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HPV-associated head and neck cancer: update and recommendations for practice


Authors: Marián Švajdler 1,2;  Jan Laco 3;  Ondrej Ondič 1,2 ;  Jana Kašpírková 1,2;  Roman Mezencev 4;  Michal Michal 1,2 ;  Alena Skálová 1,2
Authors place of work: Šiklův ústav patologie, Univerzita Karlova v Praze, Lékařská fakulta v Plzni a Fakultní nemocnice Plzeň, Česká republika 1;  Bioptická laboratoř, s. r. o., Plzeň, Česká republika 2;  Fingerlandův ústav patologie, Univerzita Karlova v Praze, Lékařská fakulta a Univerzitní nemocnice Hradec Králové, Česká republika 3;  Integrated Cancer Research Center, School of Biology and Parker H. Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA, USA 4
Published in the journal: Čes.-slov. Patol., 52, 2016, No. 3, p. 130-138
Category: Přehledový článek

Summary

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV-OSCC) represents a specific clinical and pathological entity among head and neck cancers with more favorable prognosis than corresponding HPV-negative oropharyngeal squamous cell carcinoma (SCC). HPV-OSCC most commonly displays non-keratinzing SCC histology, although number of cases presented variable morphology. Detection of transcriptionally active HPV in oropharyngeal SCCs is of critical prognostic importance, which even supersedes the importance of their formal pathological grading. This article summarizes the current state of knowledge of HPV-positive SCC of oropharynx and of other anatomical subsites of the head and neck and discusses the role of HPV detection in the diagnostics of metastatic SCC lesions of unknown origin.

Keywords:
squamous cell carcinoma – HPV – head and neck – oropharyngeal carcinoma – nasopharyngeal carcinoma – sinonasal carcinoma


Zdroje

1. de Villiers EM, Fauquet C, Broker TR, Bernard HU, zur Hausen H. Classification of papillomaviruses. Virology 2004; 324(1): 17-27.

2. de Villiers EM. Cross-roads in the classification of papillomaviruses. Virology 2013; 445(1-2): 2-10.

3. Katzenellenbogen RA, Galloway DA. Human papillomavirus-associated cancers. In: Khalili K, Jeang KT, eds. Viral oncology: Basic science and clinical applications (1st ed). New Yersey: Wiley-Blackwell; 2009: 1–23.

4. Muñoz N, Castellsagué X, de González AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine 2006; 24 Suppl 3: S3/1–10.

5. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189(1): 12–19.

6. Quint KD, Genders RE, de Koning MN, et al. Human Beta-papillomavirus infection and keratinocyte carcinomas. J Pathol 2015; 235(2): 342-354.

7. Švajdler M Jr, Mezencev R, Kašpírková J, et al. Human papillomavirus infection and p16 expression in extragenital/extraungual Bowen disease in immunocompromised patients. Am J Dermatopathol. In press 2016.

8. Syrjänen KJ, Pyrhönen S, Syrjänen SM, Lamberg MA. Immunohistochemical demonstration of human papilloma virus (HPV) antigens in oral squamous cell lesions. Br J Oral Surg 1983; 21(2): 147–153.

9. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000; 92(9): 709-720.

10. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29(32): 4294-4301.

11. Tinhofer I, Jöhrens K, Keilholz U, et al. Contribution of human papilloma virus to the incidence of squamous cell carcinoma of the head and neck in a European population with high smoking prevalence. Eur J Cancer 2015; 51(4): 514-521.

12. Garnaes E, Kiss K, Andersen L, et al. A high and increasing HPV prevalence in tonsillar cancers in Eastern Denmark, 2000-2010: the largest registry-based study to date. Int J Cancer 2015; 136(9): 2196-2203.

13. Abogunrin S, Di Tanna GL, Keeping S, Carroll S, Iheanacho I. Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. BMC Cancer 2014; 14:968.

14. Chernock RD, El-Mofty SK, Thorstad WL, Parvin CA, Lewis JS Jr. HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol 2009; 3(3): 186-194.

15. Chaturvedi AK. Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol 2012; 6: Suppl 1: S16–24.

16. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363(1): 24–35.

17. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008; 100(4): 261–269.

18. Isayeva T, Li Y, Maswahu D, Brandwein-Gensler M. Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 2012; 6: Suppl 1: S104–120.

