Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Elizabeth C Paver; Tasnia Ahmed; Hazel Burke; Robyn P M Saw; Jonathan R Stretch; Andrew J Spillane; Kerwin F Shannon; Ismael A Vergara; David E Elder; Serigne N Lo; John F Thompson; Richard A Scolyer

doi:10.1001/jamadermatol.2023.4193

. 2023 Nov 1;159(12):1359–1367. doi: 10.1001/jamadermatol.2023.4193

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Elizabeth C Paver ^1,^2,³, Tasnia Ahmed ¹, Hazel Burke ¹, Robyn P M Saw ^1,^5,⁶, Jonathan R Stretch ^1,^5,⁶, Andrew J Spillane ^1,⁵, Kerwin F Shannon ^1,^5,⁶, Ismael A Vergara ^1,^4,⁵, David E Elder ⁷, Serigne N Lo ^1,^4,⁵, John F Thompson ^1,^5,⁶, Richard A Scolyer ^1,^2,^4,^5,^✉

¹Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia

²Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia

³Department of Anatomical Pathology, The Canberra Hospital, Canberra, Australian Capital Territory, Australia

⁴Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia

⁵Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia

⁶Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia

⁷Department of Dermatology and Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia

Accepted for Publication: September 1, 2023.

Published Online: November 1, 2023. doi:10.1001/jamadermatol.2023.4193

^✉

Corresponding Author: Richard A. Scolyer, MD, Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia (richard.scolyer@health.nsw.gov.au).

Author Contributions: Drs Lo and Paver had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Paver, Elder, Lo, Scolyer.

Acquisition, analysis, or interpretation of data: Paver, Ahmed, Burke, Saw, Stretch, Spillane, Shannon, Vergara, Lo, Thompson, Scolyer.

Drafting of the manuscript: Paver, Ahmed, Burke, Vergara, Scolyer.

Critical review of the manuscript for important intellectual content: Paver, Ahmed, Saw, Stretch, Spillane, Shannon, Vergara, Elder, Lo, Thompson, Scolyer.

Statistical analysis: Paver, Ahmed, Vergara, Lo, Scolyer.

Administrative, technical, or material support: Saw, Stretch, Shannon, Scolyer.

Supervision: Scolyer.

Conflict of Interest Disclosures: Dr Saw reported personal fees from Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, and QBiotics; and support from the Melanoma Institute Australia, outside the submitted work. Dr Vergara reported research and salary support from the Melanoma Institute Australia during the conduct of the study and a patent (No. US11145412B2) outside the submitted work. Dr Thompson reported grants from the Australian National Health and Medical Research Council during the conduct of the study; advisory fees and/or honoraria/travel from Bristol Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, and Provectus; and nonfinancial support from Novartis, all outside the submitted work. Dr Lo reported support from the Melanoma Institute Australia outside the submitted work. Dr Scolyer reported grants from the Australian National Health and Medical Research Council; and personal fees from MetaOptima, F. Hoffmann-La Roche, Evaxion, Provectus, QBiotics, Novartis, Merck Sharp & Dohme, NeraCare, Amgen, Bristol Myers Squibb, Myriad Genetics, and GlaxoSmithKline, all outside the submitted work. No other disclosures were reported.

Data Sharing Statement: See Supplement 2.

Additional Contributions: The authors gratefully acknowledge the support of the B. B. and A. Miller Foundation, The Ainsworth Foundation, and our colleagues at the Melanoma Institute Australia and the Royal Prince Alfred Hospital.

^✉

Corresponding author.

PMCID: PMC10620673 PMID: 37910123

Key Points

Questions

Should primary cutaneous melanomas with features suggestive of imminent ulceration be classified as ulcerated or as nonulcerated, per the American Joint Committee on Cancer (AJCC) definition?

Findings

This retrospective case-control study of 340 patients with melanoma found that tumors with incipient ulceration were significantly thicker and more mitotically active than nonulcerated controls, and significantly more likely to have lymphovascular invasion, positive sentinel nodes, and satellite lesions.

Meaning

These findings suggest that primary melanomas with incipient ulceration may be more biologically aggressive than nonulcerated melanomas, and that pathologists should note the presence of incipient ulceration until a future AJCC guideline clarifies the classification.

Abstract

Importance

Ulceration represents a key feature in cutaneous melanoma, contributing to staging according to the current American Joint Committee on Cancer (AJCC) system. However, cases with incipient ulceration do not quite fulfill the AJCC definition of ulceration and are consequently classified as nonulcerated, presenting interpretive difficulty for pathologists. The prognostic implication of incipient ulceration is uncertain.

Objective

To evaluate the prognostic significance of incipient ulceration in cutaneous melanoma.

Design, Setting, and Participants

This case-control study consisted of resected primary cutaneous melanomas diagnosed between 2005 and 2015, identified from the Melanoma Institute Australia research database and with slides available for review at Royal Prince Alfred Hospital. Slides were reviewed by pathologists experienced in the diagnosis of melanocytic lesions to identify cases (incipient ulceration) and controls (ulcerated or nonulcerated). Incipient ulceration cases were matched at a 1:2 ratio with nonulcerated and ulcerated controls, respectively. Study analysis was conducted from March to June 2023.

Main Outcomes

Clinicopathological factors and clinical outcomes: overall survival (OS), melanoma-specific survival (MSS), and recurrence-free survival (RFS) were compared between cases and controls.

