Prognostic factors in cutaneous malignant melanoma

PROGNOSTIC FACTORS IN CUTANEOUS MALIGNANT MELANOMA A Comparative Study of Long Term and Short Term Survivors* Andrew G. Huvos, JU.D.,t Jatin P. Shah, M.D.,+ and Valerie Mike, Ph.D.§

Abstract The clinical presentation and histologic characteristics of primary melanomas of a consecutive series of 100 short term (fatal within five years) and 100 long term survivors (disease-free for ten years or longer) were studied. The clinical parameters analyzed included the history of pre-existent mole, duration of changes before diagnosis, site, elevation, ulceration, extent of pigmentation, and satellitosis around the primary lesion. Study of histologic features included analysis of exact measurements of the primary melanoma, depth of dermal invasion, tumor cell morphology, mitotic rate, intracellular pigmentation, presence or absence of giant tumor cells, blood vessel or lymphatic invasion, lateral junctional activity, and presence and extent of lymphoid response to the primary lesion. Statistically significant differences were fou~d between the long term and short term survivors with respect to se\'eral variables. It is one of the conclusions of this study that an elective node dissection would seem to be indicated in all patients with stage I melanoma who present with poor prognostic signs, that is, patients who belong to any combination of the following categories: male, primary lesion > I cm., which has ulcerated, with a deeper level of dermal penetration, with dermal lymphatic or blood vessel invasion, and a lack of lymphoid reaction around the primary lesion.

*Presented in part at the Annual ~Iecting of the American Society of Clinical Pathologists. San Francisco. California. October 19i2. tAssociate Professor of Pathology. Department of Pathology. Cornell Univcrsity Medical College. Associate Attending Pathologist. Departmcnt of Pathology. ~Icmorial Hospital for Cancer and Allied Discases. New York. New York. :l:Senior Residclll. Dcpartment of Surgery. Mcmorial Hospital for Cancer and Allied Diseases. New York. New York. §Hcad. Biostatistics Laboratory. Sloan-Kcttcring Institutc for Canccr Rcscarch. New York. Ne\\" York.

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~Ialignant melanoma of the skin is a capricious tumor in the sense that its clinical behavior is rather unpredictable. Time and again one encounters a primary melanoma that is small and superficial in its appearance but proves to be fatal within a short period. On the other hand, occasionally a patient with a rather large and invasive appearing lesion is cured after adequate therapy. There are, however, no simple clinical or histologic criteria that can serve as guidelines to determining the extent of surgical treatment of the primary lesion, or that help one to arrive at a reliable prognosis for a gi\'en patient. Of course, such a question of therapy would not arise in a patient who presents with disseminated melanoma or obvious regional lymph node metastases. Currently no thoroughly dependable criteria are available for the selection of treatment and assessment of prognosis in patients with melanoma localized to the site of the primary lesion, without clinical evidence of rcgional lymph node metastases. Wide local excision of the primary Icsion and . skin grafting when necessary have remained a universally acccptcd mode of treatnlent. However, an abundance of data in the literature is available in fa \"0 I' of as well as against e1ectivc regional lymph node dissection.12.13.16-19.29.32.39 There is general agreement that the larger the surface dimension ofthc tumor, the worse the prognosis. l • 2.11.26.40 There are several studies reporting the histologic characteristics of the primary lesion and the obsen'ed relationship of these to prognosis.2- 4. 14.24.26-28.30.31.37 The classic studies of Clark et aU' 8. 35 first reported a reproducible method of classifying dermal levels of tumor invasion, and the relationship betwecn these and the expected prognosis. This interrelationship was previously obscrvcd by ~Iehnert and Hcard,34 among others. A similar study was also reported by Cochran,9-1I who attempted to use a combination of variables to assess prognosis. The prcsent study is a retrospective analysis of the clinicopathologic characteristics of two groups of patients with primary cutaneous melanoma who were treated by similar methods at thc same institution. All the patients in one group died of their disease within five years after

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the initial surgical treatment, whereas all the patients in the second group were alive and disease-free for at least ten years after initial treatment. The purpose of this discussion is to prcsent some 20 clinicopathologic characteristics of primary melanoma that may help to decide the type and extent of thcrapy and to establish reliable prognostic criteria. MATERIALS AND METHODS

