- Email: [email protected]
Clinical aspects of sentinel lymph node biopsy in melanoma
Seminars in Diagnostic Pathology (2008) 25, 86-94
Clinical aspects of sentinel lymph node biopsy in melanoma Charlotte E. Ariyan, MD, PhD, Daniel G. Coit, MD From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY KEYWORDS Melanoma; Sentinel lymph node biopsy
Sentinel lymph node (SLN) biopsy has evolved over the years to become one of the most useful tools in the treatment of melanoma. Large, multi-institutional studies have confirmed that in experienced hands it is an accurate, reliable technique to identify tumor in the draining lymph nodes. The complications of the procedure are low, and it is generally well tolerated. The presence of melanoma in the sentinel lymph node is the most important predictive factor in patients with intermediate thickness melanomas. In patients with thin melanomas (⬍1 mm), the incidence of a positive SLN is low. The choice to perform a SLN biopsy in these patients must be weighed with risk factors such as Clark level, ulceration, sex and mitotic rate. In patients with thick melanomas (⬎4 mm), most studies have supported the prognostic value of SLN status. Patients with desmoplastic melanomas have a high risk of local recurrence, but low risk of SLN metastasis if the pathology demonstrates a pure desmoplastic form. Younger patients have a higher incidence of positive lymph nodes, yet an overall more favorable prognosis compared to older patients. Patients should understand that this procedure remains primarily a staging tool, as large prospective randomized trials have not demonstrated an overall survival benefit. © 2008 Elsevier Inc. All rights reserved.
The most common site of metastatic disease in melanoma is the draining lymph nodes. For this reason, there has been a long history of either excision or interrogation of the lymph nodes at the time of resection of the primary melanoma. This has evolved from elective lymph node dissection, to sentinel lymph node (SLN) biopsy. SLN biopsy in melanoma is an accurate staging procedure for patients. The finding of metastatic cells in the draining lymph node of a patient with clinically localized melanoma is the most powerful predictor of adverse outcome. Because there are limited options for effective adjuvant treatment for melanoma, the usefulness of detecting metastatic disease is controversial. This review will focus on the history and development of SLN biopsy.
Address reprint requests and correspondence: Daniel G. Coit, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected].
0740-2570/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2008.04.004
History Characterization of the lymphatic system In 1874, Sappey published his atlas defining the lymphatic channels and patterns of drainage of the skin. Although the entity of the lymphatic system had previously been described, he was the first to systematically characterize the pathways. By injecting mercury into the skin of cadavers, Sappey demonstrated distinct areas of drainage from each skin area. This was used to define rules, for example, that a drainage pattern will never cross the midline.1 Sappey’s understanding of the lymphatic system persisted until the recent century, when new technology allowed clarification of the lymphatic flow in real time. In 1952, Kinmonth developed the lymphangiogram, a mechanism to evaluate the lymphatics in vivo. Using blue dye and direct injection of radiopaque contrast, he demon-
Ariyan and Coit Table 1
Clinical Aspects of SLN Biopsy in Melanoma
87
Randomized trials evaluating elective lymph-node dissection (ELND) for melanoma n
Site
Thickness (mm)
FUP (years)
WLE
WLE ⫹ ELND
P value
Sim, et al
173
Any
NR
85
85
NS
Veronesi, et al24 Balch, et al21,78
553 740
Excluded midline trunk, head and Neck Extremity All
Any 1-4
Cascinelli, et al22
240
Trunk
⬎1.5
8.2 7.4 10 11
72 82 73 51
74 86 77 62
NS 0.25 0.12 0.09
Study 23
strated flow in the lymphatic system.2 Another modification of this technique used the subcutaneous injection of colloid gold, which was hypothesized to be taken up by phagocytes and transported to the draining lymph nodes. The genesis of this idea was to allow this radioactive substance to treat affected lymph nodes. However, the emission of beta and gamma particles also allowed for visualization of the lymphatic nodes on simple radiographs.3 The use of colloid gold was later used to successfully identify ambiguous sites of lymph node drainage in malignant melanoma.4,5 The technique of lymphoscintigraphy has been modified, and now employs the use of smaller molecules such as filtered technetium sulfur colloid or antimony sulfur colloid. With the widespread use of lymphoscintography, it is now evident that Sappey’s lines do not accurately predict lymphatic drainage. Cutaneous lesions from the trunk or extremity can have primary drainage that can cross the midline, and can drain to multiple nodal basins, or to unexpected nodal sites.6-12 Lymphatic drainage from head and neck sites can be especially complex.13,14 Therefore, a lymphoscintigram is essential to accurately identify the correct nodal drainage patterns in melanoma.
Importance of lymph nodes in melanoma The idea of a “sentinel” lymph node draining from a tumor site was initiated by Gould in 1960 in a model of head and neck cancer.15 Gould identified a sentinel node in the management of parotid cancer, and suggested a frozen section of this angular parotid node could be used to guide the need for a neck dissection. This concept was later applied by Cabanas in 1977, who described the sentinel nodes that drain carcinoma of the penis.16 Epidemiologic studies on large cohorts of patients have demonstrated that 50% of all metastatic disease in patients with melanoma occurs in the regional draining lymph nodes.17-19 Clearly, patients with a nodal disease have a worse prognosis; however, removing the disease in the lymph nodes has an unclear benefit on overall survival. Proponents of aggressive surgery cite the possibility that disease in the lymph node is the first step on the way to distant disease. Dissidents hypothesize that the distant spread occurs based on the biology of the primary tumor, and the lymph node disease is a predictor, but not a governor of overall survival.
Before sentinel lymph node (SLN) biopsy, there was debate regarding which patients, if any, should undergo an elective lymph node dissection. Several prospective, randomized trials failed to demonstrate a survival benefit for an elective lymph node dissection over nodal observation (Table 1).20-24,68 The long-term follow-up of the Intergroup Melanoma Surgery Trial, however, demonstrated a survival benefit for the subset of patients with a melanoma between 1 and 2 mm. This represents a low-risk group with a relative low incidence of adverse features such as ulceration.20 Although this trial provides some evidence that removal of clinically occult disease in the draining lymph nodes may be of benefit in selected subsets of melanoma patients, the procedure was still met with resistance. Lymph node dissection is associated with significant comorbidities, including a risk of permanent limb edema. Because most (approximately 80%) patients will not have metastatic disease detected in the lymph nodes, there was a need to better predict the lymph node status in a less invasive manner. This, in part, was the genesis of the SLN technique. Morton and colleagues described the technique of SLN biopsy by using blue dye. The initial technique was developed in a feline model because they have multiple draining nodes, similar to humans.25 In patients, this method correctly identified the SLN 61% to 96% of the time, with the success of identifying the SLN related to the experience of the surgeon.26 Krag and colleagues later demonstrated the efficacy of using technetium labeled colloid to identify the SLN.27 The combination of both techniques has been utilized to correctly identify the SLN in more than 96% of patients.28
Procedure At Memorial Sloan-Kettering Hospital (MSKCC) lymphoscintigraphy is performed the day of the procedure. Filtered radiolabeled sulfur colloid 0.05 mCi is injected in four sites circumferentially around the primary lesion. Real-time lymphoscintigraphy is then performed to identify the draining lymphatic channels and sentinel node(s). We have abandoned the use of a permanent tattoo over the lymph node of interest because we found that intraoperative use of a gamma counter could readily detect the “hot” node seen on imaging.
88
Figure 1
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
Blue Sentinel Node.
Surgery is performed approximately 1 to 3 hours after injection of radioactive tracer. This time point allows identification of the SLNs with a gamma counter and minimization of background from the primary injection. In addition to radioactivity, identification of the first draining node is assisted by the use of blue dye. Isosulfan blue (0.5 to 1 mL) is injected into the dermis of the lesion and allowed to travel to the draining lymph node for approximately five minutes.
An incision is made over the site of anticipated SLN and a gamma probe is used to locate the sentinel node with the visual assistance of blue dye as shown in Figure 1. Once a sentinel node is identified, it is removed and ex vivo gamma counts are obtained. Additional sentinel nodes are removed as directed by the preoperative lymphoscintigraphy. The lymph node basin is scanned with the gamma counter and additional nodes in the lymph node basin are removed which have radioactive counts 10% or greater of the hottest sentinel node.29 A representative lymphoscintigram of a melanoma of the extremity is demonstrated in Figure 2. After the nodes are removed, they are sent for routine pathologic analysis. Frozen section is generally not used to facilitate the complete analysis of the sentinel node and to avoid false negatives demonstrated with the use of frozen section.30 The nodes are analyzed in a systemic fashion as described by Cochran and colleagues, and as discussed in depth in other chapters in this series.31 The question of what constitutes a clinically significant positive node remains a subject of debate. Although recent studies have demonstrated a small, but statistically significant, worse survival for those patients with isolated tumor cells in the draining lymph nodes (⬍0.2 mm),32 other sensitive tests have not produced the same results. The authors of a number of retrospective and prospective studies initially suggested that patients with SLNs that were positive as determined by polymerase chain reaction (PCR) only had a survival worse than that of patients with nodes negative by both histology and PCR.33-38 However, this conclusion may have been attributable to the short follow-up of these low-
Figure 2 Shown is a lymphatic scan of a patient that had a 12 mm melanoma of the right posterior calf. A signal lymph node was identified by the scan in the right groin. At surgery, a single, hot node was identified with a count of 27,361 counts/10 seconds. The background count in the groin was 2 after removal of the node. Pathologic analysis did not reveal any melanoma in the SLN by H⫹E or immunohistochemistry.
