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\begin{document}

\title{Early diagnosis of oral squamous cell carcinoma may ensure better
prognosis: a case series}



\author[1]{Chiara Bramati}%
\author[1]{Silvio Abati}%
\author[1]{Stefano Bondi}%
\author[1]{Alessandra Lissoni}%
\author[1]{Gianluigi Arrigoni}%
\author[1]{Federica Filipello}%
\author[1]{Matteo Trimarchi}%
\affil[1]{IRCCS Ospedale San Raffaele}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Oral squamous cell carcinoma (OSCC) is a malignancy with high mortality
and morbidity. Early diagnosis and treatment of OSCC and other
potentially malignant lesions of the oral mucosa is the clinician's best
weapon to improve prognosis, since it greatly worsens as the disease
becomes more advanced.%
\end{abstract}%



\sloppy


\textbf{Introduction}

In Western countries, oral cancer represents a rather uncommon
malignancy, with oral squamous cell carcinoma (OSCC) being most
frequent\textsuperscript{1}. OSCC has high mortality and
morbidity\textsuperscript{2}, which significantly increases with
diagnostic delay\textsuperscript{3}. The most common risk factors for
OSCC are well known and include alcohol, use of tobacco (including
smokeless tobacco), betel quid chewing, and chronic
inflammation\textsuperscript{4,5}, which are for the most part behaviors
that can be eliminated. Primary prevention, therefore, consists in
educating the population against these behaviors\textsuperscript{6}.
Once the cancer is present, early diagnosis is the single most important
element in improving prognosis, since clinical and pathological staging
are the most important factors that influence survival
rates\textsuperscript{7}. Furthermore, treatment of an early disease,
which consists in surgical excision with tumor-free margins, prevents
the morbidity that far more invasive surgery for a more advance disease
would imply\textsuperscript{8}. The prompt recognition and correct
treatment of conditions that present a risk of transforming into cancer,
such as leucoplakias\textsuperscript{9} and erythroplakias, also play a
very important role in improving the chances of
survival\textsuperscript{10}.

OSCC mostly affects elderly men, although the latest literature seems to
suggest a growing incidence in younger patients, especially in tongue
cancer, and in particular when linked to chronic mucosal trauma caused,
for instance, by sharp dental elements\textsuperscript{11}. Furthermore,
some authors suggest that younger patients bear a more aggressive
disease, with higher locoregional recurrence rates and worse
prognosis\textsuperscript{12}.

The following case series reports four cases in which early diagnosis
was essential in ensuring good prognosis to all individuals, as all are
in good health and disease-free at the time of writing.

The present article was approved by the Ethics Committee of San Raffaele
Hospital (20210422), in accordance with the Declaration of Helsinki. All
patients gave their informed consent.

\textbf{Case presentation}

\emph{Case 1}

F.F., a 32-year-old woman who was referred to our dental clinic for a
burning sensation in correspondence of the left aspect of the tongue.
Her past history included diagnosis of skin melanoma (Breslow stage I)
about a year prior, for which she had undergone surgical excision.

Clinical examination revealed the presence of a solid, tender, ulcerated
lesion of the left tongue border, with dyskeratotic areas (Fig. 1). A
biopsy of the lesion was carried out, with histologic examination
showing the presence of a G2 squamous cell carcinoma, even though the
patient apparently showed no risk factors, as she was neither a smoker
nor a heavy drinker. Contrast-enhanced MRI confirmed the presence of a
highly vascularized solid lesion, confined to the lingual body, without
infiltration of the adjacent muscles and mandible.

The patient consequently underwent a partial marginal glossectomy with
CO\textsubscript{2} laser (type II glossectomy sec.
Ansarin)\textsuperscript{13} and sentinel lymph node biopsy. Histologic
examination confirmed the presence of a G2 SCC (Fig. 2), pT2 pN0 lesion.

At one year postoperative, the patient is currently disease free (Fig.
3), as revealed by periodic clinical examination and contrast-enhanced
MRI.

Case 2

G.B., a 61-year-old man with a history of active drinking (half a litre
of wine per day). During a routine dental examination, an
erythroleukoplakic lesion of the left retromolar area was identified
(Fig. 4). Given the risk factors presented by the patient and the
appearance of the lesion, it was decided to perform an immediate biopsy.
Histologic examination showed the presence of severe dysplasia.

Even though histologic examination did not show the presence of cancer,
given the high risk that lesions such as erythroleukoplakia carry, it
was nevertheless decided that the patient undergo surgery.

The lesion was excised by CO\textsubscript{2} laser. Histology showed
the presence of a micro-focal T1 G2 squamous cell carcinoma in the
context of a severely dysplastic mucosa (Fig. 5).

Almost two years after surgery, the patient is undergoing regular
follow-up and is disease-free.

Case 3

T. D., a 43-year-old man presented with a leukoplakic lesion of the
right tongue border (Fig. 6). A biopsy was carried out, showing a
verrucous proliferation with atypia, which was dubious for neoplasia.

