Sentinel lymph node (SLN) staging is commonly performed for patients with intermediate-thickness melanoma because it is an accurate and minimally invasive means of staging the regional nodal basin. The pathologic status of regional lymph nodes in patients with intermediate-risk melanoma is a strong predictor of survival 1. The role of SLN biopsy in patients with thin melanoma (<1 mm) is more controversial but it is typically considered in patients with other risk factors such as an elevated mitotic count, ulceration, lymphovascular invasion, or Clark’s level IV or V 2. Over 80% of patients undergoing an SLN biopsy will have negative nodes, however, and identification of additional prognostic factors among these patients is clearly important. SLN− patients can expect an improved survival relative to SLN+ patients, but the 5-year disease-specific mortality for patients with intermediate-thickness melanoma is still appreciable, at almost 10% 1. We have shown previously that information obtained from lymphoscintigraphy drainage patterns may offer additional prognostic information in SLN− patients with melanoma. Multiple lymphatic basin drainage (MLBD) in SLN− patients with truncal melanomas is an independent predictor of poorer survival 3. In addition, we have observed that the number of SLNs identified at SLN mapping is associated with poor prognostic features such as increased Breslow’s depth and lymphovascular invasion of the primary lesion, anatomic tumor site, and patient age 4. These findings suggest that host and tumor factors may interact to influence lymphangiogenesis and lymphatic drainage patterns observed at SLN mapping, and that additional prognostic information may be obtained from these observations.
In patients with melanoma of the lower extremity, sites of radiotracer uptake may include the popliteal fossa, the superficial inguinal, and the deep inguinal and pelvic nodal basins. A recent study suggests that drainage to pelvic nodes (DPN) in patients with lower extremity melanoma may have prognostic significance 5. Metastases to deep inguinal or pelvic lymph nodes have been associated with a poor prognosis, with a 5-year survival of 28–42% in patients selected for surgery 6–9. Patients with DPN do not undergo routine sampling of pelvic lymph nodes during an SLN biopsy, as these nodes are not easily accessible and are typically considered secondary echelon nodes. We reviewed our large prospective melanoma database to ask whether DPN has prognostic significance in patients with melanoma of the lower extremity. In addition, we asked whether recurrent melanoma was more common in patients with DPN at lymphatic mapping compared with patients without DPN.
Patients and methods
The study was approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center (MSKCC) and performed in accordance with Health Insurance Portability and Accountability Act regulations. The prospective melanoma database at the MSKCC was queried to identify patients with melanoma of the lower extremity or buttocks who underwent lymphoscintigraphy and an SLN biopsy at MSKCC. Four hundred one patients were identified who were treated between December 1995 and October 2008. Of these, 356 patients had successful lymphatic mapping with lymphoscintigraphy images available for rereview. Patients with multiple primary melanomas, locally recurrent melanoma, or indeterminate DPN were excluded, leaving 325 patients in the study group. All lymphoscintigraphy images were rereviewed by a single nuclear medicine radiologist (N.P.T.). Definitions of the various pathologic variables analyzed have been described previously. Mitotic rate (MR) was defined as mitoses/mm 2 and was treated as a continuous variable in the analyses. Pelvic nodal recurrence was defined as melanoma metastatic to the iliac or obturator nodes confirmed by histology or as assessed radiographically by cross-sectional imaging. Patients with melanoma recurrence in any location were only classified as having no pelvic recurrence if they had no evidence of pelvic lymphadenopathy by cross-sectional imaging performed within 6 months of the date of the last follow-up; otherwise, the patients were categorized as having pelvic nodal recurrence status unknown.
Lymphatic mapping and characterization of pelvic lymphatic drainage
Patients underwent preoperative lymphoscintigraphy using a 99mTc-labeled sulfur colloid (0.05 mCi/injection, volume 0.25 cc; MDS Nordion, Ottawa, Ontario, Canada) injected intradermally into four sites around the site of the primary lesion. Dynamic images were acquired immediately for 10 min and static images were acquired using a 57Co flood source for 5 min per view after the injection of radiolabeled colloid. Anterior and lateral images of the pelvis and of the site of primary lesion were obtained. Drainage to pelvic lymph nodes (external iliac, common iliac, or obturator lymph nodes) was determined using anterior–posterior (AP) static images outlining the body profile to approximate the location of the inguinal ligament and lateral static images to gauge the depth in the AP axis of the LNs. AP distance was defined as the distance from the AP silhouette borders at the level of the inguinal ligament. Lymph nodes were classified as ‘pelvic’ when the location was cephalad to the inguinal ligament and posterior to the anterior silhouette border by at least 1/3 the total AP distance. Confirmation of DPN was made by a single nuclear medicine radiologist (N.P.T.).
