An Early-Stage Nuclear Protein in Testis Carcinoma of the Lung in an Older Woman.

CASE PRESENTATION
A 69-year-old woman presented to the community hospital with haemoptysis. An initial chest computed tomography (CT) revealed a 20- × 15- mm solid nodule with lobulated margins in the left upper lobe. During the subsequent month, she developed progressive fatigue, paroxysmal left precordial pain, and bilateral lower limb oedema. Her medical history included well-controlled grade 1 hypertension (high-risk). The results of the physical examination and the electrocardiography scan were unremarkable. Laboratory investigations showed elevated inflammatory and tumour markers: Tumour necrosis factor alpha (11.1 pg/ml; normal <8.1), laser Doppler flow (262 U/l; normal 109–245), CRP (5.5 mg/l; normal 0-3), and neuron-specific enolase (18.8 ng/ml; normal <16.3), alongside positive antinuclear antibodies (1:100). Contrast-enhanced CT confirmed persistence of the left upper lobe nodule (Figure 1A). Subsequent positron emission tomography/CT demonstrated intense metabolic activity within the nodule (17.8 × 15.5 mm; standardized uptake value maximum > 10.8) with adjacent bronchial occlusion, and a metabolically active left hilar lymph node (6.9 × 6.0 mm; standardized uptake value maximum = 4.2). No abnormal glycolytic hypermetabolism or enlarged lymph nodes were observed in the mediastinum or right hilum (Figure 1B). The diagnostic report indicated a left lung cancer with possible left hilar lymphadenitis.
To further characterize the lesion, electromagnetic navigation bronchoscopy was performed, revealing no endobronchial abnormalities. However, histopathological evaluation of the biopsy specimen confirmed a small cell carcinoma, with negative staining for nuclear protein in testis (NUT). The patient was ultimately diagnosed with lung cancer (left upper lobe, cT1N0M0 stage, Eastern Cooperative Oncology Group performance status 0), complicated by grade 1 hypertension (high-risk category), thyroid nodules, and hepatic cysts. Following multidisciplinary evaluation, surgical resection was recommended, considering the early clinical stage and the patient’s favourable operative risk.
Three days after hospitalization, the patient underwent video-assisted thoracoscopic left upper lobectomy with mediastinal lymph node dissection (stations 5-10). Final pathological examination confirmed NUT carcinoma (NC), supported by strong NUT positivity on immunohistochemical analysis (Figure 1C and D) and NUT rearrangement (positivity rate: 30%) detected by fluorescence in situ hybridization. Surgical margins and all resected lymph nodes were tumour-free. Five days following the surgical procedure, the patient met the discharge criteria and was released from the hospital. The patient has been followed up every 3 months postoperatively; with 2 follow-up visits was to be completed so far. The most recent assessment showed the patient in good overall condition, and a chest CT revealed no signs of recurrence.

DISCUSSION
A NUT protein in testis carcinoma is a rare and highly aggressive malignancy, with approximately 51% of cases arising in midline structures such as the mediastinum. In physiological conditions, NUT protein expression is restricted to post-meiotic spermatids in adult testes. However, rearrangement of the NUT gene, which typically fuses with BRD4, BRD3, or NSD3, drives tumourigenesis and confers a poor prognosis.1 Pulmonary NC represents an exceedingly rare subtype that usually presents as a large primary lung mass with mediastinal invasion. Patients commonly present with non-specific symptoms such as cough, wheezing, chest tightness, dyspnoea, haemoptysis, and fever.2 Thoracic NC typically occurs in patients aged 40 to 50 years and is frequently diagnosed at an advanced stage, characterized by a high propensity for rapid recurrence and metastasis. Consequently, these cases are associated with an unfavourable prognosis, demonstrating a median overall survival of approximately 4.4 months.3 Due to its low incidence, non-specific clinical and laboratory manifestations, and limited clinician awareness, diagnosis is frequently delayed.
This case demonstrates 4 clinically atypical features. First, the patient’s age falls outside the typical demographic range for NC. Second, the tumour was detected at an early stage (cT1N0M0), which is uncommon compared with previous reports.4 Third, the initial bronchoscopic biopsy misclassified the tumour as a small cell carcinoma with negative NUT staining, likely due to tumour heterogeneity (especially in small biopsy samples) and the limited sensitivity (∼87%) of the NUT antibody. In such settings, NC should be suspected when morphological features such as monomorphic tumour cells with a “fried egg” appearance due to separation artifacts, absence of nuclear molding, abrupt squamous differentiation, and prominent neutrophilic infiltration are observed. Fourth, despite the initial biopsy suggesting small cell carcinoma, a multidisciplinary team recommended surgical resection based on the early clinical stage and the patient’s favourable operative risk. This decision underscores that, in carefully selected patients with localized but diagnostically challenging lung tumours, an operation can offer both diagnostic confirmation and potential survival benefit.
Therapeutic strategies for NC remain challenging. Surgical resection offers the best chance for treatment of the localized disease.5 Given the lack of durable responses to conventional therapies, inhibitors targeting BRD-NUT fusion proteins, especially BET and histone deacetylase inhibitors, show benefits by restraining tumour cell proliferation. Currently, a clinical trial investigating the BET inhibitor ZEN003694 in combination with etoposide and cisplatin is underway (NCT05019716). In the present case, however, the specific BRD fusion partner was not identified due to the unavailability of commercially approved and clinically validated fusion probes. Future testing to characterize the fusion partner, if feasible, could yield valuable insights for guiding novel therapeutic strategies.