Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis

  • Authors:
    • Piotr Donizy
    • Maciej Kaczorowski
    • Marek Leskiewicz
    • Marcin Zietek
    • Malgorzata Pieniazek
    • Cyprian Kozyra
    • Agnieszka Halon
    • Rafal Matkowski
  • View Affiliations

  • Published online on: October 6, 2014     https://doi.org/10.3892/or.2014.3531
  • Pages: 2735-2743
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Abstract

The presence of ulceration has been considered as one of the most important primary tumor characteristics of cutaneous malignant melanoma (CMM) for predicting patient outcome. Yet recently, scientific attention has been drawn towards another microscopic feature of primary tumors, the mitotic rate (MR). The present study aimed to examine the relationship between the presence of ulceration and the mitotic rate and clinicopathological characteristics and melanoma patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations. Tissue samples were obtained from 104 patients treated for CMM. In classical H&E staining, the mitotic rate and the presence of ulceration were evaluated. Non-mitogenic tumors were defined as having 0 mitoses/mm2, low mitogenic potential, 1-2 mitoses/mm2 and highly mitogenic tumors, ≥3 mitoses/mm2. In the entire group of 104 patients, a high mitotic rate (hMR) and ulceration were highly negative prognostic factors, and indicated considerably shorter overall survival, cancer-specific overall survival and disease-free survival. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in both the pT1 (P=0.001) and pT2 subgroups (P=0.006). Kaplan‑Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in the 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05). Multivariate analysis confirmed that hMR was strongly associated with an unfavorable prognosis. Ulceration had no prognostic significance in the Cox proportional hazards model. Considering the biology of melanoma, hMR seems to be a more reliable parameter than the presence of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases.

Introduction

Cutaneous malignant melanoma (CMM) is the most deadly form of skin neoplasm. With an estimated mortality of over 55,000 worldwide in 2012 which is increasing yearly and even with a more rapidly growing incidence, CMM has become a major challenge for modern oncology (1). Detailed studies are required to provide accurate risk stratification and to better identify the groups of patients in need of tailored treatment strategies.

In melanomas, multiple factors with potential prognostic value have been described over the years (25). Breslow thickness still remains the most powerful prognostic factor and is a substantial component of every CMM pathology report (6). The presence of ulceration has been considered as the second most important primary tumor characteristic for the purpose of predicting patient outcome (5). With the exception of traumatic disruption of the epidermis, ulceration has been a key element in the last two editions of the melanoma TNM staging guidelines of the American Joint Committee on Cancer (AJCC) - its presence verified in microscopic evaluation of changes in the pT stage from pTxa to pTxb (6,7).

Recently, scientific attention has been drawn towards another microscopic feature of the primary tumor, the mitotic rate (MR). The inclusion of this parameter in multivariate models confirmed its significance in risk stratification, particularly in localized melanomas (810). Additionally, several studies have indicated that MR has a higher impact than ulceration (8,11,12). As a valuable parameter that reflects tumor proliferative activity and aggressiveness, MR has recently been introduced into the AJCC melanoma staging system (6). Under current recommendations, MR is defined as the number of mitotic figures per square millimeter and a value ≥1 upstages the T subcategory of the pTNM classification from a to b, but only at the pT1 level (6). Clinically, this translates into a recommendation for sentinel lymph node biopsy for patients presenting with pT1b, although not for those with pT1a stage tumors (6).

The present study aimed to examine the relationship between key melanoma prognosticators, namely the presence of ulceration and mitotic rate against clinicopathological characteristics and patient survival, and to discuss the results in the context of AJCC melanoma staging recommendations.

