Nivolumab induced discolouration of the tongue: a case report

ABSTRACT

Currently, immune checkpoint inhibitors are used in the treatment of ovarian cancer. Immunotherapy agents occasionally cause the development of skin reactions characterized by mild erythematous and maculopapular rashes, usually involving the trunk and extremities of the body, which may occasionally present with pruritus. It is especially seen in the use of anti-PD-1 (nivolumab and pembrolizumab) treatment agents. In this case report, we present a patient who developed discoloration of the tongue toxicity after nivolumab treatment in ovarian cancer patients. Discoloration of the tongue, which is one of the rare side effects of immunotherapy, and factors that may be associated with it are discussed in this case.

1. Introduction

According to GLOBOCAN 2022 data, worldwide, ovarian cancer is one of the most common cancers in women, accounting for more than 310,000 new cases. In 2020, ovarian cancer was one of the cancers with the highest mortality rate, with nearly 207,000 deaths worldwide. This type of cancer is often diagnosed in late stages, which reduces the chances of treatment and cure. Risk factors include genetic predisposition, age, obesity and infertility, while prevention strategies are limited. With the increase in obesity and age factors, the incidence of ovarian cancer is expected to rise further in the future [1,2].

Today, the clinical success of immune checkpoint inhibitors has led to their approval for the treatment of many types of cancer, including ovarian cancer [3]. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, has demonstrated promising efficacy in several solid tumors, including melanoma, lung cancer, and renal cell carcinoma. In ovarian cancer, although response rates to nivolumab monotherapy have been modest, it has shown potential in subsets of patients with high PD-L1 expression or microsatellite instability. One of the critical advantages of nivolumab is its generally favorable toxicity profile compared to conventional chemotherapy, allowing for long-term administration and better quality of life. However, its effectiveness in ovarian cancer remains limited due to the immunosuppressive tumor microenvironment, low tumor mutational burden, and lack of predictive biomarkers. Moreover, immune-related adverse events, although less frequent than cytotoxic toxicities, can still lead to unexpected and sometimes serious complications, including rare mucocutaneous manifestations. Therefore, further studies are required to optimize patient selection and to identify combination strategies that may enhance its therapeutic benefit in ovarian cancer [4–6]. Compared to other systemic treatment approaches, these drugs, which have a lower side effect profile, cause the development of skin reactions with mild erythematous and maculopapular rashes, usually covering the trunk and extremities of the body, which may occasionally be characterized by itching. It is especially seen with the use of anti-PD-1 (nivolumab and pembrolizumab) treatment agents [7]. Maculopapular rashes, dryness, vitiligo, redness are the most common skin reactions [3,7]. In patients receiving nivolumab treatment, skin pigmentation changes in all grades were reported in 8.8% [8]. There are no case reports or studies reporting discoloration and pigmentation changes in the tongue after Nivolumab treatment in ovarian cancer patients. In this case report, a patient who developed tongue discoloration toxicity after Nivolumab treatment in ovarian cancer patients is presented.

2. Patient information

A 52-year-old female patient named F.S. applied to the doctor in April 2019 with complaints of abdominal swelling, constipation and abdominal pain for 2 months. The patient reported a dull and persistent abdominal pain localized primarily to the lower abdomen, more prominent on the left side. The pain had been ongoing for approximately two months, described as a constant pressure-like sensation, occasionally accompanied by episodes of cramping. The pain was not radiating and was partially relieved by bowel movements. There were no associated urinary symptoms. Pain severity was reported as 5/10 on a numeric rating scale. In the patient’s medical history, there was no known chronic disease, smoking and alcohol intake. In the family history, the patient’s sister had a history of breast cancer. She also underwent a partial hysterectomy in 2007 due to a benign gynecological condition (not further specified).

2.1. Clinical findings and diagnostic assessment

On abdominal USG, irregular-lobulated contoured lesions reaching 135 × 145 mm in the pelvic area were observed and CA 125: 1147 U/ml was detected. Contrast-enhanced pelvic MRI was performed for further examination and showed lesions in both ovaries (right: 75x120x120 mm) (left: 90x115x100 mm) containing solid and septated cystic areas. Diffusion restrictions and contrast uptake after IVCM (intravenous contrast media) were detected in solid areas and septa. Bilateral ovarian ca? reported. There is also fluid in the pelvic area. Contrast uptake was observed after IVCM. Peritonitis carcinomatosa has been reported.

