Abstract
Under the widely used World Health Organization (WHO) classification for the pathological diagnosis of oral premalignant lesions, dysplasia, which is graded as mild, moderate or severe, and carcinoma in situ (CIS), which is a non-invasive carcinoma, are classified as precursor lesions of oral squamous cell carcinoma. Since the first edition (Wahi et al. International histological classification of tumours no. 4, WHO, Geneva, 1971), the criterion for CIS—that all epithelial layers are replaced by atypical cells—has remained unchanged. However, this dysplasia–carcinoma sequence theory was introduced from the viewpoint of pathological changes in the uterine cervix: in contrast, almost all premalignant lesions and CIS of the oral mucosa show superficial maturation and differentiation. Based on this recognition, the squamous intraepithelial neoplasia (SIN) classification and Ljubljana classification were included in WHO’s latest edition published in 2005. Although the WHO classification is commonly used in Japan, recent developments in oral oncology have promoted modifications of the classification used in this country. In 2005, the Working Group of the Japan Society for Oral Tumours advocated iodine staining and proposed a modified SIN system, and in 2007, the Working Committee of the Japanese Society for Oral Pathology (JSOP) reported a new CIS (JSOP) definition that included differentiated-type CIS. In 2010, based on these studies, a new entity—oral intraepithelial neoplasia (OIN)—was included in the first edition of General Rules for Clinical and Pathological Studies on Oral Cancer. In this review, we focus on the OIN/CIS (JSOP) new classification of premalignant lesions in oral mucosa, which further advances the concept of SIN.
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References
Japan Society for Oral Tumors & Japanese Society of Oral & Maxillofacial Surgeons (2009) Guidelines for the treatment of oral cancer (in Japanese), 1st edn. Kanehara, Tokyo
The Ministry of Health, Labour and Welfare (2001) Labour statistics. The Ministry of Health, Labour and Welfare, Tokyo
Japan Society for Head and Neck Cancer Registry Committee (2006) Report of head and neck cancer registry of Japan: clinical statistics of registered patients 2002. Jpn J Head Neck Cancer (in Japanese) 32:15–34
Wahi PN, Cohen B, Luthra UK et al (1971) Histological ty** of oral and oropharyngeal tumours. International histological classification of tumours no. 4. World Health Organization, Geneva
Pindborg JJ, Reichart P, Smith CJ et al (1997) World Health Organization: histological ty** of cancer and precancer of the oral mucosa, 2nd edn. Springer, Berlin
Gale N, Westra W, Pilch BZ et al (2005) Epithelial precursor lesions. In: Barnes L, Everson JW, Reichart P et al (eds) World Health Organization classification of tumours, pathology and genetics, head and neck tumours. IARC Press, Lyon, pp 177–179
The Working Group 1, Scientific Committee, Japan Society for Oral Tumors (2005) General rules for the clinical and pathological studies on oral carcinoma: 1, carcinoma of the tongue. J Jpn Soc Oral Tumor (in Japanese) 17:13–86
The Working Group 1, Scientific Committee, Japan Society for Oral Tumors (2007) General rules for the clinical and pathological studies on oral carcinoma: 2, Carcinoma of the lower gingiva. J Jpn Soc Oral Tumor (in Japanese) 19:37–124
The Working Group 1, Scientific Committee, Japan Society for Oral Tumors (2008) General rules for the clinical and pathological studies on oral carcinoma: 3, carcinoma of the buccal mucosa and floor of mouth. J Jpn Soc Oral Tumor (in Japanese) 20:25–117
