Open Access

The long-term results and prognostic significance of cutaneous melanoma surgery using sentinel node biopsy with triple technique

  • Piotr Rutkowski1,
  • Konrad Szydłowski2,
  • Zbigniew I. Nowecki1,
  • Maciej Sałamacha1,
  • Tomasz Goryń1,
  • Beata Mitręga-Korab1,
  • Andrzej Pieńkowski1,
  • Wirginiusz Dziewirski1 and
  • Marcin Zdzienicki1Email author
Contributed equally
World Journal of Surgical Oncology201513:299

https://doi.org/10.1186/s12957-015-0701-8

Received: 25 November 2014

Accepted: 3 September 2015

Published: 13 October 2015

Abstract

Background

The sentinel lymph node biopsy (SLN) is a basic staging method in all primary cutaneous melanomas ≥pT1b. The standard technique is a triple technique consisting of preoperative lymphoscintigraphy, intraoperative blue-dye lymphography, and gamma-probe assessment. We performed the analysis of long-term results in a very large one-institution series of cutaneous melanoma patients.

Methods

We have analyzed treatment results of a group of 1764 consecutive patients with cutaneous melanoma, who underwent SLN biopsy between 1997 and 2008 in one tertiary center. Additionally, we have analyzed the outcomes of a group of 473 patients with positive SLN biopsy undergoing completion lymph node dissection (CLND). Median follow-up time was 5.3 years.

Results

Metastases to SLN (SLN+) were found in 19.9 %. Eight-year overall survival (OS) rate in the entire group was 73.5 %, 80 % without SLN metastases (SLN−) and 50 % in group with SLN+ (p < 0.001). Independent prognostic factors for OS were as follows: presence of metastases to SLN, primary tumor ulceration, and higher mitotic index (>5/mm2) of primary tumor. The nodal recurrences in the biopsied lymphatic basin were 5.4 %. The metastases to non-sentinel lymph nodes (NSLN found in 27 % of patients with SLN+) correlated (on multivariable logistic regression analysis) with primary tumor thickness >4 mm, SLN metastatic deposit size >1 mm, and extracapsular involvement of SLN. In an additionally analyzed SLN+ group, the NSLN involvement was related to poorer prognosis (8-year OS rate NSLN− vs NSLN+: 59.6 vs. 34.7 %, respectively). The independent prognostic factors for OS in the SLN+ group were a higher Breslow thickness and ulceration of primary tumor, metastases to more than 1 lymph nodes.

Conclusions

The long-term results confirm crucial prognostic significance of SLN biopsy in cutaneous melanoma. We identified factors related to NSLN involvement, which in the future may limit indications for CLND.

Keywords

MelanomaSentinel lymph node biopsyMitotic rateNon-sentinel lymph nodePrognosisTumor burden

Background

Several studies have already proven that sentinel lymph node (SLN) biopsy offers several benefits in the course of melanoma patient management: excellent prognostic information, better staging, avoiding unnecessary elective lymph node dissection (LND), facilitation of therapeutic lymphadenectomy, homogeneity of patient populations in clinical trials on adjuvant therapy, patients’ increased sense of safety, and accuracy of care [14].

SLN biopsy developed in the early 1990s [5], in 1999 was declared by the World Health Organization as a standard of care in the management of melanoma patients without evidence of metastases, and thereafter the American Joint Committee on Cancer (AJCC) incorporated SLN biopsy as a microstaging procedure in the TNM-staging system [6, 7]. In 2012, the American Society of Surgical Oncology and Society of Surgical Oncology confirmed that SLN biopsy is recommended in all primary melanoma patients with a Breslow thickness >1 mm and also in those patients with thinner melanomas but at the same time with other negative pathological features. Finally, the definitive analysis from the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1), which randomized patients into those who underwent SLN biopsy and others who did not, was published in 2014 [8].

Currently, we can present the long-term outcomes of SLN biopsy used in routine practice based on a very large one-institution series of cutaneous melanoma patients, and we can focus on some issues reflecting the relationship between pathological characteristics of the tumor and SLN with patients’ survival.

We performed the analysis of long-term results of SLN biopsy, and additionally, in the subgroup of patients, we analyzed the impact of new possible prognostic factors on patient outcomes, including mitotic index of the primary tumor (introduced to the AJCC staging system in 2009) and features of SLN metastases.

