakura H, et al. Factors predictive of tumour positive nonsentinel lymph nodes after tumour positive sentinel lymph node dissection for melanoma. J Clin Oncol. 2004; 22:3677-3684

MSLT –II trial Opened in 2005 and ongoing Finished patient recruitment Patients with +ve SLNB randomized to receive: Completion LN dissection Ultrasound observation of the LNs Primary outcome is melanoma-specific survival No data published yet 3992 patients Secondary outcomes include overall survival and disease-free survival, prognostic accuracy of histopathology, molecular and immunologic markers, and quality of life. Morton DL. Overview and Update of the Phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in Melanoma. Clin Exp Metastasis. 2012 Oct; 29(7): 699–706.

Thank You Questions are welcome

5840 patients, non-randomized cohort SLNB significantly improved disease free survival & regional recurrence free survival Also improved distant metastasis free survival in melanomas >1mm -4mm No significant difference in melanoma specific survival

Current guidelines American Society of Clinical Oncology & Society of Surgical Oncology1: Offer SLNB for melanoma >=1mm – 4mm SLNB recommended for thick melanomas >4mm for staging and to facilitate regional disease control SLNB recommended for thin melanomas (0.75 -1mm) when 1 or more adverse prognostic features present (ulceration, mitotic rate >=1/mm2, Clark level IV/V) 1- Wong SL, Balch CM, Hurley P, et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Joint Clinical Practice Guideline. J Clin Oncol. 2012;30:2912-18.

For those without nodal metastasis SLN –ve versus observation, with no development of clinically evident LN met No difference in the 10 year melanoma specific survival In patients with SLN –ve, SLNB provides critical prognostic information but no therapeutic benefit

MSLT -1 SLN identification rate 95.3% False omission rate 5.7% No. of false –ve SLNB/ Total no. of –ve SLNB Lower complication rate with SLNB vs LND (10.1% vs 37.2% for local complications) Local complications such as wound infection,. Separation, seroma/ haematoma The study did not look into long term morbidity for SLNB vs LND SN identification rate: 99.3% groin, 95.3% axilla, 84.5% neck Long term follow up confirmed similar rates of nodal metastasis in the 2 groups, indicating that essentially all metastases detected by SLNB would eventually become clinically evident if not removed