Materials and methods

Patients

The study group consisted of 104 patients with CMM, who were diagnosed between 2005 and 2010 and treated at the Lower Silesian Oncology Center in Wrocław, Poland. The group was selected on the basis of tissue material (paraffin blocks and histopathology slides) and the availability of medical documentation. Comprehensive clinical data were obtained from archival medical records. The diagnostic and therapeutic procedures utilized were determined from medical records in the Oncology Outpatient Clinic of the Lower Silesian Oncology Center and data provided by the Lower Silesian Cancer Registry and Civil Register Office. The study was approved by the Institutional Review Board of the Wrocław Medical University, Poland.

The clinicopathological profile of the patients included the following parameters: age and gender, primary tumor location, tumor stratification according to AJCC, presence or absence of nodal (pT or pN) and distant (pM) metastases, information on disease recurrence and sentinel lymph node biopsy (SLNB) procedures (Table I).

Table I

Clinicopathological characteristics of the cutaneous malignant melanoma patients.

Table I

Clinicopathological characteristics of the cutaneous malignant melanoma patients.

Clinicopathological characteristicsNo (%)High mitotic rate (≥3/mm2)P-valueUlcerationP-value
All patients104 (100.0)3349
Age (years)0.5980.205
 Range (21–79)a
 Mean: 56.5±15.4
 Median: 58.5
Genderb0.5760.313
 Female60 (57.7)1930
 Male44 (42.3)1419
Primary tumor locationc0.4940.056
 Head/neck15 (14.4)711
 Upper extremities18 (17.3)48
 Lower extremities25 (24.0)79
 Trunk42 (40.4)1317
 Hand/foot4 (3.8)24
Primary tumor (pT)a<0.001<0.001
 pT134 (32.7)22
 pT220 (19.2)26
 pT327 (26.0)1320
 pT423 (22.1)1621
Sentinel lymph node biopsy status (SNLB)b60 (57.7)0.0020.001
 No metastases (SNLB)48 (80.0)614
 Metastases present (SNLB+)12 (20.0)710
Regional lymph nodes status (pN)b <0.001 <0.001
 No metastases (pN)86 (82.7)2033
 Metastases present (pN+)18 (17.3)1316
Recurrenceb0.0410.093
 No87 (83.7)2438
 Yes17 (16.3)911
Distant metastasesb0.0340.147
 No99 (95.2)2945
 Yes5 (4.8)44

a P-value, Mann-Whitney’s U test;

b P-value, Fisher’s exact test;

c P-value, χ2 test.

{ label (or @symbol) needed for fn[@id='tfn4-or-32-06-2735'] } Statistically significant results (P<0.05) are indicated in bold font.

Tumor samples and histopathological evaluation

Tumor specimens were fixed in 10% buffered formalin and embedded in paraffin. All haematoxylin and eosin (H&E) stained sections were examined by two pathologists. The parameters of the primary tumor recorded in pathology reports included Breslow thickness, Clark level, growth phase, histologic type, mitotic rate (number of mitotic figures per 1 mm2), presence of ulceration, lymphangioinvasion, microsatellitosis, intensity of lymphocytic inflammatory infiltrate (TILs, tumor-infiltrating lymphocytes) and microscopic evidence of regression (Table II).

Table II

Correlations between high mitotic rate (hMR) and the presence of ulceration and histopathological characteristics of the cutaneous malignant melanoma primary tumors.

Table II

Correlations between high mitotic rate (hMR) and the presence of ulceration and histopathological characteristics of the cutaneous malignant melanoma primary tumors.