Methods

Patients

We analyzed the outcomes of 1764 consecutive patients with histologically confirmed primary cutaneous melanoma in clinical stages I–II according to the AJCC 2010 classification [9], who underwent sentinel node biopsy at the Department of Soft Tissue/Bone Sarcoma and Melanoma at the Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland (CCIO), between 1998 and 2008 (cohort 1) (Table 1). In all patients, the triple technique was used consisting of preoperative lymphoscintigraphy, blue-dye injection, and intraoperative lymphoscintigraphy with a hand-held gamma-detecting probe. We have already presented the detailed technique of SNB and of the pathologic examination of SLNs in our previous publications [1]. The false-negative cases were defined as a nodal recurrence after an initially negative SLN biopsy in the biopsied basin without preceding local or in-transit recurrences. In the case of positive SLN, all but three patients underwent completion lymph node dissection (CLND). The margin of excision of all the primaries was ≥1 cm. Each patient provided written informed consent. The study was approved by the local Bio-Ethics Committee according to Good Clinical Practice Guidelines.
Table 1

Patient characteristics of all patients undergoing SLN biopsy (cohort 1) and overall survival (OS)

Parameter

Value

N (%)

5-year OS

95 % CI

8-year OS

95 % CI

p value log-rank test

Płeć

Female

1021 (57.9 %)

84.8

(82.2–87.4)

78.6

(74.9–82.5)

0.001

Male

743 (42.1 %)

72.3

(68.5–76.4)

66.6

(61.6–72.0)

Tumor type

NM

695 (39.4 %)

74.0

(70.2–78.0)

67.5

(62.8–72.5)

0.0001

SSM

516 (29.25 %)

87.1

(83.7–90.6)

82.2

(77.0–87.9)

ALM

44 (2.49 %)

65.0

(51.0–82.8)

65.0

(51.0–82.8)

LMM

122 (6.92 %)

84.3

(76.6–92.7)

77.5

(66.7–90.1)

Other

9 (0.51 %)

83.3

(58.3–100.0)

83.3

(58.3–100.0)

NA

378 (21.43 %)

80.0

(75.0–85.4)

73.2

(66.1–81.0)

Clark level

2

253 (14.34 %)

90.7

(86.3–95.3)

84.2

(77.0–92.2)

0.001

3

818 (46.37 %)

86.1

(83.3–89.0)

78.8

(74.5–83.4)

4

490 (27.78 %)

68.7

(63.8–73.9)

65.4

(60.1–71.3)

5

110 (6.24 %)

54.7

(44.9–66.6)

47.2

(36.2–61.5)

NA

93 (5.27 %)

78.9

(69.7–89.3)

78.9

(69.7–89.3)

Ulceration of primary tumor

0

931 (52.78 %)

90.4

(88.1–92.7)

84.8

(81.0–88.8)

0.001

1

713 (40.59 %)

65.7

(61.7–70.0)

58.9

(54.1–64.3)

NA

115 (6.63 %)

79.5

(70.9–89.1)

76.5

(66.8–87.7)

Extracapsular involvement of sentinel node metastases

0

321

62.4

(56.7–68.7)

54.2

(47.5–61.7)

0

1

96

33.8

(25.1–45.6)

27.0

(18.6–39.2)

NA

1341

88.6

(86.4–90.7)

84.2

(81.0–87.4)

Mitotic index

<1/mm2

123 (15.28 %)

92.9

(86.0–100.0)

92.9

(86.0–100.0)

0.002

1/mm2

142 (17.64 %)

89.9

(81.2–99.5)

89.9

(81.2–99.5)

2–5/mm2

262 (32.55 %)

88.3

(83.3–93.6)

84.7

(78.0–92.0)

>5/mm2

278 (34.53 %)

63.1

(56.4–70.7)

61.6

(54.5–69.7)

Breslow thickness

≤1 mm

343 (19.44 %)

94.2

(91.0–97.4)

88.7

(82.7–95.2)

0.001

1.01–2.00 mm

449 (25.45 %)

91.5

(88.5–94.7)

87.8

(83.1–92.8)

2.01–4.00 mm

519 (29.42 %)

75.6

(71.1–80.3)

68.0

(61.8–74.7)

>4 mm

398 (22.56 %)

60.8

(55.5–66.6)

54.4

(48.4–61.0)

NA

55 (3.12 %)

75.4

(62.8–90.4)

70.9

(57.1–88.1)

Sentinel node metastases

No

1413 (80.10 %)

86.3

(84.1–88.5)

80.4

(77.1–83.9)

0.001

Yes

351 (19.9 %)

55.6

(50.1–61.9)

49.8

(43.7–56.8)

All patients

1764

79.5

(77.2–81.8)

73.5

(70.5–76.7)

 
All patients undergoing SLN biopsy met the following criteria:
  • Primary focus cutaneous melanoma after excisional biopsy with Breslow thickness ≥0.75 mm or ulcerated or Clark level ≥IV (all histological diagnoses were confirmed in the Department of Pathology, CCIO)

  • Clinically non-palpable regional lymph nodes

  • Absence of distant metastases (confirmed routinely by physical examination, chest X-ray, and ultrasonography of the abdominal cavity)

  • Feasibility for general anesthesia

The patients had not undergone any other preliminary selection. Only patients who met with all the conditions listed above were enrolled in the study.

