2361

Ultra-Late Recurrence (15 Years or Longer) ofCutaneous Melanoma

BACKGROUND. Melanoma can remain clinically quiescent for decades before re-Hensin Tsao, M.D., Ph.D.1

gional or distant recurrence appears. This protracted disease free interval chal-A. Benedict Cosimi, M.D.2

lenges the concept of a ‘‘cure’’ for melanoma.Arthur J. Sober, M.D.1

METHODS. To understand this prolonged dormancy better, the authors retrospec-

tively studied patients who developed recurrent melanoma 15 years or longer after1 Department of Dermatology, Harvard Medicaltheir initial diagnosis (‘‘ultra-late’’ recurrence). These cases were identified fromSchool, Massachusetts General Hospital, Bos-

ton, Massachusetts. 2766 melanoma diagnoses available in the Cancer Registry at the Massachusetts

General Hospital (MGH). Histologic features of the primary lesion were also in-2 Department of Surgery, Massachusetts Gen-cluded when possible.eral Hospital, Boston, Massachusetts.RESULTS. Twenty cases were retrieved from the MGH database. There were equal

numbers of women and men, although women were younger at the time of initial

diagnosis (mean age of women: 29.8 years vs. 43.0 years for men). No patients had

more than one primary cutaneous melanoma. The trunk was the most common

primary site (35%), although there was no predominant anatomic localization. The

average disease free interval was 17.3 years for women, 20.0 years for men, 18.1

years for patients with regional recurrence, and 19.0 years for patients with distant

metastases. Distant recurrence was the most common type of recurrence (50% of

women and 60% of men). The estimated probability of survival (5 years after

recurrence) was 0.8 for regional disease and 0.2 for distant disease. With the avail-

able histologic records, it appears that almost all tumors were Clark Level III or

IV with thicknesses ranging from 0.8–2.3 mm. In contrast to the published cases,

this study did not find that women with lower extremity melanomas were at higher

risk for developing ultra-late recurrence.

CONCLUSIONS. Ultra-late recurrence of melanoma, although uncommon, can occur

in any patient without identifiable risk factors. Because many prognostically favor-

able melanomas (thin melanomas on extremities) can recur after prolonged disease

free intervals, the possibility of delayed recurrence remains and must be kept in

mind. Cancer 1997;79:2361–70. q 1997 American Cancer Society.

KEYWORDS: melanoma, ultra-late, delayed, recurrence.Supported in part by the Marion Gardner Jack-son Trust, Bank of Boston, Trustee.

Although most melanomas recur within 10 years of primary diagno-sis, numerous reports and case series of late recurrence (beyondThe authors wish to thank Carol Venuti for as-

10 years) now exist in the literature. An estimated 0.98–6.7% of mela-sistance with the Massachusetts General Hospi-nomas recur after ¢10 years of disease free survival.1–6 For manytal Cancer Data Registry.patients and practitioners, guidelines for melanoma monitoring be-

Address for reprints: Arthur J. Sober, M.D., De- yond 10–15 years are unstructured or nonexistent because patientspartment of Dermatology, Bartlett Hall 622, are frequently considered ‘‘cured’’ after such a protracted disease freeMassachusetts General Hospital, Boston, Mas- period.sachusetts 02114.

In this article, the authors report a group of patients who experi-enced their first recurrence of melanoma ¢ 15 years after their initialReceived October 9, 1996; revisions receiveddiagnosis. They term this phenomenon ‘‘ultra-late’’ recurrence andJanuary 6, 1997, and February 18, 1997; ac-

cepted February 18, 1997. review other similar cases described in the literature.

q 1997 American Cancer Society

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2362 CANCER June 15, 1997 / Volume 79 / Number 12