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
89
Figure 3 A nomogram for the prediction of sentinel lymph node status. Each variable is assigned a number on the point scale (first line) by extending a line upwards. The total points from the sum of the variables is then used to obtain the predictive value of a positive sentinel node. (Reprinted with kind permission of Springer Science and Business Media.79)
risk patients. Kammula demonstrated that, with longer follow-up, PCR status of the sentinel node was not predictive of outcome.39 This finding was confirmed by the multiinstitutional Sun Belt Melanoma trial, which analyzed 1446 patients with negative SLNs with the use of PCR. Although 42% had PCR-positive disease, it did not translate into a difference in survival. At 30 months of follow-up, there was no difference in survival between patients with PCR-positive nodes and PCR-negative SLN=s.40 A recent meta-analysis of more than 4000 patients highlighted the lack of uniformity of the PCR procedure. In part secondary to differences in techniques, and markers tested, the overall incidence of PCR-positive SLN patients ranged from 12% to 74%, with an average of 47% of patients with histologically negative nodes having a positive PCR. Although the presence of a positive SLN by PCR did correlate with an increased hazard ratio for survival, this correlated with T stage, and was not found to be an independent predictor of outcome in the meta-analysis. The value of this technique requires further standardization and investigation before widespread clinical use.41
Indications for a SLN biopsy In early melanoma, SLN status is the most important predictor of survival.42 Although most people would favor a SLN biopsy for a melanoma ⱖ1 mm, a nomogram has been recently developed to help individualize that choice for patients, as shown in Figure 3. On the basis of the predictive factors in the model: tumor thickness,
Clark level, ulceration, site, and age, physicians can calculate the risk of a positive sentinel node and assist the patient in making the choice for a SLN biopsy.43 Recently, the importance of mitotic rate has re-emerged as an additional prognostic variable in melanoma. Larger series have demonstrated mitotic rate to be an independent factor of survival, although not at a level that is more powerful than tumor thickness.44 – 46 In addition, mitotic rate has been shown to be a predictor of positive SLN status47 and it has been recommended to be included in all pathologic analysis of melanoma.48 Future studies will continue to define the importance of mitotic rate. In general, a SLN biopsy is done for patients with a primary tumor thickness of 1 to 4 mm. The role of SLN biopsy in patients with thinner or thicker melanomas is discussed below.
SLN biopsy in thin or thick melanomas The role of SLNB in patients with thin melanomas is not well defined. This group is rapidly increasing in part secondary to improved detection of melanomas at earlier stages. Multiple retrospective studies on the yield of SLN biopsy in this population have demonstrated an overall incidence of a positive SLN of approximately 5%. A paucity of predictive factors for SLN involvement have been identified (Table 2). A study from MSKCC demonstrated only 8 positive SLNs among 223 SLN biopsies of patients with melanomas ⱕ1 mm. Patients with a primary lesion between 0.75-1 mm and Clark level IV, had a 7% incidence of a positive SLN; no positive sentinel nodes were detected in patients with le-
90 Table 2
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008 Larger studies demonstrating incidence of positive SLN in thin (ⱕ1 mm) melanoma
Study, year 80
Bachter, et al, 2001 Agenese, et al, 200381 Bleicher, et al, 200382 Rousseau, et al, 200383 Stitzenberg, et al, 200484 Wong, et al, 200649 Ranieri, et al, 200650
n
Positive SLN (%), ⱕ0.75 mm
Positive SLN, 0.75-1.0 mm
151 91 390 388 146 223 184
0/50 (0%) 1 (NR) 2/118 (1.7%) NR 3/NR 0/73 (0%) 2/86 (2%)
NR/101 (7%) 1 (NR) 6/154 (3.9%) NR 3/NR 8/150 (5.3%) 10/98 (10%)
sions that were ⬍0.75 mm and Clark III. Interestingly, of the 6 recurrences detected, 5 had a negative SLN biopsy.49 Another retrospective study of thin melanomas identified a positive SLN in 10% of patients with melanomas between 0.75 and 1 mm. In this study, there was only one death each in the SLN negative and the SLN positive group.50 Neither of these retrospective studies suggests that SLN status is highly predictive of outcome in patients with thin melanoma. More recently, a prognostic tree was developed which incorporates ulceration, sex, Clark level, and mitotic rate to identify those patients with thin melanoma who have the highest risk of recurrence.51 This may allow for enhanced guidance of the individual patient, taking into account multiple risk factors to establish the projected incidence of a positive SLN. The role of SLN biopsy in thick melanomas (ⱖ 4 mm) has not been studied in a prospective manner. This is a group of patients with a high probability of both regional nodal spread as well as systemic metastases. If the SLN status is of prognostic significance, it could help direct clinical care, as well as stratify these patients into homogeneous groups at risk for recurrence for the purposes of clinical trials of adjuvant therapy. The majority of such retrospective studies support the prognostic importance of
Table 3
Overall incidence ⫹ SLN NR (7%) 2/91 (2%) 8/272 (3%) 4/388 (1%) 6/146 (4%) 8/223 (3%) 12/184 (7%)
Predictive factors for ⫹ SLN
Age, incomplete biopsy None Predictive None Predictive Thickness, Clark level, Mitotic Index
the sentinel node status in this group of patients (Table 3). In a retrospective study with a median follow-up of 3 years, patients with thick melanomas had a significant difference in disease-free survival based on SLN status. Patients with a negative SLN had 82.4% 3 year disease-free survival, whereas patients with a positive SLN had a 58% 3 year disease-free survival.52 Additional studies have supported the prognostic value of SLN status in patients with thick melanomas,53,54 and the SLN status has been demonstrated to be the most significant factor of disease specific survival on multivariate analysis.55 Therefore, in the absence of clinically positive nodes, there is prognostic utility for a SLN biopsy in patients with thick melanomas.
SLN biopsy in desmoplastic melanomas Desmoplastic melanomas were first described by Conley in 1971 as a variant of sarcoma.56 The largest series of 280 patients with desmoplastic melanoma comes from the Sydney Melanoma Unit, where desmoplastic tumors were noted to be thick and occur in older patients in the head and neck area. The incidence of a positive SLN biopsy was low, but local recurrence was high and was associated with the presence of a close margin (⬍1 cm) or neurotropism.57 Two forms of desmoplas-
Prognostic value of SLN in thick melanoma (⬎4 mm) n
% SLN positive
Survival SLN⫺
Survival SLN⫹
P value
Notes
Gershenwald, et al, 2000
131
39%
82% 3-year DFS
58% 3-year DFS
⬍0.03
Carlson, et al, 200385
114
33%
82% 3-year OS
57% 3-year OS
0.006
SLN status most important on MV analysis SLN status important on MV analysis
Jacobs, et al, 200454 Ferrone, et al, 200455
43 126
44% 30%
53 months DFS 56% 5-year RFS
44 month DFS 32% 5-year RFS
0.02 0.0008
Caracö, et al, 200486
62
NR
55% 3-year OS
55% 3-year OS
NS
49%
68% 5-year OS
53% 5-year OS
⬍0.01
Study 52
Gutzmer, et al, 200853
152
SLN status most important on MV analysis SLN status not a predictor in thick melanomas SLN status most important on MV analysis
Abbreviations: DFS, disease-free survival; NR, not reported; NS, not significant; RFS, relapse-free survival; OS, overall survival; MV, multivariate analysis.
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
tic melanoma have now been described, pure and mixed.58 In a series at MSKCC, we have noted an extremely rare incidence of nodal metastasis and overall favorable prognosis in patients with a pure desmoplastic melanoma.59 Patients with a mixed epithelioid/desmoplastic melanoma tend to have an incidence of lymph node metastasis and overall survival similar to that of a conventional melanoma.60 Therefore, if a pathologist identifies a pure desmoplastic melanoma, we do not recommend a SLN biopsy.
