14. Differential diagnostics of precancerous
diseases. Treatment and prevention. Supervision of patients.Using of physical
methods for treatment and diagnostics.
EPIDEMIOLOGY AND
ETIOLOGY
Oral cancer is estimated to be the sixth most common cancer in the
world. More than 90% of
cancers in the mouth are squamous cell carcinomas, most frequently of the
tongue.Many primary care clinicians expect that their patients receive a
complete oral examination from their dentists. Large segments of the
population, however, lack dental insurance or do not regularly visit a dentist.
Furthermore, in a study conducted in 2005, Cruz and colleagues found that
almost 20% of dentists and 30% of dental hygienists do not routinely examine
patients for oral cancer. Primary
care clinicians must be able to recognize oral lesions and make appropriate
recommendations for follow-up.
A thorough history is critical in identifying persons at risk for oral cancer.
The most well-established risk factors are tobacco and alcohol use. People who
smoke cigarettes are 4 times more likely to develop oral cancer than are
nonsmokers. Those who smoke have a greater risk of oral cancer than those who
use smokeless tobacco.
People who consume alcohol are 3 times more likely to develop oral cancer than
nondrinkers.The type of alcohol consumed is also significant: drinking hard
alcohol is associated with a greater risk than drinking beer or wine. When
alcohol is combined with tobacco use, the incidence of cancer is markedly
increased.
Other habits may affect the risk of oral cancer. Caffeine is one of the most
widely consumed in the world. Coffee has been suspected as a carcinogen by some
researchers; however, one study actually indicated that coffee might have a
protective effect against oral cancer. The study also found no significant
adverse or protective effects associated with decaffeinated coffee or tea.
Systemic diseases such as erosive lichen planus are associated with oral
cancer. In cases of longstanding lichen planus, instances of malignant transformation
within the mucosal lesions were reported. Any process
that weakens the immune system may also promote malignant transformation
because of decreased immune surveillance. Epstein-Barr virus and human
papillomavirus are suspected of possibly
contributing to the development of oral cancer.
An occupational history may uncover additional risk factors. People who have
industrial jobs typically have a higher risk of oral cancer. Exposure to
toxins such as metal dust, solvents, paints, lacquers, and varnishes is likely
what increases the risk. The clinician should, therefore, inquire about any
toxic materials patients may encounter through their job, hobbies, or military
service.
Education is critical for those patients whose lifestyle places them at risk
for oral cancer. Patients who use tobacco or alcohol may be well aware that
they are increasing their risks of lung or liver disease, but the majority do
not consider themselves to be at increased risk for oral cancer.
The terms pre-cancer, precursor lesions,
pre-malignant, intra epithelial neoplasia and potentially malignant have
been used in the international literature to broadly describe clinical
presentations that may have a potential to become cancer. They all convey the
concept of a two-step or multi-step process of cancer development, but it is
unlikely, on a priori grounds, that there is uniformity in
the way individual patients or tissues behave. The terminology ought to reflect
our best understanding of carcinogenesis in the oral mucosa, and aspires to
engender consistency in use. The latest WHO monograph on Head and Neck Tumours
(2005) uses the term epithelial precursor lesions
The
two key components of the oral examination are inspection and palpation of both
external and intraoral structures. The examination begins with an inspection of
the head, face, and neck looking for coloration, swelling, and symmetry. Since
most head and neck cancers are unilateral, any asymmetry is investigated.
Some questions that can
be useful to investigate an oral abnormality are:
Are you aware of any
changes in your mouth?
Symptomatic lesions are often the result of an inflammatory process, while
potentially malignant lesions are generally asymptomatic.
If yes, how long have you
been aware of these changes?
A long-standing (years to decades) change or one that has not progressed since
first discovery is less likely to be a potentially malignant lesion.
Has this ever happened
before? Does the lesion come and go or is it always present?
The history of an exacerbating and remitting lesion or one that exhibits a
cyclic occurrence is less consistent with a potentially malignant lesion.
Has the lesion become
larger since you first noticed it?
Potentially malignant lesions tend to change over time. White lesions may
become mixed with a red component or develop a verrucous surface. Lesions may
become more extensive or firm or ulcerated, particularly if they undergo
malignant transformation.
