Prognostic Factors in Patients Undergoing Lymphadenectomy for Malignant Melanoma MAX H. COHEN, M.D., PH.D., ALFRED S. KETCHAM, M.D., EDWARD L. FELIX, M.D., SHOU-HUA Li, PH.D., MARIA-MAGDALENA TOMASZEWSKI, M.D., JOSE COSTA, M.D., ALAN S. RABSON, M.D., RICHARD M. SIMON, PH.D., STEVEN A. ROSENBERG, M.D., PHD.
Review of a 19 year experience in melanoma patients undergoing lymphadenectomy at the National Cancer Institute revealed that the preoperative assessment of the status of the regional lymph nodes was accurate 91% of the time when the surgeon felt the nodes were clinically positive, and accurate 79%o of the time when the nodes were judged clinically negative. The 10-year survival in patients with one to three histologically positive nodes or no positive nodes was 50-55%, compared to a 25% 8-year survival in patients with four or more histologically positive nodes. Stepwise multivariate evaluation of prognostic factors indicated that the most important factor for predicting prognosis is the number of nodes histologically involved. Node palpability was the second most important factor because of its high correlation with number of nodes histologically involved. Site of melanoma was the third most important factor, as patients with extremity (upper or lower) melanoma had a better survival (P = 0.002) than patients with axial melanoma (trunk or head and neck). Five years following lymphadenectomy there appeared to be substantial differences in survival according to differences in the level of invasion of the primary lesion, however, these differences were not nearly as pronounced 10 years following node dissection. B The division of melanoma thicknesses into 1.50 mm provided some prognostic discrimination at five years but again the differences were not pronounced 10 years following node dissection. The thickness measurements were easier to determine than the level of invasion, and more reproduceable on resubmission to the same pathologist. Four patients with melanoma less than 0.76 mm had subsequent metastases, but these may represent inadequate sampling of the primary melanoma both in our series and in the four similar patients previously reported with such thin metastasizing melanomas.
P R MANY YEARS it has been known that multiple fac-
tors influence prognosis in melanoma.1 10 Recently melanoma patients have been restudied in light of prognostic information such as level of invasion4 and thickness2 of the primary melanoma. Wanebo13'14 and Breslow2.3 have observed that in melanoma patients undergoing lymphadenectomy, patients with deeply invasive or thicker primary melaSubmitted for publication: December 23, 1976.
635
From the Surgery Branch, Laboratory of Pathology and Division of Cancer Treatment, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
nomas have an increased incidence of tumor spread to draining lymph nodes and relatively shortened survivals. These observations have been made in Stage I patients (clinically negative lymph node evaluations preoperatively). This paper presents an analysis of patients treated at the Surgery Branch of the National Cancer Institute during the 19-year period from 19551974. The purpose of this study was to assess the relative importance of level of invasion, thickness, site, sex and lymph node status in patients with malignant melanoma undergoing lymph node dissection in the presence of clinically negative regional lymph nodes (prophylactic lymph node dissection), or clinically positive lymph nodes (therapeutic lymph node dissection). Correlations among the prognostic factors were
determined. Our five and 10 year survival rates following prophylactic and therapeutic lymph node dissection were recorded as functions of the various prognostic factors. An attempt was made to assess the relative usefulness of level of invasion and thickness measurements in patients with clinically negative and clinically positive lymph nodes at a referral institution where review of the primary lesion required review of outside submitted slides. Materials and Methods Records were reviewed of patients who underwent lymph node dissection in the Surgery Branch of the National Cancer Institute between 1955 and 1974. After excluding patients whose slides of the primary lesion had been returned to the referring hospital, or whose
COHEN AND OTHERS
636 TOTAL DEAD 75
33
STILL AUVE
z
5
0.6
z
0.5
o
0.4
0.2
0.1
1
*
I.t
2
3
4
5
6
7
8
9
10 >10
YEARS
FIG. 1. Effect of site of primary.
slides
November 1977
Pathological Evaluation of a Primary Melanoma
0.3_
00 0_
9
occurred in patients who had undergone local excision more than 6 months previous to referral to NCI, with no evident local recurrence. In these patients the local site was usually not reexcised. Each patient in this series underwent lymph node dissection, whether the lymph nodes were clinically positive or not. Lymph node dissections included radical neck, axillary, and inguinal5 lymph node discections.
SITE
8 o EXTREMITY AXIAL
43
Ann. Surg.
of insufficient depth or quality for measor level of invasion, there remained 117 patients who had undergone lymphadenectomy and for whom slides of the primary melanoma were considered adequated by the pathologists for determination of level of invasion and thickness. One patient had two primary melanomas. Therefore, there were 118 melanomas in 117 patients. Sixty-one of these patients underwent "*prophylactic" lymph node dissection with clinically negative lymph nodes, and 57 node dissections were considered "therapeutic" for clinically positive lymph nodes. No patients with mucosal melanoma or level I (in situ) melanoma were included. No patient was included in this review who had evidence of melanoma beyond the regional lymph nodes. For each patient a notation was made of the sex, age and race, the location of the primary malignant melanoma and its histological type (nodular, superficial spreading, or lentigo maligna).4 The preoperative clinical evaluation of the lymph nodes was recorded, together with the subsequent operative procedure and the final pathological evaluation of the resected lymph nodes. The survival of the patient from the time of lymphadenectomy was utilized in computing survival curves. Five of the 117 patients currently have metastatic recurrent disease and are also included as survivors. The length of follow-up on each patient is indicated on the survival curves. were
urement of thickness
Surgical Treatment
Primary melanomas were treated with wide local excision and split thickness skin graft. Exceptions to this
Slides from each primary melanoma were rereviewed by three pathologists to determine or confirm the histological type, level of invasion, and thickness of the lesion. In most patients only a few slides of the primary lesion were available for review. Each patient was classified according to the deepest level of invasion on the available slides, realizing that in an unsampled area there may have been a deeper level of invasion. The histological types and levels of invasion were determined according to the methods of Clark et al.4 Lesions were categorized as superficial spreading melanoma if melanoma cells extended within the epidermis for a distance greater than three rete pegs peripheral to the area Df invasive melanoma. If the melanoma extended Iripherally less than three pegs, it was classified as a podular melanoma. Lentigo-maligna melaoma was melanoma arising in a Hutchinson's freckle. Level I melanoma represented malignant melanoma confined to the epidermis. Level II showed invasion of the papillary dermis. Level III showed melanoma along the interface between the papillary and reticular dermis. Level IV showed melanoma into the reticular dermis and level V showed invasion into subcutaneous fat. Tumor thickness was determined according to the technique of Breslow23 by means of an ocular micrometer. The maximal thickness of the lesion was measured from the top of the granular cell layer to the deepest point of the invasion. If the lesion was ulcerated, the ulcer base over the deepest point of invasion was used rather than the top of the granular cell layer.
