When is a sentinel node biopsy indicated?

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Background

Sentinel lymph node biopsy (SLNB) is a surgical technique to identify low volume metastatic disease within the draining lymph node basin in patients undergoing treatment for primary melanoma. The technique was developed as a staging procedure to identify patients with a positive draining nodal basin and thereby minimise the morbidity associated with elective lymph node dissection in patients who may not require this procedure. Numerous studies have consistently demonstrated that the status of the sentinel lymph node (SLN) reflects the status of the entire draining nodal basin as measured by elective lymph node dissection.[1] The recently revised AJCC staging system (8th edition) requires a SLNB for patients with primary melanoma greater than 1mm in thickness in order to perform microstaging of the lymph node basin and accurately allocate a pathological disease stage.[2]

The technique of SLNB has been extensively described. Briefly, it involves pre-operative lymphoscintigraphy to identify the draining nodal basin for the anatomical location of the primary melanoma. This is followed by intraoperative intradermal injection of the melanoma site with patent blue dye. Intraoperative exploration through a small incision allows the identification of SLNs. A node is considered a SLN if it has tracer uptake and/or is stained blue. This dual modality approach allows the successful identification of a SLN in over 95% of patients. SLNs are carefully examined pathologically to identify metastasis.

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Summary of systematic review results

There have been numerous large studies published since the last guidelines regarding the role of SLNB in melanoma. The most important of these publications is the final report of the Multicentre Selective Lymphadenectomy Trial (MSLT-I).[3] This was a phase III randomised controlled trial comparing wide excision of the primary melanoma and regional nodal observation with wide excision and SLNB followed by immediate completion lymph node dissection (cLND) for patients with a positive SLNB. Patients in the observation arm underwent therapeutic lymph node dissection (tLND) if they developed clinical lymph node involvement. The study included 1661 patients and the main study population was the 1347 with melanoma of Breslow thickness between 1.2 and 3.5 mm. The rate of SLN involvement in the SLNB arm was 16% and of those patients with a negative results, the rate of subsequent nodal relapse (false negative SLNB) was 4.8%[3].

The reported primary endpoint of the study[3] was melanoma specific survival (MSS) and the final report demonstrated no difference in MSS for patients with intermediate thickness melanoma between those in the SLNB group (10 year MSS =81.4%) compared with the observation group (10 year MSS = 78.3%) (HR for death=0.84; 95% CI 0.64-1.09; P=0.18). Furthermore, there was no difference in distant disease-free survival between the two groups (HR=0.89; 95% CI 0.70-1.13; P=0.34). A post-hoc latent subgroup analysis was developed in an attempt to estimate treatment effect for the subgroup of patients who were SLN positive (ie. at baseline in the biopsy arm and those who would have tested positive had SLNB been performed in the observation arm). This showed that patients with intermediate thickness melanoma and nodal metastasis had a 10-year MSS of 62.1% with lymphadenectomy compared to 41.5% with observation (HR for death=0.56; 95% CI 0.37-0.84; P=0.006).

Controversy lies in the validity of comparing two possibly biologically different groups. It is impossible to prove that all patients with micrometastases in the sentinel node would progress to clinically overt disease if left untreated. SLNB was positive in 16% of patients in the SLN arm and the estimated cumulative incidence of nodal metastases at 10 years was 21.9% (adding patients with a false negative test) compared to an estimated cumulative incidence of nodal metastasis in the observation arm of 19.5% (ratio 1.12). This suggests a 12% greater rate of nodal metastases in the SLN arm relative to the observation arm which could be explained by over-diagnosis of single cell deposits in the sentinel node which may never progress (false positive SLNB), or by late nodal recurrences still pending in the observation group, or this difference may simply be attributable to chance.i

In a multivariate analysis, the MSLT-I study showed that the status of the SLN was the strongest predictor of MSS (10 year MSS for SLN positive = 62.1% versus 85.1% for SLN negative [HR for death = 3.09; 95% CI 2.12-4.49; P<0.001]). Multiple retrospective cohort studies have confirmed on multivariate analysis that the status of the sentinel node is significantly associated with MSS and in all but one[4] the status of the SLN was the most significant predictor of MSS (HR 1.5-6.9).[5][6][7][8]

Many studies have described predictors of a positive SLN, the most consistent of these include tumour thickness, ulceration, primary location outside of HN, mitotic rate >0, decreasing age, nodular subtype and TIL grade.[8][9] Predictors of sentinel node involvement from 7,756 patients in the AJCC database are shown in Table 1.

Table 1. Statistically significant predictors of sentinel node involvement and associated rates of involvement (total 7756 patients from Balch et al.)