In the operating room, a small volume of lymphazurin blue dye was injected into the dermis surrounding the primary site. Localization of the SLNs was accomplished using a hand-held gamma probe. Lymph nodes with uptake of radiotracer (‘hot’ nodes) and/or blue dye were excised and sent for pathologic analysis as SLNs. These nodes were analyzed thoroughly after serial sectioning by specialized pathologists. After 1997, SLNs that were negative for metastatic disease by hematoxylin and eosin staining were also analyzed by immunohistochemistry. Completion lymph node dissection (CLND) was routinely presented to patients as the ‘standard approach’ in the setting of a positive SLN. A significant proportion of patients did not undergo CLND, however, and elected to undergo clinical surveillance of the nodal basin. CLND typically entailed a superficial inguinal node dissection, with removal of all nodes in the inguinofemoral triangle. Combined pelvic nodal dissection at the time of CLND was not routinely performed.
Associations of clinical and pathologic characteristics with DPN were identified using the Wilcoxon rank-sum test for continuous variables and Fisher’s exact test for categorical variables. Factors associated with DPN on univariate analysis (P≤0.2) were entered into a multivariable logistic regression model and, using a stepwise selection approach, only variables with P-value less than 0.05 were retained in the final model.
The association between DPN and time to melanoma recurrence (TTR), defined as the time from SLN biopsy to the date of first recurrence, was analyzed by Cox regression. Considering the limited number of events in the overall cohort and especially in the SLN− subgroup, we examined the prognostic utility of DPN by fitting multivariable models with DPN adjusted only for factors known to be consistently important predictors of melanoma recurrence, including tumor thickness and ulceration, for all patients and among SLN− patients. Age was also included in a multivariable model for TTR as it was found to be predictive of DPN. Thickness was categorized at cut points used in the AJCC staging system 10 (≤1.00, 1.01–2.00, 2.01–4.00, >4.00 mm). Statistical analyses were carried out using SAS 9.2 software (SAS Institute, Cary, North Carolina, USA).
Clinical and histopathologic characteristics of the study group
The median age of the study population was 56 years (range 11–95 years) and 61% of the patients were women. The majority of primary lesions were located on the thigh or the leg (71%), with 25% located on the foot and 4% on the buttocks. The median Breslow thickness was 1.7 mm (0.3–19 mm) and 32% of the primary lesions were ulcerated. Sixty-three percent of the lesions for which MR was available (N=272) had an MR of more than 1. The clinical and histopathologic characteristics of the patients are summarized in Table 1.
Incidence and predictors of drainage to pelvic nodes
Of the 325 patients, 76 (23%) showed evidence of DPN by lymphoscintigraphy. The median number of pelvic nodes identified by lymphoscintigraphy in these patients was 1 (range 1–5). In 94% of patients with DPN, the most radio intense pelvic node was of a lower intensity than the most radio intense node of the superficial inguinal nodal basin, whereas in the remainder of the cases it was isointense. By univariate analysis (Table 1), patient age (P=0.002) and Breslow’s thickness (P=0.006) were found to be significantly associated with DPN, with older patients and thicker primaries associated with DPN. The median age in the DPN group was 62 versus 54 years in the no DPN group. Seventeen percent of patients with lesions 2.00 mm or less in thickness showed DPN versus 33% of patients with primary lesions more than 2.00 mm in thickness. Both patient age and Breslow’s thickness remained significantly associated with DPN when entered into a multivariate model (Table 2).
Predictors of time to melanoma recurrence
Seventy of 325 patients (21.5%) developed recurrent disease at a median follow-up of 38 months (range 0–146 months). DPN was evaluated by univariate and multivariate analyses along with other clinical and histopathologic variables to assess its prognostic significance. The 3-year recurrence-free survival in patients with DPN was 71% [95% confidence interval (CI) 57–81%] compared with 81% (95% CI 74–86%) in patients without DPN. In SLN− patients, the 3-year recurrence-free survival was 82% (95% CI 65–91%) for patients with DPN versus 89% (95% CI 83–93%) for those with no DPN.
