Mitotic rate is associated with positive lymph nodes in patients with thin melanomas

doi:10.1016/j.jaad.2017.11.041

Journal of the American Academy of Dermatology

Volume 78, Issue 5, May 2018, Pages 935-941

https://doi.org/10.1016/j.jaad.2017.11.041 Get rights and content

Background

The American Joint Commission on Cancer will remove mitotic rate from its staging guidelines in 2018.

Objective

Using a large nationally representative cohort, we examined the association between mitotic rate and lymph node positivity among thin melanomas.

Methods

A total of 149,273 thin melanomas in the National Cancer Database were examined for their association of high-risk features of mitotic rate, ulceration, and Breslow depth with lymph node status.

Results

Among 17,204 patients with thin melanomas with data on Breslow depth, ulceration, and mitotic rate who underwent a lymph node biopsy, there was a strong linear relationship between odds of having a positive lymph node and mitotic rate (R² = 0.96, P < .0001, β = 3.31). The odds of having a positive node increased by 19% with each 1-point increase in mitotic rate (odds ratio, 1.19; 95% confidence interval, 1.17-1.21). Cases with negative nodes had a mean mitotic rate of 1.54 plus or minus 2.07 mitoses/mm² compared with 3.30 plus or minus 3.54 mitoses/mm² for those with positive nodes (P < .0001).

Limitations

The data collected do not allow for survival analyses.

Conclusions

Mitotic rate was strongly associated with the odds of having a positive lymph node and should continue to be reported on pathology reports.

Section snippets

Methods

This study was approved by the institutional review board of Vanderbilt University Medical Center and used the National Cancer Database (NCDB) melanoma file. The NCDB is a national registry that collects registry data from all Commission on Cancer–accredited facilities. It is reported to register more than 70% of all cancers occurring in the United States.¹⁶ Data captured include clinical and pathologic tumor, node, and metastasis (TNM) staging; pathologic features such as Breslow depth,

Results

There were 419,787 patients with melanoma in the NCDB from 2004 to 2013. Of these, 171,366 had a recorded Breslow depth of 0.01 to 1.00 mm. We excluded 9497 patients who were missing ulceration data and an additional 12,596 who were missing mitotic rate after 2010. Recording of these data for cases before the updated guidelines was not mandated, so we did not excluded those cases before 2010 that were missing data on mitotic rate. The final sample size included 149,273 thin melanomas (Fig 1).

Discussion

In a national database containing nearly 150,000 thin melanomas, including 17,000 cases with SLNB and data on mitotic rate, the odds of having a positive sentinel lymph node were strongly correlated with mitotic rate. Of those with an elevated mitotic rate, patients undergoing SLNB with a mitotic rate of 1 had a positive node 7.9% of the time (ranging to 44.5% with positive nodes among those with a mitotic rate of 11 or higher). With use of the 2010 AJCC staging guidelines cutoff of a mitotic

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Cited by (22)

