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BMC Cancer
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Fractal dimension of chromatin is an independent prognostic factor for survival in melanoma

Authors: Valcinir Bedin, Randall L Adam, Bianca CS de Sá, Gilles Landman, Konradin Metze

Published in: BMC Cancer | Issue 1/2010

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Abstract

Background

Prognostic factors in malignant melanoma are currently based on clinical data and morphologic examination. Other prognostic features, however, which are not yet used in daily practice, might add important information and thus improve prognosis, treatment, and survival. Therefore a search for new markers is desirable. Previous studies have demonstrated that fractal characteristics of nuclear chromatin are of prognostic importance in neoplasias. We have therefore investigated whether the fractal dimension of nuclear chromatin measured in routine histological preparations of malignant melanomas could be a prognostic factor for survival.

Methods

We examined 71 primary superficial spreading cutaneous melanoma specimens (thickness ≥ 1 mm) from patients with a minimum follow up of 5 years. Nuclear area, form factor and fractal dimension of chromatin texture were obtained from digitalized images of hematoxylin-eosin stained tissue micro array sections. Clark's level, tumor thickness and mitotic rate were also determined.

Results

The median follow-up was 104 months. Tumor thickness, Clark's level, mitotic rate, nuclear area and fractal dimension were significant risk factors in univariate Cox regressions. In the multivariate Cox regression, stratified for the presence or absence of metastases at diagnosis, only the Clark level and fractal dimension of the nuclear chromatin were included as independent prognostic factors in the final regression model.

