Clo

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Axillary Dissection in MelanomaPrognostic Variables in Node-positive Patients

RUY G. BEVILACQUA, M.O., DANIEL G. COIT, M.O., ANDRE ROGATKO, PH.D.RIAD N. YOUNES, M.O., and MURRAY F. BRENNAN, M.O.

"'e evaluated the importance of 14 clinical and pathologic vari-ables as determinants of prognosis in patients \\ith malignantme la noma and positive regionallymph nodes at axillary dissec-tion. The records of 197 patients operated 00 between 1974 and1984 were revie\\'ed.

From the Department o( Surgery and the Division o(Biostatistics, Memorial Sloan-Kettering Gancer Genter,

New York, New York

variables, subsets of patients \\ith markedly different prognosescould be generated. It is possible to predict a favorable outcomefor patients with less than 10% positÍ\'e nades, no extranodaldisease, and a primary lesion at a site other than the trunk. Itis also possible to recognize that the prognosis is very poor forpatients \\ith extranodal disease and truncal primary lesions,regardless of the percentage of positive lymph nades. Finally it\\'as verified that the prognosis is al\\'ays unfavorable \\'hen thepercentage of positÍ\'e lymph nades is very high. pc

(superficial) and proximal (deep) positive nades also wasassessed.10-13

The prognostic influence of lymph node-related vari-ables previously has not been examined exclusively forpatients undergoing axillary lymph nade dissection(ALND). In ibis study a group of patients with provedmelanoma metastatic to axillary n.°des following ALNDwas analyzed.

The main objective was to determine whether furtherprognostic information can be obtained in the patient withmalignant melanoma undergoing ALND ifwe append tothe clinical preoperative data the pathologist's evaluationof the surgical specimen.

A PRIMARY DETERMINANT of prognosis in malig-nant melanorila is the presence or absence ofpathologically involved lymph nodes. Oetailed

analyses of lymph node status has demonstrated the sig-nificance of absolute number-s and percentage2,3 of pos-itive nodes, macroscopic versus microscopic nodal in-volvement,2.9 and extranodal melanoma at node dissec-tion.7 In ilioinguinal dissection the significance of distal

Patients and Methods

The medical records of 197 patients with melanomametastatic to axillary nades undergoing ALND at Me-morial Sk>an-Kettering Cancer Center between 1974 and1984 were reviewed.

Stage was defined according to the American JointCommittee on Cancer (AJCC) system proposed in 1983(Table 1 ).14 AII patients classified as pathologic stage 111were included. Ten cases in which the largest lymph naderanged from 6 to 9 cm were included in the study group.This allowed a full evaluation ofthe importance oflymphnade size. Excluded from the analysis were patients withmetastases to two nodal groups, and patients with intransitor distant metastases.

The prognostic importance ofthe following non-lymphnode-related variables was evaluated: patient sex, age, pri-mary site, level, thickness, ulceration, and clinical stage.The primary site was designated as upper extremity, trunk,

Supported in part by NIH grant CA 01151 and grants from the Hol-lingsworth Fund and the Alhadefffamily. Dr. Bevilacqua is the recipientof a Mammadi Soudavar Memorial Fellowship.

Address reprint requests to Daniel G. Coit, M.O., Department ofSur-gery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., NewYork, NY 10021.

Accepted for publication August 3, 1989.

125

!?6 BEVILACQUA AND OTHERS Ann. Sur¡.. August 1990

thologist described the presence of visible or palpable dis-ease in the surgical specimen that was subsequently con-firmed histologically. If neither the surgeon nor the pa-thologist described visible or palpable disease in thesurgical specimen and histologic review subsequently re-vealed metastatic melanoma, the nodal involvement wasclassified as microscopic.

The surgical technique followed well-established rou-tines for ALND and included removal ofthe entire axillarycontents, with the pectoralis minor muscle, up to andincluding the levelllllymph nodes medial to it, exposingthe costoclavicular ligamento

The purpose of the operation was therapeutic in ISOpatients classified as clinical stage 111, while the intent wasprophylactic in 47 patients who were clinically under-staged as lB, IIA, or IIB (Table 2).