Histopathological characteristicsNo. (%)High mitotic rate (≥3/mm2)P-valueUlcerationP-value
Breslow thicknessa <0.001 <0.001
 <1 mm34 (32.7)22
 1.01–2.00 mm20 (19.2)25
 2.01–4.00 mm27 (26.0)1621
 >4 mm23 (22.1)1321
Clark levela <0.001 <0.001
 I0 (0.0)00
 II18 (17.3)10
 III49 (47.1)1017
 IV26 (25.0)1522
 V11 (10.6)710
Histologic typeb <0.001 <0.001
 Superficial spreading melanoma (SSM)68 (65.4)1118
 Nodular malignant melanoma (NMM)32 (30.8)2027
 Acral-lentiginous melanoma (ALM)4 (3.8)24
Mitotic ratea <0.001
 045 (43.3)4
 1–226 (25.0)16
 ≥333 (31.7)29
Ulcerationc <0.001
 No55 (52.9)4
 Yes49 (47.1)29
Lymphangioinvasionc <0.001 <0.001
 No74 (71.2)1125
 Yes30 (28.8)2224
Growth phasec0.3140.144
 Radial3 (2.9)00
 Vertical101 (97.1)3349
Tumor-infiltrating lymphocytes (TILs)b0.010 <0.001
 No18 (17.3)1013
 Nonbrisk34 (32.7)1322
 Brisk52 (50)1014
Microsatellitosisc0.0120.078
 No98 (94.2)2844
 Yes6 (5.8)55
Tumor regressionc0.4950.295
 No96 (92.3)3044
 Yes8 (7.7)35

a P-value, Mann-Whitney’s U-test;

b P-value, χ2 test;

c P-value, Fisher’s exact test.

{ label (or @symbol) needed for fn[@id='tfn8-or-32-06-2735'] } Statistically significant results (P<0.05) are indicated in bold font.

Statistical analysis

Statistical analysis was performed using the Statistica 10.0 and IBM SPSS 21 software packages. Overall survival (OS) was defined as the time between the primary surgical treatment and death, and OS was censored at last follow-up for patients who were still alive. Disease-free survival (DFS) was defined as the time between the primary surgical treatment and the date of relapse. DFS was censored at the last follow-up for patients who survived without disease recurrence or at the date of non-cancer-associated death. Cancer-specific overall survival (CSOS) was defined as the time between the primary surgical treatment and cancer-associated death, and was censored at the last follow-up for surviving patients.

A χ2 test, exact Fisher’s test in the case of 2×2 tables and Spearman’s rank correlation were used to analyze the associations between mitotic rate and the presence of ulceration and clinicopathological parameters. Differences between the means were tested with a nonparametric test (Mann-Whitney U test and Kruskal-Wallis test); the log-rank test was used to compare survival in two groups. The overall survival rate was estimated by the Kaplan-Meier method and the influence of explanatory variables on death risk was analyzed by means of the Cox proportional hazard regression. A P-value <0.05 was considered to indicate a statistically significant difference.

Results

MR and the presence of ulceration in 104 melanoma patients

The mitotic activity of the primary tumors was divided into three categories: no mitotic activity (0 mitoses/mm2), low activity (1–2 mitoses/mm2) and high mitotic rate (hMR; ≥3 mitoses/mm2) (Fig. 1A–D). No mitotic activity was detected in 45 patients (43.3%), whereas low MR was observed in 26 patients (25%). High proliferative activity was observed in 33 patients (31.7% of the study group). Analysis of MR in melanomas of various degrees of clinical advancement with regard to pT stage of the primary tumor revealed that only a small percentage of early (pT1 and pT2) tumors exhibited hMR (6 and 10%, respectively). In the advanced disease, hMR tumors accounted for 48 and 70%, respectively in T3 and T4 melanomas (Table I).

Ulceration was observed in 49% of the tumors (Fig. 2A–D). Within the pT1 group of tumors, only a small number (6%) of tissue specimens showed microscopic evidence of ulceration. Interestingly, 30% of pT2 melanomas were ulcerated. Advanced (pT3 and pT4) tumors were characterized by a significantly higher prevalence of ulceration (74 and 91%, respectively) (Table I).

