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Value and prognostic significance of mitotic rate in a retrospective series of pT1 cutaneous malignant melanoma patients
Cancer Epidemiology 36 (2012) 303–305
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Value and prognostic significance of mitotic rate in a retrospective series of pT1 cutaneous malignant melanoma patients G. Ponti a,*, A. Pollio b, A.M. Cesinaro c, G. Pellacani a, C. Magnoni a, S. Seidenari a a
Department of Internal Medicine, Division of Dermatology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy Department of Odontostomatological and Maxillofacial Sciences, Oral Medicine Unit, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy c Department of Pathology, University of Modena and Reggio Emilia, Modena, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 September 2011 Received in revised form 2 November 2011 Accepted 14 November 2011 Available online 5 December 2011
Introduction: Patients affected by thin melanomas (1 mm) generally have a good prognosis; however, some have a recurrence and eventually die of the disease. The seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, introduced mitotic rate (MR) as one of the primary criteria for staging thin melanoma. Materials and methods In this study, we sought to determine the prognostic value of mitotic rate in a retrospective cohort of localized primary cutaneous melanoma patients. Results: In total, 286 cases of pT1 primary malignant melanoma occurring in the period 2003– 2008 were evaluated. Mitotic counts were re-assessed on standard sections of cases without mitosis and with at least 1 mitosis at diagnosis; 5-year follow-up and recurrence-free survival were available for all patients. Of the 56 radically treated pT1b melanoma patients, 4 (7.1%) had recurrent disease. These data support the efficacy of the incorporation of mitogenicity into AJCC staging for localized cutaneous melanoma and indicate the difficulties in the accuracy and reproducibility of the mitotic count system. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Thin melanoma pT1 melanoma Mitotic rate Mitotic figure
1. Introduction Patients affected by thin melanomas generally have a good prognosis, however, some have a recurrence and eventually die of the disease. These ‘high risk’ thin melanoma patients can be identified using prognostic models as indicated in the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, published in 2010, which will introduce mitotic rate (MR) as one of the primary criteria for staging of thin melanoma (1.0 mm). Tumor MR is an independent prognostic factor in clinically localized primary cutaneous melanoma and Balch et al. added the criterion of ‘mitotic rate greater than or equal to one’ (or mitogenicity) as a modifier of AJCC stage I [1]. Mitogenicity is relevant because it reflects the biology of tumor progression and it is currently used to stage thin melanomas. MR is crucial for distinguishing between T1a and T1b melanomas and these changes in the classification of melanoma have critical consequences for clinical and surgical management-related decisions. In fact, the current guidelines recommend sentinel lymph node (SLN) biopsy, even for patients with stage T1b melanoma [2].
* Corresponding author. Tel.: +39 59 4222929; fax: +39 59 4224271. E-mail address: [email protected] (G. Ponti). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.11.003
Different studies have discussed the interindividual reproducibility of MR in hematoxylin and eosin (H&E)-stained section [3,4]: the determination of the MR per mm2 of tumor is usually performed at 40 magnification; counting begins at the site with the most dermal mitoses (‘hot spots’) and continues with as many directly adjacent fields of view until 1 mm2 of dermal melanoma surface has been covered. The detected mitoses should be reported as an absolute number per mm2 and for thin melanomas, whose dermal tumor surface is less than 1 mm2, the mitoses from several sections should be counted until 1 mm2 of the dermal tumor surface has been visualized [5]. The aim of the present study was to evaluate the prognostic impact and reproducibility of mitotic count in a retrospective cohort of pT1 melanoma patients and to compare the results with clinical and histopathological variables. 2. Materials and methods To evaluate the clinical and prognostic features of mitotic count, we studied all patients with pT1 malignant melanoma diagnosed between 2003 and 2008. First, malignant melanoma (MM) patient databases were accessed to identify patients with pT1 melanoma diagnoses: a specific Melanoma Registry, collecting all of the cases diagnosed in the Dermatology Department of the University of Modena, was analysed and matched with the computerized data bank of the Pathology Department. Then, we proceeded to collect
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Table 1 pT1 melanoma patients’ characteristics diagnosed at the Dermatology Department of the University of Modena (Melanoma Registry 2003–2008).
