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From the Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Helsinki University Central Hospital, Finland.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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METHODS. This was a retrospective, population-based cohort study of 167 consecutive patients who had had an eye with choroidal and ciliary body melanoma removed between 1972 and 1981. Macrophages were identified with mAb PG-M1 to the CD68 epitope, and their number and morphologic type were recorded. Kaplan-Meier and Cox regression analyses of melanoma-specific survival were performed.
RESULTS. CD68-positive macrophages could be assessed in 139 (83%) of the 167 melanomas. Their number was moderate to high in 115 (83%) of the 139 tumors, and their morphology ranged from dendritic to round. A high number of macrophages was associated with presence of epithelioid cells (P = 0.025), heavy pigmentation (P = 0.001), and high microvascular density (P = 0.001). The 10-year melanoma-specific mortality rate increased with higher numbers of macrophages (0.10 for low versus 0.57 for high numbers, P = 0.0012). The morphologic type of infiltrating macrophages was not associated with mortality. The number of macrophages was modeled by stratification, which significantly improved a Cox regression model (P < 0.001). Adjusting for the other independent indicators of metastatic death 10-year melanoma-specific mortality was 0.17 for low versus 0.45 for high numbers of macrophages.
CONCLUSIONS. The number of tumor-infiltrating CD68-positive macrophages contributes to prognosis and associates with cell type and microvascular density, which merits a further analysis of the biological role of these cells in uveal melanoma.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The number of non-neoplastic stromal cells such as macrophages may sometimes be of the same order of magnitude as the number of tumor cells.14 The number of macrophages correlates with MVD in cutaneous melanoma, breast carcinoma, and non-Hodgkin’s lymphoma.15 16 17 We recently noted that uveal melanomas including non-necrotic tumors, treated with simple enucleation, contain notable numbers of macrophages,18 and we designed the present study to assess the extent and type of macrophage infiltration in a consecutive and population-based series of patients. Our specific purpose was to determine whether infiltrating macrophages carry prognostic information and whether they are associated with other characteristics of the tumor, especially its microvascular properties.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Follow-up data for this cohort of patients was updated to December 1999 by previously described routines.10 The median follow-up time was 22 years (range, 18–26). Altogether, 50 (63%) of 80 deaths caused by uveal melanoma and all 9 deaths caused by other cancers were reconfirmed by immunohistochemistry on biopsy specimens or specimens obtained at autopsy.10 In addition, 14 deaths of melanoma had been confirmed by fine-needle aspiration biopsy.
Specimens in which less than 50% of the original melanoma remained (14 patients), the remaining tumor was entirely above Bruch’s membrane (16 patients), or the block was missing (2 patients) were excluded from the present analysis, leaving 149 specimens to be studied (inclusion rate, 89%). Unlike the criteria used in our previous analysis of microvascular patterns and density,10 13 the current criteria did not exclude specimens that were more than 50% necrotic (15 patients), so that we could determine to what extent tumor necrosis was associated with the overall number of infiltrating macrophages.