Conclusion

In general, a more aggressive behaviour is usually found in genetically unstable neoplasias with a higher number of genetic or epigenetic changes, which on the other hand, provoke a more complex chromatin rearrangement. The increased nuclear fractal dimension found in the more aggressive melanomas is the mathematical equivalent of a higher complexity of the chromatin architecture. So, there is strong evidence that the fractal dimension of the nuclear chromatin texture is a new and promising variable in prognostic models of malignant melanomas.
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Literature
1.
Carlson JA, Ross JS, Slominski AJ: New techniques in dermatopathology that help to diagnose and prognosticate melanoma. Clinics in Dermatology. 2009, 27: 75-102. 10.1016/j.clindermatol.2008.09.007.CrossRefPubMed
2.
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: 8065-75. 10.1200/JCO.2005.02.4976.CrossRefPubMed
3.
de Sa BC, Rezze GG, Scramin AP, Landman G, Neves RI: Cutaneous melanoma in childhood and adolescence: retrospective study of 32 patients. Melanoma Res. 2004, 14 (6): 487-92. 10.1097/00008390-200412000-00008.CrossRefPubMed
4.
de Sá BC, Fugimori ML, Ribeiro Kde C, Duprat Neto JP, Neves RI, Landman G: Proteins involved in pRb and p53 pathways are differentially expressed in thin and thick superficial spreading melanomas. Melanoma Res. 2009, 19 (3): 135-41. 10.1097/CMR.0b013e32831993f3.CrossRefPubMed
5.
Neto DS, Pantaleão L, de Sá BC, Landman G: Alpha-v-beta3 integrin expression in melanocytic nevi and cutaneous melanoma. J Cutan Pathol. 2007, 34 (11): 851-6. 10.1111/j.1600-0560.2007.00730.x.CrossRefPubMed
6.
Bachmann IM, Ladstein RG, Straume O, Naumov GN, Akslen LA: Tumor Necrosis is associated with increased alphavbeta3 integrin expression and poor prognosis in nodular cutaneous melanomas. BMC Cancer. 2008, 8: 362-10.1186/1471-2407-8-362.CrossRefPubMedPubMedCentral
7.
Winklmeier A, Poser I, Hoek KS, Bosserhoff AK: Loss of full length CtBP1 expression enhances the invasive potential of human melanoma. BMC Cancer. 2009, 9: 52-10.1186/1471-2407-9-52.CrossRefPubMedPubMedCentral
8.
Sousa JF, Esperafico EM: Suppression subtractive hybridization profiles of radial growth phase and metastatic melanoma cell lines reveal novel potential targets. BMC Cancer. 2008, 8: 19-10.1186/1471-2407-8-19.CrossRefPubMedPubMedCentral
9.
Kaufmann S, Kuphal S, Schubert T, Bosserhoff AK: Functional implication of Netrin expression in malignant melanoma. Cell Oncol. 2009, 31 (6): 415-22.PubMedPubMedCentral
10.
Metze K, Ferreira RC, Adam RL, Leite NJ, Ward LS, de Matos PS: Chromatin texture is size dependent in follicular adenomas but not in hyperplastic nodules of the thyroid. World J Surg. 2008, 32 (12): 2744-6. 10.1007/s00268-008-9736-0.CrossRefPubMed
11.
Ferreira RC, de Matos PS, Adam RL, Leite NJ, Metze K: Application of the Minkowski fractal dimension for the differential diagnosis in thyroid Follicular neoplasias. Cellular Oncology. 2006, 28: 5-6.
12.
Mello MRB, Metze K, Adam RA, Pereira FG, Magalhães MG, Machado Lorand-Metze I: Phenotypic subtypes of acute lymphoblastic leukemia associated with different nuclear chromatin texture. Analytical and Quantitative Cytology and Histology. 2008, 30: 175-184.
13.
Moro-Rodríguez E, Figols J, Alvira M, Uranga-Ocio JA, García-Poblete E: 13 GFAP and alpha1a-AR staining and nuclear morphometry of oligodendrogliomas by confocal microscopy and image analysis: useful parameters for predicting survival in oligodendrogliomas. Diagn Pathol. 2008, 15 (3 Suppl 1): S26-10.1186/1746-1596-3-S1-S26.CrossRef
14.
Adam RL, Leite NJ, Metze K: Image preprocessing improves Fourier-based texture analysis of nuclear chromatin. Anal Quant Cytol Histol. 2008, 30 (3): 175-84.PubMed
15.
Metze K, Lorand-Metze IG: Interpretation of the AgNOR pattern in hematologic cytology. Acta Haematol. 1993, 89 (2): 110-2. 10.1159/000204500.CrossRefPubMed
16.