MATERIALS AND METHODS survivors). The remaining 1756 patients either diedwithin 15 years of their diagnoses or had not yetAll data presented are derived from the Cancer Regis-

try at the Massachusetts General Hospital (MGH). Be- reached their 15th year of follow-up at the time ofanalysis.tween 1960 and 1996, 2766 melanoma patients (1454

males and 1312 females) were registered. A retrospec- All primary melanomas were cutaneous in origin(i.e., no ocular or mucosal melanomas); Case 12 in-tive computer-aided search identified 20 patients who

had their first recurrence ¢ 15 years after their initial volved the right eyelid skin. The precise ethnic compo-sition of the study group was unknown. There werediagnosis. All patients had histologic confirmation of

their recurrent disease whereas only 13 patients had equal numbers of men and women in the current se-ries (Table 2). However, women were younger thanpathologic records or slides available from their pri-

mary diseases. The other seven patients had docu- men at the time of their primary disease. The averageage for women at initial diagnosis was 29.8 yearsmentation of primary disease through original hospital

records. The authors did not reexamine the original whereas the average age for men was 43.0 years. Inthe current series, primary melanomas occurred mostglass slides of the primary melanomas. Because many

primary diagnoses were rendered at community hos- commonly on the trunk (7 of 20) followed by the upperextremities (6 of 20). No patients in the current seriespitals in the 1950s and early 1960s, the original speci-

mens have since been destroyed. However, all primary had a documented second primary cutaneous mela-noma.diagnoses were documented through records from the

pathology department or the hospital. Distant metastasis was the most common type ofrecurrence (55% of cases) followed by regional metas-Published information on patients with recurrent

melanoma ¢ 15 years after their primary diagnoses tasis (40%); one patient had a local recurrence. Menwere at a slightly greater risk for distant metastaseswere also compiled from a MEDLINE search between

1966–1996. For patients in the current series and the compared with women (60% vs. 50%), whereas womenwere more likely to have regional disease comparedliterature, survival analysis only included those indi-

viduals with a documented status and duration of fol- with men (50% vs. 30%). The average disease free in-terval was 17.3 years for women (range, 15–20 years),low-up. Only one type of recurrence was assigned to

a patient and this was defined by the highest stage of 20.0 years for men (range, 15–27 years), 18.1 years forpatients with regional recurrence (range, 15–20 years),disease, i.e., patients with both regional and distant

metastases were considered to have distant disease. and 19.0 years for patients with distant metastases(range, 15–27 years). As expected, patients with re-Survival curves were estimated using the Kaplan–

Meier method.7 gional metastases had better prognoses than thosewith distant disease. The estimated probability of sur-References to staging is based on the current

American Joint Committee on Cancer for staging: vival 5 years after recurrence was 80% for patients withregional recurrence and 20% for patients with distantStage I: °1.50-mm thick, no lymph node or distant

metastases; Stage II: ú1.50-mm thick, no lymph node metastases (Fig. 1A). One patient (Case 2) was alive ú4 years after lung metastases and another patientor distant metastases; Stage III: regional lymph node

and/or in-transit metastases or lymph node metasta- (Case 15) was alive ú 6 years after bone, adrenal, andgastrointestinal metastases.ses of unknown primary, no distant metastases; and

Stage IV: distant metastases. Pathology records of the primary lesion wereavailable for only a limited number of patients in theMGH series (Table 1). Ten patients had Clark Level IIIRESULTS

The authors identified 20 patients who had their first or IV invasion; one melanoma arose in the subcutisof a giant congenital mole (Case 2); and one melanomarecurrence ¢ 15 years after their initial diagnosis (Ta-

ble 1). Of 2766 total melanoma patients, only 212 are was reported to have invaded ‘‘at least the superficialdermis.’’ Case 18 had a Level II melanoma; however,known to have survived ¢ 15 years from diagnosis

and an additional 798 patients had the diagnosis of neither the thickness nor the presence of a verticalgrowth phase was determined and the specimen wasmelanoma for ¢15 years but follow-up information

was incomplete. Assuming that these 798 incomplete unavailable for review. Tumor thickness ranged from0.8–2.3 mm.follow-ups were all living and experienced no ultra-

late recurrence, the maximum number of patients who Thirty-six cases of recurrence after¢15 years werefound in various reports from the literature (Table 3).potentially survived ¢15 years after diagnosis was

1010 (212 known plus 798 assumed). Thus, the mini- The study data differed from the reported observationson several points. In contrast to the authors’ findings,mum rate of ultra-late recurrence can be calculated

to be 2.0% (20 cases divided by a pool of 1010 potential 27 of the 36 published cases (75%) were women. Al-