Is there any discomfort
or pain associated with the lesion?
Early potentially malignant lesions tend to be asymptomatic, however
development of discomfort or pain may indicate malignant transformation.
Have you started taking
any new medications or changed your oral care regimen?
Temporal association of a new environmental factor with the onset of an oral
abnormality suggests they might be related. If possible, cessation of the
environmental change may be tried to see if the potentially malignant lesion
subsides.
Do you use tobacco
products or chew betel quid?
Many leukoplakias are associated with tobacco use, and cessation of the habit
may result in resolution of the lesion.
External
examination Palpate
the head thoroughly, including the temporal muscles, temporomandibular joints,
masseter muscles, and bony mandible. Next, palpate the neck, including the
parotid and submandibular glands, the lymph nodes, and the neck musculature.
Internal
examination A
careful search is made for any areas that vary from the normal pink color of
healthy mucosa (see Figure 1). Almost all oral squamous cell carcinomas are
preceded by readily visible changes in the oral mucosa that most commonly
manifest as red or white patches.
Retract
the upper lip superiorly, and examine the mucosa and gingiva (A). Manipulate
the lip with the thumb and index finger, feeling for any submucosal lesions
(B). Examine the buccal mucosa and posterior gingiva one side at a time by
retracting the commissure of the lips laterally and then superiorly (C).
Retract the lower lip and examine the mucosa, vestibule, and anterior gingiva
(D). Next, examine the entire hard palate (E). Depress the tongue with a tongue
blade while the patient says “ahhh” (F). (This maneuver elevates the soft
palate and allows a better view of the tonsillar area.) Ask the patient to
raise his or her tongue to the roof of the mouth and examine the ventral
surface of the tongue and floor of the mouth (G). Finally, extend the tongue
out of the mouth and hold it with a 2 × 2 gauze square and examine the lateral
borders of the tongue (H).
Palpation of the oral cavity also is important. All surfaces of the buccal
mucosa, floor of mouth, and tongue should be palpated. Proper palpation is
accomplished using a bimanual technique that sandwiches the target structures.
Better tactile sensation of the soft, mobile structures of the face and oral
cavity is achieved using this method.
Visual Enhancements for Soft Tissue Evaluation
Visual
examination with a standard white light has been the cornerstone of a
comprehensive examination. Any noninvasive device that improves the clinicians
visualization and ability to achieve early detection of soft-tissue
abnormalities, especially those that are neoplastic in nature, is an invaluable
asset to the diagnostic armamentarium. Any visual enhancement device should be
used in combination with a conventional visual oral mucosal examination to
improve the evaluation, identification, and monitoring of oral mucosa and
abnormalities. Available imaging modalities include the use of reflectance and
fluorescence technology to evaluate tissue under various illumination
conditions.
Fluorescence
technology, in particular, is a noninvasive approach for assessing and aiding
in the visualization of chemical and morphological patterns of the various
tissues and substances within the oral cavity.2 Fluorescence visualization enhances
the clinicians ability to observe changes in these patterns and can aid in
evaluating both the hard- and soft-tissue structures, as well as the biological
activity of the flora and other microbial activity. These technologies do not
require the use of any mouth rinses or stains; the process simply repeats the
visual exam with the aid of the device(s).
Products such as the VELscope Vx and
the DentLight Oral Exam Light Kit enable clinicians to visually scan the entire
oral cavity for changes in the fluorescence pattern of tissue, which may
indicate an area of concern. 
The Identafi oral cancer screening device uses a multispectral fluorescence and
reflectance technology to enhance visualization of mucosal abnormalities. The
small, cordless handheld device uses a three-wavelength optical illumination
and visualization system that allows dental professionals to identify oral
mucosal abnormalities. Identafis three separate wavelengths of lightwhite, violet,
and green-amberexcite oral tissue, providing the clinician three different
illumination perspectives to visualize the area being examined. A disposable
mirror attachment assists in visualizing the area in an indirect manner.