Li LX, Crotty KA, Palmer AA, Kril JJ, Stankovic R, Scolyer RA, McCarthy SW: Differentiating benign nevi from malignant melanoma using DNA microdensitometry and karyometry and maturation: a zonal comparison, correlation and multivariate analysis. Anal Quant Cytol Histol. 2002, 24: 234-43.PubMed
17.
Li LX, Crotty KA, Palmer AA, Kril JJ, Scolyer RA, Thompson JF, McCarthy SW: Argyrophilic staining of nucleolar organizer region count and morphometry in benign and malignant melanocytic lesions. Am J Dermatopathol. 2003, 25 (3): 190-7. 10.1097/00000372-200306000-00002.CrossRefPubMed
18.
Cia EMM, Trevisan M, Metze K: Argyrophilic nucleolar organizer region (AgNOR) technique: a helpful tool for differential diagnosis in urinary cytology.
19.
Lorand-Metze I, Carvalho MA, Metze K: Relationship between morphometric analysis of nucleolar organizer regions and cell proliferation in acute leukemias. Cytometry. 1998, 32: 51-56. 10.1002/(SICI)1097-0320(19980501)32:1<51::AID-CYTO7>3.0.CO;2-I.CrossRefPubMed
20.
Jondet M, Agoli-Agbo R, Dehennin L: Automatic measurement of epithelium differentiation and classification of cervical intraneoplasia by computerized image analysis. Diagn Pathol. 2010, 5: 7-10.1186/1746-1596-5-7.CrossRefPubMedPubMedCentral
21.
Adam RL, Silva RC, Pereira FG, Leite NJ, Lorand-Metze I, Metze K: The fractal dimension of nuclear chromatin as a prognostic factor in acute precursor B lymphoblastic leukemia. Cell Oncol. 2006, 28 (1-2): 55-9.PubMedPubMedCentral
22.
Montironi R, Scarpelli M, Lopez-Beltran A, Mazzucchelli R, Alberts D, Ranger-Moore J, Bartels HG, Hamilton PW, Einspahr J, Bartels PH: Chromatin phenotype karyometry can predict recurrence in papillary urothelial neoplasms of low malignant potential. Cell Oncol. 2007, 29 (1): 47-58.PubMedPubMedCentral
23.
Lebedev DV, Filatov MV, Kuklin AI, Islamov AKh, Kentzinger E, Pantina R, Toperverg BP, Isaev-Ivanov VV: Fractal nature of chromatin organization in interphase chicken erythrocyte nuclei: DNA structure exhibits biphasic fractal properties. FEBS Lett. 2005, 579 (6): 1465-8. 10.1016/j.febslet.2005.01.052.CrossRefPubMed
24.
Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, Dekker J: Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009, 326: 289-293. 10.1126/science.1181369.CrossRefPubMedPubMedCentral
25.
Bancaud A, Huet S, Daigle N, Mozziconacci J, Beaudouin J, Ellenberg J: Molecular crowding affects diffusion and binding of nuclear proteins in heterochromatin and reveals the fractal organization of chromatin. EMBO J. 2009, 28: 3785-3798. 10.1038/emboj.2009.340.CrossRefPubMedPubMedCentral
26.
Goutzanis L, Papadogeorgakis N, Pavlopoulos PM, Katti K, Petsinis V, Plochoras I, Pantelidaki C, Kavantzas N, Patsouris E, Alexandridis C: Nuclear fractal dimension as a prognostic factor in oral squamous cell carcinoma. Oral Oncology. 2008, 44 (4): 345-353.
27.
Mashiah A, Wolach O, Sandbank J: Lymphoma and leukemia cells possess fractal dimensions that correlate with their biological features. Acta Haematologica. 2008, 142-150. 10.1159/000125551. 119
28.
Delides A, Panayiotides I, Alegakis A, Kyroudi A, Banis C, Pavlaki A, Helidonis E, Kittas C: Fractal dimension as a prognostic factor for laryngeal carcinoma. Anticancer Res. 2005, 25 (3B): 2141-4.PubMed
29.
Metze K, Ferro DP, Falconi MA, Adam RL, Ortega M, Lima CP, De Souza AC, Lorand-Metze I: Fractal characteristics of nuclear chromatin in routinely stained cytology are independent prognostic factors in patients with multiple myeloma. Virchows Archiv. 2009, 455 (S1): 7-11.
30.
Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP: Tissue microarrays for high- throughput molecular profiling of tumor specimens. Nat Med. 1998, 4: 844-7. 10.1038/nm0798-844.CrossRefPubMed
31.
Sarkar N, Chaudhuri BB: An efficient differential box-counting approach to computed fractal dimension of images. IEEE Transactions on Systems Man and Cybernetics. 1994, 24: 115-120. 10.1109/21.259692.CrossRef
32.
Metze K, Lorand-Metze I, Leite NJ, Adam RL: Goodness-of-fit of the fractal dimension as a prognostic factor. Cell Oncol. 2009, 31 (6): 503-4.PubMedPubMedCentral
