close

Вход

Забыли?

вход по аккаунту

?

348

код для вставкиСкачать
383
Survival of Patients with Melanoma of the Lower
Extremity Decreases with Distance from the Trunk
Eddy C. Hsueh, M.D.
Anthony Lucci, M.D.
Karen Qi, M.S.
Donald L. Morton, M.D.
John Wayne Cancer Institute at Saint John’s Health
Center, Santa Monica, California.
BACKGROUND. Early stage melanoma of the lower extremity is generally associated
with a favorable prognosis. However, several retrospective studies have suggested
that melanoma on the foot portends poor survival. The authors hypothesized that
the region of the lower extremity has prognostic importance.
METHODS. Between January 1, 1971, and December 31, 1991, 652 patients were
seen at the John Wayne Cancer Institute for a primary melanoma on the foot (92
patients), calf (336 patients), or thigh (224 patients). All patients had clinically or
histopathologically negative regional lymph nodes. The duration of follow-up after
first diagnosis was 9 –302 months, with a minimum of 6 years for survivors. Survival
curves were estimated by the Kaplan–Meier method. Pearson chi-square test was
used to test differences associated with the regional site of the lower-extremity
melanoma. The log rank test was used for univariate analysis, and Cox proportional
hazards regression was used for multivariate analysis.
RESULTS. Univariate analysis identified regional site, gender, Breslow depth, Clark
level, and age at diagnosis as significant for both overall survival (OS) and disease
free survival (DFS) (P ⫽ 0.0001). Multivariate analysis confirmed regional site as an
independent prognostic variable for OS (P ⫽ 0.0002) and DFS (P ⫽ 0.0005).
Ten-year rates of OS and DFS were 71% and 66%, respectively, for patients with
foot melanomas, compared with 92% and 87% for those with calf melanomas and
95% and 94% for those with thigh melanomas.
CONCLUSIONS. The prognosis for patients with primary melanoma of the lower
extremity is affected by the distance of the lesion from the trunk. Thus, distal (foot)
lesions carry a higher risk than thigh lesions. This difference should be considered
as a covariate when stratifying patients in clinical trials. Cancer 1999;85:383– 8.
© 1999 American Cancer Society.
KEYWORDS: melanoma, foot, extremity, survival, prognosis.
Presented at the Society of Surgical Oncology/First
World Congress of Surgical Oncology, San Diego,
California, March 25–29, 1998.
Supported in part by grants (CA12582 and
CA29605, awarded to Dr. Morton) from the National Cancer Institute and by funding from the
Wrather Family Foundation, Los Angeles, California.
Address for reprints: Donald L. Morton, M.D., John
Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404.
Received April 22, 1998; revision received July 16,
1998; accepted August 7, 1998.
© 1999 American Cancer Society
T
he anatomic location of a primary malignant melanoma has prognostic significance. Primary lesions of the lower extremity are
generally associated with a more favorable prognosis than truncal or
head and neck melanomas.1,2 However, several previous studies of
patients with clinically localized melanomas on the lower extremity
showed that location on the foot was an independent risk factor for
recurrent disease.3,4 We hypothesized that there was a correlation
between survival and the regional site of a lower-extremity primary
melanoma.