Variable % patients with SLN involvement
Age
<40 years 21.3
40-59 years 20.0
≥60 years 17.6
Gender
Male 20.7
Female 17.7
Location
Head/neck 15.5
Upper extremity 15.1
Trunk 21.3
Lower extremity 22.3
Tumour thickness
≤ 1.0 6.0
1.01-2.0 14.0
2.01-4.0 27.3
>4.0 39.1
Ulceration
Absent 15.6
Present 29.9
Clark Level
I/II 4.5
III 11.9
IV 21.5
V 33.9
Lymphovascular Invasion
Absent 17.3
Present 47.2


Source: Balch et al 2014[10]

SLNB is a surgical procedure which usually requires a general anaesthetic. Complication rates for SLNB vary from 5.9-13.8%[11][12] and are significantly lower than for completion or therapeutic lymphadenectomy. Complications predominantly consist of seroma and wound infections; these are usually mild, manageable and of limited duration. Complication rates are inversely correlated with procedure volume.[12]

The addition of SLNB to the management of patients with primary melanoma involves the upfront use of increased resources, which raises the question of additional cost. Morton et al performed a cost-effectiveness analysis incorporating direct Australian health care data with the outcome data from the MSLT-1 study[13]. This study found only a slight increase in cost ($24,045 compared with $23,182 per patient) but an increase in cost effectiveness given the improved disease free survival and the reduced morbidity of completion lymph node dissection compared to therapeutic lymph node dissection for patients with macroscopic nodal disease.

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Special situations

Thin melanoma

In thin melanomas (Breslow thickness <1 mm), the risk of a positive sentinel lymph node is low (<5%), however there are certain subgroups of patients at increased risk of nodal involvement. Predictors of a rate of SLN involvement of greater than 5% in melanoma less than 1 mm include Breslow thickness >0.75 mm combined with another high risk feature, such as ulceration, mitotic rate >1, Clark level IV or V or lymphovascular invasion.[14][15][16] As described for intermediate thickness melanoma, in patients with thin melanoma, SLN involvement is associated with significantly worse MSS.[14]

Thick melanoma

The risk of SLN involvement increases with Breslow thickness. The MSLT-1 study demonstrated a SLN positive rate of 33% in patients with thick melanomas. Whilst the status of the SLN remains the most significant predictor of outcome for patients with thick melanoma (HR 2.3), the procedure itself does not offer a survival benefit in this group.[17]

Desmoplastic melanoma

A positive SLN is found in 13.7% of patients with desmoplastic melanoma.[18] The rate of nodal involvement differs according to whether the melanoma is a pure or mixed DM, with much lower rates in pure DM.

Atypical spitz naevi and spitzoid melanoma

Atypical spitz naevi are more commonly seen in younger patients, SLNB can be positive in these patients however this does not reflect malignancy nor is it a predictor of outcome, therefore SLNB is not recommended. By contrast, spitzoid melanoma is a subtype of melanoma and therefore these guidelines apply.

SLN after prior wide excision

Wide local excision can interrupt lymphatic drainage patterns and therefore reduce the accuracy of SLNB. A number of studies have demonstrated that SLNB is feasible after prior WLE, but it may be inaccurate.[19][20] Where possible SLNB should be performed at the same time as WLE.

Head and neck melanoma

There is increased complexity associated with SLNB in the head and neck region compared to other sites because of the anatomical proximity of the primary site to the sentinel node in addition to more complex lymphatic drainage patterns in the head and neck.[21] As such, SLNB in the head and neck is associated with a higher false negative rate.

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Evidence summary and recommendations

Evidence summary Level References
The status of the sentinel lymph node is the most significant predictor of melanoma-specific survival for patients with melanoma >1 mm Breslow thickness. III-3, IV [5], [6], [7], [8], [17]
Overall, for patients with melanoma >1 mm thick, sentinel lymph node biopsy followed by immediate completion lymph node dissection for a positive node does not prolong melanoma specific survival or overall survival compared with not performing sentinel node biopsy (nodal observation) and delayed lymph node dissection for clinically detected nodes. II [3]
For patients with intermediate thickness melanoma (1.2-3.5mm thick) who harbour metastatic disease within the sentinel node, early intervention with sentinel lymph node biopsy may be associated with an increased melanoma specific survival compared with nodal observation. III-2 [3]
Complication rates for sentinel lymph node biopsy are low. The procedure should be performed in a centre with appropriate expertise as complication rates are inversely related to procedure volume - this particularly applies to primaries arising in the head and neck. III-3 [11], [12]

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Recommendations

Evidence-based recommendationQuestion mark transparent.png Grade
Sentinel lymph node biopsy should be considered for all patients with melanoma greater than 1 mm in thickness and for patients with melanoma greater than 0.75 mm with other high risk pathological features to provide optimal staging and prognostic information and to maximise management options for patients who are node positive.
B


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Sentinel lymph node biopsy (SLNB) should be performed at the time of the primary wide excision.