Contrast-enhanced MRI confirmed the presence of the lesion, which did
not ap-pear to infiltrate the intrinsic muscles of the tongue or
neighboring structures.

It was thus decided to surgically excise the lesion by transoral
mucosectomy with a CO\textsubscript{2} laser (type I glossectomy sec.
Ansarin)\textsuperscript{13}. Histology showed the presence of a G1
squamous cell carcinoma (1 cm in greatest dimension) in the context of a
verrucous hyperplasia with lichenoid chronic inflammation (Fig. 7).

Two years after surgery, the patient is disease free, as shown by
periodic clinical examinations and contrast-enhanced MRI.

Case 4

L. D., a 24-year-old woman presented with a leukoplakic lesion of the
right border of the tongue (Fig. 8), progressively growing in size. The
lesion was biopsied on multiple occasions. The latest histological
examination showed the presence of severe dysplasia, while the previous
one showed only moderate dysplasia. Given that the lesion was constantly
increasing in size (reaching an extension of 2 cm circa) and that the
grade of dysplasia seemed to be progressively worsening, it was decided
to surgically intervene.

The lesion was excised transorally by CO\textsubscript{2} laser.
Histologic examination showed the presence of inflammation and keratosis
(Fig. 9). Two years after the excision, the lesion has not recurred
(Fig. 10).

\textbf{Discussion}

Oral cancer is an extremely malignant condition, with a very high risk
of mortality and morbidity, albeit not common in Western countries.
Diagnostic delay can contribute greatly to poor prognosis of the
disease, since up to 50\% of oral malignancies are diagnosed in a very
advanced stage (III -- IV), which translates into poor prognosis; this
underlines the importance of early diagnosis and prevention of disease
progression\textsuperscript{3}. Overall, 5-year survival is estimated at
around 50\%\textsuperscript{1}, while for advanced stage OSCC it
decreases to 30\%\textsuperscript{14}. Clinical and pathological stage
at presentation represents the single most important prognostic factor,
with the presence of lymph node metastases being the most powerful
predictor of outcome\textsuperscript{15} since the presence of a single
node metastasis confers up to a 50\% decrease in overall
survival\textsuperscript{16}.

Up to 33\% of patients present with occult cervical disease,
undetectable by imaging techniques (mainly CT and
MRI)\textsuperscript{17}; the use of sentinel node biopsy (SNB)
represents an excellent solution in cases of T1-T2 tumors with a
clinically N0 neck\textsuperscript{17,18}. SNB is an extremely valuable
method in detecting occult node metastases in head and neck cancer, with
a negative predictive value of about 95\%, and represents a solution for
the management of a clinically N0 neck\textsuperscript{17}, as it can
better select patients for which nodal dissection is required and avoid
unnecessary surgery\textsuperscript{18}. SNB represents an alternative
to management of the neck according to DOI, as lesions with DOI
\textgreater{} 4 mm can be either treated with an upfront neck
dissection or kept under close follow-up for neck
metastases\textsuperscript{17}.

Risk factors for oral cancer include heavy use of tobacco, alcohol
drinking, and betel quid chewing\textsuperscript{6}. Chronic mucosal
trauma, originating from poor oral hygiene, poor dentition, missing
teeth or ill-fitting prosthetics\textsuperscript{19}, has been
postulated to be an etiological factor for oral cancer; this may be
particularly true for younger patients presenting with no other risk
factor for OSCC (mainly use of tobacco and alcohol)\textsuperscript{14},
as up to 30\% of nonsmokers and nondrinkers presenting with OSCC present
with some kind of dental abnormality in proximity to the
tumor\textsuperscript{20}. HPV may have a role as a risk factor,
although it cannot be considered an independent prognostic
factor\textsuperscript{21}, as for oropharyngeal
cancer\textsuperscript{22}.

Since oral cancer can be considered a highly preventable disease,
ideally screening campaigns should educate the population to eliminate
risk factors for oral cancer, mainly tobacco smoking and alcohol
consumption. This, however, has not proven to be effective.
Additionally, even though cancer awareness has greatly increased in the
last decades, the percentage of patients seeking medical attention with
an advanced stage disease has not changed significantly in the last 40
years\textsuperscript{23}. Once the carcinogenic process has been
established, the best weapon a clinician has against the disease is
early diagnosis. Unfortunately, unlike other more frequent cancers (i.e.
colorectal cancer) a population-based screening program for oral cancer
does not exist and would not be feasible or
cost-effective\textsuperscript{24}. A group of oral conditions and
diseases are known to be precursors to oral cancer; these include
leucoplakias, erythroplakias, oral lichen planus, and chronic
inflammatory lesions\textsuperscript{25}. The prompt identification of
these lesions and their treatment is of the utmost importance, as it
represents a means of pre-venting cancerous
transformation\textsuperscript{26}. As not every premalignant lesion of
the oral cavity transforms into cancer, the decision to excise the
lesion or keep the patient un-der close follow-up must be made according
to clinical and histopathological findings\textsuperscript{27,28}.