19. Patel S, Shah JP. Pharynx. In: Edge SB, Byrd DR, Carducci MA, Compton CA, eds. AJCC Cancer Staging Manual (7th ed). New York: Springer; 2009: 41-56.

20. Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer 2010; 116(9): 2166-2173.

21. Lewis JS Jr, Thorstad WL, Chernock RD, et al. p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol 2010; 34(8): 1088-1096.

22. Rodrigo JP, Heideman DA, García-Pedrero JM, et al. Time trends in the prevalence of HPV in oropharyngeal squamous cell carcinomas in northern Spain (1990-2009). Int J Cancer 2014; 134(2): 487-492.

23. Näsman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009; 125(2): 362-366.

24. Rietbergen MM, Leemans CR, Bloemena E, et al. Increasing prevalence rates of HPV attributable oropharyngeal squamous cell carcinomas in the Netherlands as assessed by a validated test algorithm. Int J Cancer 2013; 132(7): 1565-1571.

25. Klozar J, Kratochvil V, Salakova M, et al. HPV status and regional metastasis in the prognosis of oral and oropharyngeal cancer. Eur Arch Otorhinolaryngol 2008; 265 Suppl 1: S75-82.

26. Laco J, Vosmikova H, Novakova V, et al. The role of high-risk human papillomavirus infection in oral and oropharyngeal squamous cell carcinoma in non-smoking and non-drinking patients: a clinicopathological and molecular study of 46 cases. Virchows Arch 2011; 458(2): 179-187.

27. El-Mofty SK, Patil S. Human papillomavirus (HPV)-related oropharyngeal nonkeratinizing squamous cell carcinoma: characterization of a distinct phenotype. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 101(3): 339–345.

28. Westra WH. The pathology of HPV-related head and neck cancer: implications for the diagnostic pathologist. Semin Diagn Pathol 2015; 32(1): 42-53.

29. Lewis JS Jr, Chernock RD. Human papillomavirus and Epstein Barr virus in head and neck carcinomas: suggestions for the new WHO classification. Head Neck Pathol 2014; 8(1): 50-58.

30. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363(1): 24-35.

31. Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012; 30(17): 2102-2111.

32. Lewis JS Jr, Scantlebury JB, Luo J, Thorstad WL. Tumor cell anaplasia and multinucleation are predictors of disease recurrence in oropharyngeal squamous cell carcinoma, including among just the human papillomavirus-related cancers. Am J Surg Pathol 2012; 36(7): 1036–1046.

33. Lewis JS Jr, Ali S, Luo J, Thorstad WL, Madabhushi A. A quantitative histomorphometric classifier (QuHbIC) identifies aggressive versus indolent p16-positive oropharyngeal squamous cell carcinoma. Am J Surg Pathol 2014; 38(1): 128-137.

34. Nakano T, Yamamoto H, Nakashima T, et al. Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma. Hum Pathol 2016; 50(4): 51-61.

35. Huang SH, Xu W, Waldron J, et al. Refining American Joint Committee on Cancer/Union for InternationalCancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol 2015; 33(8): 836-845.

36. El-Mofty SK. Human papillomavirus-related head and neck squamous cell carcinomavariants. Semin Diagn Pathol 2015; 32(1): 23-31.

37. Cai C, Chernock RD, Pittman ME, El-Mofty SK, Thorstad WL, Lewis JS Jr. Keratinizing-type squamous cell carcinoma of the oropharynx: p16 overexpression is associated with positive high-risk HPV status and improved survival. Am J Surg Pathol 2014; 38(6): 809-815.

38. Jo VY, Mills SE, Stoler MH, Stelow EB. Papillary squamous cell carcinoma of the head and neck: frequent association with human papillomavirus infection and invasive carcinoma. Am J Surg Pathol 2009; 33(11): 1720–1724.

39. Yang CH, Huang CC, Ko MT, Wei YC, Hwang CF. Human papillomavirus infection and papillary squamous cell carcinoma in the head and neck region. Tumour Biol 2013; 34(1): 301-307.

40. Mehrad M, Carpenter DH, Chernock RD, et al. Papillary squamous cell carcinoma of the head and neck: clinicopathologic and molecular features with special reference to human papillomavirus. Am J Surg Pathol 2013; 37(9): 1349–1356.