Following the performance of a biopsy (A transvaginal ultrasound-guided needle biopsy was performed on the pelvic mass, and tissue samples were obtained for histopathological evaluation), systemic treatment was initiated with three cycles of paclitaxel (175 mg/m2) and carboplatin (carboplatin AUC:5 administered once every 21 days). Subsequent to the treatment, regression was observed on control imaging (PET CT), and the patient underwent surgery. The surgical intervention involved an extensive procedure, including hysterectomy, bilateral salpingo-oophorectomy, peritonectomy above the bladder, omentectomy, right diaphragm stripping, bilateral paracolic peritonectomy, low anterior resection, end-side anastomosis, and HIPEC (cisplatin). Histopathological analysis revealed high-grade serous carcinoma and metastases. The patient was treated with three additional cycles of paclitaxel and carboplatin.

The patient initially received neoadjuvant chemotherapy consisting of paclitaxel at a dose of 175 mg/m² and carboplatin dosed at AUC 5, administered every 21 days for 3 cycles. After interval debulking surgery combined with HIPEC using cisplatin, the patient underwent an additional 3 cycles of adjuvant paclitaxel and carboplatin chemotherapy with the same dosing and schedule. Following completion of chemotherapy, maintenance immunotherapy with nivolumab was initiated at a dose of 480 mg every 21 days. No other systemic therapies or chronic medications were administered during the treatment period, except for standard supportive care measures (e.g., antiemetics, as needed).

Following the completion of the initial chemotherapy regimen, the patient was transitioned to a maintenance treatment plan that incorporated the administration of nivolumab, an immunotherapy agent. The patient received regular nivolumab 480 mg/direct dose 1 every 21 days (Q3W). However, during the 18th cycle, the patient was admitted to the oncology unit with a complaint of discoloration of the tongue. The oncologist requested an otolaryngology consultation. The otolaryngologist’s examination revealed that the discolouration was one of the rare side effects of the immunotherapy. The patient was advised to follow up with symptomatic treatment. The diagnosis was confirmed as nivolumab-induced tongue discolouration (Figure 1). The discoloration observed on the tongue was described as a diffuse, dark brown pigmentation involving predominantly the dorsal surface, with slight extension to the lateral borders. The lesion was asymptomatic, with no associated pain, burning sensation, or dysgeusia. There were no ulcerations or plaques. The pigmentation appeared gradually over the course of 2–3 weeks prior to presentation. Notably, the pigmentation did not regress completely despite continued nivolumab treatment, but showed partial fading over time with supportive oral care. No interruption or dose adjustment of nivolumab was required. Other potential causes of tongue discoloration were carefully evaluated and ruled out. The patient had no history of smoking, alcohol use, or recent changes in diet or hygiene. There was no use of other medications or supplements known to cause oral pigmentation. Laboratory workup revealed no signs of vitamin B12, folate, or iron deficiency, and fungal infection was not suspected clinically. Therefore, given the temporal relationship with immunotherapy, absence of alternative causes, and partial improvement with continued treatment, the discoloration was attributed to nivolumab.

Figure 1.

Nivolumab-induced tongue discoloration.

2.2. Follow-up and outcomes

After the diagnosis of nivolumab-induced tongue discoloration, the patient received symptomatic treatment as recommended by the ENT specialist. The discoloration partially improved without requiring interruption of immunotherapy. The patient has continued nivolumab regularly and remains clinically stable, with no progression of oral symptoms. At the last follow-up on 6 May 2025, the patient continued to use supportive medications such as Gencort, Astonin-H, Calcimax, Fosamax, Folbiol, and Metoartal. Physical examination findings were normal. Thoracic and abdominal computed tomography examinations showed no signs of intra-abdominal recurrence or metastasis. Laboratory tests revealed that CA-125 level was within normal limits (7.4 U/mL), CRP was slightly elevated (8.8 mg/L), LDL was 108 mg/dL, and triglyceride level was 178 mg/dL. Imaging and laboratory checkups were planned again in September 2025 for disease follow-up.

3. Discussion

Nivolumab-induced tongue discoloration is a rare side effect. In this case report, a rare skin toxicity of nivolumab, tongue discoloration, is described and presented.