No. patients (%) Age (years) Sex M/F <0.75 mm (%) >0.75 mm <1 mm <1 mitose 1–4 mitoses >4 mitoses Ulceration Location Head–neck Hand Trunk Upper limbs Lower limbs Lymphnodepositive evaluation Dead melanoma related 5-year follow-up (melanoma recurrence)
pT1a no. patients (%)
pT1b no. patients (%)
pT1 no. patients (%)
230 (80.4%) 56.1 17.1 110/120 196 (68.5%) 34 (11.9%) 230 (80.4%) 0 0 0
56 (19.6%) 55.4 17.2 27/29 31 (10.8%) 25 (8.7%) 0 47 (16.4%) 4 (1.4%) 5 (1.7%)
286 (100%) 55.9 17.1 142/144 227 (79.4%) 59 (20.6%) 230 (80.4%) 47 (16.4%) 4 (1.4%) 5 (1.7%)
37 (12.9%) 2 (0.7%) 96 (35.6%) 38 (13.3%) 57 (19.9%) 0 0 0
7 (2.4%) 1 (0.35%) 18 (6.3%) 14 (4.9%) 16 (5.6%) 3 (1.05%) 2 (0.7%) 4 (1.4%)
44 (15.4%) 3 (1.05%) 114 (39.9%) 52 (18.2%) 73 (25.5%) 3 (1.05%) 2 (0.7%) 4 (1.4%)
all of the H&E-stained slides of selected cases. The pathological specimens from the primary melanomas and recurrences were reported by pathologists in the Pathology Department of the University of Modena. Later, the H&E-stained slides were reexamined by two pathologists for the confirmation of MR. In particular, mitotic counts were re-assessed on standard sections of cases of primary malignant melanoma without mitosis and with at least one mitosis at diagnosis. The mitotic count was recorded on H&E-stained sections using a light microscope (400). Mitotic figures were counted at the base of the tumors in the most active area (‘hot spots’) in a minimum of four consecutive high-power fields (HPFs) (HPF size 0.29 mm2), and the number of mitosis per mm2 was calculated. The definition of observable MFs in the hematoxylin and eosin staining was adopted according to van Diest et al. [6] and comprised the following criteria: (1) absence of nuclear membrane signifying the end of prophase; (2) presence of condensed chromosomes, either clotted (beginning metaphase), arranged in a plane (metaphase or anaphase) or in separate clots (telophase), the latter counted as one MF10; and (3) hyperchromatic nuclei and apoptotic nuclei were ignored. For all patients, a 5-year follow-up was available. Complete information on patient survival and time and cause of death was available in all cases. Last date of follow-up was September 30, 2011, and median follow-up time for survivors was 72 months (range from 41 to 98). The following variables were recorded: date of histological diagnosis, sex, age at diagnosis, anatomical site of the primary tumor, and presence of metastases at diagnosis (local, regional, distant).
