Section 2 -

Squamous Dysplasia- To SIN or not to SIN Richard J. Zarbo Pathology and Laboratory Medicine Henry Ford Health System Detroit, Michigan

Objectives Identify reasons why head and neck squamous dysplasia cannot be reliably diagnosed histologically. Recognize the diagnostic influence of clinical information on the histologic interpretation of dysplasia. Understand the clinical import and outcomes associated with currently recognized schemes of dysplasia. Appreciate a simplified taxonomy of squamous intraepithelial abnormalities that reflects limitations of histologic impression, acknowledges diagnostic uncertainty and reflects biologic potential. The Problem Despite the advancement of internationally accepted criteria for the diagnosis of oral squamous dysplasia, numerous studies attest to the difficulty, even among 'expert' pathologists, in arriving at accurate and reproducible diagnoses of squamous dysplasia. The current practice of oral and surgical pathology presents numerous challenges in the histopathologic interpretation of squamous dysplasia in the head and neck mucosa. First, any number of 18 different histopathologic features, none specific to neoplasia, may lead to the histopathologic impression of dysplasia. Requiring just 3 of these features for a diagnosis of dysplasia in any combination leads to 560 histologic appearances of dysplasia- an astonishing visual goal for pathologists to reproducibly create (accuracy) and then recreate (precision). These histopathologic features may include any combination of 1) architectural alterations like- irregular epithelial stratification (mosaic pattern), drop shaped rete ridges, or reduced cellular cohesion; 2) cytologic abnormalities like- abnormal nuclear size & shape variation, abnormal cell size & shape variation, increased nuclear-cytoplasmic ratio, increased nuclear size, increased number & size nucleoli, hyperchromasia; 3) maturation disturbances like- loss of basal cell polarity, premature single cell keratinization (dyskeratosis), keratin pearls in rete pegs; and 4) proliferative changes like- increased mitotic figures, atypical mitotic figures, mitoses in superficial ½ epithelium, basilar hyperplasia (from WHO 1997) (more than 1 layer of basaloid cells). When the precision and reproducibility of a diagnosis of dysplasia relies on innumerable combinations of relatively independent pathologic features, it is imperative that the pathologist's communication of dysplasia to the surgeon accurately reflects not only the imprecision of diagnosis, when it exists, but also the expected biologic behavior. Therefore the terminology in play must be a help rather than a hindrance to effective communication by the pathologist. Current taxonomic terminologies imply that defined diagnostic threshold cut-points can be reliably derived by the pathologist from what is essentially continuous data composed of the innumerable combinations of those 18 histopathologic abnormalities. Here the taxonomy fails the pathologist, and in turn the clinician, with a false premise that leads to an expectation of infallibility of pathologic diagnosis. The first step toward the cure is to admit that 1) thresholds for separating reactive atypia, some hyperplasias and mild dysplasia are not reproducible, 2) grading of dysplasia may be unimportant for the following reasons: many mild dysplasias are reversible any atypia/mild dysplasia in a cancer prone areas should be followed closely over time with an eye to early re-biopsy if changes are detected, some diagnoses of atypia are better understood as clinicopathologic ones, relying on good histories of trauma. Alternately, this can be a deceptive reason for a lesion in high risk area when there is any atypia noted. Dysplasias of moderate and severe degree and those with keratinization share similar rates of progression to invasive carcinoma, cannot be reliably graded and, therefore, need not be distinguished. The Solution The main objectives of pathology terminology should be 1) to reduce the classifier categories for the pathologist in order to reduce variation in pathologic interpretation, 2) to optimize communication to the clinician by recognizing inherent uncertainty in histopathologic evaluation and 3) to accurately reflecting biologic potential to direct further clinical actions. Current taxonomies of squamous dysplasia in play are 1) WHO 2005- comprising 5 categories spanning hyperplasia to carcinoma in situ, 2) SIN (Crissman 1989) and Ljubljana (Hellquist 1999)- each with 4 categories, and 3) Hellquist (1982) encompassing 3 categories over the same histologic spectrum. To that end, I favor a simplified 2-category Low Grade-High Grade taxonomy for head and neck squamous lesions, not dissimilar to the Bethesda system for cervical squamous abnormalities. The 2 categories are squamous intraepithelial lesion (SIL) to indicate a low-grade lesion and squamous intraepithelial neoplasia (SIN) to signify a high-grade neoplasia. The low end SIL of the biologic spectrum consists of many reactive and reversible squamous proliferations. Some would be called mild dysplasia, bearing features indistinguishable from reactive lesions. There is no way to define by histologic criteria which of these so-designated mild are truly irreversible neoplasias. For this reason, I have recognized all low-grade squamous lesions with the term low-grade squamous intraepithelial lesion (Low-Grade SIL), acknowledging uncertainty in identifying dysplasia as a marker of neoplasia at this level of histologic abnormality. The low-grade SIL abnormalities comprise a range of hyperplasias, keratoses and atypias, of both reactive, indeterminate and low-grade dysplastic nature that cannot be reliably identified by histologic means alone. Histologic thresholds