Mediastinal NUT carcinoma: about a case report including immunotherapy in therapeutic management

¹Department of Medical Oncology, University Hospital Center Hassan II, Fez, Morocco, ²Department of Medical Oncology, North Hospital, University Hospital of Saint-Etienne, Saint-Etienne, France

^&Corresponding author
Soukaina El Ansari, Department of Medical Oncology, University Hospital Center Hassan II, Fez, Morocco

Introduction    

NUT carcinoma (NC) is a very aggressive tumor defined by a rearrangement involving the NUTM1 gene (Nut midline carcinoma, family member 1) on chromosome 15. The disease was thought to be initially reserved for children and adolescents, but some studies have shown that NUT carcinoma can occur at any age [1,2]. Few cases are reported in the literature, it is often undiagnosed or misdiagnosed, and its true prevalence is unknown. This carcinoma mainly occurs in midline structures [3]. Herein, we report a case of Caucasian women diagnosed with a mediastinal NC treated with immunotherapy and chemotherapy. This article reports the benefit observed in terms of overall survival by the addition of immunotherapy and reviews the place of checkpoint inhibitors in the literature to provide a reference in clinical practice.

Patient and observation     

Patient information: a 36-year-old Caucasian woman consulted for dyspnea, cough as well as night sweats, increasing despite the prescription of salbutamol with a history of active smoking at a rate of 15 pack years.

Clinical findings: an injected computed tomography (CT) showed a large hypodense mediastinal mass measuring 63 mm high by 70 mm wide, invading the mediastinum with probable lymph node localizations compressing the middle and upper right lobes with a mass effect on the right bronchus (Figure 1). The patient was referred in this context to hematology for suspicion of primary lymphoma of the mediastinum. In the hematology department, she performed a positron emission tomography finding a large, intensely hypermetabolic right hilar lymph node mass extending into the mediastinum, with a max SUV at 18.2. No other metabolic anomaly was observed apart from the mediastinum-hilar lymph node mass (Figure 2).

Timeline: biopsies were performed by the trans-bronchial route. The first results of the biopsies were in favor of a carcinoma whose origin remains undetermined; the most probable hypotheses were neuroendocrine and NUT.

Diagnostic assessment: after several re-readings, results were in favor of undifferentiated infiltrating carcinoma with the anti-NUT antibody leading to a suspicion of NUT-type carcinoma. RNA panel molecular biological analysis concludes in the presence of a fusion transcript BRD4:NUTM1 consistent with the diagnosis of NUT carcinoma with the presence of a p.IIe480Met mutation of exon 2 of MAML2 and also the p.VaII60Met mutation of exon 6 of TMPRSS2.

Therapeutic intervention: after discussion of the file in multidisciplinary team meetings, the patient started a first-line combining Carboplatin AUC 6, Paclitaxel triweekly, and Pembrolizumab once every three weeks.

Follow-up and outcomes: after 3 cycles of treatment combining immunotherapy and chemotherapy, the patient was in very good general condition with the disappearance of the respiratory symptoms. Comparative CT was in favor of an excellent partial response and reduction in the size of the right mediastinal hilar mass (23 mm vs 63 mm) and its locoregional invasion without progressive lesion (Figure 3). Then the patient received 2 other courses of CARBOPLATIN, PACLITAXEL, and PEMBROLIZUPMAB. Radiotherapy of the residual sites was performed at the end of the treatment. The patient received 66 GY in 33 fractions at the mediastinal level. Given the good clinical and radiological response, we started maintenance with PEMBROLIZUMAB. After five months of maintenance with Pembrolizumab, the patient presented crippling pain in the right leg. On exploration, we objectified a progression in the bones, lungs, and lymph nodes associated with a major deterioration in general condition then the patient died 2 months later. In this case, we report a progression-free survival (PFS) at 8 months and overall survival (OS) at 10 months.

Consent: written informed consent has been obtained from the patient for the publication of this case report and accompanying images.

Discussion     

NUT carcinoma is an aggressive type of cancer that can occur anywhere along the midline of the body, including the chest, mediastinum, lungs, nasal cavity, and paranasal sinuses malignancy. Men and women are equally affected. The most common metastatic sites are lymph nodes, bone, lung, pleural, skin, and subcutaneous soft tissue [4]. In a retrospective study of 63 patients with NC, the median age was 16 years [4]. The rate of patients who had tumors located in the chest was 56% versus 21% in the head and neck. The median overall survival (OS) was 6.7 months. Another cohort study [2] showed that the median age of NC patients was 23 years and reported different tumor locations: lungs (35.3%), head and neck (35%), and mediastinum (26%). Median OS reached 5 months.

To date, there are no standard treatment recommendations for NUT cancers. Regarding systemic therapy, several drugs have been used as cisplatin, carboplatin, cyclophosphamide, etoposide, doxorubicin, actinomycin D, vinorelbine, vinblastine, paclitaxel, docetaxel, 5-fluorouracil, vincristine, ifosfamide, gemcitabine [2]. Vincristine showed a reduction in the tumor burden in one study but was insufficient to prevent tumor progression [5]. Other drugs have been reported including etoposide and vorinost [5]. No therapeutic drug has proven its effectiveness. Three pediatric patients with NC were treated in two case reports, with a sarcoma regimen that included surgery, chemotherapy, and local radiation. These three patients achieved the highest progression-free survival reaching 6, 14, and 13 years, respectively [1]. The development of immune checkpoint inhibitors (ICIs) constitutes a new therapeutic weapon against cancer. PD-L1 expression is considered a predictive biomarker of checkpoint inhibitor efficacy. There are very few data in the literature on the place of immunotherapy and PDL1 status in NC. Recently, different studies [6-8] have reported the particularity of expression of high levels of PD-L1 in NUT carcinomas. Cho et al. reported the highest PD-L1 expression in 2 cases (70% and 80%, respectively). In one study [6], tumor Proportion Score (TPS) ranged from 20% in an adult case to 0 or 1% in pediatric cases. In our case report, we don't have PDL-1 status. This case report demonstrated a slight improvement in overall survival reaching 10 months compared to other patients who were treated by only chemotherapy reaching only six or seven months of OS [2-4].

Conclusion     

NUT carcinoma is an aggressive tumor that remains challenging. Many attempts have been made in the treatment of NC but nowadays, no therapeutic standard is recommended. Immune checkpoint inhibitors need to be further explored in NC to develop therapeutic strategies that improve overall survival.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All authors have contributed to realize this study and they have read and approved the final manuscript.

Figures     

Figure 1: injected computed tomography (CT) of the patient´s chest: showing a large hypodense mediastinal mass measuring 63 mm high by 7cm wide

Figure 2: positron emission tomography (PET) scan: showing large, intensely hypermetabolic right hilar lymph node mass extending into the mediastinum, with a max SUV at 18.2

Figure 3: injected chest scan after 3 cycles of (Carboplatine, Paclitaxel, Pembrolizumab): showing a reduction in the size of the right mediastinal hilar mass syndrome (23 mm vs 63)

References