Results

Of 2284 patients with melanoma identified, 340 patients (median [IQR] age, 69 [24-94] years; 136 [68%] men; median follow-up, 7.2 years) met the criteria. The matched cohort consisted of 40 cases of incipiently ulcerated melanoma matched 1:2 with 80 nonulcerated controls, and 80 ulcerated controls. The median (IQR) Breslow thickness differed significantly between cases and controls; 2.8 (1.7-4.1) mm for incipient cases compared with 1.0 (0.6-2.1) mm and 5.3 (3.5-8.0) mm for nonulcerated and ulcerated melanomas, respectively. Median (IQR) tumor mitotic rate was 5.0 (3.0-9.0) per mm² in incipiently ulcerated cases compared with 1 (0-3.0) per mm² in nonulcerated controls and 9 (5.0-14.0) per mm² in ulcerated controls. Based on the matched cohorts, patients with nonulcerated tumors had significantly better OS (hazard ratio [HR], 0.49; 95% CI, 0.27-0.88; P = .02) and RFS (HR, 0.37; 95% CI, 0.22-0.64; P < .001) than patients with incipient ulceration. The RFS was significantly worse in ulcerated tumors compared with incipiently ulcerated cases (HR, 1.67; 95% CI, 1.07-2.60; P = .03). After adjusting for pathological factors, no statistically significant differences in clinical outcomes were observed between cases and either control group.

Conclusions and Relevance

The findings of this case-control study indicate that incipient ulceration in a primary melanoma represents an adverse prognostic feature that should be noted by pathologists in their reports and considered in future guidelines.

This case-control study investigates the prognostic implications of incipient ulceration in cutaneous melanomas, comparing survival rates among 3 groups of patients.

Introduction

The presence of ulceration in primary cutaneous melanoma is a pathological feature of adverse prognostic significance and accordingly represents an important staging criterion for melanoma in the American Joint Committee on Cancer (AJCC) staging system.^1,2,3 Ulceration is defined as full-thickness absence of an intact epidermis (including absence of stratum corneum and basement membrane) overlying a melanoma with an associated host reaction (fibrin and neutrophils), and may either be attenuative (with severe thinning and ultimate loss of the epidermis due to expansile tumor growth) or infiltrative (due to pagetoid infiltration resulting in epidermal disruption), with some tumors showing features of both.^4,5 Patients with ulcerated melanomas are allocated a higher pathological T category than those with nonulcerated melanomas due to the association of this feature with shorter disease-free survival and overall survival.^1,3 For example, a patient with a nonulcerated melanoma from 1 to 2 mm in thickness (and sentinel node negative) would be classified as stage I, whereas the same tumor with ulceration would be considered to be stage II. As the utility of adjuvant systemic therapies expands to include patients with stage II disease, this distinction becomes of critical importance.

There exists a subset of melanomas in which pathologic interpretation of the presence of ulceration is difficult, particularly when some, but not all, of the required diagnostic criteria for true ulceration are fulfilled. For example, there may be severe thinning or loss of the nucleated epidermis overlying a melanoma, with fibrin and neutrophils, but a retained stratum corneum. Cases that do not meet the AJCC criteria for ulceration are, by definition, grouped together with nonulcerated melanomas and staged accordingly. Biologically, however, these patterns of growth appear to mirror those seen in lesions demonstrating true ulceration, and would appear to represent similar biologic processes, possibly at an earlier point in time. Indeed, a similar histologic phenomenon previously described in melanoma as consumption of the epidermis has been shown to be significantly associated with the presence of ulceration and has been proposed to represent a precursor to ulceration.^6,7,8,9,10 In light of this, assessment of the prognostic implication of incipient ulceration is of potential clinical significance given that the prognosis of these patients is currently uncertain.

The objective of this study was to identify patients with primary cutaneous melanoma showing incipient ulceration and to evaluate the prognostic significance of this feature by comparing their clinicopathological features and long-term outcomes to those of patients with nonulcerated and ulcerated cutaneous melanomas. Incipient ulceration was defined as severe thinning of the epidermis (with ≤3 layers of nucleated keratinocytes and/or residual stratum corneum) directly overlying a melanoma tumor, with evidence of a host response (serum/fibrin and neutrophils) (Figure 1, A-F).

Figure 1. — A and C, Expansile tumor nodule in the superficial dermis with a severely attenuated overlying epidermis in both cases 1 and 2. B, Higher power image of case 1 showing loss of the nucleated epidermis, with residual stratum corneum only (yellow arrowheads) and associated host response (serum with neutrophils shown by black arrowheads). D, Higher power image of case 2 showing severely thinned nucleated epidermis (yellow arrowheads) with adjacent epidermal hyperplasia (white arrowheads), a thin residuum of stratum corneum (blue arrowheads), and host response (black arrowheads). E and F, Further examples of incipient ulceration with severely thinned epidermis comprising residual stratum corneum only (blue arrowheads) and evidence of a host response (black arrowheads).

Methods

This study was approved by the Melanoma Institute Australia Research Committee and the Sydney Local Health District Ethics Review Committee (protocol No. X15-0311 and 2019/ETH06854). All patients provided written consent before data collection. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design and Participants

The Melanoma Institute Australia (MIA) research database was searched for all primary cutaneous melanoma cases reported from 2005 to 2015, with the following criteria: slides available at Royal Prince Alfred Hospital (Sydney, Australia); Breslow thickness (BT) greater than 0 mm; and at least 1 follow-up record. The MIA database was also searched for cases of primary cutaneous melanoma containing an incipient ulceration in the pathology report to identify cases in which interpretation of ulceration status may have been challenging, including those reported at external laboratories. The external laboratories were contacted to access slides for re-evaluation. Only lesions with slides available were included, allowing independent pathologic assessment to be performed by MIA-affiliated pathologists from Royal Prince Alfred Hospital who were experienced in the diagnosis and reporting of melanocytic skin lesions (E.C.P. and R.A.S.). Lesions were categorized as cases (incipiently ulcerated per the aforementioned definition) or controls (consisting of nonulcerated and ulcerated lesions separately).

Six patients in the cohort had multiple primary melanomas, diagnosed either synchronously or subsequently. For the 2 patients with synchronous melanomas, only the lesion with the higher BT was evaluated. For the 4 patients with subsequent primary lesions, the first melanoma was assessed.

