Introduction

Nuclear protein in testis (NUT) carcinoma is a rare but highly malignant tumour that can occur at any age. It is caused by many changes in a gene: for example, chromosomes containing the NUT midline carcinoma family member 1 (NUTM1) gene, like chromosome 15q14, can rearrange themselves to cause a nut carcinoma. Although NUT carcinomas are most commonly found in the midline structures of the thorax, head, and neck—hence the name 'NUT midline carcinoma'—they can arise in any part of the body, such as kidneys, stomach, pancreas, bladder, soft tissue, bone, brain, salivary glands, ocular globe, and adrenal gland.¹

It is still uncertain from which specific cell NUT carcinomas originate, which makes early diagnosis difficult. Most patients are diagnosed at an advanced stage, often presenting with an invasive (the carcinoma has moved to surrounding tissues) and metastatic condition (the carcinoma has moved from its original site to other parts of the body). In some cancer conditions where the origin is unclear, it is essential to undergo more in-depth investigation, as in most cases, it could be NUT carcinoma. 

To date, no standard treatment has proven effective for NUT carcinoma, and the prognosis is extremely poor, with patients typically surviving only 6 to 9 months after diagnosis. Although NUT carcinoma has no specific pathological features, there are some common signs that doctors should use to diagnose it quickly, such as using the  IHC test to identify the NUTM1 protein. Since NUT carcinoma is a rare cancer, every patient with suspected symptoms should be tested and, if possible, offered the chance to join a clinical trial.²

Respiratory distress

Mechanism

Patients with NUT carcinoma in the thoracic midline often present with respiratory distress as a characteristic symptom. More specifically, it is caused by tumour growth in the thoracic cavity, particularly involving the trachea and the subglottic area adjacent to the thyroid, progressively invading surrounding structures and resulting in the compression of the airways and further collapse of lungs.³,⁴

Common presentations

There are several common ways respiratory distress may manifest in patients with NUT carcinoma:

• Dry cough⁴ 
• Cough^5-6
• Chest tightness⁴
• Chest pain^5-6
• Haemoptysis (blood in sputum)
• Shortness of breath (dyspnoea)^4-5-6 
• Stridor
• Sore throat
• Odynophagia (painful swallowing)⁴ 

Patients with NUT carcinoma may occasionally experience more general and nonspecific symptoms, which can lead to confusion with other common symptoms, such as:  

• Back pain
• Fever 
• Weight loss 
• Fatigue^5-7 

Clinical significance

The symptoms of respiratory distress in NUT carcinoma can easily be confused with those of more common respiratory conditions, such as asthma, mainly due to the lack of specific presentations.8 This may lead to the risk of delayed diagnosis or misdiagnosis of this highly aggressive cancer.6 Overall, it is crucial to pay attention to these symptoms, especially if they persist or worsen over time, as they can be indicative of severe conditions like NUT carcinoma. Many cases showed that progressive breathing difficulty is an urgent sign of airway compression and lung involvement.³ 

Pain

Cause of pain

Pain in NUT carcinoma comes from the tumour growing in different parts of the body, like the lungs, head, neck, bones, liver, or pelvis. Given that the tumor grows rapidly, as a consequence, it can press on organs, bones, or nerves, leading to extreme pain. All the affected patients experience this kind of pain, no matter where the tumour is located.

Pain location and type

• Chest pain: may indicate that the tumour is in the lungs, or near the ribs or pleura
• Headache: Tumours may be in the head or neck
• Abdominal or pelvic pain: tumours may be present in the lower body, like the pelvis, femur, liver, or hip

Pain can also spread (radiate) to other parts of the body, it may be difficult to determine exactly where the pain is coming from.

Pain features

Pain is one of the most important symptoms in patients with NUT carcinoma, and it affects their quality of life significantly.⁷

Pain can be:

• Often be severe
• Constant and gets worse over time
• Usually does not go away with rest

Masses

NUT carcinoma is a poorly differentiated cancer that often presents as a palpable mass that can grow rapidly. The most common areas where tumour masses are found include the neck, central chest, and paranasal sinuses.