The main objective of the statistical analysis was toassess the dependence of fue rate of death from melanomaon the explanatory variables. Time was measured fromthe date of ALND to the date of death or last follow-up.Survival was estimated for each variable by ti}e product-limit method ofKaplan and Meier.~s Log rank testl6 wasused to check for dependence of survival on each variabletaken one at a time.

Proportional hazards regressionl7 was used to incor-porate all the explanatory variables in the same modeloForward stepwise procedure and likelihood ratio tests wereused to select the variables with the greatest prognosticvalue. Interaction effects among the variables were alsoconsidered. The adequacy of the proportional hazardmodel to the data was checked by fitting separate pro-portional hazard madels to partitions of the data deter-mined by a given categorical variable. The coefficientsestimated for each partition should not differ substantiallyunless there was an interaction effect. Cumulative hazardplots were also generated to visually check the assumptionof the proportionality of the hazard rates.

Whereas in the univariate analysis age, primary lesionthickness, number of positive nades, percentage of positivenodes, and size of the largest nade were used to generatesubsets of categorical variables, in the proportional hazardsregression they were treated as continuous variables.

Pairwise associations between variables were evaluatedby a t test for linear correlation (two continuous variables),one-way analysis of variante (categorical versus contin-uous variables), or a contingency table analysis using achi square or an exact test (two categorical variables).18

To display the relationship of a continuous variableand survival time, a predictive plot was generated. Thepredicted median survival for a given set of covariates xis the time t such that

$(t) = (o.s)exp(x'p)

where ,fj is the proportional hazards regression coefficient,

TABLE l. Me/anoma Staging System (American JointCommittee on Cancer, 1983)

Primary TumorTX Unknown, cannot be assessedTO Atypical melanocytic hyperplasia, in situ, Clark lTI Clark 11, ~0.75 mmT2 Clark 11,0.76-1.50 mmT3 Clark IV, 1.51-4.0 mmT4 Clark V, >4.0 mm or satellites within 2 cm ofprimary tumor

Lymph NodesNX Unknown, cannot be assessedNO NegativeNI One regional node station, nodes mobile, ~5 cm diameter or

negative nodes and <5 intransit metastasesN2 More than one node station positive, nodes >5 cm or fixed, >5

intransit metastases, or any intransit metastases with positivenodes

DiStant MetastasesMX Unknown, cannot be assessedMO NoneMI Skin or subcutaneous tissue beyond the primary nodal afeaM2 Visceral

Stage GroupingStage lA TI, NO, MOStage lB T2, NO, MOStage IIA T3, NO, MOStage IIB T4, NO, MOStage III Any T, NI, MOStage IV Any T, N2, MO,

or Any T, any N, MI-2

Table modified from Coit and Brennan.13

or unknown (when patient and physician were unable todetermine its site). Extremity lesions were further dividedinto proximal and distal to the elbow. Trunk lesions wereclassified as midline when they were located within 3 cmoribe midline and were otherwise considered lateral. Clarklevel and Breslow thickness of alllesions not removed atMemorial Sloan-Kettering Cancer Center were reviewedby a pathologist ofthis hospital before ALND. We useda broad definition of ulceration that included all patientsdescribing bleeding of the lesion with minor trauma aswell as those with ulceration reported on histologic review.

The Iymph node-related variables analyzed includedthe number of positive lymph nodes, the percentage ofpositive nodes (number ofpositive/total number removedX 100), the size of the largest positive lymph node (inmillimeters), the highest nodal status, the level of thehighest positive node, the invasion ofsoft tissue from dis-eased nodes (extranodal disease), and the gross nodal ap-pearance (macroscopic versus microscopic metastases).

The highest nodal status was described as positive whenthe highest dissected lymph node was affected by meta-static melanoma.