Univariate analysis of factors associated with TTR in SLN− patients (n=250) showed that DPN was marginally associated with a shorter TTR but this did not reach statistical significance (P=0.07, Table 3). Primary tumor factors such as Breslow’s thickness, ulceration, MR, lymphovascular, and perineural invasion were significantly associated with TTR, as was patient age.
A multivariable analysis was carried out in all patients as well as those who were SLN−. DPN was associated with a shorter TTR in SLN− patients when tumor thickness and ulceration were entered into the model. When patient age was included in the model, the association of DPN with TTR was not significant (P=0.08) (Table 4).
Drainage to pelvic nodes does not predict the number of sentinel lymph nodes or sentinel lymph node status
The median number of SLNs removed was the same in the DPN and no DPN groups (n=2). Twenty-three percent (75/325) of patients had metastases to the SLN(s) with a median number of one positive SLN (range 1–4). There was no difference in SLN positivity between patients with and without DPN (P=0.64). Of the 76 patients with DPN, only nine (12%) underwent sampling of pelvic LNs during the SLN biopsy procedure. In all cases, the pelvic SLNs were found to be pathologically negative. Among SLN+ patients, 46% (26/56) went on to have a CLND within 4 months of the SLN biopsy in the DPN− group and similarly 47% (9/19) underwent CLND in the DPN+ group. The most common reason for patients not proceeding with CLND was patient refusal. Only four patients (4/35, 11.4%) were found to have positive non-SLN upon CLND, precluding a determination of whether DPN increased the risk of additional positive nodes at CLND.
Drainage to pelvic nodes and patterns of melanoma recurrence
Site(s) of first melanoma recurrence stratified by DPN status DPN are shown in Table 5. The most common site of isolated first recurrence in the 70 patients who developed recurrent disease was in-transit or local (regional non-nodal), occurring in almost half of the patients with recurrence. Patients with and without DPN had similar observed rates of regional non-nodal recurrence. Nodal metastases in isolation of other regional disease were found in 9.2% of patients (7/76) with DPN versus in 4% (11/249) of patients with no DPN. Among patients who recurred and had a cross-sectional imaging study to evaluate the pelvis for adenopathy within 6 months of the date of the last follow-up (N=56), 15 of 38 patients (39%) had radiographically evident pelvic nodal adenopathy or pathologically proven pelvic nodal disease in the DPN-negative group and seven of 18 patients (39%) in the DPN-positive group.
We have reported previously that the presence of MLBD is associated independently with decreased recurrence-free and overall survival in patients with truncal melanoma 3. Other investigators have reported no association of MLBD with outcome 11,12, although Porter et al. 13 reported an increased risk of SLN positivity in patients with truncal melanoma and MLBD. Our data show that radiotracer uptake in the pelvis at lymphoscintigraphy (DPN) occurs in almost a quarter of patients with melanoma of the lower extremity and buttocks. Soteldo et al.5 recently examined the prognostic value of radiotracer uptake (hot spots) in the pelvis in 104 patients with clinical stage I and II melanoma of the lower extremity or trunk. They noted pelvic recurrence in two (2.4%) of the 83 SLN− patients, slightly higher than the reported value of ∼1% seen among SLN− patients irrespective of radiotracer uptake in the pelvis 14. Moreover, they observed a 5-year disease-free survival of 69% among SLN− patients with pelvic ‘hot spots’, compared with 83% seen among all SLN− patients in the MSLT1 trial 1.
In the current study, older age and increased Breslow’s thickness were found to be associated with DPN. As others have reported previously, we found that age 15, sex 16, anatomic site 17, MR 18, ulceration 10,19,20, lymphovascular invasion 21,22, satellitosis 23,24, Breslow’s depth 10,19,23, and SLN status 1,25–27(data not shown) were associated with TTR by univariate analysis. In SLN− patients only, DPN was associated with TTR when thickness and ulceration were included in the multivariate model. Age was associated with DPN, however, and when included in the multivariate model, DPN was only marginally associated with TTR, although this did not reach statistical significance.
In almost all cases with DPN, radiotracer intensity in the pelvis was less than that in the superficial inguinal nodal basin (although precise radiotracer counts were not recorded), suggesting that in most patients, DPN represented second echelon drainage. Moreover, none of the nine patients undergoing pelvic SLN biopsy were found to have +positive pelvic SLNs. Finally, the clinical recurrence rates in the pelvis among patients who recurred were similar between patients with and without DPN, suggesting that the observation of DPN should not alter surgical management and does not appear to support routine pelvic node biopsy in these patients. Our study is limited, however, by a relatively small number of patients with clinical pelvic nodal failure and with the variable follow-up inherent in clinical practice. As pathologic assessment of the pelvic nodes seen by lymphoscintigraphy was not routinely performed, there is the possibility of a false-negative classification of SLN− patients with DPN (understaging).