Neck 

At diagnosis, many patients show lymph node involvement or distant metastases (cancer cells that have moved from its original site to another part of the body). For example, tumours can start in the submandibular gland as a palpable mass, which can persist and keep growing aggressively even after surgical removal of the solid mass. Subsequently, the tumour may spread to multiple lymph nodes, bones, lungs, liver, and distant lymph nodes, indicating a high metastatic potential.⁹

Central chest area

Pulmonary NUT carcinoma typically appears as a large mass in the main bronchi, hilum, or mediastinum. Patients often manifest symptoms related to these masses. For example, bronchial obstruction can be caused by mediastinal invasion and subsequent blockage of the airway. Moreover, tumour metastasis in bones, lungs, and pleura are also commonly seen.¹⁰

Paranasal sinuses 

Tumour masses can also develop in the paranasal sinuses, typically exhibiting rapid growth and resistance to treatment. Even after therapy, like chemotherapy or radiotherapy, they can recur and keep expanding after showing only short periods of shrinkage. Over time, these masses can enlarge further and invade surrounding bone structures and the spine, leading to permanent bone damage and loss of mobility.¹¹ 

Diagnostic implications

Imaging techniques such as computed tomography (CT) scans and magnetic resonance imaging (MRIs) can help detect potential tumour masses and determine their location.¹¹ When a biopsy has poorly differentiated tumour cells that look similar to each other and show no clear squamous features, NUT carcinoma should be considered in the diagnosis.¹² However, since the tumour cells do not have specific features, it is often difficult to accurately diagnose NUT carcinoma, especially when using small biopsy samples, making it easy to misdiagnose

Further investigation should be carried out to confirm the diagnosis and avoid misdiagnosis. Since NUT carcinoma is caused by rearrangements in the NUTM1 gene, the diagnosis can be confirmed by identifying this genetic abnormality. The diagnostic approaches include: 

• Immunohistochemistry (IHC): the most commonly used technique that detects NUT protein expression in the nuclei through immunohistochemical staining
• Alternative molecular tests: specific assays, such as FISH, RT-PCR, NGS, or classic cytogenetics, can be used to identify the gene fused with NUT1, especially when the antibody is not available¹³

Treatment

The treatment of NUT carcinoma remains a significant challenge due to its aggressive nature and rarity. Currently, there is no standard effective systemic therapy. While some patients undergo surgery and radiation, these approaches alone are often insufficient for long-term survival. In the meantime, patients are being treated with:

• Chemotherapy: platinum-based regimens and Ewing’s sarcoma-like protocols have been used with modest success, especially if administered early in the treatment course
• Targeted therapies: BET and HDAC inhibitors have demonstrated only modest and short-duration responses.
• Newer experimental treatments: these include combinations of BET inhibitors with CDK4/6 or chemotherapy, and experimental agents targeting CDK9 and p300
• Immunotherapy: checkpoint inhibitors are under investigation, even in patients without high PD-L1 expression or tumour mutation burden

Despite these efforts, survival outcomes remain poor, and further research is essential to identify more effective strategies.¹⁴

Conclusion

NUT carcinoma is a rare yet highly aggressive cancer that often presents with key symptoms such as respiratory distress, persistent and severe pain, and rapidly growing tumour masses. These symptoms typically arise due to tumour invasion of vital structures like the airways, bones, and organs, which can severely affect a patient's quality of life and overall prognosis. Given the nonspecific nature of these symptoms and the tumour’s poor differentiation, NUT carcinoma is frequently misdiagnosed or diagnosed at an advanced stage. This underscores the critical importance of increasing awareness among healthcare professionals and encouraging early recognition. 

Persistent respiratory issues, unexplained pain, or aggressive masses in midline regions should prompt consideration of this rare malignancy and lead to timely diagnostic testing, especially through immunohistochemistry for NUT protein expression. Early and accurate diagnosis may provide patients with access to targeted or experimental therapies and clinical trials, which could potentially improve survival outcomes. As research continues, raising awareness is essential to offer hope and better management for those affected by this devastating disease.