The clinico-pathological stage of the melanoma patients was determined by pathological evaluation of the primary lesion and of the dissected lymph nodes, as well as by physical examination and routine imaging examinations (chest X-ray, ultrasonography of the abdominal cavity, and computed tomography imaging, if necessary).

Patient characteristics of the cohort 1 are summarized in Table 1. In an additional 805 cases, two pathologists reviewed mitotic index per mm2. All patients had confirmed primary melanoma. Radical lymph node dissections were performed according to the technique described by Karakoussis [10]. For ilio-inguinal lymphadenectomy, we routinely excised the superficial and deep levels below the inguinal ligament to the level of the aortic bifurcation combined with obturatory lymph node dissection. Two hundred and one patients received interferon-α2b as adjuvant treatment in accordance with the European Organisation for Research and Treatment of Cancer (EORTC) 18952 trial (without significant influence on overall survival data) [11, 12].

Additionally, we analyzed all consecutive patients (N = 473) who underwent radical CLND at the Department of Soft Tissue/Bone Sarcoma and Melanoma at the CCIO between May 1995 and December 2008 due to positive SLN biopsy (cohort 2) independent of the SLN biopsy technique used (Table 2).
Table 2

Patient characteristics of patients undergoing completion lymph node dissection due to positive SLN biopsy (cohort 2) and overall survival (OS) N = 473

Parameter

Value

N (%)

5-year OS

95 % CI

8-year OS

95 % CI

p value log-rank test

Sex

Female

235 (49.6 %)

63.0

(56.4–70.5)

59.1

(52.1–67.0)

0.032

Male

238 (50.4 %)

51.2

(44.2–59.4)

44.8

(37.3–53.9)

Tumor type

NM

264

57.2

(50.6–64.6)

51.0

(44.1–59.1)

0.006

SSM

96

63.8

(53.7–75.8)

61.1

(50.5–74.1)

ALM

15

20.0

(6.3–63.8)

20.0

(6.3–63.8)

LMM

16

46.1

(25.2–84.3)

46.1

(25.2–84.3)

Other

2

100.0

(100.0–100.0)

100.0

(100.0–100.0)

NA

80

58.7

(47.4–72.7)

54.0

(42.3–68.9)

Clark level

II

29

49.4

(31.7–77.1)

43.2

(25.8–72.4)

0.068

III

154

69.8

(62.2–78.4)

61.4

(52.1–72.4)

IV

206

51.9

(44.2–60.9)

50.8

(43.1–59.9)

V

64

46.3

(34.8–61.5)

39.6

(28.3–55.3)

NA

20

63.6

(43.8–92.3)

56.5

(36.5–87.6)

Presence of ulceration of primary tumor

No

143

73.2

(65.0–82.3)

68.4

(59.5–78.7)

0.000

Yes

293

49.0

(42.7–56.1)

43.8

(37.3–51.4)

NA

37

60.9

(45.7–81.4)

57.1

(41.7–78.3)

Extracapsular involvement of sentinel node metastases

No

363

58.5

(53.0–64.7)

52.7

(46.8–59.4)

0.008

Yes

98

40.1

(27.8–57.8)

37.2

(25.1–55.2)

NA

12

68.9

(54.4–87.4)

68.9

(54.4–87.4)

Breslow thickness

≤1 mm

29

81.9

(67.3–99.8)

70.6

(53.0–94.0)

0.000

1.01–2.00 mm

56

75.6

(63.8–89.5)

75.6

(63.8–89.5)

2.01–4.00 mm

164

61.9

(53.4–71.8)

57.6

(48.1–68.9)

>4 mm

199

44.3

(37.2–52.8)

39.8

(32.6–48.6)

NA

25

60.8

(40.8–90.5)

43.4

(23.5–80.3)

Size of metastasis in sentinel node

<0.1 mm

10

87.5

(67.3–100.0)

87.5

(67.3–100.0)

0.009

0.1–1.0 mm

107

63.0

(53.6–74.2)

57.7

(47.0–71.0)

>10.0 mm

246

47.3

(40.3–55.6)

41.6

(34.4–50.4)

NA

110

56.8

(45.3–71.2)

48.4

(36.2–64.7)

Localization of metastasis in sentinel node

Subcapsular

25

79.4

(63.1–100.0)

79.4

(63.1–100.0)

0.060

Combined

165

57.8

(49.7–67.1)

51.5

(42.4–62.5)

Parenchymal

67

52.2

(40.6–67.2)

44.0

(32.0–60.6)

Multifocal

15

55.0

(32.2–93.8)

55.0

(32.2–93.8)

Extensive

75

40.8

(29.8–55.9)

38.5

(27.6–53.8)

NA

126

66.8

(57.5–77.6)

61.7

(51.8–73.5)

Presence of non-sentinel node metastases

No

341

63.9

(58.2–70.2)