Immunoperoxidase Staining
The paraffin blocks were cut at 5 µm, after which the
slides were randomly coded by an outside laboratory technician. The
code was broken only after macrophage and survival data were ready for
analysis, with all investigators masked to the outcome of individual
patients until that time. Immunostaining of macrophages was performed
using the avidin-biotinylated peroxidase complex method (Vectastain ABC
Elite Kit; Vector Laboratories, Burlingame, CA), as described
previously in detail.18
Two primary mouse monoclonal antibodies (mAbs) PG-M1 (IgG3; lot 101, diluted 1:50; Dakopatts, Klostrup, Denmark) and KP1 (IgG1; lot 038, diluted 1:100; Dakopatts) were used to recognize fixative-resistant epitopes on CD68, an intracytoplasmic 110-kDa glycoprotein that resides in lysosomal granules and is expressed by macrophages in all human tissues.19 20 A third mAb, clone 3A5 against human macrophages (IgG2b; lot 210501, diluted 1:50; Novocastra Laboratories, Newcastle-upon-Tyne, UK), was also used. Pretreatment with 0.4% (wt/vol) pepsin (FIP, 2500 U/g; E. Merck, Darmstadt, Germany) in 0.01 M hydrochloric acid for 15 minutes at 37°C enhanced immunostaining with mAb PG-M1, and pretreatment in 10 mM sodium citrate buffer (pH 6.0) for 10 minutes at 95°C enhanced immunostaining with mAbs KP1 and 3A5. In preliminary experiments, mAb 3A5 immunolabeled dendritic macrophages less effectively than mAb PG-M1, in accordance with a previous study,21 and mAb KP1 labeled fewer macrophages overall than mAb PG-M1 did. mAb KP1 also cross-reacted with melanoma cells in several tumors, as has been noted earlier in cutaneous melanoma.19 22 Consequently, mAb PG-M1 was used throughout this study as the default antibody to quantitate macrophages. The primary mAb QBEND/10 (lot 121202, diluted 1:25; Novocastra) to the CD34 epitope of endothelial cells was used to label microvessels.13
To enable evaluation of immunoreaction in pigmented tumors, the peroxidase reaction was developed with 3,3'-diaminobenzidine tetrahydrochloride and, regardless of the grade of pigmentation, melanin was then bleached with 3.0% (vol/vol) hydrogen peroxide and 1.0% (wt/vol) disodium hydrogen phosphate, as described previously.18
Grading of Infiltrating Macrophages
To develop a repeatable grading system that could be used by
other laboratories as well, specimens of uveal melanomas that were not
included in the study series were immunostained with mAb PG-M1. From
this group of specimens it was obvious that immunolabeled cells
differed not only in number but also in morphologic appearance, and
ranged from dendritic to round phagocytosing cells.
The pilot set of specimens was divided into three groups based on the overall number of cells immunopositive with mAb PG-M1 in non-necrotic areas of the tumor. Confluent necrotic areas did not influence the grading. Whereas round immunopositive cells were relatively easy to count, it was not possible to determine the number of dendritic cells reliably. For this reason, we graded the number of immunopositive cells semiquantitatively. Standard photographs that represented few (Figs. 1A 1B ), moderate number of (Figs. 1C 1D ), and many immunopositive cells (Figs. 1E 1F 1G ) were taken.
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Melanomas in the study series were subsequently graded independently by two observers under a light microscope based on the overall number of immunopositive cells and their predominant morphologic type, according to the standard photographs (Figs. 1A 1B 1C 1D 1E 1F 1G) . Discrepancies in grading were resolved by consensus under a double-headed microscope.
Grading of Microvessels
Microvascular loops and networks, consisting of at least three
back-to-back loops, were identified under a green filter according to
the criteria of Folberg et al.3
4
from sections first
bleached with potassium permanganate and oxalic acid and then stained
with periodic acid-Schiff without counterstain, as described previously
in detail.10
MVD was assessed in the most highly
vascularized area using an eyepiece with an etched graticule
corresponding to 0.313 mm2 at x200 magnification
(WK 10x/20L-H; Olympus, Tokyo, Japan).12
13
Any
immunolabeled vessel that was clearly separate from an adjacent one and
was either totally inside the graticule or touching its top or left
border was counted as a microvessel.
Statistical Analysis
Analyses were performed by computer (PC-90 software; BMDP
Statistical Software, Cork, Ireland). Exact probability distributions
were also computed (StatXact-3; Cytel Software, Cambridge, MA).
