Meta-analyses were performed to examine the utility of ultrasonography, computed tomography (CT), positron emission tomography (PET), and a combination of both (PET-CT) for the staging and ...surveillance of melanoma patients.
Patient-level data from 74 studies containing 10,528 patients (between January 1, 1990, and June, 30, 2009) were used to derive characteristics of the diagnostic tests used. Meta-analyses were conducted by use of Bayesian bivariate binomial models to estimate sensitivity and specificity. Diagnostic odds ratios ie, true-positive results/false-negative results)/(false-positive results/true-negative results) and their 95% credible intervals (CrIs) and positive predictive values were used as indicators of test performance.
Among the four imaging methods examined for the staging of regional lymph nodes, ultrasonography had the highest sensitivity (60%, 95% CrI = 33% to 83%), specificity (97%, 95% CrI = 88% to 99%), and diagnostic odds ratio (42, 95% CrI = 8.08 to 249.8). For staging of distant metastases, PET-CT had the highest sensitivity (80%, 95% CrI = 53% to 93%), specificity (87%, 95% CrI = 54% to 97%), and diagnostic odds ratio (25, 95% CrI = 3.58 to 198.7). Similar trends were observed for melanoma surveillance of lymph node involvement, with ultrasonography having the highest sensitivity (96%, 95% CrI = 85% to 99%), specificity (99%, 95% CrI = 95% to 100%), and diagnostic odds ratio (1675, 95% CrI = 226.6 to 15,920). For distant metastases, PET-CT had the highest sensitivity (86%, 95% CrI = 76% to 93%), specificity (91%, 95% CrI = 79% to 97%), and diagnostic odds ratio (67, 95% CrI = 20.42 to 229.7). Positive predictive values were likewise highest for ultrasonography in lymph node staging and for PET-CT in detecting distant metastases.
Among the compared modalities, ultrasonography was superior for detecting lymph node metastases, and PET-CT was superior for the detection of distant metastases in both the staging and surveillance of melanoma patients.
Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data ...connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment.
The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines.
Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy–treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated.
Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we ...examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (
= 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (
= 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (
< 0.01) and relative abundance of bacteria of the Ruminococcaceae family (
< 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
We assessed the impact of lymphoedema (defined as ≥10% limb volume change) on quality of life (QOL), ability to perform activities of daily living (ADLs) and coping in 277 melanoma patients. Limb ...volume was measured prospectively, pre‐operatively and every 3–6 months for 18 months post‐operatively using a perometer. Three questionnaires were administered to measure QOL, coping and impact on ADLs. Statistical analyses were conducted using longitudinal logistic regression models. At 18 months, the cumulative incidence of lymphoedema was 31% in patients with upper extremity nodal basin treatment and 40% in lower extremity nodal basin treatment patients. Patients with lower extremity lymphoedema reported lower QOL scores than those with upper extremity lymphoedema. Over 18 months, both groups with mild and moderate lymphoedema showed improvement in coping odds ratio (OR): 6.67, 95% confidence interval (CI): 3.30–13.47 and performance of ADLs (OR: 7.46, CI: 3.38–16.47). Over the course of 18 months, men were found to have poorer coping scores than women (OR: 2.91, CI: 1.35–6.27). Lymphoedema was associated with improvement in coping over time (P = 0.08) and a higher reported interference with ADLs (OR: 2.53, CI: 1.29–4.97). Patient education about lymphoedema at the time of surgical consent may improve self‐efficacy and coping ability. Effective management of lymphoedema may improve patient QOL and reduce interference with ADLs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic ...melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Background
Whether melanoma in histological contiguity with a naevus naevus‐associated melanoma (NAM) is distinctly different from melanoma arising de novo remains unclear.
Objectives
To ...determine whether the characteristics of de novo melanoma differ from NAM and are not due to naevus obliteration in thicker tumours.
Methods
We conducted a multicentre retrospective study of de novo melanoma and NAM in seven referral centres in Europe, Australia and the USA between 2006 and 2015.