Statistical Methods The survival curves for subgroups of patients were calculated by the life-table method of Kaplan and Meier,9 and were compared using the Generalized Wilcoxon Test of Gehan. Evaluation of the associations between prognostic factors was performed using the continuity corrected contingency chi-square test if the factors were non-quantitative, and the KruskalWallis rank test11 if either of the factors were quantita-
tive. All P-values given correspond to two-tailed significance levels. Results Most of the patients were male (62% vs 38% female). The 10-year survival for the females was 61%, compared to a 41% 10-year survival for the male patients (P = .20). Fifty-five per cent of the primary melanomas were superficial spreading in morphological type. Nodular melanoma was found in 44% of the primary lesions and 1% were lentigo maligna type malignant melanoma. There was no statistically significant difference in survival between patients whose primary lesions were categorized as nodular or superficial spreading (P = .17). The most frequent site of primary tumor in this series was the trunk (46% of the patients). Next in frequency was the lower extremity (26%), the head and neck region (18%) and finally the upper extremity (10%). The patients whose melanomas were in an extremity (upper or lower) had a better survival (P = 0.002) than patients with axial melanoma (trunk or head and neck), as shown in Figure 1. Patients with upper extremity melanoma had a ten-year survival of 75%, while the patients with lower extremity melanoma had a 10-year survival of 60%. Patients with melanoma in the head and neck region had a 38% 10-year survival, and patients with melanoma on the trunk had a 45% ten-year survival. Thirteen per cent ( 16/118) of the melanomas were invasive to Level II. Fifty-one per cent (60/118) showed 1.i
it
0.9
TOTAL DEAD LEVEL 16 2 0 2 23 ' 3 w~ ~ ~ 6 >>, 34 12 * ,_ 4 £ 5 4 8
0.9
O'sI-
STILL ALIVE
0.7
0 z
0.5
?
0.4-
637
LYMPHADENECTOMY FOR MALIGNANT MELANOMA
Vol. 186 * No. 5
YEARS
FIG. 2. Effect of level of invasion.
TOTAL DEAD THICKNESS 44 11 0 0-1.5mm 30 £ 73 >1.5mm STILL ALIVE
0
z
5
cc
z
0 0
>10 YEARS
FIG. 3. Effect of melanoma thickness.
invasion to Level III. Twenty-nine per cent (34/118) showed invasion to Level IV. Seven per cent (8/118) had invasion to Level V. As shown in Figure 2, patients with Level II melanoma survive significantly longer than those with Level V melanoma (P < .05). Patients with Level III-IV melanoma have intermediate survivals. In analyzing survival as a function of thickness of the primary melanoma, the best discrimination was obtained by comparing the patients with a melanoma thickness of less than 1.5 mm to those patients who had a thickness of the primary melanoma of over 1.5 mm. The proportion of patients surviving five years with "thin" melanomas was 69% compared to a five year survival of 49% for the "thick" melanomas as illustrated in Figure 3 (P = 0.07). The 10-year survivals were 47%-48% for both groups, although these figures include patients with Stage I and II disease, in contrast to data presented below. Because of the select referral pattern of our admissions, almost half (57/117) of the patients in this series had clinically positive regional lymph nodes as assessed by palpation prior to surgery. Where review of the chart revealed discrepancies in the preoperative evaluation of nodal status, the evaluation of the more senior surgeon was used for purposes of classification. The 10-year survival was 55% in the group of 61 patients whose lymph nodes were clinically negative preoperatively. The 10-year survival was 38% in the 57 patients whose lymph nodes were felt to be clinically positive preoperatively (P < 0.002). Forty-five per cent (53/118) of the lymphadenectomy specimens revealed no positive lymph nodes upon his-
COHEN AND OTHERS
638
Ann. Surg.
*
November 1977
TABLE 1. Proportion of Patients with Histologically Positive Nodes
Level of Invasion
Positive Nodes, was Clinically Negative (Stage I)
II III IV V
2/13 (15%) 4/28 (14%) 6/17 (35%) 1/3 (33%) 13/61 (21%)
Total C,
z
0.5 _
°C
0.4
Positive Nodes, was Clinically Positive (Stage II) 3/3 27/32 17/17 5/5 52/57
(100%o) (84%) (100%o) (100%o) (91%)
Clinical stage I and II (by level of invasion).
02 _ 0.1
FIG. 4. Effect of number of positive nodes.
tological examination. Thirty-five per cent (41/118) had one to three positive lymph nodes, and 20% (24/118) had four or more positive lymph nodes upon microscopic pathological examination. It can be seen in Figure 4 thatfive years postoperatively, the percentage of survival is 73% if the lymph nodes were histologically negative, 55% when one to three lymph nodes were involved, and 26% when four or more lymph nodes were involved. Ten years following surgery, the figures are 51%, 55%, and 26% respectively. Survival for patients with four or more positive nodes is statistically significantly worse than survival for patients without nodal involvement (P < 0.002) or patients with one to three positive nodes (P < .01). Among the 61 patients whose nodes were clinically negative preoperatively, (Stage I melanoma) the incidence of histologic positivity in the dissected lymph nodes was 21%. Among the 57 patients whose lymph nodes were judged preoperatively to be positive (Stage II), the likelihood of a histologically positive lymph node dissection was 91%. The data in Table I show
that when the level of invasion of the primary lesion was Level II or Level III, the incidence of microscopic positivity was 14-15% in patients whose lymph nodes were thought to be negative preoperatively. This figure increased to 35% when the primary lesion was invasive to Level IV. When the lymph nodes were clinically positive, they were histologically positive in all but five of 32 patients with Level III melanoma. Of the 22 patients with Level IV or V melanoma and clinically positive lymph nodes, all had subsequent histological confirmation of lymph node positivity. We can make no comment about Stage II, Level II patients or Stage I, Level V patients since there were only three patients in each of these latter categories. The data in Table 2 show the range of thickness observed within each Clark level in our series. The mean thickness in Level II, III, IV, and V was 0.75, 1.97, 2.95, and 4.82 respectively, with a highly significant correlation between level and thickness (P < .001). Within each level increasing thickness was not generally correlated with increasing lymph node positivity or increasing mortality. As shown in Table 3, there were four patients with metastases from primary lesions less than 0.76 mm in thickness, a phenomenon that has been reported in four previous patients.3'13 One of our four patients had a neck node metastasis documented 6 years after resection ofthe primary Level II lesion only 0.317 mm thick. the data in Table 3 show that each of the four patients had Level II or III superficial spreading melanoma with clinically and histologically positive lymph nodes. The time interval between diagnosis of the primary mela-
TABLE 2. Relationships Between Level of Invasion and Thickness, Including Patients with Erroneously Assessed Lymph Nodes Mean Thickness
Clark's Level Invasion II III IV V
+
SEM (No. of Patients)
Nodes
Nodes
Overall
Clinically Neg.,
Patients
Range of Thickness (mm)
Group
Histol. Pos.
