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].