SLN biopsy in pediatric patients and in ambiguous lesions The pediatric population represents a small proportion of patients with melanoma. The diagnosis of melanoma is often difficult and requires skilled dermatopathologists who can differentiate among Spitz nevus, melanocytic proliferation, and invasive melanoma. The pathologic challenges of this diagnosis will be discussed in more detail elsewhere in this series however, some lesions are not able to be well characterized and are labeled as “atypical,” which presents a dilemma for clinicians. In cases where the biologic potential is not discernible from the primary lesion, SLN biopsy has been suggested as a manner to further characterize the aggressiveness of the tumor. Small studies have demonstrated a high SLN positive rate of 28-44% in this population, with rates of a positive SLN correlating with increased tumor thickness.61– 63 The prognostic significance of a positive sentinel node in this patient group is unknown; not a single patient with a positive SLN has recurred in these small reported series. However, distant disease and mortality has been reported in patients with these atypical lesions.64,65 As such, we consider SLN biopsy for patients with melanocytic lesions of indeterminate biologic potential and a primary tumor thickness ⬎1 mm. For any given thickness of melanoma, younger age is a predictor of increased likelihood of SLN positivity. Multiple studies have demonstrated that SLN biopsy can be effectively performed in pediatric patients, with rates of a positive SLN that range from 25% to 60%. The wide range reflects the difficulty in establishing a uniform cohort of pediatric patients with a consistent diagnosis of melanoma. However, node-positive pediatric patients have favorable survival rates of 75% to 100%, when compared with adults with positive nodes.66 –70 These studies are difficult to interpret because the numbers are extremely small, with all reporting on experience with ⱕ20 patients. Although large studies have shown an inverse correlation between the incidence of positive SLN and age,71 trials in pediatric patients have suggested the improved survival is secondary to characteristics of the primary tumor or stage. Larger studies on the pediatric population have demonstrated a modest increase in the incidence of nodal disease in the pediatric population, with conflicting results. An analysis of the National Cancer Data Base in the United States analyzed 3,158 children between the ages of 1-19
91 years who were diagnosed with melanoma between 1985 and 2003. A high percentage of children younger than 9 years old were found to have regional (25-30%) or metastatic (6-14%) disease. The potential contributing factors, such as family history and congenital nevi, were not described. Increased stage and younger age correlated with a worse survival, yet primary tumor thickness did not.72 The Sunbelt melanoma trial, in contrast, studied 315 patients that were ⱕ30 years of age. This population did have an increased incidence of positive SLNs (24%), and this younger cohort had a statistically improved 5-year diseasespecific survival compared with an older cohort (86% vs 79% respectively, P ⫽ 0.036). This improved survival also correlated with more favorable pathologic features such as lack of ulceration, tumor thickness ⬍4 mm, and female sex.73 At MSKCC, we have noticed a 24% incidence of positive SLN=s in pediatric melanoma patients (personal communication, Dr. Kayton). Clearly, a SLN biopsy can be performed in the pediatric population. It remains unclear if node-positive disease can predict outcome better than the primary features of the tumor. Children will suffer the complications of the procedure lifelong and this risk must be balanced with the information gained from a SLN biopsy.
Complications of SLN biopsy SLN biopsy is an invasive procedure with risks secondary to the surgery and medications used. There is a 1% incidence of anaphylaxis to the blue dye74; however, the incidence of severe hypotension and cardiovascular compromise is less than 1%.75 Most patients are under anesthesia and can be managed appropriately with steroids and occasionally pressor support, as long as the scenario is recognized. Despite the fact that SLN biopsy only removes a few nodes, there is still a definable morbidity associated with the procedure. In the Sunbelt trial, the morbidity of SLN biopsy was measured in a prospective fashion. A SLN biopsy was associated with a 4% morbidity and a 1.7% incidence of limb edema.76 In the MSLT trial, the largest composite of patients with prospective follow-up, the risk of morbidity 30 days after the procedure was 13.8% with a wide local excision and SLN biopsy. This was not significantly different than the 13.9% morbidity rate observed with wide local excision alone. However, within 30 days there was an increased incidence of seroma (2.8% vs 4%) and extremity edema or phlebitis (0.75 versus 1.5%) with WLE versus SLN biopsy respectively.77
Results of SLN biopsy The Sunbelt Melanoma trial prospectively enrolled patients with the goal of analyzing molecular staging and adjuvant treatment. It also demonstrated the value of the SLN biopsy,
92
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
a procedure that can be done with a low morbidity, and provide accurate prognostic information.76 The therapeutic value of the SLN biopsy was addressed in the multicenter lymph node trial (MSLT-1). Patients with an invasive melanoma (⬎1 mm) were prospectively randomized to undergo a SLN biopsy at the time of wide local excision, with completion lymph node dissection if the SLN was positive, or, wide local excision of the primary with observation of the nodal basin. A completion lymph node dissection was performed in this group if lymph node metastasis became clinically apparent. The primary endpoint of MSLT-1 was disease-specific survival (DSS) between the 2 arms, and a secondary endpoint was to compare survival among those patients with positive lymph nodes. In a publication describing a planned third interim analysis, there was no difference in DSS between the 2 treatment groups (87% for SLN biopsy versus 86% for observation at 5 years). However, in secondary analysis of patients with nodal disease, there was a survival benefit among patients undergoing a primary SLN biopsy and completion lymph node dissection, as opposed to those who underwent a delayed node dissection (5 year DSS 72% vs 52% respectively, P ⫽ 0.007). This secondary analysis is not a randomized trial, as at the outset of the trial it is not clear which patients under observation would recur in the lymph nodes and, therefore, it is impossible to randomize for this event. However, with acknowledgment of this statistical flaw, the group of patients with a 1.2- to 3.5-mm thick melanoma that underwent an immediate SLN biopsy and completion lymph node dissection for microscopic disease, had an improved survival over the delayed lymphadenectomy group. The authors postulate that, in the absence of effective systemic adjuvant therapy, identifying nodal metastatic disease early may identify a cohort of patients in whom all clinically relevant disease is more likely to be confined to the nodes, in whom lymph node dissection is more likely to affect long term outcome. Patients with disease detected on SLN had on average only one lymph node that was microscopically positive for disease, while patients undergoing observation had an average of three lymph nodes containing macroscopic metastatic melanoma. At present, however, as the primary endpoint of the trial suggested no improvement in DSS in patients undergoing SLNB, patients should understand that the role of SLN biopsy is primarily as a staging tool in melanomas 1.2 to 3.5 mm.
patients. In addition, the presence of metastatic disease in the lymph nodes remains an important prognostic variable. These data will serve as reassurance to the majority of patients that undergo the procedure and have a negative SLN. The patients with a positive SLN have a more realistic expectation of outcome, and can be encouraged to enter into clinical trials. The lack of effective adjuvant therapy has plagued the field of melanoma, but studies continue with the hope of advancing the field. In the absence of SLN biopsy, we will not know who the high-risk patients are until they recur, and the ability to test adjuvant treatments will be difficult without appropriate pretreatment stratification Therefore, SLN biopsy should be discussed with all patients with melanoma ⬎1 mm and highly selected patients with melanoma between ⬎0.75 mm and 1.0 mm. The risks and benefits have to be individualized to each patient for this procedure that remains primarily a staging tool.
Conclusions SLN biopsy has evolved to become a minimally invasive technique to identify disease in the draining lymph nodes in patients with melanoma. Although the MSLT-1 trial did not show an improvement in overall survival with SLN biopsy, the detection of metastatic disease at the microscopic, as opposed the macroscopic level, may offer some benefit to
References 1. Morton LT: Morton’s Medical Bibliography. An annotated Check-list of Texts Illustrating the History of Medicine (Garrison and Morton). Brookfield, VT, Scolar Press, 1991 2. Kinmonth JB: Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci (Lond) 11:13-20, 1952 3. Sherman AI, Ter-Pogossian M: Lymph-node concentration of radioactive colloidal gold following interstitial injection. Cancer 6:12381240, 1953 4. Fee HJ, Robinson DS, Sample WF, et al: The determination of lymph shed by colloidal gold scanning in patients with malignant melanoma: a preliminary study. Surgery 84:626-632, 1978 5. Holmes EC, Moseley HS, Morton DL, et al: A rational approach to the surgical management of melanoma. Ann Surg 186:481-490, 1977 6. Eberbach MA, Wahl RL: Lymphatic anatomy: Functional nodal basins. Ann Plast Surg 22:25-31, 1989 7. Norman J, Cruse CW, Espinosa C, et al: Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg 162:432-437, 1991 8. Uren RF, Thompson JF, Howman-Giles R, et al: Melanoma metastases in triangular intermuscular space lymph nodes. Ann Surg Oncol 6:811, 1999 9. Thompson JF, Uren RF, Shaw HM, et al: Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy. J Am Coll Surg 189:195-204, 1999 10. O’Toole GA, Hettiaratchy S, Allan R, et al: Aberrant sentinel nodes in malignant melanoma. Br J Plast Surg 53:415-417, 2000 11. Statius Muller MG, Hennipman FA, van Leeuwen PA, et al: Unpredictability of lymphatic drainage patterns in melanoma patients. Eur J Nucl Med Mol Imaging 29:255-261, 2002 12. McHugh JB, Su L, Griffith KA, et al: Significance of multiple lymphatic basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy. Ann Surg Oncol 13:1216-1223, 2006 13. Wanebo HJ, Harpole D, Teates CD: Radionuclide lymphoscintigraphy with technetium 99m antimony sulfide colloid to identify lymphatic drainage of cutaneous melanoma at ambiguous sites in the head and neck and trunk. Cancer 55:1403-1413, 1985 14. de Wilt JH, Thompson JF, Uren RE, et al: Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg 239:544-552, 2004
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
15. Gould EA, Winship T, Philbin PH, et al: Observations on a “sentinel node” in cancer of the parotid. Cancer 13:77-78, 1960 16. Cabanas RM: An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977 17. Little JH, Davis NC: Secondary malignant melanoma in lymph nodes: Incidence, time of occurrence, and mortality. Aust N Z J Surg 48:9-13, 1978 18. Soong SJ, Harrison RA, McCarthy WH, et al: Factors affecting survival following local, regional, or distant recurrence from localized melanoma. J Surg Oncol 67:228-233, 1998 19. Meier F, Will S, Ellwanger U, et al: Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol 147:62-70, 2002 20. Balch CM, Soong S, Ross MI, et al: Long-term results of a multiinstitutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7:87-97, 2000 21. Balch CM, Soong SJ, Bartolucci AA, et al: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255-263; discussion 263-266, 1996 22. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351:793-796, 1998 23. Sim FH, Taylor WF, Ivins JC, et al: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 41:948-956, 1978 24. Veronesi U, Adamus J, Bandiera DC, et al: Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med 297:627-630, 1977 25. Wong JH, Cagle LA, Morton DL: Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 214:637-641, 1991 26. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992 27. Alex JC, Weaver DL, Fairbank JT, et al: Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:303-308, 1993 28. Albertini JJ, Cruse CW, Rapaport D, et al: Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217-224, 1996 29. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 8:192-197, 2001 30. Stojadinovic A, Allen PJ, Clary BM, et al: Value of frozen-section analysis of sentinel lymph nodes for primary cutaneous malignant melanoma. Ann Surg 235:92-98, 2002 31. Cochran AJ, Roberts A, Wen DR, et al: Update on lymphatic mapping and sentinel node biopsy in the management of patients with melanocytic tumours. Pathology 36:478-484, 2004 32. Scheri RP, Essner R, Turner RR, et al: Isolated tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol 14:2861-2866, 2077. 33. Shivers SC, Wang X, Li W, et al: Molecular staging of malignant melanoma: Correlation with clinical outcome. JAMA 280:1410-1415, 1998 34. Bostick PJ, Morton DL, Turner RR, et al: Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 17:3238-3244, 1999 35. Blaheta HJ, Ellwanger U, Shittek B, et al: Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 114:637-642, 2000 36. Li W, Stall A, Shivers SC, et al: Clinical relevance of molecular staging for melanoma: Comparison of RT-PCR and immunohisto-
93
37.