Clinically Pos., Histol. Neg.
16 60 34 8
0.32- 1.46 0.69- 7.00 0.89- 6.50 2.49-10.00
0.75 + 0.07 (16) 1.97 ± 0.16 (60) 2.95 ± 0.20 (34) 4.82 ± 0.82 (8)
0.96 + 0.02 (2) 3.45 ± 1.25 (4) 2.61 ± 0.32 (6) 6.5 (1)
None 1.86 ± 0.31 (5) None None
No. of
Vol. 186.oNO. 5
639
LYMPHADENECTOMY FOR MALIGNANT MELANOMA
TABLE 3. Patients with Metastases from Melanomas Less Than 0.76 mm in Thickness
Case No.
Thickness
Level of Invasion, Histologic Type
1 2 3 4
0.317 0.540 0.575 0.686
II-SS II-SS II-SS III-SS
Age, Sex
Location of Primary
18F 32M 63F 41F
Head & Neck Trunk Trunk Trunk
Clinical Node Status and Location Pos. Pos. Pos. Pos.
noma and lymph node dissection in these patients were zero, zero, three, and 11½/2 years respectively. The interpretation of these cases is difficult since only a few outside submitted slides on each case were available in our Pathology Department for review. Although Breslow's original thickness descriptions were also based on examination of only one to five (usually 2) outside submitted slides per case, the possibility exists with submitted slides that other, unexamined portions of the melanoma, were thicker. Thirteen (23%) of the 57 patients who underwent therapeutic node dissection for clinically positive lymph nodes did so two or more years after diagnosis of melanoma. Nine (16%) of these 57 patients underwent node dissection three or more years after the diagnosis of primary melanoma, and three (5%) of the 57 patients had an interval of five or more years between diagnosis of the primary lesion and node dissection, with the longest interval (11½/2 years) being represented by Case 3 in Table 3. In general, the status of the lymph nodes and the site of the primary melanoma were stronger prognostic indicators than the level of invasion or thickness of the primary melanoma. These two strong prognostic indicators (lymph node status, and site of primary melanoma) were also correlated with each other. For example, the data in Table 4 show that patients with melanomas on the extremity (upper or lower) had no positive nodes in 61% of cases, one to three positive nodes in 30% of cases, and four or more positive nodes in only 4 cases (9%o). In distinction, patients with axial melanoma (head and neck or trunk) TABLE 4. Relationship of Melanoma Location to Numbers of Histologically Positive, Lymph Nodes
Neck Axilla Axilla Axilla
No. Months Since
Histologic Node Postivity 1/49 11/19 9/17 12128
Status
Node Dissection
Diagnosis
NED Dead NED Alive Metastases
72 5 63 20
73 5 200 56
had no positive nodes in only 36% of cases, one to three positive nodes in 37% of cases and four or more positive nodes in 27% of cases. The association of greater lymph node positivity with axial melanomas as compared with extremity melanomas was statistically significant (P < 0.005). Nodal status and site each had an additional effect on prognosis independent of one another. The independent effect of site can be seen, for example, in the improved prognosis of node negative extremity melanoma patients compared to node negative axial melanoma patients illustrated in Figure 5. The independent effect of node status can be seen in the improved survival of negative node extremity melanoma patients compared to positive node extremity melanoma patients as shown in Figure 6 (P < .02). Among patients with histologically positive regional nodes, we examined the effect on prognosis of preoperative clinical positivity versus clinical negativity. Patients with one to three histologically positive lymph nodes had a 10 year survival of 70%o if the clinician
0 Z
U,
z
0 0
No. of Patients with
Melanoma Location
Extremity (upper or lower) Axial (head and neck or trunk)
No. pos. nodes
1-3 pos. nodes
26 (61%)
13 (30%o)
27 (36%o)
28 (37%)
4 or more pos. nodes
4
(9%O)
20 (27%)
>10
YEARS
FIG. 5. Effect of site in node negative patients.
COHEN AND OTHERS
640 TOTAL
DEAD
23
2 6
17
* *
NGATIVE
NODES
POSITIVE NODES
STLL ALIVE
0.6
ff
_
0.5
OA-
0.3
0.2
0.1 _
*t0
1
2
3
4
5 YEARS
6
7
8
9
10 >10
FIG. 6. Effect of histologic node status in extremity melanoma.
felt preoperatively that the regional lymph node area was negative for metastases. By comparison, patients with one to three histologically positive lymph nodes had a 10 year survival of 50%o when the surgeon felt preoperatively that the regional lymph node area was clinically involved (P = .06). There was a correlation between level of invasion of the primary lesion and the numbers of positive nodes in the dissected regional nodes. Table 5 illustrates the statistically significant correlation between increasing numbers of positive lymph nodes and increasingly deep levels of invasion of the primary lesion (P < 0.05). The level of invasion appeared to affect the survival in patients with histologically negative lymph nodes, as there were no deaths among the 11 node-negative Level II patients. In contrast, the 10 year survival rate in 29 node-negative Level III patients and 11 nodenegative Level IV patients was 51-53%. There were only two patients with node-negative Level V melanoma in this series, precluding analysis of that group. TABLE 5. Relationship of Level of Invasion to Numbers of Histologically Positive Lymph Nodes
November 1977
In patients with one to three positive lymph nodes, the level of invasion did not appear to affect survival, although there were significant numbers of patients only in the Level III (17 patients) and Level IV (19 patients) groups. Among patients with no positive lymph nodes, those with primary melanomas less than 1.5 mm in thickness had a 74% five-year survival after node dissection, compared to 54% five-year survival in patients with melanomas over 1.5 mm in thickness (P = .06). In considering patients who had one to three positive lymph nodes, there was no difference in survival between patients with melanomas less or greater than 1.5 mm in thickness. Similarly, in considering patients with four or more positive lymph nodes, there was also no difference in survival between those patients with thin melanomas and thick melanomas. Thus, the thickness and level of invasion of the primary lesion was of prognostic importance in patients with histologically negative, but not histologically positive lymph nodes. Females with melanoma had a slightly better prognosis than males with melanoma. The sex of the patient was not correlated with level of invasion or with number of lymph nodes containing tumor. However, there was a significant correlation between sex and site of the primary lesion. As seen in Table 6, the primary melanoma was located on the extremity in 51% of female patients as compared to only 27% of the male patients. The better prognosis associated with the extremity lesions indicates that the better overall prognosis of melanomas in female patients may be due to the fact that more melanomas occur on the extremities in this patient group. Cox's6 life-table regression model for a stepwise multivariate evaluation of prognostic factors indicated that the most important factor for predicting prognosis is number of lymph nodes histologically involved. The second and third most important factors were node palpability and site of melanoma, and these factors remain important even after adjustment for the effect of histological node involvement.