41. Begun S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol 2008; 32(7): 1044–1050.

42. Chernock RD, Lewis JS Jr, Zhang Q, El-Mofty SK. Human papillomavirus positive basaloid squamous cell carcinoma of the upper aerodigestive tract: a distinct clinicopathologic and molecular subtype of basaloid squamous cell carcinoma.Human Pathol 2010; 41(7): 1016–1023.

43. Cardesa A, Zidar N, Alos L. Adenosquamous carcinoma. In: Barnes EL, Eveson JW, Reichart P, Sideransky D, eds. Pathology and genetics of head and neck tumors. World Health Organization Classification of Tumors. Lyon: IARC Press; 2005: 130-131.

44. Masand RP, El-Mofty SK, Ma XJ, Luo Y, Flanagan JJ, Lewis JS Jr. Adenosquamous carcinoma of the head and neck: relationship to human papillomavirus and review of literature. Head Neck Pathol 2011; 5(2): 108–116.

45. Radkay-Gonzalez L, Faquin W, McHugh JB, Lewis JS Jr, Tuluc M, Seethala RR. Ciliated adenosquamous carcinoma: expanding the phenotypic diversity of human papillomavirus-associated tumors. Head Neck Pathol. In press 2015.

46. Wenig BM. Lymphoepithelial-like carcinomas of the head and neck. Semin Diagn Pathol 2015; 32(1): 74-86.

47. Peterrsson F. Nasopharyngeal carcinoma: a review. Semin Diagn Pathol 2015; 32(1): 54-73.

48. Perez-Ordoñez B. An update on Epstein-Barr virus and nasopharyngeal carcinogenesis. Head Neck Pathol 2007; 1(2): 141-145.

49. Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein-Barr virus in epithelial malignancies. J Pathol 2015; 235(2): 323-333.

50. Singhi AD, Stelow EB, Mills SE, Westra WH. Lymphoepitheliallike carcinoma of the oropharynx: a morphologic variant of HPV related head and neck carcinoma. Am J Surg Pathol 2010; 34(6): 800–805.

51. Carpenter D, El-Mofty SK, Lewis JS Jr. Undifferentiated carcinoma of the oropharynx: a human papillomavirus-associated tumor with favorable prognosis. Mod Pathol 2011; 24(10): 1306–1312.

52. Bishop JA, Montgomery EA, Westra WH. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol 2014; 38(2): 257–264.

53. Watson RF, Chernock RD, Wang X, et al. Spindle cell carcinomas of the head and neck rarely harbor transcriptionally-active human papillomavirus. Head Neck Pathol 2013; 7(3): 250–257.

54. Bishop JA, Westra WH. Human papillomavirus-related small cell carcinoma of the oropharynx. Am J Surg Pathol 2011; 35(11): 1679–1684.

55. Kraft S, Faquin WC, Krane JF. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol 2012; 36(3): 321–30.

56. Singhi AD, Califano J, Westra WH. High-risk human papillomavirus in nasopharyngeal carcinoma. Head Neck 2012; 34(2): 213–218.

57. Lewis JS Jr, Ukpo OC, Ma XJ, et al. Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas--a tissue microarray study utilizing E6/E7 mRNA in situ hybridization. Histopathology 2012; 60(6): 982– 991.

58. Bishop JA, Ma XJ, Wang H, et al. Detection of transcriptionally active high-risk HPV in patients with head and neck squamous cell carcinoma as visualized by a novel E6/E7 mRNA in situ hybridization method. Am J Surg Pathol 2012; 36(12): 1874–1882.

59. Chernock RD, Wang X, Gao G, et al. Detection and significance of human papillomavirus, CDKN2A(p16) and CDKN1A(p21) expression in squamous cell carcinoma of the larynx. Mod Pathol 2013; 26(2): 223–231.

60. Lingen MW, Xiao W, Schmitt A, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol 2013; 49(1): 1–8.

61. Bishop JA, Guo TW, Smith DF, et al. Human papillomavirus-related carcinomas of the sinonasal tract. Am J Surg Pathol 2013; 37(2): 185–192.

62. Thavaraj S. Human papillomavirus-associated neoplasms of the sinonasal tract and nasopharynx. Semin Diagn Pathol 2016; 33(2): 104-111.