As proposed by the World Health Organization, any lesion of the oral
mucosa that does not regress within two weeks after elimination of the
possible cause (i.e. sharp teeth causing trauma) must be
biopsied\textsuperscript{29}. The identification of any suspect lesion
of the oral mucosa starts with clinical examination, which consists in
visual and tactile inspection of the oral cavity and can be carried out,
for instance, in the context of a dental
appointment\textsuperscript{7,30}. Biopsy remains the gold standard in
diagnosis, while a series of other tools are starting to be used as aids
in diagnosis; these include toluidine blue staining, autofluorescence
imaging, and salivary biomarkers for point-of-care
testing\textsuperscript{6,31}.

In all four cases presented herein, diagnosis was established starting
from a simple clinical inspection carried out in the context of a dental
appointment, which was nevertheless able to guarantee good prognosis.
All lesions were thus diagnosed and excised in the early stages, making
it possible to considerably reduce the morbidity associated with the
disease and its treatment when in an advanced stage. In case 1, after
the diagnosis of OSCC was made, it was also decided to carry out a
sentinel lymph node biopsy. As histological examination showed the
absence of any node metastases, it was possible to avoid further
unnecessary surgery on the neck, while still obtaining oncological
radicality. In case 3, however, the neck was managed according to DOI:
pre-operative MRI showed the presence of a lesion with a maximum DOI of
3 mm, so that the surgical excision was carried out without performing a
neck dissection. Onco-logical radicality was achieved nonetheless, as
periodical clinical examinations and MRI imaging still demonstrate no
recurrence and a N0 neck at two years postoperative.

In case 2, the decision to excise the erythroplakic lesion was taken
before the diagnosis of OSCC was made, as the initial histology only
showed the presence of high-grade dysplasia. As is well known,
erythroplakia is the single most dangerous pre-cancerous lesion of the
oral cavity, as up to 85\% if erythroplakias show histological signs of
carcinoma once biopsied or excised\textsuperscript{32,33}. Indeed, in
our case, histological examination of the entire lesion revealed the
presence of a G2 squamous cell carcinoma, which was thus eradicated in
its very early stages, avoiding the need for far more extensive surgery
had the lesion been allowed to grow in size. Case 4 represents an
example of a lesion (leucoplakia) that is not cancerous in itself, but
which carries a risk of transforming into cancer\textsuperscript{31},
even though not as high as that of erythroplakia\textsuperscript{32}.
Given that the lesion was rapidly increasing in size and its grade of
dysplasia rapidly worsening, it was decided to completely excise the
lesion surgically. Histological examination did not show the presence of
cancerous foci; nevertheless, by excising the lesion in its entirety,
the need for periodic biopsies was eliminated, while eradicating the
risk of malignant transformation.

\textbf{Conclusions}

OSCC is an extremely malignant condition, with very poor prognosis when
di-agnosed at an advanced stage. The best weapon to improve prognosis is
to diagnose oral cancer as early as possible. Diagnosis starts with a
simple visual and tactile ex-amination of the oral cavity, which can be
carried out in the context of a dental ap-pointment. The cases presented
herein show how early diagnosis, starting from a sim-ple examination of
the oral cavity, can ensure very good prognosis.

\textbf{Author Contributions} : Conceptualization, C.B. and M.T.;
validation, S.A., S.B., M.T. and A.L.; data curation, S.A., F.F. and
G.A.; writing---original draft preparation, C.B.; writing---review and
editing, S.B., M.T., A.L. All authors have read and agreed to the
published version of the manuscript.

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\textbf{Figure legends}

\begin{itemize}
\tightlist
\item
  \textbf{Figure 1.} Case 1: pre-operative appearance of the lesion
\item
  \textbf{Figure 2.} Case 1: squamous cell carcinoma associated with
  keratin pearl formation, infiltrating the intrinsic lingual muscle.
  (H\&E)
\item
  \textbf{Figure 3.} Case 1: fully healed post-operative appearance of
  the tongue
\item
  \textbf{Figure 4.} Case 2: erythroleukoplakic lesion of the left
  retromolar area
\item
  \textbf{Figure 5.} Case 2: squamous cell carcinoma with basaloid
  features, demarcated by a mild layer of lymphocytes and plasma cells
  (H\&E).
\item
  \textbf{Figure 6.} Case 3: a vast leukoplakic lesion of the right
  tongue border (2.5 x 2.5 cm) with a squamous cell carcinoma of 1 cm in
  greatest dimension in its context.
\item
  \textbf{Figure 7.} Case 3: well differentiated squamous cell carcinoma
  characterized by finger-like growth, infiltrating the superficial
  layers of the intrinsic lingual muscle. (H\&E)
\item
  \textbf{Figure 8.} Case 4: pre-operative appearance of the leukoplakic
  lesion
\item
  \textbf{Figure 9.} Case 4: Superficial resection of squamous epithelia
  showing keratosis and dyskeratosis with mild nuclear irregularity of
  the squamous epithelia. (H\&E)
\item
  \textbf{Figure 10.} Case 4: post-operative, fully healed, appearance
  of the tongue
\end{itemize}\selectlanguage{english}
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\FloatBarrier
\end{document}