The Working Group 1, Scientific Committee, Japan Society for Oral Tumors (2009) General rules for the clinical and pathological studies on oral carcinoma: 3, carcinoma of the upper gingiva and palate. J Jpn Soc Oral Tumor (in Japanese) 20:25–117
Japan Society for Oral Tumors (2010) General rules for clinical and pathological studies on oral cancer (in Japanese), 1st edn. Kanehara, Tokyo
Working Committee of New Histopathological Criteria for Borderline Malignancies of the Oral Mucosa, Japanese Society for Oral Pathology (2007) Oral CIS (JSOP) catalogue: histopathological variations. Sunashobo Publishing, Tokyo
Amagasa T, Yamashiro M, Uzawa N (2011) Oral premalignant lesions: from a clinical perspective. Int J Clin Oncol. doi:10.1007/s10147-010-0157-3
Robbins SL, Cortran RS (1979) Pathologic basis of disease, 2nd edn. Saunders, Philadelphia
Editorial (1962) An international agreement on histological terminology for the lesions of the uterine cervix. Acta Cytol 6:235–236
Reagan JW, Hamonic MJ (1956) Dysplasia of the uterine cervix. Ann N Y Acad Sci 63:1236–1244
Poulsen HE, Taylor CW, Sobin LH (1975) Histological ty** of female genital tract tumours, International histological classification of tumours, No. 13. World Health Organization, Geneva
Bouquot JE, Speight PM, Farthing PM (2006) Epithelial dysplasia of the oral mucosa-diagnostic problems and prognostic features. Curr Diagn Pathol 12:11–21
Broders AC (1932) Carcinoma in situ contrasted with benign penetrating epithelium. J Am Med Assoc 99:1670–1674
Richart RM (1966) Influence of diagnostic and therapeutic procedures on the distribution of cervical intraepithelial neoplasia. Cancer 19:1635–1638
Richart RM (1973) Cervical intraepithelial neoplasia. Pathol Ann 8:301–328
Kurman RJ, Solomon D (1994) The Bethesda system for reporting cervical/vaginal diagnoses. Springer, New York
World Health Organization (1973) Report of a meeting of investigations on the histological classification of precancerous lesions. World Health Organization, Geneva
Warnakulasuriya S, Johnson NW, Van der Waal I (2007) Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 36:575–580
Napier SS, Speight PM (2008) Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 37:1–10
WHO Collaborating Centre for Oral Precancerous Lesions (1978) Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg 46:518–539
Pindborg JJ (1980) Oral cancer and precancer. John Wright & Sons, Bristol
Pindborg JJ, Reibel J, Holmstrup P (1985) Subjectivity in evaluating oral epithelial dysplasia, carcinoma in situ and initial carcinoma. J Oral Pathol 14:689–708
Karabulut A, Reibel J, Therkildsen MH et al (1995) Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med 24:198–200
Holmstrup P, Vedtofte P, Reibel J et al (2006) Longterm treatment outcome of oral premalignant lesions. Oral Oncol 42:461–474
Warnakulasuriya S, Reibel J, Bouquot J et al (2008) Oral epithelial dysplasia classification system: predictive value, utility, weakness and scope for improvement. J Oral Pathol Med 37:127–133
Kujan O, Oliver RJ, Khattab A et al (2007) Why oral histopathology suffers inter-observer variability on grading oral epithelial dysplasia: an attempt to understand the sources of variation. Oral Oncol 43:224–231
Kujan O, Oliver RJ, Khattab A et al (2006) Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Oral Oncol 42:987–993
Ficher DJ, Epstein JB, Morton TH et al (2004) Interobserver reliability in the histopathologic diagnosis of oral pre-malignant and malignant lesions. J Oral Pathol Med 33:65–70
Tabor MP, Braakhuis BJM, Van der Waal JE et al (2003) Comparative molecular and histological grading of epithelial dysplasia of the oral cavity and the oropharynx. J Pathol 199:354–360
Abbey L, Kaugars GE, Gunsolley JC et al (1995) Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol 80:188–191