3. Results In total, 286 consecutive cases of pT1 melanoma (1 mm) occurring in the period 2003–2008 were included in this study (median age 56.5 years, median thickness. . .mm, range from 0.01 to 1.0 mm). Of these, 230 patients were pT1a and 56 were pT1b (56 with mitosis and 5 with ulceration at diagnosis). All primary melanomas were completely excised with histologically confirmed clear margins. Four (7,1%) recurrent melanomas (3 locoregional and 1 distant melanoma metastasis) were registered among the 56 pT1b patients with at least a single mitosis at diagnosis during the 5-year follow-up. None of the 230 pT1a patients reported recurrent melanoma in the same period of follow-up (Table 1). A concordance of 85% with the original mitotic figure count was revealed; in about 15% of cases, the MR was underestimated because it was reported as an index of 0.5 mm or <1 mm2 and not as a whole number. Statistical studies comparing the mitotic rate with other variables like as thickness, ulceration, Clark level, age, sex, localization and SLNB were performed and included in Table 2. Statistical analysis to study the factors predicting melanomaspecific survival was presented in Fig. 1. 4. Discussion Our finding of about 10% recurrent melanomas among pT1b patients is in agreement with the recurrence rate reported by an earlier large epidemiological study [7] and confirmed the critical
Table 2 Comparison of diagnostic parameters between pT1a and pT1b patients. pT1A
Mitoses/mm2 Ulceration Thickness (mm) Thickness < 0.75 (mm) Thickness > 0.75 mm <1 mm Clark level LNS LNS+
pT1B
Mean
95% CI
Median
0 0 0.48 0.22 0.41 0.16 0.88 0.07
0 0 0.46–0.51 0.39–0.44 0.85–0.9
0 0 0.44 0.4 0.87
2.3 0.48 0.22 0.42 0
2.2–2.4 0.17–0.27 0
2 0 0
25th and 75th percentile 0 0 0.11–0.65 0.11–0.52 0.8–0.9 2–3 0 0
P Value (Mann–Whitney test)
Mean
95% CI
Median
25th and 75th percentile
1.84 2.72 0.09 0.3 0.67 0.21 0.52 0.13 0.89 0.08
1.1–2.6 0.01–0.17 0.63–0.74 0.48–0.57 0.85–0.92
1 0 0.69 0.52 0.9
1–1 0 0.49–0.96 0.25–0.72 0.8–1
2.8 0.53 0.54 0.5 0.1 0.3
2.6–2.9 0.4–0.67 0.01–0.2
3 1 0
2–4 1–1 0–1
<0.0001 <0.0003 0.7 <0.0001 <0.0003
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Current guidelines recommend sentinel lymph node biopsy (SLN) for patients with stage pT1b melanomas [1,5,11], however, in our opinion, there are no clear evidence-based recommendations for those patients just with thin lesions and it is unclear which patients with thin melanoma should be recommended to receive more intrusive management (e.g., SLN biopsy and close follow-up) and which patients should simply be observed less frequently to detect additional primary lesions and the rare local recurrence or metastasis. Although the ability to draw conclusions was limited by the size and design of this retrospective study, our data support the efficacy of the incorporation of mitogenicity – even a single mitosis figure – into AJCC staging for melanoma, as currently, there are some practical difficulties in the detection and quantification of MR that will be resolved with immunohistochemical approaches. Conflict of interest disclosures The authors declare that they have no competing interests to disclose. Acknowledgements The authors would like to thank Silvana Ciardo and Carmelo Guarneri for their participation in the study. Fig. 1. pT1a, pT1b survival proportions.
prognostic role of even a single mitotic figure detected at primary melanoma evaluation. However, in our study, the re-evaluation of MR on a series selected retrospectively cast some doubts on the reproducibility of the mitotic figure count and indicates the requirement of further tools for more accurate MR quantification. The guidelines suggest that MR should be determined by first examining the tumor and identifying the ‘hot spot’ of greatest mitotic activity if one exists. Then the number of mitoses should be counted in contiguous high-power fields totaling 1 mm2. In most microscopes, this will be about 3 to 4 HPFs; however, the field area should be determined in individual microscopes by determining the diameter of a high-power field by using a stage micrometer or a ruler. The rate should be given as a whole number and tumors with a solitary mitosis in the dermal component (even though the total tumor volume occupies several square millimeters) are reported as having an index of 1 mm2 rather than an index of <1 mm2 [5,8]. However, this method is prone to practical and theoretical disadvantages and is susceptible to interobserver variability. Nuclear and cytoplasmic changes such as apoptosis, karyorrhexis and technique artifacts can obscure the accurate identification and quantification of MR. Despite a relatively high level of concordance among our pathologists in the assessment of MR, reliable staging is not possible in all cases. New approaches to this problem include the use of molecular biology techniques, immunohistochemistry (Ki-67; anti-pHH3) [9,10], and various methods of histological sectioning. In our in progress experience, Ki-67 immunohistochemistry analysis can improve the accuracy of mitotic figure assessment.