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Ultra-Late Recurrence of Cutaneous Melanoma/Tsao et al. 2363

TABLE 1MGH Patients with Ultra-Late (¢15 Years) Recurrence

Age (yrs) LocationPrimary Gender Primary Path DFI (yrs) Recurrence Follow-up

39 M L chest CM (NOS) 26 Dist: lung DOD (7 mos)35 M L post neck SubQ MMa 27 Dist: lung

29 Reg: supraclavicular LN NED (48 mos)23 F L scapula CM (NOS) 21 Dist: subcutaneous

ELND neg 22 Dist: brain DOD (6 mos)29 F L chest CM (NOS) 15 Dist: lung, skin, adrenal

ELND neg brain DOD (9 mos)27 F R forearm SSM (III/0.8)b 16 Dist: brain, lung, adrenal DOD (1 mo)32 M L arm CM (NOS) 18 Dist: lung, liver, bone DOD (10 mos)34 F R thigh SSM (III/0.82) 20 Reg: R inguinal LN NED (43 mos)33 F L scapula Nod (III) 15 Reg: L axillary LN DOD (10 mos)

ELND neg49 M L shoulder CM (III) 15 Dist: GI, lung

ELND neg 16 Dist: brain, bone, scalp DOD (24 mos)14 F R scalp Nod (IV) 17 Reg: R supraclavicular LN NED (120 mos)44 F L arm CM (NOS) 16 Dist: pancreas DOD (8 mos)37 M R eyelid CM (IV) 20 Dist: lung, subQ, skin ?44 M L thigh CMc 19 Reg: L inguinal LN NED (132 mos)

ELND neg39 M Midback CM (NOS) 18 Reg: R axillary LN NED (120 mos)38 F R thigh CM (NOS) 16 Dist: bone, adrenal, GI

ELND neg 17 Dist: lung19 Dist: kidney NED (72 mos)

57 M L upp arm Nod (III/2.2) 19 Dist: skin Dead/stroke (33 mos)ELND pos

40 M R abdomen SSM (III/0.95) 20 Local skin NED (24 mos)32 F R thigh SSM (II) 20 Reg: R inguinal LN AWD (2 weeks)d

44 M L arm SSM (III–IV/2.3) 18 Reg: L axillary LN AWD (4 weeks)d

24 F R arm SSM (III/1.2) 18.5 Reg: R axillary LN ?

MGH: Massachusetts General Hospital, M: male; F: female; Path: pathology; L: left; R: right; post: posterior; DFI: disease free interval; ELND: elective lymph node dissection; neg: negative; pos: positive; CM:

cutaneous melanoma; NOS: not otherwise specified; Nod: nodular; SSM: superficial spreading melanoma; subQ: subcutaneous; mm: melanoma; Dist: distant recurrence; Reg: regional recurrence; LN: lymph node;

DOD: dead of disease; NED: alive with no evidence of disease; AWD: alive with known disease; GI: gastrointestinal.a Patient had a subcutaneous melanoma arise within a large garment type congenital nevus.b Data in parentheses represents (Clark Level/thickness in mm).c Specimen unavailable. Pathology report describes involvement of at least the superficial dermis; however, thickness and depth were not given.d Given short duration of follow-up, patients were not used in survival analysis.

though these women were also younger than their not the tendency for women to recur with regionalinvolvement. From the literature, 64% of patients withmale counterparts at the time of their primary diagno-

sis (36.6 years vs. 41.0 years), the disparity in age was lower extremity lesions had regional recurrencewhereas all patients with truncal melanomas had dis-not as great as that observed with patients in the cur-

rent study. Another major difference was the anatomic tant metastases.Approximately 39% of all previously reportedsite of the primary lesion: the majority of patients in

the published cases had their lesions on the lower cases of ultra-late recurrence (14 of 36) were lowerextremity melanomas with regional recurrence. Thisextremities (61%). This difference most likely reflects

the increased proportion of women with melanomas was the largest subgroup, with women comprising86% of these cases (12 of 14). In the current study,on their extremities.