33.
Lorand-Metze I, Pinheiro MP, Ribeiro E, de Paula EV, Metze K: Factors influencing survival in myelodysplastic syndromes in a Brazilian population: comparison of FAB andWHO classifications. Leukemia Research. 2004, 28: 587-594. 10.1016/j.leukres.2003.11.001.CrossRefPubMed
34.
Homsi J, Kashani-Sabet M, Messina JL, Daud A: Cutaneous melanoma:prognostic factors. Cancer Control. 2005, 12 (4): 223-9.PubMed
35.
Li LXL, Crotty KA, Scolyer RA, Thompson JF, Kril JJ, Palmer AA, McCarthy SW: Use of multiple cytometric markers improves discrimination between benign and malignant melanocytic lesions: a study of DNA microdensitometry, karyometry, argyrophilic staining of nucleolar organizer regions and MIB1- Ki67 immunoreactivity. Melanoma Research. 2003, 13: 581-586. 10.1097/00008390-200312000-00007.CrossRefPubMed
36.
Kossard S, WilkinsoN B: Nucleolar organizer regions and image-analysis nuclear morphometry of small-cell (nevoid) melanoma. Journal of Cutaneous Pathology. 22 (2): 132-136. 10.1111/j.1600-0560.1995.tb01395.x.
37.
Rieger E, Hofmann-Wellenhof R, Soyer HP, Kofler R, Cerroni L, Smolle J, Kerl H: Comparison of proliferative activity as assessed by proliferating cell nuclear antigen (PCNA) and Ki-67 monoclonal antibodies in melanocytic skin lesions. A quantitative immunohistochemical study. J Cutan Pathol. 1993, 20: 229-36. 10.1111/j.1600-0560.1993.tb00648.x.CrossRefPubMed
38.
39.
Balázs M, Adám Z, Treszl A, Bégány A, Hunyadi J, Adány R: Chromosomal imbalances in primary and metastatic melanomas revealed by comparative genomic hybridization. Cytometry. 2001, 46 (4): 222-32. 10.1002/cyto.1131.CrossRefPubMed
40.
Misteli T: Beyond the Sequence: Cellular Organization of Genome Function. Cell. 2007, 128 (4): 787-800. 10.1016/j.cell.2007.01.028.CrossRefPubMed
41.
Gilbert N, Boyle S, Fiegler H, Woodfine K, Carter NP, Bickmore WA: Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers. Cell. 2004, 118: 555-566. 10.1016/j.cell.2004.08.011.CrossRefPubMed
42.
Mascolo M, Vecchione ML, Ilardi G, Scalvenzi M, Molea G, Di Benedetto M, Nugnes L, Siano M, De Rosa G, Staibano S: Overexpression of Chromatin Assembly Factor-1/p60 helps to predict the prognosis of melanoma patients. BMC Cancer. 2010, 10 (1): 63-10.1186/1471-2407-10-63.CrossRefPubMedPubMedCentral
43.
Rothhammer T, Bosserhoff AK: Epigenetic events in malignant melanoma. Pigment Cell Res. 20: 92-111. 10.1111/j.1600-0749.2007.00367.x.
44.
Mossbacher U, Knollmayer S, Binder M, Steiner A, Wolff K, Pehamberger H: Increased nuclear volume in metastasizing "thick" melanomas. J Invest Dermatol. 1996, 106 (3): 437-40. 10.1111/1523-1747.ep12343580.CrossRefPubMed
45.
Talve LA, Collan YU, Ekfors TO: Primary malignant melanoma of the skin. Relationships of nuclear DNA content, nuclear morphometric variables, Clark level and tumor thickness. Anal Quant Cytol Histol. 1997, 19 (1): 62-74.PubMed
46.
Mandelbrot BB: Stochastic models for the Earth's relief, the shape and the fractal dimension of the coastlines, and the number-area rule for islands. Proc Natl Acad Sci USA. 1975, 72 (10): 3825-3828. 10.1073/pnas.72.10.3825.CrossRefPubMedPubMedCentral
47.
Paumgartner D, Losa G, Weibel ER: Resolution effect on the stereological estimation of surface and volume and its interpretation in terms of fractal dimensions. J Microsc. 1981, 21 (Pt 1): 51-63.CrossRef
48.
Grosberg AY, Nechaev S, Shakhnovich E: The role of topological constraints in the kinetics of collapse of macromolecules. J Phys France. 49: 2095-2100. 10.1051/jphys:0198800490120209500.
49.
50.
Gonzato G, Mulargia F, Marzocchi W: Practical application of fractal analysis: Problems and solutions. Geophysical Journal International. 1998, 132-275.
Metadata
Title
Fractal dimension of chromatin is an independent prognostic factor for survival in melanoma
Authors
Valcinir Bedin
Randall L Adam
Bianca CS de Sá
Gilles Landman
Konradin Metze
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-260

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