We recorded the following parameters for all patients: age at diagnosis, sex, race and ethnicity, date of diagnosis of primary tumor, BT, Clark level, anatomical location of primary tumor, tumor mitotic rate (TMR), ulceration category, and AJCC stage at diagnosis. Age, sex, and race and/or ethnicity were self-reported. The clinical outcomes that we analyzed included recurrence-free survival (RFS), melanoma-specific survival (MSS), and overall survival (OS). Time to event was calculated from the date of melanoma diagnosis until the date of (1) any recurrence (local, regional, or distant recurrence; or death if it occurred first) for RFS time; (2) death due to melanoma for MSS; and (3) death from any cause for OS.

The analysis cohort included patients with incipiently ulcerated cutaneous melanomas (cases) and 2 separately matched groups of patients with nonulcerated and ulcerated melanomas (controls), respectively. For each incipiently ulcerated case, 2 nonulcerated and 2 ulcerated controls were directly matched using the individual propensity scores method. The propensity score for a lesion to be incipiently ulcerated was calculated using 2 separate multivariable logistic regressions that included patients’ characteristics (sex, age, and primary melanoma site). The 2 matching analyses were performed using (1) 40 incipiently ulcerated and 193 nonulcerated melanoma cases and (2) 40 incipiently ulcerated and 107 truly ulcerated melanomas. The matching process did not include BT because it would have reduced the number of cases with matched controls and would have introduced statistical bias related to overmatching. Instead, to account for the importance of pathologic factors, they were used as adjustment factors in the multivariable analyses.

Statistical Analysis

Clinicopathologic factors were compared between groups (incipiently ulcerated vs nonulcerated; incipiently ulcerated vs ulcerated) before and after matching. An unknown category was created for cases missing pathologic factors. Survival outcomes within each category were described using the Kaplan-Meier method. Log-rank tests were used to assess survival differences between groups. Potential clinical outcome differences between cases and controls were further assessed by univariable and multivariable Cox regression analysis using the matched cohorts.

The multivariable analysis included variables that showed a P value < .20 from the univariable analysis; tests were 2-tailed. All statistical analyses were performed using R, version 4.0.3 (R Foundation for Statistical Computing), March to June 2023.

Results

A total of 2284 patients with melanoma were identified for the study period (2005-2015). Of these patients, 340 (median [IQR] age, 69 [24-94] years; 136 [68%] men and 64 [32%] women) met the inclusion criteria, including slide availability. Of these, the melanomas of 40 patients met the histologic criteria for incipient ulceration, as defined. At a matching ratio of 1:2, we identified 80 patients with nonulcerated primary cutaneous melanomas (from 193) and 80 patients with truly ulcerated primary cutaneous melanomas (from 107) for the control groups (Table). The final matched analysis cohort consisted of 200 patients. Median (IQR) follow-up time was 7.2 (5.9-10.2) years. Clinical and pathologic characteristics of the study population are presented in eTable 1 in Supplement 1. Given that nearly all (>95%) were White patients, we did not include race and ethnicity in the analysis.

Table. Clinicopathologic Characteristics of Patients With Incipiently Ulcerated Melanoma Compared With Nonulcerated and Ulcerated Control Groups, Before and After Matching.

Characteristic	Incipient ulceration (n = 40)	Nonulcerated control				Ulcerated control
		Before matching (n = 193)		After matching (n = 80)		Before matching (n = 107)		After matching (n = 80)
		No. (%)	P value	No. (%)	P value	No. (%)	P value	No. (%)	P value
Sex^a
Female	15 (37.5)	61 (31.6)	.47	25 (31.3)	.49	39 (36.4)	.91	24 (30.0)	.41
Male	25 (62.5)	132 (68.4)	.47	55 (68.8)	.49	68 (63.6)	.91	56 (70.0)	.41
Age, y^a
Median (range)	69 (24-93)	66 (20-95)	.52	69 (25-91)	.61	71 (33-94)	.35	70 (33-94)	.49
First, third quartile	58, 76	57, 77	.52	58, 76	.61	61, 81	.35	61, 81	.49
Primary site^a
Head and neck	10 (25.0)	57 (29.5)	.20	20 (25.0)	> .99	30 (28.0)	.98	23 (28.8)	.93
Lower limb	15 (37.5)	46 (23.8)		30 (37.5)		37 (34.5)		26 (32.5)
Trunk	7 (17.5)	58 (30.1)		15 (18.8)		18 (16.7)		16 (20.0)
Upper limb	8 (20.0)	32 (16.6)		15 (18.8)		21 (19.6)		15 (18.8)
BT, mm
Median (range)	2.8 (0.5-14.2)	1.1 (0-19.0)	<.001	1.0 (0.2-9.0)	<.001	5.5 (1.0-29.0)	<.001	5.3 (1.0-29.0)	<.001
First, third quartile	1.7, 4.1	0.6, 2.1	<.001	0.6, 1.7	<.001	3.5, 8.0	<.001	3.2, 8.0	<.001
Mitoses (per mm²)
Median (range)	5.0 (0-25.0)	1.0 (0-34.0)	<.001	1.0 (0-24.0)	<.001	9.0 (1.0-46.0)	.02	9.0 (1.0-40.0)	.07
First, third quartile	3.0, 9.0	0, 3.0	<.001	0, 2.50	<.001	5.0, 14.0	.02	5.0, 14.0	.07
Mitoses (categorized)
0	1 (2.5)	75 (38.9)	<.001	31 (38.8)	<.001	0	.01	0	.03
1-5	21 (52.5)	95 (49.2)		41 (51.3)		33 (30.8)		27 (33.8)
>5	18 (45.0)	22 (11.4)		8 (10.0)		72 (67.3)		53 (66.3)
Unknown	0	1 (0.5)		NA		2 (1.9)		NA
Melanoma subtype
SSM	17 (42.5)	116 (60.1)	.001	53 (66.3)	.005	26 (24.3)	.14	19 (23.8)	.08
ALM	7 (17.5)	7 (3.6)		4 (5.0)		13 (12.1)		7 (8.8)
DM	3 (7.5)	21 (10.9)		8 (10.0)		17 (15.9)		13 (16.3)
LMM	2 (5.0)	32 (16.6)		11 (13.8)		4 (3.7)		3 (3.8)
NM	11 (27.5)	16 (8.3)		4 (5.0)		43 (40.2)		36 (45.0)
Other	0	1 (0.5)		N/A		4 (3.7)		2 (2.5)
AJCC stage at diagnosis
I	4 (10.0)	135 (70.0)	<.001	60 (75.0)	<.001	2 (1.9)	.12	1 (1.3)	.11
II	26 (65.0)	47 (24.4)		14 (17.5)		57 (53.2)		45 (57.7)
III	10 (25.0)	9 (4.7)		5 (6.3)		38 (35.6)		27 (34.6)
IV	0	2 (1.0)		1 (1.3)		6 (5.6)		5 (6.4)
Missing						4 (3.7)
Lymphovascular invasion
Absent	31 (77.5)	179 (92.7)	.01	72 (90.0)	.03	77 (72.0)	.60	62 (77.5)	> .99
Present	8 (20.0)	6 (3.1)		4 (5.0)		23 (21.5)		16 (20.0)
Unknown	1 (2.5)	8 (4.1)		4 (5.0)		7 (6.5)		2 (2.5)
Sentinel lymph node biopsy status
Negative	17 (42.5)	52 (26.9)	<.001	23 (28.8)	.05	27 (25.2)	.12	21 (26.3)	.19
No SLNB	17 (42.5)	137 (71.0)		55 (68.8)		56 (52.3)		45 (56.3)
Positive	6 (15.0)	4 (2.1)		2 (2.5)		24 (22.4)		14 (17.5)
Satellites
No	35 (87.5)	173 (89.6)	.07	70 (87.5)	.02	84 (78.5)	.34	65 (81.3)	.63
Unknown	1 (2.5)	18 (9.3)		9 (11.3)		11 (10.3)		6 (7.5)
Yes	4 (10.0)	2 (1.0)		1 (1.3)		12 (11.2)		9 (11.3)