The level of the highest positive node was referred toas 1 when lateral, 11 when behind, and III when medial tothe pectoralis minor muscle.

The gross nodal appearance was defined as macroscopicwhen either the operating surgeon or the prospecting pa-

128 BEVILACQUA AND OTHERS

The following lymph node-related variables were"prog-nostically important by uriivariate analysis: number andpercentage of positive lymph nodes, highest nodal status,presence or absence of extranodal disease, and micro-scopic or macroscopic nodal appearance (Table 3). Con-versely the size ofthe largest positive node (p = 0.87) andthe level of the highest positive node (p = 0.78) were ofno prognostic value.

In the multivariate analysis, only variables that weresignificant in the univariate approach were considered.From the 197 patients, only 147 had complete informa-tion on all these variables and these made up the the mul-tivariate sample. Three variables were selected into thefinal proportional hazards regression: percentage of pos-itive lymph nodes, extranodal disease, and site ofthe pri-mary lesiono No other lymph node-related variable showedindependent prognostic importance in the proportionalhazard regression. The hypothesis that all the regressioncoefficients were zero was rejected (p < 0.001). Table 4

Ann. Sur¡.' August 1990

shows the summary ofthe multivariate analysis in termsof likelihoad ratio tests, coefficients, and standard errorsof the selected variables.

Table 5 shows the associations between lymph node-related variables. Percentage of positive nades and ex-tranadal disease, variables that were selected in the mul-tivariate model, are uncorrelated. The other variables,which were not selected in, are highly correlated, mainlywith percentage.

As most previous investigators have considered the ab-solute number rather iban percentage of positive nades,the association ofabsolute number, percentage, and totalnumber of recovered nades \\'as further analyzed. Thecorrelation between percentage and number of positivenades was high (r = 0.85, p < 0.001). Percentage of pos-itive nades did not correlate with the total number ofrecovered nades (r = 0.05, p = 0.13). Using the samecutoff points defined in the univariate analysis, Table 6shows that a low positive lymph nade percentage (10%

TABLE 3. Univariate AnalJ'sis ofLymph Node-related Variables

Five-yearSurvival :t SE

(%)

Ten-yearSur\1val j: SE

(%)

Number ofPatients

Cox-Mantel(p)Variable

Number of positive Iymph nodes1 102

433121

49.9:!: 5.536.9:!: 7.417.4:!: 7.2

42.6:t 6.136.9:t 7.48.7:t 7.1

<0.001

92313143

48.1:t 6.026.9:t 8.318.4:t 7.1

39.9:t 6.526.9:t 8.39.2:t 7.4*

163277

42.4:t 4.114.8:t 6.8

36.5 z 4.615!8 z 6.8

58.5:!: 8.532.8:!: 4.0

41149

7

47.2:t 9.929.4:t 4.4

0.002

163277

41.7 Z 4.117.8 Z 7~S

36.1:t 4.911.8:t 1.5

37.6 z 6.541.8 z 7.427.8 Z 9.5

NS66482459

37.6:!: 6.530.3:!: 9.127.8:!: 9.5

2-3>3Undetennined

Percentage of Positive LymphNodes

<1010-20>20Undetennined

Status oftheHighest DissectedLymph Node

NegativePositiveUndetennined

NodalAppearanceMicroscopicMacroscopicUndetennined

Extranodal DiseaseAbsentPresentUndetennined

Size ofthe Largest Lymph Node(mm)

<2020-40>40Undetermined

Level ofthe Highest PositiveLymph Node

NS31.7:t 8.338.5:t 13.522.2 :t 13.8

26.4 j: 8.428.8 j: 13.122.2 j: 13.8

41139

134

111111Undetermined

.Survival at 107 months (Iast follow-up).NS, not significant.