PATIENTS AND METHODS
Patient Population
The study population was drawn from all patients seen at our
institution between January 1, 1971, and December 31, 1991, for a
lower-extremity primary melanoma corresponding to American Joint
384
CANCER January 15, 1999 / Volume 85 / Number 2
TABLE 1
Patient Demographics
TABLE 2
Distribution of ELND in Three Subgroups According to Location,
Breslow Depth, and Invasion of Primary Melanoma
Primary site
ELND
Thigh (%)
Calf (%)
Foot (%)
224
336
92
P valuea
Location
Total
Tumor status of regional
lymph nodes
Histologically
negativeb
Clinically negative
Gender
Male
Female
Clark levelc
ⱕIII
⬎III
Unknown
Breslow depthc
Median
ⱕ1.5 mm
⬎1.5 mm
Unknown
Age (yrs) at diagnosis
Median
⬍60
ⱖ60
Thigh
0.334
104 (46%)
120 (54%)
154 (46%)
182 (54%)
50 (54%)
42 (46%)
62 (23%)
162 (77%)
72 (21%)
264 (79%)
37 (40%)
55 (60%)
157 (70%)
60 (27%)
7 (3%)
227 (67%)
103 (31%)
6 (2%)
41 (45%)
47 (51%)
4 (4%)
0.96
149 (66%)
42 (19%)
33 (15%)
1.00
205 (61%)
94 (28%)
37 (11%)
1.40
44 (48%)
32 (35%)
16 (17%)
41
199 (89%)
25 (11%)
45
258 (77%)
78 (23%)
51
65 (71%)
27 (29%)
Calf
0.001
Foot
⬍0.0001
Breslow depth
Yes (%)
No (%)
ⱕ1.5 mm
⬎1.5 mm
Unknown
ⱕ1.5 mm
⬎1.5 mm
Unknown
ⱕ1.5 mm
⬎1.5 mm
Unknown
56 (25%)
33 (15%)
15 (7%)
74 (22%)
63 (19%)
17 (5%)
18 (20%)
24 (26%)
8 (9%)
93 (42%)
9 (4%)
18 (8%)
131 (39%)
31 (9%)
20 (6%)
26 (28%)
8 (9%)
8 (9%)
53 (24%)
47 (21%)
4 (2%)
79 (24%)
72 (21%)
3 (1%)
18 (20%)
32 (35%)
0 (0%)
104 (46%)
13 (9%)
3 (1%)
148 (44%)
31 (9%)
3 (1%)
23 (25%)
15 (16%)
4 (4%)
Clark level
0.003
Thigh
Calf
⬍0.0001
a
P value by Pearson chi-square test.
“Histologically negative” refers to patients who underwent elective lymph node dissection (ELND).
Patients with a tumor positive ELND specimen were excluded from the study.
c
Clark level was recorded for 635 patients, and Breslow depth was recorded for 566 patients.
Foot
ⱕIII
⬎III
Unknown
ⱕIII
⬎III
Unknown
ⱕIII
⬎III
Unknown
ELND: elective lymph node dissection.
b
Committee on Cancer Stage I or II.5 All patients were
diagnosed at our institution or referred to us within 3
months of diagnosis. We did not include patients with
subungual lesions because their prognosis is considered poor.6 – 8 We also excluded any patient undergoing elective lymph node dissection (ELND) if histopathologic analysis of the lymph node specimen
revealed metastases. Informed consent was obtained
from all patients prior to any surgical procedure.
The study patients were divided into foot, calf,
and thigh groups according to the regional site of the
lower-extremity melanoma. After exclusion of 54 patients who had tumor positive ELND specimens (18
patients in the foot group, 25 in the calf group, and 11
in the thigh group), there were 652 study patients: 92
with primary melanoma on the foot (52 dorsal and 40
plantar), 336 with primary melanoma on the calf, and
224 with primary melanoma on the thigh. Approximately half of the patients in each group had undergone ELND (Table 1). Those who did not usually had
thin (ⱕ1.5 mm Breslow depth and/or ⱕ Clark level III)
primary lesions (Table 2). The study group contained
a disproportionate number of females, consistent with
previous reports of a higher incidence of lower-ex-
tremity melanoma in women.9,10 The Breslow depth of
the primary and the presenting age of the patient
tended to increase as the extremity site of the primary
moved from thigh to calf to foot. Seventeen patients
(3%) received adjuvant polyvalent melanoma cell vaccine (5 in the foot group, 7 in the calf group, and 5 in
the thigh group).
The median follow-up time was 142 months
(range, 9 –302 months); survivors were followed for at
least 72 months.
Statistical Analysis
Survival curves were estimated by the nonparametric
Kaplan–Meier method. Log rank test was used for
univariate analysis to determine differences between
curves. Overall survival (OS) was defined as the period
between the diagnosis of primary melanoma and
death. Disease free survival (DFS) was defined as the
period between excision of a primary melanoma and
pathologic or radiographic documentation of recurrence. A probability value of ⬍ 0.05 was considered
significant. Multivariate analysis was performed by
Cox proportional hazard regression using only the
variables that were significant in univariate analysis.
When applicable, Pearson chi-square test was used to
test the correlation between subgroups of two vari-
Survival and Lower-Extremity Melanoma/Hsueh et al.