Two consecutivc series of 100 patients, each with a documented diagnosis of malignant melanoma for whom the histologic slides of the primal'}' tumor were available, were selected for this study. One series consistcd of short term survivors (dead within five years) and the other of long term survivors (disease-free for tcn years or longer). All these patients were trcated by similar methods at the ~Iemorial Sloan-Kettering Cancer Center, between 1946 and 1969. A retrospectivc rcvicw of their clinical rccords was performed detailing clinical information pertaining to their presenting symptoms, physical findings, and stage of disease at the time of presentation. The clinical information recorded for each patient includcd the age, sex, history of previous mole, duration of changes in the primary lesion, and site of the primary tumor. Also noted wcrc the gross features of the lesion, such as elevation, ulceration, pigmentation, and occurrence of satellites. The presence or absence of clinically suspicious regional lymph nodes was also recorded, as was the clinical stage of thc discasc. The histologic slides of the primary tumor were then intensively stu~ied. At the time of the microscopic review the pathologist had no knowledge as to whether the patient was a short term or a. long term survivor. Whenever technically adcquatc slides were not available, additional histologic sections were cut froin available paraffin blocks to obtain the appropriate representati\'e material of the primary tumor. Only hematoxylin and eosin stained slides were studied. Th~ histologic features examined included the surface dimension of the

CUTANEOUS MALIGNANT MELANO},[A-Huvos, SHAH, MIld:

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Petersen Clar\ etal. etat. & McGovern Stage I

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Figure 1. Classification of melanoma by dcpth of ill\'asion ,,'jlh comparison to othcr sLUdics (refs. 7. 30. 37). (~Iodificd aftc." ~Ichncrt. J. II.. and Ilcard. J. L: Staging of malignal1l mclanoma by dcpth of im'asion. Amcr. j. Sm'g.• 110: 168-176, HJ65.)

primary tumor (maximal diameter of the specimen), its cross sectional appearance, the depth of dermal penetration, the cell type of the primary lesion (chieOy epithelioid or spindle cell), intracellular pigment production, the presence and extent of the lymphocytic reaction around the primary tumor, the mitotic rate (high or low), the presence of giant tumor cells, epidermal hyperplasia, junctional activity (microscopic evidence of junctional changes in the pre-existent nevus), and finally dermal vascular tumor invasion (lymphatics or blood vessels). The depth and extent of dermal invasion were described according to criteria originally reported by ~Iehnert and Heard3~ (Fig. I). Lel'el 0: The tumor is intraepidermal with an, intact basement membrane (noninvasive melanoma in situ). Let'el 1: The lesion extends into the papillary dermis (papillary dermal level). Let'el 2: The tumor invades the reticular dermis (reticular dermal le"el), and Let'el 3: The tumor reaches into the subcutaneous adipose tissue (subcutaneous fat level). . The information so derived from the clinical t:ecords and the review of the histologic material was then analyz~d for the two groups of patients. In examining these variables for prognostic significance we were facing the problems associated with any retrospective study. But we believe that the variables can be considered comparable for the two groups, for the purposes of establishing a profile of the

population of short term and long term survivors. That is, we will treat the data as if we had a random sample of size 100 of each of the two populations. RESULTS The average age at diagnosis was 52 years for short term and 41 years for long term survivors, and this is essentially in agreement with the poorer prognosis reported for older patients. The distribution of patients by sex is shown in Figure' 2. Although approx, imately half the overall sample were males (103/200), 67 of these were among the short term survivors. Sixty-four of the long term sun-ivaI'S were females. Figure 3 indicates the distribution of our patients by clinical stage. There. were no stage III cases among the long terlll survi,·ors. Cliriical stage I indicates primary, melanomas without regional. or distant metastases, stage II includes all patients with metastases limited to regional l)'Illph nodes, and stage I I I indicates metastatic disease beyond the regional lymph nodes or disseminated disease. 19 Of the patients in clinical stage I. approximately the same proportion among the short term survivors (33 per cent) as among the long term survivors (25 per cent) had undergone elective node dissection. And since the first group consists of patients who died of their diseasc within fivc ycars, thc slightly higher proportion in that group does not introduce an invalidating bias into our study.

