Paragangliomas are rare, usually benign neuroendocrine tumours originating from the paraganglionic bodies of the parasympathetic and sympathetic nervous system, most often located at the bifurcation of the common carotid artery. Inflammatory bowel diseases (IBD) are associated with an increased risk of cancer for various reasons: malignancies directly related to IBD, connected with the drugs used and those co-occurring independently [1]. Clinicians are often faced with the challenge of treating patients with both pathologies while also maintaining a balance between the risk of cancer occurrence or recurrence associated with immunosuppressive drugs and the potential IBD worsening. There is growing evidence that the risk for recurrent and new cancer in patients with a previous history of cancer is not increased with thiopurines, anti-TNF-a, and biological agents especially vedolizumab and ustekinumab [1]. In this case report we present a patient diagnosed with paraganglioma and recent Crohn’s disease (CD).
A 52-year-old patient was admitted to the hospital due to abdominal pain, diarrhoea up to 6 stools a day, general weakness, and dizziness for 3 years with noticeable intensity from a few days. The patient had a medical history of paraganglioma with involvement of the bones of the skull base (surgically treated with the G-Knife method 5 years ago with incomplete resection and adjuvant radiotherapy), bilateral petrous bone tumor, unspecified polyarthritis, gastroesophageal reflux, depression, and chronic neuropathic pain requiring the use of strong opioids. On admission, laboratory tests showed high levels of inflammation markers (C-reactive protein (CRP) 243.2 mg/l, WBC 13.4 G/l). Abdomen ultrasonography (USG) revealed thickening of the walls of the large intestine to 8–9 mm with swelling of the surrounding fatty tissue. Computed tomography additionally showed lack of colon haustration with inflammatory congestion of the intestinal mesentery. Microbiological stool tests for toxins excluded infection with Clostridioides difficile but detected the presence of Escherichia Coli STEC. Colonoscopy visualised numerous deep linear ulcers covered with fibrin with swollen and hyperaemic mucosa in the cecum, ascending, transverse, and descending colon with normal rectum, which suggested CD. The patient started dedicated treatment with intravenous steroid therapy (hydrocortisone) with subsequent conversion to oral treatment (prednisone) and gradual dose reduction, azathioprine in a dose adjusted to body weight (2–2.5 mg/kg) and mesalazin. After temporary improvement, the patient returned to the hospital 2 months later presenting similar symptoms: diffuse abdominal pain, diarrhoea, and fever up to 39ºC. This time, leukopaenia (WBC 2.9 G/l), anaemia (HGB 7.5 g/dl), and elevated CRP levels (86 mg/l) were observed in laboratory tests. A persistent image of intestinal inflammation in abdominal USG was seen, as reflected by thickened colon walls up to 7–8 mm. Treatment was modified due to leukopaenia – the dose of azathioprine was reduced by half, and intravenous steroid therapy was restarted. In further additional tests faecal calprotectin levels were high (2340 µg/g) with inadequate levels of thiopurine metabolites (6-thioguanine (6-TGN): 2221.15 pmol/8 × 108 RBC with 6-methylmercaptopurine (6-MMP): 477.22 pmol/8 × 108 RBC), which led to discontinuation of azathioprine and qualification to biological treatment. Due to its promising safety profile in patients with oncological history, vedolizumab was chosen as the first-line drug among biological drugs. On the follow-up visits the patient, after 4 doses of vedolizumab so far (administered with intervals according to the drug progamme), reported less abdominal pain, reduction in the number of stools, normal morphology results, and significantly lower calprotectin levels (76 µg/g) without signals of recurrence of the neoplastic process. The patient remains under the care of the IBD and oncological outpatient clinic to this day.
The goal of IBD management is to modify and control the disease course with the use of 5-aminosalicylic acid (5-ASA), immunomodulators (IMM – azathioprine, 6-mercaptopurine, and methotrexate) and biologic agents (for example anti-tumour necrosis factor [TNF]-a drugs or anti-integrins) [2]. The risk of opportunistic infections and cancer development are the main long-term adverse effects of immunosuppressive therapy in IBD, which increases with the earlier diagnosis of IBD, longer life-expectancy, and longer exposure to immunomodulating agents [1, 2]. Malignancies occurring in patients with IBD can be generally divided into three groups: IBD-associated, drug-related, and sporadic. IBD-related cancers are, for example, colorectal cancer (with the risk at least 2-fold higher than in the general population), small-bowel adenocarcinoma (with the risk 20–30 times higher in CD than in the general population), or cholangiocarcinoma [1]. As for the drugs used in IBD, the highest risk for cancer is connected to thiopurines (lymphomas, myeloproliferative syndromes, non-melanoma skin cancers, cervical carcinoma) as they interfere with DNA replication. There is no evidence of an overall increased risk of cancer in IBD patients treated with anti-TNF-a monotherapy, although the risk of lymphoma and melanoma may be increased [3].
Vedolizumab (VDZ) is a gut-selective antibody to a4b7 integrin mostly expressed in the gastrointestinal tract, which blocks T-lymphocyte migration into the gut. Due to its specificity, vedolizumab came into the spotlight in patients with previous cancer – except for digestive cancers – because of the reported low risk of new cancer connected with its use [4]. According to Colombel et al., among 2830 vedolizumab-exposed patients, only 18 (< 1%) were diagnosed with malignancy [5]. Another study by Vedamurthy et al. also reported the safety of the use of VDZ in patients with a history of malignancy with no risk increase for new or recurrent cancers [6]. Moreover, the latest ECCO guidelines also confirm low probability of new or recurrent malignancy in patients with IBD treated with vedolizumab [7]. However, many reports are limited by low event rates, exclusion of older patients and those with prior malignancy.
There are no clear guidelines on the management of patients with IBD and a history of uncommon malignancies, like paragangliomas. They are usually benign tumours with an estimated incidence of 1 in 300,000, which develop from cells of the paraganglia – cells derived from embryonic nervous tissue, found near the adrenal glands, some blood vessels, and nerves. There are suggestions that immunomodulation therapy should be suspended during active cancer therapy, and cancer patients should avoid combination therapy and JAK (Janus kinase) inhibitors as evidence on their use in these patients is insufficient and there are other therapies with more favourable safety profiles [1]. What is more, current recommendations are cautious with the use of immunomodulatory therapies (mainly anti-TNF-a and anti-integrines) in patients with cancer history for a period of 2–5 years from cancer diagnosis because of proven higher incidence of recurrence at this time. Nevertheless, there is more and more evidence of the safety of decreasing this time, particularly for low-risk patients [1, 4, 6]. Additionally, as more data are collected, they show that risk for recurrent and new cancer in patients with IBD is not increased with thiopurines or anti-TNF-a agents and VDZ, which was also confirmed in the last ECCO guidelines [7]. Moreover, the Polish drug program of CD biological treatment and most of the characteristics of the products does not prohibit the use of immunomodulators but emphasise the need for special monitoring of such patients. Nevertheless, there is insufficient evidence to decide on the use of VDZ in patients with active malignancy, and its longer safety requires further investigation [7].
In conclusion, according to the current data, the use of vedolizumab is not associated with increased risk of malignancy. Nevertheless, the treatment of patients with inflammatory bowel diseases and a history of oncological diseases remains challenging and requires an individual and multidisciplinary approach, including a gastroenterologist, an oncologist, and considering the patient’s preferences. The patients should be carefully surveilled and educated and should undergo all the cancer screening programs adequate to their age.