In the literature, regional recurrence was the most three women with lower extremity primaries recurredregionally.common type (47%) followed by distant (42%) and

local (8%). However, when grouped by gender, 59% of The disease free intervals, as categorized by ageand type of recurrence, were similar between the cur-the women had regional disease and 87% of the men

had distant disease. The current study data support rent series and published cases (approximately 18–20years). Again, women recurred slightly earlier thanthe tendency for men to recur with distant disease but

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TABLE 2Comparison of MGH Study with Published Cases

MGH study Literature MGH study LiteratureParameter (n Å 20) (n Å 36) Parameter (n Å 20) (n Å 36)

GenderWomen 10 (50%) 27 (75%)Men 10 (50%) 8 (22%)

Age at primary diagnosis (yrs)Womenõ20 1 (10%) 1 (4%)20–30 4 (40%) 9 (33%)31–40 4 (40%) 9 (33%)41–50 1 (10%) 4 (15%)ú50 0 4 (15%)

Mean (range) 29.8 (14–44) 36.6 (15–60)Menõ20 0 020–30 0 031–40 6 (60%) 5 (63%)41–50 3 (30%) 0ú50 1 (10%) 3 (38%)Mean (range) 43.0 (32–57) 41.0 (33–54)

Sites of primary tumorHead and neck 3 (15%) 2 (6%)Trunk 7 (35%) 7 (19%)Lower extrem 4 (20%) 22 (61%)Upper extrem 6 (30%) 4 (11%)Choroid 0 1 (3%)

Type of recurrenceTotal

Local 1 (5%) 3 (8%)Regional 8 (40%) 17 (47%)Distant 11 (55%) 15 (42%)

By genderWomen

Local 0 3 (11%)Regional 5 (50%) 16 (59%)Distant 5 (50%) 8 (30%)

MenLocal 1 (10%) 0Regional 3 (30%) 1 (13%)Distant 6 (60%) 7 (88%)

By site of primaryHead and neck

Local 0 1 (50%)Regional 1 (33%) 1 (50%)Distant 2 (67%) 0TrunkLocal 1 (14%) 0Regional 2 (29%) 0Distant 4 (57%) 7 (100%)

Lower extremLocal 0 2 (9%)Regional 3 (75%) 14 (64%)Distant 1 (25%) 6 (27%)

Upper extremLocal 0 0Regional 2 (33%) 3 (75%)Distant 4 (67%) 1 (25%)

Mean disease-free interval (yrs) (range)Gender

Women 17.3 (15–20) 18.5 (15–26)Men 20.0 (15–27) 20.1 (15–35)

Type of recurrenceLocal 20 (n Å 1) 18.7 (15–22.8)Regional 18.1 (15–20) 20.4 (15–26)Distant 19.0 (15–27) 19.0 (15–35)

MGH: Massachusetts General Hospital; Extrem: extremity.

men (18.2 years vs. 20.1 years). The estimated proba- several trends. Except for four cases invasive to LevelII (one in the current series and three in the literature)bility of survival 5 years after recurrence was approxi-

mately 40% for the published regional disease and 20% and two cases invasive to at least ‘‘superficial dermis,’’all other informative primary melanomas exhibitedfor the reported distant disease (Fig. 1A). When the

current study data were combined with those re- Clark Level III or IV invasion. For all ultra-late recur-rences, no primaries deeper than Level IV or thickerported, the overall 5-year survival was approximately

55% after regional recurrence and approximately 20% than 2.5 mm have been described.after distant recurrence (Fig. 1B).

