Primary pulmonary nuclear protein of the testis (NUT) midline carcinoma (NMC) is an extremely rare, highly aggressive thoracic malignancy that presents significant diagnostic and therapeutic challenges, characterized by heterogeneous clinical manifestations, frequent misdiagnosis, and a poor prognosis. This case report details two patients with advanced primary pulmonary NMC treated with a multimodal strategy combining anti-angiogenic agents, platinum-based chemotherapy, and radiotherapy—achieving overall survival (OS) of 32 and 13 months, respectively, which far exceeds the currently reported median OS of approximately 6.7 months for advanced NMC. A systematic literature review of 86 published cases (2011–2024) was also conducted, summarizing current diagnostic methods (such as immunohistochemistry for nuclear NUT expression and fluorescence in situ hybridization (FISH) for NUTM1 rearrangement) and treatment modalities for NMC. Findings indicate that multimodal therapy incorporating anti-angiogenic agents yields superior clinical outcomes compared to conventional monotherapy, especially for patients ineligible for surgery. The report also highlights diagnostic pitfalls, such as overlapping histopathological features with squamous cell carcinoma, and underscores how integrating anti-angiogenic therapy addresses the aggressive biology of NMC, offering a new therapeutic direction for this refractory malignancy.
The first patient, a 31-year-old non-smoking male, presented in April 2021 with a 1-month persistent cough. Thoracoabdominal contrast-enhanced CT revealed a 4.7 cm × 3.4 cm mass at the right middle lobe bronchial root, accompanied by mediastinal/hilar lymphadenopathy and suspected distant metastases (pulmonary and left gastric lymph nodes), staged as IVA (cT3N3M1b). Transbronchial biopsy showed poorly differentiated epithelioid cells with focal squamous differentiation (keratin pearls), and immunohistochemistry confirmed diffuse nuclear NUT expression, along with positive squamous markers (CK5/6, CK7, p40) and negative neuroendocrine/thyroid 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 a partial response (PR), followed by concurrent radiotherapy (50 Gy/25 fractions) to left gastric lymph nodes for locoregional control. Anti-angiogenic therapy with anlotinib was initiated in December 2021, maintaining stable disease until August 2022 (15-month progression-free survival, PFS). Subsequent lines of therapy (BET inhibitor, immunotherapy, histone deacetylase inhibitor) failed to control progression, and the patient died of multiple organ dysfunction syndrome (MODS) in January 2024, with an OS of 32 months—4.8 times the median OS for advanced NMC.
The second patient, a 26-year-old non-smoking female, was diagnosed incidentally via routine screening with a 10.0 cm × 5.5 cm lobulated mass in the right middle-lower lung lobe, hilar/mediastinal lymphadenopathy, and bilateral adnexal/pelvic metastases (largest lesion 22 cm × 13 cm), staged as IVB (cT4N2M1c). Biopsies of pulmonary and pelvic lesions showed poorly differentiated carcinoma with geographic necrosis and focal keratinization; immunohistochemistry confirmed nuclear NUT expression and squamous 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 no lesion reduction. Second-line treatment involved six cycles of paclitaxel-albumin conjugate, cisplatin, and bevacizumab (anti-angiogenic agent), achieving PR after two cycles and stable disease thereafter, followed by two cycles of maintenance therapy (paclitaxel-albumin + bevacizumab). Progression (new hilar lymphadenopathy) occurred at 7 months (PFS = 7 months). Hypofractionated radiotherapy (37.5 Gy/15 fractions) controlled primary/mediastinal lesions but not peritoneal metastases; subsequent combination therapy (gemcitabine, nedaplatin, anlotinib, durvalumab) was halted due to grade 3 hepatotoxicity and pneumonia. The patient died of acute hypoxic respiratory failure 13 months post-diagnosis—nearly double the median OS for 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 via IHC and FISH (C52 clone, 100% specificity) is the diagnostic gold standard, though NGS can also detect NUTM1 fusions (87% of NMC cases involve BRD4-NUTM1) for additional confirmation. Therapeutically, traditional monotherapies or conventional multimodal regimens (chemotherapy ± radiotherapy) showed limited efficacy, with a median PFS of 2.1 months. In contrast, integrating anti-angiogenic agents (anlotinib, bevacizumab) in the two cases enhanced chemotherapy delivery via vascular normalization, reduced tumor hypoxia to improve radiosensitivity, and inhibited dissemination by downregulating VEGF-related pathways (CXCR4, MMP9)—extending PFS and OS. While BET inhibitors and immunotherapies showed promise in preclinical studies, their clinical efficacy remains limited, emphasizing the need for early integration of anti-angiogenic therapy in NMC management. This report challenges the therapeutic pessimism surrounding NMC, proposing anti-angiogenic-based multimodal therapy as a viable strategy to improve outcomes for this rare, aggressive malignancy.
ＤＯＩ：10.1007/s11684-025-1145-3