Mitotic rate as a predictive factor for positive sentinel lymph nodes in pT1 and pT2 melanomas
2023, Journal of Plastic, Reconstructive and Aesthetic Surgery
Sentinel lymph node biopsy is a crucial step in the management of patients affected by melanoma. The decision whether to perform it or not is based on different histological parameters, but the mitotic rate is no longer considered a prognostic variable after the release of the 8th edition of the American Joint Committee on Cancer (AJCC) guidelines. Our objective was to investigate the risk factors that increase the chance for sentinel lymph node positivity in melanomas with a Breslow thickness of less than 2.00 mm, including the mitotic count. A retrospective single-center study was performed on a homogenous cohort of 408 patients treated for cutaneous melanoma. Histological and clinical features were gathered and correlated with the increased risk for sentinel lymph node positivity by means of univariate and multivariate analyses. A statistically significant correlation between a high mitotic index and a positive sentinel lymph node was found in pT1 and pT2 patients, suggesting that in the case of pT1a melanoma with a high number of mitoses, a discussion about whether a sentinel lymph node biopsy is required should be done.
Mitotic Rate as a Prognostic Factor in Melanoma: Implications for Disease Management
2021, Actas Dermo-Sifiliograficas
High Mitotic Rate Predicts Sentinel Lymph Node Involvement in Thin Melanomas
2020, Journal of Surgical Research
Citation Excerpt :
In the absence of ulceration, a high MR identifies a population of patients with T1 lesions that should be considered for SLN biopsy. Consistent with prior investigations, our analysis also demonstrated tumor location18,19 and ulceration6,13,15,18,20,21 to significantly influence SLN positivity. Unlike prior studies, depth was not associated with an increase in SLN positivity.
Indications for sentinel lymph node (SLN) biopsy in the population with thin melanoma have frequently changed over time. The objective of our study was to evaluate T1 melanoma pathologic features predictive of SLN positivity with a primary focus on identifying a specific mitotic value that is most predictive of lymph node disease. Further detailed predictive features would help physicians select patients with thin melanoma for SLN biopsy.
The Surveillance, Epidemiology, and End Results database was queried for all patients diagnosed with trunk or extremity cutaneous melanoma with ≤1 mm depth who underwent SLN biopsy between the years of 2010 and 2013. Patient demographics and tumor characteristics including depth, mitotic rate (MR), ulceration, and tumor location were evaluated. MR was dichotomized at multiple cut points to identify the ideal number of mitosis for MR as a predictor of SLN status. Multivariable logistic regression analyses were performed to identify the factors affecting nodal positivity and the impact of MR threshold. Kaplan-Meir curves were used for overall survival (OS) analysis.
Factors significantly associated with SLN positivity in the entire cohort included MR (P < 0.001, OR 1.24, 95% CI 1.18-1.31), tumor location (P = 0.017, OR 1.48, 95% CI 1.07-2.05), and ulceration (P < 0.001, OR 2.01, 95% CI 1.39-2.93,). An MR ≥ 4 was significant for SLN positivity (P = 0.049, OR 1.08, 95% CI 1.01-1.38). Mean OS was 46.7 mo for MR < 4 compared with 43.2 mo for MR ≥ 4 (P < 0.001).
MR ≥ 4 was significant and associated with SLN positivity in thin melanomas and asulceration. Thus, MR ≥ 4 should be considered as an indication for SLN biopsy in thin melanoma.
Genotoxic potential of a novel PDE-4B inhibitor Apremilast by chromosomal aberration and micronucleus assay in mice
2020, Saudi Pharmaceutical Journal
Citation Excerpt :
At low concentration Apremilast does not show cereblon binding. MI is the ratio of the number of cells undergoing mitotic division to the total number of cells (Wheless et al., 2018). MI is the measure of proliferation of cells (Bedekovics et al., 2018).
Researchers have confirmed that chronic administration of drugs at high doses causes genotoxicity which serve as first step in development of cancers. Apremilast, a phosphodiesterase-4 inhibitor is Food and Drug Administration (FDA) approved drug for Psoriatic Arthritis. The present study designed to conduct genotoxicity testing using the genotoxic study which give simple, sensitive, economical and fast tools for the assessment of damage of genetic material.
To conduct genotoxicity study of Apremilast, 60 Swiss albino male mice divided into 6 groups (n = 10). Group1 served as a normal control group without any treatment, Group 2 treated as a disease control and administered with cyclophosphamide 40 mg/kg, IP. Group 3, 4, 5 and 6 treated as test groups and received 10, 20, 40 and 80 mg/kg/day Apremilast respectively. The total duration of study was 13 weeks. At termination day animals were sacrificed and chromosomal aberration assay (BMCAA) and micronucleus assay (BMMNA) were performed to know the genotoxicity potential of Apremilast.
The results indicates significant rise in chromosomal aberrations (CA) frequency in bone marrow cells and decrease in the MI of the disease control animals as well as Apremilast treated groups. Further significant (p < 0.001; p < 0.0001) increase in score of micronucleated polychromatic erythrocytes (MNPCEs) and percentage of micronucleated PCEs per 1000 PCEs and decrease in the ratio of polychromatic/normochromatic erythrocytes (PCE/NCE) was observed in micronucleus assay. Genotoxic effect increases with the increase of Apremilast dose. Conclusion: Finding of present indicates that Apremilast shows genotoxic potential on high administration although further detailed toxicity studies required for confirmations.
Pathology of Melanoma
2020, Surgical Clinics of North America
Citation Excerpt :
It has recently been excluded from the AJCC staging for melanoma.69 It is an independent predictor, however, of SLN positivity and survival in melanoma patients.106,107 Thus, the prognostic value of mitosis in melanoma may be considered in clinical decision making.
Potential predictive value of cofilin-1 for metastasis occurrence in a small cohort of Argentinian patients with mid-low Breslow thickness melanoma
2019, Pathology Research and Practice
Citation Excerpt :
This is again related to the value of cofilin-1, in this case a little above the average value. Patients with melanomas with low values of BT generally have favorable outcomes, but there is a subgroup of them who will display recurrence or metastatic disease [13,47]. Our statistical analysis showed that we can set a cutoff for BT and the probability of metastasis occurrence considering the cofilin-1 level, adding evidence to the role of this protein as a prognostic biomarker in melanoma.
Nowadays, histopathological criteria for melanocytic lesions are the mainstay prognostic factors for melanoma. However, there are cases in which these parameters fall short to predict melanoma spread.
We recently demonstrated a correlation of cofilin-1 levels, a key protein for tumor invasion, with different histopathological parameters associated with melanoma malignancy as well as a negative correlation with survival. In order to broaden our previous findings, we aim to estimate the probability of a melanoma to metastasize as a function of both a conventional histopathological parameter (Breslow thickness, BT) and cofilin-1’s immunohistochemical expression levels, which we propose as a potential marker for metastasis.
We used a Bayesian approach to analyze clinical and cofilin-1 datasets formerly obtained from a patients' small cohort diagnosed with malignant melanocytic lesions since 2000 until 2008; classified at different tumor stages with or without detected metastasis and with at least 5 years of clinical follow-up.
Low BT values exhibited wide variance to predict metastasis occurrence, while the differential diagnostic value of cofilin-1 confirmed BT diagnosis or resulted more precise to predict outcome. Particularly, the probability of metastasis estimation improved when cofilin-1 was combined with BT for specific cases, where BT displayed large uncertainties.
Our analysis and the cofilin-1 determination provided statistically significant prognostic value in mid-low BT melanomas, which could complement further evaluation criteria to assist diagnosis and treatment decision-making. Moreover, the combined use of cofilin-1 with BT, if validated in follow-up studies, would be feasible to help patients’ selection for treatment and optimize health resources.