63. Alos L, Moyano S, Nadal A, et al. Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer 2009; 115(12): 2701–2709.

64. Larque AB, Hakim S, Ordi J, et al. High-risk human papillomavirus is transcriptionally active in a subset of sinonasal squamous cell carcinomas. Mod Pathol 2014; 27(3): 343–351.

65. Laco J, Sieglová K, Vošmiková H, et al. The presence of high-risk human papillomavirus (HPV) E6/E7 mRNA transcripts in a subset of sinonasal carcinomas is evidence of involvement of HPV in its etiopathogenesis. Virchows Arch 2015; 467(4): 405-415.

66. Robinson M, Suh YE, Paleri V, et al. Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population. Infect Agent Cancer 2013; 8(1): 30.

67. Lin Z, Khong B, Kwok S, et al. Human papillomavirus 16 detected in nasopharyngeal carcinomas in white Americans but not in endemic southern Chinese patients. Head Neck 2014; 36(5): 709–714.

68. Dogan S, Hedberg ML, Ferris RL, Rath TJ, Assaad AM, Chiosea SI. Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a low-incidence population. Head Neck 2014; 36(4): 511–516.

69. Stenmark MH, McHugh JB, Schipper M, et al. Nonendemic HPV-positive nasopharyngeal carcinoma: association with poor prognosis. Int J Radiat Oncol Biol Phys 2014; 88(3): 580–588.

70. Švajdler M Jr, Kašpírková J, Mezencev R, et al. Human papillomavirus and Epstein-Barr virus in nasopharyngeal carcinoma in a non-endemic eastern european population. Neoplasma 2016; 63(1): 107-114.

71. Salazar CR, Smith RV, Garg MK, et al. Human papillomavirus-associated head and neck squamous cell carcinoma survival: a comparison by tumor site and initial treatment. Head Neck Pathol 2014; 8(1):77-87.

72. Arrangoiz R, Galloway TJ, Papavasiliou P, Ridge JA, Lango MN. Metastatic cervical carcinoma from an unknown primary: literature review. Ear Nose Throat J 2014; 93(4-5): E1–E10.

73. Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches, Head Neck 2013; 35(1): 123-132.

74. Park JM, Jung CK, Choi YJ, et al. The use of an immunohistochemical diagnostic panel to determine the primary site of cervical lymph node metastases of occult squamous cell carcinoma. Hum Pathol 2010; 41(3): 431-437.

75. Layfield LJ. Fine-needle aspiration in the diagnosis of head and neck lesions: a review and discussion of problems in differential diagnosis. Diagn Cytopathol 2007; 35(12): 798-805.

76. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon. Head Neck 2008; 30(7): 898-903.

77. Regauer S, Mannweiler S, Anderhuber W, et al. Cystic lymph node metastases of squamous cell carcinoma of Waldeyer‘s ring origin. Br J Cancer 1999; 79(9-10): 1437-1442.

78. Granström G, Edström S. The relationship between cervical cysts and tonsillar carcinoma in adults. J Oral Maxillofac Surg 1989; 47(1): 16-20.

79. Flanagan PM, Roland NJ, Jones AS. Cervical node metastases presenting with features of branchial cysts. J Laryngol Otol 1994; 108(12): 1068-1071.

80. Gourin GC, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts. Laryngoscope 2000; 110(10 Pt 1): 1637-1641.

81. Thompson LD, Heffner DK. The clinical importance of cystic squamous cell carcinomas in the neck: a study of 136 cases. Cancer 1998; 82(5): 944-956.

82. Verma K, Mandal S, Kapila K. Cystic change in lymph nodes with metastatic squamous cell carcinoma. Acta Cytol 1995; 39(3): 478-80.

83. Mehrad M, Zhao H, Gao G, Wang X, Lewis JS Jr. Transcriptionally-active human papillomavirus is consistently retained in the distant metastases of primary oropharyngeal carcinomas. Head Neck Pathol 2014; 8(2): 157-163.

84. Morani AC, Eisbruch A, Carey TE, Hauff SJ, Walline HM, Mukherji SK. Intranodal cystic changes: a potential radiologic signature/biomarker to assess the human papillomavirus status of cases with oropharyngeal malignancies. J Comput Assist Tomogr 2013; 37(3): 343-345.