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Sentinel lymph node biopsy (SLNB) should be performed in a centre with expertise in the procedure, including nuclear medicine, surgery and pathology to optimise the accuracy of the test.


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Patients being considered for sentinel lymph node biopsy (SLNB) should be given an opportunity to fully discuss the risks and benefits with a clinician who performs this procedure.


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A consideration of sentinel lymph node biopsy (SLNB) forms an important part of the multidisciplinary management of patients with clinically node negative cutaneous melanoma.


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Sentinel lymph node biopsy provides accurate staging of the lymph node basin by presenting a high-yield, low volume tissue sample for histopathological assessment. Not surprisingly, there is an increased rate of detection of micrometastatic disease when increasing numbers of sections are evaluated pathologically including when supplemented by immunohistochemistry for melanoma associated antigens. However there is no consensus as to the optimal number of sections that should be examined, the levels at which they should be cut from the paraffin block and which immunostains should be utilised.


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Sentinel lymph nodes (SLNs) should be removed intact, preferably with a thin rim of surrounding adipose tissue and be devoid of crush or diathermy artefacts that may complicate pathological assessment. The pathology request form should indicate the number of removed SLNs and their anatomical locations and the specimens clearly labelled. Any “second tier” lymph nodes or non-SLNs that have also been removed should be indicated as such on the request form and the specimens clearly labelled. The pathologist should slice the SLN using either the bivalving procedure along its longitudinal axis through the median plane or cut the SLN into multiple transverse slices using the “bread loaf” technique to make available the largest cut surface area of lymph node tissue for pathological examination. To identify low volume metastases, pathologists should examine multiple haematoxylin-eosin and immunohistochemically-stained sections from each SLN. Sections from each slice of all SLNs should be stained with both H&E and immunohistochemistry for melanoma associated antigens. HMB-45, S100, SOX10, Melan A and tyrosinase have all been utilised as immunohistochemical stains. As per AJCC guidelines, in patients with positive SNs, the single largest maximum dimension (measured in millimeters to the nearest 0.1 mm using an ocular micrometer) of the largest discrete metastatic melanoma deposit should be recorded in the pathology report. Routine frozen section examination of SNs from melanoma patients is not recommended.

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Conclusions

Sentinel lymph node biopsy is primarily a staging procedure which provides the best means of prognostic stratification for patients with melanoma greater than 1 mm thick and for some patients with thin melanoma with high risk features. Recently published data demonstrate that adjuvant systemic therapy for patients with resected stage III disease has a major impact in extending patient relapse-free survival and overall survival. This benefit has been shown for both immunotherapy[22][23] and molecular targeted therapy (for patients harbouring a BRAF mutation)[24] and includes patients with SLN- positive disease (link to systemic therapies chapters to be added once published). While these drugs are not currently subsidised in Australia on the PBS, SLNB provides patients with the necessary information to be aware of their recurrence risk and to seek access to adjuvant therapies where available.

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Footnote

i A Cochrane review has been performed regarding the use of SLNB for melanoma (Kyrgidis et al). This review has not been cited in the evidence as the NHMRC recommendations for developers of guidelines suggest that a “systematic review should consist of at least two studies” (p. 16).[25] The paper by Kyrgidis et al only cites a single study, the MSLT-1 study[3] which is extensively discussed in the guidelines.