Fisher’s exact and Pearson’s 
2 tests were
used to compare proportions in unordered contingency tables, and
Kruskal-Wallis and Jonckheere-Terpstra tests were used to compare
proportions in singly and doubly ordered contingency tables,
respectively.23
24
P < 0.05 was
considered statistically significant. The weighted 
statistic was
used to estimate chance-corrected interobserver agreement in grading
the number and type of macrophages.24
The number of macrophages was analyzed as an ordered (few, moderate,
many CD68-immunopositive cells) and the predominant morphologic type of
macrophages as an unordered three-category variable (dendritic,
intermediate, round CD68-immunopositive cells). Cell type was collapsed
into two categories according to the presence or absence of epithelioid
cells (spindle, nonspindle) and tumor location according to the
presence or absence of ciliary body involvement.4
10
Largest basal tumor diameter (LBD) was divided in three categories
according to the size of the tumor (
10 mm, 10–15 mm, >15
mm).4
10
Degree of pigmentation in each tumor was graded
semiquantitatively by sorting unstained 5-µm-thick paraffin-embedded
sections into three groups that represented amelanotic to weak,
moderate, and strong pigmentation. Microvascular loops and networks
were analyzed as a combined variable that considered networks to be an
advanced stage of loops (no loops, loops without networks,
networks).10
MVD was divided in quartiles.13
Univariate analysis of survival time data were based on the Kaplan-Meier product-limit method,25 and a trend version of this test was used if the categories analyzed were ordered. In pair-wise comparisons, probabilities were adjusted according to Bonferroni.24 Patients judged to die of causes unrelated to uveal melanoma were censored at the time of death. Equality of follow-up between groups was ascertained by comparing Kaplan-Meier curves with reverse censoring.25
Because no previous study on macrophage infiltration and survival in uveal melanoma was available, formal sample-size calculation for the Kaplan-Meier analysis was not feasible. Power analysis by simulation26 indicated that the present study had 80% power to detect a 0.25 difference in 20-year survival (or a hazard ratio of 1.9), and 95% power to detect a 0.32 difference in survival (or a hazard ratio of 2.4).
Multivariate analysis of melanoma-specific survival was based on the Cox proportional hazards model.25 27 The assumption of proportional hazards was assessed by adding each covariate by log time interaction to the model and assessing the significance of the product term using the partial likelihood ratio test.27 LBD and MVD were analyzed as continuous variables, the latter using square root–transformed counts, which rendered it normally distributed.12 13 The three unordered categories of the type of macrophages were modeled with two design variables.27 A main-effects model was adjusted for the effect of tumor pigmentation and macrophages.13 The number of variables in the final model was restricted to four, based on a rule that requires at least 15 to 20 events per variable.25 The regression coefficients and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Number and Type of Macrophages
Immunostaining with mAb PG-M1 to the CD68 epitope was satisfactory
in 139 (93%) of the 149 specimens of uveal melanoma studied.
Immunopositive cells were easily recognizable and mainly infiltrated
diffusely (Figs. 1A
1B
1C
1D
1E
1F
1G)
, but in some areas they arranged roughly along
microvascular loops, networks, and other microvascular patterns (Fig. 1H)
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After consensus, the number of CD68-immunopositive cells was semiquantitatively graded as few in 24 tumors (17%; 95% CI, 11–25), moderate in 71 tumors (51%; 95% CI, 43–60), and many in 44 tumors (32%; 95% CI, 24–40). The predominant type of infiltrating cells was graded as dendritic type in 30 tumors (22%; 95% CI, 15–29), intermediate in 82 tumors (59%; 95% CI, 50–67), and round in 27 tumors (19%; 95% CI, 13–27).
Interobserver Agreement
The two investigators agreed on the number of CD68-immunopositive
cells in 80% (95% CI, 72–86) of specimens. No two-category
discrepancies occurred. They agreed on the predominant type of
CD68-immunopositive cells in 67% (95% CI, 58–75) of specimens, and
solved a discrepancy of two categories twice. All discrepancies
resulted from deciding whether the infiltration was sufficiently
monotonous to allow categorization of type as dendritic or round,
rather than intermediate. The interobserver agreement (weighted )
was 0.77 (95% CI, 0.69–0.85) for grading the number and 0.60 (95%
CI, 0.49–0.71) for grading the type of CD68-immunopositive cells.
