Oral cavity cancer in two young patients with ulcerative colitis, a case report

Abstract

Patients with Inflammatory Bowel Disease (IBD) are at increased risk of developing malignancies. IBD patients with oral cavity cancer may have reduced survival compared with the general population. This article describes two IBD patients, non-smokers, on long-term use of mesalazine with the development of oral cavity cancer. In IBD the clinician should be aware of possible head and neck malignancies and in case of doubt a biopsy should be performed, even in the absence of standard risk factors.

Keywords:

• Inflammatory bowel diseases
• ulcerative colitis
• immunosuppressants
• oral cavity
• head and neck cancer

Introduction

The inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis, are chronic idiopathic disorders causing inflammation of the gastro-intestinal tract. In North America and Europe, over 1,5 million and 2 million people suffer from these diseases, respectively [1,2]. Chronic inflammation is a risk factor for the development of intestinal and extra-intestinal malignancies [3].

The risk of the development of head and neck cancer in IBD patients is still unclear. Although, a few case reports have been published [4,5]. Furthermore, an increased risk of head and neck cancer was found in men with Crohn’s disease compared to the Finnish population expectations [6]. A recent, mendelian randomized study showed that there may be a positive causal effect of IBD for oral cavity carcinomas, but not for oropharyngeal carcinomas [7]. Here, we describe two cases of oral cavity squamous cell carcinoma arising in IBD. Notably, these are relatively young patients, who did not smoke nor used excessive amounts of alcohol.

Case 1

A 38-year-old male patient presented with a painful lesion on the right lateral border of the tongue (Figure 1a). His medical history showed a left sided ulcerative colitis (Mayo score 2) for which he received mesalazine with doses between 1 to 3 gram a day for 5 years with good response. The years leading up to the cancer diagnosis, the disease was in remission and he had two times a (sub)clinical flare at the time he stopped his medication. He never smoked, did not use drugs, and had a limited intake of alcohol (less than 5 units per week). Clinical examination showed a raised white lesion on the right lateral border of the tongue, not passing the midline. Palpation of the neck revealed no lymphadenopathy. Biopsy of the lesion showed squamous cell carcinoma. The diagnostic workup included chest x-ray, ultrasonography, MR imaging, and SPECT-CT-scan (for sentinal node imaging). An intraoral ultrasonography showed a depth of invasion of 2 mm of the primary tumor. Neck ultrasonography showed no lymphadenopathy. On MR imaging the tumor on the right lateral border of the tongue was 12 × 11 mm, with a depth of invasion of 5 mm, and without lymphadenopathy. The chest x-ray showed no distant metastasis. The SPECT-CT showed five sentinel nodes located in level IB, II and II/III on the right side of the neck and level IB and II on the left side of the neck. After discussion in our multidisciplinary head and neck cancer tumor board, according to the Dutch Head and Neck Cancer guidelines, the tumor was removed via a transoral thulium laser resection and a sentinel node procedure was performed (Figure 1b). Histopathological examination showed a squamous cell carcinoma, with a maximal diameter of 22 mm, depth of invasion of 9.6 mm, the resection marge was less than 1 mm on several planes because of the spiky growth pattern (Figure 1c and d). The specimen showed neither perineural growth nor vaso-invasion. One lymph node from the sentinel node procedure was positive, located in level IB on the left side of the neck, with a maximal diameter of 0.3 mm without extranodal extension. Consequently, re-operation was deemed necessary including a re-resection of the right side of the tongue, reconstruction with a free radial forearm flap, a neck dissection of levels I-III on the right side, I-IV on the left side, and a tracheotomy. Histopathology reported a squamous cell carcinoma of the lateral border of the tongue carcinoma with (again) positive margins, with a spiky growth pattern and a micrometastasis without extranodal extension in level Ib on the left side. This resulted in the following reclassification: pT2N2cM0. We expected to be unable to perform a radical resection, without severe impairment of oral function in a subsequent surgical procedure. After a discussion in the Multidisciplinary Tumor Board and shared decision making with the patient, he was planned for adjuvant chemoradiation:photon irradiation with 33 fractions of 2 gray with 7 concurrent cycles of Cisplatin of 30 mg/m². Currently, the disease-free survival exceeds 4 years. Since his chemotherapy, his complaints from the ulcerative colitis disappeared. In between he used mesalazine rectal suppositories 500 mg a day for 3 months because of complaints and a proven ulcerative proctitis (Mayo score 1) at endoscopy and currently he does not use any medication for his ulcerative colitis.

Figure 1. Case 1: imaging and microscopy.

a: Pre-operative picture of the painful lesion on the right lateral border of the tongue.

b: Axial fused SPET-CT scan after peritumoral injections with a technetium-99m labeled radiotracer followed by lymphoscintigraphy. Circles indicate the sentinel node located in cervical lymph node level Ib.

c: Slide of the surgical specimen by light microscopy with histology on 5 µm tissue section with haematoxylin and eosin (H&E) staining, representing the spiky growth pattern of the squamous cell carcinoma (magnification 45x).

d: Slide of the surgical specimen by light microscopy with histology on 5 μm tissue section with cytokeratin AE1/3 staining highlighting the infiltrative growth of the neoplastic cells (magnification 45x).