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A further breakdown of the data by sex and clinical stage revealed a disproportionately large number of males in stage II at the time of first diagnosis. 37 per cent (38/103) as compared to 14 per cent (14/97) females. However. even alllong stage 1 patients. 59 per cent of the males (35/59) were among the short term survivors, as compared to 25 per cent (20/81) of the females. This is in agreement with the poorer prognosis generally reported for male patients.7.1I.2o.27.33.37 The reported durations of changes in the primary lesion (e.g.. size, color) are summarized in Figure 4; this information was not available for ten patients in each group. As can be seen from the figure, slightly more of the long term sunivors reported longer durations. The' Q\'erall median was six months. The sites of occurrence of the primary

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lesion in the two groups are shown in Figure 5, summarized according to the four categories: head and neck, trunk, upper extremities, and lower extremities. No really striking differences' can be observed between the two groups. The recorded surface dimension of the lesion was that of the histologic specimen, the measurement of which was obtained under the microscope. These figures tend to be smaller than corresponding clinical measuremcnts, since tissue shrinks after surgical removal and during histologic preparation. The distribution of reported dimensions is shown in Figure 6. The mean size was 1.3 em. for short term survivors and 1 em. for long term survivors, with an Q\'erall median of 1 em. The distribution of patients by the dermal level of il1\'asion is given in Figurc 7: In 78 of the 100 long term survivors the

Stage I Localized melanoma Stage 1/ Metastasis to regional lymph nodes Stage 1/1 Dissaminated melanoma

Figure 3. Distribution of patients br clinical stage of disease.

CUTANEOUS MALIGNANT

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Figure 6. Sizc of primary Icsions (microscopic mcasurcmcnt).

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GROUP I: Differences Statistically Significant Sex - male Duration

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Statistically'significant diffcrenccs in long tcrm and short tcrm sun'il'Ors.

featurcs studied, the information was of a dichotomous nature. The characteristic was cither present or absent (c.g., ulceration), or it fell into one of two catcgories (e.g., mitotic ratc: high or low). This fact

primary tumors extcnded to dermalle\'eI I only. On the other hand, in only 55 of the 100 short tcrm survivors was the primary Icsion contained at Icvel I. For all other clinical and histologic

GROUP II: Differences Not Statistically Significant Origin previous mole Elevation Satellites

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Differcnccs in long tcrm and shon tcrm sun'inns not statistically significant.

CUTANEOUS r-.IALIGNANT MELANOMA-Huvos, SHAll, r-.hKE made it possible to summarize the results compactly in a single table (Figs. 8, 9). The main features already discussed were also included, reduced to binary categories. The overall median was used to divide the data regarding duration and surface dimension into two groups. Clinical stages II and III were grouped together against stage I, and dermal levels of invasion 2 and 3 against levels 0 and I. For all these variables it was sufficient to give only the proportion occurring in one category, since the sum of the two proportions is I. For example, if 67 per cent of the short term survivors were male, we know that 33 per cent were female, and so forth. Figure 8 lists the results for the ten variables for which the observed proportions for the two groups were found to be significantly different at the 1'=.05 level (two sided tests). Corresponding results for the eight variables for which the differences were not statistically significant are shown in Figure 9. The difference in sex distribution of the two groups has been mentioned already; 67 per cent of the short term survivors were male, as compared to 36 per cent of the long term survivors. The difference in survival in the various clinical stages of the disease was to be expected; 45 per cent of short term sun'ivors were in stages II and III, butonly 15 percentof the surviving gl'oup were in stage I I. The duration of changes (63 per cent under six months in one group versus 38 per cent in the other) and the size of the lesion (51 per cent over I em. versus 31 per cent) were also different for the two groups, shorter duration and larger size being associated with short term survival. The likeliest explanation for this seeming paradox lies in the fact that highly anaplastic, rapidly growing lesions may be more lethal than those of slow growth potential. The majority of lesions were pigmented in both groups (97 per cent versus 88 per cent); but a great difference was observed with respect to ulceration (70 per cent versus 24 per cent) and dermal blood "essel or lymphatic invasion (71 per cent versus 12 per cent); the presence of these was associated with short term survival. As expected, a greater percentage of short