Brothwell DJ, Lewis DW, Bradley G et al (2003) Observer agreement in the grading of oral epithelial dysplasia. Commun Dent Oral Epidemiol 31:300–305
Speight PM, Farthing PM, Bouquot JE (1996) The pathology of oral cancer and precancer. Curr Diagn Pathol 3:165–176
Reibel J (2003) Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit Rev Oral Biol Med 14:47–62
Lee JJ, Hong WK, Hittelman WN et al (2000) Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 6:1702–1710
Schepman KP, van der Meij EH, Smeele LE et al (1998) Malignant transformation of oral leukoplakia: a follow-up study of a hospital-based population of 166 patients with oral leukoplakia from the Netherlands. Oral Oncol 34:270–275
Shafer WG (1975) Oral carcinoma in situ. Oral Surg 39:227–238
Crissman JD, Zarbo RJ (1989) Dysplasia, in situ carcinoma, and progression to invasive squamous cell carcinoma of the upper aerodigestive tract. Am J Surg Pathol 13:5–16
Crissman JD, Sakr WA (2001) Squamous intraepithelial neoplasia of upper aerodigestive tract. In: Gnepp DR (ed) Diagnostic surgical pathology of the head and neck. Saunders, Philadelphia, pp 1–17
Sakr WA, Gale N, Gnepp DR et al (2009) Squamous intraepithelial neoplasia of the upper aerodigestive tract. In: Gnepp DR (ed) Diagnostic surgical pathology of the head and neck, 2nd edn. Saunders, Philadelphia, pp 1–44
Kuffer R, Lombardi T (2002) Premalignant lesions of the oral mucosa. A discussion about the place of oral intraepithelial neoplasia (OIN). Oral Oncol 38:125–130
Crissman JD, Zarbo RJ, Drozdowicz S et al (1988) Carcinoma in situ and microinvasive squamous carcinoma of the laryngeal glottis. Arch Otolaryngol Head Neck Surg 114:299–307
Blackwell KE, Fu YS, Calcaterra TC (1995) Laryngeal dysplasia. A clinico-pathologic study. Cancer 75:457–463
Kambic V, Gale N, Ferluga D (1992) Laryngeal hyperplastic lesions, follow-up study and application of lectins and anticytokeratins for their evaluation. Pathol Res Pract 188:1067–1077
Kambic V (1997) Epithelial hyperplatic lesions––a challenging topic in laryngology. Acta Otolaryngol Suppl 527:7–11
Hellquist H, Cardesa A, Gale N et al (1999) Criteria for grading in Ljubljana classification of epithelial hyperplastic laryngeal lesions. A study by members of the working group on epithelial hyperplastic laryngeal lesions of the European Society of Pathology. Histopathology 34:226–233
Crissman JD (1982) Laryngeal keratosis preceding laryngeal carcinoma. A report of four cases. Arch Otolaryngol 108:445–448
Crissman JD, Visscher DW, Sarkar FH (1993) Premalignant lesion of the upper aerodigestive tract: biomakers of genetic alterations, proliferation, and differentiation. J Cell Biochem Suppl 17F:192–198
Warnakulasuriya S (2001) Histological grading of oral epithelial dysplasia: revisited. J Pathol 194:294–297
Gale N, Michaels L, Luzar B et al (2009) Current review on squamous intraepithelial lesions of the larynx. Histopathology 54:639–656
Kambic V, Lenart I (1971) Notre classification des hyperplasies de l'epithelium du larynx au point de vue prognostic. JFORL 20:1145–1150
Gale N, Kambic V, Michaels L et al (2000) The Ljubljana classification: a practical strategy for the diagnosis of laryngeal precancerous lesions. Adv Anat Pathol 7:240–251
Michaels L (1997) The Kambic–Gale method of assessment of epithelial hyperplastic lesions of the larynx in comparison with the dysplasia grade method. Acta Otolaryngol 527:17–20
Eversole LR (2009) Dysplasia of the upper aerodigestive tract squamous epithelium. Head Neck Pathol 3:63–68
Fleskens S, Slootweg P (2009) Grading systems in head and neck dysplasia: their prognostic value, weakness and utility. Head Neck Oncol 1:1–8