Vol.212oNo.2 AXILLARY DISSECTION IN MELANOMA

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TABLE 4. Final Proportional Hazard Regression Model.Variables o/ Prognostic Importance

Number of PositiveNodes

likelihoodRatio Test

(p)Regression

Coefficient :!: SEVariable2-3 >31

Percentage of positive nodesExtranodaI diseaseSite

0.0040.0120.019

0.017 :t 0.0050.850 :t 0.3070.573 :t 0.248

<1010-20>20

825

10206

o6

24Percentage of Positive Nodes

Both variables transformed to categorical, using the same cutoff pointsas in the univariate analysis.

1, combining the independently significant variables ofpercentage of positive lymph nades, extranodal disease,and primary site. The four distinct curves, situated at pro-gressively lower levels on the Y axis, show how the pre-dicted median survival rafe varies as a function of thevariables selected into the proportional hazards regressionmodelo

Discussion

Lymph node dissection in malignant melanoma isbased on the hypothesis that the disease is locoregionalin a proportion of patients with regionallymph node me-tastases. Iftheoperation is performed at ibis stage all ma-lignant foci may be eradicated and the patient cured.

Decades of observations have shown the difficulty iñachieving ibis goal. A significant proportion of patients

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AXILLARY LYMPH NOOE DISSECTION IN MELANOMAPREDICTED MEDIAN SURVIVAL (MONTHS) BY PERCENT

OF POSITIVE LYMPH NODES

or less) in 89.1 % of the cases is associated with only onepositive lymph nade. Conversely 77.4% of patients Withmore iban 20% positive nades had more iban three pos-itive nades in the axil1a.

The number ofrecovered nades varied from la to 59for the patients with a positive nade percentage of 10%or less, which is similar to the range of 4 to 67 for patientswith a positive nade percentage greater iban 10%. There-fore, in the absence of a correlation between the numberofpositive nades and the total number ofrecovered nades,the possibility of a pathology bias (9fthe type 'the moreyou search the more you find') can be discarded.

In ibis groupoflymph node-positive patients, the sur-vival of clinical stage less iban 111 versus clinical stage 111patients was significantly different in the univariate anal-ysis (Table 2). However ibis variable was notincluded inthe multivariate modelo This can be explained by the as-sociation of clinical stage and percentage of positive nades.The percentage of positive nades in the subset of clinicalstage less iban 1lI was 9.5% (:t6.3%) and in clinical stage111 it was 16.5% (:t20%), a significant difference by t test(p = 0.03).

The prognosis in node-positive patients is expressed asthe estimated median survival rate in months in Figure

100 PDSITIVE NDDES

.EXTRANDDAL -.SITE OTHER THAN TRUNK

.EXTRANDDAL -.SITE TRUNK

.EXTRANDDAL +. SITE OTHER THAN TRUNK

.EXTRANDDAL +. SITE TRUNK

TABLE S. Associations Between LymphNode-related Variables

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Variables p ~ 80

:;Percentage of positive Iymph nades and §

Number of positive Iymph nades <0.00 l. V) 60

Size ofthe largest Iymph nade <0.001* ~Highest nade status <0.00 1 t CLevel ofthe highest positive nade <0.001:1: ~Gross nodal appearance O.OIOt c 40Extranodal disease ~ NSt ~

Extranodal disease and cHighest nade status 0.015§ ~Number of positive Iymph nades NSt a.. 205ize ofthe largest Iymph nade NStGross nodal appearance NS§Level ofthe highest positive nade NS"

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129TABLE 6. Percentage o/ Positive Nodes Versus

Number o/ Positive Nades

~

-" :=::::=::~:::;::!=t"--- --+o I I I I I

o 20 40 60 80 100

PERCENT OF POSITIVE NODES

FIGo lo Predicted median survival of patients with the melanoma met-asta tic to axillary lymph nades as a function of percentage of positivenades, presente of extranadaI disease, and site ofthe primaryo

~

NS, not significant..t test for linear correlation.t t test.* One-way analysis ofvariance.§ehi square.11 Exact test for r X c contingency tables.

130 BEVlLACQUA ANO OTHERS

with positive nodes will die, even ifthe Iymphadenéctomy-is performed when the nades are clinically negative. Con-

versely some patients with clinically and pathologicallypositive nades removed will survive. This demonstratesthe importance of defining variables that could help inthe definition of true locoregional disease.

