Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro‐tumourigenicity

Davies, John R.; Muralidhar, Sathya; Randerson-Moor, Juliette A.; Harland, Mark; O’Shea, Sally J.; Diaz, Joey Mark S.; Walker, Christy; Nsengimana, Jérémie; Laye, Jonathan P.; Mell, Tracey; Chan, May P.; Appleton, Lizzie; Birkeälv, Sofia; Adams, David J.; Cook, Graham P.; Ball, Graham; Bishop, D. Timothy; Newton-Bishop, Julia

doi:10.1111/pcmr.13023

Cited by 5 publications

(4 citation statements)

References 69 publications

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“…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 . 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 .…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Paver,

Ahmed,

Burke

et al. 2023

JAMA Dermatol

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ImportanceUlceration 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.ObjectiveTo evaluate the prognostic significance of incipient ulceration in cutaneous melanoma.Design, Setting, and ParticipantsThis 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 OutcomesClinicopathological factors and clinical outcomes: overall survival (OS), melanoma-specific survival (MSS), and recurrence-free survival (RFS) were compared between cases and controls.ResultsOf 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 &lt; .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 RelevanceThe 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Paver,

Ahmed,

Burke

et al. 2023

JAMA Dermatol

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“…The presence of ulceration denotes a highly proliferative lesion, often associated with a high mitotic rate, but not all thick melanomas with important mitotic activity are ulcerated, which suggests the influence of other additional factors in the development of ulceration [ 36 , 37 , 38 ]. Because of the aggressive biological behavior associated with ulceration, a hypothesis was issued stating that this develops as a consequence of some intrinsic biological factors of the tumor, supporting dissemination and loss of epidermis integrity [ 36 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Invasive Cutaneous Melanoma: Evaluating the Prognostic Significance of Some Parameters Associated with Lymph Node Metastases

Vița,

Jurescu,

Văduva

et al. 2023

Medicina

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Background and Objectives: This study aimed to assess the clinical-pathological profile of patients with invasive cutaneous melanomas and to identify the parameters with a prognostic role in the lymph nodal spread of this malignant tumor. Materials and Methods: We performed a retrospective study on patients with invasive cutaneous melanomas who underwent surgery in the “Pius Brînzeu” County Clinical Emergency Hospital from Timișoara, Romania, and were evaluated for the status of loco-regional lymph nodes. We selected and analyzed some parameters searching for their relationship with lymph node metastases. Results: We identified 79 patients with invasive cutaneous melanomas (29 men and 50 women, mean age 59.36 years). A percentage of 58.3% of melanomas had Breslow tumor thickness >2 mm; 69.6% of melanomas showed a Clark level IV–V. Tumor ulceration was present in 59.5% of melanomas. A mitotic rate of ≥5 mitoses/mm2 was observed in 48.1% of melanomas. Tumor-infiltrating lymphocytes (TILs), non-brisk, were present in 59.5% of cases and 22.8% of patients had satellite/in-transit metastasis (SINTM). Tumor regression was identified in 44.3% of cases. Lymph nodes metastases were found in 43.1% of patients. Statistical analysis showed that lymph node metastases were more frequent in melanomas with Breslow thickness >2 mm (p = 0.0002), high Clark level (p = 0.0026), mitotic rate >5 mitoses/mm2 (p = 0.0044), ulceration (p = 0.0107), lymphovascular invasion (p = 0.0182), SINTM (p = 0.0302), and non-brisk TILs (p = 0.0302). Conclusions: The Breslow thickness >2 mm, high Clark level, high mitotic rate and ulceration are the most important prognostic factors for lymph nodal spread in cutaneous melanomas. However, some melanomas without these clinical-pathological features can have an unexpected, aggressive evolution, which entails the necessity of close and prolonged clinical follow-up of patients, including those with lesions considered without risk.

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“… 10 The association between low vitamin D and ulceration has been hypothesized to be the result of altered Wnt/β-catenin signaling. 22 In 2017, von Schuckmann et al showed that patients who regularly used statins, aspirin or NSAIDs were less likely to be diagnosed with an ulcerated melanoma when incidence was adjusted for age, sex, thickness and mitotic rate (OR 0.68, 95% CI 0.46–1.00). 23 While early epidemiologic studies suggested that statins may prevent melanoma development, more recent studies do not support this finding.…”

Section: Introductionmentioning

confidence: 99%

Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype

Barricklow¹,

DiVincenzo²,

Carson³

et al. 2022

CCID

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The presence of ulceration in melanoma is associated with poor clinical outcomes and is the third most powerful predictor of survival in the AJCC Melanoma Staging System after tumor thickness and mitotic activity. The aggressive biological behavior associated with ulceration has been hypothesized to be the result of an intrinsic biological attribute that favors dissemination and presents locally with the loss of epidermal integrity. Among the features of ulcerated melanoma, many show promise as potential prognostic tools, markers of differential immunogenicity and indicators of oncogenic drivers of invasion and metastasis. The incidence of ulcerated melanoma is greater in males, increases with age and with systemic inflammatory risk factors (diabetes, smoking, low vitamin D, elevated body mass index). Patients with ulcerated primary tumors seem to exclusively benefit from adjuvant interferon (IFN) therapy, which is likely the consequence of an altered tumor microenvironment. When ulceration is present, there is a higher density of macrophages and dendritic cells and enhanced expression of pro-inflammatory cytokines, such as IL-6. There is also an increased expression of proteins involved in tumor antigen presentation in ulcerated melanomas. Histologically, vascular density, vasculogenic mimicry and angiotropism are all significantly correlated with ulceration in melanoma. The presence of ulceration is associated with reduced protein expression of E-cadherin and PTEN and elevated levels of N-cadherin and the matrix metalloproteinases. Differential microRNA expression also holds promise as a potential prognostic biomarker of malignancy and disease spread within the setting of ulceration. However, the molecular and cellular differences associated with the ulcerated state are complex and further study will aid in determining how these differences can be harnessed to improve care for patients with melanoma.

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Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro‐tumourigenicity

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 5 publications

References 69 publications

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Prognostic Significance of Incipient Ulceration in Primary Cutaneous Melanoma

Invasive Cutaneous Melanoma: Evaluating the Prognostic Significance of Some Parameters Associated with Lymph Node Metastases

Ulcerated Cutaneous Melanoma: A Review of the Clinical, Histologic, and Molecular Features Associated with a Clinically Aggressive Histologic Phenotype

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