Correlations between hMR and clinicopathological parameters

A high mitotic rate was significantly correlated with higher advancement of the primary tumor (pT; P<0.001), the presence of nodal and distant metastases (P<0.001 and P=0.034, respectively), positive status for sentinel lymph node (P=0.002) and disease recurrence (P=0.041). Furthermore, hMR was strongly associated with deeper infiltration according to Breslow thickness (P<0.001) and Clark level (P<0.001), the presence of ulceration (P<0.001), lymphangioinvasion (P<0.001), microsatellitosis (P=0.012) and histologic type (nodular) of the primary tumor (P<0.001). Interestingly, hMR was related to a lower intensity of lymphocytic inflammatory infiltrate (P=0.01). No other significant correlations were found between hMR and the other analyzed clinicopathological parameters, including gender, age, location and growth phase of the primary tumor and microscopic evidence of its regression (Table II).

Correlations between the presence of ulceration and clinicopathological parameters

The presence of ulceration was significantly correlated with higher advancement of the primary tumor (pT; P<0.001) and with the presence of metastases in sentinel lymph nodes (P=0.001) and regional lymph nodes (P<0.001). It was further demonstrated that the presence of ulceration was associated with deeper tumor infiltration according to Breslow thickness (P<0.001) and Clark level (P<0.001), hMR (P<0.001), lymphangionvasion (P<0.001) and histologic type (nodular and acral-lentiginous) of the primary tumor (P<0.001). Another relationship was revealed between a decrease in lymphocytic inflammatory infiltrate intensity and ulceration of the primary tumor (P<0.001). No further correlations were found regarding the presence of ulceration and other analyzed clinicopathological characteristics (Table II).

Impact of a high mitotic rate and ulceration on the 5-year survival in melanoma patients

In the entire group of 104 patients, hMR was a highly negative prognostic factor, and indicated considerably shorter OS, CSOS and DFS (P=0.002, P=0.004 and P<0.001, respectively) (Fig. 3A, C and E). Similar relationships were observed for ulceration, which also acted as a negative prognosticator for the entire study population (P=0.001 for OS, P=0.003 for CSOS and P=0.003 for DFS) (Fig. 3B, D and F).

An important aspect of this study was to analyze the prognostic significance of hMR and the presence of ulceration in particular pT stages of primary tumor advancement. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in the pT1 (P=0.001) and pT2 subgroups (P=0.006) (Fig. 4A and B). Kaplan-Meier analysis of the remaining subsets (pT3 and pT4) did not reveal any important differences in 5-year survival with regard to MR values (Fig. 4C and D).

The presence of ulceration also had a prognostic significance for early melanomas, but only for pT1 tumors (P=0.05) (Fig. 5A). Kaplan-Meier analysis of the other groups (pT2–T4) did not show any influence of ulceration on the 5-year survival (Fig. 5B–D).

Multivariable Cox regression analysis

Multivariate analysis confirmed that a high mitotic rate and the presence of distant metastases were strongly associated with an unfavorable prognosis (hMR: P=0.005; HR, 1.247; 95% CI, 1.069–1.456; pM: P=0.001; HR, 5.071; 95% CI, 1.883–13.656). Ulceration had no prognostic significance in the Cox proportional hazards model.

Discussion

The aim of the present study was to investigate the relevance of the mitotic rate and primary tumor ulceration for the prognosis of CMM, as well as correlations with other clinicopathological features. In our study group of 104 patients, hMR and the presence of ulceration were highly negative prognostic factors, strongly correlated with shorter overall and cancer-specific overall survival. An important aspect of the study was to analyze the prognostic significance of hMR and the presence of ulceration in particular pT stages of primary tumor advancement. Notably, hMR appeared to have a statistically significant negative impact on survival in early melanomas in the pT1 (P=0.001) and pT2 subgroups (P=0.006), whereas Kaplan-Meier analysis for pT3 and pT4 tumors did not reveal any important differences in 5-year survival with regard to MR values. The presence of ulceration also had a prognostic significance, but only for pT1 melanomas (P=0.05). Kaplan-Meier analysis of other groups (pT2–T4) did not show any influence of ulceration on 5-year survival.