Although OUT primary interest was to evaluate lymphnode-related variables, truncal versus nontruncal site wasultimately included in OUT considerations because it wasthe only non-lymph node-related variable maintainingsignificance both in the univariate and multivariate anal-yses. This finding contrasts with the results of other studiesin stage 111 malignant melanomaS.22 in which site was notan independent predictor of outcome. As shown in Table2, site was significant only when subdivided into twogroups, trunk and nontrunk. Further subdivision of siteinto proximal \'ersus distal extremity or midline versuslateral trunk obscured its significance as an independantpredictor of outcome.

Five lymph node-related variables, number and per-centage ofpositive nades, status ofthe highest nade, mac-roscopic nodal appearance, and presence of extranodaldisease, were statistically significant by the univariateanalysis. Only two of these, percentage of positive nadesand presence of extranodal disease, were independentpredictors of survival in the multivariate analysis. Thisdisagreement is only apparent because most bf the sig-nificant univariate variables are associated with percentageof positive nades (Table 5).

Two lymph node-related variables, level of the highestpositive nade and size of the largest lymph nade, werenot significant in predicting survival, even in the univariateanalysis.

The level ofthe highest positive lymph nade is ~ conceptborrowed from breast cancer surgery were it was intro-duced by Berg23 in 1955 at Memorial Sloan-KetteringCancer Center. However it is important to note that, evenfor these tumors, this variable was not universally acceptedas an independant predictor of survival. Smith et al?4have shown that when breast cancer patients with equalnumbers of positive nades are considered there is no sta-tistically significant difference in survival when stratifiedby the level of positive nades.

The outcome related to this variable in the present studymay have been obscured by another factor. The infor-mation concerning the level ofthe highest positive Iymphnade was missing in 68% ofthe studied patients. This factlimits its power in estimating prognosis. On the otherhand, we observed a statistically significant associationbetwe~n this variable and percentage of positive lymphnodes: This raises the possibility thatany information thatcould possibly be derived from the level ofhighest positiveIymph node is already represented in the final model bythe percentage of positive nades.

Ann Sur¡.. AuBUSl 1990

Size of the largest positive lymph node is included inthe AJCC staging system as a significant prognostic factorin patients with melanoma metastatic to regional nodes(Table 1). In this review, however, this variable was notsignificant, even in the univariate analysis. This negativeresult is strengthened by the fact that this observation wasavailable for 138 (70%) of the patients. Furthermore itmust be stressed that patients with very large nodes (in10 cases measuring more than 5 cm) were included in thestudy group. Another important finding was that size ofthe largest node and percentage of positive lymph nodesbear a statisticalIy significant correlation (r = 0.35, p< 0.001) and we could repeat here the comments alreadymade for the level of highest positive node.

The majority of studies analyzing lymph node-relatedvariables in stage 111 melanoma have concluded that thenumber of positive lymph nodes is the most significantprognostic factor.I-8 In this study both percentage andabsolute number ofpositive nodes were significant in theunivariate analysis. Of these two highly correlated vari-ables (r = 0.85), percentage was the more predictive ofsurvival and hence was selected intothe final mulitvariatemodelo

The analysis ofFigure 1, in which the predicted mediansurvival time of four groups of patients is represented, ledus to some important conclusions. It clearly indicates thatit is possible to prediet a very favorable outcome for pa-tients with less than 10% positive nodes, no extranodaldisease, and primary lesion at a site other than trunk,independent of primary lesion thickness. It also showsthat the prognosis is very poor in patients with extranodaldisease and truncal primary lesions, regardless the per-centage ofpositive lymph nodes. FinalIy it confirms thatwhen the percentage ofpositive lymph nodes is very high,the prognosis is unfavorable for any combination ofthosetwo other significant variables.