Microscopic Evaluation and Cytology
Full-thickness surgical
biopsy with a microscopic examination is the accepted method of diagnosing
cancer and many other mucosal conditions. The role of a biopsy is to rule out a
malignancy and to establish the appropriate diagnosis for the patients
condition. All other modalities, including toluidine blue staining and
cytology, are adjunctive procedures to aid in determining if and where a
surgical biopsy would be appropriate and most beneficial. Staining and cytology
are not substitutes for the traditional gold standard surgical biopsy
technique of removing architecturally intact tissue. In the majority of cases,
a lesion that is worthy of a staining or cytology procedure may be better
served by a surgical biopsy that will render a diagnosis.
Another adjunctive
screening procedure, brush cytology, involves the collection of transepithelial
mucosa cells by means of a minimally invasive sterile, plastic-handled nylon
bristle brushwith little or no discomfort to the patient. Disaggregated epithelial
cells are acquired by vigorous brushing of the oral lesion with a sterile nylon
bristle brush. This technique is used primarily to screen a suspicious
leukoplakia or erythroplakia of the mouth in order to aid in determining the
presence or lack of premalignant dysplastic change. Brush cytology is an
effective system for ruling out the presence of abnormal, atypical, and
dysplastic cells in areas that have been properly brushed. The cells are
transferred to and fixed on a glass slide or placed in a special liquid
preservative/fixative in a bottle; the collected sample is then sent to the
laboratory for processing and histological evaluation.
The use of liquid-based
cytology in the oral cavity is a relatively new screening technique that has
also been proven effective when an area of abnormality has been discovered. Not
only can it be used for the detection of dysplastic cells, but it also can be
used to detect other oral conditions such as herpes simplex infection and
candidiasis. Brush cytology may also aid the clinician in determining if the
lesion detected should be observed or treated, or if an immediate invasive
full-thickness biopsy procedure with intact architecture should be performed.
Salivary diagnostics has
become a reality: patients rinse with specialized solutions and expectorate
into a funneled collection tube that is processed and analyzed at the
laboratory. Due to the simplicity and noninvasive nature of salivary collection
and testing, these screening modalities strongly appeal to clinicians. The
saliva that is collected can be evaluated at the laboratory for the status and
susceptibility to both oral and systemic conditions.
Precancer Classification
The following six classes
were used: 1) Acquired microscopic precancers; 2) acquired large lesions with
microscopic atypia; 3) Precursor lesions occurring with inherited hyperplastic
syndromes that progress to cancer; 4) Acquired diffuse hyperplasias and diffuse
metaplasias; 5) Currently unclassified entities; and 6) Superclass and modifiers.
1. Acquired microscopic
precancers
These are the lesions that most people think of
when they hear the term precancer. All of the so-called intraepithelial
neoplasias fall into this category. Most examples of the microscopic precancers
occur commonly (actinic keratosis, cervical dysplasia). They tend to be
multifocal. They tend to be non-inherited lesions, often with an identifiable
causation (e.g. sunlight, human papillomavirus infection). They seldom occur in
children. Exceptions are inherited diseases that heighten sensitivity to a
causal agent, such as the early appearance of actinic keratoses in children
with Xeroderma Pigmentosum. Morphologically, they tend to have a high degree of
nuclear atypia. The microscopic epithelial precancers grow by a subtle
replacement of the normal mucosa, without producing a mass, despite many
replicative cycles of growth. They progress to invasive cancer while still
relatively small. The term dysplasia is often applied to these lesions.
Dysplasia, in the context of precancer, is somatically inherited nuclear
atypia. Cytologists use the morphologic features of dysplasia to identify
precancer cells. Class 1 precancers often have an identifiable non-dysplastic
stage that precedes the appearance of nuclear atypia (e.g. squamous metaplasia
of bronchus, Barrett's esophagus without atypia, junctional nevus, intestinal
metaplasia of stomach).