The negative effect of elevated MR on patient survival has been addressed in numerous studies and currently, this parameter, albeit in a very limited way, affects the TNM staging of CMM (6,8,1014). However, there are other examples in the literature indicating a far greater significance of MR than that provided by the current version of AJCC recommendations. In the study of Zettersten et al increased MR negatively impacted overall survival in a population of patients with thick (>4 mm) CMM (15). Nagore et al demonstrated that in 823 localized invasive tumors, MR was the most important prognostic factor of disease-free survival in a multivariable analysis when Breslow thickness was considered as a continuous variable (16).

Considering our results, the mitotic rate emerged as a powerful parameter providing information on patient survival, and on other crucial clinicopathological features. Thus hMR is related to more advanced metastatic cancers and to greater risk of disease recurrence. The relationship between hMR and distant metastases has been recently reported by Murali et al (17). Moreover, our study confirms an association between hMR and positivity of SNLB, which supports the validity of the AJCC recommendation to upstage from pT1a to pT1b based on increased MR (8,9,14). An inverse correlation between MR and TIL grade has been noted by Azimi et al (18), but refuted by others (16).

Another aspect of our study was the analysis of the prognostic significance of ulceration and investigation of correlations between ulceration status and other clinicopathological parameters. There are examples in the literature which demonstrate that the impact of ulceration on melanoma pathology is unclear. Meanwhile, according to some studies, ulceration loses its role as an independent adverse prognostic factor when MR is included in multivariable models (12,17,19). Eigentler et al reported that the presence or absence of ulceration does not influence survival in multivariable analyses of putative CMM prognostic factors among pT1 and pT4 tumors, while it remains significant in intermediate (pT2 and pT3) melanomas. However, MR was not considered in this study (20). It should be said here that determining a universal and coherent definition of tumor-derived (and only tumor-derived) ulceration is another problem, resulting in inter-observer reproducibility that is not entirely satisfactory (21).

In regards to the other correlations observed between ulceration and clinicopathological characteristics, our data are generally concordant with other reports. Whereas no differences relating to the presence of ulceration were found in regards to gender, age and primary tumor location, the findings support the broad consensus that ulcerated lesions are thicker and more deeply invasive (5,22,23). An association between ulcerated melanomas and nodular histologic type has also been previously observed (22). In accordance with our results, the presence of ulceration has been postulated as a predictor of sentinel lymph node involvement (14,24). An interesting aspect reported by Balch et al and confirmed by our study is the relationship between scanty lymphocytic infiltrate and the presence of ulceration (25).

Considering the biology of melanoma, MR seems to be a more reliable parameter than the presence or otherwise of ulceration. The value of MR categorizes melanomas into tumors with low or high proliferative potential, thus giving direct information concerning their capacity to infiltrate deeper layers of the dermis and, potentially, to generate regional lymph node and distant metastases. MR is a much more objective parameter than ulceration and its origin is never artifactual. Instead, it always reflects the true biology of the tumor, independently of the infiltration depth and extent of epidermal disruption. In the authors’ opinion, ulceration is a valuable parameter that mirrors the invasive potential of melanoma cells, albeit, primarily in moderately advanced (pT1 and pT2) tumors. In these cases, the etiopathogenesis of ulceration, strictly related to the destructive influence of neoplastic melanocytes (so called consumption of the epidermis), is doubtlessly cancer related.

In more deeply infiltrating (pT3, pT4) tumors, ulceration loses its role as an objective parameter associated with the nature of melanoma cells and reflecting their aggressive behavior. In advanced melanomas, the ulceration may be etiologically unrelated to epidermal consumption by cancer cells and may be only a morphological manifestation of a purely mechanical external injury. Although an analogous situation may also occur in non-advanced tumors, it is much less probable.