Koren R, Kristt D, Shvero J et al (2002) The spectrum of laryngeal neoplasia: the pathologist’s view. Pathol Res Pract 198:709–715
Sllamniku B, Bauer W, Painter C et al (1989) The transformation of laryngeal keratosis into invasive carcinoma. Am J Otolaryngol 10:42–54
Crissman JD (1982) Laryngeal keratosis preceding laryngeal carcinoma: a report of four cases. Arch Otolaryngal 108:445–448
Gale N, Zidar N, Fischinger J et al (2000) Clinical applicability of the Ljubljana classification of epithelial hyperplastic laryngeal lesions. Clin Otolaryngol 25:227–232
McLaren KM, Burnett RA, Goodlad JR et al (2000) Consistency of histopathological reporting of laryngeal dysplasia. Histopathol 37:460–463
Kambic V (1997) Epithelial hyperplastic lesions: a challenging topic in laryngology. Acta Otolaryngol 527:7–11
Frangez I, Gale N, Luzar B (1997) The interpretation of leukoplakia in laryngeal pathology. Acta Otolaryngol 527:142–144
Blackwell KB, Calcaterra TC, Fu YS (1995) Laryngeal dysplasia: epidemiology and treatment outcome. Ann Otol Rhinol Laryngol 104:596–602
Mahajan M, Hazarey VK (2004) An assessment of oral epithelial dysplasia using criteria of ‘Smith & Pindborg grading system’ & ‘Ljubljana grading system’ in oral precancerous lesions’. J Oral Maxillofac Pathol 8:73–81
Zerdoner D (2003) The Ljubljana classification: its application to grading oral epithelial hyperplasia. J Craniomaxillofacial Surg 31:75–79
Shibahara T, Tanaka Y (2000) New method for detecting early oral cancer––a study of image uptake analysis with magnifying endoscopy. Oral tumors (in Japanese) 22:2–9
Kurita H, Kurashina K (1996) Vital staining with iodine solution in delineating the border of oral dysplastic lesions. Oral Surg Oral Med Oral Pathol 81:275–280
Epstein JB, Scully C, Spinelli JJ (1992) Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Patho Med 21:160–163
Sugimachi K, Kitamura K, Baba K et al (1992) Endoscopic diagnosis of early carcinoma of the esophagus using Lugol’s solution. Gastrointest Endosc 38:657–661
Inoue H, Kumagai Y, Yoshida T et al (2000) High-magnification endoscopic diagnosis of the superficial esophageal cancer. Dig Endosc 12:32–35
Inoue H, Honda T, Nagai K et al (1997) Ultra high magnification endoscopic observation of carcinoma in situ of esophagus. Dig Endosc 9:16–18
Kumagai Y, Monma K, Kawada K (2004) Magnifying chromoendoscopy of the esophagus: in vivo pathological diagnosis using an endocytoscopy system. Endoscopy 36:590–594
Inoue H, Sasajima K, Kaga M et al (2006) Endoscopic in vivo evaluation of tissue atypia in the esophagus using a newly designed integrated endocytoscope: a pilot trial. Endoscopy 38:891–895
Jonathan C (2007) Advanced digestive endoscopy: comprehensive atlas of high resolution endoscopy and narrowband imaging. Blackwell, New York
Muto M, Ugumori T, Sano Y et al (2005) Narrow band imaging combined with magnified endoscopy for the cancer at the head and neck region. Dig Endosc 17:S23–S24
Muto M, Nakane M, Kitada C et al (2004) Squamous cell carcinoma in situ in oropharyngeal and hypopharyngeal mucosal sites. Cancer 101:1375–1381
Shimizu M, Nagata K, Yamaguchi H et al (2009) Squamous intraepithelial neoplasia of the esophagus: past, present, and future. J Gastroenterol 44:103–112
Takubo K, Aida J, Sawabe M et al (2007) Early squamous cell carcinoma of the esophagus: the Japanese viewpoint. Histopathology 51:733–742
Saku T (2008) Superficial carcinoma––a new approach to pathological diagnosis of CIS. Pathol Clin Med (in Japanese) 26:548–561
Syafriadi M, Ida-Yonemochi H, Ikarashi T et al (2003) Carcinoma in situ of the oral mucosal has a definite tendency towards keratinization. Oral Med Pathol 8:43–44
