In 2015, the World Health Organization (WHO) revised its 2004 classification of lung tumors to reflect the impact of genetic, clinical, and radiologic advances in the field.1 Among the revisions in 2015 was the inclusion of NUT carcinoma.
“NUT carcinoma is a very rare and highly lethal cancer. It often presents in the midline and it is also called ‘midline carcinoma’,” explained José Francisco Corona-Cruz, MD, a thoracic surgical oncologist at the National Cancer Institute Mexico. “It usually affects young patients and prognosis is usually poor as most tumors are aggressive and no effective therapy is known yet.”
The main feature on this tumor is the rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14 and other genes. At the time of the WHO publication, fewer than 100 cases of NUT carcinoma had been reported.2
More recently, a study of 141 patients with NUT carcinoma taken from the International NUT Midline Carcinoma Registry examined clinicopathologic variables and survival outcomes. Chau and colleagues3 reported a median age of diagnosis of 23.6 years, and median overall survival of 6.5 months. About half of the included patients had primary tumors of thoracic origin and thoracic primary was associated with the poorest prognosis.
Because of its rareness, most other research on this tumor is based on case reports, Dr. Corona-Cruz said.
At the 2021 World Conference on Lung Cancer, Yuichi Saito, MD, of Teikyo University Hospital, Tokyo, Japan, and colleagues presented a case report detailing surgery for a small pulmonary NUT carcinoma.
The case was an asymptomatic 82-year-old man. The patient had formerly chosen to smoke and underwent nephrectomy for left renal cell carcinoma 15 years prior and partial nephrectomy for right renal cell carcinoma 5 years prior to diagnosis. His family history included a father with gastric cancer, mother with thyroid cancer, and a brother with a brain tumor. Tumor markers included normal carcinoembryonic antigen (CEA; 2.8 ng/nL), normal C-terminus of cytokeratin (CRFRA; 2.1 ng/mL), elevated progastrin-releasing peptide (ProGRP; 115 pg/mL), and elevated SCC antigen (2.7 ng/mL).
A metastatic tumor was suspected, and surgery was performed. The main tumor was completely resected by surgery. Pathology resulted in a diagnosis of primary pulmonary NUT midline carcinoma. BRD4-NUT fusion gene was detected by fluorescence in situ hybridization and confirmed by RNA sequencing.
WHO noted that pathologically NUT carcinoma “consists of sheets and nests of small-sized to intermediate-sized undifferentiated cells with a monomorphic appearance. Immunohistochemistry is positive in more than 50% of tumor cells with a speckled nuclear positivity.”
In the case report, pathology described small round tumor cells and positive tumor nuclei with a speckled pattern.
Approximately 3 months after surgery, the patient had mediastinal lymph node metastasis and underwent radiotherapy (60 Gy/30fr). Six months later, the patient had right supraclavicular lymph node metastasis and underwent additional radiotherapy (50Gy/20fr). The patient remains alive 17 months after resection.
Survival almost 1.5 years after diagnosis is considered a prolonged survival compared with previous reports, Dr. Corona-Cruz said. However, he noted that the tumor was detected as an incidental finding.
Indeed, Dr. Saito and colleagues said that this early detection and treatment was essential for this patient’s long-term prognosis.
“Recurrence survey must be performed carefully even after complete resection,” Dr. Saito wrote. “Multimodality treatment should be considered for long-term survival of patients with NUT carcinoma.”
Limited Options, Limited Knowledge
Indeed, in many cases of NUT carcinoma, treatment options are limited and there is no standard management strategy for primary lung NUT carcinoma.
Patients with NUT carcinoma with the BRD4-NUT oncoprotein, like the one in the case report, may qualify for treatment with a bromodomain and extraterminal brodomain (BRD) inhibitor. A 2016 study of OTX015/MK-8628, a novel oral BET inhibitor, evaluated the efficacy of the drug in four patients with advanced-stage NUT carcinoma with confirmed fusions.4 Two patients responded rapidly with tumor regression and symptom relief, according to the study. One patient had disease stabilization.
More recently, a phase I study of molibresib, another BRD inhibitor, was tested in 65 patients with NUT carcinoma and other solid tumors.5 Among 19 patients with NUT carcinoma, four had confirmed or unconfirmed partial response, eight has stable disease, and four had no disease progression for more than 6 months. However, three of four patients who remained on treatment longer than 6 months had nonthoracic primary tumors, the researchers noted.
Unfortunately, BET inhibitors are not widely available and due to the rarity of the disease, data remain limited.
According to Witold Rzyman, MD, of Medical University of Gdansk, Poland, the Polish National Cancer Registry has registered two cases of NUT carcinoma in the lung since 2015.
“Due to its very rare occurrence in the lung and the relatively short period of recognition of NUT as a lung cancer, it is difficult to objectively assess its incidence, as some may not be adequately diagnosed,” Dr. Rzyman said. “Hence the data from our central database may be inadequate.”
Clinicians who think they may have a case of NUT carcinoma are encouraged to contact the NUT Midline Carcinoma Registry, which is willing to provide pathologic review to assist in diagnosis and aims to collect clinical data on the disease and its response to treatment. To learn more, visit nmcregistry.org.
- 1. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors. Impact of genetic, clinical and radiologic advances since the 2004 classification. Journal of Thoracic Oncology.2015;10(9):1243-1260.
- 2. Saito Y, et al. Surgery for small pulmonary NUT carcinoma: case report. P41.02. Presented at: 2021 World Conference on Lung Cancer.
- 3. Chau NG, Ma C, Danga K, et al. An anatomical site and genetic-based prognostic model for patients with nuclear protein in testis (NUT) midline carcinoma: analysis of 124 patients. JNCI Cancer Spectrum. 2019;doi:10.1093/jncics/pkz094.
- 4. Stathis A, Zucca E, Bekradda M, et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov. 2016;doi:10/1158/2159-8290.
- 5. Piha-Paul SA, Hann CL, French CA, et al. Phase 1 study of molibresib (GSK525762), a bromodomain and extra-terminal domain protein inhibitor, in NUT carcinoma and other solid tumors. JNCI Cancer Spectrum.2020;doi:10.1093/jncics/pkz093.