The favorable prognosis of patients with clinicalIy neg-ative but histologically positive regional nodes (pathologicstage 111 and clinical stage less than 111) relative to that ofpatients with clinically and histologically positive regionalnodes, has been reported by several authors.2,4 In this re-view we found this to be true only in the univariate anal-ysis. Patients who were clinicalIy staged less than 111 hada significantly lower percentage of positive nodes. There-fore we must conclude that any possible prognostic ad-vantage in this subset ofpatients must be associated witha lower tumor burden. Both univariate and multivariateanalysis demonstrated the prognosticimportance of a lowpercentage of positive lymph nodes and absence of ex-tranodal disease. In addition to that smalI number of pos-itive lymph nodes, microscopic disease and negativehighest dissected lymph node were also univariately sig-nificant. AII these elements are indicators of limited re-gional involvement.

AXILLARY DISSECfION IN MELANOMA 131

9. Fonner JG, Woodruff J, Schottenfeld D, MacLean B. Biostatisticalbasis of elective nade dissection for malignant melanoma. AnnSurg 1977; 186:101-103.

10. Fonner JG, Booher RJ, Pack GT. Results of groin dissection formalignant melanoma in 220 patients. Surgery 1964; 55:485-494.

11. McCarthy JG, Haagensen CD, Heter FP. The role of groin dissectionin the management of melanoma of the lower extremity. AnnSurg 1974; 179:156-159.

12. Fínck SJ, Giuliano AE, Mann BD, Monon DL. Results ofilioinguinaldissection for stage 1I melanoma. Ann Surg 1982; 196: 180-186.

13. Coit 00, Brennan MF. Extent oflymph nade dissection in mela-noma ofthe trunk orlowerextremity. Arch Surg 1989; 124:162-166.

14. Beahrs OH, Myers MW, eds. Manual for Staging of Cancer, 2ndEdition. Philadelphia: JB Saunders, 1983.

15. Kaplan EL, Meier P. Nonparametric estimation from incompleteobservations. J Am Stat Assoc 1958; 53:457-481.

16. Mantel N. Evaluation of survival data and two new rank arder sta-tistics arising in its consideration. Cancer Chemother Rep 1966;50:163-170.

17. Cox DR. Regression models and life tables (with discussion). J RStat Soc 1972; 34: 187-220.

18. Pagano M, Halversen KT. An algorithm for finding the exact sig-nificance levels in r x c contingency tables. Journal ofthe Amer-ican Statistcal Association 1981; 76:931-934.

19. Link CL. Confidente intervals for the survival function using Cox'sproportional-hazard model with covariates. Biometrics 1984; 40:601-610.

20. Hel\er G, Simonoff JS. Prediction in censored survival data: a com-parison ofthe proponional hazards and linear regression models.Biometrika (In press).

21. Dixon WJ. BMDP Statistical Software. University of~fornia Press,Berkeley, CA, 1985.

22. Roses DF, Provet JA, Harris MN, et al. Prognosis ofpatients withpathologic stage 1I cutaneous melanoma. Ann Surg 1985; 201:103-107.

23. Berg JW. The significance of axillary nade levels in the study ofbreast carcinoma. Cancer 1955; 8:776-778.

24. Smith JA, Gamez-Araujo JJ, Gallager HS, et al. Carcinoma afiliebreast: analysis oftotailymph nade involvement versus leve! ofmetastasis. Cancer 1977; 39:527-532.

25. McCarthy WH, Shaw HM, Thompson JF, Milton GW. Time andfréquency ofrecurrence ofcutaneous stage I malignant melanomawith guidelines for fol\ow-up studies. Surg Gynecol Obstet 1988;166:497-502.

Although this paper was not designed to anaIyze thetiming of ALND, it re-emphasizes the importance of earlyregional control of the disease, which should be achievedby an elective operation or by short follow-up intervals:25

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Acknowledgments

The autho~ thank Margaret Pete~, R.N., for assistance in assemblingthe data, and the Department of Pathology for their consistent and uni-forro evaluation ofthe surgical specimens.

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