Discussion In our series the preoperative clinical evaluation was quite accurate, with 91% of the patients with clinically TABLE 6. Relationship between Sex of the Patient and Site of the Primary Melanoma
No. of Patients with
Level of Invasion
No tumor in nodes
1-3 nodes
4 or more
positive
positive
2 3 4 5
1 1(69%) 29 (48%) 11 (32%) 2 (25%)
4 (25%)
17 (28%) 19 (56%)
1 14 4 5
1 (13%)
Ann. Surg.
(6%) (23%) (12%) (62%)
Site Sex
Axial
Extremity
Male Female
55 (73%) 22 (49o)
20 (27%) 23 (51%)
Vol. 186 * No. 5
LYMPHADENECTOMY FOR MALIGNANT MELANOMA
positive lymph nodes subsequently shown to have metastasis by pathologic examination, with 100o accuracy in patients with Level IV and V melanoma and clinical positivity. Similarly the preoperative evaluation was correct 79Wo of the time when the nodes were judged clinically to be negative. Secondly, the 10-year survival of patients with one to three histologically positive nodes was 55%, which is high compared to previous reports which usually do not measure survival as a function of the number of positive nodes. Patients with four or more positive nodes had an 8 year survival rate of only 25% by comparison. In the subgroup of patients with clinically negative histologically positive nodes the 10-year survival was 70%o, while the subgroup with clinically positive histologically positive nodes had a 10-year survival of 50o Clark et al.4 separated cutaneous melanomas into nodular, superficial spreading and lentigo maligna types according to their histological and clinical characteristics and related the level of invasion of the primary lesion to prognosis. Breslow then reported that tumor thickness was a better indicator of prognosis than level of invasion in Stage I melanoma.3 Also, each of 54 patients with thickness less than 0.76 mm was free of disease over five years from melanoma excision, whether prophylactic lymph nodes dissection was performed (10 patients) or not performed (44 patients). However, in our series, containing a large proportion of patients with Stage II disease, four patients with melanomas thinner than 0.76 mm experienced recurrence. As Dr. Breslow has stated, the thickness measurements are relatively easy to perform3 and the pathologists who measured the thickness in our series learned the technique from Dr. Breslow whose independent measurements on a series of primary melanomas was identical to their measurements. We found the thickness measurements to be easier to make than assignment of Clark's levels and more reproducible in subsequent blind re-evaluation by the same pathologists. However, the thickness of most lesions in our series and in Breslow's series was based on analysis of several representative sections through the lesion,3 rather than exhaustive serial sectioning and the possibility of sampling errors exists. In our study the division of thicknesses into 1.50 mm provided the best prognostic discrimination, as in the study of Hansen and McCarten.8 With regard to prognostic implications of Clark's levels of invasion we were interested to observe in our series the difference between the five and 10-year results. Five years following lymph node dissection, there appeared to be substantial differences in survival according to differences in the original Clark level
641
of invasion. These differences were not as pronounced at 10 years following lymph node dissection. We found the site of the melanoma and the lymph node status to be more strongly correlated with prognosis than the level of invasion or the thickness of the primary lesion. Of the patients that underwent lymphadenectomy for clinically positive nodes, the interval between removal of the primary lesion and lymphadenectomy was two or more years in 23% of the patients, and five or more years in 5% of the patients. We therefore feel that if the regional lymph nodes are not dissected at the time the primary lesion is removed, they should be carefully followed for at least five years. We have not addressed ourselves to the question of selection of patients for prophylactic lymphadenectomy, since we are impressed as is Breslow3 and others with the hazards of using data from retrospective, nonrandomized studies. There is in progress a prospective, randomized World Health Organization Cooperative Trial on 553 clinical Stage I extremity melanoma patients randomized to receive or not receive a prophylactic lymph node dissection at the time of presentation. With the majority of the patients now having been followed for five years, there is no difference in survival between patients with lower extremity melanoma randomly allocated to receive either prophylactic lymph node dissection or not,12 even among patients with large or deeply invasive melanomas. If these data should be corroborated, the primary value of the factors we have discussed would appear to be for identification of patients with poorer or more favorable prognoses, for consideration for adjuvant treatment protocols, rather than for identification of patients that would benefit from a prophylactic node dissection.
Acknowledgment The authors are grateful for a review of the manuscript by Dr. Alexander Breslow.
References 1. Allen, A. C. and Spitz, S.: Malignant Melanomas. A Clinicopathologic Analysis of the Criteria for Diagnosis and Prognosis. Cancer, 6:1, 1953. 2. Breslow, A.: Thickness Cross-Sectional Areas and Depth of Invasion in the Prognosis of cutaneous Melanoma. Ann. Surg., 172:902, 1970. 3. Breslow, A.: Tumor thickness, Level of Invasion and Node Dissection in Stage I Cutaneous Melanoma. Ann. Surg., 182: 572, 1976. 4. Clark, W. H., From, L., Bernardino, E. A. and Mihm, M. C.: The Histogenesis and Biologic Behavior of Primary Human and Malignant Melanomas of the Skin. Cancer Res., 29:705,
1969. 5. Cohen, M. H., Schour, L., Felix, E. L., et al.: Staging Laparotomy in the Treatment of Metastatic Melanoma of the Lower Extremities. Ann. Surg., 192:710, 1975.
642
COHEN AND OTHERS
6. Cox, D. R.: Regression Models and Life-Tables. J. R. Statist. Soc. B 34:187, 1972. 7. Gehan, E. A.: A Generalized Wilcoxon Test for Comparing Arbitrarily Singly-Censored Samples. Biometrika., 52:203, 1965. 8. Hansen, M. G. and McCarten, A. B.: Tumor thickness and Lymphocytic Infiltration in Malignant Melanoma of the Head and Neck. Am. J. Surg., 28:557, 1974. 9. Kaplan, E. L., and Meier, P.: Non-parametric Estimation from Incomplete Observations. J. Am. Statistic. Assoc., 53:457, 1958. 10. McNeer, G. and DasGupta, T.: Prognosis in Malignant Melanoma. Surgery, 56:512, 1964.
Ann.
Surg. *
November 1977
11. Siegel, S.: Non-Parametric Statistics for the Behavioral Sciences. 1956. p. 184, New York, McGraw-Hill. 12. Veronese, U.:Preliminary Results of Clinical Trial I of the World Health Organization Collaborating Centers for the Evaluation of Methods of Diagnosis and Treatment of Melanoma. Presented at the Cancer Research Center of the USSR, September 20-22, Moscow, Russia, 1976. 13. Wanebo, H. J., Fortner, J. G., Woodruff, J., et al.: Selection of the Optimum Surgical Treatment of Stage I Melanoma by Depth of Microinvasion: Use of the Combined Microstage Technique (Clark-Breslow). Ann. Surg., 192:302, 1975. 14. Wanebo, H. J., Woodruff, J. and Fortner, J. G.: Malignant Melanoma of the Extremities: A Clinicopathologic Study Using Levels of Invasion (Microstage). Cancer, 35:666, 1975.