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Abbreviations: AJCC, American Joint Committee on Cancer; ALM, acral lentiginous melanoma; BT, Breslow thickness; DM, desmoplastic melanoma; LMM, lentigo maligna melanoma; NM, nodular melanoma; SSM, superficial spreading melanoma.

^{^a}

Included in the matching process.

Ulceration category was significantly associated with multiple pathologic features, including BT, TMR, melanoma subtype, AJCC stage, and sentinel lymph node status (eTable 1 in Supplement 1). No significant associations were observed between ulceration category and age, sex, or anatomical primary tumor site.

Primary cutaneous melanomas showing incipient ulceration had a median BT and TMR that were intermediate between nonulcerated and ulcerated melanomas (eTable 1 in Supplement 1). In the matched groups, tumors with incipient ulceration remained significantly thicker than nonulcerated tumors (median BT, 2.8 vs 1.0 mm) with a difference in median BT of 1.8 mm (95% CI, 1.1-2.8; P < .001). Ulcerated melanomas were significantly thicker than melanomas with incipient ulceration (5.3 vs 2.8 mm), with a difference in median BT of 2.5 mm (95% CI, 0.4 – 3.8; P < .001) (Table). In some cases, features of incipient ulceration were present at the edge of areas of true ulceration (Figure 1G and H). Incipient ulceration was observed more often in tumors arising in acral skin, with 23.7% of melanomas in acral sites showing incipient ulceration compared with 10.3% of nonacral melanomas (eTable 2 in Supplement 1).

Univariable and multivariable Cox regression analyses of factors predicting survival are presented in eTable 3 in Supplement 1. In the univariable models, compared with incipiently ulcerated cases, nonulcerated tumors had significantly better OS (HR, 0.49; 95% CI, 0.27-0.88; P = .02; eTable 3A in Supplement 1) and RFS (HR, 0.37; 95% CI, 0.22-0.64; P < .001; eTable 3C in Supplement 1), while ulcerated tumors showed significantly worse RFS (HR, 1.67; 95% CI, 1.07-2.60; P = .03). There was no significant difference in MSS (eTable 3B in Supplement 1). Multivariable analyses did not show any significant differences in OS, MSS, or RFS between cases and controls (eTable 3 in Supplement 1). The median (IQR) OS for patients with incipient ulceration was 7.9 (3.4-13.4) years, compared with 3.7 (1.6-10.4) years for those with ulcerated tumors and 10.4 (7.3 to not reached) years for those with nonulcerated tumors (95% CI, 2.1-6.5; P < .001) (Figure 2). Kaplan-Meier curves of survival stratified by the category of ulceration and separated into stage groups are presented in Figure 2.

We also evaluated the associations among TMR, BT, and ulceration category (Figure 3). As TMR increased, a significantly higher proportion of cases showed incipient or true ulceration, a trend that was observed in both thinner (≤2 mm) and thicker (>2 mm) tumors (eTable 4 in Supplement 1). Thinner tumors with a high TMR (>5 per mm²) showed the greatest proportion of cases with incipient ulceration (30.0%), while thicker mitotically active cutaneous melanomas had a higher proportion with true ulceration (69.6%; eTable 4 in Supplement 1).

Discussion

Since the early 1950s, the presence of ulceration in melanoma has been recognized as an important adverse prognostic feature, remaining a key parameter contributing to pathologic staging.^1,11,12 However, interpretive difficulty may be met when a melanoma shows incipient ulceration, characterized by evidence of a host response but with a retained thin residuum of epidermis. These cases may be subject to interobserver variability due to the overlapping features with truly ulcerated melanomas, although according to the current AJCC definition (8th edition)¹ should strictly be classified as nonulcerated.

Our study demonstrated, however, that melanomas with incipient ulceration were significantly thicker and more mitotically active than nonulcerated melanomas and were significantly more likely to be associated with other poor prognostic features including lymphovascular invasion, sentinel lymph node positivity, and the presence of satellite lesions. On univariable analyses, patients with nonulcerated tumors had significantly better OS and RFS than those with incipiently ulcerated tumors; however, no differences in survival outcomes were seen on multivariable analyses, possibly due to the moderate number of incipient ulceration cases available for inclusion in the study. Nevertheless, the findings suggest that incipiently ulcerated tumors may represent a biologically more aggressive disease population than nonulcerated tumors, despite being currently grouped together for staging purposes.

