Rapid Progression of Primary Pulmonary NUT Midline Carcinoma: A Case Report and Literature Review

ABSTRACT

Primary pulmonary nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare malignancy with characteristics that resemble those of squamous cell carcinoma, thus making it prone to both misdiagnosis and missed diagnosis. Primary pulmonary NMC is highly malignant and associated with poor prognosis, with no standardised effective treatments for patients who cannot undergo surgery. Concurrent or sequential chemoradiotherapy is considered an effective approach, and some targeted drugs have been clinically tested and demonstrated favourable results. We present a case of primary pulmonary NMC with cervical lymph node metastasis, in which the patient experienced temporary symptom relief after receiving anlotinib and chemotherapy combined with immunotherapy. However, the condition rapidly worsened, and the patient died within 1 month of diagnosis. We believe that combining anlotinib with chemotherapy as well as reducing the chemotherapy interval can be effective in the treatment of primary pulmonary NMC.

We present the case of a patient with primary pulmonary nuclear protein in testis midline carcinoma, which is prone to misdiagnosis, who experienced poor treatment outcomes and a short overall survival duration. Anlotinib may provide an effective treatment option for select patient subgroups, and shortened chemotherapy could particularly benefit disease control in genetically defined cases.

1. Introduction

Nuclear protein in testis (NUT), a transcriptional product of the NUMT gene, is usually limited to expression in the ovaries and testes. We present a case of a patient who presented with rapid primary pulmonary NMC progression.

2. Case Report

A 55‐year‐old male was admitted to our hospital with a 1‐month history of cough and sputum production. The patient developed a cough 1 month prior that was accompanied by a small amount of yellow sputum and underwent chest computed tomography (CT), which revealed a mass in the right lung with multiple nodules in both lungs (Figure 1A). However, the patient refused the treatment. After 10 days, the patient had developed breathing difficulties with blood streaks in the sputum. Chest CT revealed an increase in the size of a lesion in the right lung (Figure 1B), and bronchoscopy revealed atypical cells. Immunohistochemical markers did not show definitive patterns and did not support the diagnosis of small‐cell carcinoma; however, the proliferation index was high. The patient was admitted to our hospital for confirmation of the diagnosis. The tumour marker test results were as follows: gastrin‐releasing peptide precursor: 21.27 pg/mL; carcinoembryonic antigen: 1.48 ng/mL; cancer antigen (CA): 125,222.4 U/mL (0–53); CA 1991, CA 242, CA 724 and cytokeratin 19 fragments: 2.53 ng/mL (0–2.08); abnormal prothrombin: 81.54 mAU/mL (11.21–32.01); and neuron‐specific enolase: 206 ng/mL (0–16.3). Chest radiography was performed as the patient required high‐flow oxygen inhalation (Figure 1C). Additionally, cervical lymph node biopsy revealed a poorly differentiated cancer (Figure 2A), and immunohistochemical results supported the diagnosis of primary pulmonary NMC. Immunohistochemical findings were as follows: CK8/18 (+) (Figure 2D), CK7 (−), TTF‐1 (8G7G3/1) (−), napsin A (−), P40 (−), CgA (−), Syn (−), CD56 (−), INSM (individual+), Ki67 (positivity rate of 80%) (Figure 2B), CK5/6 (−), P53 (wild‐type), Rb (+), INI‐1 (+), BRG‐1 (+), nut (+) (Figure 2C), CD99 (−) and PSA (−).

FIGURE 1.

Radiological findings. (A) Chest computed tomography (CT) showing a mass shadow (white arrow). (B) Chest and enhanced CT images. Compared to the previous chest CT, this CT scan shows an increase in the size of the mass, accompanied by obstructive pneumonia (white arrow). (C) Chest radiograph from the patient's initial visit to the hospital (white arrow). (D) Chest radiograph on the second visit to the hospital (white arrow).

FIGURE 2.

Pathological findings. (A) Haematoxylin and eosin (H&E) staining, the white arrows indicate malignant cells; (B–D) immunohistochemical staining of Ki67, nuclear protein in testis (NUT) and CK818, respectively, the white arrows indicate immunohistochemical positive cells.

The patient's general condition was poor, with an Eastern Cooperative Oncology Group (ECOG) score of 3, which did not meet the chemotherapy criteria. After multidisciplinary consultation involving the respiratory medicine, oncology, pharmacy and thoracic surgery departments, it was ultimately decided to temporarily administer anlotinib orally for treatment. After 7 days of treatment, the patient's coughing and breathing difficulties significantly improved, the condition improved, and the ECOG score increased. Therefore, the regimen was adjusted to include a combination of serplulimab, albumin‐paclitaxel, loplatin and anlotinib. After the regimen was implemented, the amount of blood in the sputum increased, as the worsening of haemoptysis was related to anlotinib. Anlotinib was therefore discontinued at that time.