Associations with Other Variables
The number of CD68-immunopositive cells was significantly
associated with four known prognostic indicators (Table 1)
. Melanomas with large basal diameter (P =
0.031, Jonckheere-Terpstra test), heavy pigmentation (P = 0.001), epithelioid cells (P = 0.025, Kruskal-Wallis
test), and high MVD (P = 0.001, Jonckheere-Terpstra
test) had significantly more immunopositive cells than small and weakly
pigmented melanomas, melanomas without epithelioid cells, and melanomas
with low MVD, respectively, but overlap between categories was noted
(Figs. 2A 2B)
. In addition, females had significantly more immunopositive cells
than males (P = 0.010, Kruskal-Wallis test).
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Neither the number nor the predominant type of immunopositive cells was significantly associated with involvement of the ciliary body, presence of microvascular loops and networks, presence of extraocular extension, and presence of more than 50% necrosis (Table 1) .
Univariate Analysis of Survival
At the end of the follow-up, 37 (22%) of 167 patients were alive
without evidence of recurrent melanoma, 80 (48%) had died of
metastatic uveal melanoma, 49 (29%) had died of other causes, and 1
(1%) had died of unknown cause. Melanoma-specific mortality was
comparable between patients included in and excluded from the present
study (P = 0.52 Mantel-Cox test, difference between curves).
Melanoma-specific mortality was significantly associated with the number of CD68-immunopositive cells (P = 0.0012, Mantel-Cox test, linear trend; Fig. 2C ). The 10-year cumulative probability of survival was 0.90 (95% CI, 0.77–1.0) for few, 0.58 (95% CI, 0.46–0.70) for moderate numbers of, and 0.43 (95% CI, 0.27–0.58) for many immunopositive cells. The difference occurred because tumors with few immunopositive cells had better prognosis than those with moderate (P = 0.043 Mantel-Cox test, Bonferroni correction) and high numbers of immunopositive cells (P = 0.003). No significant difference in mortality was observed between melanomas with moderate and high numbers of immunopositive cells (P = 0.25). In contrast, the predominant type of CD68-immunopositive cells identified with mAb PG-M1 was not significantly associated with melanoma-specific mortality (P = 0.66, Mantel-Cox test; Fig. 2D ). The results of univariate Cox regression for all variables that fulfilled the proportional hazards assumption, a prerequisite for using Cox analysis that requires that the relative hazard not change over time, are presented in Table 2 .
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2 = 5.48; 1 df;
P = 0.019, indicating that the risk changes over time,
and hazard is not proportional) and was modeled by stratification.
A multivariate Cox regression model previously fitted to this data
set13
was adjusted for the effect of immunopositive
macrophages and tumor pigmentation. The presence of microvascular loops
and networks, the presence of epithelioid cells, LBD, and MVD retained
their significance in the model stratified by the number of
CD68-immunopositive cells (Table 2)
. The predominant type of
macrophages and tumor pigmentation did not enter the model. This model
was strongly preferred to the nonstratified model that disregarded the
number of macrophages (likelihood ratio = 245.1–227.7,
P < 0.001 2 test, 1
df, indicating that the stratified model predicted
melanoma-specific mortality more precisely than the nonstratified
model). After adjustment, the melanoma-specific 10-year survival
differed by 0.28 between patients with high and low numbers of
macrophages. The difference in survival slightly decreased over long
follow-up time (Fig. 3)
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In our hands, mAb PG-M1 to the CD68 epitope immunostained macrophages more uniformly than mAbs KP1 and 3A5 did, and it was used as the default antibody in the present study. All the antibodies used were superior to antibodies recognizing epitopes shared by macrophages and granulocytes, such as RPN.701, OKM1 to the CD11b epitope, and Leu-M3 to the CD14 epitope, which have previously revealed only a few immunopositive cells (<19 cells/mm2) in uveal melanoma.29 31 Differences in immunostaining patterns between mAbs against the CD68 epitope may result from variable glycosylation.32 mAb PG-M1 has shown a more restricted reactivity with the highly glycosylated and antigenically heterogeneous CD68 molecule than other mAbs to CD68.19 During differentiation of monocytes into macrophages, the expression of CD68 increases markedly, but the function of the CD68 epitope has remained unknown both in macrophages and in other cell types.33 Some antibodies to the CD68 epitope such as mAb KP1 reportedly cross-react with cutaneous melanoma cells.19 22 We found mAb KP1 also reacted with tumor cell cytoplasm in some uveal melanomas. No such cross-reactivity was observed with mAbs 3A5 and PG-M1 to the CD68 epitope, and we did not observe cells that would morphologically have been transitional between typical tumor cells and dendritic cells. The possibility that some immunopositive cells might still be neoplastic cannot be completely ruled out, especially in that diverse other tumors such as cutaneous melanoma, renal clear-cell carcinoma, meningioma, glioblastoma, malignant fibrous histiocytoma, xanthogranuloma, and granular cell myoblastoma have occasionally reacted with mAb PG-M1.19 32