Incipient ulceration, as defined in this study, shares some features with a similar histologic phenomenon in melanoma previously described as consumption of the epidermis, defined as thinning of the epidermis directly overlying groups of melanocytes with loss of rete ridges^8,10 (but without evidence of a host response, as specified in our definition). This feature has previously been shown to be significantly associated with the presence of ulceration, BT, and the presence of mitoses.^6,8 We observed a similar strong association among TMR, BT, and ulceration category, with higher rates of incipient or true ulceration seen with increasing TMR and BT (eTable 4 in Supplement 1; Figure 3).

TMR has been identified as an important independent predictor of survival in patients with melanoma.^5,13 We found that incipiently ulcerated tumors had a median TMR that was significantly higher than that of nonulcerated tumors but did not differ significantly from those with true ulceration after matching (Table). Interestingly, thinner tumors (BT ≤2 mm) with a high TMR (>5 per mm²) represented the group with the highest proportion of incipient ulceration (30%), while thicker tumors (>2 mm) with a high TMR were much more likely to show true ulceration (eTable 4 in Supplement 1).

The size of a melanoma tumor has been shown to be prognostically significant, with larger cutaneous melanomas (calculated using various methods including the macroscopic largest diameter,¹⁴ the microscopic width of the invasive component,¹⁵ and the calculated tumor area¹⁶) associated with worse outcomes. The extent of ulceration (defined as either a percentage of the width of the dermal invasive melanoma or its diameter in millimeters) has also been shown to have prognostic significance, with more extensively ulcerated tumors having worse prognosis than minimally ulcerated tumors.¹⁷ Interestingly, we observed that incipient ulceration was often present at the edges of true ulceration, similar to the consumption of the epidermis adjacent to ulceration observed by others.^8,9 which suggests that these features lie on a continuum. In some cases, incipient ulceration was seen in tissue slices adjacent to the slice(s) with true ulceration, raising the possibility that in a subset of cases of incipient ulceration, true ulceration may exist nearby, simply unprofiled in the sections.

Taking these findings and observations together, it seems likely that for many tumors, the mitotic rate, size, thickness, and presence of ulceration are all interrelated parameters: the most biologically aggressive cutaneous melanomas show rapid proliferation, resulting in larger, thicker tumors that initially cause attenuation or consumption of the overlying epidermis, possibly followed by a phase of incipient ulceration before becoming truly ulcerated. This theory is supported by evidence that of the 2 recognized patterns of ulceration in melanoma,⁵ only the attenuative type appears to be an independent predictor of MSS.¹⁸ The biological mechanism of ulceration in this setting is likely to be multifactorial, although the rate of tumor growth seems to be a key factor. A melanoma tumor with a speed of growth exceeding that of the normal keratinocytes may lead to epidermal attenuation and eventual ulceration. Indeed, pathways associated with cellular proliferation have been shown through genomic and transcriptomic analyses to be upregulated in ulcerated tumors compared with nonulcerated tumors.¹⁹ Hypoxia may also be a contributing factor; rapidly proliferating malignant cells may compress the small vessels supplying the epidermis and deplete the microenvironment of oxygen with their own high metabolic demands.²⁰ These deficits may produce keratinocyte ischemia, loss of epidermal integrity, and ultimately ulceration. Whether ulceration represents purely a secondary effect of rapid tumor growth (ie, a robust surrogate marker of aggressive tumor biology) or whether the act of ulceration itself also contributes to the poorer outcomes associated with this feature is not yet fully understood.

A higher proportion of both true and incipient ulceration was observed in tumors at acral sites compared with nonacral tumors (52.6% and 23.7% in acral vs 28.8% and 10.3% in nonacral tumors; P < .001). The high frequency of ulceration in acral tumors has previously been recognized and reported to be greater than 60%,²¹ with consumption of epidermis also identified in as many as 75% of cases.⁹ This finding is of interest because one would expect acral skin, with its prominent stratum corneum, to be inherently more resistant to ulceration. However, acral melanoma is known to differ biologically from other cutaneous cutaneous melanomas, with poorer prognosis and a different distribution of molecular aberrations.²² Indeed, the usefulness of ulceration as a prognostic marker in acral melanoma has been called into question, with a recent study²¹ demonstrating that ulceration was only significantly associated with worse survival for thin (≤1 mm) acral tumors. A previous report²³ of prognostic features in acral lentiginous melanoma found that although TMR was significantly associated with the presence of ulceration, only TMR (not ulceration) was independently correlated with MSS. Further exploration of the relative prognostic significance of pathologic features in acral melanoma may be warranted.

Additional challenges in interpreting ulceration status occur in relation to other clinical and biological factors. Several cases in our study were characterized by a very thin nucleated epidermal layer underneath a fibrinoinflammatory exudate, sometimes with adjacent epidermal hyperplasia (eg, Figure 1D). This appearance may represent the re-epithelialization of a melanoma that was previously ulcerated, and indeed was often observed at the edge of true ulceration or in tissue sections from adjacent to sections with true ulceration. Although the term incipient ulceration would not technically be correct in these cases because ulceration has already occurred, such cases are still captured by our histologic definition, acknowledging that it is impossible to be completely certain of the temporal course of a disease process based on histologic findings at a single time point. Cases of re-epithelialization presumably carry the same risk as truly ulcerated tumors; however, owing to the thin (regenerating) epidermal layer, they are considered to be nonulcerated by the current AJCC definition¹ of ulceration. Re-epithelialization and reactive epidermal hyperplasia have been shown to be correlated significantly with ulceration and reported as present in up to 13% of cutaneous melanomas.¹⁸

Differentiating traumatic ulceration from true biological ulceration can present another challenge, and in some cases, may be impossible.^24,25 The distinction is important, however, as traumatic ulceration is of no prognostic significance.⁴ Although the presence of sharply demarcated (squared off) epidermis at the edge of the ulcer may be helpful for recognizing traumatic ulceration,⁴ we propose that an absence of mitotic activity may serve as an additional interpretive clue. In our study, true ulceration was only present in tumors with mitoses, and ulceration was not seen among those with a TMR of 0, which suggests that when a melanoma shows little to no mitotic activity, the probability that it is truly, biologically ulcerated is very low, and the possibility of traumatic ulceration should be considered.