2. Acquired large lesions
with morphologic atypia
These lesions tend to have a uniform appearance throughout most of
their long existence, even from the smallest size (i.e. they have a long,
stable growth phase). They tend not to have precursor lesions from identifiable
microscopic precancers (e.g. class 2 lesions do not seem to arise from class 1
lesions). Their chance of becoming malignant usually increases as the size of
the lesion increases. When they become malignant, there is usually a
morphologically apparent focus from within the large lesion that has crowding,
irregular growth pattern and marked cellular atypia that is strikingly different
from the surrounding cells. This focus enlarges, shows frank invasion, and is
the presumed origin of the cancer that develops from the precancer. These
lesions tend not to regress spontaneously. They tend to be long-lived and do
not progress to cancer without first growing to a large size. These lesions are
often multiple but do not occur in large numbers (hundreds) unless there is a
germline mutation. Prototypical acquired large precancers are colon adenoma and
myelodysplasia
3. Precursor lesions occurring
with inherited hyperplastic syndromes that often progress to cancer
These lesions tend to occur very rarely in the general population,
but may occur with a high probability (sometimes 100%) in patients carrying the
germline mutation. The prototypical lesions are the Ret-gene disorders.
Mutations in the RET gene are associated with the disorders multiple endocrine
neoplasia, type IIA (MEN2A), multiple endocrine neoplasia, type IIB (MEN2B),
and hereditary medullary thyroid carcinoma.
Lesions in this general category tend to have a single gene
mutation that may be the only lesion found in the precursor lesions. The
precuror lesions tend to have the morphology of simple hyperplasias, without
much nuclear atypia. Precursor lesions tend to be multiple, sometimes occurring
in the hundreds, and bilateral in paired organs. These lesions tend to occur in
a much younger population than the acquired precancers. The resulting cancers
can also occur at a relatively young age.
4. Acquired diffuse
hyperplasias and diffuse metaplasias
With few exceptions, acquired small focal metaplasias and
hyperplasias have a very low chance of progression to cancer, and have been
excluded from the classification schema because they rarely result in cancer
without first growing into diffuse lesions (the class 4 lesions) or acquiring
nuclear atypia (class 1 lesions).
Diffuse metaplastic lesions commonly precede cancers. It is
presumed that all bronchogenic squamous dysplasia arises from squamous
metaplasia. The normal bronchus simply does not have any squamous cells. The
squamous cells in bronchial squamous dysplasia must have originated from a
metaplastic focus for directly from non-squamous bronchial cells that
differentiated directly to a dysplastic squamous phenotype.
The prototypical lesions are the diffuse Barrett's esophagus,
diffuse intestinal metaplasia of stomach, and diffuse endometrial hyperplasia.
These lesions tend to have chronic identifiable causes (e.g. gastroesophageal
reflux disease, post lye ingestion esophagus, chronic gastritis, long-term
tamoxifen therapy), and tend not to regress so long as the causation persists.
Small foci of dysplastic precancers (Class 1) may arise from the diffuse
hyperplasias and metaplasias.
This class of precursor may include the so-called regressing
cancers, such as helicobacter-associated maltomas and AIDS-associated Kaposi's
sarcoma that can grow as multiple tumors, all of which can quickly regress when
the causative agent is withdrawn (e.g. after antibiotic treatment for
Helicobacter or after normal immune status is restored after withdrawal of
cyclosporine in transplant recipients). This class may also include secondary
aplastic anemia (e.g. benzene toxicity), where the marrow is repopulated by an
emerging population of hyperplastic cells that carry a a heightened risk of
progressing to acute leukemia.
5. Currently unclassified
entities
Most precancers will fall into one of the first four described
classes. However, classifications may contain a subset of cases that defy
facile classification. For example, the platypus has challenged animal
classifiers. Aristotle had no trouble recognizing that dolphins were mammals,
but it took the scientific community two millennia to agree.
We have created an "unclassified" category of precancers
for the current draft classification
6. Superclass and modifiers
A superclass is created to contain general precancer terms (e.g.
precancer, dysplasia)
A much earlier working group of the World
Health Organisation proposed in 1978 that clinical presentations of the oral
cavity that are recognized as precancerous (hereafter referred to as
potentially malignant disorders see above) be classified into two broad
groups, as lesions and conditions, with the following definitions:
- a precancerous lesion is a morphologically altered tissue in which oral
cancer is more likely to occur than in its apparently normal counterpart;
- a precancerous condition is a generalized state associated with a significantly
increased risk of cancer.