385
TABLE 3
Correlation of Clinical Variables with Overall Survival
Variables
Primary site
Foot
Calf
Thigh
Gender
Male
Female
Breslow depth
ⱕ1.5 mm
⬎1.5 mm
Clark level
ⱕIII
⬎III
Age (yrs) at diagnosis
⬍60
ⱖ60
ELND
Yes
No
n
5-yr rate of
OS
10-yr rate of
OS
92
336
224
77%
94%
97%
71%
92%
95%
171
481
88%
95%
81%
93%
398
168
98%
83%
97%
76%
425
210
97%
85%
95%
81%
522
130
94%
87%
92%
82%
308
344
92%
94%
88%
92%
P value
(univariate)
P value
(multivariate)
0.0001
0.0002
0.0001
0.0093
0.0001
0.0001a
0.0001
0.1103a
0.0002
0.0359
0.1456
—
OS: overall survival; ELND: elective lymph node dissection.
a
Regression analysis included only those patients for whom both Breslow and Clark measurements were available.
ables. All statistical analyses were two-tailed and performed using Statistical Analysis System software (SAS
Institute, Inc., Cary, NC).
RESULTS
Overall Survival
Univariate analysis with the log rank test showed that
OS of patients with lower-extremity melanoma was
significantly (P ⫽ 0.0001) affected by the primary’s
regional site, Breslow depth and Clark level, and the
patient’s gender and age at diagnosis (Table 3). There
was no significant difference in OS whether or not
ELND was performed (P ⫽ 0.1456). There was also no
significant correlation between acral lentiginous histology and OS (P ⫽ 0.737).
Male patients older than 60 years with a thick
primary melanoma on the foot tended to have the
worst prognosis. The 5-year and 10-year OS rates for
patients with a foot primary were 77% and 71%, respectively, in sharp contrast to 94% and 92% for calf
primaries and 97% and 95% for thigh primaries (Fig.
1). Although there was no significant difference in OS
between calf and thigh groups (P ⫽ 0.1168), there was
a statistically significant difference between patients
with primaries on the foot versus more proximal regions (Fig. 1). For patients with foot melanoma, there
was no difference in OS for dorsal versus plantar location of the primary (P ⫽ 0.9588).
Multivariate analysis confirmed regional site of a
FIGURE 1. Overall survival curves, estimated by the Kaplan–Meier method
for patients with melanoma of the thigh, calf, and foot, are shown.
lower-extremity melanoma as an independent prognostic variable for OS (P ⫽ 0.0002) (Table 3). Also
significant on multivariate analysis were gender (P ⫽
0.0093), Breslow depth (P ⫽ 0.0001), and age at diagnosis (P ⫽ 0.0359).
Figure 2 illustrates the survival differences associated with the three regional sites according to thickness of the primary lesion. It is noteworthy that pa-
386
CANCER January 15, 1999 / Volume 85 / Number 2
thickness lesions again showed shorter survival for
patients with melanoma on the foot. DFS of patients
with thin (ⱕ1.5 mm) lesions on the foot was similar to
DFS of patients with thicker primaries on the thigh
(Fig. 4). Patients with thick (⬎1.5 mm) lesions on the
foot had the shortest DFS.
DISCUSSION
FIGURE 2. Overall survival curves are shown for patients with melanoma of
the thigh, calf, and foot, with further stratification by thickness.
tients with thin (ⱕ1.5 mm) lesions on the foot had a
survival similar to that of patients with thicker (⬎1.5
mm) lesions on the thigh. Patients with thick (⬎1.5
mm) lesions on the foot had the worst OS.
Disease Free Survival
The patient’s age and gender, ELND, and the lowerextremity melanoma’s regional site, Breslow depth,
and Clark level were significant with respect to DFS in
univariate analysis (Table 4). There was no significant
correlation between DFS and acral lentiginous histology (P ⫽ 0.6993). For patients with a foot primary,
there was also no significant difference in DFS for
dorsal versus plantar location (P ⫽ 0.9512). Again, the
5-year and 10-year rates were lower among patients
with foot primaries (73% and 66%, respectively) than
among patients with calf primaries (91% and 87%) or
thigh primaries (96% and 94%) (Fig. 3). Intergroup
differences in DFS were statistically significant for patients with foot versus calf primaries (P ⫽ 0.0001) and
for those with calf versus thigh primaries (P ⫽ 0.0144).
Of the patients who experienced recurrence, 42% (13
patients) in the foot group, 44% (17 patients) in the
calf group, and 56% (9 patients) in the thigh group had
regional lymph node recurrence with or without concurrent distant metastases.