Case 2

A 59-year-old male patient presented with a painful ulcer on the right lateral border of the tongue (Figure 2a). His medical history showed left sided ulcerative colitis (Mayo score 3) since 1986 for which he received several immunosuppressants, he started with prednisone and mesalazine 3200 mg a day. From 1999 until 2008 he used 100 to 200 mg azathioprine a day next to mesalazine 1600 to 3200 mg a day with good respons, afterwards he used monotherapy mesalazine 1600 mg a day. The years leading up to the cancer diagnosis, the disease activity was low and there were no (sub)clinical flares. He never smoked, did not use drugs, and had a limited intake of alcohol (less than 5 units per week). Preoperative clinical inspection showed an ulcer on the right lateral border of the tongue with a maximal diameter of 15 mm. Palpation of the lateral border of the tongue revealed a superficial induration. Palpation of the neck revealed no abnormalities. The diagnostic workup included a biopsy, followed by imaging (chest x-ray, ultrasonography, MR imaging, and SPECT-CT-scan for sentinal node imaging). An intraoral and neck ultrasonography showed a primary tumor with a depth of invasion of 6 mm and on level IB a lymph node of 6 mm. On MR imaging the largest dimension of the tumor on the right lateral border of the tongue was 9 mm with a depth of invasion of 7 mm, without lymphadenopathy. The chest x-ray showed no distant metastasis. The SPECT-CT showed two sentinel nodes located in level II and III on the right side of the neck. After discussion in our multidisciplinary head and neck cancer tumor board, according to the Dutch Head and Neck Cancer guidelines, the surgical workup included a transoral thulium laser resection and a sentinel node procedure was performed (Figure 2b). Histopathological examination showed a moderately differentiated squamous cell carcinoma, with a diameter of 17 mm, depth of invasion of 3.0 mm, the resection marge was > 5 mm on all planes (Figure 2c and d). The specimen showed neither perineural growth nor vaso-invasion. The lymph nodes from the sentinel node procedure, located in level II and III on the right side of the neck, were tumor negative. This resulted in the following classification: pT1N0(sn)M0. Consequently, follow-up was recommended every 3 months with ultrasonography. Currently, the disease-free survival is almost 4 years. Currently, he uses mesalazine 1600 mg a day and his ulcerative colitis with a good response.

Figure 2. Case 2: imaging and microscopy.

a: Pre-operative picture of the painful ulcus on the right lateral border of the tongue.

b: Axial fused SPET-CT image after peritumoral injections with a technetium-99m labeled radiotracer followed by lymphoscintigraphy. Arrow indicates the sentinel node with low uptake.

c: Slide of the surgical specimen by light microscopy with histology of squamous cell carcinoma on 5 µm tissue section with H&E staining (magnification 32x).

d: Slide of the surgical specimen by light microscopy with histology of squamous cell carcinoma on 5 μm tissue section with H&E staining, high power magnification showing neoplastic cells infiltrating the muscle tissue (magnification 180x).

Discussion

In this case report, we describe two patients with IBD and the development of oral cavity cancer.

Oral cavity cancer represents a major health problem worldwide. The annual global incidence of lip/oral cavity cancer is estimated at approximately 378.000 cases [8]. Survival is poor, with a 5-year survival rate of about 50%, and has not markedly improved in recent decades [9]. However, the oral cavity is accessible to physical examination, so detection at an early stage, which is considered the best means of improving survival, is possible. Oral cavity squamous cell carcinoma is historically linked to well‐known behavioral risk factors such as tobacco smoking and alcohol consumption [9].

Nowadays, ENT/head and neck surgeons are aware of human papillomavirus (HPV) as an etiological cause of oropharyngeal cancers, however, the role of HPV in the development of squamous cell carcinoma of the oral cavity remains unclear [10,11]. Recently, attention has been paid to the possible relationship between IBD patients, the use of immunosuppressants and the development of oral cavity cancer [4,5,12–14], but the precise risk factor needs further investigation. It has been shown that IBD patients with oral cavity head and neck cancer may have reduced survival compared with the general population [14]. Information regarding the risk, morbidity, and survival rate of oral cancer in patients with IBD is scarce. However, in a retrospective study based on the Finnish national register databases, without patient-related information on the possible risk factors and information on the patients’ medications (e.g. immunosuppressants) or oral manifestations, an increased risk of head and neck cancer was found in men with Crohn’s disease compared to the Finnish population expectations [6]. Furthermore, mendelian randomized study showed that there may be a positive causal effect of IBD for oral cavity carcinomas [7].

It is known that solid organ transplant recipients who use immunosuppressive therapy have a higher risk for developing head and neck cancer. In a recent large case-control study, head and neck cancer in transplanted patients was associated with a decreased overall survival [15]. The increasing and long-term use of immunosuppressive drugs for IBD patients is associated with adverse effects like increased risk of certain malignancies [16]. So, there is a need to assess the consequences of chronic immunosuppression to the oral cavity.

Until now, no articles were published in ENT literature. Therefore, we hope to raise awareness amongst ENT/head and neck surgeons with this manuscript, for the presence of oral cavity cancer in case of a oral cavity lesion in this group of patients.

Oral screening for IBD patients has been proposed [12,13]. However, the incidence of head and neck cancer in the IBD population is low. Katsanos et al. reported only 7 out of 7294 IBD patients (0,15%) to have oral cancer [13]. So, increased awareness rather than active screening for head and neck cancer in IBD patients might be a more feasible option [14].

Potential difficulties in medical and dental prophylaxis and care in immunosuppressed patients with IBD can be experienced because of changes in the oral enviroment and the potential implications of dysfunction of the antioxidant barrier in saliva. Therefore, we emphasize the importance of a multidisciplinary approach to managing the oral health of IBD patients. [17]

In conclusion, in case of a lesion in the oral cavity in IBD patients, the clinician should be aware of a possible malignancies, even in young patients without risk factors, such as smoking and drinking alcohol and therefore a biopsy should be performed.

Informed consent statement

Written informed consent was obtained from all subjects involved in the study.

Institutional review board statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and ethical review and approval was waived for this study based on the design of the study, and according to the national guidelines.

Conflicts of interest

The authors declare no conflict of interest.

Data availability statement

Data available on request from the authors.