Pathologic records of the primary melanomas DISCUSSIONDelayed, or late, recurrence of melanoma is often de-most often listed Clark Levels and/or thickness. Al-

though several series included additional features fined as recrudescence of disease ¢ 10 years after ini-tial diagnosis and treatment. The incidence of delayed(e.g., mitoses, host response, and ulceration), the ac-

tual number of ultra-late cases with these expanded recurrence has been reported to range from 0.93%4 to6.7%.2 In the largest series to date, Crowley and Seiglerdescriptions were too few for meaningful analysis. No

series included tumor growth phase descriptions. reported an incidence of 2.4% based on 7104 mela-noma patients seen at the Duke University MelanomaWhen the current series was combined with the

reported cases, the limited pathology data revealed Clinic.5

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Ultra-Late Recurrence of Cutaneous Melanoma/Tsao et al. 2365

FIGURE 1. (A) Kaplan–Meier esti-mates of survival after ultra-late recur-rence based on authors’ data (Massa-chusetts General Hospital (MGH) (–l –) abbreviations: loc: local recur-

rence; reg: regional recurrence; dist:distant recurrence) and data publishedin the literature (LIT (– / –) abbrevi-ations: loc: local recurrence; reg: re-gional recurrence; dist: distant recur-rence). The longest length of survivalis indicated in parentheses next to theappropriate curve. (B) Kaplan–Meierestimate of survival after ultra-late re-currence based on all data. The lon-gest length of survival is indicated inparentheses next to the appropriatecurve.

As data from various registries have accumulated, No difference was found between women andmen in their risk for ultra-late recurrence. In two oflong term follow-up information has become avail-

able. Using the database from the MGH Cancer Regis- the largest series of patients with late recurrence (¢10years), neither the Sydney Melanoma Unit (SMU)3 nortry and Pigmented Lesion Clinic, the authors have

identified 20 patients who had their first recurrence, the Duke University Melanoma Unit5 found a signifi-cant difference in recurrence by gender. Furthermore,on average, 19 years after their primary diagnosis. In

defining ‘‘ultra-late’’ recurrence, the authors selected in the Duke series, the authors state that approxi-mately equal numbers of female and male patientsa subset of patients with at least 15 years of disease

free survival. Of 2766 melanoma patients seen MGH recurred between 15–25 years (i.e., ultra-late recur-rence). However, when individual cases of ultra-latesince 1960, the minimum estimate of the recurrence

rate after surviving at least 15 years is 2.0%. recurrence (¢15 years) were extracted from the litera-

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TABLE 3Reports of Cases with Ultra-Late Recurrence

LocationRef Age Gender primary Path DFI (yrs) Recurrence Follow-up

21 35 M Chest CM (NOS) 35 Dist: visceral DOD (18 mos)47 F L calf CM (II/1.9)a 18 Local DOD (23 mos)

Reg: lymph node22 29 F Upper arm SSM (IV/1.6) 15.7 SubQ (? in transit)c DOD (18 mos)

51 M Back Nod (IV/1.5) 16.4 Distant DOD (4 mos)27 F Upper arm SSM (IV/0.7) 17.9 Reg: lymph node DOD (11 mos)39 F Face LMM (II/0.4) 18.2 Local NED (5 mos)

9 31 F L leg CM (NOS) 26 Reg: in transit NED (276 mos)25 F R leg CM (NOS) 17.5 Dist: skin AWD (4 mos)

3 28 F Leg Nod (1.6) 17 Dist: lung NED (175 mos)52 M Chest SSM (0.3) 16 Dist: disseminated DOD (1 mos)29 F Leg CM (NOS) 19 Reg: lymph node DOD (71 mos)34 M Back CM (NOS) 24 Dist: skin DOD (18 mos)33 M Back SSM (2.1) 16 Dist: skin DOD (11 mos)33 M Leg SSM (2.1) 19 Reg: lymph node NED (63 mos)54 M Back CM (NOS) 19 Dist: lymph node DOD (24 mos)39 F Leg SSM (2.2) 22 Reg: lymph node NED (160 mos)51 F Face CM (NOS) 17 Reg: lymph node NED (11 mos)37 F Ankle SSM (1.4) 20 Reg: in transit NED (34 mos)

4 39 F L shin SSM (II/1.2) 15.3 Local DOD (Ç18 mos)Reg: in transit

2 39 F L leg CM (NOS) 16 Reg: lymph node DOD (37 mos)39 F L leg Nod (III/2.5) 23 Reg: in transit, lymph node DOD (31 mos)24 F R leg Nod (III/1.7) 21 Reg: lymph node NED (56 mos)22 F L forearm CMb 20 Reg: lymph node NED (43 mos)