Although the patient was discharged after successful chemotherapy, he gradually experienced progressive haemoptysis, and anlotinib was discontinued. After discharge, the dyspnoea improved significantly over a short period of time; however, the patient visited our hospital 18 days later with gradually worsening symptoms. Chest radiography revealed rapid tumour progression (Figure 1D), and given that the patient's general condition was poor and dyspnoea was evident (ECOG 4), further chemotherapy was not feasible. Anlotinib was re‐administered orally; however, the patient died of respiratory failure 3 days later.

3. Discussion

The lungs are one of the sites most commonly affected by NMC; however, reports on primary pulmonary NMC are relatively scarce. The largest concentrated study to date, published in the Journal of Thoracic Oncology in 2015, retrospectively analysed the clinical characteristics of eight patients with pulmonary NMC. However, the average overall survival (OS) of the eight patients was 2.2 months [1], which was much lower than the average OS of 5.5 months of 119 patients with primary pulmonary NMC reported by Giridhar et al. [2]. Furthermore, the currently reported OS of patients with untreated primary pulmonary NMC is only 1.3 months.

A patient treated at the West China Hospital of Sichuan University reportedly had an OS of 24 months and currently remains the patient with the longest reported survival period. After the initial diagnosis and surgical treatment, the patient received four cycles of adjuvant chemotherapy with a regimen of three cycles of etoposide combined with cisplatin (EP) and programmed cell death protein 1 inhibitors, and one cycle of EP combined with vascular‐targeted drugs. Subsequently, the patient had an asymptomatic survival period of up to 12 months; however, the patient rapidly developed systemic metastases after disease recurrence. Radiotherapy is effective for treating this disease [3]. In the present case, the patient presented multiple systemic metastases and was treated with anlotinib.

Owing to the high degree of malignancy and rapid tumour progression, most patients are diagnosed after the opportunity to undergo surgery. The prognosis varies according to the organ involved [4, 5]; for example, the prognosis of mandibular tumours is better than that of primary pulmonary NMC after resection [5]. Among the reported surgical cases, the current average OS for individuals who undergo surgery only is 3.54 months, which can be extended by combining adjuvant and neoadjuvant chemotherapy [6].

Giridhar et al. retrospectively analysed the treatment‐prognosis association in 119 patients with NMC and reported that radiation therapy was an independent positive factor affecting prognosis, thus recommending a dose of > 50 Gy [2].

The average OS of patients who received chemotherapy alone was 5.58 months, indicating that chemotherapy can help prolong patient survival; however, no chemotherapy regimen is currently standardised. Chemotherapy regimens can be selected based on pathological or imaging similarities with small‐cell or squamous‐cell carcinoma. Taxanes combined with platinum (TP) are the most commonly administered chemotherapy regimens, followed by EP, docetaxel combined with platinum (DP), and pemetrexed combined with platinum (AP) regimens. According to a literature review by Storck et al. on the treatment of children with NMC due to sarcoma, the use of an SSG IV chemotherapy regimen attains encouraging results [7]. The patient in this report was readmitted to the hospital 18 days later because his breathing difficulties recurred after his symptoms improved; however, the symptoms gradually worsened over time, which hindered further chemotherapy. However, it is possible to shorten the chemotherapy interval to achieve the goal of rapidly alleviating patient symptoms, which should be further studied.

Xie et al. reported a series of five patients who received PD1/PDL1 as second‐ or higher‐line treatment, among whom the OS was 4.1 months, which was 2.8 months longer than that of patients with untreated primary pulmonary NMC [8]. Currently, immunotherapy for NMC is mostly administered in the form of combined treatments, which makes it difficult to observe the efficacy of a single immunotherapy. Thus, more evidence from single immunotherapy or randomised controlled trials is needed to determine the optimal treatment regimen [6, 9, 10].

Currently, vascular‐targeted drugs are used in combination with chemotherapy, and anlotinib improves patient survival rates and is an effective NMC treatment [11]. In the present patient, early anlotinib treatment significantly improved symptoms; however, the patient developed a bloody cough, which led to treatment termination. Despite resuming treatment with anlotinib after the haemoptysis had resolved, the tumour progressed rapidly, and the patient died of multiple organ failure.