Review of a 19 year experience in melanoma patients undergoing lymphadenectomy at the National Cancer Institute revealed that the preoperative assessment of the status of the regional lymph nodes was accurate 91% of the time when the surgeon felt the nodes were clinically positive, and accurate 79%o of the time when the nodes were judged clinically negative. The 10-year survival in patients with one to three histologically positive nodes or no positive nodes was 50-55%, compared to a 25% 8-year survival in patients with four or more histologically positive nodes. Stepwise multivariate evaluation of prognostic factors indicated that the most important factor for predicting prognosis is the number of nodes histologically involved. Node palpability was the second most important factor because of its high correlation with number of nodes histologically involved. Site of melanoma was the third most important factor, as patients with extremity (upper or lower) melanoma had a better survival (P = 0.002) than patients with axial melanoma (trunk or head and neck). Five years following lymphadenectomy there appeared to be substantial differences in survival according to differences in the level of invasion of the primary lesion, however, these differences were not nearly as pronounced 10 years following node dissection. B The division of melanoma thicknesses into 1.50 mm provided some prognostic discrimination at five years but again the differences were not pronounced 10 years following node dissection. The thickness measurements were easier to determine than the level of invasion, and more reproduceable on resubmission to the same pathologist. Four patients with melanoma less than 0.76 mm had subsequent metastases, but these may represent inadequate sampling of the primary melanoma both in our series and in the four similar patients previously reported with such thin metastasizing melanomas.
P R MANY YEARS it has been known that multiple fac-
tors influence prognosis in melanoma.1 10 Recently melanoma patients have been restudied in light of prognostic information such as level of invasion4 and thickness2 of the primary melanoma. Wanebo13'14 and Breslow2.3 have observed that in melanoma patients undergoing lymphadenectomy, patients with deeply invasive or thicker primary melaSubmitted for publication: December 23, 1976.
635
From the Surgery Branch, Laboratory of Pathology and Division of Cancer Treatment, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
nomas have an increased incidence of tumor spread to draining lymph nodes and relatively shortened survivals. These observations have been made in Stage I patients (clinically negative lymph node evaluations preoperatively). This paper presents an analysis of patients treated at the Surgery Branch of the National Cancer Institute during the 19-year period from 19551974. The purpose of this study was to assess the relative importance of level of invasion, thickness, site, sex and lymph node status in patients with malignant melanoma undergoing lymph node dissection in the presence of clinically negative regional lymph nodes (prophylactic lymph node dissection), or clinically positive lymph nodes (therapeutic lymph node dissection). Correlations among the prognostic factors were
determined. Our five and 10 year survival rates following prophylactic and therapeutic lymph node dissection were recorded as functions of the various prognostic factors. An attempt was made to assess the relative usefulness of level of invasion and thickness measurements in patients with clinically negative and clinically positive lymph nodes at a referral institution where review of the primary lesion required review of outside submitted slides. Materials and Methods Records were reviewed of patients who underwent lymph node dissection in the Surgery Branch of the National Cancer Institute between 1955 and 1974. After excluding patients whose slides of the primary lesion had been returned to the referring hospital, or whose
COHEN AND OTHERS
636 TOTAL DEAD 75
33
STILL AUVE
z
5
0.6
z
0.5
o
0.4
0.2
0.1
1
*
I.t
2
3
4
5
6
7
8
9
10 >10
YEARS
FIG. 1. Effect of site of primary.
slides
November 1977
Pathological Evaluation of a Primary Melanoma
0.3_
00 0_
9
occurred in patients who had undergone local excision more than 6 months previous to referral to NCI, with no evident local recurrence. In these patients the local site was usually not reexcised. Each patient in this series underwent lymph node dissection, whether the lymph nodes were clinically positive or not. Lymph node dissections included radical neck, axillary, and inguinal5 lymph node discections.
SITE
8 o EXTREMITY AXIAL
43
Ann. Surg.
of insufficient depth or quality for measor level of invasion, there remained 117 patients who had undergone lymphadenectomy and for whom slides of the primary melanoma were considered adequated by the pathologists for determination of level of invasion and thickness. One patient had two primary melanomas. Therefore, there were 118 melanomas in 117 patients. Sixty-one of these patients underwent "*prophylactic" lymph node dissection with clinically negative lymph nodes, and 57 node dissections were considered "therapeutic" for clinically positive lymph nodes. No patients with mucosal melanoma or level I (in situ) melanoma were included. No patient was included in this review who had evidence of melanoma beyond the regional lymph nodes. For each patient a notation was made of the sex, age and race, the location of the primary malignant melanoma and its histological type (nodular, superficial spreading, or lentigo maligna).4 The preoperative clinical evaluation of the lymph nodes was recorded, together with the subsequent operative procedure and the final pathological evaluation of the resected lymph nodes. The survival of the patient from the time of lymphadenectomy was utilized in computing survival curves. Five of the 117 patients currently have metastatic recurrent disease and are also included as survivors. The length of follow-up on each patient is indicated on the survival curves. were
urement of thickness
Surgical Treatment
Primary melanomas were treated with wide local excision and split thickness skin graft. Exceptions to this
Slides from each primary melanoma were rereviewed by three pathologists to determine or confirm the histological type, level of invasion, and thickness of the lesion. In most patients only a few slides of the primary lesion were available for review. Each patient was classified according to the deepest level of invasion on the available slides, realizing that in an unsampled area there may have been a deeper level of invasion. The histological types and levels of invasion were determined according to the methods of Clark et al.4 Lesions were categorized as superficial spreading melanoma if melanoma cells extended within the epidermis for a distance greater than three rete pegs peripheral to the area Df invasive melanoma. If the melanoma extended Iripherally less than three pegs, it was classified as a podular melanoma. Lentigo-maligna melaoma was melanoma arising in a Hutchinson's freckle. Level I melanoma represented malignant melanoma confined to the epidermis. Level II showed invasion of the papillary dermis. Level III showed melanoma along the interface between the papillary and reticular dermis. Level IV showed melanoma into the reticular dermis and level V showed invasion into subcutaneous fat. Tumor thickness was determined according to the technique of Breslow23 by means of an ocular micrometer. The maximal thickness of the lesion was measured from the top of the granular cell layer to the deepest point of the invasion. If the lesion was ulcerated, the ulcer base over the deepest point of invasion was used rather than the top of the granular cell layer.