References [1] Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206. [2] Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, et al. 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 2011;29(June (16)):2199–205 [Epub 25 April 2011]. [3] Scolyer RA, Thompson JF, Shaw HM, McCarthy SW. The importance of mitotic rate as a prognostic factor for localized primary cutaneous melanoma. J Cutan Pathol 2006;33(May (5)):395–6 [author reply 397–399]. [4] Gershenwald JE, Soong SJ. Balch CM; American Joint Committee on Cancer (AJCC) Melanoma Staging Committee. 2010 TNM staging system for cutaneous melanoma and beyond. Ann Surg Oncol 2010;17(Jun (6)):1475–7. [5] Garbe C, Eigentler TK, Bauer J, Blo¨dorn-Schlicht N, Fend F, Hantschke M, et al. Histopathological diagnostics of malignant melanoma in accordance with the recent AJCC classification 2009: Review of the literature and recommendations for general practice. J Dtsch Dermatol Ges 2011;9(September (9)):690–9. [6] van Diest PJ, Baak JP, Matze-Cok P, Wisse-Brekelmans EC, van Galen CM, Kurver PH, et al. Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol 1992;23:603–7. [7] Gimotty PA, Botbyl J, Soong SJ, Guerry D. A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2005;23(31):8065–75. [8] The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Melanoma (Version 2.2010) & 2010 National Comprehensive Cancer Network, Inc. [WWW document]. URL: http://www.nccn.org [accessed on 23 August 2010]. [9] Ladstein RG, Bachmann IM, Straume O, Akslen LA. Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3 MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma. BMC Cancer 2010; 10(April):140. [10] Casper DJ, Ross KI, Messina JL, Sondak VK, Bodden CN, McCardle TW, et al. Use of anti-phosphohistone H3 immunohistochemistry to determine mitotic rate in thin melanoma. Am J Dermatopathol 2010;32(7):650–4. [11] Bichakjian CK, Halpern AC, Johnson TM, Hood A, Grichnik JM, Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 2011;65(5):1032–47.
Contents lists available at SciVerse ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Value and prognostic significance of mitotic rate in a retrospective series of pT1 cutaneous malignant melanoma patients G. Ponti a,*, A. Pollio b, A.M. Cesinaro c, G. Pellacani a, C. Magnoni a, S. Seidenari a a
Department of Internal Medicine, Division of Dermatology, University of Modena and Reggio Emilia, via del Pozzo 71, 41100 Modena, Italy Department of Odontostomatological and Maxillofacial Sciences, Oral Medicine Unit, School of Medicine and Surgery, Federico II University of Naples, Naples, Italy c Department of Pathology, University of Modena and Reggio Emilia, Modena, Italy b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 September 2011 Received in revised form 2 November 2011 Accepted 14 November 2011 Available online 5 December 2011
Introduction: Patients affected by thin melanomas (1 mm) generally have a good prognosis; however, some have a recurrence and eventually die of the disease. The seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, introduced mitotic rate (MR) as one of the primary criteria for staging thin melanoma. Materials and methods In this study, we sought to determine the prognostic value of mitotic rate in a retrospective cohort of localized primary cutaneous melanoma patients. Results: In total, 286 cases of pT1 primary malignant melanoma occurring in the period 2003– 2008 were evaluated. Mitotic counts were re-assessed on standard sections of cases without mitosis and with at least 1 mitosis at diagnosis; 5-year follow-up and recurrence-free survival were available for all patients. Of the 56 radically treated pT1b melanoma patients, 4 (7.1%) had recurrent disease. These data support the efficacy of the incorporation of mitogenicity into AJCC staging for localized cutaneous melanoma and indicate the difficulties in the accuracy and reproducibility of the mitotic count system. ß 2011 Elsevier Ltd. All rights reserved.