term survivors had more deeply invasive tumors (44 per cent versus 22 per cent), whereas less lymphoid response to the tumor was observed in this group (10 per cent versus 38 per cent). As seen in Figure 9, the two groups were similar with respect to the remaining variables. The m~ority of lesions arose from a previous mole (77 per cent versus 71 per cent), were elevated (77 per cent ,'ersus 67 per cent), of predominantly epithelioid cell type (94 per cent versus 90 per cent), high mitotic rate (69 per cent versus 58 per cent), and demonstrated junctional activity (58 per cent ,'ersus 60 per cent) and extensive intracellular pigmentation (95 per tcnt versus 93 per cent). Epidermal hyperplasia was observed in a minority of cases (34 per cent versus 28 per cent), and satellites occurred only rarely (5 per cent versus 8 per cent). The analysis just described ,,'as also carried out with the two groups broken down further, by clinical stage. Perhaps surprisingly, essentially the same pattern was observed for short term and long term survivors in clinical stages I and II as had been seen for the total, or, alternatively, short term survi"ors were similar with respect to thesc variables across the three clinical stage groups, just as long term survivors ,,:ere similar across stages I and I I. That is, except for the distribution by sex discussed earlier, thcre was no evidence of a correlation between the stage of the disease and thc othcr characteristics under study. In an attempt to gain further insight into the data, the correlation coefficient (equivalent to X2 in this case) was computed for each pair of variables. Thc results are shown in Figure lOin the usual format for a correlation matrix. If the association between a pair of variables was not statistically significant at 1'=.05 for either group, thc corresponding entry is O. If it was significant at 1'=.05 for short term survivors, long term survi"ors, or both, the cntries are S, L, or B, respectively. With this many significance tests being carried out, one has to expect a .certain number of spurious correlations. Thus the results should be interpreted .cautiously, with a view toward detecting items of true clinical significance. It is intercsting that the clinical stage

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was not correlatcd with thc duration of changes; nor was it correlated with any other .variable among the short tcrm survivors, and only with sex and elevation among long tcrm survivors. Thc first of thcsc has already bccn discusscd; thc sccond is probably mcaningless. Thc correlations that were prescnt for both survivor groups perhaps warrant bricf comment. Thc lcvcl of invasion vcrsus blood \'cssel or lymphatic invasion can be undcrstood in tcrms of the aggressivencss of the primary lesion, which is expresscd by its ability both to infiltratc dccper into the dermis and to permeate intradel;mal blood vessels and 1}'l11phatics.1. 21. 27 As for mitotic rate versus giant tumor cells, the increascd dcgrec of malignant change is manifcstcd by a brisk mitotic rate and cellular anaplasia, expressed by the prcscncc of numerous giant tumor cclls. On the question of pigmentation \'ersus intracellular pigment production, it was not vcry surprising that the clinically apprcciatcd pigmentation of thc lesion closely correlatcd with thc microscopic evaluation of intracellular pigmentation of

2

tumor cells. Finally, thc qucstion of junctional activity \'ersus cell morphology: the cpithelioid cell type of lesion seemed morc likely to be associated with junctional activity but this relationship is not clear. Similarly, no significance can be attributcd to thc obscrvcd relationship bctween junctional activity and lymphoid response or depth of invasionP' 41 As can be seen in Figure lO,junctional activity was correlated with fivc additional variables, two in the short term survivor group and three in thc group oflong term survi\'ors. Dcrmal depth of invasion revealed some association with a total of ten variables; in addition to the two already discussed, there wcrc fivc correlations restricted to short tcrm survivors and three in the long tcrm group. Elevation of the primary lesion was associatcd with ninc variables, some of which wcrc to be cxpected. Howevcr, the overall clinicopathologic significance of these observcd correlations is not always complctely clear. Of greatest intcrcst, pcrhaps, arc the negativc findings, c.g., the fact that clinical stagc and duration of changc did not seem to havc an ef-

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1- 5 L 0 Duration 2-- 0 0 Stage 3---0 Size 4 Pigmentation 5 Ulceration 6 Depth of invasion 7 Giant tumor cells 8 Lymphoid infiltrate 9 Bloodvessel/lymph.inv.10 11 Origin Elevation 12 13 Satellites Epidermal hyperplasia 14 15 Cell morphology 16 Mitotic rate "ntracellular pigment 17 18 Junctional activity

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5: P <.05 for short term survivors L: P <.05 for long term survivors {B: P < ,05 for both groups

Figure 10. Sunlluary of clinicopathologic correlations found. If the obscrvcd association bctwccn a pair of variablcs was not statistically significant at P = .05 for cith~r long tcrm or short tcrm survivors, thc corrcsponding cntry is O. If it was significant at P = ,05 for short term survivors, long term survivors, or both, the entrics are S, L, or B, respccth·cly.