Statistical Methods The survival curves for subgroups of patients were calculated by the life-table method of Kaplan and Meier,9 and were compared using the Generalized Wilcoxon Test of Gehan. Evaluation of the associations between prognostic factors was performed using the continuity corrected contingency chi-square test if the factors were non-quantitative, and the KruskalWallis rank test11 if either of the factors were quantita-
tive. All P-values given correspond to two-tailed significance levels. Results Most of the patients were male (62% vs 38% female). The 10-year survival for the females was 61%, compared to a 41% 10-year survival for the male patients (P = .20). Fifty-five per cent of the primary melanomas were superficial spreading in morphological type. Nodular melanoma was found in 44% of the primary lesions and 1% were lentigo maligna type malignant melanoma. There was no statistically significant difference in survival between patients whose primary lesions were categorized as nodular or superficial spreading (P = .17). The most frequent site of primary tumor in this series was the trunk (46% of the patients). Next in frequency was the lower extremity (26%), the head and neck region (18%) and finally the upper extremity (10%). The patients whose melanomas were in an extremity (upper or lower) had a better survival (P = 0.002) than patients with axial melanoma (trunk or head and neck), as shown in Figure 1. Patients with upper extremity melanoma had a ten-year survival of 75%, while the patients with lower extremity melanoma had a 10-year survival of 60%. Patients with melanoma in the head and neck region had a 38% 10-year survival, and patients with melanoma on the trunk had a 45% ten-year survival. Thirteen per cent ( 16/118) of the melanomas were invasive to Level II. Fifty-one per cent (60/118) showed 1.i
it
0.9
TOTAL DEAD LEVEL 16 2 0 2 23 ' 3 w~ ~ ~ 6 >>, 34 12 * ,_ 4 £ 5 4 8
0.9
O'sI-
STILL ALIVE
0.7
0 z
0.5
?
0.4-
637
LYMPHADENECTOMY FOR MALIGNANT MELANOMA
Vol. 186 * No. 5
YEARS
FIG. 2. Effect of level of invasion.
TOTAL DEAD THICKNESS 44 11 0 0-1.5mm 30 £ 73 >1.5mm STILL ALIVE
0
z
5
cc
z
0 0
>10 YEARS
FIG. 3. Effect of melanoma thickness.
invasion to Level III. Twenty-nine per cent (34/118) showed invasion to Level IV. Seven per cent (8/118) had invasion to Level V. As shown in Figure 2, patients with Level II melanoma survive significantly longer than those with Level V melanoma (P < .05). Patients with Level III-IV melanoma have intermediate survivals. In analyzing survival as a function of thickness of the primary melanoma, the best discrimination was obtained by comparing the patients with a melanoma thickness of less than 1.5 mm to those patients who had a thickness of the primary melanoma of over 1.5 mm. The proportion of patients surviving five years with "thin" melanomas was 69% compared to a five year survival of 49% for the "thick" melanomas as illustrated in Figure 3 (P = 0.07). The 10-year survivals were 47%-48% for both groups, although these figures include patients with Stage I and II disease, in contrast to data presented below. Because of the select referral pattern of our admissions, almost half (57/117) of the patients in this series had clinically positive regional lymph nodes as assessed by palpation prior to surgery. Where review of the chart revealed discrepancies in the preoperative evaluation of nodal status, the evaluation of the more senior surgeon was used for purposes of classification. The 10-year survival was 55% in the group of 61 patients whose lymph nodes were clinically negative preoperatively. The 10-year survival was 38% in the 57 patients whose lymph nodes were felt to be clinically positive preoperatively (P < 0.002). Forty-five per cent (53/118) of the lymphadenectomy specimens revealed no positive lymph nodes upon his-
COHEN AND OTHERS
638
Ann. Surg.
*
November 1977
TABLE 1. Proportion of Patients with Histologically Positive Nodes
Level of Invasion
Positive Nodes, was Clinically Negative (Stage I)
II III IV V
2/13 (15%) 4/28 (14%) 6/17 (35%) 1/3 (33%) 13/61 (21%)
Total C,
z
0.5 _
°C
0.4
Positive Nodes, was Clinically Positive (Stage II) 3/3 27/32 17/17 5/5 52/57
(100%o) (84%) (100%o) (100%o) (91%)
Clinical stage I and II (by level of invasion).
02 _ 0.1
FIG. 4. Effect of number of positive nodes.
tological examination. Thirty-five per cent (41/118) had one to three positive lymph nodes, and 20% (24/118) had four or more positive lymph nodes upon microscopic pathological examination. It can be seen in Figure 4 thatfive years postoperatively, the percentage of survival is 73% if the lymph nodes were histologically negative, 55% when one to three lymph nodes were involved, and 26% when four or more lymph nodes were involved. Ten years following surgery, the figures are 51%, 55%, and 26% respectively. Survival for patients with four or more positive nodes is statistically significantly worse than survival for patients without nodal involvement (P < 0.002) or patients with one to three positive nodes (P < .01). Among the 61 patients whose nodes were clinically negative preoperatively, (Stage I melanoma) the incidence of histologic positivity in the dissected lymph nodes was 21%. Among the 57 patients whose lymph nodes were judged preoperatively to be positive (Stage II), the likelihood of a histologically positive lymph node dissection was 91%. The data in Table I show
that when the level of invasion of the primary lesion was Level II or Level III, the incidence of microscopic positivity was 14-15% in patients whose lymph nodes were thought to be negative preoperatively. This figure increased to 35% when the primary lesion was invasive to Level IV. When the lymph nodes were clinically positive, they were histologically positive in all but five of 32 patients with Level III melanoma. Of the 22 patients with Level IV or V melanoma and clinically positive lymph nodes, all had subsequent histological confirmation of lymph node positivity. We can make no comment about Stage II, Level II patients or Stage I, Level V patients since there were only three patients in each of these latter categories. The data in Table 2 show the range of thickness observed within each Clark level in our series. The mean thickness in Level II, III, IV, and V was 0.75, 1.97, 2.95, and 4.82 respectively, with a highly significant correlation between level and thickness (P < .001). Within each level increasing thickness was not generally correlated with increasing lymph node positivity or increasing mortality. As shown in Table 3, there were four patients with metastases from primary lesions less than 0.76 mm in thickness, a phenomenon that has been reported in four previous patients.3'13 One of our four patients had a neck node metastasis documented 6 years after resection ofthe primary Level II lesion only 0.317 mm thick. the data in Table 3 show that each of the four patients had Level II or III superficial spreading melanoma with clinically and histologically positive lymph nodes. The time interval between diagnosis of the primary mela-
TABLE 2. Relationships Between Level of Invasion and Thickness, Including Patients with Erroneously Assessed Lymph Nodes Mean Thickness
Clark's Level Invasion II III IV V
+
SEM (No. of Patients)
Nodes
Nodes
Overall
Clinically Neg.,
Patients
Range of Thickness (mm)
Group
Histol. Pos.
Clinically Pos., Histol. Neg.
