Primary pulmonary nuclear protein of testis (NUT) midline cancer (NMC) is an extremely rare, highly aggressive malignant disease of the thoracic cavity that poses significant diagnostic and therapeutic challenges and is characterized by heterogeneous clinical manifestations, frequent misdiagnosis, and poor prognosis.

This case report describes two patients with advanced primary pulmonary NMC who were treated with a multimodal strategy that combined anti-angiogenic agents, platinum-based chemotherapy, and radiotherapy – and achieved an overall survival time (OS) of 32 and 13 months, respectively, far exceeding the currently reported median OS of about 6.7 months for advanced NMC.

A systematic literature review of 86 published cases (2011–2024) was also conducted, summarizing the current diagnostic methods (such as immunohistochemistry for nuclear NUT expression and fluorescence in situ hybridization (FISH) for NUTM1 rearrangement) and treatment modalities for NMC.

According to the authors, the results indicate that multimodal therapy with antiangiogenic agents leads to superior clinical outcomes compared to conventional monotherapy, especially in patients who are not eligible for surgery.

The report also highlights diagnostic pitfalls, such as overlapping histopathological features with squamous cell carcinoma, and highlights how the integration of anti-angiogenic therapy addresses the aggressive biology of NMC and provides a new therapeutic direction for this refractory malignancy. The first patient, a 31-year-old non-smoker, presented in April 2021 with a cough that had persisted for a month. A contrast-enhanced thoracic abdominal CT showed a 4.7 cm × 3.4 cm mass at the bronchial root of the right middle lobe, accompanied by mediastinal/hilar lymphadenopathy and suspected distant metastases (pulmonary and left gastric lymph nodes) classified as IVA (cT3N3M1b). Transbronchial biopsy revealed poorly differentiated epithelial cells with focal squamous differentiation (keratin beads), and immunohistochemistry confirmed diffuse nuclear NUT expression as well as positive squamous cell markers (CK5/6, CK7, p40) and negative neuroendocrine/thyroidal markers.

Next-generation sequencing (NGS) identified a BRD4-NUTM1 rearrangement, confirming the diagnosis. First-line therapy included six cycles of albumin-bound paclitaxel plus cisplatin (May–October 2021), achieving partial remission (PR) followed by concomitant radiotherapy (50 Gy/25 fractions) of the left gastric lymph nodes for locoregional control. In December 2021, antiangiogenic therapy with anlotinib was initiated, which made the disease stable until August 2022 (15 months of progression-free survival, PFS). Subsequent lines of therapy (BET inhibitor, immunotherapy, histone deacetylase inhibitor) were unable to control disease progression, and the patient died in January 2024 from multiple organ failure (MODS) with an overall survival time (OS) of 32 months – 4.8 times the median OS in advanced NMC. The second patient, a 26-year-old non-smoker, was accidentally diagnosed with a 10.0 cm × 5.5 cm lobular mass in the right middle lower lobe of the lung, hilar/mediastinal lymphadenopathy, and bilateral adnexal/pelvic metastases (largest lesion 22 cm × 13 cm) classified as IVB (cT4N2M1c).

Biopsies of the lung and pelvic lesions showed poorly differentiated carcinoma with geographic necrosis and focal keratinization; immunohistochemistry confirmed nuclear NUT expression and squamous cell markers (CK5/6, p40, p63), while FISH detected NUTM1 rearrangement. First-line therapy (tislelizumab, paclitaxel liposome, nedaplatin) was discontinued after one cycle due to severe weight loss, fatigue and lack of lesion reduction. Second-line treatment included six cycles of paclitaxel-albumin conjugate, cisplatin and bevacizumab (anti-angiogenic agent), achieving partial remission (PR) after two cycles and then stabilization of the disease, followed by two cycles of maintenance therapy (paclitaxel albumin + bevacizumab). After 7 months, progression (new hilar lymphadenopathy) occurred (PFS = 7 months). Hypofractionated radiotherapy (37.5 Gy/15 fractions) controlled the primary/mediastinal lesions but not peritoneal carcinosis; the subsequent combination therapy (gemcitabine, nedaplatin, anlotinib, durvalumab) was discontinued due to grade 3 hepatotoxicity and pneumonia. The patient died of acute hypoxic lung failure 13 months after diagnosis – almost twice as long as the median OS in metastatic NMC.

The literature review highlighted critical diagnostic challenges: 22% of cases were initially misdiagnosed, most commonly as squamous cell carcinoma due to overlapping immunohistochemical markers (CK5/6+, p40+, TTF-1–/Syn–). Nuclear NUT expression by IHC and FISH (C52 clone, 100% specificity) is the diagnostic gold standard, although NGS can also detect NUTM1 fusions (87% of NMC cases involve BRD4-NUTM1) and thus provides additional confirmation. Therapeutically, traditional monotherapies or conventional multimodal therapies (chemotherapy ± radiotherapy) showed limited efficacy with a median PFS of 2.1 months. In contrast, the integration of antiangiogenic agents (anlotinib, bevacizumab) in the two cases improved chemotherapy through vascular normalization, reduced tumor hypoxia to improve radiation sensitivity, and inhibited spread by downregulating VEGF-related signaling pathways (CXCR4, MMP9) – prolonging PFS and OS. While BET inhibitors and immunotherapies have shown promise in preclinical studies, their clinical efficacy remains limited, highlighting the need for early integration of antiangiogenic therapy into the treatment of NMC.

The report challenges the therapeutic pessimism regarding NMC and proposes antiangiogenic multimodal therapy as a viable strategy to improve outcomes in this rare, aggressive malignancy.

Original Paper:

Anti-angiogenic therapy as a beacon of hope in the battle against pulmonary NUT midline carcinoma | Frontiers of Medicine

Editor: X-Press Journalistenbüro GbR

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