CUTANEOUS MALIGNANT MELANOMA-Huvos,

feel on other clinicopathologic characteristics of the lesion. The sample size here has been sufficiently large so that it is statistically meaningful to emphasize negati"e results. In a second phase of the data analysis, currently in progress, a combination of these variables is used under various models to estimate prognosis,36

COMMENTS Allen and Spitz2 reported in 1953 that patients with superficial melanomas, i.e., melanomas with minimal dermal infiltration, have a much higher survival rate (74 per cent) compared to the Q\'erall survival rate of 26 per cent for all melanomas. Subsequent studies by Lund and Ihnen 29 and Mehnert and Heard 34 reported comparable results using similar criteria. Wrigllt42 stressed the importance of the degree of cellularity and cellula.' anaplasia, rather than the depth of invasion. These characteristics were confirmed by Allen and Spitz2 in their analysis of superficial lesions, wherein mitoses were decreased in numbers in 72 per cent of the five year survivors, as compared to 53 per cent of those who died. Jones-Williams et al. 24 reported similar results in relation to cellular anaplasia. Breslow5. 6 introduced the concept of tumor volume as a parameter of prognosis whereby he included size, depth of invasion, and elevation of the primary tumor. Clark et al.,7.8 in their extensive studies; reported three major types of melanomas and described the depth of dermal invasion with a direct relationship to prognosis. One of the recent criticisms leveled against the Clark and ~IcGovern method of classifying malignant melanomas by typing the lesion (nodular malignant melanoma, malignant melanoma arising in Hutchinson's melanotic freckle, and superficial spreading melanoma) and establishing the depth of dermal penetration is that it can be carried out properly only by "research" methods unavailable to the average pathology laboratory.7, 8,15,23,25.28.30.35.38 This contention can be safcly refuted, as in

SIIAII,

MIKE

a recent study of I 19 cases of cutaneous malignant melanoma of the head and neck region, which were successfully classified according to this method without using histologic step sectioning of the primary lesionsP' 22 Accurate assessment of the depth of melanoma penetration naturally presupposes an intimate knowledge of the histologic configuration of the different layers of the dermis. There is such a wide variation in the thickness of the epidermis and dermis in the ,'arious regions of the body that depth of invasion should be coupled with the tumor volume to arrive at a more meaningful prognostic parameter. 5. 6 It is also well known that the papillary dermis in which some of the adnexal structures are located is especially variable in thickness and the prccise microscopic structure of the reticular dermis, particularly in obese individuals, is difficult to scparate from the subcutaneous tissue (Icvel 3). Anothcr definitc sourcc of difficulty appears to be the rather arbitrary. allocation of the dermal papillary reticular interface (Clark's level III) cven when ap-

-----

PlaqUJEe~_. . . . . . . ._ ......

..:-

Elevated with cyst

Crater

Figure 11. Silhouelles of lesions in which dermal depth of im·asion is dilTicult to evaluate.