In May 2018, anlotinib was first approved as a third‐line treatment for refractory advanced non‐small cell lung cancer (NSCLC) [2] and has shown efficacy in patients. The vascular endothelial growth factor receptor 2 (VEGFR2) polymorphism 4397T>C is a promising biomarker for predicting the survival rate of patients with NSCLC who receive anlotinib [12]. Anlotinib improves tumour responses to ositinib and other chemotherapeutic drugs [13]. In addition, anlotinib increases the sensitivity of pulmonary blastomas to chemotherapy in vivo [14]. It has been suggested that tumour growth can be suppressed by inhibiting the activation of the fibroblast growth factor receptor (FGFR) signalling pathway, thereby playing a positive role in overcoming resistance to chemotherapy.

In the present study, anlotinib prolonged OS, and the progression‐free survival (PFS) rates suggest that anlotinib can be used as a third‐line or later treatment option for patients with advanced NSCLC. Notably, anlotinib provides clinical benefits in terms of PFS, OS, objective response rate, and disease control rate [15, 16]. A previous study reported that radiotherapy combined with anlotinib was an effective treatment for orbital NMC. Furthermore, palliative radiotherapy combined with anlotinib significantly alleviated the progression of primary lesions in NMC, thereby providing a therapeutic option for treating primary pulmonary NMC. Therefore, anlotinib may play a positive role in improving radiation sensitivity.

However, this requires further investigation. In the present study, we observed that a patient who was initially treated with anlotinib achieved rapid remission. However, when anlotinib was re‐administered as third‐line therapy, the patient experienced rapid disease progression and ultimately died. A possible explanation for this is that his condition rapidly deteriorated to an irreversible state. This finding underscores the importance of early diagnosis and treatment for patients with NMC and rapid disease progression.

Patients treated with bromine domain end‐effector motif inhibitors and histone deacetylase inhibitors as posterior‐line therapies had an average OS of 7.45 months. However, this treatment regimen did not show significant therapeutic benefits, which may have been due to misdiagnosis or late‐stage disease in most patients [6]. For example, Xie et al. reported an NMC case series in which 91.7% of patients with pulmonary NMC harboured the BRD4‐NUT fusion gene. Patients with concurrent somatic mutations in the genes involved in the PI3K/AKT pathway exhibited significantly worse OS, thus suggesting the potential therapeutic efficacy of PI3K/AKT pathway inhibitors in this subset of patients [17].

Several case reports have described the progression of NMC during subsequent treatment cycles. In the present case, the patient showed significant relief in the early stages of chemotherapy combined with immunotherapy; however, the patient's condition rapidly deteriorated before the next cycle of chemotherapy. These findings suggest that shortening the treatment cycle may be beneficial in the treatment of NMC. However, careful consideration of the drug treatment cycle and the potential adverse reactions is necessary.

In conclusion, pulmonary NMC is a rare primary malignant tumour that affects the lungs. It progresses rapidly, is prone to misdiagnosis, and has a short OS, thus emphasising the need for standardised treatment approaches. We believe that anlotinib could provide an effective treatment option for certain patient subgroups and that shortening the chemotherapy duration might be particularly beneficial in controlling disease progression in patients with specific genetic profiles. This report was constrained by the inability to obtain digital lung CT scans, which rendered it difficult to conduct further radiomic analyses. Therefore, well‐designed large‐scale long‐term follow‐up studies are urgently required to verify these preliminary observations.

Author Contributions

R.G., X.L. and C.L.D. conceived and designed the research. R.G., J.Y.Y., J.Y. and C.L.D. analysed the data. R.G., Y.Y., J.Y. and C.L.D. interpreted the results of the article. R.G., J.Y.Y., J.Y. and C.L.D. prepared the figures. R.G. and C.L.D. drafted the manuscript. R.G. and C.L.D. edited and revised the manuscript. R.G., J.Y.Y., J.Y. and C.L.D. approved the final version of the manuscript.

Ethics Statement

This study involved human participants and was approved by the Ethics Committee of the Second Hospital of Jilin University (approval number: 2025‐212). All the procedures were performed in accordance with the principles of the Declaration of Helsinki.

Consent

The authors declare that written informed consent was obtained from the patient for the publication of this manuscript and the accompanying images using the consent form provided by the journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Gao R., Yu J., Lv X., and Dong C., “Rapid Progression of Primary Pulmonary NUT Midline Carcinoma: A Case Report and Literature Review,” Respirology Case Reports 13, no. 8 (2025): e70293, 10.1002/rcr2.70293.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analysed during the current study.