Keywords: Thin melanoma pT1 melanoma Mitotic rate Mitotic figure
1. Introduction Patients affected by thin melanomas generally have a good prognosis, however, some have a recurrence and eventually die of the disease. These ‘high risk’ thin melanoma patients can be identified using prognostic models as indicated in the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, published in 2010, which will introduce mitotic rate (MR) as one of the primary criteria for staging of thin melanoma (1.0 mm). Tumor MR is an independent prognostic factor in clinically localized primary cutaneous melanoma and Balch et al. added the criterion of ‘mitotic rate greater than or equal to one’ (or mitogenicity) as a modifier of AJCC stage I [1]. Mitogenicity is relevant because it reflects the biology of tumor progression and it is currently used to stage thin melanomas. MR is crucial for distinguishing between T1a and T1b melanomas and these changes in the classification of melanoma have critical consequences for clinical and surgical management-related decisions. In fact, the current guidelines recommend sentinel lymph node (SLN) biopsy, even for patients with stage T1b melanoma [2].
* Corresponding author. Tel.: +39 59 4222929; fax: +39 59 4224271. E-mail address: [email protected] (G. Ponti). 1877-7821/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.canep.2011.11.003
Different studies have discussed the interindividual reproducibility of MR in hematoxylin and eosin (H&E)-stained section [3,4]: the determination of the MR per mm2 of tumor is usually performed at 40 magnification; counting begins at the site with the most dermal mitoses (‘hot spots’) and continues with as many directly adjacent fields of view until 1 mm2 of dermal melanoma surface has been covered. The detected mitoses should be reported as an absolute number per mm2 and for thin melanomas, whose dermal tumor surface is less than 1 mm2, the mitoses from several sections should be counted until 1 mm2 of the dermal tumor surface has been visualized [5]. The aim of the present study was to evaluate the prognostic impact and reproducibility of mitotic count in a retrospective cohort of pT1 melanoma patients and to compare the results with clinical and histopathological variables. 2. Materials and methods To evaluate the clinical and prognostic features of mitotic count, we studied all patients with pT1 malignant melanoma diagnosed between 2003 and 2008. First, malignant melanoma (MM) patient databases were accessed to identify patients with pT1 melanoma diagnoses: a specific Melanoma Registry, collecting all of the cases diagnosed in the Dermatology Department of the University of Modena, was analysed and matched with the computerized data bank of the Pathology Department. Then, we proceeded to collect
G. Ponti et al. / Cancer Epidemiology 36 (2012) 303–305
304
Table 1 pT1 melanoma patients’ characteristics diagnosed at the Dermatology Department of the University of Modena (Melanoma Registry 2003–2008).
No. patients (%) Age (years) Sex M/F <0.75 mm (%) >0.75 mm <1 mm <1 mitose 1–4 mitoses >4 mitoses Ulceration Location Head–neck Hand Trunk Upper limbs Lower limbs Lymphnodepositive evaluation Dead melanoma related 5-year follow-up (melanoma recurrence)
pT1a no. patients (%)
pT1b no. patients (%)
pT1 no. patients (%)
230 (80.4%) 56.1 17.1 110/120 196 (68.5%) 34 (11.9%) 230 (80.4%) 0 0 0
56 (19.6%) 55.4 17.2 27/29 31 (10.8%) 25 (8.7%) 0 47 (16.4%) 4 (1.4%) 5 (1.7%)
286 (100%) 55.9 17.1 142/144 227 (79.4%) 59 (20.6%) 230 (80.4%) 47 (16.4%) 4 (1.4%) 5 (1.7%)
37 (12.9%) 2 (0.7%) 96 (35.6%) 38 (13.3%) 57 (19.9%) 0 0 0
7 (2.4%) 1 (0.35%) 18 (6.3%) 14 (4.9%) 16 (5.6%) 3 (1.05%) 2 (0.7%) 4 (1.4%)
44 (15.4%) 3 (1.05%) 114 (39.9%) 52 (18.2%) 73 (25.5%) 3 (1.05%) 2 (0.7%) 4 (1.4%)
all of the H&E-stained slides of selected cases. The pathological specimens from the primary melanomas and recurrences were reported by pathologists in the Pathology Department of the University of Modena. Later, the H&E-stained slides were reexamined by two pathologists for the confirmation of MR. In particular, mitotic counts were re-assessed on standard sections of cases of primary malignant melanoma without mitosis and with at least one mitosis at diagnosis. The mitotic count was recorded on H&E-stained sections using a light microscope (400). Mitotic figures were counted at the base of the tumors in the most active area (‘hot spots’) in a minimum of four consecutive high-power fields (HPFs) (HPF size 0.29 mm2), and the number of mitosis per mm2 was calculated. The definition of observable MFs in the hematoxylin and eosin staining was adopted according to van Diest et al. [6] and comprised the following criteria: (1) absence of nuclear membrane signifying the end of prophase; (2) presence of condensed chromosomes, either clotted (beginning metaphase), arranged in a plane (metaphase or anaphase) or in separate clots (telophase), the latter counted as one MF10; and (3) hyperchromatic nuclei and apoptotic nuclei were ignored. For all patients, a 5-year follow-up was available. Complete information on patient survival and time and cause of death was available in all cases. Last date of follow-up was September 30, 2011, and median follow-up time for survivors was 72 months (range from 41 to 98). The following variables were recorded: date of histological diagnosis, sex, age at diagnosis, anatomical site of the primary tumor, and presence of metastases at diagnosis (local, regional, distant).