The number of macrophages was associated with three known high-risk indicators: LBD, presence of epithelioid cells, and high MVD in areas of densest vascularization.12 13 In spite of the different methodology of the COMS study, it also found significantly higher numbers of macrophages in uveal melanomas with epithelioid cells.30 Similarly, the number of infiltrating macrophages increased with LBD in both studies, and both showed a significant association between heavy pigmentation and a high number of infiltrating macrophages,30 suggesting that these associations are genuine. No association was observed between the number of macrophages and presence of microvascular loops and networks, which is another independent high-risk indicator for metastasis in uveal melanoma.4 10 However, immunopositive cells could cluster around these and other microvascular patterns, and a biologically significant qualitative association is not excluded by the present study.
An association between the number of infiltrating macrophages and high MVD has been recently observed in certain other cancers, including cutaneous melanoma.15 16 17 Because macrophages contain a number of cytokines and growth factors, this association has been taken as evidence that macrophages might promote angiogenesis.15 16 17 34 35 A statistical association is not proof of a causal relationship, however, and experimental studies are needed to investigate this theory. Especially uveal melanoma, in which the relative contribution of classic angiogenesis and tumor-cell–driven vasculogenesis is open,1 2 a more complex role for macrophages in remodeling microvasculature may apply.
Our population-based analysis of survival of 139 consecutive patients with choroidal and ciliary body melanoma showed a strong association between increased melanoma-specific mortality and increasing number of CD68-positive macrophages by univariate Kaplan-Meier analysis. The cumulative 10- and 20-year melanoma-specific probabilities of survival were 0.47 and 0.42 lower, respectively, when the number of infiltrating macrophages was high rather than low. No association between mortality and the predominant type of infiltrating macrophages was observed. When the number of infiltrating macrophages by stratification was considered, the fit of our Cox proportional hazards model improved significantly. Moreover, a clinically significant survival difference of 0.28 remained after adjusting for other factors.
It is important to determine which biological link, if any, exists between a high number of macrophages, presence of epithelioid cells, and high MVD, because this probably reveals useful insights into the progression and metastasis of uveal melanoma. The presence of a high number of macrophages in aggressive melanomas might either be an indication of a host response mounted against more malignant tumors,35 whether mediated by macrophages themselves or by other events, or it may simply be indirect evidence of an aggressive tumor that has a high cell turnover rate and, consequently, a greater demand for phagocytosing cells.
A corollary of the present study is that the presence of macrophages in uveal melanomas that have been conservatively managed cannot automatically be ascribed to treatment effect.31 36 Macrophages also constitute a nonneoplastic cell population that is a potential source for cross-reactivity in melanomas studied by immunohistochemical methods.18 28 The response of infiltrating macrophages to tumor destruction and their possible role in host defenses against metastasis after conservative management of uveal melanoma are relevant questions to be examined in future research.
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Footnotes |
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Submitted for publication October 6, 2000; revised January 29, 2001; accepted February 21, 2001.
Commercial relationships policy: N.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Teemu Mäkitie, Ophthalmic Pathology Laboratory, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FIN-00029 HUS, Finland. teemu.makitie{at}hus.fi
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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and IL-1 Int J Cancer 85,182-188[Medline][Order article via Infotrieve]
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