59.6

(53.5–66.3)

0.000

Yes

132

41.4

(32.9–52.2)

34.7

(25.9–46.6)

LND basin

Axillary

261

56.4

(49.8–64.0)

49.5

(42.1–58.1)

0.316

Neck

3

50.0

(12.5–100.0)

50.0

(12.5–100.0)

Inguinal

174

63.0

(55.4–71.5)

59.0

(51.2–68.1)

Other

35

28.9

(14.3–58.6)

28.9

(14.3–58.6)

Number of metastatic nodes

1

259

66.3

(60.0–73.3)

62.7

(55.9–70.3)

0.000

2–3

150

48.6

(40.0–59.0)

44.5

(35.7–55.3)

>3

50

38.2

(26.0–56.0)

24.3

(13.5–43.8)

NA

14

0.0

(63.3–100.0)

0.0

(63.3–100.0)

All patients

473

57.3

(52.3–62.7)

52.3

(47.0–58.1)

0.000

All patients were followed carefully with a median follow-up time of 4.9 years (range: 6–151 months; cohort 1) and 5.4 years (range: 6–174 months; cohort 2). Postoperative follow-up consisted of physical examination and routine imaging investigations (chest X-ray and ultrasound examination of the abdominal cavity; chest/abdominal computed tomography examination was done for follow-up in SLN-positive or symptomatic patients). Routinely, surveillance was recommended every 3 months for the first 2 years, every 4 months in year 3, every 6 months for years 4–5, and thereafter annually.

Pathological examination

The SLNs were evaluated by serial sectioning, and H&E staining was performed first. If this was negative, other slides were stained with immunohistochemical methods. The amount of SLN tumor burden was measured according to the Rotterdam criteria [13], which consist of the measure of the maximum diameter (in any direction) of the largest lesion on a slide (N = 363). All positive slides were examined, and this process of measuring the largest lesion was repeated. The largest value overall (which is the largest diameter measured anywhere on one slide in one patient) has been defined as the amount of SLN tumor burden (in mm). If a patient had multiple positive SLNs, the largest maximum diameter of any of the SLNs was the largest overall and thus the amount of SN tumor burden for this patient. Categories were made for SLN tumor burden as follows: <0.1 (sub-micrometastases), 0.1–1.0, and >1.0 mm. The location of the metastases was also recorded, according to the Dewar criteria for the microanatomic location of the metastasis [14] (N = 347). This was either subcapsular, parenchymal, combined, multifocal, or extensive.

Statistical analyses

The statistical analysis was done using R 3.0.1 statistical software (R Core Team (2013). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/). Packages: survival (Therneau T (2013). “A Package for Survival Analysis in S”. R package version 2.37-4, URL: http://CRAN.R-project.org/package=survival).

Logistic regression and survival analysis methods were used in the analysis. Potential risk factors of positive SLN (cohort 1) and metastases to non-sentinel lymph nodes (NSLN) (cohort 2) were investigated using univariate and multivariate logistic regression model. Variables with p < 0.10 were included in the initial stage of multivariate model building. Backward variable selection was then used to construct the final model.

The Kaplan-Meier estimates and Cox regression model were used in survival analysis. Patient’s survival was described using 5- and 8-year survival probability (with 95 % confidence interval) and survival curve plots. Overall survival (OS) time for the assessment of the prognostic value of clinical and pathological parameters was calculated from the date of primary tumor excision to the date of the most recent follow-up (censored data) or death. Clinical and pathological parameters are as follows: gender, primary tumor Breslow thickness (≤1.0 vs. 1.01–2.0 vs. 2.01–4.0 vs. >4.0 mm), presence of ulceration of primary lesion, primary tumor level of invasion according to Clark (II, III, IV, V), primary tumor pathological type (nodular melanoma [NM], superficial spreading melanoma [SSM], acral lentiginous melanoma [ALM], lentigo malignant melanoma [LMM], others), mitotic index of primary tumor (<1/mm2, 1/mm2, 2–5/mm2, >5/mm2; cohort 1 only), and presence of metastases to SLN (cohort 1 only), and additionally in cohort 2: localization of lymphadenectomy (inguinal vs. axillary), number of lymph nodes with metastases (1 vs. 2–3 vs. ≥4), presence of extracapsular invasion in involved lymph nodes, presence of metastases to NSLN (assessed after CLND), size of metastases to SLN according to the Rotterdam criteria, and microanatomic location of the metastasis in SLN (subcapsular, combined, parenchymal, multifocal, extensive) were tested as a factors affecting patients survival.

The multivariate Cox model was used to identify independent risk factors affecting patients’ survival. Procedure of final model building was the same as in case logistic regression model. The differences were considered statistically significant if the p values were <0.05.

