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Reference: Bouquot JE, Gresham M, Adibi SA. Slimy, sloughing keratosis of unknown cause – Idiopathic
subcorneal acantholytic keratosis (ISAK). J Texas Dent Assoc 2021; 138: in press.
TDJ Case of the Month:
Slimy, Sloughing Keratosis of Unknown Cause
Jerry E. Bouquot, DDS, MSD, DABOMP, DABOM(Hon), , FICD, FACD *
Makayla Grisham, DDS **
Shawn Adibi DDS, MEd, FAAOM ***
* Emeritus Professor & Past Chair, Department of Diagnostic & Biomedical
Sciences, University of Texas School of Dentistry at Houston, Houston, Texas
** Resident in Oral & Maxillofacial Pathology, Department of Diagnostic Sciences,
University of North Carolina, Chapel Hill, North Carolina
# Professor, Department of General Dentistry & Public Health Dentistry, University
of Texas School of Dentistry at Houston, Houston, Texas
Send Correspondence to:
Dr. J. E. Bouquot
212 Tibbs Road
Morgantown, WV 26508
Phone (cell): 281-745-2330
bouquot@aol.com
Email addresses:
Jerry.Bouquot@uth.tmc.edu
mbg26@unc.edu
Shawn.Adibi@uth.tmc.edu
Key words: hyperkeratosis, acantholysis, oral disease
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1Oral and Maxillofacial Pathology Case of the Month
Clinical history:
This 27 year old woman has been experiencing intermmitently “peeling skin” of her oral mucosa for more
than 6 years, with no noticeable change in severity or frequency of “episodes.” Her dentist noticed it on
several occasions but did nothing for it since it was asymptomatic and “seemed not to bother her much at
all.” It occurred repeatedly in the same two locations, producing at both sites a “slimy” white patch which
slowly developed, starting as gray and then becoming more and more white over several days, eventually
starting to slough off. The patches were never symptomatic and for the most part were relativey well
demarcated. There has never been ulceration or mucosal erythema, and every 3-5 days she has “treated”
it by gently scraping the white film or pseudomembrane off with a damp wash cloth; within 5-8 days it
would start over again.
At her request she was referred to an Oral & Maxillofacial Pathologist who saw two areas with thick white
keratotic plaques, with peripheral regions of gray/semitranslucency (Figure 1). The patient said that they
were typical of past involvement and had always recurred in those two sites.
Figure 1: Gray/white plaques at examination. A) Right maxillary buccal and vestibular mucosa (abfraction also
present on premolars); B) Same lesion after gentle tongue blade pushing from the edge toward the center, with the
white material easily peeling off, with normal underlying mucosa; C) Left mandibular gingival/vestibular
pseudomembrane: D) Same lesion after being gently scraped with a tongue blade (for a pap smear sample), showing
normal underlying mucosa.
The white plaques at this examination were five days old, and the previous episode concluded 7 days
prior to their onset, after she “wiped the slim off.” The plaques could be easily peeled off of the underlying
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A
CD
B
mucosa with gentle tongue blade pressure and the mucosa looked perfectly normal after their removal.
Essentially, then, they were more like pseudomembranes than true mucosal plaques. The patient
indicated that the plaques typically could not be scrapped off until day 3 or 4.
Pseudomembranes were scaped into a biopsy bottle; after fixation they were centrifuged into a compact
conglomerate, then processed for H&E histopathologic examination. Under the microscope the sample
was consist of of a uniformly thick layer of orthokeratin that did not seem necrotic or inflamed (Figures 2a
& 2b)
Figure 2: Microscopic appearance of the lesions. A) Scraped off maxillary pseudomembranes were comprised of
uniformly thick, non-necrotic orthokeratin; B) Same as A, showing residual nuclei and a complete lack of inflammatory
cells; C) Biopsy of mandibular lesion showing thick hyperkeratosis with the upper keratin pulling away from the lowest
layers of keratin, with epithelial atrophy and occasional lymphocytes in the subepithelial stroma; D) Higher power of C
showing keratin pulling away from normal appearing spinous layer (arrow).
A tentative diagnosis of TIME (toothpaste-induced mucosal etching), a mild chemical burn associated with
whitening toothpastes and mouthwashes, was suggested.1 However, the patient claimed to have never
used such a product. Nevertheless, over the next six months, she tried different types and brands of
nonwhitening toothpastes, brands without sodium lauryl sulfate (Sensodyne) and baking soda brands
(Arm & Hammer). No changes were noted in her oral lesions with any of these products. Topical and
systemic prednisolone treatments were also ineffective.
Page 3 of 7
A
CD
B
The patient asked that a biopsy be performed in an attempt to “solve this problem.” Accordingly, she
returned to the dental school on day 4 of a new episode of pseudomembrane formation. Microscopic
evaluation of her mandibular lesion showed no inflammatory changes, but the epithelium was hyperplastic
and there was an abnormally thickened layer of orthokeratin on the surface. The full keratin layer was
literally tearing away from the underlying epithelial cells (Figures 2c & 2d). Epithelial cells under the tear,
and those adjacent to it, appeared completely normal. A portion of the biopsy was processed for
immunofluorescence in order to rule out pemphigus, pemphigoid, lichen planus, etc. This was completely
negative.
What is the final diagnosis?
See page ____ for the answer and discussion.