38.
39.
40.
41.
42.
43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
chemistry staining in sentinel lymph nodes of patients with melanoma. Ann Surg 231:795-803, 2000 Goydos JS, Patel KN, Shin WJ, et al: Patterns of recurrence in patients with melanoma and histologically negative but RT-PCR-positive sentinel lymph nodes. J Am Coll Surg 196:196-204; discussion 204-205, 2003 Ribuffo D, Gradilone A, Vonella M, et al: Prognostic significance of reverse transcriptase-polymerase chain reaction-negative sentinel nodes in malignant melanoma. Ann Surg Oncol 10:396-402, 2003 Kammula US, Ghossein R, Bhattacharya S, et al: Serial follow-up and the prognostic significance of reverse transcriptase-polymerase chain reaction—staged sentinel lymph nodes from melanoma patients. J Clin Oncol 22:3989-3996, 2004 Scoggins CR, Ross MI, Reintgen DS, et al: Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 24:2849-2857, 2006 Mocellin S, Hoon DS, Pilati P, et al: Sentinel lymph node molecular ultrastaging in patients with melanoma: A systematic review and meta-analysis of prognosis. J Clin Oncol 25:1588-1595, 2007 Gershenwald JE, Thompson W, Mansfield PF, 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 17:976-983, 1999 Wong SL, Kattan MW, McMasters KM, et al: 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 12:282-288, 2005 Azzola MF, Shaw HM, Thompson JF, 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 97:1488-1498, 2003 Attis MG, Vollmer RT: Mitotic rate in melanoma: a reexamination. Am J Clin Pathol 127:380-384, 2007 Barnhill RL, Fine JA, Roush GC, et al: Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer 78:427-432, 1996 Paek SC, Griffith KA, Johnson TM, et al: The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma. Cancer 109:100-108, 2007 Compton CC, Barnhill R, Wick MR, et al: Protocol for the examination of specimens from patients with melanoma of the skin. Arch Pathol Lab Med 127:1253-1262, 2003 Wong SL, Brady MS, Busam KJ, et al: Results of sentinel lymph node biopsy in patients with thin melanoma. Ann Surg Oncol 13:302-309, 2006 Ranieri JM, Wagner JD, Wenck S, et al: The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol 13: 927-932, 2006 Gimotty PA, Elder DE, Fraker DL, et al: Identification of high-risk patients among those diagnosed with thin cutaneous melanomas. J Clin Oncol 25:1129-1134, 2007. Gershenwald JE, Mansfield PF, Lee JE, et al: Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (⬎ or ⫽ 4 mm) primary melanoma. Ann Surg Oncol 7:160-165, 2007 Gutzmer R., Satzger I, Thoms KM, et al: Sentinel lymph node status is the most important prognostic factor for thick (⬎ or ⫽ 4 mm) melanomas. J Dtsch Dermatol Ges 6:198-203, 2008 Jacobs IA, Chang CK, Salti GI: Role of sentinel lymph node biopsy in patients with thick (⬎4 mm) primary melanoma. Am Surg 70:59-62, 2004 Ferrone CR, Panageas KM, Busam K, et al: Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 9:637-645, 2002 Conley J, Lattes R, Orr W: Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 28:914-936, 1971
94
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
57. Quinn MJ, Crotty KA, Thompson JF, et al: Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer 83:1128-1135, 1988 58. Busam KJ, Mujudar U, Hummer AJ, et al: Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 28:1518-1525, 2008 59. Gyorki DE, Busam K, Panageas K, et al: Sentinel lymph node biopsy for patients with cutaneous desmoplastic melanoma. Ann Surg Oncol 10:403-407, 2003 60. Hawkins WG, Busam KJ, Ben-Porat L, et al: Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg Oncol 12:207-213, 2005 61. Su LD, Fullen DR, Sondak VK, et al: Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 97:499-507, 2003 62. Murali R, Sharma RN, Thompson JF, et al: Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with spitzoid features (so-called atypical spitzoid tumors). Ann Surg Oncol 15:302309, 2008 63. Gamblin TC, Edington H, Kirkwood JM, et al: Sentinel lymph node biopsy for atypical melanocytic lesions with spitzoid features. Ann Surg Oncol 13:1664-1670, 2006 64. Barnhill RL, Argenyi ZB, From L, et al: Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 30:513-520, 1999 65. Cerroni L, Kerl H: Tutorial on melanocytic lesions. Am J Dermatopathol 23:237-241, 2001 66. Kogut KA, Fleming M, Pappo AS, et al: Sentinel lymph node biopsy for melanoma in young children. J Pediatr Surg 35:965-966, 2000. 67. Neville HL, Andrassy RJ, Lally KP, et al: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35:961-964, 2000 68. Toro J, Ranieri JM, Havlik RJ, et al: Sentinel lymph node biopsy in children and adolescents with malignant melanoma. J Pediatr Surg 38:1063-1065, 2003 69. Butter A, Hui T, Chapdelaine J, et al: Melanoma in children and the use of sentinel lymph node biopsy. J Pediatr Surg 40:797-800, 2005 70. Roaten JB, Partrick DA, Pearlman N, et al: Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents. J Pediatr Surg 40:232-235, 2005 71. Chao C, Martin RC 2nd, Ross MI, et al: Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 11:259-264, 2004 72. Lange JR, Palis BE, Chang DC, et al: Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. J Clin Oncol 25:1363-1368, 2007
73. Chagpar RB, Ross MI, Reintgen DS, et al: Factors associated with improved survival among young adult melanoma patients despite a greater incidence of sentinel lymph node metastasis. J Surg Res 143:164-168, 2007 74. Leong SP, Donegan E, Heffernon W, et al: Adverse reactions to isosulfan blue during selective sentinel lymph node dissection in melanoma. Ann Surg Oncol 7:361-366, 2000. 75. Montgomery LL, Thorne AC, Van Zee KJ, et al: Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer. Anesth Analg 95:385-388, 2002 76. McMasters KM, Noyes RD, Reintgen DS, et al: Lessons learned from the Sunbelt Melanoma Trial. J Surg Oncol 86:212-223, 2004 77. Morton DL, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006 78. Balch CM, Soong SJ, Smith T, et al: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8:101108, 2001 79. Wong SL, Kattan MW, McMasters KM, et al: 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 12:282-288, 2005 80. Bachter D, Michl C, Büchels H, et al: The predictive value of the sentinel lymph node in malignant melanomas. Recent Results Cancer Res 158:129-136, 2001 81. Agnese DM, Abdessalam SF, Burak WE Jr, et al: Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 134:542-547, 2003; discussion 547-548 82. Bleicher RJ, Essner R, Foshag LJ, et al: Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas. J Clin Oncol 21:13261331, 2003 83. Rousseau DL Jr, Ross MI, Johnson MM, et al: Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol 10:569-574, 2003 84. Stitzenberg KB, Groben PA, Stern SL, et al: Indications for lymphatic mapping and sentinel lymphadenectomy in patients with thin melanoma (Breslow thickness ⬍ or ⫽1.0 mm). Ann Surg Oncol 11:900906, 2004. 85. Carlson GW, Murray DR, Hestley A, et al: Sentinel lymph node mapping for thick (⬎or⫽4-mm) melanoma: should we be doing it? Ann Surg Oncol 10:408-415, 2003 86. Caracó C, Celentano E, Lastoria S, et al: Sentinel lymph node biopsy does not change melanoma-specific survival among patients with Breslow thickness greater than four millimeters. Ann Surg Oncol 11:198S-202S, 2004 (suppl 3)
Clinical aspects of sentinel lymph node biopsy in melanoma Charlotte E. Ariyan, MD, PhD, Daniel G. Coit, MD From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY KEYWORDS Melanoma; Sentinel lymph node biopsy
Sentinel lymph node (SLN) biopsy has evolved over the years to become one of the most useful tools in the treatment of melanoma. Large, multi-institutional studies have confirmed that in experienced hands it is an accurate, reliable technique to identify tumor in the draining lymph nodes. The complications of the procedure are low, and it is generally well tolerated. The presence of melanoma in the sentinel lymph node is the most important predictive factor in patients with intermediate thickness melanomas. In patients with thin melanomas (⬍1 mm), the incidence of a positive SLN is low. The choice to perform a SLN biopsy in these patients must be weighed with risk factors such as Clark level, ulceration, sex and mitotic rate. In patients with thick melanomas (⬎4 mm), most studies have supported the prognostic value of SLN status. Patients with desmoplastic melanomas have a high risk of local recurrence, but low risk of SLN metastasis if the pathology demonstrates a pure desmoplastic form. Younger patients have a higher incidence of positive lymph nodes, yet an overall more favorable prognosis compared to older patients. Patients should understand that this procedure remains primarily a staging tool, as large prospective randomized trials have not demonstrated an overall survival benefit. © 2008 Elsevier Inc. All rights reserved.