85. Yasui T, Morii E, Yamamoto Y, et al. Human papillomavirus and cystic node metastasis in oropharyngeal cancer and cancer of unknown primary origin. PLoS One 2014; 9(4): e95364.

86. Begum S, Gillison ML, Ansari-Lari MA, Shah K, Westra WH. Detection of human papillomavirus in cervical lymph nodes: a highly effective strategy for localizing site of tumor origin. Clin Cancer Res 2003; 9(17): 6469-6475.

87. El-Mofty SK, Zhang MQ, Davila RM. Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma. Head Neck Pathol 2008; 2(3): 163-168.

88. Weiss D, Koopmann M, Raudack C. Prevalence and impact on clinicopathological characteristics of human papillomavirus-16 DNA in cervical lymph node metastases of head and neck squamous cell carcinoma. Head Neck 2011; 33(6): 856-862.

89. Park GC, Lee M, Roh JL, et al. Human papillomavirus and p16 detection in cervical lymph node metastases from an unknown primary tumor. Oral Oncol 2012; 48(12): 1250-1256.

90. Zhang GZ, Liu ZL, Gong JS, Cheng ZQ, Ke C. Cystic metastatic nasopharyngeal carcinoma presenting as branchial cleft cyst: report of two cases and review of the literature. J Oral Maxillofac Surg 2014; 72(11): 2366-2374.

91. Švajdler M Jr, Kašpírková J, Hadravský L, et al. Origin of cystic squamous cell carcinoma metastases in head and neck lymph nodes: Addition of EBV testing improves diagnostic accuracy. Pathol Res Pract. In press 2016.

92. Bergeron C, Ronco G, Reuschenbach M, et al. The clinical impact of using p16(INK4a) immunochemistry in cervical histopathology and cytology: an update of recent developments. Int J Cancer 2015; 136(12): 2741–2751.

93. Venuti A, Paolini F. HPV detection methods in head and neck cancer. Head Neck Pathol 2012; 6 Suppl 1: S63-74.

94. Grønhøj Larsen C, Gyldenløve M, Jensen DH, et al. Correlation between human papillomavirus and p16 overexpression in oropharyngeal tumours: a systematic review. Br J Cancer 2014; 110(6): 1587-1594.

95. Lewis JS Jr. p16 Immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 2012; 6 Suppl 1: S75-S82.

96. Cao D, Begum S, Ali SZ, Westra WH. Expression of p16 in benign and malignant cystic squamous lesions of the neck. Hum Pathol 2010; 41(4): 535-539.

97. Yuan J, Knorr J, Altmannsberger M, et al. Expression of p16 and lack of pRB in primary small cell lung cancer. J Pathol 1999; 189(3): 358-362.

98. Hartley CP, Steinmetz HB, Memoli VA, Tafe LJ. Small cell neuroendocrine carcinomas of the lung do not harbor high-risk human papillomavirus. Hum Pathol 2015; 46(4): 577-582.

99. Wadsworth B, Bumpous JM, Martin AW, Nowacki MR, Jenson AB, Farghaly H. Expression of p16 in sinonasal undifferentiated carcinoma (SNUC) without associated human papillomavirus (HPV). Head Neck Pathol 2011; 5(4): 349-354.

100. Doxtader EE, Katzenstein AL. The relationship between p16 expression and high-risk human papillomavirus infection in squamous cell carcinomas from sites other than uterine cervix: a study of 137 cases. Hum Pathol 2012; 43(3): 327-332.

101. Alexander RE, Hu Y, Kum JB, et al. p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. Mod Pathol 2012; 25(11): 1526-1533.

102. Kašpírková J, Ondič O, Černá K, Skálová A. Možnosti průkazu biologicky relevantní papilomavirové infekce u maligních nádorů hlavy a krku v diagnostické patologii. Cesk Patol 2013; 49(1): 29-34.

103. Bishop JA, Lewis JS Jr, Rocco JW, Faquin WC. HPV-related squamous cell carcinoma of the head and neck: An update on testing in routine pathology practice. Semin Diagn Pathol 2015; 32(5): 344-351.

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Patológia Súdne lekárstvo Toxikológia

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Česko-slovenská patologie

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