Limitations

This study was limited by its retrospective nature and by the relatively small number of cases meeting the study criteria. Nevertheless, the findings strongly suggest that primary melanomas with incipient ulceration are a more biologically aggressive population than truly nonulcerated melanomas; associated with other poor prognostic features (including higher BT, higher TMR, LVI, sentinel lymph node positivity, and satellite lesions); and often seen at the edge of or adjacent to true ulceration.

Conclusions

The findings of this retrospective case-control study indicate that the classification of primary melanomas with incipient ulceration as nonulcerated and assigning them a lower-risk pathologic T stage may not be appropriate. Moving forward, pathologists should comment on the presence of incipient ulceration in pathology reports of primary melanomas, so that related data on this feature can continue to be collected. Additional studies investigating the significance of this uncommon but important pathologic feature are warranted. Future editions of the AJCC staging system should consider acknowledging this interpretive challenge and provide guidance on how primary melanomas with incipient ulceration should be classified.

Supplement 1.

eTable 1. Clinicopathological characteristics stratified by ulceration category, after matching

eTable 2. Association between ulceration status and location (acral vs non-acral skin)

eTable 3. A, Univariable and multivariable Cox regression for Overall survival; B, univariable and multivariable Cox regression for melanoma-specific survival; and C, univariable and multivariable Cox regression for recurrence-free survival

eTable 4. Association between ulceration category and TMR, stratified by BT category

Click here for additional data file.^{(964.3KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(13.1KB, pdf)}

References

1.Gershenwald JE, Scolyer RA, Hess KR, et al. AJCC Cancer Staging Manual. Melanoma of the Skin. Springer; 2017:563-585. [Google Scholar]
2.Gershenwald JE, Scolyer RA. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th edition and beyond. Ann Surg Oncol. 2018;25(8):2105-2110. doi: 10.1245/s10434-018-6513-7 [DOI] [PubMed] [Google Scholar]
3.Gershenwald JE, Scolyer RA, Hess KR, et al. ; for members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform . Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(6):472-492. doi: 10.3322/caac.21409 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Scolyer RA, Shaw HM, Thompson JF, et al. Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas. Am J Surg Pathol. 2003;27(12):1571-1576. doi: 10.1097/00000478-200312000-00011 [DOI] [PubMed] [Google Scholar]
5.Azzola MF, Shaw HM, Thompson JF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97(6):1488-1498. doi: 10.1002/cncr.11196 [DOI] [PubMed] [Google Scholar]
6.Bønnelykke-Behrndtz LM, Schmidt H, Damsgaard TE, et al. Consumption of the epidermis: a suggested precursor of ulceration associated with increased proliferation of melanoma cells. Am J Dermatopathol. 2015;37(11):841-845. doi: 10.1097/DAD.0000000000000382 [DOI] [PubMed] [Google Scholar]
7.Bønnelykke-Behrndtz ML, Steiniche T. Ulcerated Melanoma: Aspects and Prognostic Impact. In: Ward WH, Farma JM, eds. Cutaneous Melanoma: Etiology and Therapy. Codon; 2017. doi: 10.15586/codon.cutaneousmelanoma.2017.ch5 [DOI] [PubMed] [Google Scholar]
8.Walters RF, Groben PA, Busam K, et al. Consumption of the epidermis: a criterion in the differential diagnosis of melanoma and dysplastic nevi that is associated with increasing Breslow depth and ulceration. Am J Dermatopathol. 2007;29(6):527-533. doi: 10.1097/DAD.0b013e318156e0a7 [DOI] [PubMed] [Google Scholar]
9.Ohata C, Nakai C, Kasugai T, Katayama I. Consumption of the epidermis in acral lentiginous melanoma. J Cutan Pathol. 2012;39(6):577-581. doi: 10.1111/j.1600-0560.2012.01914.x [DOI] [PubMed] [Google Scholar]
10.Hantschke M, Bastian BC, LeBoit PE. Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus. Am J Surg Pathol. 2004;28(12):1621-1625. doi: 10.1097/00000478-200412000-00011 [DOI] [PubMed] [Google Scholar]
11.Tompkins VN. Cutaneous melanoma: ulceration as a prognostic sign. Cancer. 1953;6(6):1215-1218. doi: [DOI] [PubMed] [Google Scholar]
12.McGovern VJ, Shaw HM, Milton GW, McCarthy WH. Ulceration and prognosis in cutaneous malignant melanoma. Histopathology. 1982;6(4):399-407. doi: 10.1111/j.1365-2559.1982.tb02737.x [DOI] [PubMed] [Google Scholar]
13.Kashani-Sabet M, Miller JR III, Lo S, et al. Reappraisal of the prognostic significance of mitotic rate supports its reincorporation into the melanoma staging system. Cancer. 2020;126(21):4717-4725. doi: 10.1002/cncr.33088 [DOI] [PubMed] [Google Scholar]
14.Ma Q, Suo H, Zhu L, et al. Prognostic significance of tumor size for primary invasive cutaneous melanoma: A population-based study, 2004-2016. Cancer Med. 2020;9(13):4561-4571. doi: 10.1002/cam4.3065 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Bamford M, Udensi L, Khanna A, O’Riordan M, Saldanha G. Comparison of the prognostic value of microscopically measured invasive width versus macroscopic width in cutaneous melanoma shows the superiority of microscopic invasive width measurement. J Cutan Pathol. 2022;49(6):536-542. doi: 10.1111/cup.14220 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Saldanha G, Yarrow J, Elsheikh S, O’Riordan M, Uraiby H, Bamford M. Development and initial validation of calculated tumor area as a prognostic tool in cutaneous malignant melanoma. JAMA Dermatol. 2019;155(8):890-898. doi: 10.1001/jamadermatol.2019.0621 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.In ’t Hout FE, Haydu LE, Murali R, Bonenkamp JJ, Thompson JF, Scolyer RA. Prognostic importance of the extent of ulceration in patients with clinically localized cutaneous melanoma. Ann Surg. 2012;255(6):1165-1170. doi: 10.1097/SLA.0b013e31824c4b0b [DOI] [PubMed] [Google Scholar]
18.Bønnelykke-Behrndtz ML, Schmidt H, Christensen IJ, et al. Prognostic stratification of ulcerated melanoma: not only the extent matters. Am J Clin Pathol. 2014;142(6):845-856. doi: 10.1309/AJCPW56PHGLFTKZC [DOI] [PubMed] [Google Scholar]
19.Davies J, Muralidhar S, Randerson-Moor J, et al. Ulcerated melanoma: systems biology evidence of inflammatory imbalance towards pro-tumorigenicity. Pigment Cell Melanoma Res. 2022;35(2):252-267. doi: 10.1111/pcmr.13023 [DOI] [PubMed] [Google Scholar]
20.Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the tumor microenvironment that influence immune cell functions: hypoxia, oxidative stress, metabolic alterations. Cancers (Basel). 2020;12(12):3802. doi: 10.3390/cancers12123802 [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Wei X, Wu D, Chen Y, et al. Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study. Br J Dermatol. 2022;186(6):977-987. doi: 10.1111/bjd.21026 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Newell F, Wilmott JS, Johansson PA, et al. Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity. Nat Commun. 2020;11(1):5259. doi: 10.1038/s41467-020-18988-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Phan A, Touzet S, Dalle S, Ronger-Savlé S, Balme B, Thomas L. Acral lentiginous melanoma: histopathological prognostic features of 121 cases. Br J Dermatol. 2007;157(2):311-318. doi: 10.1111/j.1365-2133.2007.08031.x [DOI] [PubMed] [Google Scholar]
24.Ruiter DJ, Spatz A, van den Oord JJ, Cook MG; Pathology Committee of the European Organization Research and Treatment of Cancer (EORTC) Melanoma Group . Pathologic staging of melanoma. Semin Oncol. 2002;29(4):370-381. doi: 10.1053/sonc.2002.34116 [DOI] [PubMed] [Google Scholar]
25.Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ, Barnhill RL. Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 2003;39(13):1861-1865. doi: 10.1016/S0959-8049(03)00325-3 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. Clinicopathological characteristics stratified by ulceration category, after matching