The results presented in the current study on pelvic nodal disease and DPN are in concordance with those published elsewhere. Kaoutzanis et al. 28 recently reported on 82 patients with primary melanoma of the lower trunk or extremity, of whom 11 had pelvic nodes removed at the time of SLN biopsy, none of which indicated metastatic disease despite being radioactively ‘hot’. Chu et al. 29 reported on 40 patients with positive inguinal sentinel nodes who underwent, in an unselected manner, an inguinopelvic dissection by a single surgeon. The rate of synchronous pelvic metastases as determined by pathology in these patients was noted to be 11.9%. Although there was a trend for more patients having secondary pelvic drainage as noted by lymphoscintigraphy in the pelvic metastases group versus no metastases group (80 vs. 56%), this difference was not statistically significant (P=0.63).
Preclinical murine studies suggest that an increase in peritumoral lymphatics secondary to lymphangiogenesis is associated with increased nodal metastases and worse outcome 30. The association we observed between Breslow’s thickness and DPN is consistent with more aggressive tumors eliciting more or altered lymphatic channel networks 31,32.
Finally, DPN was associated with increased age, a known negative prognostic factor for patients with melanoma 33. Interestingly, despite the fact that young patients are more likely to have positive SLNs, the outcome is poorer in the older age groups 34,35. Altered or enhanced lymphangiogenesis in the older patient may contribute toward the poorer survival observed in ways that are currently not understood.
DPN is commonly observed in patients undergoing SLN mapping with extremity melanoma. It occurs more often in older patients and in those with increased Breslow’s thickness. We observed a marginal association of DPN with TTR in SLN− patients, suggesting that it may be a marker of more aggressive tumor biology.
Conflicts of interest
There are no conflicts of interest.
1. Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355:1307–1317
3. Jimenez RE, Panageas K, Busam KJ, Brady MS. Prognostic implications of multiple lymphatic basin drainage in patients with truncal melanoma. J Clin Oncol. 2005;23:518–524
4. Schmidt CR, Panageas KS, Coit DG, Patel A, Brady MS. An increased number of sentinel lymph nodes is associated with advanced Breslow depth and lymphovascular invasion in patients with primary melanoma. Ann Surg Oncol. 2009;16:948–952
5. Soteldo J, Ratto EL, Gandini S, Trifiro G, Mazzarol G, Tosti G, et al. Pelvic sentinel lymph node biopsy
in melanoma patients: is it worthwhile? Melanoma Res. 2010;20:133–137
6. Karakousis CP, Emrich LJ, Driscoll DL, Rao U. Survival after groin dissection for malignant melanoma. Surgery. 1991;109:119–126
7. Allan CP, Hayes AJ, Thomas JM. Ilioinguinal lymph node dissection for palpable metastatic melanoma to the groin. ANZ J Surg. 2008;78:982–986
8. Badgwell B, Xing Y, Gershenwald JE, Lee JE, Mansfield PF, Ross MI, Cormier JN. Pelvic lymph node dissection is beneficial in subsets of patients with node-positive melanoma. Ann Surg Oncol. 2007;14:2867–2875
9. Mann GB, Coit DG. Does the extent of operation influence the prognosis in patients with melanoma metastatic to inguinal nodes? Ann Surg Oncol. 1999;6:263–271
10. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–6206
11. Federico AC, Chagpar AB, Ross MI, Martin RC, Noyes RD, Goydos JS, et al. Effect of multiple-nodal basin drainage on cutaneous melanoma. Arch Surg. 2008;143:632–637 discussion 637–638
12. McHugh JB, Su L, Griffith KA, Schwartz JL, Wong SL, Cimmino V, et al. Significance of multiple lymphatic basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy
. Ann Surg Oncol. 2006;13:1216–1223
13. Porter GA, Ross MI, Berman RS, Lee JE, Mansfield PF, Gershenwald JE. Significance of multiple nodal basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy
. Ann Surg Oncol. 2000;7:256–261