23 30 F L shin SSM (IV/1.2) 15.3 Dist: skin DOD (Ç18 mos)24 60 F Leg Nod (IV) 16 Dist: visceral DOD (24 mos)

36 M Thigh SSM (IV) 15 Dist: skin NED (60 mos)30 F Hand SSM (III) 15 Dist: visceral DOD (6 mos)

25 45 F L leg SSM (III) 18 Reg: in transit NED (õ12 mos)42 F Sacral SSM (IV) 18 Reg: lymph node AWD (õ24 mos)

Dist: skin6 Included in the current series26 15 F Leg CM (NOS) 26 Dist: widespread DOD (?)27 40 F R Leg CM (NOS) 15 Local ?

Reg: lymph node28 ? Leg CM (NOS) 20 Reg: lymph node NED (96 mos)29 52 F Heel SSM (III/1.35) 16.4 Reg inguinal LN DOD (18 mos)

33 F Leg CM (NOS) 15 Local NED (60 mos)53 F Leg SSM (IV/ú1.85) 22.8 Local NED (216 mos)44 F Eye Choroidal M 19 Dist: liver DOD (5 mos)

5 49 patients with ú16 years of disease free interval. However, individual information not available.

Path: pathology; M: male; F: female; L: left; R: right; DFI: disease free interval; CM: cutaneous melanoma; NOS: not otherwise specified; Nod: nodular, SSM: superficial spreading melanoma; LMM: lentigo maligna

melanoma; subQ: subcutaneous; Dist: distant recurrence; Reg: regional recurrence; LN: lymph node; in transit: in-transit metastases; DOD: dead of disease; NED: alive with no evidence of disease; AWD: alive

with disease.a Data in parentheses presents (Clark Level/thickness in mm).b Report describes involvement of at least the superficial dermis; however, thickness and depth were not given.c Recurrence type unclear from report and therefore not assigned.

ture, the cumulative data suggested an increased risk seven cases were premenopausal women. Radermanet al. reviewed the literature in 1986 and found thatfor women. The report of ten men from the current

series more than doubles the number of known male 89% of cases of late recurrence were premenopausalwomen.8 Levy et al.9 contributed 4 cases of youngpatients with ultra-late recurrence described in the

literature. Briele et al. first noted women as being at women with late recurrence and found that 64% ofpublished cases were women. Much of the speculationgreater risk for late recurrence2 because six of their

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Ultra-Late Recurrence of Cutaneous Melanoma/Tsao et al. 2367

on the predominance of women in late recurrence ports of ultra-late recurrence (¢15 years) (Tables 2and 3) show comparable rates (approximately 45%)disease is based on the well documented survival ad-

vantage of women with melanoma10 and the idea that for distant and regional recurrence.3,5 Thus, a higherpercentage of patients in the current study recurredgonadal hormones may confer a resistance to dis-

ease.2,8 A major reason for better survival in women with distant disease. Because most of the reported dataoriginated from melanoma units in surgical depart-may be the prognostically favorable location of mela-

nomas in women (i.e., lower extremities) rather than ments, a referral bias may exist. Surgical centers tendto attract patients with recurrent disease who havethe endocrinologic milieu. Furthermore, if more

women than men are alive at 15 years, more women lymph node disease; therefore, their pool of regionalrecurrent melanomas would be larger than that of ancan be expected to experience ultra-late recurrence.

However, this selection bias cannot explain the re- oncology-based center. Furthermore, the impact ofelective lymph node dissection (ELND) on subsequentported 3-fold difference in ultra-late recurrence (27

women vs. 8 men) because the ratio of women to men disease has not been clarified. In terms of overall sur-vival, Balch et al.11 documented a benefit with ELNDalive at 15 years is only approximately 1.2 to 1.3.10

Delayed recurrence may be an entity mechanistically whereas Sim et al.12 and Veronesi et al.13 failed to re-produce these findings in prospective trials. However,distinct from survival and therefore conclusions drawn

from survival data may not be relevant. Finally, be- does the early removal of a draining lymph node basinincrease the risk for distant metastases in patients whocause most of the literature is comprised of case com-

munications, a reporting bias may explain the appar- do experience delayed recurrence? Five of 7 of theultra-late recurrence patients in the current study whoent excess of female patients. Pooled data from various

databases should provide a more accurate delineation underwent initial ELND developed distant diseasewhereas 7 of 10 late recurrence (ú10 years) patientsof the late and ultra-late recurrence phenomena.