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Original articleMitotic rate is associated with positive lymph nodes in patients with thin melanomas

Background

Objective

Methods

Results

Limitations

Conclusions

Section snippets

Methods

Results

Discussion

Melanoma incidence and Breslow tumour thickness development in the central Alpine region of South Tyrol from 1998 to 2012: a population-based study

J Eur Acad Dermatol Venereol

Ten-year audit of melanoma in a central England population

Acta Derm Venereol

Increasing time trends of thin melanomas in the Netherlands: what are the explanations of recent accelerations?

Eur J Cancer

Time trends and latitudinal differences in melanoma thickness distribution in Australia, 1990-2006

Int J Cancer

Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006

J Am Acad Dermatol

Update on thin melanoma: outcome of an International Workshop

Adv Anat Pathol

Thin melanoma with nodal involvement: analysis of demographic, pathologic, and treatment factors with regard to prognosis

Ann Surg Oncol

Final version of 2009 AJCC melanoma staging and classification

J Clin Oncol

Prognostication in thin cutaneous melanomas

Arch Pathol Lab Med

Thin primary cutaneous malignant melanoma: a prognostic tree for 10-year metastasis is more accurate than American Joint Committee on Cancer Staging

J Clin Oncol

Identification of high-risk patients among those diagnosed with thin cutaneous melanomas

J Clin Oncol

Predictors of regional nodal disease in patients with thin melanomas

Ann Surg Oncol

Sentinel lymph node biopsy in patients with thin primary cutaneous melanoma

Ann Surg

Mitotic rate for thin melanomas: should a single mitotic figure warrant a sentinel lymph node biopsy?

Dermatol Surg

Using the National Cancer Database for outcomes research: a review

JAMA Oncol

Original article
Mitotic rate is associated with positive lymph nodes in patients with thin melanomas