----------------------------------------------------------------------------
Idiopathic Subcortical Acantholytic Keratosis (ISAK)
Oral and Maxillofacial Pathology Case of the Month (from page ____)
This clinically was most similar to TIME, a common but much underreported chemical burn of oral
mucosa from oral hygiene products (Figure 3).1 However, no etiology could be identified and there was no
microscopic evidence of a chemical “burn” of superficial cells, so it must represent a different problem.
Figure 3. Example of TIME, i.e. hyperkeratosis and superficial chemical burn from whitening toothpaste. A) Grayish
white keratotic plaque can be scraped off with finger; B) Subkeratin tearing/clefting (arrow) with enlarged, pale
superficial keratoinocytes damaged by low pH, also with atrophy of epithelium and chronic inflammation of the
stroma.
Page 4 of 7
AB
If not TIME, what can it be? We usually assume a sloughing mucosal pseudomembrane represents a
collapsed bulla or large blister, presumably from an autoimmune or allergic attack, e.g. pemphigus,
pemphoid, IgA disease, bullous lichen planus, etc., or sometimes from developmental flaws of
skin/membrane integrity.2 The epithelium from the top of such a ruptured bulla easily scrapes off, but this
leaves an open ulcer or prominent erythematous base, not the normal mucosa of the present lesion.
Furthermore, the above bullous disorders are distinguished, one from another, by specific
immunofluorescence patterns and the location of the lysis or disruption of the squamous epithelium:
between keratinocytes (rupture of the intercellular bridges) or at the level of the basement membrane
(multiple levels, actually). The present lesion was negative to immunofluorescence, starts life as
hyperkeratosis, not a blister, and its lysis occurs in an extremely unusual microscopic location:
immediately beneath the keratin layer or in the lowest levels of that layer.
It should here be noted that there are several oral white keratotic patches which can be partially peeled
away (Table 1), but they all have known causes, different histopathology and/or clinical features quite
different from the present entity.1-3,99 There are, likewise, a few skin lesions characterized by lysis
(acantholysis) and excess keratin. One of them, acantholytic hyperkeratosis, would seem by its very
terminology to fit perfectly, but its epithelial lysis occurs much lower in the epithelium and it is a
developmental, inherited disorder with a very early onset.
In fact, only one skin lesion, subcorneal pustular dermatitis (Sneddon-Wilkinson disease), shows epithelial
lysis immediate beneath a thickened keratin layer. It differs significantly, however, in that it clinically
mimicks pimples and microscopically has thousands of neutrophils in the cleft/lysis beneath the keratin
layer.4-6 This disease appears to be produced by a monoclonal gammopathy, although some consider it to
be a variant of pustular psoriasis. No oral lesions have been reported, and our present case shows
absolutely no neutrophils.
It appears that this woman’s lesion has not been previously reported. We recommend a diagnostic name
of idiopathic subcorneal acantholytic keratosis (ISAK), name that reflects: A) Our inability to identify a
cause; B) A site-specific rupture of intercellular bridges between the flattened surface keratinocytes and
the underlying more rounded spinous layer cells; C) Excessively thick keratin layer.
Page 5 of 7
Table 1. White oral and plaques that can be scrapped off, completely or partially (altered from Neville et
al.)1-3
Disease Cause Comment
White coated tongue Bacteria Only a small part can be scraped off, with difficulty
Psuedomembranous
candidiasis Fungus Scraps off, often completely and easily, but usually reveals
erythema of the underlying mucosa
Moriscatio buccarum Cheek biting Portions can be completely scraped off, but not frequently
White sponge nevus Developmenta
l anomaly
Sometimes the top half of the whitish epithelium can be
peeled off
Leukoedema Developmenta
l anomaly
Very rarely, the top half of the whitish macule can be
peeled off
Thermal burn Pizza, etc. Painful, abrupt onset, erythema/ ulcer of affected mucosa
Cotton roll burn
Desiccation
from contact
with cotton roll
Painful, difficult to slough off, can usually scrape off only a
small amount
Acid burn Aspirin, etc. Painful; only top portion of wound sloughs off, may be
erythematous and ulcerated beneath
TIME (toothpaste-
induced mucosal
etching)
Chemicals in
toothpaste or
mouthwash
Sloughs off easily and completely, leaving normal
appearing underlying mucosa; recurs frequently
Mucous patch Secondary
syphilis
Can be scraped off with difficulty and not completely;
disappears on its own in a week or two
Diptheria slough Diptheria Thick necrotic layer can ce scrapped off with difficulty
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References
1. Bouquot JE, Koeppen RA, Haddad Y. Toothpaste-induced mucosal etching (TIME). J Texas Dent
Assoc 2014; 131:574-576, 610-612.
2. Neville B, Damm D, Allen C, Bouquot J. Oral and Maxillofacial Pathology, 3rd edition.
Philadelphia: W. B. Saunders, 2008.
3. McDonald G, Bouquot J. White sponge nevus. Texas Dental Journal, 2008; 125:692-693, 707-
708.
4. Cheng S, Edmonds E, Ben-Gashir M, Yu RC. Subcorneal pustular dermatosis: 50 years on. Clin
Exp Dermatol. 2008;33:229–233.
5. Ranieri P, Bianchetti A, Trabucchi M. Sneddon-Wilkinson disease: a case report of a rare disease
in a nonagenarian. J Am Geriatr Soc. 2009;57:1322–1323.
6. Ceccarelli G, Molinelli E, Campanati A, Goteri G, Offidani A. Sneddon-Wilkinson Disease and
Monoclonal Gammopathy of Undetermined Significance in the Elderly: Case Report. Case Rep
Dermatol. 2019 Jul 10;11(2):209-214.
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