Results

Survival analysis (from the date of primary tumor excision) in all patients undergoing SLN biopsy (cohort 1)

The patient characteristics and the results of an univariate analysis of the impact of individual factors on overall survival are shown in (Table 1). The median Breslow thickness of the entire group was 2.3 mm. In the analyzed subgroup of 805 patients with known mitotic index of primary tumor, we have observed the high correlation between increasing Breslow thickness and higher mitotic rate (Spearman’s correlation coefficient 0.425, p value <0.001).

The median 5-year and 8-year OS rates were 79.5 % (95 % confidence interval [CI]: 77.2–81.8 %) and 73.5 % (95 % CI: 70.5–76.7 %), respectively, in the entire group of patients who underwent SLN biopsy.

According to the multivariate analysis, we have identified three of the most important factors negatively influencing OS: mitotic index >5/mm2 (hazard ratio [HR] = 1.1) (Fig. 1), presence of ulceration of primary tumor (HR = 4.1), and the presence of metastases to SLN (HR = 2.2) (Fig. 2) (Table 2).
Fig. 1

Overall survival curves according to mitotic index of primary tumor in all patients undergoing SLNB (cohort 1) (1, <1/mm2; 2, 1/mm2; 3, 2–5/mm2; 4. >5/mm2)

Fig. 2

Overall survival curves according the presence of metastases to SLN (0—no metastases, 1—metastases to SLN) in all patients undergoing SLN biopsy (cohort 2)

Factors influencing on the presence metastases to SLN

In 351 cases (19.9 %), we found positive SLNs (347 of them underwent completion lymph node dissection [CLND]). Based on the univariate logistic regression model, we have found the following factors related to presence of metastases to SLN: male gender (p = 0.002), Clark level >II (p < 0.01), presence of ulceration of primary tumor (p < 0.001), and Breslow thickness of primary tumor >2 mm (p < 0.001). In multivariate analysis (Table 3), male gender Clark level IV or V and ulceration of the primary tumor were independently related to the presence of metastases to SLN.
Table 3

Multivariate analysis for overall survival in patients undergoing SLN biopsy (cohort 1)

Parameter

HR

95 % CI

p value

Mitotic index

1.071

1.01–1.136

0.021

Ulceration

4.114

1.766–9.585

0.001

Presence of metastases in SLN

2.184

1.125–4.24

0.021

Moreover, in pT1 tumors (Breslow thickness ≤1.00 mm) with known mitotic index (n = 139), we have not found any metastases to SLNs in cases with MI < 1/mm2 (0/40); for 46 tumors with MI = 1/mm2, we detected four SLNs+ (8.7 %); and for 53 tumors with MI > 1/mm2, we found metastases in three SLNs (6 %) (Fig. 3).
Fig 3

Relationship between mitotic index of primary tumor and SLN positivity in pT1 group

The SLN biopsy failure rate (defined as nodal recurrences in the biopsied regional basin without simultaneous or previous local/in-transit recurrences) was 6.3 % (90/1413 SLN negative or calculated as false-negative rate 20 % 90/351 + 90). Median time to nodal relapses after false-negative SLN biopsy was 16 months.

Analysis of factors influencing on outcomes in CLND group /cohort 2/

The patient characteristics and factors in relation to 5-year and 8-year OS rates are shown in Table 4. According to the univariate analysis, the following factors had a negative impact on the overall survival of patients after CLND: male gender, ALM primary tumor type, higher primary tumor Breslow thickness (>2 mm), ulceration of primary tumor, number of lymph node with metastases >1 (Fig. 4), extracapsular extension of nodal metastases (Fig. 5), the presence of metastases to non-sentinel lymph nodes (NSLN) (Fig. 6), the size of metastases to SLN according to Rotterdam criteria ≥1.0 mm (Fig. 7), and with the borderline significance other than subcapsular microanatomic location of the metastasis to SLN.
Table 4

Multivariate model—factors related to metastases in sentinel nodes

Variable

OR

ORL

ORU

p value

Sex (male)

1.392

1.075

1.801

0.012

Clark III

1.635

0.986

2.711

0.056

Clark IV

3.440

2.067

5.725

0.000

Clark V

6.034

3.262

11.161

0.000

Ulceration of primary tumor

2.586

1.981

3.376

0.000

Fig. 4

Overall survival curves according to number of lymph node with metastases in group of patients with positive SLN biopsy after CLND (cohort 2) (1–1, 2–2–3, 3 > 3)

Fig. 5

Overall survival curves according to extracapsular extension of nodal metastases (0—no extracapsular extension, 1—extracapsular extension) in group of patients with positive SLN biopsy after CLND (cohort 2)

Fig. 6

Overall survival curves according to the presence of metastases to non-sentinel lymph nodes (0—metastases to SLN only, 1—metastases to SLN and NSLN) in group of patients with positive SLN biopsy after CLND (cohort 2)