16 60 34 8
0.32- 1.46 0.69- 7.00 0.89- 6.50 2.49-10.00
0.75 + 0.07 (16) 1.97 ± 0.16 (60) 2.95 ± 0.20 (34) 4.82 ± 0.82 (8)
0.96 + 0.02 (2) 3.45 ± 1.25 (4) 2.61 ± 0.32 (6) 6.5 (1)
None 1.86 ± 0.31 (5) None None
No. of
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639
LYMPHADENECTOMY FOR MALIGNANT MELANOMA
TABLE 3. Patients with Metastases from Melanomas Less Than 0.76 mm in Thickness
Case No.
Thickness
Level of Invasion, Histologic Type
1 2 3 4
0.317 0.540 0.575 0.686
II-SS II-SS II-SS III-SS
Age, Sex
Location of Primary
18F 32M 63F 41F
Head & Neck Trunk Trunk Trunk
Clinical Node Status and Location Pos. Pos. Pos. Pos.
noma and lymph node dissection in these patients were zero, zero, three, and 11½/2 years respectively. The interpretation of these cases is difficult since only a few outside submitted slides on each case were available in our Pathology Department for review. Although Breslow's original thickness descriptions were also based on examination of only one to five (usually 2) outside submitted slides per case, the possibility exists with submitted slides that other, unexamined portions of the melanoma, were thicker. Thirteen (23%) of the 57 patients who underwent therapeutic node dissection for clinically positive lymph nodes did so two or more years after diagnosis of melanoma. Nine (16%) of these 57 patients underwent node dissection three or more years after the diagnosis of primary melanoma, and three (5%) of the 57 patients had an interval of five or more years between diagnosis of the primary lesion and node dissection, with the longest interval (11½/2 years) being represented by Case 3 in Table 3. In general, the status of the lymph nodes and the site of the primary melanoma were stronger prognostic indicators than the level of invasion or thickness of the primary melanoma. These two strong prognostic indicators (lymph node status, and site of primary melanoma) were also correlated with each other. For example, the data in Table 4 show that patients with melanomas on the extremity (upper or lower) had no positive nodes in 61% of cases, one to three positive nodes in 30% of cases, and four or more positive nodes in only 4 cases (9%o). In distinction, patients with axial melanoma (head and neck or trunk) TABLE 4. Relationship of Melanoma Location to Numbers of Histologically Positive, Lymph Nodes
Neck Axilla Axilla Axilla
No. Months Since
Histologic Node Postivity 1/49 11/19 9/17 12128
Status
Node Dissection
Diagnosis
NED Dead NED Alive Metastases
72 5 63 20
73 5 200 56
had no positive nodes in only 36% of cases, one to three positive nodes in 37% of cases and four or more positive nodes in 27% of cases. The association of greater lymph node positivity with axial melanomas as compared with extremity melanomas was statistically significant (P < 0.005). Nodal status and site each had an additional effect on prognosis independent of one another. The independent effect of site can be seen, for example, in the improved prognosis of node negative extremity melanoma patients compared to node negative axial melanoma patients illustrated in Figure 5. The independent effect of node status can be seen in the improved survival of negative node extremity melanoma patients compared to positive node extremity melanoma patients as shown in Figure 6 (P < .02). Among patients with histologically positive regional nodes, we examined the effect on prognosis of preoperative clinical positivity versus clinical negativity. Patients with one to three histologically positive lymph nodes had a 10 year survival of 70%o if the clinician
0 Z
U,
z
0 0
No. of Patients with
Melanoma Location
Extremity (upper or lower) Axial (head and neck or trunk)
No. pos. nodes
1-3 pos. nodes
26 (61%)
13 (30%o)
27 (36%o)
28 (37%)
4 or more pos. nodes
4
(9%O)
20 (27%)
>10
YEARS
FIG. 5. Effect of site in node negative patients.
COHEN AND OTHERS
640 TOTAL
DEAD
23
2 6
17
* *
NGATIVE
NODES
POSITIVE NODES
STLL ALIVE
0.6
ff
_
0.5
OA-
0.3
0.2
0.1 _
*t0
1
2
3
4
5 YEARS
6
7
8
9
10 >10
FIG. 6. Effect of histologic node status in extremity melanoma.
felt preoperatively that the regional lymph node area was negative for metastases. By comparison, patients with one to three histologically positive lymph nodes had a 10 year survival of 50%o when the surgeon felt preoperatively that the regional lymph node area was clinically involved (P = .06). There was a correlation between level of invasion of the primary lesion and the numbers of positive nodes in the dissected regional nodes. Table 5 illustrates the statistically significant correlation between increasing numbers of positive lymph nodes and increasingly deep levels of invasion of the primary lesion (P < 0.05). The level of invasion appeared to affect the survival in patients with histologically negative lymph nodes, as there were no deaths among the 11 node-negative Level II patients. In contrast, the 10 year survival rate in 29 node-negative Level III patients and 11 nodenegative Level IV patients was 51-53%. There were only two patients with node-negative Level V melanoma in this series, precluding analysis of that group. TABLE 5. Relationship of Level of Invasion to Numbers of Histologically Positive Lymph Nodes
November 1977
In patients with one to three positive lymph nodes, the level of invasion did not appear to affect survival, although there were significant numbers of patients only in the Level III (17 patients) and Level IV (19 patients) groups. Among patients with no positive lymph nodes, those with primary melanomas less than 1.5 mm in thickness had a 74% five-year survival after node dissection, compared to 54% five-year survival in patients with melanomas over 1.5 mm in thickness (P = .06). In considering patients who had one to three positive lymph nodes, there was no difference in survival between patients with melanomas less or greater than 1.5 mm in thickness. Similarly, in considering patients with four or more positive lymph nodes, there was also no difference in survival between those patients with thin melanomas and thick melanomas. Thus, the thickness and level of invasion of the primary lesion was of prognostic importance in patients with histologically negative, but not histologically positive lymph nodes. Females with melanoma had a slightly better prognosis than males with melanoma. The sex of the patient was not correlated with level of invasion or with number of lymph nodes containing tumor. However, there was a significant correlation between sex and site of the primary lesion. As seen in Table 6, the primary melanoma was located on the extremity in 51% of female patients as compared to only 27% of the male patients. The better prognosis associated with the extremity lesions indicates that the better overall prognosis of melanomas in female patients may be due to the fact that more melanomas occur on the extremities in this patient group. Cox's6 life-table regression model for a stepwise multivariate evaluation of prognostic factors indicated that the most important factor for predicting prognosis is number of lymph nodes histologically involved. The second and third most important factors were node palpability and site of melanoma, and these factors remain important even after adjustment for the effect of histological node involvement.