eTable 2. Association between ulceration status and location (acral vs non-acral skin)

eTable 4. Association between ulceration category and TMR, stratified by BT category

Click here for additional data file.^{(964.3KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(13.1KB, pdf)}

[doi230053r1] 1.Gershenwald JE, Scolyer RA, Hess KR, et al. AJCC Cancer Staging Manual. Melanoma of the Skin. Springer; 2017:563-585. [Google Scholar]

[doi230053r2] 2.Gershenwald JE, Scolyer RA. Melanoma staging: American Joint Committee on Cancer (AJCC) 8th edition and beyond. Ann Surg Oncol. 2018;25(8):2105-2110. doi: 10.1245/s10434-018-6513-7 [DOI] [PubMed] [Google Scholar]

[doi230053r3] 3.Gershenwald JE, Scolyer RA, Hess KR, et al. ; for members of the American Joint Committee on Cancer Melanoma Expert Panel and the International Melanoma Database and Discovery Platform . Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(6):472-492. doi: 10.3322/caac.21409 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r4] 4.Scolyer RA, Shaw HM, Thompson JF, et al. Interobserver reproducibility of histopathologic prognostic variables in primary cutaneous melanomas. Am J Surg Pathol. 2003;27(12):1571-1576. doi: 10.1097/00000478-200312000-00011 [DOI] [PubMed] [Google Scholar]

[doi230053r5] 5.Azzola MF, Shaw HM, Thompson JF, et al. Tumor mitotic rate is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma: an analysis of 3661 patients from a single center. Cancer. 2003;97(6):1488-1498. doi: 10.1002/cncr.11196 [DOI] [PubMed] [Google Scholar]

[doi230053r6] 6.Bønnelykke-Behrndtz LM, Schmidt H, Damsgaard TE, et al. Consumption of the epidermis: a suggested precursor of ulceration associated with increased proliferation of melanoma cells. Am J Dermatopathol. 2015;37(11):841-845. doi: 10.1097/DAD.0000000000000382 [DOI] [PubMed] [Google Scholar]

[doi230053r7] 7.Bønnelykke-Behrndtz ML, Steiniche T. Ulcerated Melanoma: Aspects and Prognostic Impact. In: Ward WH, Farma JM, eds. Cutaneous Melanoma: Etiology and Therapy. Codon; 2017. doi: 10.15586/codon.cutaneousmelanoma.2017.ch5 [DOI] [PubMed] [Google Scholar]

[doi230053r8] 8.Walters RF, Groben PA, Busam K, et al. Consumption of the epidermis: a criterion in the differential diagnosis of melanoma and dysplastic nevi that is associated with increasing Breslow depth and ulceration. Am J Dermatopathol. 2007;29(6):527-533. doi: 10.1097/DAD.0b013e318156e0a7 [DOI] [PubMed] [Google Scholar]

[doi230053r9] 9.Ohata C, Nakai C, Kasugai T, Katayama I. Consumption of the epidermis in acral lentiginous melanoma. J Cutan Pathol. 2012;39(6):577-581. doi: 10.1111/j.1600-0560.2012.01914.x [DOI] [PubMed] [Google Scholar]