3. Results In total, 286 consecutive cases of pT1 melanoma (1 mm) occurring in the period 2003–2008 were included in this study (median age 56.5 years, median thickness. . .mm, range from 0.01 to 1.0 mm). Of these, 230 patients were pT1a and 56 were pT1b (56 with mitosis and 5 with ulceration at diagnosis). All primary melanomas were completely excised with histologically confirmed clear margins. Four (7,1%) recurrent melanomas (3 locoregional and 1 distant melanoma metastasis) were registered among the 56 pT1b patients with at least a single mitosis at diagnosis during the 5-year follow-up. None of the 230 pT1a patients reported recurrent melanoma in the same period of follow-up (Table 1). A concordance of 85% with the original mitotic figure count was revealed; in about 15% of cases, the MR was underestimated because it was reported as an index of 0.5 mm or <1 mm2 and not as a whole number. Statistical studies comparing the mitotic rate with other variables like as thickness, ulceration, Clark level, age, sex, localization and SLNB were performed and included in Table 2. Statistical analysis to study the factors predicting melanomaspecific survival was presented in Fig. 1. 4. Discussion Our finding of about 10% recurrent melanomas among pT1b patients is in agreement with the recurrence rate reported by an earlier large epidemiological study [7] and confirmed the critical
Table 2 Comparison of diagnostic parameters between pT1a and pT1b patients. pT1A
Mitoses/mm2 Ulceration Thickness (mm) Thickness < 0.75 (mm) Thickness > 0.75 mm <1 mm Clark level LNS LNS+
pT1B
Mean
95% CI
Median
0 0 0.48 0.22 0.41 0.16 0.88 0.07
0 0 0.46–0.51 0.39–0.44 0.85–0.9
0 0 0.44 0.4 0.87
2.3 0.48 0.22 0.42 0
2.2–2.4 0.17–0.27 0
2 0 0
25th and 75th percentile 0 0 0.11–0.65 0.11–0.52 0.8–0.9 2–3 0 0
P Value (Mann–Whitney test)
Mean
95% CI
Median
25th and 75th percentile
1.84 2.72 0.09 0.3 0.67 0.21 0.52 0.13 0.89 0.08
1.1–2.6 0.01–0.17 0.63–0.74 0.48–0.57 0.85–0.92
1 0 0.69 0.52 0.9
1–1 0 0.49–0.96 0.25–0.72 0.8–1
2.8 0.53 0.54 0.5 0.1 0.3
2.6–2.9 0.4–0.67 0.01–0.2
3 1 0
2–4 1–1 0–1
<0.0001 <0.0003 0.7 <0.0001 <0.0003
G. Ponti et al. / Cancer Epidemiology 36 (2012) 303–305
305
Current guidelines recommend sentinel lymph node biopsy (SLN) for patients with stage pT1b melanomas [1,5,11], however, in our opinion, there are no clear evidence-based recommendations for those patients just with thin lesions and it is unclear which patients with thin melanoma should be recommended to receive more intrusive management (e.g., SLN biopsy and close follow-up) and which patients should simply be observed less frequently to detect additional primary lesions and the rare local recurrence or metastasis. Although the ability to draw conclusions was limited by the size and design of this retrospective study, our data support the efficacy of the incorporation of mitogenicity – even a single mitosis figure – into AJCC staging for melanoma, as currently, there are some practical difficulties in the detection and quantification of MR that will be resolved with immunohistochemical approaches. Conflict of interest disclosures The authors declare that they have no competing interests to disclose. Acknowledgements The authors would like to thank Silvana Ciardo and Carmelo Guarneri for their participation in the study. Fig. 1. pT1a, pT1b survival proportions.