Discussion In our series the preoperative clinical evaluation was quite accurate, with 91% of the patients with clinically TABLE 6. Relationship between Sex of the Patient and Site of the Primary Melanoma
No. of Patients with
Level of Invasion
No tumor in nodes
1-3 nodes
4 or more
positive
positive
2 3 4 5
1 1(69%) 29 (48%) 11 (32%) 2 (25%)
4 (25%)
17 (28%) 19 (56%)
1 14 4 5
1 (13%)
Ann. Surg.
(6%) (23%) (12%) (62%)
Site Sex
Axial
Extremity
Male Female
55 (73%) 22 (49o)
20 (27%) 23 (51%)
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LYMPHADENECTOMY FOR MALIGNANT MELANOMA
positive lymph nodes subsequently shown to have metastasis by pathologic examination, with 100o accuracy in patients with Level IV and V melanoma and clinical positivity. Similarly the preoperative evaluation was correct 79Wo of the time when the nodes were judged clinically to be negative. Secondly, the 10-year survival of patients with one to three histologically positive nodes was 55%, which is high compared to previous reports which usually do not measure survival as a function of the number of positive nodes. Patients with four or more positive nodes had an 8 year survival rate of only 25% by comparison. In the subgroup of patients with clinically negative histologically positive nodes the 10-year survival was 70%o, while the subgroup with clinically positive histologically positive nodes had a 10-year survival of 50o Clark et al.4 separated cutaneous melanomas into nodular, superficial spreading and lentigo maligna types according to their histological and clinical characteristics and related the level of invasion of the primary lesion to prognosis. Breslow then reported that tumor thickness was a better indicator of prognosis than level of invasion in Stage I melanoma.3 Also, each of 54 patients with thickness less than 0.76 mm was free of disease over five years from melanoma excision, whether prophylactic lymph nodes dissection was performed (10 patients) or not performed (44 patients). However, in our series, containing a large proportion of patients with Stage II disease, four patients with melanomas thinner than 0.76 mm experienced recurrence. As Dr. Breslow has stated, the thickness measurements are relatively easy to perform3 and the pathologists who measured the thickness in our series learned the technique from Dr. Breslow whose independent measurements on a series of primary melanomas was identical to their measurements. We found the thickness measurements to be easier to make than assignment of Clark's levels and more reproducible in subsequent blind re-evaluation by the same pathologists. However, the thickness of most lesions in our series and in Breslow's series was based on analysis of several representative sections through the lesion,3 rather than exhaustive serial sectioning and the possibility of sampling errors exists. In our study the division of thicknesses into 1.50 mm provided the best prognostic discrimination, as in the study of Hansen and McCarten.8 With regard to prognostic implications of Clark's levels of invasion we were interested to observe in our series the difference between the five and 10-year results. Five years following lymph node dissection, there appeared to be substantial differences in survival according to differences in the original Clark level
641
of invasion. These differences were not as pronounced at 10 years following lymph node dissection. We found the site of the melanoma and the lymph node status to be more strongly correlated with prognosis than the level of invasion or the thickness of the primary lesion. Of the patients that underwent lymphadenectomy for clinically positive nodes, the interval between removal of the primary lesion and lymphadenectomy was two or more years in 23% of the patients, and five or more years in 5% of the patients. We therefore feel that if the regional lymph nodes are not dissected at the time the primary lesion is removed, they should be carefully followed for at least five years. We have not addressed ourselves to the question of selection of patients for prophylactic lymphadenectomy, since we are impressed as is Breslow3 and others with the hazards of using data from retrospective, nonrandomized studies. There is in progress a prospective, randomized World Health Organization Cooperative Trial on 553 clinical Stage I extremity melanoma patients randomized to receive or not receive a prophylactic lymph node dissection at the time of presentation. With the majority of the patients now having been followed for five years, there is no difference in survival between patients with lower extremity melanoma randomly allocated to receive either prophylactic lymph node dissection or not,12 even among patients with large or deeply invasive melanomas. If these data should be corroborated, the primary value of the factors we have discussed would appear to be for identification of patients with poorer or more favorable prognoses, for consideration for adjuvant treatment protocols, rather than for identification of patients that would benefit from a prophylactic node dissection.
Acknowledgment The authors are grateful for a review of the manuscript by Dr. Alexander Breslow.
References 1. Allen, A. C. and Spitz, S.: Malignant Melanomas. A Clinicopathologic Analysis of the Criteria for Diagnosis and Prognosis. Cancer, 6:1, 1953. 2. Breslow, A.: Thickness Cross-Sectional Areas and Depth of Invasion in the Prognosis of cutaneous Melanoma. Ann. Surg., 172:902, 1970. 3. Breslow, A.: Tumor thickness, Level of Invasion and Node Dissection in Stage I Cutaneous Melanoma. Ann. Surg., 182: 572, 1976. 4. Clark, W. H., From, L., Bernardino, E. A. and Mihm, M. C.: The Histogenesis and Biologic Behavior of Primary Human and Malignant Melanomas of the Skin. Cancer Res., 29:705,
1969. 5. Cohen, M. H., Schour, L., Felix, E. L., et al.: Staging Laparotomy in the Treatment of Metastatic Melanoma of the Lower Extremities. Ann. Surg., 192:710, 1975.
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COHEN AND OTHERS
6. Cox, D. R.: Regression Models and Life-Tables. J. R. Statist. Soc. B 34:187, 1972. 7. Gehan, E. A.: A Generalized Wilcoxon Test for Comparing Arbitrarily Singly-Censored Samples. Biometrika., 52:203, 1965. 8. Hansen, M. G. and McCarten, A. B.: Tumor thickness and Lymphocytic Infiltration in Malignant Melanoma of the Head and Neck. Am. J. Surg., 28:557, 1974. 9. Kaplan, E. L., and Meier, P.: Non-parametric Estimation from Incomplete Observations. J. Am. Statistic. Assoc., 53:457, 1958. 10. McNeer, G. and DasGupta, T.: Prognosis in Malignant Melanoma. Surgery, 56:512, 1964.
Ann.
Surg. *
November 1977
11. Siegel, S.: Non-Parametric Statistics for the Behavioral Sciences. 1956. p. 184, New York, McGraw-Hill. 12. Veronese, U.:Preliminary Results of Clinical Trial I of the World Health Organization Collaborating Centers for the Evaluation of Methods of Diagnosis and Treatment of Melanoma. Presented at the Cancer Research Center of the USSR, September 20-22, Moscow, Russia, 1976. 13. Wanebo, H. J., Fortner, J. G., Woodruff, J., et al.: Selection of the Optimum Surgical Treatment of Stage I Melanoma by Depth of Microinvasion: Use of the Combined Microstage Technique (Clark-Breslow). Ann. Surg., 192:302, 1975. 14. Wanebo, H. J., Woodruff, J. and Fortner, J. G.: Malignant Melanoma of the Extremities: A Clinicopathologic Study Using Levels of Invasion (Microstage). Cancer, 35:666, 1975.
