Discussion
The aim of reporting this case was mainly to discuss the possible links
between malignant transformation to oral SCC in physiological conditions
such as pregnancy, in order to better understand the physiopathology
underlying this transformation, especially in a potentially malignant
condition like OLP, diagnosed concomitantly to the oral cancer. It is
interesting to notice that, although similar cases are still rare, an
increasing tendency of tongue cancer’s incidence has been described in
recent years in young women [20].
Indeed, oral cancers, especially SCC, are usually diagnosed in older men
with heavy tobacco and alcohol consumption. However, it is interesting
to note that recently, the frequency of oral cancer affecting young
people has increased, particularly in young women between 18 and 44
years of age [18]. Several epidemiological studies, such as that of
Murphy et al, noticed in 2016 a 60% increase in tongue cancers in
patients under the age of 40 when comparing cohorts from 1973 to 1984
and from 1985 to 1997 [19]. Deneuve and al. confirmed in their study
published in 2021 a significant increase of the incidence of tongue
cancer in women aged 30 and 40 in France from 1990 to 2018 [4]. The
incidence of tongue cancer also increased significantly in the United
States between 2001 and 2019, more particularly in women under 50 years
old according to Burus et al, 2024 [5]. In addition, It is important
to emphasize that the age of first pregnancy is increasing and the age
at which cancers occur is decreasing. Taking into account these two
parameters, it is therefore likely that the incidence of malignant
tumors during pregnancy will increase in the coming years [22].
Tobacco and alcohol consumption are known to be associated with oral
cancer, but not in young patients. Other risk factors are also being
studied, such as viral infections, particularly human papillomavirus,
oral traumatism, oncogenic factors and genetic predisposition [17].
Some pathological or physiological conditions can accelerate the
malignant transformation of oral lesions, among which inflammatory
diseases and pregnancy are the most studied [23].
Indeed, cancer may occur approximately in 1 out of 1,000 pregnancies.
The most frequent cancer types encountered during pregnancy are breast
cancers (46%) and hematological cancers (18%) [17]. With lower
frequency, cervix, ovary, brain cancers and melanomas may be associated
with pregnancy. Oral cancers are rare and occur in only 2% of pregnancy
cancer cases [18] with 65% of diagnoses made after the first
trimester of pregnancy and an average mortality rate of 36 % [17]
[24].
Concerning OLP, it has been classified as an Oral Potentially Malignant
Disorder (OPMD) by the WHO experts. The term “potentially malignant”
has been introduced in 2007 [12] because “precancerous” implies
that the malignant transformation is the most likely evolution of all
these lesions, which is often not the case. Since 2020, OPMDs are
associated with an increased risk of occurrence of cancers of the lip or
oral cavity [10].
The frequency of malignant transformation of OLP differs among authors.
It is estimated between 2 to 5%, based on some studies with a follow-up
duration of 6 to 10 years [11]. A review of the literature in 2014,
screening a large sample of patients (7,806 patients) from 16
retrospective selected studies, showed a frequency of 0 to 3.5%
[25]. Another review relying on retrospective studies over a 77-year
period, showed a frequency ranging from 0 to 12.5%
[26]. A slight female predominance has been
noted and the most common site of malignant transformation is the tongue
[27] [25]. The
most recent meta-analysis was published in 2019 [28] grouped 82
studies with 26,742 patients. It revealed a reported OLP malignant
transformation of 1.14% and a statistically significant increased
malignant transformation risk for the tongue (RR=1.82). They conclude
that the malignant transformation potential of OLPs is probably
underestimated in the literature given that most authors consider OLPs,
oral lichenoid lesions (OLLs) and lichenoid reactions (LRs) to be
low-risk OPMDs.
Patients with lichenoid lesions were also sometimes included in the past
in studies evaluating the transformation rate of OLP, as the diagnosis
criteria of OLP have progressively changed and became more accurate from
2003 to 2020. The disappearance of the criterion: “absence of
epithelial dysplasia” from the past OLP description may also be
confusing. Indeed, the experts group recommends not to use the term
“oral lichenoid dysplasia” to describe OLP or lichenoid disorders with
an epithelial dysplasia. They recommend to describe each entity
separately, which may be confusing for cases described before 2020.
The mechanisms underlying the malignant transformation of the OLP give
rise to several hypotheses: chronic inflammation is the most discussed.
Indeed, inflammation may damage keratinocytes DNA, through a phenomenon
of oxidative stress, which may over time result in cancer. The resulting
intraepithelial neoplasia may become invasive after several years of
alternation between inflammatory and scarring states of OLP [29].
Concerning the described clinical case, this hypothesis does not explain
the malignant transformation, as the appearance of OLP, which seems
recent or even concomitant with the appearance of the malignant
transformation. In addition, the clinical form diagnosed was not
atrophic. The latter represent the most likely OLP stage to degenerate
with the erosive form. Adding to the concomitancy of OLP diagnosis with
SCC, our patient was in a particular physiological state, with a
primiparous pregnancy. Changes that occur in the immune system during
pregnancy are widely studied and are potentially likely to promote
neoplastic growth.