To sum up, both hMR and ulceration have a very significant influence on the outcome of patients with cutaneous melanoma. However, as stressed above, it is hMR that is a much more objective parameter, more accurately reflecting the biology of a particular tumor. Because of our relatively small study population, further larger-scale investigations are needed to more precisely determine the pathophysiological role and prognostic significance of hMR and ulceration, particularly in patients with early melanoma, in whom more intensive therapy and/or more extensive post-operative follow-up may be justified in order to improve the prognosis.

Acknowledgements

This study was supported by Wroclaw Medical University research grant Pbmn108.

References

1 

Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: GLOBOCAN 2012 Cancer Incidence and Mortality Worldwide. IARC CancerBase V1.0. (11)International Agency for Research on Cancer; Lyon: 2013

2 

Clark WH Jr, From L, Bernardino EA and Mihm MC: The histogenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 29:705–727. 1969.PubMed/NCBI

3 

Breslow A: Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 172:902–908. 1970. View Article : Google Scholar : PubMed/NCBI

4 

Balch CM, Murad TM, Soong SJ, Ingalls AL, Halpern NB and Maddox WA: A multifactorial analysis of melanoma: prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg. 188:732–742. 1978.PubMed/NCBI

5 

Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH and Morabito A: Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 19:3622–3634. 2001.

6 

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ and Sondak VK: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 27:6199–6206. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A Jr, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA and Thompson JF: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 19:3635–3648. 2001.PubMed/NCBI

8 

Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, Flaherty KT, Gimotty PA, Johnson T, Johnson MM, Leong SP, Ross MI, Byrd DR, Cascinelli N, Cochran AJ, Eggermont AM, McMasters KM, Mihm MC Jr, Morton DL and Sondak VK: Prognostic significance of mitotic rate in localized primary cutaneous melanoma: an analysis of patients in the multi-institutional American Joint Committee on Cancer melanoma staging database. J Clin Oncol. 29:2199–2205. 2011. View Article : Google Scholar

9 

Kesmodel SB, Karakousis GC, Botbyl JD, Canter RJ, Lewis RT, Wahl PM, Terhune KP, Alavi A, Elder DE, Ming ME, Guerry D, Gimotty PA, Fraker DL, Czerniecki BJ and Spitz FR: Mitotic rate as a predictor of sentinel lymph node positivity in patients with thin melanomas. Ann Surg Oncol. 12:449–458. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Ding S, Byrd DR, Cascinelli N, Cochran AJ, Coit DG, Eggermont AM, Johnson T, Kirkwood JM, Leong SP, McMasters KM, Mihm MC Jr, Morton DL, Ross MI and Sondak VK: Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 28:2452–2459. 2010. View Article : Google Scholar

11 

Azzola MF, Shaw HM, Thompson JF, Soong SJ, Scolyer RA, Watson GF, Colman MH and Zhang Y: 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. 97:1488–1498. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Barnhill RL, Katzen J, Spatz A, Fine J and Berwick M: The importance of mitotic rate as a prognostic factor for localized cutaneous melanoma. J Cutan Pathol. 32:268–273. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Francken AB, Shaw HM, Thompson JF, Soong SJ, Accortt NA, Azzola MF, Scolyer RA, Milton GW, McCarthy WH, Colman MH and McGovern VJ: The prognostic importance of tumor mitotic rate confirmed in 1317 patients with primary cutaneous melanoma and long follow-up. Ann Surg Oncol. 11:426–433. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Spatz A, Stock N, Batist G and van Kempen LC: The biology of melanoma prognostic factors. Discov Med. 10:87–93. 2010.PubMed/NCBI

15 

Zettersten E, Sagebiel RW, Miller JR III, Tallapureddy S, Leong SP and Kashani-Sabet M: Prognostic factors in patients with thick cutaneous melanoma (>4 mm). Cancer. 94:1049–1056. 2002. View Article : Google Scholar