The occurrence of vitiligo-like skin discolouration has been documented in patients diagnosed with melanoma who have undergone treatment with anti-PD-1/anti-PD-L1 immunotherapies. Clinically, the lesions manifest as bilateral, multiple or hypo- or depigmented macules. The occurrence of immune checkpoint inhibitor-induced vitiligo can be attributed to a cross-reaction to antigens shared by melanoma cells and normal melanocytes. While rare, cases of this phenomenon have also been observed in other types of cancer. Prospective study [9] revealed an incidence of 7.5% for nivolumab, although it suggests a higher incidence of approximately 25% [10,11]. Although nivolumab has been reported to cause vitiligo-like skin changes in melanoma patients, discoloration of the tongue has not been reported in any case. Although vitiligo-like depigmentation has been commonly reported in melanoma patients receiving immune checkpoint inhibitors (ICIs), it is crucial to clearly distinguish this phenomenon from mucosal hyperpigmentation, as the two represent different pathophysiological processes. Vitiligo-like lesions are characterized by melanocyte destruction resulting in hypopigmented or depigmented macules, whereas hyperpigmentation involves increased melanin production or melanocyte stimulation, leading to darker discoloration. The clinical presentation in our case is more consistent with mucosal hyperpigmentation rather than hypopigmentation. Therefore, previously cited literature on ICI-induced vitiligo may not be entirely applicable. Our case may instead represent a rare instance of ICI-induced mucocutaneous hyperpigmentation, which has been described in a limited number of reports involving both skin and mucosal membranes. The underlying mechanisms of such pigmentation changes remain unclear, but proposed explanations include immune-mediated melanocyte stimulation, drug – melanin binding, or inflammatory responses that increase melanin synthesis.

In addition to immune-mediated melanocyte stimulation, mucocutaneous hyperpigmentation associated with ICIs may result from pigment accumulation such as melanin or hemosiderin deposition. Several case reports have described such pigmentary changes in patients receiving ICIs, highlighting a spectrum of mucocutaneous adverse events beyond classic vitiligo-like depigmentation [5,8,12,13]. These pigment accumulations may be due to localized inflammation, vascular leakage, or drug-melanin interactions, though exact pathogenesis remains to be elucidated. Given that mucosal hyperpigmentation has been rarely documented in patients treated with nivolumab, this report contributes to a better understanding of the spectrum of mucocutaneous adverse events associated with immune checkpoint inhibitors. Accurate classification and management of such reactions require further clinical observation and, when possible, histopathological confirmation. Future case series and observational studies are warranted to clarify whether mucosal hyperpigmentation represents a distinct immune-related adverse event or an incidental finding. Our case highlights the importance of recognizing this rare presentation and encourages more comprehensive reporting in the literature [8,12–14]. In addition, no such side effects were observed in patients who started nivolumab treatment for ovarian cancer. Based on the results of these cases, it is important to inform patients and their relatives before starting treatment that nivolumab-associated tongue discoloration is an expected side effect and may occur, albeit rarely. It is also important to take a detailed history of all patients receiving nivolumab and to closely monitor, classify and record skin reactions [15,16]. The extent to which skin reactions affect the patient’s participation in daily life, whether they limit or interfere with self-care should be questioned in detail. Immunotherapy-associated skin reactions are usually not a toxicity that requires discontinuation of treatment, but in rare cases, it may be necessary to temporarily or permanently stop treatment in some patients. Corticosteroids can be started based on the patient’s complaints. Especially spots on the tongue may lead to a negative body image perception. Changes in the patient’s body image due to skin reactions may lead to restriction of the patient’s social relations or negative effects on quality of life, and may cause patients to interrupt or refuse treatment. Therefore, it is very important to plan and effectively manage appropriate counseling in patients [17,18]. When it develops, it should be explained about regular oral care, brushing with soft toothbrushes and moisturizing the teeth.

3.1. Limitations

One of the main limitations of this case report is the lack of histopathological confirmation of the tongue discoloration. Although the clinical presentation, timing of symptom onset, and exclusion of alternative causes support the diagnosis of nivolumab-induced pigmentation, a biopsy was not performed. This limits the ability to definitively establish causality. Additionally, as this is a single case report, the findings should be interpreted with caution and cannot be generalized without further supporting data from larger case series or studies.

Funding Statement

This paper was not funded.

Author contributions

EDA: Conceptualization; Data Curation; Formal Analysis; Investigation; Methodology; Writing – Original Draft; Writing – Review & Editing. DY: Conceptualization; Data Curation; Formal Analysis; Investigation; Methodology; Writing – Original Draft; Writing – Review & Editing. All authors meet the ICMJE criteria for authorship and have approved the final version of the manuscript.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Immunotherapy for their review work. A reviewer on this manuscript has disclosed affiliations with Ono Pharmaceutical, Bristol Myers-Squibb and MSD. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Article highlights

• A rare case of tongue hyperpigmentation was observed in a patient receiving nivolumab for ovarian cancer.

• The pigmentation appeared without associated pain or ulceration and was confined to the dorsal surface of the tongue.

• Differential diagnoses included melanoma, lichen planus, and drug-induced pigmentation; histopathology confirmed benign pigmentation.

• No interruption of immunotherapy was required; the pigmentation remained stable with regular monitoring.

• Clinicians should be aware of this rare but benign immune-related mucocutaneous color change to avoid unnecessary interventions.

Ethical declaration

The authors state that they have obtained verbal and written informed consent from the patient for the inclusion of her medical and treatment history within this case report.