The most common site of metastatic disease in melanoma is the draining lymph nodes. For this reason, there has been a long history of either excision or interrogation of the lymph nodes at the time of resection of the primary melanoma. This has evolved from elective lymph node dissection, to sentinel lymph node (SLN) biopsy. SLN biopsy in melanoma is an accurate staging procedure for patients. The finding of metastatic cells in the draining lymph node of a patient with clinically localized melanoma is the most powerful predictor of adverse outcome. Because there are limited options for effective adjuvant treatment for melanoma, the usefulness of detecting metastatic disease is controversial. This review will focus on the history and development of SLN biopsy.
Address reprint requests and correspondence: Daniel G. Coit, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected].
0740-2570/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semdp.2008.04.004
History Characterization of the lymphatic system In 1874, Sappey published his atlas defining the lymphatic channels and patterns of drainage of the skin. Although the entity of the lymphatic system had previously been described, he was the first to systematically characterize the pathways. By injecting mercury into the skin of cadavers, Sappey demonstrated distinct areas of drainage from each skin area. This was used to define rules, for example, that a drainage pattern will never cross the midline.1 Sappey’s understanding of the lymphatic system persisted until the recent century, when new technology allowed clarification of the lymphatic flow in real time. In 1952, Kinmonth developed the lymphangiogram, a mechanism to evaluate the lymphatics in vivo. Using blue dye and direct injection of radiopaque contrast, he demon-
Ariyan and Coit Table 1
Clinical Aspects of SLN Biopsy in Melanoma
87
Randomized trials evaluating elective lymph-node dissection (ELND) for melanoma n
Site
Thickness (mm)
FUP (years)
WLE
WLE ⫹ ELND
P value
Sim, et al
173
Any
NR
85
85
NS
Veronesi, et al24 Balch, et al21,78
553 740
Excluded midline trunk, head and Neck Extremity All
Any 1-4
Cascinelli, et al22
240
Trunk
⬎1.5
8.2 7.4 10 11
72 82 73 51
74 86 77 62
NS 0.25 0.12 0.09
Study 23
strated flow in the lymphatic system.2 Another modification of this technique used the subcutaneous injection of colloid gold, which was hypothesized to be taken up by phagocytes and transported to the draining lymph nodes. The genesis of this idea was to allow this radioactive substance to treat affected lymph nodes. However, the emission of beta and gamma particles also allowed for visualization of the lymphatic nodes on simple radiographs.3 The use of colloid gold was later used to successfully identify ambiguous sites of lymph node drainage in malignant melanoma.4,5 The technique of lymphoscintigraphy has been modified, and now employs the use of smaller molecules such as filtered technetium sulfur colloid or antimony sulfur colloid. With the widespread use of lymphoscintography, it is now evident that Sappey’s lines do not accurately predict lymphatic drainage. Cutaneous lesions from the trunk or extremity can have primary drainage that can cross the midline, and can drain to multiple nodal basins, or to unexpected nodal sites.6-12 Lymphatic drainage from head and neck sites can be especially complex.13,14 Therefore, a lymphoscintigram is essential to accurately identify the correct nodal drainage patterns in melanoma.
Importance of lymph nodes in melanoma The idea of a “sentinel” lymph node draining from a tumor site was initiated by Gould in 1960 in a model of head and neck cancer.15 Gould identified a sentinel node in the management of parotid cancer, and suggested a frozen section of this angular parotid node could be used to guide the need for a neck dissection. This concept was later applied by Cabanas in 1977, who described the sentinel nodes that drain carcinoma of the penis.16 Epidemiologic studies on large cohorts of patients have demonstrated that 50% of all metastatic disease in patients with melanoma occurs in the regional draining lymph nodes.17-19 Clearly, patients with a nodal disease have a worse prognosis; however, removing the disease in the lymph nodes has an unclear benefit on overall survival. Proponents of aggressive surgery cite the possibility that disease in the lymph node is the first step on the way to distant disease. Dissidents hypothesize that the distant spread occurs based on the biology of the primary tumor, and the lymph node disease is a predictor, but not a governor of overall survival.
Before sentinel lymph node (SLN) biopsy, there was debate regarding which patients, if any, should undergo an elective lymph node dissection. Several prospective, randomized trials failed to demonstrate a survival benefit for an elective lymph node dissection over nodal observation (Table 1).20-24,68 The long-term follow-up of the Intergroup Melanoma Surgery Trial, however, demonstrated a survival benefit for the subset of patients with a melanoma between 1 and 2 mm. This represents a low-risk group with a relative low incidence of adverse features such as ulceration.20 Although this trial provides some evidence that removal of clinically occult disease in the draining lymph nodes may be of benefit in selected subsets of melanoma patients, the procedure was still met with resistance. Lymph node dissection is associated with significant comorbidities, including a risk of permanent limb edema. Because most (approximately 80%) patients will not have metastatic disease detected in the lymph nodes, there was a need to better predict the lymph node status in a less invasive manner. This, in part, was the genesis of the SLN technique. Morton and colleagues described the technique of SLN biopsy by using blue dye. The initial technique was developed in a feline model because they have multiple draining nodes, similar to humans.25 In patients, this method correctly identified the SLN 61% to 96% of the time, with the success of identifying the SLN related to the experience of the surgeon.26 Krag and colleagues later demonstrated the efficacy of using technetium labeled colloid to identify the SLN.27 The combination of both techniques has been utilized to correctly identify the SLN in more than 96% of patients.28
Procedure At Memorial Sloan-Kettering Hospital (MSKCC) lymphoscintigraphy is performed the day of the procedure. Filtered radiolabeled sulfur colloid 0.05 mCi is injected in four sites circumferentially around the primary lesion. Real-time lymphoscintigraphy is then performed to identify the draining lymphatic channels and sentinel node(s). We have abandoned the use of a permanent tattoo over the lymph node of interest because we found that intraoperative use of a gamma counter could readily detect the “hot” node seen on imaging.
88
Figure 1
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
Blue Sentinel Node.
Surgery is performed approximately 1 to 3 hours after injection of radioactive tracer. This time point allows identification of the SLNs with a gamma counter and minimization of background from the primary injection. In addition to radioactivity, identification of the first draining node is assisted by the use of blue dye. Isosulfan blue (0.5 to 1 mL) is injected into the dermis of the lesion and allowed to travel to the draining lymph node for approximately five minutes.
An incision is made over the site of anticipated SLN and a gamma probe is used to locate the sentinel node with the visual assistance of blue dye as shown in Figure 1. Once a sentinel node is identified, it is removed and ex vivo gamma counts are obtained. Additional sentinel nodes are removed as directed by the preoperative lymphoscintigraphy. The lymph node basin is scanned with the gamma counter and additional nodes in the lymph node basin are removed which have radioactive counts 10% or greater of the hottest sentinel node.29 A representative lymphoscintigram of a melanoma of the extremity is demonstrated in Figure 2. After the nodes are removed, they are sent for routine pathologic analysis. Frozen section is generally not used to facilitate the complete analysis of the sentinel node and to avoid false negatives demonstrated with the use of frozen section.30 The nodes are analyzed in a systemic fashion as described by Cochran and colleagues, and as discussed in depth in other chapters in this series.31 The question of what constitutes a clinically significant positive node remains a subject of debate. Although recent studies have demonstrated a small, but statistically significant, worse survival for those patients with isolated tumor cells in the draining lymph nodes (⬍0.2 mm),32 other sensitive tests have not produced the same results. The authors of a number of retrospective and prospective studies initially suggested that patients with SLNs that were positive as determined by polymerase chain reaction (PCR) only had a survival worse than that of patients with nodes negative by both histology and PCR.33-38 However, this conclusion may have been attributable to the short follow-up of these low-
Figure 2 Shown is a lymphatic scan of a patient that had a 12 mm melanoma of the right posterior calf. A signal lymph node was identified by the scan in the right groin. At surgery, a single, hot node was identified with a count of 27,361 counts/10 seconds. The background count in the groin was 2 after removal of the node. Pathologic analysis did not reveal any melanoma in the SLN by H⫹E or immunohistochemistry.