Izumo T (2009) Squamous intraepithelial neoplasia (SIN) of the oral mucosa. Oral Tumors (in Japanese) 22:15–24
Hamilton SR, Aaltonen LA (2000) World Health Organization classification of tumours: pathology and genetics of tumours of the digestive system. IARC Press, Lyon, pp 9–19
Pitiyage G, Tilakaratne WM, Tavhvash M et al (2009) Molecular markers in oral epithelial dysplasia: review. J Oral Pathol Med 38:737–752
Hunter K, Thurlow JK, Fleming J et al (2006) Divergent routes to oral cancer. Cancer Res 66:7405–7413
Braakhuis BJM, Leemans CR, Brakenhoff RH (2004) A genetic progression model of oral cancer: current evidence and clinical implications. J Oral Pathol Med 33:317–322
Brieger J, Jacob R, Riazimand HS et al (2003) Chromosomal aberrations in premalignant and malignant squamous epithelium. Cancer Genet Cytogenet 144:148–155
Ha PK, Pilkington TA, Westra WH et al (2002) Progression of microsatellite instability from premalignant lesion to tumors of head and neck. Int J Cancer 102:615–617
Gelb AB, Kamel OW, LeBrun DP et al (1992) Estimation of tumor growth fractions in archival formalin-fixed, paraffin-embedded tissues using two anti-PCNA/cyclin monoclonal antibodies: factors affecting reactivity. Am J Pathol 141:1453–1458
Scott RE, Wilke MS, Wille JJ et al (1988) Human squamous carcinoma cells express complex defects in the control of proliferation and differentiation. Am J Pathol 133:374–380
Lindberg K, Rheinwald jG (1989) Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 134:89–98
Klijanienko J, Micheau C, Carluc-Caillaud JM (1989) Significance of keratin 13 and 6 expression in normal, dysplasic and malignant squamous epithelium of pyriform fossa. Virchow Arch A Pathol Anat 416:121–124
Coltrera MD, Zarbo RJ, Sakr WA et al (1992) Markers for dysplasia of the upper aerodigestive tract. Suprabasal expression of PCNA, p53, CK19 in alcohol-fixed, embedded tissue. Am J Pathol 141:817–825
Ogden GR, Chisholm DM, Adi M et al (1993) Cytokeratin expression in oral cancer and its relationship to tumor differentiation. J Oral Pathol Med 22:82–86
Kobayashi T, Ida H, Cheng J et al (2005) Histopathological evaluation of borderline malignancies of the oral mucosa by the aid of immunohistochemistry for keratin species and Ki-67. Oral Med Pathol 10:45
Kondoh N, Ohkura S, Arai M et al (2007) Gene expression signature that can discriminate oral leukoplakia subtypes and squamous cell carcinoma. Oral Oncol 43:455–462
Ohkura S, Kondoh N, Arai M et al (2005) Differential expression on the keratin-4, -13, -14, -17 and transglutaminase 3 genes during the development of oral squamous cell carcinoma from leukoplakia. Oral Oncol 41:607–613
Whipple ME, Mendez E, Farwell DG et al (2004) A genomic predictor of oral squamous cell carcinoma. Laryngoscope 114:1354–1364
Roepman P, Weesels LFK, Kettelarij N et al (2005) An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinoma. Nat Genet 37:182–186
Bloor BK, Seddon SV, Morgan PR (2001) Gene expression of differentiation-specific keratins in oral epithelial dysplasia and squamous cell carcinoma. Oral Oncol 37:251–261
Londono-Vallejo JA (2008) Telomere instability and cancer. Biochimie 90:73–82
Luzar B, Poljak M, Marin IJ et al (2003) Telomerase reaction is an early event in laryngeal carcinogenesis. Mod Pathol 16:841–848
Aida J, Izumo T, Shimomura N et al (2010) Telomere lengths in the oral epithelia with and without carcinoma. Eur J Cancer 46:430–439
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Izumo, T. Oral premalignant lesions: from the pathological viewpoint. Int J Clin Oncol 16, 15–26 (2011). https://doi.org/10.1007/s10147-010-0169-z
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DOI: https://doi.org/10.1007/s10147-010-0169-z