14. Essner R, Scheri R, Kavanagh M, Torisu-Itakura H, Wanek LA, Morton DL. Surgical management of the groin lymph nodes in melanoma in the era of sentinel lymph node dissection. Arch Surg. 2006;141:877–882 discussion 882–884
15. Balzi D, Carli P, Giannotti B, Buiatti E. Skin melanoma in Italy: a population-based study on survival and prognostic factors. Eur J Cancer. 1998;34:699–704
16. Garbe C, Buttner P, Bertz J, Burg G, d'Hoedt B, Drepper H, et al. Primary cutaneous melanoma. Identification of prognostic groups and estimation of individual prognosis for 5093 patients. Cancer. 1995;75:2484–2491
17. Masback A, Olsson H, Westerdahl J, Ingvar C, Jonsson N. Prognostic factors in invasive cutaneous malignant melanoma: a population-based study and review. Melanoma Res. 2001;11:435–445
18. Azzola MF, Shaw HM, Thompson JF, Soong SJ, Scolyer RA, Watson GF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97:1488–1498
19. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, et al. Multivariate analysis of prognostic factors among 2313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452–2459
20. Egberts F, Momkvist A, Egberts JH. Clinicopathologic prognostic markers of survival: an analysis of 259 patients with malignant melanoma ≥1 mm. Tumour Biol. 2010;31:8–15
21. Kimsey TF, Cohen T, Patel A, Busam KJ, Brady MS. Microscopic satellitosis in patients with primary cutaneous melanoma: implications for nodal basin staging. Ann Surg Oncol. 2009;16:1176–1183
22. Petersson F, Diwan AH, Ivan D, Gershenwald JE, Johnson MM, Harrell R, Prieto VG. Immunohistochemical detection of lymphovascular invasion with D2-40 in melanoma correlates with sentinel lymph node status, metastasis and survival. J Cutan Pathol. 2009;36:1157–1163
23. Nagore E, Oliver V, Botella-Estrada R, Moreno-Picot S, Insa A, Fortea JM. Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis. Melanoma Res. 2005;15:169–177
24. Day CL Jr., Harrist TJ, Gorstein F, Sober AJ, Lew RA, Friedman RJ, et al. Malignant melanoma. Prognostic significance of ‘microscopic satellites’ in the reticular dermis and subcutaneous fat. Ann Surg. 1981;194:108–112
25. Kunte C, Geimer T, Baumert J, Konz B, Volkenandt M, Flaig M, et al. Prognostic factors associated with sentinel lymph node positivity and effect of sentinel status on survival: an analysis of 1049 patients with cutaneous melanoma. Melanoma Res. 2010;20:330–337
26. Gershenwald JE, Thompson W, Mansfield PF, Lee JE, Colome MI, Tseng CH, et al. Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol. 1999;17:976–983
27. Debarbieux S, Duru G, Dalle S, Beatrix O, Balme B, Thomas L. Sentinel lymph node biopsy
in melanoma: a micromorphometric study relating to prognosis and completion lymph node dissection. Br J Dermatol. 2007;157:58–67
28. Kaoutzanis C, Barabas A, Allan R, Hussain M, Powell B. When should pelvic sentinel lymph nodes be harvested in patients with malignant melanoma? J Plast Reconstr Aesthet Surg. 2012;65:85–90
29. Chu CK, Delman KA, Carlson GW, Hestley AC, Murray DR. Inguinopelvic lymphadenectomy following positive inguinal sentinel lymph node biopsy
in melanoma: true frequency of synchronous pelvic metastases. Ann Surg Oncol. 2011;18:3309–3315
30. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science. 2002;296:1883–1886
31. Liu B, Ma J, Wang X, Su F, Li X, Yang S, et al. Lymphangiogenesis and its relationship with lymphatic metastasis and prognosis in malignant melanoma. Anat Rec (Hoboken). 2008;291:1227–1235
32. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol. 2003;162:1951–1960
33. Macdonald JB, Dueck AC, Gray RJ, Wasif N, Swanson DL, Sekulic A, et al. Malignant melanoma in the elderly: different regional disease and poorer prognosis. J Cancer. 2011;2:538–543
34. Sondak VK, Taylor JM, Sabel MS, Wang Y, Lowe L, Grover AC, et al. Mitotic rate and younger age are predictors of sentinel lymph node positivity: lessons learned from the generation of a probabilistic model. Ann Surg Oncol. 2004;11:247–258
35. Paek SC, Griffith KA, Johnson TM, Sondak VK, Wong SL, Chang AE, et al. The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma. Cancer. 2007;109:100–108