[doi230053r10] 10.Hantschke M, Bastian BC, LeBoit PE. Consumption of the epidermis: a diagnostic criterion for the differential diagnosis of melanoma and Spitz nevus. Am J Surg Pathol. 2004;28(12):1621-1625. doi: 10.1097/00000478-200412000-00011 [DOI] [PubMed] [Google Scholar]

[doi230053r11] 11.Tompkins VN. Cutaneous melanoma: ulceration as a prognostic sign. Cancer. 1953;6(6):1215-1218. doi: [DOI] [PubMed] [Google Scholar]

[doi230053r12] 12.McGovern VJ, Shaw HM, Milton GW, McCarthy WH. Ulceration and prognosis in cutaneous malignant melanoma. Histopathology. 1982;6(4):399-407. doi: 10.1111/j.1365-2559.1982.tb02737.x [DOI] [PubMed] [Google Scholar]

[doi230053r13] 13.Kashani-Sabet M, Miller JR III, Lo S, et al. Reappraisal of the prognostic significance of mitotic rate supports its reincorporation into the melanoma staging system. Cancer. 2020;126(21):4717-4725. doi: 10.1002/cncr.33088 [DOI] [PubMed] [Google Scholar]

[doi230053r14] 14.Ma Q, Suo H, Zhu L, et al. Prognostic significance of tumor size for primary invasive cutaneous melanoma: A population-based study, 2004-2016. Cancer Med. 2020;9(13):4561-4571. doi: 10.1002/cam4.3065 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r15] 15.Bamford M, Udensi L, Khanna A, O’Riordan M, Saldanha G. Comparison of the prognostic value of microscopically measured invasive width versus macroscopic width in cutaneous melanoma shows the superiority of microscopic invasive width measurement. J Cutan Pathol. 2022;49(6):536-542. doi: 10.1111/cup.14220 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r16] 16.Saldanha G, Yarrow J, Elsheikh S, O’Riordan M, Uraiby H, Bamford M. Development and initial validation of calculated tumor area as a prognostic tool in cutaneous malignant melanoma. JAMA Dermatol. 2019;155(8):890-898. doi: 10.1001/jamadermatol.2019.0621 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r17] 17.In ’t Hout FE, Haydu LE, Murali R, Bonenkamp JJ, Thompson JF, Scolyer RA. Prognostic importance of the extent of ulceration in patients with clinically localized cutaneous melanoma. Ann Surg. 2012;255(6):1165-1170. doi: 10.1097/SLA.0b013e31824c4b0b [DOI] [PubMed] [Google Scholar]

[doi230053r18] 18.Bønnelykke-Behrndtz ML, Schmidt H, Christensen IJ, et al. Prognostic stratification of ulcerated melanoma: not only the extent matters. Am J Clin Pathol. 2014;142(6):845-856. doi: 10.1309/AJCPW56PHGLFTKZC [DOI] [PubMed] [Google Scholar]

[doi230053r19] 19.Davies J, Muralidhar S, Randerson-Moor J, et al. Ulcerated melanoma: systems biology evidence of inflammatory imbalance towards pro-tumorigenicity. Pigment Cell Melanoma Res. 2022;35(2):252-267. doi: 10.1111/pcmr.13023 [DOI] [PubMed] [Google Scholar]

[doi230053r20] 20.Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the tumor microenvironment that influence immune cell functions: hypoxia, oxidative stress, metabolic alterations. Cancers (Basel). 2020;12(12):3802. doi: 10.3390/cancers12123802 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r21] 21.Wei X, Wu D, Chen Y, et al. Prognostic value of ulceration varies across Breslow thicknesses and clinical stages in acral melanoma: a retrospective study. Br J Dermatol. 2022;186(6):977-987. doi: 10.1111/bjd.21026 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r22] 22.Newell F, Wilmott JS, Johansson PA, et al. Whole-genome sequencing of acral melanoma reveals genomic complexity and diversity. Nat Commun. 2020;11(1):5259. doi: 10.1038/s41467-020-18988-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[doi230053r23] 23.Phan A, Touzet S, Dalle S, Ronger-Savlé S, Balme B, Thomas L. Acral lentiginous melanoma: histopathological prognostic features of 121 cases. Br J Dermatol. 2007;157(2):311-318. doi: 10.1111/j.1365-2133.2007.08031.x [DOI] [PubMed] [Google Scholar]

[doi230053r24] 24.Ruiter DJ, Spatz A, van den Oord JJ, Cook MG; Pathology Committee of the European Organization Research and Treatment of Cancer (EORTC) Melanoma Group . Pathologic staging of melanoma. Semin Oncol. 2002;29(4):370-381. doi: 10.1053/sonc.2002.34116 [DOI] [PubMed] [Google Scholar]

[doi230053r25] 25.Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ, Barnhill RL. Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 2003;39(13):1861-1865. doi: 10.1016/S0959-8049(03)00325-3 [DOI] [PubMed] [Google Scholar]

PERMALINK

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Elizabeth C Paver, MBBS

Tasnia Ahmed, MSc

Hazel Burke, BAppSc

Robyn P M Saw, MS

Jonathan R Stretch, DPhil

Andrew J Spillane, MD

Kerwin F Shannon, MBBS

Ismael A Vergara, PhD

David E Elder, MB, ChB

Serigne N Lo, PhD

John F Thompson, MD

Richard A Scolyer, MD

Key Points

Questions

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes

Results

Conclusions and Relevance

Introduction

Figure 1. Histopathologic (Hematoxylin-Eosin Staining) Findings in 2 Typical Cases of Melanoma With Incipient Ulceration.

Methods

Study Design and Participants

Statistical Analysis

Results

Table. Clinicopathologic Characteristics of Patients With Incipiently Ulcerated Melanoma Compared With Nonulcerated and Ulcerated Control Groups, Before and After Matching.

Figure 2. Overall Survival, Melanoma-Specific Survival, and Recurrence-Free Survival for Patients With Melanoma With Incipient Ulceration vs Nonulcerated and Ulcerated Control Groups, by Combined T-Stage Categories (T1 and T2 vs T3 and T4).

Figure 3. Association Among TMR, BT, and Ulceration Category.

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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