References

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  2. Gershenwald JE, Scolyer RA, Hess KR et al.. Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al, eds.. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017. p. 563-85.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 2014 Feb 13;370(7):599-609 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24521106.
  4. Speijers MJ, Bastiaannet E, Sloot S, Suurmeijer AJ, Hoekstra HJ. Tumor Mitotic Rate Added to the Equation: Melanoma Prognostic Factors Changed? : A Single-Institution Database Study on the Prognostic Value of Tumor Mitotic Rate for Sentinel Lymph Node Status and Survival of Cutaneous Melanoma Patients. Ann Surg Oncol 2015 Jan 21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25605514.
  5. 5.0 5.1 Teixeira V, Vieira R, Coutinho I, Cabral R, Serra D, Julião MJ, et al. Prediction of sentinel node status and clinical outcome in a melanoma centre. J Skin Cancer 2013;2013:904701 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24455276.
  6. 6.0 6.1 Tejera-Vaquerizo A, Nagore E, Herrera-Acosta E, Martorell-Calatayud A, Martín-Cuevas P, Traves V, et al. Prediction of sentinel lymph node positivity by growth rate of cutaneous melanoma. Arch Dermatol 2012 May;148(5):577-84 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22250187.
  7. 7.0 7.1 Venna SS, Thummala S, Nosrati M, Leong SP, Miller JR 3rd, Sagebiel RW, et al. Analysis of sentinel lymph node positivity in patients with thin primary melanoma. J Am Acad Dermatol 2013 Apr;68(4):560-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23182069.
  8. 8.0 8.1 8.2 Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 2012 Jul 20;30(21):2678-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22711850.
  9. Fadaki N, Li R, Parrett B, Sanders G, Thummala S, Martineau L, et al. Is head and neck melanoma different from trunk and extremity melanomas with respect to sentinel lymph node status and clinical outcome? Ann Surg Oncol 2013 Sep;20(9):3089-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23649930.
  10. Balch CM, Thompson JF, Gershenwald JE, Soong SJ, Ding S, McMasters KM, et al. Age as a predictor of sentinel node metastasis among patients with localized melanoma: an inverse correlation of melanoma mortality and incidence of sentinel node metastasis among young and old patients. Ann Surg Oncol 2014 Apr;21(4):1075-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24531700.
  11. 11.0 11.1 Kretschmer L, Thoms KM, Peeters S, Haenssle H, Bertsch HP, Emmert S. Postoperative morbidity of lymph node excision for cutaneous melanoma-sentinel lymphonodectomy versus complete regional lymph node dissection. Melanoma Res 2008 Feb;18(1):16-21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18227703.
  12. 12.0 12.1 12.2 Roaten JB, Pearlman N, Gonzalez R, Gonzalez R, McCarter MD. Identifying risk factors for complications following sentinel lymph node biopsy for melanoma. Arch Surg 2005 Jan;140(1):85-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15655211.
  13. Morton RL, Howard K, Thompson JF. The cost-effectiveness of sentinel node biopsy in patients with intermediate thickness primary cutaneous melanoma. Ann Surg Oncol 2009 Apr;16(4):929-40 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18825458.
  14. 14.0 14.1 Han D, Zager JS, Shyr Y, Chen H, Berry LD, Iyengar S, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol 2013 Dec 10;31(35):4387-93 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24190111.
  15. Bartlett EK, Gimotty PA, Sinnamon AJ, Wachtel H, Roses RE, Schuchter L, et al. Clark level risk stratifies patients with mitogenic thin melanomas for sentinel lymph node biopsy. Ann Surg Oncol 2014 Feb;21(2):643-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24121883.
  16. Murali R, Haydu LE, Quinn MJ, Saw RP, Shannon K, Spillane AJ, et al. Sentinel lymph node biopsy in patients with thin primary cutaneous melanoma. Ann Surg 2012 Jan;255(1):128-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21975320.
  17. 17.0 17.1 Gyorki DE, Sanelli A, Herschtal A, Lazarakis S, McArthur GA, Speakman D, et al. Sentinel Lymph Node Biopsy in T4 Melanoma: An Important Risk-Stratification Tool. Ann Surg Oncol 2015 Oct 15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26471491.
  18. Han D, Zager JS, Yu D, Zhao X, Walls B, Marzban SS, et al. Desmoplastic melanoma: is there a role for sentinel lymph node biopsy? Ann Surg Oncol 2013 Jul;20(7):2345-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23389470.
  19. Ariyan S, Ali-Salaam P, Cheng DW, Truini C. Reliability of lymphatic mapping after wide local excision of cutaneous melanoma. Ann Surg Oncol 2007 Aug;14(8):2377-83 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17541771.
  20. Leong WL, Ghazarian DM, McCready DR. Previous wide local excision of primary melanoma is not a contraindication for sentinel lymph node biopsy of the trunk and extremity. J Surg Oncol 2003 Mar;82(3):143-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12619055.
  21. de Rosa N, Lyman GH, Silbermins D, Valsecchi ME, Pruitt SK, Tyler DM, et al. Sentinel node biopsy for head and neck melanoma: a systematic review. Otolaryngol Head Neck Surg 2011 Sep;145(3):375-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21540313.
  22. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 2016 Nov 10;375(19):1845-1855 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/27717298.
  23. Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891423.
  24. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 2017 Sep 10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/28891408.
  25. National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for guideline developers. Canberra: National Health and Medical Research Council; 2009 Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/guidelines/developers/nhmrc_levels_grades_evidence_120423.pdf.

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Appendices