These changes include an increase in progesterone and glucocorticoids.
These hormones may affect T cell differentiation, varying the Th1/Th2
balance. T helper type 1 (Th1) cells are mainly involved in
cell-mediated immunity (production of pro-inflammatory cytokines) while
T helper type 2 (Th2) cells are involved in the stimulation of humoral
immunity (production of anti-inflammatory cytokines). These two hormones
inhibit the development of Th1 and increase the development of Th2
[30]. Th2 cytokines predominate during pregnancy and would inhibit
the proliferation and function of natural killer cells which are
important in the immune regulation and suppression of tumors, thus
potentially promoting neoplastic growth [23]. Progesterone Induced
Blocking Factor (PIBF) therefore reduces inflammatory phenomena
(inflammatory cytokines, production of non-cytotoxic antibodies,
inhibition of NK) in order to create immune-tolerance between the mother
and the fetus to carry the pregnancy at term [31]. However, some
authors show that the effect of waning antitumor immunity during
pregnancy is slight and does not affect the prognosis [22].
The association of human papillomavirus (HPV) in oral cancer is also
well discussed in the literature. Patients concerned are almost younger,
with no alcohol-smoking intake, and a trans-suspected sexual
transmission with oropharynx preferential localizations. In fact, HPV
was found to be associated with approximately 45.6% of SCC of the
oropharynx versus 10.5% for oral SCC [32]. The analysis of
histological samples of a great cohort of patients confirms these data
and found only 2.2% oral SCC positive for HPV DNA and only 7.9% with
an immunopositive P16 marking [33]. For OLP, the levels of HPV 16
and 18, were found significantly higher on OLP lesions than on healthy
mucosa, and that more specifically in atrophic or erosive OLP forms
[34]. However, the tongue, which appears to be the most common site
of oral cancers during pregnancy, does not have a propensity for HPV
receptors unlike posterior oropharyngeal cancer [18].
Concerning the choice of maintaining the pregnancy or aborting and
starting treatment, Mhallem Gziri et al, in 2011, shows in their review
including 17 cases of pregnant women with tongue cancer, a wide
variation in treatment strategy, illustrating the lack of
standardization of treatment when tongue cancers are treated during
pregnancy. There are basically two treatment schemes. First, the child
may be deliberately aborted or put at risk by major surgery during
pregnancy. Second, the patient may compromise by minimizing risk to the
fetus but using less than ideal treatment. No treatment modality is
entirely free from immediate or delayed risk to the fetus and only the
magnitude of the risk is reduced [17].
For cancer treatment, the fetus is exposed to one or more risks linked
to surgery and anesthesia in all stages of pregnancy. During the first
trimester, teratogenic effects of drugs and spontaneous abortion are the
most serious problems. It is possible to end the pregnancy in order to
concentrate on cancer treatment depending on the tumor stage. The second
trimester is relatively the safest time to perform surgery, but it still
carries considerable risk to the fetus. It is more complicated to end a
pregnancy, that’s why there is a strong possibility at this stage of
performing oral cancer treatment while continuing the pregnancy. All
along pregnancy, the risk of hypoxemia exists, and in the third
trimester, premature term may result from anesthesia and surgery. That
is why a cesarean section may be performed after 30 to 34 weeks of
gestation, or labor may be induced [22]. It is recommended to
consider termination of pregnancy if the tumor is large or metastasized
at an early age of pregnancy, thereby complicating fetal and maternal
outcomes [18].
The management of pregnant patients with tongue cancer has evolved over
time. The review of Murphy et al. [21] identified the treatment
procedures described for 32 cases of pregnant women with SCC of the
tongue. The authors excluded cases of regional recurrence of SCC of the
tongue during pregnancy. Surgery was found to increasingly play an
important role in the management of these patients. For this, several
criteria have been proposed to maximize the smooth running of these
surgeries. Rapid induction is recommended to decrease the risk of
miscarriage and deep vein thrombosis. Continuous and strict monitoring
of circulation, respiration, maternal and fetal heart rate
intraoperatively is recommended. Adequate monitoring to avoid
hypotension, hypoglycemia, hypothermia, premature contractions or fetal
distress is also necessary. On the surgical side, the procedure must be
carried out quickly, taking care to minimize blood loss. Because
cell-mediated and humoral immunity are impaired during pregnancy, the
risk of postoperative infection is high. Antibiotic therapy is therefore
recommended. Sufficient maternal analgesia is important, also to avoid
premature contractions. It is important to avoid the use of teratogenic
drugs (such as tetracycline antibiotics and phenobarbital). The
combination of pregnancy and surgery induces a hypercoagulable state
that favors the development of thromboembolism and, therefore,
preventive anticoagulant treatment is necessary. Taking care of maternal
well-being is the best guarantee to ensure the health of the fetus.
[17] [21].