Moderators: Dr. Antonio Cardesa and Dr. Bruce Wenig
Section 2 -
Squamous Dysplasia- To SIN or not to SIN
Richard J. Zarbo
Pathology and Laboratory Medicine
Henry Ford Health System
- 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
- Understand the clinical import and outcomes associated with currently recognized schemes of
- Appreciate a simplified taxonomy of squamous intraepithelial abnormalities that reflects limitations
of histologic impression, acknowledges diagnostic uncertainty and reflects biologic potential.
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
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
|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 ||- ||- ||-|
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