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
89
Figure 3 A nomogram for the prediction of sentinel lymph node status. Each variable is assigned a number on the point scale (first line) by extending a line upwards. The total points from the sum of the variables is then used to obtain the predictive value of a positive sentinel node. (Reprinted with kind permission of Springer Science and Business Media.79)
risk patients. Kammula demonstrated that, with longer follow-up, PCR status of the sentinel node was not predictive of outcome.39 This finding was confirmed by the multiinstitutional Sun Belt Melanoma trial, which analyzed 1446 patients with negative SLNs with the use of PCR. Although 42% had PCR-positive disease, it did not translate into a difference in survival. At 30 months of follow-up, there was no difference in survival between patients with PCR-positive nodes and PCR-negative SLN=s.40 A recent meta-analysis of more than 4000 patients highlighted the lack of uniformity of the PCR procedure. In part secondary to differences in techniques, and markers tested, the overall incidence of PCR-positive SLN patients ranged from 12% to 74%, with an average of 47% of patients with histologically negative nodes having a positive PCR. Although the presence of a positive SLN by PCR did correlate with an increased hazard ratio for survival, this correlated with T stage, and was not found to be an independent predictor of outcome in the meta-analysis. The value of this technique requires further standardization and investigation before widespread clinical use.41
Indications for a SLN biopsy In early melanoma, SLN status is the most important predictor of survival.42 Although most people would favor a SLN biopsy for a melanoma ⱖ1 mm, a nomogram has been recently developed to help individualize that choice for patients, as shown in Figure 3. On the basis of the predictive factors in the model: tumor thickness,
Clark level, ulceration, site, and age, physicians can calculate the risk of a positive sentinel node and assist the patient in making the choice for a SLN biopsy.43 Recently, the importance of mitotic rate has re-emerged as an additional prognostic variable in melanoma. Larger series have demonstrated mitotic rate to be an independent factor of survival, although not at a level that is more powerful than tumor thickness.44 – 46 In addition, mitotic rate has been shown to be a predictor of positive SLN status47 and it has been recommended to be included in all pathologic analysis of melanoma.48 Future studies will continue to define the importance of mitotic rate. In general, a SLN biopsy is done for patients with a primary tumor thickness of 1 to 4 mm. The role of SLN biopsy in patients with thinner or thicker melanomas is discussed below.
SLN biopsy in thin or thick melanomas The role of SLNB in patients with thin melanomas is not well defined. This group is rapidly increasing in part secondary to improved detection of melanomas at earlier stages. Multiple retrospective studies on the yield of SLN biopsy in this population have demonstrated an overall incidence of a positive SLN of approximately 5%. A paucity of predictive factors for SLN involvement have been identified (Table 2). A study from MSKCC demonstrated only 8 positive SLNs among 223 SLN biopsies of patients with melanomas ⱕ1 mm. Patients with a primary lesion between 0.75-1 mm and Clark level IV, had a 7% incidence of a positive SLN; no positive sentinel nodes were detected in patients with le-
90 Table 2
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008 Larger studies demonstrating incidence of positive SLN in thin (ⱕ1 mm) melanoma
Study, year 80
Bachter, et al, 2001 Agenese, et al, 200381 Bleicher, et al, 200382 Rousseau, et al, 200383 Stitzenberg, et al, 200484 Wong, et al, 200649 Ranieri, et al, 200650
n
Positive SLN (%), ⱕ0.75 mm
Positive SLN, 0.75-1.0 mm
151 91 390 388 146 223 184
0/50 (0%) 1 (NR) 2/118 (1.7%) NR 3/NR 0/73 (0%) 2/86 (2%)
NR/101 (7%) 1 (NR) 6/154 (3.9%) NR 3/NR 8/150 (5.3%) 10/98 (10%)
sions that were ⬍0.75 mm and Clark III. Interestingly, of the 6 recurrences detected, 5 had a negative SLN biopsy.49 Another retrospective study of thin melanomas identified a positive SLN in 10% of patients with melanomas between 0.75 and 1 mm. In this study, there was only one death each in the SLN negative and the SLN positive group.50 Neither of these retrospective studies suggests that SLN status is highly predictive of outcome in patients with thin melanoma. More recently, a prognostic tree was developed which incorporates ulceration, sex, Clark level, and mitotic rate to identify those patients with thin melanoma who have the highest risk of recurrence.51 This may allow for enhanced guidance of the individual patient, taking into account multiple risk factors to establish the projected incidence of a positive SLN. The role of SLN biopsy in thick melanomas (ⱖ 4 mm) has not been studied in a prospective manner. This is a group of patients with a high probability of both regional nodal spread as well as systemic metastases. If the SLN status is of prognostic significance, it could help direct clinical care, as well as stratify these patients into homogeneous groups at risk for recurrence for the purposes of clinical trials of adjuvant therapy. The majority of such retrospective studies support the prognostic importance of
Table 3
Overall incidence ⫹ SLN NR (7%) 2/91 (2%) 8/272 (3%) 4/388 (1%) 6/146 (4%) 8/223 (3%) 12/184 (7%)
Predictive factors for ⫹ SLN
Age, incomplete biopsy None Predictive None Predictive Thickness, Clark level, Mitotic Index
the sentinel node status in this group of patients (Table 3). In a retrospective study with a median follow-up of 3 years, patients with thick melanomas had a significant difference in disease-free survival based on SLN status. Patients with a negative SLN had 82.4% 3 year disease-free survival, whereas patients with a positive SLN had a 58% 3 year disease-free survival.52 Additional studies have supported the prognostic value of SLN status in patients with thick melanomas,53,54 and the SLN status has been demonstrated to be the most significant factor of disease specific survival on multivariate analysis.55 Therefore, in the absence of clinically positive nodes, there is prognostic utility for a SLN biopsy in patients with thick melanomas.
SLN biopsy in desmoplastic melanomas Desmoplastic melanomas were first described by Conley in 1971 as a variant of sarcoma.56 The largest series of 280 patients with desmoplastic melanoma comes from the Sydney Melanoma Unit, where desmoplastic tumors were noted to be thick and occur in older patients in the head and neck area. The incidence of a positive SLN biopsy was low, but local recurrence was high and was associated with the presence of a close margin (⬍1 cm) or neurotropism.57 Two forms of desmoplas-
Prognostic value of SLN in thick melanoma (⬎4 mm) n
% SLN positive
Survival SLN⫺
Survival SLN⫹
P value
Notes
Gershenwald, et al, 2000
131
39%
82% 3-year DFS
58% 3-year DFS
⬍0.03
Carlson, et al, 200385
114
33%
82% 3-year OS
57% 3-year OS
0.006
SLN status most important on MV analysis SLN status important on MV analysis
Jacobs, et al, 200454 Ferrone, et al, 200455
43 126
44% 30%
53 months DFS 56% 5-year RFS
44 month DFS 32% 5-year RFS
0.02 0.0008
Caracö, et al, 200486
62
NR
55% 3-year OS
55% 3-year OS
NS
49%
68% 5-year OS
53% 5-year OS
⬍0.01
Study 52
Gutzmer, et al, 200853
152
SLN status most important on MV analysis SLN status not a predictor in thick melanomas SLN status most important on MV analysis
Abbreviations: DFS, disease-free survival; NR, not reported; NS, not significant; RFS, relapse-free survival; OS, overall survival; MV, multivariate analysis.
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
tic melanoma have now been described, pure and mixed.58 In a series at MSKCC, we have noted an extremely rare incidence of nodal metastasis and overall favorable prognosis in patients with a pure desmoplastic melanoma.59 Patients with a mixed epithelioid/desmoplastic melanoma tend to have an incidence of lymph node metastasis and overall survival similar to that of a conventional melanoma.60 Therefore, if a pathologist identifies a pure desmoplastic melanoma, we do not recommend a SLN biopsy.
SLN biopsy in pediatric patients and in ambiguous lesions The pediatric population represents a small proportion of patients with melanoma. The diagnosis of melanoma is often difficult and requires skilled dermatopathologists who can differentiate among Spitz nevus, melanocytic proliferation, and invasive melanoma. The pathologic challenges of this diagnosis will be discussed in more detail elsewhere in this series however, some lesions are not able to be well characterized and are labeled as “atypical,” which presents a dilemma for clinicians. In cases where the biologic potential is not discernible from the primary lesion, SLN biopsy has been suggested as a manner to further characterize the aggressiveness of the tumor. Small studies have demonstrated a high SLN positive rate of 28-44% in this population, with rates of a positive SLN correlating with increased tumor thickness.61– 63 The prognostic significance of a positive sentinel node in this patient group is unknown; not a single patient with a positive SLN has recurred in these small reported series. However, distant disease and mortality has been reported in patients with these atypical lesions.64,65 As such, we consider SLN biopsy for patients with melanocytic lesions of indeterminate biologic potential and a primary tumor thickness ⬎1 mm. For any given thickness of melanoma, younger age is a predictor of increased likelihood of SLN positivity. Multiple studies have demonstrated that SLN biopsy can be effectively performed in pediatric patients, with rates of a positive SLN that range from 25% to 60%. The wide range reflects the difficulty in establishing a uniform cohort of pediatric patients with a consistent diagnosis of melanoma. However, node-positive pediatric patients have favorable survival rates of 75% to 100%, when compared with adults with positive nodes.66 –70 These studies are difficult to interpret because the numbers are extremely small, with all reporting on experience with ⱕ20 patients. Although large studies have shown an inverse correlation between the incidence of positive SLN and age,71 trials in pediatric patients have suggested the improved survival is secondary to characteristics of the primary tumor or stage. Larger studies on the pediatric population have demonstrated a modest increase in the incidence of nodal disease in the pediatric population, with conflicting results. An analysis of the National Cancer Data Base in the United States analyzed 3,158 children between the ages of 1-19
91 years who were diagnosed with melanoma between 1985 and 2003. A high percentage of children younger than 9 years old were found to have regional (25-30%) or metastatic (6-14%) disease. The potential contributing factors, such as family history and congenital nevi, were not described. Increased stage and younger age correlated with a worse survival, yet primary tumor thickness did not.72 The Sunbelt melanoma trial, in contrast, studied 315 patients that were ⱕ30 years of age. This population did have an increased incidence of positive SLNs (24%), and this younger cohort had a statistically improved 5-year diseasespecific survival compared with an older cohort (86% vs 79% respectively, P ⫽ 0.036). This improved survival also correlated with more favorable pathologic features such as lack of ulceration, tumor thickness ⬍4 mm, and female sex.73 At MSKCC, we have noticed a 24% incidence of positive SLN=s in pediatric melanoma patients (personal communication, Dr. Kayton). Clearly, a SLN biopsy can be performed in the pediatric population. It remains unclear if node-positive disease can predict outcome better than the primary features of the tumor. Children will suffer the complications of the procedure lifelong and this risk must be balanced with the information gained from a SLN biopsy.