This took account of worldwide experience
that oral precancer has clinically diverse appearances. A range of
precancerous lesions and conditions was recognized in that report. These are
listed in Table 1. The distinction between a
precancerous lesion and a precancerous condition was considered not just
academic. At the time these terms were coined, it was considered that the
origin of a malignancy in the mouth of a patient known to have a precancerous
lesion would correspond with the site of precancer. On the other hand, in
precancerous conditions, cancer may arise in any anatomical site of the mouth
or pharynx. It is now known that even the clinically normal appearing mucosa
in a patient harbouring a precancerous lesion may have dysplasia on the contralateral
anatomic site or molecular aberrations
in other oral mucosal sites suggestive of a pathway to malignant
transformation, and that cancer could subsequently arise in apparently normal
tissue . The current Working Group, therefore, did not favour subdividing
precancer to lesions and conditions and the consensus view was to refer to all
clinical presentations that carry a risk of cancer under the term potentially
malignant disorders to reflect their widespread anatomical distribution.
|
Precancerous lesions |
Precancerous
conditions |
|
Leukoplakia |
Submucous fibrosis |
|
Erythroplakia |
Actinic keratosis |
|
Palatal lesions in reverse smokers |
Lichen planus Discoid lupus erythematosus |
|
Table 1. Classification
of precancerous lesions and conditions [WHO] |
|
Common oral lesions
Two
common premalignant lesions of the oral cavity are leukoplakia and
erythroplakia. Prompt treatment of these dysplastic lesions may diminish the
risk of disease progression.
When
an area of concern is discovered through this examination, the clinician needs
to ask the appropriate questions to help ascertain the potential cause and the
proper course of action. Having a comprehensive understanding of how the
technology responds to various conditions, as well as knowledge of the disease
processes, will help guide the practitioner to successful outcomes. The
clinician must develop a systematic and science-based methodology for handling
all of the findings. This underscores the need for thorough education on all
the technologies that are being incorporated.
Leukoplakia generally manifests as asymptomatic, white,
macular lesions that do not wipe off (see Figure 2). The lesions may be
isolated or diffuse in nature and occur most commonly on the tongue, the floor
of the mouth, and the buccal mucosa.
Erythroplakia manifests as a patch of macular or ulcerated red
lesions (see Figure 3). The lesions appear in the same locations as leukoplakia
and can be asymptomatic or mildly painful. The incidences of dysplasia and
carcinoma are higher in red lesions than in white lesions. Biopsy is indicated
for any abnormality present for more than 14 days without an obvious etiology,
such as trauma.
Most oral cancer lesions are painless, but some are accompanied by pain.Pain
unfortunately often indicates the cancer has invaded the adjacent structures,
making a cure unlikely. Any patient presenting with orofacial pain requires a
thorough examination.
Squamous cell carcinoma can manifest on any mucosal surface but most commonly
appears on the lateral and ventral tongue (75%), followed by the floor of the
mouth (15%- 20%). About 10% of carcinomas are found on the buccal mucosa, 10%
on the gingival surfaces, 10% to 15% on the soft palate, and 5% on the hard
palate.
Fig 1. leucoplakia
Causes
Leukoplakia is primarily caused by the use of tobacco. Other
possible etiological agents implicated are HPV, Candida albicans and possibly
alcohol. Simultaneously serum levels of patients with leukoplakia were found to
be low in Vit A,B-12,C & folic acid,in a study conducted in India. Most
result from chronic irritation of mucous membranes by carcinogens. Bloodroot,
otherwise known as sanguinaria, is also believed to be associated with
leukoplakia.5% to 25% of leukoplakias are premalignant lesions; therefore, all
leukoplakias should be treated as premalignant lesions by dentists and
physicians - they require histologic evaluation or biopsy. Hairy leukoplakia,
which is associated with HIV infection and other diseases of severe immune
deficiency can go on to develop lymphoma when associated with HIV.
Treatment
The treatment of leukoplakia mainly involves avoidance of
predisposing factors tobacco cessation, abstinence from alcohol and
avoidance of chronic irritants, e.g., the sharp edges of teeth. A biopsy should
be done, and the lesion surgically excised if pre-cancerous changes or cancer
is detected.Taking beta-carotene orally seems to induce remission in patients
with oral leukoplakia. Further research is needed to confirm these results.