Approximately 72% of the reported ultra-late cases who underwent ELND at SMU3 and 9 of 17 late recur-rence patients who underwent ELND at Duke5 subse-had primary lesions on extremity sites whereas 50%

of the primary lesions in the current study were found quently developed distant metastases. Because four offive of the ELND patients in the current study withon the extremities. Six of 10 female patients in the

current study (60%) had lesions on extremity sites distant metastases had no lymph node involvement atthe time of surgery, the tumor may have metastasizedwhereas 6 of 10 male patients (60%) had lesions on

axial sites. For late recurrence, neither Crowley and hematogenously to a systemic site early in the diseasewithout regional involvement. Alternatively, the pri-Seigler5 nor Shaw et al.3 described a predominant ana-

tomic site; however, the latter group did find a propen- mary melanoma may have drained to an unsampledlymph node group or may have already spreadsity for women to develop extremity lesions and men

to develop axial lesions. This gender-biased distribu- through the lymphatics prior to ELND. Finally, resid-ual undissected lymph nodes may be a source for sub-tion, which has been described for all melanomas10

regardless of recurrence, probably explains the greater sequent metastases.Men have a higher risk of distant metastases bothproportion of lower extremity lesions in the published

literature. in the current series and the reported cases (60% dis-tant disease in the current series and 88% distant dis-In the current series, the average age at time of

diagnosis was 29.8 years for women and 43 years for ease reported). Balch et al. reported that 63% of pa-tients who present with Stage I and II disease andmen. When the published data were examined, the

difference in age between women and men was less develop Stage IV disease have had primaries on axialsites.10 Because 6 of 10 men (60%) from the currentdramatic (7 years vs. 13 years), but the trend was main-

tained. In the current study, older patients may be series and 6 of 8 men (75%) from the previously re-ported cases had axial lesions, the high rate of distantselected against given the long delay to recurrence.

Because the average disease free interval in the current metastases in men may be attributable to the axiallocation of their primaries. Similarly, Shaw et al. foundstudy was approximately 19 years, a significant pro-

portion of patients who develop their primary mela- that 61% of the men in their study with late recurrencehad distant metastatic disease and only 1 man devel-noma at the reported median age (44 years for women,

48 years for men10) would probably not survive this oped disseminated disease from an extremity primarytumor.3interval and die from other causes.

Approximately 55% of the patients in the current As expected, both the current study data and thepublished data show that local recurrence carries thestudy recurred with distant disease whereas another

40% had regional recurrence. However, published se- best prognosis followed by regional and then distantmetastases. The estimated survival 5 years after recur-ries of late (¢10 years) recurrence and published re-

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2368 CANCER June 15, 1997 / Volume 79 / Number 12

rence was 80% for the patients in the current study In 1989, Clark et al.16 reported that only melano-mas in a vertical growth phase had metastatic poten-with ultra-late regional recurrence and 20% for pa-

tients with ultra-late visceral recurrence. When data tial. In that study, approximately 20% of melanomasin Level II and 96% of melanomas in Levels III, IV, orfrom the current series and previously reported cases

are combined, the estimated 5-year survival after re- V exhibited a vertical growth phase. Therefore, almostall melanomas deeper than Level II have a verticalcurrence was approximately 55% for ultra-late regional

recurrence and approximately 20% for ultra-late dis- growth phase and can potentially metastasize. Be-cause most of the diagnoses relevant to this study weretant disease (Fig. 1B). Several studies have addressed

survival after initial recurrence of cutaneous mela- made before radial and vertical growth phase tumorswere described, the authors can only use Clark Levelsnoma. A 1991 study from MGH found that in patients

with soft tissue, lymph node, and visceral recurrence as a guide. All but four of the informative ultra-latecases (Case 18 in the current series and three of the(1–218 months after surgical therapy for clinical Stage