Complications of SLN biopsy SLN biopsy is an invasive procedure with risks secondary to the surgery and medications used. There is a 1% incidence of anaphylaxis to the blue dye74; however, the incidence of severe hypotension and cardiovascular compromise is less than 1%.75 Most patients are under anesthesia and can be managed appropriately with steroids and occasionally pressor support, as long as the scenario is recognized. Despite the fact that SLN biopsy only removes a few nodes, there is still a definable morbidity associated with the procedure. In the Sunbelt trial, the morbidity of SLN biopsy was measured in a prospective fashion. A SLN biopsy was associated with a 4% morbidity and a 1.7% incidence of limb edema.76 In the MSLT trial, the largest composite of patients with prospective follow-up, the risk of morbidity 30 days after the procedure was 13.8% with a wide local excision and SLN biopsy. This was not significantly different than the 13.9% morbidity rate observed with wide local excision alone. However, within 30 days there was an increased incidence of seroma (2.8% vs 4%) and extremity edema or phlebitis (0.75 versus 1.5%) with WLE versus SLN biopsy respectively.77
Results of SLN biopsy The Sunbelt Melanoma trial prospectively enrolled patients with the goal of analyzing molecular staging and adjuvant treatment. It also demonstrated the value of the SLN biopsy,
92
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
a procedure that can be done with a low morbidity, and provide accurate prognostic information.76 The therapeutic value of the SLN biopsy was addressed in the multicenter lymph node trial (MSLT-1). Patients with an invasive melanoma (⬎1 mm) were prospectively randomized to undergo a SLN biopsy at the time of wide local excision, with completion lymph node dissection if the SLN was positive, or, wide local excision of the primary with observation of the nodal basin. A completion lymph node dissection was performed in this group if lymph node metastasis became clinically apparent. The primary endpoint of MSLT-1 was disease-specific survival (DSS) between the 2 arms, and a secondary endpoint was to compare survival among those patients with positive lymph nodes. In a publication describing a planned third interim analysis, there was no difference in DSS between the 2 treatment groups (87% for SLN biopsy versus 86% for observation at 5 years). However, in secondary analysis of patients with nodal disease, there was a survival benefit among patients undergoing a primary SLN biopsy and completion lymph node dissection, as opposed to those who underwent a delayed node dissection (5 year DSS 72% vs 52% respectively, P ⫽ 0.007). This secondary analysis is not a randomized trial, as at the outset of the trial it is not clear which patients under observation would recur in the lymph nodes and, therefore, it is impossible to randomize for this event. However, with acknowledgment of this statistical flaw, the group of patients with a 1.2- to 3.5-mm thick melanoma that underwent an immediate SLN biopsy and completion lymph node dissection for microscopic disease, had an improved survival over the delayed lymphadenectomy group. The authors postulate that, in the absence of effective systemic adjuvant therapy, identifying nodal metastatic disease early may identify a cohort of patients in whom all clinically relevant disease is more likely to be confined to the nodes, in whom lymph node dissection is more likely to affect long term outcome. Patients with disease detected on SLN had on average only one lymph node that was microscopically positive for disease, while patients undergoing observation had an average of three lymph nodes containing macroscopic metastatic melanoma. At present, however, as the primary endpoint of the trial suggested no improvement in DSS in patients undergoing SLNB, patients should understand that the role of SLN biopsy is primarily as a staging tool in melanomas 1.2 to 3.5 mm.
patients. In addition, the presence of metastatic disease in the lymph nodes remains an important prognostic variable. These data will serve as reassurance to the majority of patients that undergo the procedure and have a negative SLN. The patients with a positive SLN have a more realistic expectation of outcome, and can be encouraged to enter into clinical trials. The lack of effective adjuvant therapy has plagued the field of melanoma, but studies continue with the hope of advancing the field. In the absence of SLN biopsy, we will not know who the high-risk patients are until they recur, and the ability to test adjuvant treatments will be difficult without appropriate pretreatment stratification Therefore, SLN biopsy should be discussed with all patients with melanoma ⬎1 mm and highly selected patients with melanoma between ⬎0.75 mm and 1.0 mm. The risks and benefits have to be individualized to each patient for this procedure that remains primarily a staging tool.
Conclusions SLN biopsy has evolved to become a minimally invasive technique to identify disease in the draining lymph nodes in patients with melanoma. Although the MSLT-1 trial did not show an improvement in overall survival with SLN biopsy, the detection of metastatic disease at the microscopic, as opposed the macroscopic level, may offer some benefit to
References 1. Morton LT: Morton’s Medical Bibliography. An annotated Check-list of Texts Illustrating the History of Medicine (Garrison and Morton). Brookfield, VT, Scolar Press, 1991 2. Kinmonth JB: Lymphangiography in man; a method of outlining lymphatic trunks at operation. Clin Sci (Lond) 11:13-20, 1952 3. Sherman AI, Ter-Pogossian M: Lymph-node concentration of radioactive colloidal gold following interstitial injection. Cancer 6:12381240, 1953 4. Fee HJ, Robinson DS, Sample WF, et al: The determination of lymph shed by colloidal gold scanning in patients with malignant melanoma: a preliminary study. Surgery 84:626-632, 1978 5. Holmes EC, Moseley HS, Morton DL, et al: A rational approach to the surgical management of melanoma. Ann Surg 186:481-490, 1977 6. Eberbach MA, Wahl RL: Lymphatic anatomy: Functional nodal basins. Ann Plast Surg 22:25-31, 1989 7. Norman J, Cruse CW, Espinosa C, et al: Redefinition of cutaneous lymphatic drainage with the use of lymphoscintigraphy for malignant melanoma. Am J Surg 162:432-437, 1991 8. Uren RF, Thompson JF, Howman-Giles R, et al: Melanoma metastases in triangular intermuscular space lymph nodes. Ann Surg Oncol 6:811, 1999 9. Thompson JF, Uren RF, Shaw HM, et al: Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy. J Am Coll Surg 189:195-204, 1999 10. O’Toole GA, Hettiaratchy S, Allan R, et al: Aberrant sentinel nodes in malignant melanoma. Br J Plast Surg 53:415-417, 2000 11. Statius Muller MG, Hennipman FA, van Leeuwen PA, et al: Unpredictability of lymphatic drainage patterns in melanoma patients. Eur J Nucl Med Mol Imaging 29:255-261, 2002 12. McHugh JB, Su L, Griffith KA, et al: Significance of multiple lymphatic basin drainage in truncal melanoma patients undergoing sentinel lymph node biopsy. Ann Surg Oncol 13:1216-1223, 2006 13. Wanebo HJ, Harpole D, Teates CD: Radionuclide lymphoscintigraphy with technetium 99m antimony sulfide colloid to identify lymphatic drainage of cutaneous melanoma at ambiguous sites in the head and neck and trunk. Cancer 55:1403-1413, 1985 14. de Wilt JH, Thompson JF, Uren RE, et al: Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg 239:544-552, 2004
Ariyan and Coit
Clinical Aspects of SLN Biopsy in Melanoma
15. Gould EA, Winship T, Philbin PH, et al: Observations on a “sentinel node” in cancer of the parotid. Cancer 13:77-78, 1960 16. Cabanas RM: An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977 17. Little JH, Davis NC: Secondary malignant melanoma in lymph nodes: Incidence, time of occurrence, and mortality. Aust N Z J Surg 48:9-13, 1978 18. Soong SJ, Harrison RA, McCarthy WH, et al: Factors affecting survival following local, regional, or distant recurrence from localized melanoma. J Surg Oncol 67:228-233, 1998 19. Meier F, Will S, Ellwanger U, et al: Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol 147:62-70, 2002 20. Balch CM, Soong S, Ross MI, et al: Long-term results of a multiinstitutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7:87-97, 2000 21. Balch CM, Soong SJ, Bartolucci AA, et al: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255-263; discussion 263-266, 1996 22. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351:793-796, 1998 23. Sim FH, Taylor WF, Ivins JC, et al: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results. Cancer 41:948-956, 1978 24. Veronesi U, Adamus J, Bandiera DC, et al: Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N Engl J Med 297:627-630, 1977 25. Wong JH, Cagle LA, Morton DL: Lymphatic drainage of skin to a sentinel lymph node in a feline model. Ann Surg 214:637-641, 1991 26. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992 27. Alex JC, Weaver DL, Fairbank JT, et al: Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol 2:303-308, 1993 28. Albertini JJ, Cruse CW, Rapaport D, et al: Intraoperative radiolympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217-224, 1996 29. McMasters KM, Reintgen DS, Ross MI, et al: Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol 8:192-197, 2001 30. Stojadinovic A, Allen PJ, Clary BM, et al: Value of frozen-section analysis of sentinel lymph nodes for primary cutaneous malignant melanoma. Ann Surg 235:92-98, 2002 31. Cochran AJ, Roberts A, Wen DR, et al: Update on lymphatic mapping and sentinel node biopsy in the management of patients with melanocytic tumours. Pathology 36:478-484, 2004 32. Scheri RP, Essner R, Turner RR, et al: Isolated tumor cells in the sentinel node affect long-term prognosis of patients with melanoma. Ann Surg Oncol 14:2861-2866, 2077. 33. Shivers SC, Wang X, Li W, et al: Molecular staging of malignant melanoma: Correlation with clinical outcome. JAMA 280:1410-1415, 1998 34. Bostick PJ, Morton DL, Turner RR, et al: Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase-polymerase chain reaction in early-stage melanoma patients. J Clin Oncol 17:3238-3244, 1999 35. Blaheta HJ, Ellwanger U, Shittek B, et al: Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol 114:637-642, 2000 36. Li W, Stall A, Shivers SC, et al: Clinical relevance of molecular staging for melanoma: Comparison of RT-PCR and immunohisto-
93
37.