Hairy leukoplakia is a white patch on the side of the tongue with a corrugated or
hairy appearance.
Causes
Hairy leukoplakia is seen in severe defects of immunity,
particularly in HIV infection. The cause of this condition is an opportunistic
infection by the Epstein-Barr virus (EBV). After the primary EBV infection has
been overcome, the virus stays latent in the B cells and also causes lytic
infection in the oropharynx, controlled by the immune system. Uncontrolled
lytic infection in the oropharynx is manifested as oral hairy leukoplakia in immunosuppressed
hosts. Oral hairy leukoplakia is not associated with any malignant potential. In 1992,
the University of Connecticut School of Dental Medicine reported on two cases
of oral hairy leukoplakia occurring in patients without any risk factors for HIV
infection, or any other evidence of immune deficiency. It has been observed in
patients on steroid therapy.
Treatment
The condition does not cause any other symptoms and does not
require any treatment. If treatment is required, acyclovir or valacyclovir is sometimes
used.
Proliferative Verrucous Leukoplakia
Etiology
Some associated with human
papillomavirus types 16 and 18
Role of tobacco and other risk factors
Represents a clinicopathologic spectrum
of disease
Multiple lesions develop from hyperkeratosis
and/or verrucous
hyperplasia to verrucous carcinoma or
papillary squamous cell
carcinoma
Clinical Presentation
Slowly progressive and persistent
Initially a flat hyperkeratotic to warty
surface
Surface may be friable
Typically multiple and recurrent
Seen in middle-aged to elderly patients
Diagnosis
Based upon appearance, clinical course,
and microscopic
diagnosis (ie, clinical-pathologic
correlation)
Microscopic diagnoses include epithelial
hyperplasia, hyperkeratosis,
verrucous hyperplasia, atypical
papillary-verrucal
proliferation, verrucous or
well-differentiated squamous cell
carcinoma
Differential Diagnosis
Idiopathic leukoplakia
Oral warts/condyloma
Verrucous/squamous cell carcinoma
Treatment
Surgical excision
Mucosal stripping or excision for benign
lesions
Wide excision to resection for advanced
lesions
Laser ablation for benign/atypical
lesions
Systemic retinoids to control keratosis
Prognosis
Progression to carcinoma frequently
occurs, usually many
years after initial lesion(s) develops.
Fair to good prognosis after malignant
transformation
Frequent follow-up visits recommended
and surgical intervention
as new/recurrent lesions develop
Morsicatio Buccarum/Labiorum
(Cheek and Lip Chewing)
Etiology
Chronic, low-grade biting habit
Clinical Presentation
Shaggy, white, keratotic surface
Surface often appears granular to
macerated
More uniform keratotic surface may
develop over time if habit
continues
Most common sites are lip and buccal
mucosa
Microscopic Findings
Very irregular, fimbriated surface
keratin
Surface bacterial colonization
No connective tissue changes
Diagnosis
Presentation
Biopsy
Differential Diagnosis
Leukoedema
Leukoplakia
Lichen planus
Lichenoid tissue reactions
Treatment
Elimination of hyperfunction habit
Prognosis
Excellent
Reference:
1. Danilevskiy
M.F. et al. Diseases of the mucous membrane of the mouth. - K.:
"Medytsyna", 2010.
2. Bruch
J.M. Clinical oral medicine and pathology/ J.M. Bruch, N.S. Treister//
London.:Humana Press, 2010
3. Cawson
R. E. Cawsons essentials of oral pathology and oral medicine. Seventh edition/
Cawson R. E. et. al. //Elsevier science limited, 2002.
4. Slootweg
P. Dental pathology a practical introduction/ P.J. Slootweg// Berlin.:
Springer, 2007.
5. Da
Silva J.D. Oxford American Handbook of Clinical Dentistry (Oxford American
Handbooks in Medicine) / J.D. Da Silva et al.// Oxford University Press, 2007.
Information was prepared by Sukhovolets I.O.