Fig. 7

Overall survival curves according to the size of metastases to SLN according to Rotterdam criteria (SLN tumor size: 1, <0.1 mm; 2, 0.1–1.0 mm; 3, >1.0 mm) in group of patients with positive SLN biopsy after CLND (cohort 2)

According to the multivariate analysis, we have confirmed and identified that in the CLND group the most important factors negatively influencing OS are as follows: features of primary tumor (higher Breslow thickness >2.0 mm [HR = 1.01], presence of ulceration [HR = 2.5], and ALM tumor type [p = 4.8]) and features of nodal metastases (number of involved nodes >1 [HR = 2.05]) (Table 5).
Table 5

Multivariate model—factors related to metastases to non-sentinel nodes

Zmienna

OR

ORL

ORU

p value

Extracapsular metastases

2.022

0.939

4.352

0.072

Breslow thickness

1.102

1.042

1.166

0.001

Maximal diameter of metastatic deposit

1.068

1.013

1.126

0.015

Factors influencing on the presence of metastases to non-sentinel lymph node (NSLN)

In 132 of 473 patients (27.9 %), we have identified additional metastases in NSLSN afer CLND.

The presence of metastases to NSLN correlated according to univariate and multivariate analyses (Table 6) with extracapsular metastases to SLN (p < 0.001), primary tumor Breslow thickness >2 mm (p < 0.001), and maximal diameter of metastases to SLN according to Rotterdam analyzed as a continuous variable (p < 0.001).
Table 6

Multivariate Cox regression model for overall survival in patients with positive sentinel lymph nodes undergoing completion lymph node dissection (cohort 2)

Zmienna

HR

95 % P.U.

p

Type: 2 SSM

1.214

0.778–1.892

0.393

Type: 3 ALM

4.858

2.545–9.273

0

Type: 4 LMM

1.824

0.84–3.961

0.129

Type: 5 other

0

0–Inf

0.995

Ulceration: 1

2.532

1.645–3.896

0

Breslow

1.014

1.005–1.023

0.002

Number of lymph nodes involved >1

2.05

1.453–2.893

0

Discussion

We have confirmed the importance of SLN biopsy as a tool for accurate staging and prognosis assessment in the routine practice of patients with cutaneous melanoma. The presence of metastases to SLN found in up to 20 % of patients [8, 15] is related to almost twice less survival after 8 years from primary tumor excision as compared to patients with SLN-negative tumors. The randomized study MSLT-1 assessing prospectively the value of SLN biopsy found SLN status, Breslow thickness, ulceration presence, and localization of the primary tumor on the trunk as the independent prognostic factors related to death from melanoma in intermediate-thickness tumors [8]. We also found SLN status and ulceration of the primary tumor as independent prognostic factors for OS in the entire group of patients undergoing SLN biopsy. However, we have also demonstrated the independent negative value of high mitotic index of the primary tumor in this group of patients (which correlates with the tumor Breslow thickness). This newly introduced criterion for melanoma staging and prognosis replaced Clark’s level of invasion for thin melanomas and is thought to be related with patients’ survival [9, 16]. We also found the inverse correlation between primary tumor mitotic rate and OS, especially pronounced for a mitotic index higher than 5/mm2. Our results highlight the value of routine pathologic reporting of the mitotic index of primary melanoma as it is an independent prognostic factor for patients with localized primary melanomas in clinical stages I and II undergoing SLN biopsy and it is the first one-institution comprehensive study including pathological review aiming at the standardization of technique of mitotic rate assessment.

The use of SLNB reliably identifies melanoma patients with nodal micrometastases, enabling clinicians to identify patients with occult nodal metastases that would otherwise take months or years to become clinically palpable—it has been confirmed by the MSLT-1 trial data that cumulative rates of nodal involvement in patients undergoing SLN biopsy or not are similar. Currently, the positive result of SLN biopsy is a major manifestation of stage III melanomas. The results of the current study confirmed our previous data, as well as data from the AJCC staging database, demonstrating that in a group of patients with micrometastases both primary tumor features as well as nodal characteristics have independent prognostic value for OS assessment [17, 18]. Our results indicate also the heterogeneity of patients undergoing CLND due to positive SLN, which is strictly related to tumor load. The number of nodal metastases is still a very powerful independent predictor of survival among all patients with micrometastatic stage III disease, but microanatomic features of SLN metastases should also be taken into account when the patient’s prognosis is discussed.

In view of the SLN positivity in only one of five patients, some studies tried to predict SLN status in patients undergoing SLN biopsy [19, 20]. Although we did not analyze patients’ age as a prognostic factor [21] in our database due to differently used cutoff values in different databases and because we have focused on pathological features of primary tumor, we have confirmed that the Clark level of invasion and ulceration of primary tumor and additionally male gender correlated independently with SLN positivity. The results of our study underlines the position of ASCO and SSO, that in very thin melanomas up to 1 mm according to Breslow, the presence of a mitotic rate ≥1/mm2 can be an additional feature to propose to the patient to undergo SLN biopsy [22, 23].