38.
39.
40.
41.
42.
43.
44.
45. 46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
chemistry staining in sentinel lymph nodes of patients with melanoma. Ann Surg 231:795-803, 2000 Goydos JS, Patel KN, Shin WJ, et al: Patterns of recurrence in patients with melanoma and histologically negative but RT-PCR-positive sentinel lymph nodes. J Am Coll Surg 196:196-204; discussion 204-205, 2003 Ribuffo D, Gradilone A, Vonella M, et al: Prognostic significance of reverse transcriptase-polymerase chain reaction-negative sentinel nodes in malignant melanoma. Ann Surg Oncol 10:396-402, 2003 Kammula US, Ghossein R, Bhattacharya S, et al: Serial follow-up and the prognostic significance of reverse transcriptase-polymerase chain reaction—staged sentinel lymph nodes from melanoma patients. J Clin Oncol 22:3989-3996, 2004 Scoggins CR, Ross MI, Reintgen DS, et al: Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol 24:2849-2857, 2006 Mocellin S, Hoon DS, Pilati P, et al: Sentinel lymph node molecular ultrastaging in patients with melanoma: A systematic review and meta-analysis of prognosis. J Clin Oncol 25:1588-1595, 2007 Gershenwald JE, Thompson W, Mansfield PF, 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 17:976-983, 1999 Wong SL, Kattan MW, McMasters KM, et al: 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 12:282-288, 2005 Azzola MF, Shaw HM, Thompson JF, 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 97:1488-1498, 2003 Attis MG, Vollmer RT: Mitotic rate in melanoma: a reexamination. Am J Clin Pathol 127:380-384, 2007 Barnhill RL, Fine JA, Roush GC, et al: Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer 78:427-432, 1996 Paek SC, Griffith KA, Johnson TM, et al: The impact of factors beyond Breslow depth on predicting sentinel lymph node positivity in melanoma. Cancer 109:100-108, 2007 Compton CC, Barnhill R, Wick MR, et al: Protocol for the examination of specimens from patients with melanoma of the skin. Arch Pathol Lab Med 127:1253-1262, 2003 Wong SL, Brady MS, Busam KJ, et al: Results of sentinel lymph node biopsy in patients with thin melanoma. Ann Surg Oncol 13:302-309, 2006 Ranieri JM, Wagner JD, Wenck S, et al: The prognostic importance of sentinel lymph node biopsy in thin melanoma. Ann Surg Oncol 13: 927-932, 2006 Gimotty PA, Elder DE, Fraker DL, et al: Identification of high-risk patients among those diagnosed with thin cutaneous melanomas. J Clin Oncol 25:1129-1134, 2007. Gershenwald JE, Mansfield PF, Lee JE, et al: Role for lymphatic mapping and sentinel lymph node biopsy in patients with thick (⬎ or ⫽ 4 mm) primary melanoma. Ann Surg Oncol 7:160-165, 2007 Gutzmer R., Satzger I, Thoms KM, et al: Sentinel lymph node status is the most important prognostic factor for thick (⬎ or ⫽ 4 mm) melanomas. J Dtsch Dermatol Ges 6:198-203, 2008 Jacobs IA, Chang CK, Salti GI: Role of sentinel lymph node biopsy in patients with thick (⬎4 mm) primary melanoma. Am Surg 70:59-62, 2004 Ferrone CR, Panageas KM, Busam K, et al: Multivariate prognostic model for patients with thick cutaneous melanoma: importance of sentinel lymph node status. Ann Surg Oncol 9:637-645, 2002 Conley J, Lattes R, Orr W: Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 28:914-936, 1971
94
Seminars in Diagnostic Pathology, Vol 25, No 2, May 2008
57. Quinn MJ, Crotty KA, Thompson JF, et al: Desmoplastic and desmoplastic neurotropic melanoma: experience with 280 patients. Cancer 83:1128-1135, 1988 58. Busam KJ, Mujudar U, Hummer AJ, et al: Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 28:1518-1525, 2008 59. Gyorki DE, Busam K, Panageas K, et al: Sentinel lymph node biopsy for patients with cutaneous desmoplastic melanoma. Ann Surg Oncol 10:403-407, 2003 60. Hawkins WG, Busam KJ, Ben-Porat L, et al: Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg Oncol 12:207-213, 2005 61. Su LD, Fullen DR, Sondak VK, et al: Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 97:499-507, 2003 62. Murali R, Sharma RN, Thompson JF, et al: Sentinel lymph node biopsy in histologically ambiguous melanocytic tumors with spitzoid features (so-called atypical spitzoid tumors). Ann Surg Oncol 15:302309, 2008 63. Gamblin TC, Edington H, Kirkwood JM, et al: Sentinel lymph node biopsy for atypical melanocytic lesions with spitzoid features. Ann Surg Oncol 13:1664-1670, 2006 64. Barnhill RL, Argenyi ZB, From L, et al: Atypical Spitz nevi/tumors: lack of consensus for diagnosis, discrimination from melanoma, and prediction of outcome. Hum Pathol 30:513-520, 1999 65. Cerroni L, Kerl H: Tutorial on melanocytic lesions. Am J Dermatopathol 23:237-241, 2001 66. Kogut KA, Fleming M, Pappo AS, et al: Sentinel lymph node biopsy for melanoma in young children. J Pediatr Surg 35:965-966, 2000. 67. Neville HL, Andrassy RJ, Lally KP, et al: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35:961-964, 2000 68. Toro J, Ranieri JM, Havlik RJ, et al: Sentinel lymph node biopsy in children and adolescents with malignant melanoma. J Pediatr Surg 38:1063-1065, 2003 69. Butter A, Hui T, Chapdelaine J, et al: Melanoma in children and the use of sentinel lymph node biopsy. J Pediatr Surg 40:797-800, 2005 70. Roaten JB, Partrick DA, Pearlman N, et al: Sentinel lymph node biopsy for melanoma and other melanocytic tumors in adolescents. J Pediatr Surg 40:232-235, 2005 71. Chao C, Martin RC 2nd, Ross MI, et al: Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol 11:259-264, 2004 72. Lange JR, Palis BE, Chang DC, et al: Melanoma in children and teenagers: an analysis of patients from the National Cancer Data Base. J Clin Oncol 25:1363-1368, 2007
73. Chagpar RB, Ross MI, Reintgen DS, et al: Factors associated with improved survival among young adult melanoma patients despite a greater incidence of sentinel lymph node metastasis. J Surg Res 143:164-168, 2007 74. Leong SP, Donegan E, Heffernon W, et al: Adverse reactions to isosulfan blue during selective sentinel lymph node dissection in melanoma. Ann Surg Oncol 7:361-366, 2000. 75. Montgomery LL, Thorne AC, Van Zee KJ, et al: Isosulfan blue dye reactions during sentinel lymph node mapping for breast cancer. Anesth Analg 95:385-388, 2002 76. McMasters KM, Noyes RD, Reintgen DS, et al: Lessons learned from the Sunbelt Melanoma Trial. J Surg Oncol 86:212-223, 2004 77. Morton DL, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006 78. Balch CM, Soong SJ, Smith T, et al: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8:101108, 2001 79. Wong SL, Kattan MW, McMasters KM, et al: 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 12:282-288, 2005 80. Bachter D, Michl C, Büchels H, et al: The predictive value of the sentinel lymph node in malignant melanomas. Recent Results Cancer Res 158:129-136, 2001 81. Agnese DM, Abdessalam SF, Burak WE Jr, et al: Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 134:542-547, 2003; discussion 547-548 82. Bleicher RJ, Essner R, Foshag LJ, et al: Role of sentinel lymphadenectomy in thin invasive cutaneous melanomas. J Clin Oncol 21:13261331, 2003 83. Rousseau DL Jr, Ross MI, Johnson MM, et al: Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients. Ann Surg Oncol 10:569-574, 2003 84. Stitzenberg KB, Groben PA, Stern SL, et al: Indications for lymphatic mapping and sentinel lymphadenectomy in patients with thin melanoma (Breslow thickness ⬍ or ⫽1.0 mm). Ann Surg Oncol 11:900906, 2004. 85. Carlson GW, Murray DR, Hestley A, et al: Sentinel lymph node mapping for thick (⬎or⫽4-mm) melanoma: should we be doing it? Ann Surg Oncol 10:408-415, 2003 86. Caracó C, Celentano E, Lastoria S, et al: Sentinel lymph node biopsy does not change melanoma-specific survival among patients with Breslow thickness greater than four millimeters. Ann Surg Oncol 11:198S-202S, 2004 (suppl 3)