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propriate (e.g., trichrome) special stains are employed. In studying the malignant melanomas, some of them were found to have an exuberant pseudoepitheliomatous growth pattern. Others showed elevation without pendunculation, the so-called verrucous pattern of growth. Some others again showed surface depression (Fig. 11). These odd shapes of tumor growth make the proper evaluation of the dermal depth of invasion very difficult. We have previously reported the need for elective node dissection in stage I melanoma. 19 However, that conclusion was based on the clinical behavior of patients in clinical stage I. The recurrence rates in patients with elective node dissection were much lower than in those whose regional nodes were not dissected. Unfortunately we were unable to obtain the histologic material from the primary tumors in all these patients to further promulgate our studies. However, on the basis of the findings of this present study, we may be justified in drawing the following conclusion. An elective node dissection would seem to be indicated in all patients with stage I melanoma who present with poor prognostic signs, that is, patients who belong to any combination of the following categories: male, primary lesion larger than 1 cm., ulcerated, level of dermal penetration 2 or 3, with dermal lymphatic or blood vessel invasion, and a lack of lymphoid reaction around the primary lesion. If these criteria are used to offer an elective node dissection, one may anticipate better salvage and lower recurrence rates as well as decreased mortality rates. The possibility of arriving at such anticipated results can be seen from the study by ~Iehnert and Heard,34 in which they were able to demonstrate, at least in part, the value of node dissection in lesions involving deeper strata of the dermis. The point made by Dellon and Ketcham 16 in their comment about an article by Conrad 12 is well taken. If truly meaningful results are to be expected with the currently available information, a randomized, well controlled prospective study that considers the histologic criteria as well as the surgical treatment should be undertaken.

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REFERENCES I. Allen, A. C.:

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8. 9. 10. II. 12. 13.

14. 15. 16. 17.

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~lelanocarcinol11as. III The Skin: A Clinicopathological Treatise. I\'ew York, Grune & Stratton, Inc., 1967, pp. 953-1014. Allen, A. C., and Spitz, S.: ~Ialignant melanolna: a clinicopathological analysis of the criteria for diagnosis and prognosis. Cancer, 6: 1-45, 1953. Beardmore, G. L., Quinn, R. L., and Little,j. H.: ~Ialignant melanoma in Queensland: pathology of 105 fatal cutaneous melanomas. Pathology,2:2i7-286, 1970. Bodenham, D. C.: A study of 650 observed malignant melanomas in the South West region. Ann. Roy. CoIl. Surg. Eng., 43:218239,1968. Breslow, A.: Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann. Surg., 172:902-908, 1970. Breslow, A.: A prospecth'e study of tumor thickness and depth of invasion in the prognosis of cutaneous melanoma. (Abstract,) Helsinki, Finland, International Academy of Pathology Congress, 1972. Clark, W. H., Jr., From, L., Bernardino, E. A., and Mihm, ~1. C.: The histogenesis and the biologic behavior of primary human malignant melanoma of the skin. Cancer Res., 29:705726,1969. Clark, W. II., and :\Iihm, :\1. C.: Lentigo maligna and lentigomaligna melanoma. Am. J. Path., 55:39-67, 1969. Cochran, A. J.: Histology and prognosis in malignant melanoma. J. Path., 97:459-468, 1969. Cochran, A. j.: :\Iethod of assessing prognosis in patients with malignant melanoma. Lancet, 2:1062-1064,1968. Cochran, A. J.: Malignant melanoma. A review of 10 years' experience in Glasgow. Cancer, 23: . 1190-1199, 1969. Conrad, F. G.: Treatment of malignant mela'noma, Arch. Surg., 104:587-593, 1972. Das Gupta, T. K.: Current concepts of malignant melanoma. III Surgery Annual. I\'ew York, Appleton-Century-Crofts, 1970-197 I, pp. 183-206. Davis, 1\'. C., Herron, j. j., and :\IcLeod, G. R.: :\Ialignant melanoma in Queensland: analysis of 400 skin lesions. Lancet, 2 :407-410, 1966. DeCosse,j.J., and ~lcl\'eer, G.: Superficial melanoma. Arch. Surg., 99:531-534, I!J69. Dellon, A. L., and Ketcham, A. S.: Surgical treatment of stage I melanoma. Arch. Surg., 105: 738-739, 1973. Donnellan, :\1. J., Seemayer, T., Huvos, A. G., Mike, V., and Strong, E. W.: Clinicopathologic study of cutaneous melanoma of the head and neck. Am. j. Surg., 124:450-455, 1972. Fortner, J. G., Booher, R. J., and Pack, G. T.: Results of groin dissection for malignant melanoma in 220 patients. Surgery, 55:485-494, 1964. Goldsmith, H. S., Shah, j. 1'., and Kim, D. H.: Prognostic significance of lymph node dissection in the treatment of malignant melanoma. Cancer, 26:606-609, 1970. Grinspan, D., Abulafia, J., and Bozza, 1\'. 0.:

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