16 

Nagore E, Oliver V, Botella-Estrada R, Moreno-Picot S, Insa A and Fortea JM: Prognostic factors in localized invasive cutaneous melanoma: high value of mitotic rate, vascular invasion and microscopic satellitosis. Melanoma Res. 15:169–177. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Murali R, Haydu LE, Long GV, Quinn MJ, Saw RP, Shannon K, Spillane AJ, Stretch JR, Kefford RF, Thompson JF and Scolyer RA: Clinical and pathologic factors associated with distant metastasis and survival in patients with thin primary cutaneous melanoma. Ann Surg Oncol. 19:1782–1789. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Azimi F, Scolyer RA, Rumcheva P, Moncrieff M, Murali R, McCarthy SW, Saw RP and Thompson JF: Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 30:2678–2683. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Han D, Zager JS, Shyr Y, Chen H, Berry LD, Iyengar S, Djulbegovic M, Weber JL, Marzban SS, Sondak VK, Messina JL, Vetto JT, White RL, Pockaj B, Mozzillo N, Charney KJ, Avisar E, Krouse R, Kashani-Sabet M and Leong SP: Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 31:4387–4393. 2013. View Article : Google Scholar : PubMed/NCBI

20 

Eigentler TK, Buettner PG, Leiter U and Garbe C: Impact of ulceration in stages I to III cutaneous melanoma as staged by the American Joint Committee on Cancer Staging System: an analysis of the German Central Malignant Melanoma Registry. J Clin Oncol. 22:4376–4383. 2004. View Article : Google Scholar

21 

Spatz A, Cook MG, Elder DE, Piepkorn M, Ruiter DJ and Barnhill RL: Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas. Eur J Cancer. 39:1861–1865. 2003. View Article : Google Scholar : PubMed/NCBI

22 

Taylor RC, Patel A, Panageas KS, Busam KJ and Brady MS: Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 25:869–875. 2007. View Article : Google Scholar : PubMed/NCBI

23 

Ostmeier H, Fuchs B, Otto F, Mawick R, Lippold A, Krieg V and Suter L: Can immunohistochemical markers and mitotic rate improve prognostic precision in patients with primary melanoma? Cancer. 85:2391–2399. 1999. View Article : Google Scholar : PubMed/NCBI

24 

Niakosari F, Kahn HJ, McCready D, Ghazarian D, Rotstein LE, Marks A, Kiss A and From L: Lymphatic invasion identified by monoclonal antibody D2–40, younger age, and ulceration: predictors of sentinel lymph node involvement in primary cutaneous melanoma. Arch Dermatol. 144:462–467. 2008.

25 

Balch CM, Wilkerson JA, Murad TM, Soong SJ, Ingalls AL and Maddox WA: The prognostic significance of ulceration of cutaneous melanoma. Cancer. 45:3012–3017. 1980. View Article : Google Scholar : PubMed/NCBI

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December-2014
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Spandidos Publications style
Donizy P, Kaczorowski M, Leskiewicz M, Zietek M, Pieniazek M, Kozyra C, Halon A and Matkowski R: Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis. Oncol Rep 32: 2735-2743, 2014
APA
Donizy, P., Kaczorowski, M., Leskiewicz, M., Zietek, M., Pieniazek, M., Kozyra, C. ... Matkowski, R. (2014). Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis. Oncology Reports, 32, 2735-2743. https://doi.org/10.3892/or.2014.3531
MLA
Donizy, P., Kaczorowski, M., Leskiewicz, M., Zietek, M., Pieniazek, M., Kozyra, C., Halon, A., Matkowski, R."Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis". Oncology Reports 32.6 (2014): 2735-2743.
Chicago
Donizy, P., Kaczorowski, M., Leskiewicz, M., Zietek, M., Pieniazek, M., Kozyra, C., Halon, A., Matkowski, R."Mitotic rate is a more reliable unfavorable prognosticator than ulceration for early cutaneous melanoma: A 5-year survival analysis". Oncology Reports 32, no. 6 (2014): 2735-2743. https://doi.org/10.3892/or.2014.3531