Our study also highlights the fact that although the procedure of SLN biopsy may be quite accurate, it misses 20 % of positive nodes in patients with primary melanoma (this false-negative rate is consistent with other studies) [24].

The presence of metastases to NSLN is a highly negative prognostic factor for patient survival analyzed recently by other authors [2528], and they found up to 30 % of SLN-positive cases after CLND (27 % in our series). According to our analysis, the positivity of NSLN is related to a 50 % higher chance of death after 8 years as compared to patients with metastases limited to SLN only. It may support the hypothesis that SLN may be a physiological barrier for melanoma spreading. It is one of the reasons for prediction of the necessity to perform CLND after positive SLN. After many attempts by different authors, there is still no universal approach based on morphologic criteria to not allow performing CLND in selected SLN-positive cases. We have confirmed in our group of patients that the Rotterdam criteria for assessment of tumor burden in SLN give the prognostic information, and this pathological factor is closely associated with the presence of metastases to additional NSLN after CLND, which has been suggested previously [14, 29, 30]. A combination of patients’ characteristics, primary tumor, and SLN features was proposed recently as a new scoring system [non-sentinel node risk score (N-SNORE)] for prediction of NSLN involvement [31]. This system includes two of the pathological factors found by us as independently related to the presence of NSLN metastases: maximum size of the largest tumor deposit in SLN (although with different categorization than according to Rotterdam criteria) and perinodal lymphatic invasion of SLN (described by us as extracapsular extension). We suggest also that primary a Breslow thickness >2 mm is independently related to NSLN metastases, but we did not analyze the regression of a primary tumor as Wevers et al. did [31]. We are convinced that further studies (as the Minitube trial organized by the EORTC Melanoma Group) will establish the criteria used to limit of performance of the unnecessary CLND [32], but currently, CLND is still the standard of care in every case of positive SLN biopsy.

Conclusions

Using a large comprehensive patient cohort with long-term results, we have confirmed the crucial prognostic significance of SLN biopsy in cutaneous melanoma. We have also identified factors related to NSLN involvement, what may in the future limit indications for completion lymph node dissection in selected patients, although prospective studies are necessary. SLN biopsy currently provides more important prognostic information than can be derived from characteristics of the primary tumor only. For the patient with clinically node-negative disease, primary tumor ulceration and mitotic rate are very important factors in predicting the patient’s outcome. Nodal metastases tumor burden influences the prognosis of patients with positive SLN biopsy.

Notes

Abbreviations

AJCC: 

American Joint Committee on Cancer

ALM: 

acral lentiginous melanoma

ASCO: 

American Society of Clinical Oncology

CCIO: 

Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland

CI: 

confidence interval

CLND: 

completion lymph node dissection

EORTC: 

European Organisation for Research and Treatment of Cancer

HR: 

hazard ratio

LMM: 

lentigo malignant melanoma

LND: 

lymph node dissection

MSLT-1: 

Multicenter Selective Lymphadenectomy Trial-1

NA: 

not available

NM: 

nodular melanoma

NSLN: 

non-sentinel lymph node

OR: 

odds ratio

ORL: 

lower range of odds ratio

ORU: 

upper range of odds ratio

SLN: 

sentinel lymph node

SSM: 

superficial spreading melanoma

SSO: 

Society of Surgical Oncology

TNM: 

tumor node metastasis

Declarations

Acknowledgements

We thank Daniel Rabczenko for statistical advice.

The study was supported by the Polish National Science Centre grant no. 2011/03/B/NZ5/04513.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
(2)
Department of General Surgery