for separating these low-grade squamous lesions that are not completely histologically normal are not reproducible. Regardless, these lesions are deserving of clinical follow-up because the epithelium is not normal and histologic criteria are not reliable in distinguishing which are incipient neoplasia. Moreover, often, one or the other may be favored by integrating 1) clinical knowledge of oral site of involvement, especially high risk areas such as lateral-ventral tongue, floor of mouth and retromolar trigone-tonsillar pillar complex and 2) clinical knowledge of prior trauma, inflammation, infection, repair or radiation. In fact, the WHO 1990 book recognized this histologic blindness for any low grade atypical lesion in a high risk oral site, with the following qualifying language- "slight degrees of epithelial dysplasia do not indicate any great danger for the patient (although special reference should be made to certain high risk sites, such as floor of mouth and ventral surface of tongue where importance should be attached to even slight dysplasia". The squamous abnormalities that I have designated high-grade squamous intraepithelial neoplasia (High-Grade SIN) are often easier to recognize by their more pronounced histologic and cytologic departure from normal epithelium. These are much more likely to represent irreversible neoplastic changes within the epithelium. But again, there is imprecise separation of histologic boundaries defining a spectrum designated by the terms moderate dysplasia, severe (with or without keratinization) dysplasia and carcinoma in situ. From experience in the laryngeal mucosa, there appears to be little merit in subclassifying these high grade histologic changes as they share a similar biologic behavior with a 12.5-14% risk of progression to invasive carcinoma that is greatly increased by 3-fold when the changes are more diffuse than localized in distribution. Therefore, the HG-SIN lesions should be completely removed, preferably with clear margins. If that is not possible, the lesions should be subject to close clinical surveillance. For the pathologist, these biopsied lesions should be carefully dissected, completely embedded and adequately sectioned to exclude the possibility of early invasive cancer. WHO 2005 Ljubljana 2000 SIN 1989 Hellquist 1982 SIL SIN Hyperplasia Simple hyperplasia Hyperplasia Hyperplasia or Keratosis with or without Mild dysplasia SIL=Hyperplasia Keratosis Atypia, indeterminate & reactive Mild dysplasia Mild dysplasia Abnormal hyperplasia SIN I - - Moderate dysplasia Atypical hyperplasia SIN II Moderate dysplasia SIN=Moderate dysplasia Severe dysplasia - SIN III Severe dysplasia & carcinoma in situ Severe dysplasia Carcinoma in situ Carcinoma in situ Carcinoma in situ - - - References Abbey LM, Kaugars GE, Gunsolley JC, Burns JC, Page DG, Svirsky JA, Eisenberg E, Krutchkoff DJ, Cushing M: Intraexaminer and interexaminer reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral med Oral Pathol Oral Radiol Endod 80:188-191, 1995. Barnes L, Everson JW, Reichart P, Sidransky D (eds.) World Health Organization (WHO) Classification of Tumours. Pathology & Genetics. Head and Neck Tumours. IARC Press, Lyon, 2005, pp. 177-179. Brothwell DJ, Lewis DW, Bradley G, Leong I, Jordan RCK, Mock D, Leake JL: Observer agreement in the grading of oral epithelial dysplasia. Community Dent Oral Epidemiol 31:300-305, 2003. Crissman JD, Zarbo RJ, Drozdowicz S, Jacobs J, Ahmad K, Weaver A: Carcinoma in situ and microinvasive squamous carcinoma of the laryngeal glottis. Arch Otolaryngol 114:299-307, 1988. Crissman JD and Zarbo RJ: Dysplasia, In-situ Carcinoma and Progression in Squamous Cell Carcinoma of the Upper Aerodigestive Tract. Am J Surg Pathol 13 [Suppl 1]:5-16,1989. Crissman JD, Zarbo RJ: Quantitation of DNA ploidy in squamous intraepithelial neoplasia of the laryngeal glottis. Arch Otolaryngol 117:182-188, 1991. Hellquist H, Lundgren J, Olaffson J: Hyperplasia, keratosis, dysplasia and carcinoma in situ of the vocal cords- a follow-up study. Clin Otolaryngol 7:11-27, 1982. Hellquist HB, Cardesa A, Gale N, Kambic V, Michaels L: Criteria for grading in the 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, 1999. Karabulut KA, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E: Observer variability in the histologic assessment of oral premalignant lesions. J Oral Pathol Med 24:198-200, 1995. Mashberg A. Erythroplasia v. leukoplasia in the diagnosis of early asymptomatic oral squamous carcinoma. N Engl J Med 297:109–110, 1977. McClatchey KD, Zarbo RJ: The Jaws and Oral Cavity. Chapter 19. In Mills SE (ed.): Sternberg's Diagnostic Surgical Pathology. 4th Edition. Philadelphia: Lippincott, 2004, pp. 879-932. Pindborg JJ, Reibel J, Holmstrup P: Subjectivity in evaluating oral epithelial dysplasia. Carcinoma in situ and initial carcinoma. J Oral Pathol 14:698-708, 1985. Pindborg JJ, Reichart PA, Smith CJ, van der Waal, I: World Health Organization (WHO) International Histological Classification of Tumours. Histological Typing of Cancer and Precancer of the Oral Mucosa. Springer-Verlag: Berlin, 1997, pp. 24-26. Pindborg JJ, Jolst O, Renstrup G, Roed-Petersen B. Studies in oral leukoplakia: a preliminary report on the period prevalence of malignant transformation in leukoplakia based on a follow-up study of 248 patients. J Am Dent Assoc 76:767–771. 1968. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 53:563–568, 1984. Shafer WG: Oral carcinoma in situ. Oral Surg Med Pathol 39:227-238, 1975. Wenig BM. Squamous cell carcinoma of the upper aerodigestive tract. Precursors and problematic variants. Mod Pathol 15:229-254, 2002. WHO Collaborating Center for Oral Precancerous Lesions. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Med Pathol 46:518–539, 1978.