Results
In a total of 9474 localized melanomas, de novo melanoma was associated with thicker tumours and body site differences compared with NAM. In the subset of T1 melanomas (n = 5307), similar body site differences were found in multivariate analysis by body site. When compared with NAM, de novo melanoma was more likely to affect older individuals (≥ 70 years) when located on the head/neck odds ratio (OR) 4·65, 95% confidence interval (CI) 2·55–8·46, the trunk (OR 1·82, 95% CI 1·40–2·36) or the upper extremity (OR 1·69, 95% CI 1·14–2·50), was more likely to affect female patients when located on the lower extremities (OR 1·36, 95% CI 1·03–1·80), and was more likely to be of the nodular melanoma subtype (OR 2·23, 95% CI 1·14–4·35) when located on the trunk. De novo melanoma was less likely to have regression present compared with NAM.
Conclusions
Clinicopathological and body site differences between de novo melanoma and NAM support the divergent pathway model of development. These differences were also found in thin melanomas, suggesting that de novo melanomas are different from NAM and their differences are not due to the obliteration of naevus remnants in thicker tumours.
What is already known about this topic?
Cutaneous melanoma appears de novo in approximately 70% of cases and has adjacent naevus remnants on histological examination naevus‐associated melanoma (NAM) in the remaining 30% of cases.
Whether melanoma arising de novo is a biological type distinct from NAM remains unclear.
Robust conclusions on the differences between de novo melanoma and NAM have been hindered by the possible obliteration of naevus in thicker melanomas.
What does this study add?
In 9474 patients with localized melanoma there were body site differences for de novo melanoma compared with NAM, supporting the divergent pathway model of melanoma development.
In 5307 T1 melanomas there were similar body site associations for de novo melanoma and older age at diagnosis, female sex, the nodular subtype and absence of regression.
These findings suggest that de novo melanomas are different from NAM and the differences are not due to the obliteration of naevus remnants in thicker tumours.
Linked Comment: J. Wiggins and D. Polsky. Br J Dermatol 2021; 185:9–10.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in ...any cancer lineage. To determine the prevalence of AKT E17K mutations in melanoma, the most aggressive form of skin cancer, we analysed 137 human melanoma specimens and 65 human melanoma cell lines for the previously described activating mutation of AKT1, and for analogous mutations in AKT2 and AKT3. We identified a single AKT1 E17K mutation. Remarkably, a previously unidentified AKT3 E17K mutation was detected in two melanomas (from one patient) as well as two cell lines. The AKT3 E17K mutation results in activation of AKT when expressed in human melanoma cells. This represents the first report of AKT mutations in melanoma, and the initial identification of an AKT3 mutation in any human cancer lineage. We have also identified the first known human cell lines with naturally occurring AKT E17K mutations.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC).
The prognostic factors analysis described in the companion publication (this ...issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system.
Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy.
This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.
To compare the effect of pathologic sentinel lymph node (SLN) status with that of other known prognostic factors on recurrence and survival in patients with stage I or II cutaneous melanoma.
We ...reviewed the records of 612 patients with primary cutaneous melanoma who underwent lymphatic mapping and SLN biopsy between January 1991 and May 1995 to determine the effects of tumor thickness, ulceration, Clark level, location, sex, and SLN pathologic status on disease-free and disease-specific survival.
In the 580 patients in whom lymphatic mapping and SLN biopsy were successful, the SLN was positive by conventional histology in 85 patients (15%) but negative in 495 patients (85%). SLN status was the most significant prognostic factor with respect to disease-free and disease-specific survival by univariate and multiple covariate analyses. Although tumor thickness and ulceration influenced survival in SLN-negative patients, they provided no additional prognostic information in SLN-positive patients.
Lymphatic mapping and SLN biopsy is highly accurate in staging nodal basins at risk for regional metastases in primary melanoma patients and identifies those who may benefit from earlier lymphadenectomy. Furthermore, pathologic status of the SLN in these patients with clinically negative nodes is the most important prognostic factor for recurrence. The information from SLN biopsy is particularly helpful in establishing stratification criteria for future adjuvant trials.
The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and ...cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal.
There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients.
This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (< or = 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients.
The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.
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