References

  1. Nowecki ZI, Rutkowski P, Nasierowska-Guttmejer A, Ruka W. Sentinel lymph node biopsy melanoma patients with clinically negative regional lymphin melanoma patients with clinically negative regional lymph nodes--one institution’s experience. Melanoma Res. 2003;13(1):35–43.Google Scholar
  2. Vuylsteke RJ, van Leeuwen PA, Statius Muller MG, Gietema HA, Kragt DR, Meijer S. Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results. J Clin Oncol. 2003;21(6):1057–65.Google Scholar
  3. 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(3):976–83.Google Scholar
  4. Thompson JF, Shaw HM. Sentinel node mapping for melanoma: results of trials and current applications. Surg Oncol Clin N Am. 2007;16(1):35–54.View ArticlePubMedGoogle Scholar
  5. Morton DL, Wen DR, Wong JH, Economou JS, Cagle LA, Storm FK, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392–9.Google Scholar
  6. Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16):3635–48.Google Scholar
  7. Balch CM, Soong SJ, Gershenwald JE, Thompson, JF, Reintgen DS, Cascinelli N, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622–34.Google Scholar
  8. 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;370(7):599–609.Google Scholar
  9. 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(36):6199–206.Google Scholar
  10. Karakousis CP. Therapeutic node dissections in malignant melanoma. Ann Surg Oncol. 1998;5(6):473–82.View ArticlePubMedGoogle Scholar
  11. Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366(9492):1189–96.Google Scholar
  12. Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol. 2007;34(6):509–15.View ArticlePubMedGoogle Scholar
  13. van Akkooi AC, Nowecki ZI, Voit C, Schafer-Hesterberg G, Michej W, de Wilt JH, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg. 2008;248(6):949–55.Google Scholar
  14. van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol. 2006;17(10):1578–85.Google Scholar
  15. Beger J, Hansel G, Kronert C, Fuchs M, Tanner C, Schonlebe J, et al. A 10-year analysis of primary cutaneous malignant melanoma with sentinel lymph node biopsy and long-term follow-up. Int J Dermatol. 2013;52(2):220–30.Google Scholar
  16. Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, et al. Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 2011;29(16):2199–205.Google Scholar
  17. Nowecki ZI, Rutkowski P, Michej W. The survival benefit to patients with positive sentinel node melanoma after completion lymph node dissection may be limited to the subgroup with a primary lesion Breslow thickness greater than 1.0 and less than or equal to 4 mm (pT2-pT3). Ann Surg Oncol. 2008;15(8):2223–34.View ArticlePubMedGoogle Scholar
  18. Balch CM, Gershenwald JE, Soong SJ, Thompson, JF, Ding S, Byrd DR, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452–9.Google Scholar
  19. Wong SL, Kattan MW, McMasters KM, Coit DG. A nomogram that predicts the presence of sentinel node metastasis in melanoma with better discrimination than the American Joint Committee on Cancer staging system. Ann Surg Oncol. 2005;12(4):282–8.Google Scholar
  20. White RL, Jr Ayers GD, Stell VH, Ding S, Gershenwald JE, Salo JC, et al. Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593–600.Google Scholar
  21. 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;21(4):1075–81.Google Scholar
  22. Wong SL, Balch CM, Hurley P, Agarwala SS, Akhurst TJ, Cochran A, 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(23):2912–8.Google Scholar
  23. Mozzillo N, Pennacchioli E, Gandini S, Caraco C, Crispo A, Botti G, et al. Sentinel node biopsy in thin and thick melanoma. Ann Surg Oncol. 2013;20(8):2780–6.Google Scholar
  24. Testori A, De Salvo GL, Montesco MC, Trifiro G, Mocellin S, Landi G, et al. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol. 2009;16(7):2018–27.Google Scholar
  25. Ghaferi AA, Wong SL, Johnson TM, Lowe L, Chang AE, Cimmino VM, et al. Prognostic significance of a positive nonsentinel lymph node in cutaneous melanoma. Ann Surg Oncol. 2009;16(11):2978–84.Google Scholar
  26. Jakub JW, Huebner M, Shivers S, Nobo C, Puleo C, Harmsen WS, et al. The number of lymph nodes involved with metastatic disease does not affect outcome in melanoma patients as long as all disease is confined to the sentinel lymph node. Ann Surg Oncol. 2009;16(8):2245–51.Google Scholar
  27. van der Ploeg AP, van Akkooi AC, Haydu LE, Scolyer RA, Murali R, Verhoef C, et al. The prognostic significance of sentinel node tumour burden in melanoma patients: an international, multicenter study of 1539 sentinel node-positive melanoma patients. Eur J Cancer. 2014;50(1):111–20.Google Scholar
  28. Pasquali S, Mocellin S, Mozzillo N, Maurichi A, Quaglino P, Borgognoni L, et al. Nonsentinel lymph node status in patients with cutaneous melanoma: results from a multi-institution prognostic study. J Clin Oncol. 2014;32(9):935–41.Google Scholar
  29. Gershenwald JE, Andtbacka RH, Prieto VG, Johnson MM, Diwan AH, Lee JE, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26(26):4296–303.Google Scholar
  30. Govindarajan A, Ghazarian DM, McCready DR,Leong WL. Histological features of melanoma sentinel lymph node metastases associated with status of the completion lymphadenectomy and rate of subsequent relapse. Ann Surg Oncol. 2007;14(2):906–12.Google Scholar
  31. Wevers KP, Murali R, Bastiaannet E, Scolyer RA, Suurmeijer AJ, Thompson JF, et al. Assessment of a new scoring system for predicting non-sentinel node positivity in sentinel node-positive melanoma patients. Eur J Surg Oncol. 2013;39(2):179–84.Google Scholar
  32. Nagaraja V, Eslick GD. Is complete lymph node dissection after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? A meta-analysis. Eur J Surg Oncol. 2013;39(7):669–80.View ArticlePubMedGoogle Scholar

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© Rutkowski et al. 2015

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