Multivariate analysis established foot primary as
an independent prognostic variable influencing DFS
(P ⫽ 0.0005) (Table 4). Breslow depth (P ⫽ 0.0001),
Clark level (P ⫽ 0.0129), and age at diagnosis (P ⫽
0.0016) were also significantly correlated with DFS on
multivariate analysis. ELND and gender were not significantly correlated with DFS on regression analysis.
Intergroup comparisons of patients with same-
Although several studies have reported a high risk of
recurrence for melanoma on the foot,3,4,11,12 their
study populations were small and/or included patients with subungual melanoma, which is prognostically distinct from other extremity lesions.6 – 8 Das
Gupta and Brasfield6 reported a 5-year survival rate of
38% for subungual melanoma, with a median survival
of 10 months when lymph node metastases developed. Pack and Oropeza7 reported 5-year OS and DFS
rates of 48% and 30%, respectively, in their study of
subungual melanoma patients. Heaton et al.8 noted a
5-year OS rate of 59% for 46 subungual melanoma
patients. Our study demonstrated site-dependent differences in survival for patients with lower-extremity
melanomas other than subungual melanoma. There
was a significant difference in OS for patients with foot
versus calf or thigh primaries, and a significant difference in DFS for all three subgroups.
We cannot explain the worsening of prognosis with
distance from the trunk. Although the incidence of recurrence was higher in the foot group, the relative proportions of regional and distant recurrence were similar
among the three groups. The higher proportion of patients undergoing ELND for a foot melanoma (54%) versus a calf melanoma (46%) or thigh melanoma (46%)
argues against underdiagnosis of clinically occult regional lymph node metastases as an explanation for the
poor outcome in the foot group. In addition, there was
no significant correlation between ELND and survival.
There is a reportedly higher incidence of acral lentiginous histology for foot melanomas,13 however several
studies have shown that histologic type does not predict
survival.4,14 In our study, acral lentiginous histology was
not significantly correlated with either OS or DFS. Furthermore, among patients in the foot group there was no
difference in survival associated with acral (plantar) versus nonacral (dorsal) melanomas. In our study population, Breslow depth tended to increase with distance
from the trunk (Table 1), but comparison of patients
with lesions of the same thickness showed that survival
was still shorter among those with more distal lesions.
Furthermore, primary location on the foot was independent of thickness in multivariate analysis. Similarly, although lower-extremity primary site was associated with
gender and age (Table 1), it was also an independent
prognostic variable in multivariate analysis.
Survival and Lower-Extremity Melanoma/Hsueh et al.
387
TABLE 4
Correlation of Clinical Variables with Disease Free Survival
Variables
Primary site
Foot
Calf
Thigh
Gender
Male
Female
Breslow depth
ⱕ1.5 mm
⬎1.5 mm
Clark level
ⱕIII
⬎III
Age (yrs) at diagnosis
⬍60
ⱖ60
ELND
Yes
No
n
5-yr rate of
DFS
10-yr rate of
DFS
92
336
224
73%
91%
96%
66%
87%
94%
171
481
84%
92%
79%
89%
398
168
96%
76%
95%
68%
425
210
96%
78%
94%
72%
522
130
92%
80%
89%
74%
308
344
87%
92%
83%
90%
P value
(univariate)
P value
(multivariate)
0.0001
0.0005
0.0003
0.0652
0.0001
0.0001a
0.0001
0.0129a
0.0001
0.0016
0.0254
0.3459
DFS: disease free survival; ELND: elective lymph node dissection.
a
Regression analysis included only those patients for whom both Breslow and Clark measurements were available.
FIGURE 4. Disease free survival curves are shown for patients with melaFIGURE 3.
noma of the thigh, calf, and foot, with further stratification by thickness.
There is no adequate anatomic or physiologic explanation for poorer survival of patients with primary
melanomas on the foot versus other lower-extremity
sites. Delay in diagnosis has been noted for patients
with acrally located melanoma.15 This may explain the
thicker melanomas found in the foot group than in the
other two groups (Table 1). The longer duration of
active disease may contribute to the worse survival in
this group. Variations in rates of lymphatic flow sec-
ondary to repeated tissue compression in a weightbearing area have been observed.16 Compression may
enhance the lymphatic passage of tumor cells from a
primary melanoma on the foot, thereby increasing the
incidence of disease recurrence. However, there is
little evidence to implicate this as the cause of worse
prognosis for the foot group.