I cutaneous melanoma), the 5-year postrecurrence published cases) (Tables 1 and 3) were Level III andIV melanomas. In the Duke series, 12% of their latesurvival rates were 49%, 38%, and 11%, respectively.14

Balch et al. found that 30–40% of patients with delayed recurrent melanomas were from Level II primaries;however, vertical growth phase was not assessed inlymph node involvement and 5% of patients with vis-

ceral recurrence were alive 5 years after recurrence these tumors. The Level II melanomas that do recurmay represent the subgroup of Level II tumors thatregardless of the disease free interval.10 With regard to

survival among patients with early versus late recur- exhibit a vertical growth phase. Although less likely,radial growth phase melanomas may theoretically me-rence, Pearlman et al. performed a case–control study

of 35 patients with early recurrence (median 26.7 tastasize but remain clinically dormant for muchlonger periods.months) and 35 patients with late recurrence (median,

127 months) and found no statistically significant dif- Levy et al. found a significant difference betweenthe thickness of early recurrent and late recurrent dis-ference in prognoses for regional and distant metasta-

ses.15 However, the current study data suggest that ease (3.4 mm vs. 1.9 mm).9 From a purely statisticalperspective, there appears to be a ‘‘whittling down’’a subgroup of patients with prolonged disease free

intervals may have a better prognosis and longer than phenomenon in that patients with thicker lesions re-cur earlier, thereby leaving patients with thinner le-expected post recurrence survival. One component of

this apparent survival advantage may the combination sions to recur later. Slingluff et al.1 found that the 5-year risk of recurrence for melanomas measuring 4.0of aggressive surgical eradication of metastatic disease

and adjunctive chemotherapy/immunotherapy. Mar- mm was approximately 75% the first year after diagno-sis but decreased to 30% after 5 years of disease freekowitz et al. found that up to 18% of visceral recur-

rence patients treated at MGH with intensive combi- survival. At this 5-year disease free point, the risk ofrecurrence for melanomas 0.75–4.0-mm thick wasnation modalities were alive 10 years after their initial

recurrence.14 In other words, some patients who are also approximately 30%. Therefore, with time, thinnerlesions have a risk of recurrence similar to thicker le-able to live with metastatic disease will continue to

live after gross eradication of disease. As the authors’ sions.1 Day et al. postulated that the initial metastasesfrom most lethal melanomas occur at a threshold tu-database and databases at various centers expand, fur-

ther studies on the prognosis of patients with ultra- mor volume/thickness and the disease free intervalrepresents the growth period of the tumor in the ec-late recurrence will undoubtedly be needed.

Retrieving archival pathology for this study was topic site; therefore, the smaller the initial tumor me-tastasis, the longer the delay to clinical detection ofdifficult given the lengthy interval. Because MGH

serves as a referral center, many primary specimens recurrent disease.17 However, from overall experience,ultra-late recurrence can occur in patients with thinwere generated from community hospitals and de-

stroyed after 20 years. However, inclusion in the study melanomas (õ1.0-mm thick). Melanomas can appar-ently metastasize at very small tumor volumes.required the confirmation of metastatic disease and

specimen or records of primary pathology. Of cases It is unclear what biologic events occur during thelengthy disease free interval. If the melanoma itself iscollected from the literature, all ultra-late recurrence

melanoma patients had primary tumors measuring inherently unaggressive, one would expect better thanpredicted survival after recurrence. The current studyõ2.5 mm. As expected, most primaries exhibited Level

III and IV invasion. The current study results are con- data suggest that ultra-late regional recurrence mayhave a better prognosis compared with early regionalsistent with the Duke series which found 83% of their

cases measured õ3.0 mm, with 83% in Levels III and recurrence; however, more accurate delineation of theprognosis requires more patients. Alternatively, meta-IV.5

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Ultra-Late Recurrence of Cutaneous Melanoma/Tsao et al. 2369

static melanoma may be suppressed by the immune ing on overall survival after diagnosis or recurrencestill remains to be established.system only to escape immunosurveillance after many

years. Greene et al. found an excess of melanoma inrenal transplant recipients on immunosuppression.18 REFERENCES

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