prognostic role of even a single mitotic figure detected at primary melanoma evaluation. However, in our study, the re-evaluation of MR on a series selected retrospectively cast some doubts on the reproducibility of the mitotic figure count and indicates the requirement of further tools for more accurate MR quantification. The guidelines suggest that MR should be determined by first examining the tumor and identifying the ‘hot spot’ of greatest mitotic activity if one exists. Then the number of mitoses should be counted in contiguous high-power fields totaling 1 mm2. In most microscopes, this will be about 3 to 4 HPFs; however, the field area should be determined in individual microscopes by determining the diameter of a high-power field by using a stage micrometer or a ruler. The rate should be given as a whole number and tumors with a solitary mitosis in the dermal component (even though the total tumor volume occupies several square millimeters) are reported as having an index of 1 mm2 rather than an index of <1 mm2 [5,8]. However, this method is prone to practical and theoretical disadvantages and is susceptible to interobserver variability. Nuclear and cytoplasmic changes such as apoptosis, karyorrhexis and technique artifacts can obscure the accurate identification and quantification of MR. Despite a relatively high level of concordance among our pathologists in the assessment of MR, reliable staging is not possible in all cases. New approaches to this problem include the use of molecular biology techniques, immunohistochemistry (Ki-67; anti-pHH3) [9,10], and various methods of histological sectioning. In our in progress experience, Ki-67 immunohistochemistry analysis can improve the accuracy of mitotic figure assessment.
References [1] Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199–206. [2] Thompson JF, Soong SJ, Balch CM, Gershenwald JE, Ding S, Coit DG, et al. 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 2011;29(June (16)):2199–205 [Epub 25 April 2011]. [3] Scolyer RA, Thompson JF, Shaw HM, McCarthy SW. The importance of mitotic rate as a prognostic factor for localized primary cutaneous melanoma. J Cutan Pathol 2006;33(May (5)):395–6 [author reply 397–399]. [4] Gershenwald JE, Soong SJ. Balch CM; American Joint Committee on Cancer (AJCC) Melanoma Staging Committee. 2010 TNM staging system for cutaneous melanoma and beyond. Ann Surg Oncol 2010;17(Jun (6)):1475–7. [5] Garbe C, Eigentler TK, Bauer J, Blo¨dorn-Schlicht N, Fend F, Hantschke M, et al. Histopathological diagnostics of malignant melanoma in accordance with the recent AJCC classification 2009: Review of the literature and recommendations for general practice. J Dtsch Dermatol Ges 2011;9(September (9)):690–9. [6] van Diest PJ, Baak JP, Matze-Cok P, Wisse-Brekelmans EC, van Galen CM, Kurver PH, et al. Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol 1992;23:603–7. [7] Gimotty PA, Botbyl J, Soong SJ, Guerry D. A population-based validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 2005;23(31):8065–75. [8] The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Melanoma (Version 2.2010) & 2010 National Comprehensive Cancer Network, Inc. [WWW document]. URL: http://www.nccn.org [accessed on 23 August 2010]. [9] Ladstein RG, Bachmann IM, Straume O, Akslen LA. Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3 MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma. BMC Cancer 2010; 10(April):140. [10] Casper DJ, Ross KI, Messina JL, Sondak VK, Bodden CN, McCardle TW, et al. Use of anti-phosphohistone H3 immunohistochemistry to determine mitotic rate in thin melanoma. Am J Dermatopathol 2010;32(7):650–4. [11] Bichakjian CK, Halpern AC, Johnson TM, Hood A, Grichnik JM, Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol 2011;65(5):1032–47.