In summary, lower-extremity melanoma can be
prognostically stratified on the basis of regional site
(foot versus calf versus thigh), with foot lesions carry-
Disease free survival curves, estimated by the Kaplan–Meier
method for patients with melanoma of the thigh, calf, and foot, are shown.
388
CANCER January 15, 1999 / Volume 85 / Number 2
ing the highest risk of recurrence and the lowest rates
of survival. Meticulous cutaneous examination of the
foot, including the interdigital web space, is vital for
early detection of foot melanoma. Because of the significant difference in survival between foot melanoma
and other lower-extremity melanoma (exclusive of
subungual melanoma), future adjuvant trials involving
lower-extremity melanoma should consider site of primary in the leg as a stratification factor.
6.
7.
8.
9.
10.
REFERENCES
1.
2.
3.
4.
5.
Lewis MH, Hill JT, Leopold JG, Hughes LE. Guidelines for
management of malignant melanoma of the lower limb
based on a study of long-term behaviour. Clin Oncol 1982;
8:341–9.
Balch CM, Soong S-J, Shaw HM, Urist MM, McCarthy WH.
An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In: Balch CM, Houghton AN, Milton,
GW, Sober AJ, Soong S-J, editors. Cutaneous melanoma. 2nd
edition. Philadelphia: J. B. Lippincott, 1992:165.
Day CL Jr., Sober AJ, Kopf AW, Lew RA, Mihm MC Jr.,
Hennessey P, et al. A prognostic model for clinical stage I
melanoma of the lower extremity: location on foot as independent risk factor for recurrent disease. Surgery 1981;89:
599 – 603.
Urist MM, Balch CM, Soong S, Shaw HM, Milton GW, Maddox WA. The influence of surgical margins and prognostic
factors predicting the risk of local recurrence in 3445 patients with primary cutaneous melanoma. Cancer 1985;55:
1398 – 402.
Fleming ID, Cooper JS, Henson DE, Hutter RVP, Kennedy BJ,
Murphy GP, et al., editors. AJCC cancer staging manual. 5th
edition. Philadelphia: Lippincott-Raven, 1997.
11.
12.
13.
14.
15.
16.
Das Gupta T, Brasfield R. Subungual melanoma: 25-year
review of cases. Ann Surg 1965;161:545–52.
Pack GT, Oropeza R. Subungual melanoma. Surg Gynecol
Obstet 1967;124:571– 82.
Heaton KM, el-Naggar A, Ensign LG, Ross MI, Balch CM.
Surgical management and prognostic factors in patients
with subungual melanoma. Ann Surg 1994;219:197–204.
Fortin PT, Freiberg AA, Rees R, Sondak VK, Johnson TM.
Malignant melanoma of the foot and ankle. J Bone Joint Surg
Am 1995;77:1396 – 403.
Hutchinson BL. Malignant melanoma in the lower extremity: a comprehensive overview. Clin Podiatr Med Surg 1986;
3:533–50.
Day CL Jr., Lew RA, Mihm MC Jr., Sober AJ, Harris MN, Kopf
AW, et al. A multivariate analysis of prognostic factors for
melanoma patients with lesions greater than or equal to 3.65
mm in thickness. The importance of revealing alternating
Cox models. Ann Surg 1982;195:44 –9.
Barnes BC, Seigler HF, Saxby TS, Kocher MS, Harrelson JM.
Melanoma of the foot. J Bone Joint Surg Am 1994;76:892– 8.
Feibleman CE, Stoll H, Maize JC. Melanomas of the palm,
sole, and nailbed: a clinicopathologic study. Cancer 1980;46:
2492–504.
Sondergaard K, Olsen G. Malignant melanoma of the foot: a
clinicopathological study of 125 primary cutaneous malignant melanomas. Acta Pathol Microbiol Scand (A) 1980;88:
275– 83.
Metzger S, Ellwanger U, Stroebel W, Schiebel U, Rassner G,
Fierlbeck G. Extent and consequences of physician delay in
the diagnosis of acral melanoma. Melanoma Res 1998;8:
181– 6.
Ikomi F, Hunt J, Hanna G, Schmid-Schonbein GW. Interstitial fluid, plasma protein, colloid, and leukocyte uptake into
initial lymphatics. J Appl Physiol 1996;81:2060 –7.
Документ
Категория
Без категории
Просмотров
2
Размер файла
95 Кб
Теги
348
1/--страниц
Пожаловаться на содержимое документа